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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Treatment of Middle East Respiratory Syndrome with a combination of lopinavir-ritonavir and interferon-β1b (MIRACLE trial): study protocol for a randomized controlled trial</title><author><name sortKey="Arabi, Yaseen M" sort="Arabi, Yaseen M" uniqKey="Arabi Y" first="Yaseen M." last="Arabi">Yaseen M. Arabi</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Intensive Care Department,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff27"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 8948</institution-id><institution-id institution-id-type="GRID">grid.4991.5</institution-id><institution>International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) University of Oxford, Old Road Campus, Roosevelt Drive,</institution></institution-wrap>Oxford, OX3 7FZ UK</nlm:aff></affiliation></author><author><name sortKey="Alothman, Adel" sort="Alothman, Adel" uniqKey="Alothman A" first="Adel" last="Alothman">Adel Alothman</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Department of Medicine,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Balkhy, Hanan H" sort="Balkhy, Hanan H" uniqKey="Balkhy H" first="Hanan H." last="Balkhy">Hanan H. Balkhy</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Department of Infection Prevention and Control,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Al Dawood, Abdulaziz" sort="Al Dawood, Abdulaziz" uniqKey="Al Dawood A" first="Abdulaziz" last="Al-Dawood">Abdulaziz Al-Dawood</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Intensive Care Department,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Aljohani, Sameera" sort="Aljohani, Sameera" uniqKey="Aljohani S" first="Sameera" last="Aljohani">Sameera Aljohani</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Department of Pathology and Laboratory Medicine,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Al Harbi, Shmeylan" sort="Al Harbi, Shmeylan" uniqKey="Al Harbi S" first="Shmeylan" last="Al Harbi">Shmeylan Al Harbi</name><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Pharmaceutical Care Department,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Kojan, Suleiman" sort="Kojan, Suleiman" uniqKey="Kojan S" first="Suleiman" last="Kojan">Suleiman Kojan</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Department of Medicine,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Al Jeraisy, Majed" sort="Al Jeraisy, Majed" uniqKey="Al Jeraisy M" first="Majed" last="Al Jeraisy">Majed Al Jeraisy</name><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Pharmaceutical Care Department,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Deeb, Ahmad M" sort="Deeb, Ahmad M" uniqKey="Deeb A" first="Ahmad M." last="Deeb">Ahmad M. Deeb</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Intensive Care Department,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Assiri, Abdullah M" sort="Assiri, Abdullah M" uniqKey="Assiri A" first="Abdullah M." last="Assiri">Abdullah M. Assiri</name><affiliation><nlm:aff id="Aff8"><institution-wrap><institution-id institution-id-type="GRID">grid.415696.9</institution-id><institution>Infection Prevention and Control, Ministry of Health,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Al Hameed, Fahad" sort="Al Hameed, Fahad" uniqKey="Al Hameed F" first="Fahad" last="Al-Hameed">Fahad Al-Hameed</name><affiliation><nlm:aff id="Aff9"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Jeddah, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Intensive Care Department,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Jeddah, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Alsaedi, Asim" sort="Alsaedi, Asim" uniqKey="Alsaedi A" first="Asim" last="Alsaedi">Asim Alsaedi</name><affiliation><nlm:aff id="Aff9"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Jeddah, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff11"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Department of Infection Prevention and Control,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Jeddah, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Mandourah, Yasser" sort="Mandourah, Yasser" uniqKey="Mandourah Y" first="Yasser" last="Mandourah">Yasser Mandourah</name><affiliation><nlm:aff id="Aff12"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9759 8141</institution-id><institution-id institution-id-type="GRID">grid.415989.8</institution-id><institution>Department of Intensive Care Services,</institution><institution>Prince Sultan Military Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Almekhlafi, Ghaleb A" sort="Almekhlafi, Ghaleb A" uniqKey="Almekhlafi G" first="Ghaleb A." last="Almekhlafi">Ghaleb A. Almekhlafi</name><affiliation><nlm:aff id="Aff12"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9759 8141</institution-id><institution-id institution-id-type="GRID">grid.415989.8</institution-id><institution>Department of Intensive Care Services,</institution><institution>Prince Sultan Military Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Sherbeeni, Nisreen Murad" sort="Sherbeeni, Nisreen Murad" uniqKey="Sherbeeni N" first="Nisreen Murad" last="Sherbeeni">Nisreen Murad Sherbeeni</name><affiliation><nlm:aff id="Aff13"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9759 8141</institution-id><institution-id institution-id-type="GRID">grid.415989.8</institution-id><institution>Infectious Diseases Division,</institution><institution>Prince Sultan Military Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Elzein, Fatehi Elnour" sort="Elzein, Fatehi Elnour" uniqKey="Elzein F" first="Fatehi Elnour" last="Elzein">Fatehi Elnour Elzein</name><affiliation><nlm:aff id="Aff13"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9759 8141</institution-id><institution-id institution-id-type="GRID">grid.415989.8</institution-id><institution>Infectious Diseases Division,</institution><institution>Prince Sultan Military Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Memon, Javed" sort="Memon, Javed" uniqKey="Memon J" first="Javed" last="Memon">Javed Memon</name><affiliation><nlm:aff id="Aff14"><institution-wrap><institution-id institution-id-type="GRID">grid.415252.5</institution-id><institution>Intensive Care Section, Department of Medicine,</institution><institution>King Abdulaziz Hospital,</institution></institution-wrap>Alahsa, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Taha, Yusri" sort="Taha, Yusri" uniqKey="Taha Y" first="Yusri" last="Taha">Yusri Taha</name><affiliation><nlm:aff id="Aff15"><institution-wrap><institution-id institution-id-type="GRID">grid.415252.5</institution-id><institution>Department of Medicine,</institution><institution>King Abdulaziz Hospital,</institution></institution-wrap>Alahsa, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Almotairi, Abdullah" sort="Almotairi, Abdullah" uniqKey="Almotairi A" first="Abdullah" last="Almotairi">Abdullah Almotairi</name><affiliation><nlm:aff id="Aff16"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0593 1832</institution-id><institution-id institution-id-type="GRID">grid.415277.2</institution-id><institution>Department of Critical Care Medicine,</institution><institution>King Fahad Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Maghrabi, Khalid A" sort="Maghrabi, Khalid A" uniqKey="Maghrabi K" first="Khalid A." last="Maghrabi">Khalid A. Maghrabi</name><affiliation><nlm:aff id="Aff17"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2191 4301</institution-id><institution-id institution-id-type="GRID">grid.415310.2</institution-id><institution>Department of Critical Care Medicine,</institution><institution>King Faisal Specialist Hospital and Research,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Qushmaq, Ismael" sort="Qushmaq, Ismael" uniqKey="Qushmaq I" first="Ismael" last="Qushmaq">Ismael Qushmaq</name><affiliation><nlm:aff id="Aff18"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2191 4301</institution-id><institution-id institution-id-type="GRID">grid.415310.2</institution-id><institution>Department of Medicine,</institution><institution>King Faisal Specialist Hospital and Research Center,</institution></institution-wrap>Jeddah, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Al Bshabshe, Ali" sort="Al Bshabshe, Ali" uniqKey="Al Bshabshe A" first="Ali" last="Al Bshabshe">Ali Al Bshabshe</name><affiliation><nlm:aff id="Aff19">Department of Critical Care Medicine, King Khalid University, Aseer Central Hospital, Abha, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Kharaba, Ayman" sort="Kharaba, Ayman" uniqKey="Kharaba A" first="Ayman" last="Kharaba">Ayman Kharaba</name><affiliation><nlm:aff id="Aff20">Department of Critical Care, King Fahad Hospital, Ohoud Hospital, Al-Madinah Al-Monawarah, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Shalhoub, Sarah" sort="Shalhoub, Sarah" uniqKey="Shalhoub S" first="Sarah" last="Shalhoub">Sarah Shalhoub</name><affiliation><nlm:aff id="Aff21"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0573 8987</institution-id><institution-id institution-id-type="GRID">grid.415271.4</institution-id><institution>Department of Medicine,</institution><institution>King Fahad Armed Forces Hospital,</institution></institution-wrap>Jeddah, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Jose, Jesna" sort="Jose, Jesna" uniqKey="Jose J" first="Jesna" last="Jose">Jesna Jose</name><affiliation><nlm:aff id="Aff22"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>Department of Biostatistics and Bioinformatics, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Fowler, Robert A" sort="Fowler, Robert A" uniqKey="Fowler R" first="Robert A." last="Fowler">Robert A. Fowler</name><affiliation><nlm:aff id="Aff23"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2157 2938</institution-id><institution-id institution-id-type="GRID">grid.17063.33</institution-id><institution>AMR Infection Control and Publications AIP/PED/HSE/HQ, Institute of Health Policy Management and Evaluation,</institution><institution>University of Toronto,</institution></institution-wrap>Toronto, ON Canada</nlm:aff></affiliation><affiliation><nlm:aff id="Aff24"><institution-wrap><institution-id institution-id-type="GRID">grid.416745.5</institution-id><institution>Department of Critical Care Medicine,</institution><institution>Sunnybrook Hospital,</institution></institution-wrap>2075 Bayview Avenue, Room D478, Toronto, ON Canada</nlm:aff></affiliation><affiliation><nlm:aff id="Aff25"><institution-wrap><institution-id institution-id-type="GRID">grid.416745.5</institution-id><institution>Department of Medicine,</institution><institution>Sunnybrook Hospital,</institution></institution-wrap>2075 Bayview Avenue, Room D478, Toronto, ON Canada</nlm:aff></affiliation></author><author><name sortKey="Hayden, Frederick G" sort="Hayden, Frederick G" uniqKey="Hayden F" first="Frederick G." last="Hayden">Frederick G. Hayden</name><affiliation><nlm:aff id="Aff26"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9136 933X</institution-id><institution-id institution-id-type="GRID">grid.27755.32</institution-id><institution>Department of Medicine, Division of Infectious Diseases and International Health,</institution><institution>University of Virginia School of Medicine,</institution></institution-wrap>Charlottesville, VA USA</nlm:aff></affiliation></author><author><name sortKey="Hussein, Mohamed A" sort="Hussein, Mohamed A" uniqKey="Hussein M" first="Mohamed A." last="Hussein">Mohamed A. Hussein</name><affiliation><nlm:aff id="Aff22"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>Department of Biostatistics and Bioinformatics, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">29382391</idno><idno type="pmc">5791210</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791210</idno><idno type="RBID">PMC:5791210</idno><idno type="doi">10.1186/s13063-017-2427-0</idno><date when="2018">2018</date><idno type="wicri:Area/Pmc/Corpus">000470</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000470</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Treatment of Middle East Respiratory Syndrome with a combination of lopinavir-ritonavir and interferon-β1b (MIRACLE trial): study protocol for a randomized controlled trial</title><author><name sortKey="Arabi, Yaseen M" sort="Arabi, Yaseen M" uniqKey="Arabi Y" first="Yaseen M." last="Arabi">Yaseen M. Arabi</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Intensive Care Department,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff27"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 8948</institution-id><institution-id institution-id-type="GRID">grid.4991.5</institution-id><institution>International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) University of Oxford, Old Road Campus, Roosevelt Drive,</institution></institution-wrap>Oxford, OX3 7FZ UK</nlm:aff></affiliation></author><author><name sortKey="Alothman, Adel" sort="Alothman, Adel" uniqKey="Alothman A" first="Adel" last="Alothman">Adel Alothman</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Department of Medicine,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Balkhy, Hanan H" sort="Balkhy, Hanan H" uniqKey="Balkhy H" first="Hanan H." last="Balkhy">Hanan H. Balkhy</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Department of Infection Prevention and Control,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Al Dawood, Abdulaziz" sort="Al Dawood, Abdulaziz" uniqKey="Al Dawood A" first="Abdulaziz" last="Al-Dawood">Abdulaziz Al-Dawood</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Intensive Care Department,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Aljohani, Sameera" sort="Aljohani, Sameera" uniqKey="Aljohani S" first="Sameera" last="Aljohani">Sameera Aljohani</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Department of Pathology and Laboratory Medicine,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Al Harbi, Shmeylan" sort="Al Harbi, Shmeylan" uniqKey="Al Harbi S" first="Shmeylan" last="Al Harbi">Shmeylan Al Harbi</name><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Pharmaceutical Care Department,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Kojan, Suleiman" sort="Kojan, Suleiman" uniqKey="Kojan S" first="Suleiman" last="Kojan">Suleiman Kojan</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Department of Medicine,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Al Jeraisy, Majed" sort="Al Jeraisy, Majed" uniqKey="Al Jeraisy M" first="Majed" last="Al Jeraisy">Majed Al Jeraisy</name><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Pharmaceutical Care Department,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Deeb, Ahmad M" sort="Deeb, Ahmad M" uniqKey="Deeb A" first="Ahmad M." last="Deeb">Ahmad M. Deeb</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Intensive Care Department,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Assiri, Abdullah M" sort="Assiri, Abdullah M" uniqKey="Assiri A" first="Abdullah M." last="Assiri">Abdullah M. Assiri</name><affiliation><nlm:aff id="Aff8"><institution-wrap><institution-id institution-id-type="GRID">grid.415696.9</institution-id><institution>Infection Prevention and Control, Ministry of Health,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Al Hameed, Fahad" sort="Al Hameed, Fahad" uniqKey="Al Hameed F" first="Fahad" last="Al-Hameed">Fahad Al-Hameed</name><affiliation><nlm:aff id="Aff9"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Jeddah, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Intensive Care Department,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Jeddah, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Alsaedi, Asim" sort="Alsaedi, Asim" uniqKey="Alsaedi A" first="Asim" last="Alsaedi">Asim Alsaedi</name><affiliation><nlm:aff id="Aff9"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Jeddah, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff11"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Department of Infection Prevention and Control,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Jeddah, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Mandourah, Yasser" sort="Mandourah, Yasser" uniqKey="Mandourah Y" first="Yasser" last="Mandourah">Yasser Mandourah</name><affiliation><nlm:aff id="Aff12"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9759 8141</institution-id><institution-id institution-id-type="GRID">grid.415989.8</institution-id><institution>Department of Intensive Care Services,</institution><institution>Prince Sultan Military Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Almekhlafi, Ghaleb A" sort="Almekhlafi, Ghaleb A" uniqKey="Almekhlafi G" first="Ghaleb A." last="Almekhlafi">Ghaleb A. Almekhlafi</name><affiliation><nlm:aff id="Aff12"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9759 8141</institution-id><institution-id institution-id-type="GRID">grid.415989.8</institution-id><institution>Department of Intensive Care Services,</institution><institution>Prince Sultan Military Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Sherbeeni, Nisreen Murad" sort="Sherbeeni, Nisreen Murad" uniqKey="Sherbeeni N" first="Nisreen Murad" last="Sherbeeni">Nisreen Murad Sherbeeni</name><affiliation><nlm:aff id="Aff13"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9759 8141</institution-id><institution-id institution-id-type="GRID">grid.415989.8</institution-id><institution>Infectious Diseases Division,</institution><institution>Prince Sultan Military Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Elzein, Fatehi Elnour" sort="Elzein, Fatehi Elnour" uniqKey="Elzein F" first="Fatehi Elnour" last="Elzein">Fatehi Elnour Elzein</name><affiliation><nlm:aff id="Aff13"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9759 8141</institution-id><institution-id institution-id-type="GRID">grid.415989.8</institution-id><institution>Infectious Diseases Division,</institution><institution>Prince Sultan Military Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Memon, Javed" sort="Memon, Javed" uniqKey="Memon J" first="Javed" last="Memon">Javed Memon</name><affiliation><nlm:aff id="Aff14"><institution-wrap><institution-id institution-id-type="GRID">grid.415252.5</institution-id><institution>Intensive Care Section, Department of Medicine,</institution><institution>King Abdulaziz Hospital,</institution></institution-wrap>Alahsa, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Taha, Yusri" sort="Taha, Yusri" uniqKey="Taha Y" first="Yusri" last="Taha">Yusri Taha</name><affiliation><nlm:aff id="Aff15"><institution-wrap><institution-id institution-id-type="GRID">grid.415252.5</institution-id><institution>Department of Medicine,</institution><institution>King Abdulaziz Hospital,</institution></institution-wrap>Alahsa, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Almotairi, Abdullah" sort="Almotairi, Abdullah" uniqKey="Almotairi A" first="Abdullah" last="Almotairi">Abdullah Almotairi</name><affiliation><nlm:aff id="Aff16"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0593 1832</institution-id><institution-id institution-id-type="GRID">grid.415277.2</institution-id><institution>Department of Critical Care Medicine,</institution><institution>King Fahad Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Maghrabi, Khalid A" sort="Maghrabi, Khalid A" uniqKey="Maghrabi K" first="Khalid A." last="Maghrabi">Khalid A. Maghrabi</name><affiliation><nlm:aff id="Aff17"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2191 4301</institution-id><institution-id institution-id-type="GRID">grid.415310.2</institution-id><institution>Department of Critical Care Medicine,</institution><institution>King Faisal Specialist Hospital and Research,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Qushmaq, Ismael" sort="Qushmaq, Ismael" uniqKey="Qushmaq I" first="Ismael" last="Qushmaq">Ismael Qushmaq</name><affiliation><nlm:aff id="Aff18"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2191 4301</institution-id><institution-id institution-id-type="GRID">grid.415310.2</institution-id><institution>Department of Medicine,</institution><institution>King Faisal Specialist Hospital and Research Center,</institution></institution-wrap>Jeddah, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Al Bshabshe, Ali" sort="Al Bshabshe, Ali" uniqKey="Al Bshabshe A" first="Ali" last="Al Bshabshe">Ali Al Bshabshe</name><affiliation><nlm:aff id="Aff19">Department of Critical Care Medicine, King Khalid University, Aseer Central Hospital, Abha, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Kharaba, Ayman" sort="Kharaba, Ayman" uniqKey="Kharaba A" first="Ayman" last="Kharaba">Ayman Kharaba</name><affiliation><nlm:aff id="Aff20">Department of Critical Care, King Fahad Hospital, Ohoud Hospital, Al-Madinah Al-Monawarah, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Shalhoub, Sarah" sort="Shalhoub, Sarah" uniqKey="Shalhoub S" first="Sarah" last="Shalhoub">Sarah Shalhoub</name><affiliation><nlm:aff id="Aff21"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0573 8987</institution-id><institution-id institution-id-type="GRID">grid.415271.4</institution-id><institution>Department of Medicine,</institution><institution>King Fahad Armed Forces Hospital,</institution></institution-wrap>Jeddah, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Jose, Jesna" sort="Jose, Jesna" uniqKey="Jose J" first="Jesna" last="Jose">Jesna Jose</name><affiliation><nlm:aff id="Aff22"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>Department of Biostatistics and Bioinformatics, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Fowler, Robert A" sort="Fowler, Robert A" uniqKey="Fowler R" first="Robert A." last="Fowler">Robert A. Fowler</name><affiliation><nlm:aff id="Aff23"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2157 2938</institution-id><institution-id institution-id-type="GRID">grid.17063.33</institution-id><institution>AMR Infection Control and Publications AIP/PED/HSE/HQ, Institute of Health Policy Management and Evaluation,</institution><institution>University of Toronto,</institution></institution-wrap>Toronto, ON Canada</nlm:aff></affiliation><affiliation><nlm:aff id="Aff24"><institution-wrap><institution-id institution-id-type="GRID">grid.416745.5</institution-id><institution>Department of Critical Care Medicine,</institution><institution>Sunnybrook Hospital,</institution></institution-wrap>2075 Bayview Avenue, Room D478, Toronto, ON Canada</nlm:aff></affiliation><affiliation><nlm:aff id="Aff25"><institution-wrap><institution-id institution-id-type="GRID">grid.416745.5</institution-id><institution>Department of Medicine,</institution><institution>Sunnybrook Hospital,</institution></institution-wrap>2075 Bayview Avenue, Room D478, Toronto, ON Canada</nlm:aff></affiliation></author><author><name sortKey="Hayden, Frederick G" sort="Hayden, Frederick G" uniqKey="Hayden F" first="Frederick G." last="Hayden">Frederick G. Hayden</name><affiliation><nlm:aff id="Aff26"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9136 933X</institution-id><institution-id institution-id-type="GRID">grid.27755.32</institution-id><institution>Department of Medicine, Division of Infectious Diseases and International Health,</institution><institution>University of Virginia School of Medicine,</institution></institution-wrap>Charlottesville, VA USA</nlm:aff></affiliation></author><author><name sortKey="Hussein, Mohamed A" sort="Hussein, Mohamed A" uniqKey="Hussein M" first="Mohamed A." last="Hussein">Mohamed A. Hussein</name><affiliation><nlm:aff id="Aff22"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>Department of Biostatistics and Bioinformatics, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author></analytic><series><title level="j">Trials</title><idno type="eISSN">1745-6215</idno><imprint><date when="2018">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p id="Par1">It had been more than 5 years since the first case of Middle East Respiratory Syndrome coronavirus infection (MERS-CoV) was recorded, but no specific treatment has been investigated in randomized clinical trials. Results from in vitro and animal studies suggest that a combination of lopinavir/ritonavir and interferon-β1b (IFN-β1b) may be effective against MERS-CoV. The aim of this study is to investigate the efficacy of treatment with a combination of lopinavir/ritonavir and recombinant IFN-β1b provided with standard supportive care, compared to treatment with placebo provided with standard supportive care in patients with laboratory-confirmed MERS requiring hospital admission.</p></sec><sec><title>Methods</title><p id="Par2">The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. Hospitalized adult patients with laboratory-confirmed MERS will be enrolled in this recursive, two-stage, group sequential, multicenter, placebo-controlled, double-blind randomized controlled trial. The trial is initially designed to include 2 two-stage components. The first two-stage component is designed to adjust sample size and determine futility stopping, but not efficacy stopping. The second two-stage component is designed to determine efficacy stopping and possibly readjustment of sample size. The primary outcome is 90-day mortality.</p></sec><sec><title>Discussion</title><p id="Par3">This will be the first randomized controlled trial of a potential treatment for MERS. The study is sponsored by King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. Enrollment for this study began in November 2016, and has enrolled thirteen patients as of Jan 24-2018.</p></sec><sec><title>Trial registration</title><p id="Par4">ClinicalTrials.gov, ID: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT02845843">NCT02845843</ext-link>. Registered on 27 July 2016.</p></sec><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1186/s13063-017-2427-0) contains supplementary material, which is available to authorized users.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Arabi, Ym" uniqKey="Arabi Y">YM Arabi</name></author><author><name sortKey="Balkhy, Hh" uniqKey="Balkhy H">HH Balkhy</name></author><author><name sortKey="Hayden, Fg" uniqKey="Hayden F">FG Hayden</name></author><author><name sortKey="Bouchama, A" uniqKey="Bouchama A">A Bouchama</name></author><author><name sortKey="Luke, T" uniqKey="Luke T">T Luke</name></author><author><name sortKey="Baillie, Jk" uniqKey="Baillie J">JK Baillie</name></author><author><name sortKey="Al Omari, A" uniqKey="Al Omari A">A Al-Omari</name></author><author><name sortKey="Hajeer, Ah" uniqKey="Hajeer A">AH Hajeer</name></author><author><name sortKey="Senga, M" uniqKey="Senga M">M Senga</name></author><author><name sortKey="Denison, Mr" uniqKey="Denison M">MR Denison</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zaki, Am" uniqKey="Zaki A">AM Zaki</name></author><author><name sortKey="Van Boheemen, S" uniqKey="Van Boheemen S">S van Boheemen</name></author><author><name sortKey="Bestebroer, Tm" uniqKey="Bestebroer T">TM Bestebroer</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author><author><name sortKey="Fouchier, Ra" uniqKey="Fouchier R">RA Fouchier</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mo, Y" uniqKey="Mo Y">Y Mo</name></author><author><name sortKey="Fisher, D" uniqKey="Fisher D">D Fisher</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Falzarano, D" uniqKey="Falzarano D">D Falzarano</name></author><author><name sortKey="De Wit, E" uniqKey="De Wit E">E de Wit</name></author><author><name sortKey="Rasmussen, Al" uniqKey="Rasmussen A">AL Rasmussen</name></author><author><name sortKey="Feldmann, F" uniqKey="Feldmann F">F Feldmann</name></author><author><name sortKey="Okumura, A" uniqKey="Okumura A">A Okumura</name></author><author><name sortKey="Scott, Dp" uniqKey="Scott D">DP Scott</name></author><author><name sortKey="Brining, D" uniqKey="Brining D">D Brining</name></author><author><name sortKey="Bushmaker, T" uniqKey="Bushmaker T">T Bushmaker</name></author><author><name sortKey="Martellaro, C" uniqKey="Martellaro C">C Martellaro</name></author><author><name sortKey="Baseler, L" uniqKey="Baseler L">L Baseler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shalhoub, S" uniqKey="Shalhoub S">S Shalhoub</name></author><author><name sortKey="Farahat, F" uniqKey="Farahat F">F Farahat</name></author><author><name sortKey="Al Jiffri, A" uniqKey="Al Jiffri A">A Al-Jiffri</name></author><author><name sortKey="Simhairi, R" uniqKey="Simhairi R">R Simhairi</name></author><author><name sortKey="Shamma, O" uniqKey="Shamma O">O Shamma</name></author><author><name sortKey="Siddiqi, N" uniqKey="Siddiqi N">N Siddiqi</name></author><author><name sortKey="Mushtaq, A" uniqKey="Mushtaq A">A Mushtaq</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Khalid, M" uniqKey="Khalid M">M Khalid</name></author><author><name sortKey="Al Rabiah, F" uniqKey="Al Rabiah F">F Al Rabiah</name></author><author><name sortKey="Khan, B" uniqKey="Khan B">B Khan</name></author><author><name sortKey="Al Mobeireek, A" uniqKey="Al Mobeireek A">A Al Mobeireek</name></author><author><name sortKey="Butt, Ts" uniqKey="Butt T">TS Butt</name></author><author><name sortKey="Al, Me" uniqKey="Al M">ME Al</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Omrani, As" uniqKey="Omrani A">AS Omrani</name></author><author><name sortKey="Saad, Mm" uniqKey="Saad M">MM Saad</name></author><author><name sortKey="Baig, K" uniqKey="Baig K">K Baig</name></author><author><name sortKey="Bahloul, A" uniqKey="Bahloul A">A Bahloul</name></author><author><name sortKey="Abdul Matin, M" uniqKey="Abdul Matin M">M Abdul-Matin</name></author><author><name sortKey="Alaidaroos, Ay" uniqKey="Alaidaroos A">AY Alaidaroos</name></author><author><name sortKey="Almakhlafi, Ga" uniqKey="Almakhlafi G">GA Almakhlafi</name></author><author><name sortKey="Albarrak, Mm" uniqKey="Albarrak M">MM Albarrak</name></author><author><name sortKey="Memish, Za" uniqKey="Memish Z">ZA Memish</name></author><author><name sortKey="Albarrak, Am" uniqKey="Albarrak A">AM Albarrak</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hart, Bj" uniqKey="Hart B">BJ Hart</name></author><author><name sortKey="Dyall, J" uniqKey="Dyall J">J Dyall</name></author><author><name sortKey="Postnikova, E" uniqKey="Postnikova E">E Postnikova</name></author><author><name sortKey="Zhou, H" uniqKey="Zhou H">H Zhou</name></author><author><name sortKey="Kindrachuk, J" uniqKey="Kindrachuk J">J Kindrachuk</name></author><author><name sortKey="Johnson, Rf" uniqKey="Johnson R">RF Johnson</name></author><author><name sortKey="Olinger, Gg" uniqKey="Olinger G">GG Olinger</name></author><author><name sortKey="Frieman, Mb" uniqKey="Frieman M">MB Frieman</name></author><author><name sortKey="Holbrook, Mr" uniqKey="Holbrook M">MR Holbrook</name></author><author><name sortKey="Jahrling, Pb" uniqKey="Jahrling P">PB Jahrling</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Falzarano, D" uniqKey="Falzarano D">D Falzarano</name></author><author><name sortKey="De Wit, E" uniqKey="De Wit E">E de Wit</name></author><author><name sortKey="Martellaro, C" uniqKey="Martellaro C">C Martellaro</name></author><author><name sortKey="Callison, J" uniqKey="Callison J">J Callison</name></author><author><name sortKey="Munster, Vj" uniqKey="Munster V">VJ Munster</name></author><author><name sortKey="Feldmann, H" uniqKey="Feldmann H">H Feldmann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chan, Jf" uniqKey="Chan J">JF Chan</name></author><author><name sortKey="Chan, Kh" uniqKey="Chan K">KH Chan</name></author><author><name sortKey="Kao, Ry" uniqKey="Kao R">RY Kao</name></author><author><name sortKey="To, Kk" uniqKey="To K">KK To</name></author><author><name sortKey="Zheng, Bj" uniqKey="Zheng B">BJ Zheng</name></author><author><name sortKey="Li, Cp" uniqKey="Li C">CP Li</name></author><author><name sortKey="Li, Pt" uniqKey="Li P">PT Li</name></author><author><name sortKey="Dai, J" uniqKey="Dai J">J Dai</name></author><author><name sortKey="Mok, Fk" uniqKey="Mok F">FK Mok</name></author><author><name sortKey="Chen, H" uniqKey="Chen H">H Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Al Tawfiq, Ja" uniqKey="Al Tawfiq J">JA Al-Tawfiq</name></author><author><name sortKey="Momattin, H" uniqKey="Momattin H">H Momattin</name></author><author><name sortKey="Dib, J" uniqKey="Dib J">J Dib</name></author><author><name sortKey="Memish, Za" uniqKey="Memish Z">ZA Memish</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lau, Sk" uniqKey="Lau S">SK Lau</name></author><author><name sortKey="Lau, Cc" uniqKey="Lau C">CC Lau</name></author><author><name sortKey="Chan, Kh" uniqKey="Chan K">KH Chan</name></author><author><name sortKey="Li, Cp" uniqKey="Li C">CP Li</name></author><author><name sortKey="Chen, H" uniqKey="Chen H">H Chen</name></author><author><name sortKey="Jin, Dy" uniqKey="Jin D">DY Jin</name></author><author><name sortKey="Chan, Jf" uniqKey="Chan J">JF Chan</name></author><author><name sortKey="Woo, Pc" uniqKey="Woo P">PC Woo</name></author><author><name sortKey="Yuen, Ky" uniqKey="Yuen K">KY Yuen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Faure, E" uniqKey="Faure E">E Faure</name></author><author><name sortKey="Poissy, J" uniqKey="Poissy J">J Poissy</name></author><author><name sortKey="Goffard, A" uniqKey="Goffard A">A Goffard</name></author><author><name sortKey="Fournier, C" uniqKey="Fournier C">C Fournier</name></author><author><name sortKey="Kipnis, E" uniqKey="Kipnis E">E Kipnis</name></author><author><name sortKey="Titecat, M" uniqKey="Titecat M">M Titecat</name></author><author><name sortKey="Bortolotti, P" uniqKey="Bortolotti P">P Bortolotti</name></author><author><name sortKey="Martinez, L" uniqKey="Martinez L">L Martinez</name></author><author><name sortKey="Dubucquoi, S" uniqKey="Dubucquoi S">S Dubucquoi</name></author><author><name sortKey="Dessein, R" uniqKey="Dessein R">R Dessein</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zielecki, F" uniqKey="Zielecki F">F Zielecki</name></author><author><name sortKey="Weber, M" uniqKey="Weber M">M Weber</name></author><author><name sortKey="Eickmann, M" uniqKey="Eickmann M">M Eickmann</name></author><author><name sortKey="Spiegelberg, L" uniqKey="Spiegelberg L">L Spiegelberg</name></author><author><name sortKey="Zaki, Am" uniqKey="Zaki A">AM Zaki</name></author><author><name sortKey="Matrosovich, M" uniqKey="Matrosovich M">M Matrosovich</name></author><author><name sortKey="Becker, S" uniqKey="Becker S">S Becker</name></author><author><name sortKey="Weber, F" uniqKey="Weber F">F Weber</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De Wilde, Ah" uniqKey="De Wilde A">AH de Wilde</name></author><author><name sortKey="Raj, Vs" uniqKey="Raj V">VS Raj</name></author><author><name sortKey="Oudshoorn, D" uniqKey="Oudshoorn D">D Oudshoorn</name></author><author><name sortKey="Bestebroer, Tm" uniqKey="Bestebroer T">TM Bestebroer</name></author><author><name sortKey="Van Nieuwkoop, S" uniqKey="Van Nieuwkoop S">S van Nieuwkoop</name></author><author><name sortKey="Limpens, Rw" uniqKey="Limpens R">RW Limpens</name></author><author><name sortKey="Posthuma, Cc" uniqKey="Posthuma C">CC Posthuma</name></author><author><name sortKey="Van Der Meer, Y" uniqKey="Van Der Meer Y">Y van der Meer</name></author><author><name sortKey="Barcena, M" uniqKey="Barcena M">M Barcena</name></author><author><name sortKey="Haagmans, Bl" uniqKey="Haagmans B">BL Haagmans</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jankovic, Sm" uniqKey="Jankovic S">SM Jankovic</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hurwitz, Bj" uniqKey="Hurwitz B">BJ Hurwitz</name></author><author><name sortKey="Jeffery, D" uniqKey="Jeffery D">D Jeffery</name></author><author><name sortKey="Arnason, B" uniqKey="Arnason B">B Arnason</name></author><author><name sortKey="Bigley, K" uniqKey="Bigley K">K Bigley</name></author><author><name sortKey="Coyle, P" uniqKey="Coyle P">P Coyle</name></author><author><name sortKey="Goodin, D" uniqKey="Goodin D">D Goodin</name></author><author><name sortKey="Kaba, S" uniqKey="Kaba S">S Kaba</name></author><author><name sortKey="Kirzinger, S" uniqKey="Kirzinger S">S Kirzinger</name></author><author><name sortKey="Lynch, S" uniqKey="Lynch S">S Lynch</name></author><author><name sortKey="Mandler, R" uniqKey="Mandler R">R Mandler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gottesman, Mh" uniqKey="Gottesman M">MH Gottesman</name></author><author><name sortKey="Friedman Urevich, S" uniqKey="Friedman Urevich S">S Friedman-Urevich</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Huang, X" uniqKey="Huang X">X Huang</name></author><author><name sortKey="Xu, Y" uniqKey="Xu Y">Y Xu</name></author><author><name sortKey="Yang, Q" uniqKey="Yang Q">Q Yang</name></author><author><name sortKey="Chen, J" uniqKey="Chen J">J Chen</name></author><author><name sortKey="Zhang, T" uniqKey="Zhang T">T Zhang</name></author><author><name sortKey="Li, Z" uniqKey="Li Z">Z Li</name></author><author><name sortKey="Guo, C" uniqKey="Guo C">C Guo</name></author><author><name sortKey="Chen, H" uniqKey="Chen H">H Chen</name></author><author><name sortKey="Wu, H" uniqKey="Wu H">H Wu</name></author><author><name sortKey="Li, N" uniqKey="Li N">N Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chu, Cm" uniqKey="Chu C">CM Chu</name></author><author><name sortKey="Cheng, Vc" uniqKey="Cheng V">VC Cheng</name></author><author><name sortKey="Hung, If" uniqKey="Hung I">IF Hung</name></author><author><name sortKey="Wong, Mm" uniqKey="Wong M">MM Wong</name></author><author><name sortKey="Chan, Kh" uniqKey="Chan K">KH Chan</name></author><author><name sortKey="Chan, Ks" uniqKey="Chan K">KS Chan</name></author><author><name sortKey="Kao, Ry" uniqKey="Kao R">RY Kao</name></author><author><name sortKey="Poon, Ll" uniqKey="Poon L">LL Poon</name></author><author><name sortKey="Wong, Cl" uniqKey="Wong C">CL Wong</name></author><author><name sortKey="Guan, Y" uniqKey="Guan Y">Y Guan</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Chan, Jf" uniqKey="Chan J">JF Chan</name></author><author><name sortKey="Yao, Y" uniqKey="Yao Y">Y Yao</name></author><author><name sortKey="Yeung, Ml" uniqKey="Yeung M">ML Yeung</name></author><author><name sortKey="Deng, W" uniqKey="Deng W">W Deng</name></author><author><name sortKey="Bao, L" uniqKey="Bao L">L Bao</name></author><author><name sortKey="Jia, L" uniqKey="Jia L">L Jia</name></author><author><name sortKey="Li, F" uniqKey="Li F">F Li</name></author><author><name sortKey="Xiao, C" uniqKey="Xiao C">C Xiao</name></author><author><name sortKey="Gao, H" uniqKey="Gao H">H Gao</name></author><author><name sortKey="Yu, P" uniqKey="Yu P">P Yu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, Uj" uniqKey="Kim U">UJ Kim</name></author><author><name sortKey="Won, Ej" uniqKey="Won E">EJ Won</name></author><author><name sortKey="Kee, Sj" uniqKey="Kee S">SJ Kee</name></author><author><name sortKey="Jung, Si" uniqKey="Jung S">SI Jung</name></author><author><name sortKey="Jang, Hc" uniqKey="Jang H">HC Jang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Spanakis, N" uniqKey="Spanakis N">N Spanakis</name></author><author><name sortKey="Tsiodras, S" uniqKey="Tsiodras S">S Tsiodras</name></author><author><name sortKey="Haagmans, Bl" uniqKey="Haagmans B">BL Haagmans</name></author><author><name sortKey="Raj, Vs" uniqKey="Raj V">VS Raj</name></author><author><name sortKey="Pontikis, K" uniqKey="Pontikis K">K Pontikis</name></author><author><name sortKey="Koutsoukou, A" uniqKey="Koutsoukou A">A Koutsoukou</name></author><author><name sortKey="Koulouris, Ng" uniqKey="Koulouris N">NG Koulouris</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author><author><name sortKey="Koopmans, Mp" uniqKey="Koopmans M">MP Koopmans</name></author><author><name sortKey="Tsakris, A" uniqKey="Tsakris A">A Tsakris</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Min, Ck" uniqKey="Min C">CK Min</name></author><author><name sortKey="Cheon, S" uniqKey="Cheon S">S Cheon</name></author><author><name sortKey="Ha, Ny" uniqKey="Ha N">NY Ha</name></author><author><name sortKey="Sohn, Km" uniqKey="Sohn K">KM Sohn</name></author><author><name sortKey="Kim, Y" uniqKey="Kim Y">Y Kim</name></author><author><name sortKey="Aigerim, A" uniqKey="Aigerim A">A Aigerim</name></author><author><name sortKey="Shin, Hm" uniqKey="Shin H">HM Shin</name></author><author><name sortKey="Choi, Jy" uniqKey="Choi J">JY Choi</name></author><author><name sortKey="Inn, Ks" uniqKey="Inn K">KS Inn</name></author><author><name sortKey="Kim, Jh" uniqKey="Kim J">JH Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chan, Aw" uniqKey="Chan A">AW Chan</name></author><author><name sortKey="Tetzlaff, Jm" uniqKey="Tetzlaff J">JM Tetzlaff</name></author><author><name sortKey="Altman, Dg" uniqKey="Altman D">DG Altman</name></author><author><name sortKey="Laupacis, A" uniqKey="Laupacis A">A Laupacis</name></author><author><name sortKey="Gotzsche, Pc" uniqKey="Gotzsche P">PC Gotzsche</name></author><author><name sortKey="Krleza Jeric, K" uniqKey="Krleza Jeric K">K Krleza-Jeric</name></author><author><name sortKey="Hrobjartsson, A" uniqKey="Hrobjartsson A">A Hrobjartsson</name></author><author><name sortKey="Mann, H" uniqKey="Mann H">H Mann</name></author><author><name sortKey="Dickersin, K" uniqKey="Dickersin K">K Dickersin</name></author><author><name sortKey="Berlin, Ja" uniqKey="Berlin J">JA Berlin</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Bellomo, R" uniqKey="Bellomo R">R Bellomo</name></author><author><name sortKey="Ronco, C" uniqKey="Ronco C">C Ronco</name></author><author><name sortKey="Kellum, Ja" uniqKey="Kellum J">JA Kellum</name></author><author><name sortKey="Mehta, Rl" uniqKey="Mehta R">RL Mehta</name></author><author><name sortKey="Palevsky, P" uniqKey="Palevsky P">P Palevsky</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Banks, Pa" uniqKey="Banks P">PA Banks</name></author><author><name sortKey="Bollen, Tl" uniqKey="Bollen T">TL Bollen</name></author><author><name sortKey="Dervenis, C" uniqKey="Dervenis C">C Dervenis</name></author><author><name sortKey="Gooszen, Hg" uniqKey="Gooszen H">HG Gooszen</name></author><author><name sortKey="Johnson, Cd" uniqKey="Johnson C">CD Johnson</name></author><author><name sortKey="Sarr, Mg" uniqKey="Sarr M">MG Sarr</name></author><author><name sortKey="Tsiotos, Gg" uniqKey="Tsiotos G">GG Tsiotos</name></author><author><name sortKey="Vege, Ss" uniqKey="Vege S">SS Vege</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="O Toole, Dm" uniqKey="O Toole D">DM O'Toole</name></author><author><name sortKey="Golden, Am" uniqKey="Golden A">AM Golden</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Almekhlafi, Ga" uniqKey="Almekhlafi G">GA Almekhlafi</name></author><author><name sortKey="Albarrak, Mm" uniqKey="Albarrak M">MM Albarrak</name></author><author><name sortKey="Mandourah, Y" uniqKey="Mandourah Y">Y Mandourah</name></author><author><name sortKey="Hassan, S" uniqKey="Hassan S">S Hassan</name></author><author><name sortKey="Alwan, A" uniqKey="Alwan A">A Alwan</name></author><author><name sortKey="Abudayah, A" uniqKey="Abudayah A">A Abudayah</name></author><author><name sortKey="Altayyar, S" uniqKey="Altayyar S">S Altayyar</name></author><author><name sortKey="Mustafa, M" uniqKey="Mustafa M">M Mustafa</name></author><author><name sortKey="Aldaghestani, T" uniqKey="Aldaghestani T">T Aldaghestani</name></author><author><name sortKey="Alghamedi, A" uniqKey="Alghamedi A">A Alghamedi</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Arabi, Y" uniqKey="Arabi Y">Y Arabi</name></author><author><name sortKey="Deeb, Am" uniqKey="Deeb A">AM Deeb</name></author><author><name sortKey="Aqeel, H" uniqKey="Aqeel H">H Aqeel</name></author><author><name sortKey="Balkhy, H" uniqKey="Balkhy H">H Balkhy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ippolito, G" uniqKey="Ippolito G">G Ippolito</name></author><author><name sortKey="Lanini, S" uniqKey="Lanini S">S Lanini</name></author><author><name sortKey="Brouqui, P" uniqKey="Brouqui P">P Brouqui</name></author><author><name sortKey="Di Caro, A" uniqKey="Di Caro A">A Di Caro</name></author><author><name sortKey="Vairo, F" uniqKey="Vairo F">F Vairo</name></author><author><name sortKey="Fusco, Fm" uniqKey="Fusco F">FM Fusco</name></author><author><name sortKey="Krishna, S" uniqKey="Krishna S">S Krishna</name></author><author><name sortKey="Capobianchi, Mr" uniqKey="Capobianchi M">MR Capobianchi</name></author><author><name sortKey="Kyobe Bosa, H" uniqKey="Kyobe Bosa H">H Kyobe-Bosa</name></author><author><name sortKey="Puro, V" uniqKey="Puro V">V Puro</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Macklin, R" uniqKey="Macklin R">R Macklin</name></author><author><name sortKey="Cowan, E" uniqKey="Cowan E">E Cowan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schafer, H" uniqKey="Schafer H">H Schafer</name></author><author><name sortKey="Muller, Hh" uniqKey="Muller H">HH Muller</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Trials</journal-id><journal-id journal-id-type="iso-abbrev">Trials</journal-id><journal-title-group><journal-title>Trials</journal-title></journal-title-group><issn pub-type="epub">1745-6215</issn><publisher><publisher-name>BioMed Central</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">29382391</article-id><article-id pub-id-type="pmc">5791210</article-id><article-id pub-id-type="publisher-id">2427</article-id><article-id pub-id-type="doi">10.1186/s13063-017-2427-0</article-id><article-categories><subj-group subj-group-type="heading"><subject>Study Protocol</subject></subj-group></article-categories><title-group><article-title>Treatment of Middle East Respiratory Syndrome with a combination of lopinavir-ritonavir and interferon-β1b (MIRACLE trial): study protocol for a randomized controlled trial</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Arabi</surname><given-names>Yaseen M.</given-names></name><address><phone>+966 (11) 801-1111</phone><email>arabi@ngha.med.sa</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref><xref ref-type="aff" rid="Aff27">27</xref></contrib><contrib contrib-type="author"><name><surname>Alothman</surname><given-names>Adel</given-names></name><address><email>othmanaf@hotmail.com</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Balkhy</surname><given-names>Hanan H.</given-names></name><address><email>BalkhyH@ngha.med.sa</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Al-Dawood</surname><given-names>Abdulaziz</given-names></name><address><email>aldawooda@hotmail.com</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>AlJohani</surname><given-names>Sameera</given-names></name><address><email>JOHANIS@ngha.med.sa</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Al Harbi</surname><given-names>Shmeylan</given-names></name><address><email>Harbishm@ngha.med.sa</email></address><xref ref-type="aff" rid="Aff6">6</xref><xref ref-type="aff" rid="Aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Kojan</surname><given-names>Suleiman</given-names></name><address><email>smkojan@yahoo.com</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Al Jeraisy</surname><given-names>Majed</given-names></name><address><email>JeraisyM@NGHA.MED.SA</email></address><xref ref-type="aff" rid="Aff6">6</xref><xref ref-type="aff" rid="Aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Deeb</surname><given-names>Ahmad M.</given-names></name><address><email>rn_a_deeb@hotmail.com</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Assiri</surname><given-names>Abdullah M.</given-names></name><address><email>abasiri@me.com</email></address><xref ref-type="aff" rid="Aff8">8</xref></contrib><contrib contrib-type="author"><name><surname>Al-Hameed</surname><given-names>Fahad</given-names></name><address><email>Hameedf@ngha.med.sa</email></address><xref ref-type="aff" rid="Aff9">9</xref><xref ref-type="aff" rid="Aff10">10</xref></contrib><contrib contrib-type="author"><name><surname>AlSaedi</surname><given-names>Asim</given-names></name><address><email>asimalsaedi@gmail.com</email></address><xref ref-type="aff" rid="Aff9">9</xref><xref ref-type="aff" rid="Aff11">11</xref></contrib><contrib contrib-type="author"><name><surname>Mandourah</surname><given-names>Yasser</given-names></name><address><email>mandourah@hotmail.com</email></address><xref ref-type="aff" rid="Aff12">12</xref></contrib><contrib contrib-type="author"><name><surname>Almekhlafi</surname><given-names>Ghaleb A.</given-names></name><address><email>gmekhlafi@yahoo.com</email></address><xref ref-type="aff" rid="Aff12">12</xref></contrib><contrib contrib-type="author"><name><surname>Sherbeeni</surname><given-names>Nisreen Murad</given-names></name><address><email>nismysh@hotmail.com</email></address><xref ref-type="aff" rid="Aff13">13</xref></contrib><contrib contrib-type="author"><name><surname>Elzein</surname><given-names>Fatehi Elnour</given-names></name><address><email>fatehielzein@yahoo.com</email></address><xref ref-type="aff" rid="Aff13">13</xref></contrib><contrib contrib-type="author"><name><surname>Memon</surname><given-names>Javed</given-names></name><address><email>jmemon786@yahoo.com</email></address><xref ref-type="aff" rid="Aff14">14</xref></contrib><contrib contrib-type="author"><name><surname>Taha</surname><given-names>Yusri</given-names></name><address><email>tahayu@ngha.med.sa</email></address><xref ref-type="aff" rid="Aff15">15</xref></contrib><contrib contrib-type="author"><name><surname>Almotairi</surname><given-names>Abdullah</given-names></name><address><email>aalmotairi@kfmc.med.sa</email></address><xref ref-type="aff" rid="Aff16">16</xref></contrib><contrib contrib-type="author"><name><surname>Maghrabi</surname><given-names>Khalid A.</given-names></name><address><email>kmaghrabi@kfshrc.edu.sa</email></address><xref ref-type="aff" rid="Aff17">17</xref></contrib><contrib contrib-type="author"><name><surname>Qushmaq</surname><given-names>Ismael</given-names></name><address><email>iqushmaq@kfshrc.edu.sa</email></address><xref ref-type="aff" rid="Aff18">18</xref></contrib><contrib contrib-type="author"><name><surname>Al Bshabshe</surname><given-names>Ali</given-names></name><address><email>albshabshe@yahoo.com</email></address><xref ref-type="aff" rid="Aff19">19</xref></contrib><contrib contrib-type="author"><name><surname>Kharaba</surname><given-names>Ayman</given-names></name><address><email>a7yman@hotmail.com</email></address><xref ref-type="aff" rid="Aff20">20</xref></contrib><contrib contrib-type="author"><name><surname>Shalhoub</surname><given-names>Sarah</given-names></name><address><email>sarah.shalhoub@googlemail.com</email></address><xref ref-type="aff" rid="Aff21">21</xref></contrib><contrib contrib-type="author"><name><surname>Jose</surname><given-names>Jesna</given-names></name><address><email>joseje@ngha.med.sa</email></address><xref ref-type="aff" rid="Aff22">22</xref></contrib><contrib contrib-type="author"><name><surname>Fowler</surname><given-names>Robert A.</given-names></name><address><email>rob.fowler@sunnybrook.ca</email></address><xref ref-type="aff" rid="Aff23">23</xref><xref ref-type="aff" rid="Aff24">24</xref><xref ref-type="aff" rid="Aff25">25</xref></contrib><contrib contrib-type="author"><name><surname>Hayden</surname><given-names>Frederick G.</given-names></name><address><email>FGH@hscmail.mcc.virginia.edu</email></address><xref ref-type="aff" rid="Aff26">26</xref></contrib><contrib contrib-type="author"><name><surname>Hussein</surname><given-names>Mohamed A.</given-names></name><address><email>Husseinmo2@NGHA.MED.SA</email></address><xref ref-type="aff" rid="Aff22">22</xref></contrib><contrib contrib-type="author"><collab>And the MIRACLE trial group<contrib-group><contrib contrib-type="author"><name><surname>Arabi</surname><given-names>Yaseen M.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Alothman</surname><given-names>Adel</given-names></name></contrib><contrib contrib-type="author"><name><surname>Balkhy</surname><given-names>Hanan H</given-names></name></contrib><contrib contrib-type="author"><name><surname>Al-Dawood</surname><given-names>Abdulaziz</given-names></name></contrib><contrib contrib-type="author"><name><surname>AlJohani</surname><given-names>Sameera</given-names></name></contrib><contrib contrib-type="author"><name><surname>Al Harbi</surname><given-names>Shmeylan</given-names></name></contrib><contrib contrib-type="author"><name><surname>Kojan</surname><given-names>Suleiman</given-names></name></contrib><contrib contrib-type="author"><name><surname>Al Jeraisy</surname><given-names>Majed</given-names></name></contrib><contrib contrib-type="author"><name><surname>Deeb</surname><given-names>Ahmad M.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Jose</surname><given-names>Jesna</given-names></name></contrib><contrib contrib-type="author"><name><surname>Hussein</surname><given-names>Mohamed A.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Al Muhaidib</surname><given-names>Mohammed</given-names></name></contrib><contrib contrib-type="author"><name><surname>Sadat</surname><given-names>Musharaf</given-names></name></contrib><contrib contrib-type="author"><name><surname>Al Anizi</surname><given-names>Hala</given-names></name></contrib><contrib contrib-type="author"><name><surname>Dael</surname><given-names>Reggie</given-names></name></contrib><contrib contrib-type="author"><name><surname>Assiri</surname><given-names>Abdullah M</given-names></name></contrib><contrib contrib-type="author"><name><surname>AlMazroa</surname><given-names>Mohammad</given-names></name></contrib><contrib contrib-type="author"><name><surname>Asiri</surname><given-names>Ayed</given-names></name></contrib><contrib contrib-type="author"><name><surname>Memish</surname><given-names>Ziad A</given-names></name></contrib><contrib contrib-type="author"><name><surname>Ghazal</surname><given-names>Sameeh S</given-names></name></contrib><contrib contrib-type="author"><name><surname>Alfaraj</surname><given-names>Sarah H</given-names></name></contrib><contrib contrib-type="author"><name><surname>Bafaqeeh</surname><given-names>Fahad</given-names></name></contrib><contrib contrib-type="author"><name><surname>Al Harthy</surname><given-names>Abdulrahman</given-names></name></contrib><contrib contrib-type="author"><name><surname>Al Sulaiman</surname><given-names>Mohammed</given-names></name></contrib><contrib contrib-type="author"><name><surname>Mady</surname><given-names>Ahmed</given-names></name></contrib><contrib contrib-type="author"><name><surname>Mandourah</surname><given-names>Yasser</given-names></name></contrib><contrib contrib-type="author"><name><surname>AlMekhlafi</surname><given-names>Ghaleb. A.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Sherbeeni</surname><given-names>Nisreen Murad</given-names></name></contrib><contrib contrib-type="author"><name><surname>Elzein</surname><given-names>Fatehi Elnour</given-names></name></contrib><contrib contrib-type="author"><name><surname>Muhammed</surname><given-names>Reema</given-names></name></contrib><contrib contrib-type="author"><name><surname>Al Samirrai</surname><given-names>Shatha</given-names></name></contrib><contrib contrib-type="author"><name><surname>Awad</surname><given-names>Shatha</given-names></name></contrib><contrib contrib-type="author"><name><surname>Cabal</surname><given-names>Rylen Cabio</given-names></name></contrib><contrib contrib-type="author"><name><surname>Malibary</surname><given-names>Abdulrauf Ahmad</given-names></name></contrib><contrib contrib-type="author"><name><surname>Al Onazi</surname><given-names>Bander</given-names></name></contrib><contrib contrib-type="author"><name><surname>Aljuhani</surname><given-names>Maha</given-names></name></contrib><contrib contrib-type="author"><name><surname>Vince</surname><given-names>Melven</given-names></name></contrib><contrib contrib-type="author"><name><surname>Almotairi</surname><given-names>Abdullah</given-names></name></contrib><contrib contrib-type="author"><name><surname>Al Enani</surname><given-names>Mushira</given-names></name></contrib><contrib contrib-type="author"><name><surname>Alqurashi</surname><given-names>Alaa</given-names></name></contrib><contrib contrib-type="author"><name><surname>Alenezi</surname><given-names>Fatimah</given-names></name></contrib><contrib contrib-type="author"><name><surname>Alkhani</surname><given-names>Nada</given-names></name></contrib><contrib contrib-type="author"><name><surname>Maghrabi</surname><given-names>Khalid A.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Al-Hameed</surname><given-names>Fahad</given-names></name></contrib><contrib contrib-type="author"><name><surname>AlSaedi</surname><given-names>Asim</given-names></name></contrib><contrib contrib-type="author"><name><surname>Thaqafi</surname><given-names>Abdulhakeem</given-names></name></contrib><contrib contrib-type="author"><name><surname>Al Oraabi</surname><given-names>Ohoud</given-names></name></contrib><contrib contrib-type="author"><name><surname>Rifai</surname><given-names>Jalal</given-names></name></contrib><contrib contrib-type="author"><name><surname>Elsamadisi</surname><given-names>Pansy</given-names></name></contrib><contrib contrib-type="author"><name><surname>Hendy</surname><given-names>Medhat S.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Basher</surname><given-names>Sara AbuBaker</given-names></name></contrib><contrib contrib-type="author"><name><surname>Abduldhaher</surname><given-names>Muhammed</given-names></name></contrib><contrib contrib-type="author"><name><surname>Bajhamoum</surname><given-names>Wael</given-names></name></contrib><contrib contrib-type="author"><name><surname>Qushmaq</surname><given-names>Ismael</given-names></name></contrib><contrib contrib-type="author"><name><surname>Shalhoub</surname><given-names>Sarah</given-names></name></contrib><contrib contrib-type="author"><name><surname>Taha</surname><given-names>Yusri</given-names></name></contrib><contrib contrib-type="author"><name><surname>Memon</surname><given-names>Javed</given-names></name></contrib><contrib contrib-type="author"><name><surname>Bashir</surname><given-names>Shahinaz</given-names></name></contrib><contrib contrib-type="author"><name><surname>Al-Dossary</surname><given-names>Ibraheem</given-names></name></contrib><contrib contrib-type="author"><name><surname>Al Mekhloof</surname><given-names>Saleh</given-names></name></contrib><contrib contrib-type="author"><name><surname>Al-Muhainy</surname><given-names>Bader</given-names></name></contrib><contrib contrib-type="author"><name><surname>Suliman</surname><given-names>Shehab</given-names></name></contrib><contrib contrib-type="author"><name><surname>Alshahrani</surname><given-names>Mohammed S.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Al Bshabshe</surname><given-names>Ali</given-names></name></contrib><contrib contrib-type="author"><name><surname>Kharaba</surname><given-names>Ayman</given-names></name></contrib><contrib contrib-type="author"><name><surname>Al Jabri</surname><given-names>Ahmad</given-names></name></contrib><contrib contrib-type="author"><name><surname>Farid</surname><given-names>Magdy</given-names></name></contrib><contrib contrib-type="author"><name><surname>Alaidarous</surname><given-names>Alawi</given-names></name></contrib><contrib contrib-type="author"><name><surname>Alseraihi</surname><given-names>Wael</given-names></name></contrib><contrib contrib-type="author"><name><surname>Shahada</surname><given-names>Husam</given-names></name></contrib><contrib contrib-type="author"><name><surname>Shimi</surname><given-names>Jinish</given-names></name></contrib><contrib contrib-type="author"><name><surname>Riaz</surname><given-names>Syed</given-names></name></contrib><contrib contrib-type="author"><name><surname>Alharthi</surname><given-names>Bader</given-names></name></contrib><contrib contrib-type="author"><name><surname>Yasin</surname><given-names>Osama</given-names></name></contrib><contrib contrib-type="author"><name><surname>Khathlan</surname><given-names>Mohammad</given-names></name></contrib><contrib contrib-type="author"><name><surname>Fowler</surname><given-names>Robert A.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Hayden</surname><given-names>Frederick G.</given-names></name></contrib></contrib-group></collab></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Intensive Care Department,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Department of Medicine,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff4"><label>4</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Department of Infection Prevention and Control,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff5"><label>5</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Department of Pathology and Laboratory Medicine,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff6"><label>6</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff7"><label>7</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Pharmaceutical Care Department,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff8"><label>8</label><institution-wrap><institution-id institution-id-type="GRID">grid.415696.9</institution-id><institution>Infection Prevention and Control, Ministry of Health,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff9"><label>9</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Jeddah, Saudi Arabia</aff><aff id="Aff10"><label>10</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Intensive Care Department,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Jeddah, Saudi Arabia</aff><aff id="Aff11"><label>11</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id><institution-id institution-id-type="GRID">grid.415254.3</institution-id><institution>Department of Infection Prevention and Control,</institution><institution>King Abdulaziz Medical City,</institution></institution-wrap>Jeddah, Saudi Arabia</aff><aff id="Aff12"><label>12</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9759 8141</institution-id><institution-id institution-id-type="GRID">grid.415989.8</institution-id><institution>Department of Intensive Care Services,</institution><institution>Prince Sultan Military Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff13"><label>13</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9759 8141</institution-id><institution-id institution-id-type="GRID">grid.415989.8</institution-id><institution>Infectious Diseases Division,</institution><institution>Prince Sultan Military Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff14"><label>14</label><institution-wrap><institution-id institution-id-type="GRID">grid.415252.5</institution-id><institution>Intensive Care Section, Department of Medicine,</institution><institution>King Abdulaziz Hospital,</institution></institution-wrap>Alahsa, Saudi Arabia</aff><aff id="Aff15"><label>15</label><institution-wrap><institution-id institution-id-type="GRID">grid.415252.5</institution-id><institution>Department of Medicine,</institution><institution>King Abdulaziz Hospital,</institution></institution-wrap>Alahsa, Saudi Arabia</aff><aff id="Aff16"><label>16</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0593 1832</institution-id><institution-id institution-id-type="GRID">grid.415277.2</institution-id><institution>Department of Critical Care Medicine,</institution><institution>King Fahad Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff17"><label>17</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2191 4301</institution-id><institution-id institution-id-type="GRID">grid.415310.2</institution-id><institution>Department of Critical Care Medicine,</institution><institution>King Faisal Specialist Hospital and Research,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff18"><label>18</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2191 4301</institution-id><institution-id institution-id-type="GRID">grid.415310.2</institution-id><institution>Department of Medicine,</institution><institution>King Faisal Specialist Hospital and Research Center,</institution></institution-wrap>Jeddah, Saudi Arabia</aff><aff id="Aff19"><label>19</label>Department of Critical Care Medicine, King Khalid University, Aseer Central Hospital, Abha, Saudi Arabia</aff><aff id="Aff20"><label>20</label>Department of Critical Care, King Fahad Hospital, Ohoud Hospital, Al-Madinah Al-Monawarah, Saudi Arabia</aff><aff id="Aff21"><label>21</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0573 8987</institution-id><institution-id institution-id-type="GRID">grid.415271.4</institution-id><institution>Department of Medicine,</institution><institution>King Fahad Armed Forces Hospital,</institution></institution-wrap>Jeddah, Saudi Arabia</aff><aff id="Aff22"><label>22</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0580 0891</institution-id><institution-id institution-id-type="GRID">grid.452607.2</institution-id><institution>Department of Biostatistics and Bioinformatics, King Saud Bin Abdulaziz University for Health Sciences,</institution><institution>King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff23"><label>23</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2157 2938</institution-id><institution-id institution-id-type="GRID">grid.17063.33</institution-id><institution>AMR Infection Control and Publications AIP/PED/HSE/HQ, Institute of Health Policy Management and Evaluation,</institution><institution>University of Toronto,</institution></institution-wrap>Toronto, ON Canada</aff><aff id="Aff24"><label>24</label><institution-wrap><institution-id institution-id-type="GRID">grid.416745.5</institution-id><institution>Department of Critical Care Medicine,</institution><institution>Sunnybrook Hospital,</institution></institution-wrap>2075 Bayview Avenue, Room D478, Toronto, ON Canada</aff><aff id="Aff25"><label>25</label><institution-wrap><institution-id institution-id-type="GRID">grid.416745.5</institution-id><institution>Department of Medicine,</institution><institution>Sunnybrook Hospital,</institution></institution-wrap>2075 Bayview Avenue, Room D478, Toronto, ON Canada</aff><aff id="Aff26"><label>26</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9136 933X</institution-id><institution-id institution-id-type="GRID">grid.27755.32</institution-id><institution>Department of Medicine, Division of Infectious Diseases and International Health,</institution><institution>University of Virginia School of Medicine,</institution></institution-wrap>Charlottesville, VA USA</aff><aff id="Aff27"><label>27</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 8948</institution-id><institution-id institution-id-type="GRID">grid.4991.5</institution-id><institution>International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) University of Oxford, Old Road Campus, Roosevelt Drive,</institution></institution-wrap>Oxford, OX3 7FZ UK</aff></contrib-group><pub-date pub-type="epub"><day>30</day><month>1</month><year>2018</year></pub-date><pub-date pub-type="pmc-release"><day>30</day><month>1</month><year>2018</year></pub-date><pub-date pub-type="collection"><year>2018</year></pub-date><volume>19</volume><elocation-id>81</elocation-id><history><date date-type="received"><day>8</day><month>5</month><year>2017</year></date><date date-type="accepted"><day>20</day><month>12</month><year>2017</year></date></history><permissions><copyright-statement>© The Author(s). 2018</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold>This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>) applies to the data made available in this article, unless otherwise stated.</license-p></license></permissions><abstract id="Abs1"><sec><title>Background</title><p id="Par1">It had been more than 5 years since the first case of Middle East Respiratory Syndrome coronavirus infection (MERS-CoV) was recorded, but no specific treatment has been investigated in randomized clinical trials. Results from in vitro and animal studies suggest that a combination of lopinavir/ritonavir and interferon-β1b (IFN-β1b) may be effective against MERS-CoV. The aim of this study is to investigate the efficacy of treatment with a combination of lopinavir/ritonavir and recombinant IFN-β1b provided with standard supportive care, compared to treatment with placebo provided with standard supportive care in patients with laboratory-confirmed MERS requiring hospital admission.</p></sec><sec><title>Methods</title><p id="Par2">The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. Hospitalized adult patients with laboratory-confirmed MERS will be enrolled in this recursive, two-stage, group sequential, multicenter, placebo-controlled, double-blind randomized controlled trial. The trial is initially designed to include 2 two-stage components. The first two-stage component is designed to adjust sample size and determine futility stopping, but not efficacy stopping. The second two-stage component is designed to determine efficacy stopping and possibly readjustment of sample size. The primary outcome is 90-day mortality.</p></sec><sec><title>Discussion</title><p id="Par3">This will be the first randomized controlled trial of a potential treatment for MERS. The study is sponsored by King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. Enrollment for this study began in November 2016, and has enrolled thirteen patients as of Jan 24-2018.</p></sec><sec><title>Trial registration</title><p id="Par4">ClinicalTrials.gov, ID: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT02845843">NCT02845843</ext-link>. Registered on 27 July 2016.</p></sec><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1186/s13063-017-2427-0) contains supplementary material, which is available to authorized users.</p></sec></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>Coronavirus</kwd><kwd>MERS</kwd><kwd>Antiviral</kwd><kwd>Saudi Arabia</kwd><kwd>Clinical trial</kwd><kwd>Lopinavir/ritonavir</kwd><kwd>Interferon-β1b</kwd></kwd-group><funding-group><award-group><funding-source><institution>king Abdullah International Medical Research Center</institution></funding-source><award-id>RC15/142</award-id></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2018</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1" sec-type="introduction"><title>Background</title><p id="Par19">Since the first report of infection with the Middle East Respiratory Syndrome coronavirus (MERS-CoV) was published in 2012, the World Health Organization has been notified of 2123 laboratory-confirmed infections with MERS-CoV from 27 countries and at least 740 reported deaths (case fatality 35%) [<xref ref-type="bibr" rid="CR1">1</xref>]. There is no specific therapy of proven efficacy available and no potential treatment has been tested in a randomized clinical trial (RCT) for evaluation [<xref ref-type="bibr" rid="CR2">2</xref>–<xref ref-type="bibr" rid="CR4">4</xref>]. Based on results from in vitro and animal studies of MERS-CoV infection, the guanosine analog ribavirin, in combination with interferon alpha (IFN-α), has been used to treat patients with MERS [<xref ref-type="bibr" rid="CR5">5</xref>–<xref ref-type="bibr" rid="CR8">8</xref>]. However, the concentration of ribavirin required to inhibit MERS-CoV in vitro exceeds peak levels in the blood after therapeutic doses in humans [<xref ref-type="bibr" rid="CR9">9</xref>–<xref ref-type="bibr" rid="CR11">11</xref>]. Furthermore, retrospective studies with IFN-α2a, IFN-α2b or IFN-β1a in combination with ribavirin have not shown a clear benefit in patients with MERS [<xref ref-type="bibr" rid="CR6">6</xref>–<xref ref-type="bibr" rid="CR8">8</xref>, <xref ref-type="bibr" rid="CR12">12</xref>].</p><p id="Par20">MERS-CoV attenuates the interferon (IFN) response of the innate immune system, and this mechanism is thought to impair the antiviral adaptive type 1 T-helper cell (Th-1) immune response [<xref ref-type="bibr" rid="CR13">13</xref>–<xref ref-type="bibr" rid="CR15">15</xref>]. In vitro, IFN-α and IFN-β have inhibitory effects on MERS-CoV and on the closely related coronavirus, Severe Acute Respiratory Syndrome (SARS)-CoV, but MERS-CoV appears to be significantly more sensitive than SARS-CoV to IFN effects [<xref ref-type="bibr" rid="CR15">15</xref>, <xref ref-type="bibr" rid="CR16">16</xref>]. Among IFN subtypes, IFN-β1b causes the greatest in vitro inhibition of MERS-CoV, and has a significantly lower ratio of the half-maximal effective concentration (EC) to the maximal plasma concentration (EC<sub>50</sub>:C<sub>max</sub>) than IFN-α2a, IFN-α2b or IFN-β1a, indicating potentially greater efficacy [<xref ref-type="bibr" rid="CR9">9</xref>, <xref ref-type="bibr" rid="CR11">11</xref>]. This observation may also partially explain the lack of clear benefit associated with the use of IFN-α2a, IFN-α2b or IFN-β1a in combination with ribavirin. Recombinant IFN-β1b (Betaseron®, Bayer, Leverkusen, Germany) is approved for multiple sclerosis [<xref ref-type="bibr" rid="CR17">17</xref>–<xref ref-type="bibr" rid="CR19">19</xref>].</p><p id="Par21">Based on in vitro data, the combination of lopinavir and ritonavir has been considered as a candidate therapy for MERS. Lopinavir and ritonavir are antiretroviral protease inhibitors used in combination for the treatment of human immunodeficiency virus (HIV) infection and have limited side effects [<xref ref-type="bibr" rid="CR20">20</xref>]. The combination of lopinavir/ritonavir (Kaletra®, Abbott Laboratories, Chicago, IL, USA) has also been used for the treatment of SARS. In one study, the combination of lopinavir/ritonavir used in 41 patients with SARS was associated with significantly fewer adverse clinical outcomes (acute respiratory distress syndrome or death) 21 days after the onset of symptoms compare to ribavirin alone used in 111 historical controls (2.4% versus 28.8%, <italic>p</italic> = 0.001) [<xref ref-type="bibr" rid="CR21">21</xref>]. However, the historical nature of the control comparison does not allow for a valid estimate of efficacy. In a high-throughput screening for antiviral compounds, lopinavir inhibited the replication of MERS-CoV at levels below those that occur in the circulation after a single oral dose of lopinavir/ritonavir (400 mg lopinavir with 100 mg ritonavir), suggesting that the drug can achieve therapeutic levels in vivo [<xref ref-type="bibr" rid="CR16">16</xref>, <xref ref-type="bibr" rid="CR22">22</xref>]. The effects of lopinavir/ritonavir, IFN-β1b and mycophenolate mofetil (MMF), all of which have shown viral inhibitory effects in vitro, have been tested in common marmosets with severe MERS-CoV infection [<xref ref-type="bibr" rid="CR23">23</xref>]. The animals treated with lopinavir/ritonavir or IFN-β1b had improved clinical, radiological, pathological and viral-load outcomes compared with untreated animals. By contrast, treatment with MMF resulted in severe or fatal disease, with higher mean viral loads than in untreated animals. Untreated animals and MMF-treated animals had a mortality of 67% by 36 h compared to 0–33% among animals treated with lopinavir/ritonavir or IFN-β1b [<xref ref-type="bibr" rid="CR23">23</xref>].</p><p id="Par22">In one case from the 2015 Korean MERS outbreak, lopinavir/ritonavir used in combination with ribavirin and IFN-α2a resulted in defervescence, virological clearance and survival [<xref ref-type="bibr" rid="CR24">24</xref>]. In another case from Greece, lopinavir/ritonavir combined with IFN and ribavirin was started on day 13 of a MERS illness and was followed 2 days later by clearance of viremia, although viral ribonucleic acid (RNA) persisted in the respiratory secretions until the fourth week of illness and the patient subsequently died [<xref ref-type="bibr" rid="CR25">25</xref>]. During the Korean outbreak of MERS, most patients that developed respiratory illness received triple antiviral therapy composed of pegylated interferon (IFN)-α, ribavirin, and lopinavir/ritonavir; however, data about the efficacy of this approach are lacking [<xref ref-type="bibr" rid="CR26">26</xref>]. These findings, together with the availability and safety profiles of lopinavir/ritonavir and IFN-β1b, suggest that the combination of these agents has potential efficacy for the treatment of patients with MERS.</p><p id="Par23">The objective of the MIRACLE trial (the <italic>M</italic>ERS-CoV <italic>I</italic>nfection t<italic>R</italic>eated with <italic>A C</italic>ombination of <italic>L</italic>opinavir/ritonavir and int<italic>E</italic>rferon-β1b) is to assess the efficacy of administering a combination of lopinavir/ritonavir and recombinant IFN-β1b to hospitalized adults with laboratory-confirmed MERS. The study is designed as recursive, two-stage, group sequential, multicenter, randomized, placebo-controlled, double-blind trial. We report the study protocol according to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) template [<xref ref-type="bibr" rid="CR27">27</xref>].</p></sec><sec id="Sec2" sec-type="materials|methods"><title>Methods</title><sec id="Sec3"><title>Study design</title><p id="Par24">The study is a recursive, two-stage, group sequential, multicenter, randomized, placebo-controlled, double-blind trial [<xref ref-type="bibr" rid="CR28">28</xref>]. The trial is initially designed with 2 two-stage components with two interim analyses and one final analysis. The first two-stage component is designed to adjust sample size and determine futility stopping, but not efficacy stopping. The second two-stage component is designed to determine efficacy stopping and possibly readjustment of sample size to maintain conditional power at the final analysis.</p></sec><sec id="Sec4"><title>Study population</title><sec id="Sec5"><title>Inclusion criteria at eligibility assessment</title><p id="Par25"><list list-type="order"><list-item><p id="Par26">Adult (defined as ≥ 18 years of age)</p></list-item><list-item><p id="Par27">Laboratory confirmation of MERS-CoV infection by reverse-transcription polymerase chain reaction (RT-PCR) from any diagnostic sampling source, and</p></list-item><list-item><p id="Par28">New organ dysfunction that is judged to be related to MERS including: hypoxia defined as requirement of supplemental oxygen to maintain oxygen saturations > 90%, hypotension (systolic blood pressure < 90 mmHg) or the need for vasopressor/inotropic medication, renal impairment (increase of creatinine by 50% from baseline, glomerular filtration rate reduction by > 25% from baseline or urine output of < 0.5 ml/kg for 6 h – risk stage by RIFLE criteria) [<xref ref-type="bibr" rid="CR29">29</xref>], neurological pathology (reduction of Glasgow Coma Scale by 2 or more, i.e., 13 or lower of 15 points), thrombocytopenia (<150,000 platelets/mm<sup>3</sup>) or gastrointestinal symptoms that require hospitalization (e.g., severe nausea, vomiting, diarrhea or/and abdominal pain).</p></list-item></list></p></sec><sec id="Sec6"><title>Exclusion criteria at eligibility assessment</title><p id="Par29"><list list-type="order"><list-item><p id="Par30">Suicidal ideation based on history (contraindication to IFN-β1b)</p></list-item><list-item><p id="Par31">Known allergy or hypersensitivity reaction to lopinavir/ritonavir or to recombinant IFN-β1b, including, but not limited to, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria or angioedema</p></list-item><list-item><p id="Par32">Elevated alanine aminotransferase (ALT) more than five-fold the upper limit in the hospital’s laboratory</p></list-item><list-item><p id="Par33">Use of medications that are contraindicated with lopinavir/ritonavir and that cannot be replaced or stopped during the study period, such as CYP3A inhibitors (see Table <xref rid="Tab1" ref-type="table">1</xref>)<table-wrap id="Tab1"><label>Table 1</label><caption><p>Lopinavir/ritonavir interactions with drugs commonly used in the intensive-care unit</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Drug</th><th>Possible interaction</th><th>Management</th><th>Action at enrollment</th><th>Action after enrollment</th></tr></thead><tbody><tr><td>Amiodarone</td><td><p>Increased risk of amiodarone toxicity (hypotension, bradycardia, sinus arrest).</p><p>Increased QT-interval prolongation</p></td><td>Concurrent use is contraindicated</td><td>At the time of enrollment, amiodarone therapy with no alternative is an exclusion criterion</td><td><p>Consider alternatives to amiodarone.</p><p>If no alternative to amiodarone is available, consider using a reduced dose.</p><p>Monitor for increased amiodarone serum concentrations, altered liver function test results and evidence of QT-interval prolongation</p></td></tr><tr><td>Fentanyl</td><td>Concurrent use of fentanyl and CYP3A4 inhibitors may result in an increased risk of fentanyl toxicity, resulting in fatal respiratory depression</td><td><p>In non-mechanically ventilated patients, concurrent use is contraindicated.</p><p>In mechanically ventilated patients, avoid fentanyl or use reduced doses</p></td><td><p>Consider alternatives to fentanyl.</p><p>Use lower doses and adjust the dose to target analgesia and sedative effects</p></td><td><p>Consider alternatives to fentanyl.</p><p>Use lower doses and adjust the dose to target analgesia and sedative effects</p></td></tr><tr><td>Fluconazole</td><td>Increased ritonavir exposure and risk of QT-interval prolongation</td><td><p>Avoid concomitant use if possible</p><p>If fluconazole is required, closely monitor electrocardiogram for QT-interval prolongation</p></td><td>Use alternatives to fluconazole</td><td><p>Use alternatives to fluconazole.</p><p>Fluconazole-mediated CYP3A4 inhibition may continue for 4–5 days after discontinuation because of its long half-life</p></td></tr><tr><td>Midazolam</td><td>Increased midazolam plasma concentrations, which can lead to midazolam toxicity</td><td><p>In non-mechanically ventilated patients, concurrent use is contraindicated.</p><p>In mechanically ventilated patients, avoid use of midazolam if possible. If needed, use reduced midazolam doses and monitor effects</p></td><td><p>Consider alternatives to midazolam.</p><p>Use lower doses and adjust the dose to target sedative effects</p></td><td><p>Consider alternatives to midazolam.</p><p>Use lower doses and adjust the dose to target sedative effects.</p><p>If the concomitant use of midazolam and lopinavir/ritonavir is required, closely monitor patients for midazolam adverse effects (excessive sedation, confusion and respiratory depression) and consider using a reduced midazolam dose</p></td></tr><tr><td>Quetiapine</td><td>Increased risk of QT-interval prolongation, <italic>torsades de pointes</italic> or other notable ventricular tachyarrhythmias</td><td>Concomitant administration is contraindicated</td><td>Use alternatives to quetiapine</td><td><p>Use alternatives to quetiapine.</p><p>If concomitant use is required, reduce the quetiapine dose to one sixth of the standard dose, and when the lopinavir/ritonavir is discontinued, the dose of quetiapine should subsequently be increased to the standard dose</p></td></tr><tr><td>Rifampin</td><td><p>Decreased lopinavir/ritonavir plasma concentrations.</p><p>Rifampin may enhance the toxic effect of lopinavir, specifically increasing the risk of hepatocellular toxicity</p></td><td>Concurrent use is contraindicated</td><td>If concomitant use is required, rifabutin 150 mg every other day or 150 mg three times a week is recommended for concomitant use with lopinavir/ritonavir</td><td>If concomitant use is required, rifabutin 150 mg every other day or 150 mg three times a week is recommended for concomitant use with lopinavir/ritonavir</td></tr><tr><td>Sildenafil</td><td>Increased sildenafil plasma levels, thereby increasing the risk for sildenafil adverse effects (hypotension, visual changes and priapism)</td><td>Concurrent use of lopinavir/ritonavir and sildenafil is contraindicated</td><td>Stop sildenafil if possible. If not possible, sildenafil use is an exclusion criterion for this study</td><td>Do not use sildenafil</td></tr><tr><td>Simvastatin</td><td>Increased risk of myopathy or rhabdomyolysis</td><td>Concomitant use of lopinavir/ritonavir with simvastatin is contraindicated</td><td>Stop simvastatin if possible. If needed, consider fluvastatin, pitavastatin or pravastatin as alternatives, because these drugs have the least potential for interaction</td><td>Do not use simvastatin. If needed, consider fluvastatin, pitavastatin or pravastatin as alternatives, because these drugs have the least potential for interaction</td></tr><tr><td>Atorvastatin</td><td>Atorvastatin AUC increased by 488%. Increased risk of myopathy or rhabdomyolysis</td><td>Monitor for signs of atorvastatin toxicity (rhabdomyolysis and myopathy)</td><td>Consider discontinuation of atorvastatin. If discontinuation is not possible, use with caution at the lower end of the dosing range (10–40 mg per day)</td><td>Consider alternative agents (pravastatin, fluvastatin or rosuvastatin), because these drugs have the least potential for interaction</td></tr><tr><td>Voriconazole</td><td>Decreased plasma concentrations of voriconazole and decreased voriconazole efficacy</td><td>Concomitant administration is contraindicated</td><td>Use alternatives to voriconazole. If no alternative exists, voriconazole use is an exclusion criterion for this study</td><td><p>Use alternatives to voriconazole or use with therapeutic drug monitoring. Voriconazole dose may need to be increased. If no alternative is available, discontinue lopinavir/ritonavir and continue the use of IFN-β1b.</p><p>Consider another antifungal for aspergillosis</p></td></tr><tr><td>Phenytoin</td><td>Both phenytoin and ritonavir plasma concentrations may be decreased</td><td>Use with caution</td><td>Use with caution</td><td>Monitor phenytoin levels during co-administration. Adjustment of the phenytoin or fosphenytoin dose may be warranted</td></tr></tbody></table><table-wrap-foot><p>The information in this table was obtained from Lexicomp (<ext-link ext-link-type="uri" xlink:href="http://www.wolterskluwercdi.com/lexicomp-online/">http://www.wolterskluwercdi.com/lexicomp-online/</ext-link>) and Micromedex (<ext-link ext-link-type="uri" xlink:href="https://www.micromedexsolutions.com/home/dispatch">https://www.micromedexsolutions.com/home/dispatch</ext-link>). Abbreviations: <italic>AUC</italic> area under the (receiver operating characteristic) curve, <italic>CYP3A4</italic> cytochrome P450-3A4</p></table-wrap-foot></table-wrap></p></list-item><list-item><p id="Par35">Pregnancy – eligible and consenting female participants of childbearing age will be tested for pregnancy before enrollment in the study</p></list-item><list-item><p id="Par36">Known HIV infection, because of concerns about the development of resistance to lopinavir/ritonavir if used without combination with other anti-HIV drugs, or</p></list-item><list-item><p id="Par37">Patient likely to be transferred to a non-participating hospital within 72 h.</p></list-item></list></p></sec></sec><sec id="Sec7"><title>Trial intervention</title><p id="Par38">Informed consent will be obtained from eligible patients or their substitute decision-makers (for patients lacking decision-making capacity). All patients who provide informed consent will be randomly allocated into one of two study groups.</p><sec id="Sec8"><title>Intervention group</title><p id="Par39">The intervention group will receive the standard of care as well as lopinavir/ritonavir and recombinant IFN-β1b. Lopinavir/ritonavir (400 lopinavir mg/100 mg ritonavir) will be administered every 12 h for 14 days in tablet form. For patients who are unable to take medications by mouth, the lopinavir/ritonavir (400 lopinavir mg/100 mg ritonavir) will be administered as a 5-ml suspension every 12 h for 14 days via a pre-existing or newly placed nasogastric tube. IFN-β1b will be administered as 0.25-mg/ml subcutaneous injections on alternate days for 14 days (for a total of seven doses).</p></sec><sec id="Sec9"><title>Control group</title><p id="Par40">The control group will receive standard of care as well as placebo treatment for 14 days at the same frequency as the intervention group, to maintain blinding. One placebo will be given every 12 h and will comprise a sucrose tablet or capsule, or 5 ml of normal saline via nasogastric tube for patients who are unable to take medications by mouth. Patients in the control group will receive 1 ml of normal saline by subcutaneous injection on alternate days.</p></sec></sec><sec id="Sec10"><title>Co-interventions</title><p id="Par41">Patients in both study arms will receive standard supportive care (e.g., oral/and or intravenously administered fluids according to basal daily requirements or blood pressure support, oral or parenteral nutrition, venous thromboembolism prophylaxis, antibiotic therapy for infections, supplemental oxygen or mechanical ventilation for hypoxia or ventilation needs) at the discretion of the treating teams. Recommendations regarding current standards of care that are consistent with best clinical practices and World Health Organization guidelines will be provided to the treating teams. Data on the use of antimicrobials and corticosteroids, and aspects of respiratory, cardiovascular and renal support will be collected but not protocolized. All patients will be tested for HIV on enrollment; however, results of testing may be delayed > 24 h for some patients; therefore, we will not delay randomization while waiting HIV status. In patients who are discovered to be HIV positive, the intervention will be discontinued and outcome data will be collected as per protocol, as these patients will be included in the intention-to-treat analysis. We will have a separate on-treatment analysis that will not include these patients. Treatment of HIV infection will be as per the treating team.</p></sec><sec id="Sec11"><title>Randomization, allocation and blinding</title><sec id="Sec12"><title>Randomization</title><p id="Par42">Patients will be randomly assigned to one of the two intervention arms by a variable-size block, computer-generated randomization procedure, which will ensure that the two arms contain equal numbers of patients. Randomization will be stratified according to center and according to whether the patients require mechanical ventilation (invasive or non-invasive) at the time of enrollment.</p></sec><sec id="Sec13"><title>Allocation</title><p id="Par43">Patient allocation will follow a concealed process using sealed, fully opaque, numbered envelopes.</p></sec><sec id="Sec14"><title>Blinding</title><p id="Par44">The intervention will be blinded for the research team (principal investigator, co-investigators, research coordinators and the Steering Committee), treating team (physicians, bedside nurses and clinical pharmacists), outcome assessors (including the laboratory personnel) and study patients. Pharmacists who prepare the study medication, dosing nurses (who administer the medication) and the study statistician will not be blinded. This approach was chosen because placebos that exactly match the medications in appearance are not available.</p></sec></sec><sec id="Sec15"><title>Study drug preparation and administration</title><sec id="Sec16"><title>Storage and handling</title><p id="Par45">Lopinavir/ritonavir and recombinant IFN-β1b will be stored in a secure area in the pharmacy at room temprature or refrigerator at 2–8 °C according to standard hospital procedures and the product monograph. A temperature log with daily minimum and maximum temperature readings will be kept by the site pharmacist. Any temperature excursion will be reported immediately to an unblinded project officer from the sponsor, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. The sodium chloride (0.9%) ampoules and the starch capsules will be stored in a restricted area at room temperature.</p></sec><sec id="Sec17"><title>Study drug composition and dispensing</title><p id="Par46">At patient randomization by the site investigator or by appropriately delegated study personnel, a sealed envelope containing the patient allocation will be delivered to the pharmacy. The unblinded pharmacist will open the envelope and dispense the study drug in a tamperproof sealed box to blind the treatment assignment. The sealed, opaque box will be labeled to include the following information: name and number of clinical trial protocol, patient study number and site number. The box will only be opened by the unblinded study nurse.</p></sec><sec id="Sec18"><title>Administration</title><p id="Par47">Unblinded dosing nurses, who will not be responsible for the direct clinical care of the patients, nor other study procedures including assessment of the study outcomes, will administer the treatment. A second un-blinded nurse will check the treatment regimen for each patient according to local hospital regulations for medication administration. The dosing nurses will maintain blinding by the following measures: (1) pulling the screens around the patients’ bed areas while the dose is administered and ensuring that no members of the treating team are present; (2) discarding any labels and the used syringe in a way that ensures that the identity of the medication is not revealed; and (3) avoiding any discussion regarding the study drug with other hospital staff, except the unblinded pharmacist.</p></sec><sec id="Sec19"><title>Duration of the intervention</title><p id="Par48">The study interventions will continue for 14 days according to the protocol. Medications will be discontinued in patients who are well enough to be discharged from the hospital, even if this occurs before 14 days have elapsed.</p></sec></sec><sec id="Sec20"><title>Frequency and duration of follow-up</title><p id="Par49">Patients will be followed daily until discharge from hospital or day 28, whichever comes first (Fig. <xref rid="Fig1" ref-type="fig">1</xref>). After day 28, the patients will be followed only to document their ICU, hospital, 90-day mortality and length of stay. Collection of this information may require telephone interviews with patients or next of kin. Figure <xref rid="Fig1" ref-type="fig">1</xref> shows the schedule of enrollment, intervention and assessment for the MIRACLE trial according to the SPIRIT template. The SPIRIT Checklist is given in Additional file <xref rid="MOESM1" ref-type="media">1</xref>.<fig id="Fig1"><label>Fig. 1</label><caption><p>Schedule of enrollment, intervention and assessment for the MIRACLE trial according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) template [<xref ref-type="bibr" rid="CR27">27</xref>]. Arrows indicate periods of continuous or daily collection or assessment, whereas “X” indicates collection on specific days. * ± 2 days except D0 and D3. <sup>‡</sup>Assessed by the clinical pharmacist. <sup>§</sup>Tests on sputum, tracheal aspirate, broncheoalveolar lavage and nasopharyngeal swab to be continued twice weekly until two consecutive tests are negative. <sup>||</sup>Mandatory for intubated patients, optional for non-intubated patients. <sup>¶</sup>Hemoglobin, white blood cells, neutrophils, lymphocytes and platelets. <sup>#</sup>Blood urea nitrogen, creatinine, potassium, sodium, chloride, bicarbonate, glucose and albumin. ∞Serum bilirubin, gamma-glutamyl transferase, alanine transaminase and aspartate aminotransferase. **Serum thyroxine, triiodothyronine and thyroid-stimulating hormone. Abbreviations: <italic>ACTH</italic> adrenocorticotropic hormone, <italic>MERS-CoV</italic> Middle East Respiratory Syndrome coronavirus, <italic>SOFA</italic> Sequential Organ Failure Assessment</p></caption><graphic xlink:href="13063_2017_2427_Fig1_HTML" id="MO1"></graphic></fig></p></sec><sec id="Sec21"><title>MERS-CoV RT-PCR testing</title><p id="Par50">Diagnostic RT-PCR will be preformed per each hospital protocol in its own hospital laboratory or in the reference laboratory of the Saudi Ministry of Health. Additionally, respiratory and blood samples will be sent to King Abdullah International Research Center for semi-quantitative viral-load testing. The testing procedure includes extracting ribonucleic acid (RNA) from respiratory and serum specimens using the MagNA Pure 96 Viral NA Kit (Roche Applied Science, Indianapolis, IN, USA). The extracted nucleic acids will be tested by rRT-PCR targeting the upstream MERS-CoV envelope protein gene (upE) and open-reading frame 1a (ORF1a) regions of the MERS-CoV genome on a LightCycler 480 System (Roche Diagnostics, Mannheim, Germany) [<xref ref-type="bibr" rid="CR30">30</xref>]. A positive control for ORF1a and upE rRT-PCR is performed according to the manufacturer’s instructions. We will document cycle thresholds (C<sub>t</sub>) for upE and ORF1a which indicate the start of exponential amplification. For diagnostic purposes, we consider a cycle threshold (C<sub>t</sub>) of < 35 the cutoff for upE and ORF1a in line with the cutoff used by the Saudi Arabia Ministry of Health reference laboratory. If C<sub>t</sub> values are ≥ 35, the test will be repeated using different samples, preferably from the lower respiratory tract, to avoid false-positive results. We will use C<sub>t</sub> values as semi-quantitative measures for viral RNA load.</p></sec><sec id="Sec22"><title>Study outcomes</title><sec id="Sec23"><title>Primary outcome</title><p id="Par51"><list list-type="order"><list-item><p id="Par52">90-day mortality</p></list-item></list></p></sec><sec id="Sec25"><title>Secondary clinical outcomes</title><p id="Par57"><list list-type="order"><list-item><p id="Par58">Mortality in the ICU, mortality in the hospital and 28-day mortality</p></list-item><list-item><p id="Par59">Sequential Organ Failure Assessment (SOFA) scores at baseline and on study days 1, 3, 7, 14, 21 and 28</p></list-item><list-item><p id="Par60">Organ support, according to the number of days within the first 28 days after enrollment when patients do not receive specific forms of support:<list list-type="alpha-lower"><list-item><p id="Par61">Supplemental oxygen-free days</p></list-item><list-item><p id="Par62">Renal replacement therapy-free days</p></list-item><list-item><p id="Par63">Vasopressor-free days</p></list-item><list-item><p id="Par64">Invasive or non-invasive mechanical ventilation-free days</p></list-item><list-item><p id="Par65">Organ support-free days (that is, days free of invasive mechanical ventilation, renal replacement therapy and vasopressors)</p></list-item><list-item><p id="Par66">Extracorporeal circulation support-free days</p></list-item></list></p></list-item><list-item><p id="Par67">ICU-free days and hospital length of stay:<list list-type="alpha-lower"><list-item><p id="Par68">ICU-free days are the number of days when patients are not being cared for in the ICU during the first 28 days after enrollment. Patients who die within 28 days will be assigned the value “0”</p></list-item><list-item><p id="Par69">The hospital length of stay will be calculated as the number of days between admission and discharge from the hospital. Because of the competing risk effect of death on length of stay, length of stay will be also reported for survivors alone</p></list-item></list></p></list-item></list></p></sec><sec id="Sec26"><title>Secondary laboratory outcomes</title><p id="Par70"><list list-type="order"><list-item><p id="Par71">Viral replication kinetics will be calculated by determining viral RNA loads as reflected by C<sub>t</sub> values by semi-quantitative PCR in serial samples of upper and lower respiratory tract secretions and blood, collected twice per week. Quantitative PCR, which may be more sensitive than C<sub>t</sub> values, will be used if it becomes available during the trial</p></list-item><list-item><p id="Par72">Time to clearance from the lower respiratory tract will be determined from the results of RT-PCR analyses of lower respiratory tract secretions or nasopharyngeal swabs in non-intubated patients who are unable to give sputum samples; clearance will be defined as two negative RT-PCR results not followed by a positive one. Patients who die before clearance will be censored at the time of death</p></list-item><list-item><p id="Par73">Planned sub-studies will examine cytokine, chemokine and immune responses in serially collected blood samples. A detailed protocol of this sub-study will be published separately</p></list-item></list></p></sec><sec id="Sec27"><title>Safety outcomes</title><p id="Par74"><list list-type="order"><list-item><p id="Par75">Safety outcomes will be assessed from serious adverse event reports. The following serious adverse events will be documented at any time during the study period:<list list-type="alpha-lower"><list-item><p id="Par76">acute pancreatitis (defined as having two of the following three features: (1) abdominal pain consistent with acute pancreatitis; (2) serum lipase or amylase at least three times greater than the upper limit of normal; and (3) characteristic findings of acute pancreatitis on contrast-enhanced computed tomography) [<xref ref-type="bibr" rid="CR31">31</xref>] or magnetic resonance imaging</p></list-item><list-item><p id="Par77">elevation of ALT to more than five-fold upper normal limit</p></list-item><list-item><p id="Par78">anaphylaxis</p></list-item><list-item><p id="Par79">bleeding diathesis (INR > 3 without anticoagulant therapy)</p></list-item></list></p></list-item><list-item><p id="Par80">The following data regarding adverse drug reactions will be assessed with the treating team and recorded daily for 14 days and then at 21 days and 28 days after enrollment:<list list-type="alpha-lower"><list-item><p id="Par81">Allergic or sensitivity/hypersensitivity reactions, including rash, urticaria, tongue edema, bronchospasm, dyspnea and skin necrosis at the injection site</p></list-item><list-item><p id="Par82">Gastrointestinal signs or symptoms, including nausea, vomiting, abdominal pain and diarrhea</p></list-item><list-item><p id="Par83">Neurological symptoms, including fatigue, headache, insomnia, psychosis, depression and mania</p></list-item></list></p></list-item></list></p></sec><sec id="Sec28"><title>Functional outcomes</title><p id="Par84">Data will be collected at baseline before the current illness and at 90 days and may require telephone interviews with the patients or next of kin to determine the patients’ status according to the Karnofsky Performance Scale, which is a scale from 100 (indicating “Normal,” no complaints; no evidence of disease) to 0 (indicating death) [<xref ref-type="bibr" rid="CR32">32</xref>].</p></sec></sec><sec id="Sec29"><title>Safety measures</title><sec id="Sec30"><title>Drug interactions</title><p id="Par85">A clinical pharmacist and the treating physician will evaluate each patient at the time of enrollment and daily throughout the study period until day 14 to identify any interactions between the investigated treatments and other drugs, and they will take action accordingly. Table <xref rid="Tab1" ref-type="table">1</xref> summarizes common medications that may interact with lopinavir/ritonavir and a suggested action plan.</p></sec><sec id="Sec31"><title>Liver function tests</title><p id="Par86">Elevated liver enzymes are common in MERS infection due to the liver involvement in the disease. Based on analysis of our historical data, liver enzymes were not more elevated in patients treated with ribavirin and IFN-α. Based on HIV literature, aminotransferase elevation levels (more than five times the upper limit of normal) occur in 3 to 10% of patients taking lopinavir/ritonavir-containing antiretroviral regimens [<xref ref-type="bibr" rid="CR33">33</xref>]. These laboratory abnormalities are usually asymptomatic and self-limited and often resolve even without discontinuation of the drug [<xref ref-type="bibr" rid="CR33">33</xref>]. Clinically apparent hepatotoxicity due to lopinavir/ritonavir occurs, but is rare, with symptoms or jaundice appear usually after 1 to 8 weeks of starting therapy [<xref ref-type="bibr" rid="CR33">33</xref>]. The hepatotoxicity is usually self-limited; although fatal cases have been reported [<xref ref-type="bibr" rid="CR33">33</xref>]. The treating team should discontinue or minimize concomitant use of any medication that has hepatotoxic potential.</p></sec><sec id="Sec32"><title>Rules regarding premature discontinuation of treatment</title><p id="Par87">The study intervention will be suspended if the subject develops any of above defined serious adverse events occurred: (1) acute pancreatitis; (2) elevation of ALT to more than five-fold the upper normal limit; (3) anaphylaxis; and (4) bleeding diathesis. These events will be reviewed by at least two people with a third as necessary, all of whom are blinded to the intervention allocation, to adjudicate these events by looking at the study data/clinical records. In case of premature discontinuation of treatment, other aspects of the study procedures, such as data collection and laboratory testing, will be continued and patient data will be included in the intention-to-treat analysis.</p></sec><sec id="Sec33"><title>Unblinding</title><p id="Par88">Breaking of blinding can be occur in the event that the treating team believes that there is a very strong reason to know the study drug allocation and after discussion with the study principal investigator. In all such cases, the adverse event necessitating emergency unblinding will be reported as a serious adverse event.</p></sec><sec id="Sec34"><title>Serious adverse events</title><p id="Par89">Any unexpected, medical occurrence that results in death, prolonged hospitalization, persistent or significant disability or incapacity, which is judged to be causally related to the study intervention, will be reported as a serious adverse event to the Institutional Review Board and the Data Safety Monitoring Board. Potential serious adverse events for the trial are defined above and include (1) acute pancreatitis; (2) severe elevation of ALT to more than five-fold the upper normal limit; (3) anaphylaxis; and (4) bleeding diathesis.</p></sec></sec><sec id="Sec35"><title>Study management</title><sec id="Sec36"><title>Steering Committee</title><p id="Par90">The Steering Committee, led by the principal investigator, will be responsible for overseeing the conduction of the trial, providing training for new sites, ensuring compliance with the study procedures, addressing challenges that occur at all sites, reviewing serious adverse events and formulating the statistical analysis plan.</p></sec><sec id="Sec37"><title>Data Safety Monitoring Board</title><p id="Par91">The Data Safety Monitoring Board, which is responsible for reviewing reports regarding the safety of the study patients and protocol adherence, may make recommendations to continue or terminate the study on the basis of the results from the interim analysis. The board will meet at the beginning of the study and at 6-monthly intervals thereafter, or as needed.</p></sec><sec id="Sec38"><title>Quality control and assurance</title><p id="Par92">Several procedures to ensure data quality and protocol compliance are undertaken including: (1) Training sessions for the study team in the participating centers prior to study commencement; (2) Startup meetings for all sites, either on site or remotely; and (3) Monitoring visits before, during and at the close out of the study.</p></sec><sec id="Sec39"><title>Study drug distribution to other centers</title><p id="Par93">The Investigational Drug Unit at King Abdullah International Medical Research Center will distribute the study medication and the placebo to other centers. Randomization and blinding will be performed at the local pharmacy of each hospital according to the procedures described above.</p></sec></sec><sec id="Sec40"><title>Ethical issues</title><p id="Par94">The MIRACLE study is approved by the Scientific Committee and the Institutional Review Boards of the participating sites and registered at the Saudi Food and Drug Authority (SFDA).</p><p id="Par95">The study will be conducted in accordance with the ethical principles of the Declaration of Helsinki and the International Council for Harmonization–Good Clinical Practice guidelines. Informed consent will be obtained from patients or their substitute decision-makers. Site invistigators will explain the objectives of the trial and its potential risks and benefits to patients when possible, or to substitute decision-makers, during the process of obtaining consent. No compensation is provided for enrollment in the trial.</p><p id="Par96">Patient personal data are de-identified. Data from all centers will be stored on a secure place at King Abdullah International Medical Research Center, Riyadh. A list of names/hospital numbers and unique study identification (ID) will be kept in a separate location to the trial data, which has only the associated unique subject ID attached to it.</p></sec><sec id="Sec41"><title>Statistical analysis</title><p id="Par97">Baseline clinical and demographic characteristics will be summarized and reported using descriptive statistics. Categorical variables will be reported as numbers and percentages, and will be compared using the chi-square test or Fisher’s exact test, as appropriate. Continuous variables will be reported as means and standard deviations or as medians and interquartile ranges, and will be compared using Student’s <italic>t</italic> test or the Mann-Whitney <italic>U</italic> test, as appropriate.</p><p id="Par98">The primary analysis will be conducted according to the intention-to-treat principle and will be unadjusted. Per-protocol analysis will be performed and reported separately. The primary analysis will examine the difference in primary outcome between groups and will be reported as absolute risk reduction, with a 95% confidence interval. We do not anticipate imbalances between the two groups. Secondary analysis will be conducted using multiple logistic regression analysis in which death within 90 days will be modeled as the dependent variable and a set of baseline variables that are strongly believed to affect the outcome of MERS-CoV infection will be included as independent variables. Those variables will include at minimum age, community-acquired versus hospital-acquired infection, mechanical ventilation, center, and SOFA score [<xref ref-type="bibr" rid="CR34">34</xref>]. The multivariable analysis will also include clinically important and unequally distributed baseline variables between the two groups (<italic>p</italic> < 0.05). Median survival time will be summarized and reported using Kaplan-Meier curves and will be compared between the study groups using the log-rank test. Statistical tests for variables other than the primary outcome will be performed using a two-sided alpha value of 5% to denote significance level.</p><p id="Par99">If patient numbers permits (e.g., no fewer than five patients in subgroups of interest), stratified analysis will be carried out between the following subgroups:<list list-type="order"><list-item><p id="Par100">Patients with and without mechanical ventilation at the time of randomization</p></list-item><list-item><p id="Par101">Patients with different Acute Physiology and Chronic Health Evaluation II (APACHE II) disease-severity scores at the time of randomization stratified to high (above median) and low (below median) APACHE II scores</p></list-item><list-item><p id="Par102">Patients receiving and those not receiving vasopressors at the time of randomization</p></list-item><list-item><p id="Par103">Patients with ≤ 7 and > 7 days between onset of symptoms to enrollment</p></list-item><list-item><p id="Par104">Patients receiving and those not receiving renal replacement therapy at randomization</p></list-item></list></p></sec><sec id="Sec42"><title>Interim analysis and continuous study planning</title><p id="Par105">Because of the uncertainty surrounding the recruitment rate and the efficacy level of the treatment, the trial is designed as recursive, two-stage, group sequential randomized trial [<xref ref-type="bibr" rid="CR28">28</xref>]. The trial is designed initially to have 2 two-stage components with two interim analyses and one final analysis (Fig. <xref rid="Fig2" ref-type="fig">2</xref>). The first two-stage component is designed to determine futility stopping and adjust sample size, but not efficacy stopping. The second two-stage component is designed to determine efficacy stopping and possibly readjustment of sample size to maintain conditional power at the final analysis. A classic two-group design requires a total of 194 subjects (97 subjects per group) to have a 80% power at a significant level of 2.5% (one-sided test) to detect 20% absolute risk reduction in 90-day mortality among subjects receiving treatment (20%) compared to the control group (40%). The trial will start the first two-stage design with 136 subjects (68 subjects per group). We will conduct the first interim analysis when the total subject with 90 days of follow-up reaches 34 subjects (17 per group), which is about 17.5% of the total sample size needed for classical design. We use the method of summing of stage-wise <italic>p</italic> value to determine the one-sided stopping boundaries in the first two-stage design listed in Table <xref rid="Tab2" ref-type="table">2</xref>. At the first interim analysis we will use the stage-wise <italic>p</italic> values obtained from the chi-square test for difference in proportion to determine whether the trial will be stopped for futility or not. Should the trial continue, sample size re-estimation based on the observed effect size will be determined using the following formula assuming a conditional power of 80%:<fig id="Fig2"><label>Fig. 2</label><caption><p>Schematic illustration of the MIRACLE trial design with 2 two-stage components with two interim analyses and one final analysis. Raw <italic>p</italic> values are obtained from the one-sided chi-square for difference in proportion at each interim analysis</p></caption><graphic xlink:href="13063_2017_2427_Fig2_HTML" id="MO2"></graphic></fig><table-wrap id="Tab2"><label>Table 2</label><caption><p>Stopping boundaries</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Boundary</th><th>Value</th><th>Comment</th></tr></thead><tbody><tr><td>Efficacy stopping boundary (α<sub>11</sub>)</td><td>0</td><td>No stopping for efficacy</td></tr><tr><td>Efficacy stopping boundary (β<sub>11</sub>)</td><td>0.2</td><td>Stop the trial for futility if less than stage-wise <italic>p</italic> value</td></tr><tr><td>Efficacy stopping boundary (α<sub>12</sub>)</td><td>0.2250</td><td>Stop trial for efficacy at the second stage or recalculate based on conditional power at first interim analysis</td></tr></tbody></table></table-wrap><disp-formula id="Equa"><alternatives><tex-math id="M1">\documentclass[12pt]{minimal}
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\begin{document}$$ n12={\left[\frac{\sqrt{2}\sigma }{\delta}\left({\theta}^{-1}\left(1-\alpha 12+p11\right)-{\theta}^{-1}\left(1- Pc\right)\right)\right]}^2 $$\end{document}</tex-math><mml:math id="M2"><mml:mi>n</mml:mi><mml:mn>12</mml:mn><mml:mo>=</mml:mo><mml:msup><mml:mfenced close="]" open="["><mml:mrow><mml:mfrac><mml:mrow><mml:msqrt><mml:mn>2</mml:mn></mml:msqrt><mml:mi>σ</mml:mi></mml:mrow><mml:mi>δ</mml:mi></mml:mfrac><mml:mfenced close=")" open="("><mml:mrow><mml:msup><mml:mi>θ</mml:mi><mml:mrow><mml:mo>−</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mfenced close=")" open="("><mml:mrow><mml:mn>1</mml:mn><mml:mo>−</mml:mo><mml:mi>α</mml:mi><mml:mn>12</mml:mn><mml:mo>+</mml:mo><mml:mi>p</mml:mi><mml:mn>11</mml:mn></mml:mrow></mml:mfenced><mml:mo>−</mml:mo><mml:msup><mml:mi>θ</mml:mi><mml:mrow><mml:mo>−</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mfenced close=")" open="("><mml:mrow><mml:mn>1</mml:mn><mml:mo>−</mml:mo><mml:mi>P</mml:mi><mml:mi>c</mml:mi></mml:mrow></mml:mfenced></mml:mrow></mml:mfenced></mml:mrow></mml:mfenced><mml:mn>2</mml:mn></mml:msup></mml:math><graphic xlink:href="13063_2017_2427_Article_Equa.gif" position="anchor"></graphic></alternatives></disp-formula></p><p id="Par106">Based on the estimated sample size, we will recalculate the conditional error and set the parameters for the second of the two stages. At the second interim analysis, should the trial continue for efficacy, sample size readjustment will be made based on the previous formula and new boundaries will be calculated for the final-stage analysis.</p><p id="Par107">Upon completion, the results of the trial is planned to be submitted to peer-reviewed journal. Authorship will follow the Uniform Requirements for Manuscripts Submitted to Biomedical Journals [<xref ref-type="bibr" rid="CR35">35</xref>].</p></sec></sec><sec id="Sec43" sec-type="discussion"><title>Discussion</title><p id="Par108">This study will be the first randomized controlled trial of a treatment for MERS-CoV infection. Although this type of study provides the best method for determining treatment efficacy during disease outbreaks [<xref ref-type="bibr" rid="CR36">36</xref>, <xref ref-type="bibr" rid="CR37">37</xref>], conducting a randomized controlled trial is logistically challenging [<xref ref-type="bibr" rid="CR37">37</xref>, <xref ref-type="bibr" rid="CR38">38</xref>] since the distribution of MERS cases is sporadic and unpredictable, both geographically and temporally, necessitating the involvement of several centers in the trial to ensure adequate recruitment. This requirement contributes greatly to the planning and administration associated with the trial.</p><p id="Par109">To overcome the uncertainty in recruitment rate and efficacy of the trial’s treatment we designed the trial using recursive, two-stage adaptive design, which is a relatively new method for group sequential trials [<xref ref-type="bibr" rid="CR28">28</xref>]. The approach is based on the conditional error principle which allows for continuous adjustment of the trial parameters using data observed during prior stages without inflating type I error [<xref ref-type="bibr" rid="CR39">39</xref>]. Another advantage of this method is the flexibility in setting the timing and the number of needed interim analyses. Such flexibility is necessary in situations where recruitment rate is unpredictable and sudden flux in patient recruitment could happen at any time.</p><p id="Par110">For many emerging infectious diseases, including MERS, patients are often treated with therapeutics on the basis of minimal evidence. For example, patients with MERS have been treated with ribavirin and IFN-α despite the lack of clinical trials exploring the effectiveness of this treatment combination. If these patients had been included in a properly designed study, conclusive evidence might have been generated. Performing such a trial meets a critical need.</p><p id="Par111">Some limitations to our study design should be noted. Complete blinding was not feasible because of the unavailability of appropriate placebo; therefore, the study is unblinding to the dosing nurses and the dispensing pharmacist, both of whom are not otherwise involved in the patient care. However, blinding will be maintained to all other members of the clinical and research team. Because of the sporadic and unpredictable nature of the disease, the number of patients from some sites may be low.</p><sec id="Sec44"><title>Trial status</title><p id="Par112">The MIRACLE trial has already been approved by the Institutional Review Boards at eight hospitals and by the Scientific Advisory Board at the Ministry of Health in Saudi Arabia and the Saudi Food and Drug Authority. Enrollment for this study began in November 2016, and has enrolled thirteen patients as of Jan 24-2018. At present, eight sites have completed the regulatory requirements and are actively screening for eligible patients; 12 other centers are in progress.</p></sec></sec><sec sec-type="supplementary-material"><title>Additional file</title><sec id="Sec45"><p><supplementary-material content-type="local-data" id="MOESM1"><media xlink:href="13063_2017_2427_MOESM1_ESM.doc"><label>Additional file 1:</label><caption><p>SPIRIT 2013 Checklist: recommended items to address in a clinical trial protocol and related documents*. (DOC 120 kb)</p></caption></media></supplementary-material></p></sec></sec></body><back><glossary><title>Abbreviations</title><def-list><def-item><term>ALT</term><def><p id="Par5">Alanine aminotransferase</p></def></def-item><def-item><term>APACHE II</term><def><p id="Par6">Acute Physiology and Chronic Health Evaluation II</p></def></def-item><def-item><term>Ct</term><def><p id="Par7">Threshold cycle</p></def></def-item><def-item><term>EC</term><def><p id="Par8">Effective concentration</p></def></def-item><def-item><term>HIV</term><def><p id="Par9">Human immunodeficiency virus</p></def></def-item><def-item><term>IFN</term><def><p id="Par10">Interferon</p></def></def-item><def-item><term>IFN-α</term><def><p id="Par11">Interferon alpha</p></def></def-item><def-item><term>IFN-β1b</term><def><p id="Par12">Interferon beta-1b</p></def></def-item><def-item><term>MERS-CoV</term><def><p id="Par13">Middle East Respiratory Syndrome coronavirus</p></def></def-item><def-item><term>MIRACLE trial</term><def><p id="Par14">the <italic>M</italic>ERS-CoV <italic>I</italic>nfection t<italic>R</italic>eated with <italic>A C</italic>ombination of <italic>L</italic>opinavir/ritonavir and int<italic>E</italic>rferon β1b</p></def></def-item><def-item><term>MMF</term><def><p id="Par15">Mycophenolate mofetil</p></def></def-item><def-item><term>RT-PCR</term><def><p id="Par16">Reverse-transcription polymerase chain reaction</p></def></def-item><def-item><term>SARS</term><def><p id="Par17">Severe Acute Respiratory Syndrome</p></def></def-item><def-item><term>SPIRIT</term><def><p id="Par18">Standard Protocol Items: Recommendations for Interventional Trials</p></def></def-item></def-list></glossary><ack><title>Acknowledgements</title><p>We would like to acknowledge Maria D Van Kerkhove, PhD, MERS-CoV Technical Lead, High Threat Pathogens, Global Infectious Hazards Management, Health Emergencies Program, World Health Organization, Geneva, Switzerland for her support the MERS therapeutic program.</p><p>We would like to acknowledge the Data Safety Monitoring Board (DSMB) Chair and members:</p><p>Greg S Martin, MD (Chair)</p><p>Professor of Medicine</p><p>Associate Division Director, Critical Care Division of Pulmonary,</p><p>Allergy, Critical Care and Sleep</p><p>Emory University School of Medicine</p><p>Section Chief and Director, Medical and Coronary Intensive Care</p><p>Grady Memorial Hospital</p><p>David A Schoenfeld, PhD (Member)</p><p>Professor of Medicine, Harvard Medical School</p><p>Professor in the Department of Biostatistics,</p><p>Harvard School of Public Health</p><p>Sharon L Walmsley, MSc, MD, FRCPC (Member)</p><p>Senior Scientist, Toronto General Research Institute (TGRI)</p><p>Shannon Carson, MD (Member)</p><p>Professor of Medicine</p><p>Division Chief, Pulmonary Diseases and Critical Care Medicine</p><p>University of North Carolina at Chapel Hill School of Medicine</p><p>The MIRACLE trial group</p><p>Riyadh, Kingdom of Saudi Arabia:</p><p>King Abdulaziz Medical City: Yaseen M. Arabi, Adel Alothman, Hanan H Balkhy, Abdulaziz Al-Dawood, Sameera AlJohani, Shmeylan Al Harbi, Suleiman Kojan, Majed Al Jeraisy, Ahmad M Deeb, Jesna Jose, Mohamed A Hussein, Mohammed Al Muhaidib, Sadat Musharaf, Hala Al Anizi, Reggie Dael</p><p>Ministry of Health: Abdullah M Assiri, Mohammad AlMazroa</p><p>Prince Mohammed bin Abdulaziz Hospital: Ayed Asiri, Ziad A Memish, Sameeh S Ghazal, Sarah H Alfaraj, Fahad Bafaqeeh</p><p>King Saud Medical City: Abdulrahman Al Harthy, Mohammed Al Sulaiman, Ahmed Mady</p><p>Prince Sultan Military Medical City: Yasser Mandourah, Ghaleb A Almekhlafi, Nisreen Murad Sherbeeni, Fatehi Elnour Elzein, Reema Muhammed, Shatha Al Samirrai, Shatha Awad, Rylen Cabio Cabal, Bander Al Onazi, Maha Aljuhani, Melven Vince, Abdulrauf Ahmad Malibary</p><p>King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia: Abdullah Almotairi, Mushira Al Enani, Alaa Alqurashi, Fatimah Alenezi, Nada Alkhani</p><p>King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia: Khalid A. Maghrabi.</p><p>Jeddah, Kingdom of Saudi Arabia</p><p>King Abdulaziz Medical City: Fahad Al-Hameed, Asim AlSaedi, Abdulhakeem Thaqafi, Ohoud Al Oraabi, Jalal Rifai, Pansy Elsamadisi, Medhat S Hendy, Sara AbuBaker Basher</p><p>King Abdullah Medical Complex: Muhammed Abduldhaher, Wael Bajhamoum</p><p>King Faisal Specialist Hospital and Research Center, Jeddah, Kingdom of Saudi Arabia: Ismael Qushmaq</p><p>King Fahad Armed Forces Hospital: Sarah Shalhoub</p><p>Alahsa, Kingdom of Saudi Arabia</p><p>King Abdulaziz Hospital: Yusri Taha, Javed Memon, Shahinaz Bashir, Ibraheem Al-Dossary, Saleh Al Mekhloof</p><p>King Fahad Hospital: Bader Al-Muhainy</p><p>Dammam, Kingdom of Saudi Arabia</p><p>Dammam Medical Complex: Shehab Suliman</p><p>Al Khobar, Kingdom of Saudi Arabia</p><p>King Fahad Hospital of the University-Dammam University: Mohammed S Alshahrani.</p><p>Abha, Kingdom of Saudi Arabia</p><p>Aseer Central Hospital: Ali Al Bshabshe</p><p>Al-Madinah Al-Monawarah, Kingdom of Saudi Arabia</p><p>King Fahad Hospital: Ayman Kharaba, Ahmad Al Jabri</p><p>Ohoud Hospital: Ayman Kharaba, Magdy Farid, Alawi Alaidarous, Wael Alseraihi, Husam Shahada, Jinish Shimi</p><p>Taif, Kingdom of Saudi Arabia</p><p>King Faisal Hospital: Bader Alharthi, Osama Yasin</p><p>Buraidah, Kingdom of Saudi Arabia</p><p>Buraidah Central Hospital: Mohammed Alkathlan</p><p>Toronto, Canada</p><p>University of Toronto: Robert A Fowler</p><p>Charlottesville, VA, USA</p><p>University of Virginia School of Medicine: Frederick G Hayden</p><sec id="FPar1"><title>Funding</title><p id="Par113">The study sponsor does not have any role in the study design, collection, management, analysis or interpretation of the data, or in writing the report. King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs MNGHA, Mail Code: 1515 PO Box 22490 Riyadh 11426, Kingdom of Saudi Arabia</p></sec><sec id="FPar2" sec-type="data-availability"><title>Availability of data and materials</title><p id="Par114">The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.</p></sec></ack><notes notes-type="author-contribution"><title>Authors’ contributions</title><p>YA conception and design, trial sites management, analytical plan, drafting of the manuscript, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. AA conception and design, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. HB conception and design, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. AD conception and design, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. SJ conception and design, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. SH conception and design, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. SK conception and design, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. MJ conception and design, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. AMD conception and design, trial sites management, drafting the manuscript, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. AMA trial sites management, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. FH trial site management, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. AS trial site management, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. YM trial site management, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. GM trial site management, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. NMS trial site management, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. FEZ trial site management, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. JM trial site management, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. YT trial site management, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. AM trial site management, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. KM trial site management, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. IQ trial site management, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. AB trial site management, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. AK trial site management, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. SS trial site management, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. JJ analytical plan, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. RAF conception and design, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. FGH conception and design, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. MAH analytical plan, critical revision of the manuscript for important intellectual content, approval of the final version to be published and agreement to be accountable for all aspects of the work. All authors read and approved the final manuscript.</p></notes><notes><title>Ethics approval and consent to participate</title><p id="Par115">The MIRACLE study is approved by the Scientific Committee and the Institutional Review Board at King Abdulaziz Medical City (RC15/142) and registered at the Saudi Food and Drug Authority (SFDA). The approval of the Ethics Committees and the SFDA will be secured from each participated sites before starting patient recruitment. Patients who meet the eligibility criteria or substitute decision-makers (for patients lacking decision-making capacity) of eligible patients will be approached to obtain informed consent for enrollment.</p></notes><notes><title>Consent for publication</title><p id="Par116">Not applicable.</p></notes><notes notes-type="COI-statement"><title>Competing interests</title><p id="Par117">The authors declare that they have no competing interests.</p></notes><notes><title>Publisher’s Note</title><p id="Par118">Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></notes><ref-list id="Bib1"><title>References</title><ref id="CR1"><label>1.</label><mixed-citation publication-type="other">World Health Organization: Middle East respiratory syndrome coronavirus (MERS-CoV). <ext-link ext-link-type="uri" xlink:href="http://www.who.int/emergencies/mers-cov/en/">http://www.who.int/emergencies/mers-cov/en/</ext-link>. Accessed 14 Jan 2018.</mixed-citation></ref><ref id="CR2"><label>2.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Arabi</surname><given-names>YM</given-names></name><name><surname>Balkhy</surname><given-names>HH</given-names></name><name><surname>Hayden</surname><given-names>FG</given-names></name><name><surname>Bouchama</surname><given-names>A</given-names></name><name><surname>Luke</surname><given-names>T</given-names></name><name><surname>Baillie</surname><given-names>JK</given-names></name><name><surname>Al-Omari</surname><given-names>A</given-names></name><name><surname>Hajeer</surname><given-names>AH</given-names></name><name><surname>Senga</surname><given-names>M</given-names></name><name><surname>Denison</surname><given-names>MR</given-names></name><etal></etal></person-group><article-title>Middle East Respiratory Syndrome</article-title><source>N Engl J Med</source><year>2017</year><volume>376</volume><issue>6</issue><fpage>584</fpage><lpage>94</lpage><pub-id pub-id-type="doi">10.1056/NEJMsr1408795</pub-id><pub-id pub-id-type="pmid">28177862</pub-id></element-citation></ref><ref id="CR3"><label>3.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zaki</surname><given-names>AM</given-names></name><name><surname>van Boheemen</surname><given-names>S</given-names></name><name><surname>Bestebroer</surname><given-names>TM</given-names></name><name><surname>Osterhaus</surname><given-names>AD</given-names></name><name><surname>Fouchier</surname><given-names>RA</given-names></name></person-group><article-title>Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia</article-title><source>N Engl J Med</source><year>2012</year><volume>367</volume><issue>19</issue><fpage>1814</fpage><lpage>20</lpage><pub-id pub-id-type="doi">10.1056/NEJMoa1211721</pub-id><pub-id pub-id-type="pmid">23075143</pub-id></element-citation></ref><ref id="CR4"><label>4.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mo</surname><given-names>Y</given-names></name><name><surname>Fisher</surname><given-names>D</given-names></name></person-group><article-title>A review of treatment modalities for Middle East Respiratory Syndrome</article-title><source>J Antimicrob Chemother</source><year>2016</year><volume>71</volume><issue>12</issue><fpage>3340</fpage><lpage>50</lpage><pub-id pub-id-type="doi">10.1093/jac/dkw338</pub-id><pub-id pub-id-type="pmid">27585965</pub-id></element-citation></ref><ref id="CR5"><label>5.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Falzarano</surname><given-names>D</given-names></name><name><surname>de Wit</surname><given-names>E</given-names></name><name><surname>Rasmussen</surname><given-names>AL</given-names></name><name><surname>Feldmann</surname><given-names>F</given-names></name><name><surname>Okumura</surname><given-names>A</given-names></name><name><surname>Scott</surname><given-names>DP</given-names></name><name><surname>Brining</surname><given-names>D</given-names></name><name><surname>Bushmaker</surname><given-names>T</given-names></name><name><surname>Martellaro</surname><given-names>C</given-names></name><name><surname>Baseler</surname><given-names>L</given-names></name><etal></etal></person-group><article-title>Treatment with interferon-alpha2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques</article-title><source>Nat Med</source><year>2013</year><volume>19</volume><issue>10</issue><fpage>1313</fpage><lpage>7</lpage><pub-id pub-id-type="doi">10.1038/nm.3362</pub-id><pub-id pub-id-type="pmid">24013700</pub-id></element-citation></ref><ref id="CR6"><label>6.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Shalhoub</surname><given-names>S</given-names></name><name><surname>Farahat</surname><given-names>F</given-names></name><name><surname>Al-Jiffri</surname><given-names>A</given-names></name><name><surname>Simhairi</surname><given-names>R</given-names></name><name><surname>Shamma</surname><given-names>O</given-names></name><name><surname>Siddiqi</surname><given-names>N</given-names></name><name><surname>Mushtaq</surname><given-names>A</given-names></name></person-group><article-title>IFN-alpha2a or IFN-beta1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study</article-title><source>J Antimicrob Chemother</source><year>2015</year><volume>70</volume><issue>7</issue><fpage>2129</fpage><lpage>32</lpage><pub-id pub-id-type="doi">10.1093/jac/dkv085</pub-id><pub-id pub-id-type="pmid">25900158</pub-id></element-citation></ref><ref id="CR7"><label>7.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Khalid</surname><given-names>M</given-names></name><name><surname>Al Rabiah</surname><given-names>F</given-names></name><name><surname>Khan</surname><given-names>B</given-names></name><name><surname>Al Mobeireek</surname><given-names>A</given-names></name><name><surname>Butt</surname><given-names>TS</given-names></name><name><surname>Al</surname><given-names>ME</given-names></name></person-group><article-title>Ribavirin and interferon-alpha2b as primary and preventive treatment for Middle East respiratory syndrome coronavirus: a preliminary report of two cases</article-title><source>Antivir Ther</source><year>2015</year><volume>20</volume><issue>1</issue><fpage>87</fpage><lpage>91</lpage><pub-id pub-id-type="doi">10.3851/IMP2792</pub-id><pub-id pub-id-type="pmid">24831606</pub-id></element-citation></ref><ref id="CR8"><label>8.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Omrani</surname><given-names>AS</given-names></name><name><surname>Saad</surname><given-names>MM</given-names></name><name><surname>Baig</surname><given-names>K</given-names></name><name><surname>Bahloul</surname><given-names>A</given-names></name><name><surname>Abdul-Matin</surname><given-names>M</given-names></name><name><surname>Alaidaroos</surname><given-names>AY</given-names></name><name><surname>Almakhlafi</surname><given-names>GA</given-names></name><name><surname>Albarrak</surname><given-names>MM</given-names></name><name><surname>Memish</surname><given-names>ZA</given-names></name><name><surname>Albarrak</surname><given-names>AM</given-names></name></person-group><article-title>Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study</article-title><source>Lancet Infect Dis</source><year>2014</year><volume>14</volume><issue>11</issue><fpage>1090</fpage><lpage>5</lpage><pub-id pub-id-type="doi">10.1016/S1473-3099(14)70920-X</pub-id><pub-id pub-id-type="pmid">25278221</pub-id></element-citation></ref><ref id="CR9"><label>9.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hart</surname><given-names>BJ</given-names></name><name><surname>Dyall</surname><given-names>J</given-names></name><name><surname>Postnikova</surname><given-names>E</given-names></name><name><surname>Zhou</surname><given-names>H</given-names></name><name><surname>Kindrachuk</surname><given-names>J</given-names></name><name><surname>Johnson</surname><given-names>RF</given-names></name><name><surname>Olinger</surname><given-names>GG</given-names><suffix>Jr</suffix></name><name><surname>Frieman</surname><given-names>MB</given-names></name><name><surname>Holbrook</surname><given-names>MR</given-names></name><name><surname>Jahrling</surname><given-names>PB</given-names></name><etal></etal></person-group><article-title>Interferon-beta and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays</article-title><source>J Gen Virol</source><year>2014</year><volume>95</volume><issue>Pt 3</issue><fpage>571</fpage><lpage>7</lpage><pub-id pub-id-type="doi">10.1099/vir.0.061911-0</pub-id><pub-id pub-id-type="pmid">24323636</pub-id></element-citation></ref><ref id="CR10"><label>10.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Falzarano</surname><given-names>D</given-names></name><name><surname>de Wit</surname><given-names>E</given-names></name><name><surname>Martellaro</surname><given-names>C</given-names></name><name><surname>Callison</surname><given-names>J</given-names></name><name><surname>Munster</surname><given-names>VJ</given-names></name><name><surname>Feldmann</surname><given-names>H</given-names></name></person-group><article-title>Inhibition of novel beta coronavirus replication by a combination of interferon-alpha2b and ribavirin</article-title><source>Sci Rep</source><year>2013</year><volume>3</volume><fpage>1686</fpage><pub-id pub-id-type="doi">10.1038/srep01686</pub-id><pub-id pub-id-type="pmid">23594967</pub-id></element-citation></ref><ref id="CR11"><label>11.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chan</surname><given-names>JF</given-names></name><name><surname>Chan</surname><given-names>KH</given-names></name><name><surname>Kao</surname><given-names>RY</given-names></name><name><surname>To</surname><given-names>KK</given-names></name><name><surname>Zheng</surname><given-names>BJ</given-names></name><name><surname>Li</surname><given-names>CP</given-names></name><name><surname>Li</surname><given-names>PT</given-names></name><name><surname>Dai</surname><given-names>J</given-names></name><name><surname>Mok</surname><given-names>FK</given-names></name><name><surname>Chen</surname><given-names>H</given-names></name><etal></etal></person-group><article-title>Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus</article-title><source>J Infect</source><year>2013</year><volume>67</volume><issue>6</issue><fpage>606</fpage><lpage>16</lpage><pub-id pub-id-type="doi">10.1016/j.jinf.2013.09.029</pub-id><pub-id pub-id-type="pmid">24096239</pub-id></element-citation></ref><ref id="CR12"><label>12.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Al-Tawfiq</surname><given-names>JA</given-names></name><name><surname>Momattin</surname><given-names>H</given-names></name><name><surname>Dib</surname><given-names>J</given-names></name><name><surname>Memish</surname><given-names>ZA</given-names></name></person-group><article-title>Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study</article-title><source>Int J Infect Dis</source><year>2014</year><volume>20</volume><fpage>42</fpage><lpage>6</lpage><pub-id pub-id-type="doi">10.1016/j.ijid.2013.12.003</pub-id><pub-id pub-id-type="pmid">24406736</pub-id></element-citation></ref><ref id="CR13"><label>13.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lau</surname><given-names>SK</given-names></name><name><surname>Lau</surname><given-names>CC</given-names></name><name><surname>Chan</surname><given-names>KH</given-names></name><name><surname>Li</surname><given-names>CP</given-names></name><name><surname>Chen</surname><given-names>H</given-names></name><name><surname>Jin</surname><given-names>DY</given-names></name><name><surname>Chan</surname><given-names>JF</given-names></name><name><surname>Woo</surname><given-names>PC</given-names></name><name><surname>Yuen</surname><given-names>KY</given-names></name></person-group><article-title>Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment</article-title><source>J Gen Virol</source><year>2013</year><volume>94</volume><issue>Pt 12</issue><fpage>2679</fpage><lpage>90</lpage><pub-id pub-id-type="doi">10.1099/vir.0.055533-0</pub-id><pub-id pub-id-type="pmid">24077366</pub-id></element-citation></ref><ref id="CR14"><label>14.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Faure</surname><given-names>E</given-names></name><name><surname>Poissy</surname><given-names>J</given-names></name><name><surname>Goffard</surname><given-names>A</given-names></name><name><surname>Fournier</surname><given-names>C</given-names></name><name><surname>Kipnis</surname><given-names>E</given-names></name><name><surname>Titecat</surname><given-names>M</given-names></name><name><surname>Bortolotti</surname><given-names>P</given-names></name><name><surname>Martinez</surname><given-names>L</given-names></name><name><surname>Dubucquoi</surname><given-names>S</given-names></name><name><surname>Dessein</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>Distinct immune response in two MERS-CoV-infected patients: can we go from bench to bedside?</article-title><source>PLoS One</source><year>2014</year><volume>9</volume><issue>2</issue><fpage>e88716</fpage><pub-id pub-id-type="doi">10.1371/journal.pone.0088716</pub-id><pub-id pub-id-type="pmid">24551142</pub-id></element-citation></ref><ref id="CR15"><label>15.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zielecki</surname><given-names>F</given-names></name><name><surname>Weber</surname><given-names>M</given-names></name><name><surname>Eickmann</surname><given-names>M</given-names></name><name><surname>Spiegelberg</surname><given-names>L</given-names></name><name><surname>Zaki</surname><given-names>AM</given-names></name><name><surname>Matrosovich</surname><given-names>M</given-names></name><name><surname>Becker</surname><given-names>S</given-names></name><name><surname>Weber</surname><given-names>F</given-names></name></person-group><article-title>Human cell tropism and innate immune system interactions of human respiratory coronavirus EMC compared to those of severe acute respiratory syndrome coronavirus</article-title><source>J Virol</source><year>2013</year><volume>87</volume><issue>9</issue><fpage>5300</fpage><lpage>4</lpage><pub-id pub-id-type="doi">10.1128/JVI.03496-12</pub-id><pub-id pub-id-type="pmid">23449793</pub-id></element-citation></ref><ref id="CR16"><label>16.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>de Wilde</surname><given-names>AH</given-names></name><name><surname>Raj</surname><given-names>VS</given-names></name><name><surname>Oudshoorn</surname><given-names>D</given-names></name><name><surname>Bestebroer</surname><given-names>TM</given-names></name><name><surname>van Nieuwkoop</surname><given-names>S</given-names></name><name><surname>Limpens</surname><given-names>RW</given-names></name><name><surname>Posthuma</surname><given-names>CC</given-names></name><name><surname>van der Meer</surname><given-names>Y</given-names></name><name><surname>Barcena</surname><given-names>M</given-names></name><name><surname>Haagmans</surname><given-names>BL</given-names></name><etal></etal></person-group><article-title>MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-alpha treatment</article-title><source>J Gen Virol</source><year>2013</year><volume>94</volume><issue>Pt 8</issue><fpage>1749</fpage><lpage>60</lpage><pub-id pub-id-type="doi">10.1099/vir.0.052910-0</pub-id><pub-id pub-id-type="pmid">23620378</pub-id></element-citation></ref><ref id="CR17"><label>17.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jankovic</surname><given-names>SM</given-names></name></person-group><article-title>Injectable interferon beta-1b for the treatment of relapsing forms of multiple sclerosis</article-title><source>J Inflamm Res</source><year>2010</year><volume>3</volume><fpage>25</fpage><lpage>31</lpage><pub-id pub-id-type="doi">10.2147/JIR.S9480</pub-id><pub-id pub-id-type="pmid">22096354</pub-id></element-citation></ref><ref id="CR18"><label>18.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hurwitz</surname><given-names>BJ</given-names></name><name><surname>Jeffery</surname><given-names>D</given-names></name><name><surname>Arnason</surname><given-names>B</given-names></name><name><surname>Bigley</surname><given-names>K</given-names></name><name><surname>Coyle</surname><given-names>P</given-names></name><name><surname>Goodin</surname><given-names>D</given-names></name><name><surname>Kaba</surname><given-names>S</given-names></name><name><surname>Kirzinger</surname><given-names>S</given-names></name><name><surname>Lynch</surname><given-names>S</given-names></name><name><surname>Mandler</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>Tolerability and safety profile of 12- to 28-week treatment with interferon beta-1b 250 and 500 microg QOD in patients with relapsing-remitting multiple sclerosis: a multicenter, randomized, double-blind, parallel-group pilot study</article-title><source>Clin Ther</source><year>2008</year><volume>30</volume><issue>6</issue><fpage>1102</fpage><lpage>12</lpage><pub-id pub-id-type="doi">10.1016/j.clinthera.2008.06.013</pub-id><pub-id pub-id-type="pmid">18640466</pub-id></element-citation></ref><ref id="CR19"><label>19.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gottesman</surname><given-names>MH</given-names></name><name><surname>Friedman-Urevich</surname><given-names>S</given-names></name></person-group><article-title>Interferon beta-1b (betaseron/betaferon) is well tolerated at a dose of 500 microg: interferon dose escalation assessment of safety (IDEAS)</article-title><source>Mult Scler</source><year>2006</year><volume>12</volume><issue>3</issue><fpage>271</fpage><lpage>80</lpage><pub-id pub-id-type="doi">10.1191/135248506ms1261oa</pub-id><pub-id pub-id-type="pmid">16764339</pub-id></element-citation></ref><ref id="CR20"><label>20.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Huang</surname><given-names>X</given-names></name><name><surname>Xu</surname><given-names>Y</given-names></name><name><surname>Yang</surname><given-names>Q</given-names></name><name><surname>Chen</surname><given-names>J</given-names></name><name><surname>Zhang</surname><given-names>T</given-names></name><name><surname>Li</surname><given-names>Z</given-names></name><name><surname>Guo</surname><given-names>C</given-names></name><name><surname>Chen</surname><given-names>H</given-names></name><name><surname>Wu</surname><given-names>H</given-names></name><name><surname>Li</surname><given-names>N</given-names></name></person-group><article-title>Efficacy and biological safety of lopinavir/ritonavir based anti-retroviral therapy in HIV-1-infected patients: a meta-analysis of randomized controlled trials</article-title><source>Sci Rep</source><year>2015</year><volume>5</volume><fpage>8528</fpage><pub-id pub-id-type="doi">10.1038/srep08528</pub-id><pub-id pub-id-type="pmid">25704206</pub-id></element-citation></ref><ref id="CR21"><label>21.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chu</surname><given-names>CM</given-names></name><name><surname>Cheng</surname><given-names>VC</given-names></name><name><surname>Hung</surname><given-names>IF</given-names></name><name><surname>Wong</surname><given-names>MM</given-names></name><name><surname>Chan</surname><given-names>KH</given-names></name><name><surname>Chan</surname><given-names>KS</given-names></name><name><surname>Kao</surname><given-names>RY</given-names></name><name><surname>Poon</surname><given-names>LL</given-names></name><name><surname>Wong</surname><given-names>CL</given-names></name><name><surname>Guan</surname><given-names>Y</given-names></name><etal></etal></person-group><article-title>Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings</article-title><source>Thorax</source><year>2004</year><volume>59</volume><issue>3</issue><fpage>252</fpage><lpage>6</lpage><pub-id pub-id-type="doi">10.1136/thorax.2003.012658</pub-id><pub-id pub-id-type="pmid">14985565</pub-id></element-citation></ref><ref id="CR22"><label>22.</label><mixed-citation publication-type="other">Abbott Laboratories. Product Information: Kaletra®. <ext-link ext-link-type="uri" xlink:href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021226s030lbl.pdf">https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021226s030lbl.pdf</ext-link>. Accessed 14 Jan 2018.</mixed-citation></ref><ref id="CR23"><label>23.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chan</surname><given-names>JF</given-names></name><name><surname>Yao</surname><given-names>Y</given-names></name><name><surname>Yeung</surname><given-names>ML</given-names></name><name><surname>Deng</surname><given-names>W</given-names></name><name><surname>Bao</surname><given-names>L</given-names></name><name><surname>Jia</surname><given-names>L</given-names></name><name><surname>Li</surname><given-names>F</given-names></name><name><surname>Xiao</surname><given-names>C</given-names></name><name><surname>Gao</surname><given-names>H</given-names></name><name><surname>Yu</surname><given-names>P</given-names></name><etal></etal></person-group><article-title>Treatment with lopinavir/ritonavir or interferon-beta1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset</article-title><source>J Infect Dis</source><year>2015</year><volume>212</volume><issue>12</issue><fpage>1904</fpage><lpage>13</lpage><pub-id pub-id-type="doi">10.1093/infdis/jiv392</pub-id><pub-id pub-id-type="pmid">26198719</pub-id></element-citation></ref><ref id="CR24"><label>24.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kim</surname><given-names>UJ</given-names></name><name><surname>Won</surname><given-names>EJ</given-names></name><name><surname>Kee</surname><given-names>SJ</given-names></name><name><surname>Jung</surname><given-names>SI</given-names></name><name><surname>Jang</surname><given-names>HC</given-names></name></person-group><article-title>Combination therapy with lopinavir/ritonavir, ribavirin and interferon-alpha for Middle East respiratory syndrome</article-title><source>Antivir Ther</source><year>2016</year><volume>21</volume><issue>5</issue><fpage>455</fpage><lpage>9</lpage><pub-id pub-id-type="doi">10.3851/IMP3002</pub-id><pub-id pub-id-type="pmid">26492219</pub-id></element-citation></ref><ref id="CR25"><label>25.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Spanakis</surname><given-names>N</given-names></name><name><surname>Tsiodras</surname><given-names>S</given-names></name><name><surname>Haagmans</surname><given-names>BL</given-names></name><name><surname>Raj</surname><given-names>VS</given-names></name><name><surname>Pontikis</surname><given-names>K</given-names></name><name><surname>Koutsoukou</surname><given-names>A</given-names></name><name><surname>Koulouris</surname><given-names>NG</given-names></name><name><surname>Osterhaus</surname><given-names>AD</given-names></name><name><surname>Koopmans</surname><given-names>MP</given-names></name><name><surname>Tsakris</surname><given-names>A</given-names></name></person-group><article-title>Virological and serological analysis of a recent Middle East respiratory syndrome coronavirus infection case on a triple combination antiviral regimen</article-title><source>Int J Antimicrob Agents</source><year>2014</year><volume>44</volume><issue>6</issue><fpage>528</fpage><lpage>32</lpage><pub-id pub-id-type="doi">10.1016/j.ijantimicag.2014.07.026</pub-id><pub-id pub-id-type="pmid">25288266</pub-id></element-citation></ref><ref id="CR26"><label>26.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Min</surname><given-names>CK</given-names></name><name><surname>Cheon</surname><given-names>S</given-names></name><name><surname>Ha</surname><given-names>NY</given-names></name><name><surname>Sohn</surname><given-names>KM</given-names></name><name><surname>Kim</surname><given-names>Y</given-names></name><name><surname>Aigerim</surname><given-names>A</given-names></name><name><surname>Shin</surname><given-names>HM</given-names></name><name><surname>Choi</surname><given-names>JY</given-names></name><name><surname>Inn</surname><given-names>KS</given-names></name><name><surname>Kim</surname><given-names>JH</given-names></name><etal></etal></person-group><article-title>Comparative and kinetic analysis of viral shedding and immunological responses in MERS patients representing a broad spectrum of disease severity</article-title><source>Sci Rep</source><year>2016</year><volume>6</volume><fpage>25359</fpage><pub-id pub-id-type="doi">10.1038/srep25359</pub-id><pub-id pub-id-type="pmid">27146253</pub-id></element-citation></ref><ref id="CR27"><label>27.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chan</surname><given-names>AW</given-names></name><name><surname>Tetzlaff</surname><given-names>JM</given-names></name><name><surname>Altman</surname><given-names>DG</given-names></name><name><surname>Laupacis</surname><given-names>A</given-names></name><name><surname>Gotzsche</surname><given-names>PC</given-names></name><name><surname>Krleza-Jeric</surname><given-names>K</given-names></name><name><surname>Hrobjartsson</surname><given-names>A</given-names></name><name><surname>Mann</surname><given-names>H</given-names></name><name><surname>Dickersin</surname><given-names>K</given-names></name><name><surname>Berlin</surname><given-names>JA</given-names></name><etal></etal></person-group><article-title>SPIRIT 2013 statement: defining standard protocol items for clinical trials</article-title><source>Ann Intern Med</source><year>2013</year><volume>158</volume><issue>3</issue><fpage>200</fpage><lpage>7</lpage><pub-id pub-id-type="doi">10.7326/0003-4819-158-3-201302050-00583</pub-id><pub-id pub-id-type="pmid">23295957</pub-id></element-citation></ref><ref id="CR28"><label>28.</label><mixed-citation publication-type="other">Chang, M. Adaptive Design Theory and implementation using SAS and R, 2nd ed. Chapman and Hall/CRC. 2014. Pp. 153–180.</mixed-citation></ref><ref id="CR29"><label>29.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bellomo</surname><given-names>R</given-names></name><name><surname>Ronco</surname><given-names>C</given-names></name><name><surname>Kellum</surname><given-names>JA</given-names></name><name><surname>Mehta</surname><given-names>RL</given-names></name><name><surname>Palevsky</surname><given-names>P</given-names></name><collab>Acute Dialysis Quality Initiative workgroup</collab></person-group><article-title>Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group</article-title><source>Crit Care</source><year>2004</year><volume>8</volume><issue>4</issue><fpage>R204</fpage><lpage>212</lpage><pub-id pub-id-type="doi">10.1186/cc2872</pub-id><pub-id pub-id-type="pmid">15312219</pub-id></element-citation></ref><ref id="CR30"><label>30.</label><mixed-citation publication-type="other">Corman VM, Eckerle I, Bleicker T, Zaki A, Landt O, Eschbach-Bludau M, van Boheemen S, Gopal R, Ballhause M, Bestebroer TM, 39, et al. Detection of a novel human coronavirus by real-time reverse-transcription polymerase chain reaction. Euro Surveill. 2012;17(39).</mixed-citation></ref><ref id="CR31"><label>31.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Banks</surname><given-names>PA</given-names></name><name><surname>Bollen</surname><given-names>TL</given-names></name><name><surname>Dervenis</surname><given-names>C</given-names></name><name><surname>Gooszen</surname><given-names>HG</given-names></name><name><surname>Johnson</surname><given-names>CD</given-names></name><name><surname>Sarr</surname><given-names>MG</given-names></name><name><surname>Tsiotos</surname><given-names>GG</given-names></name><name><surname>Vege</surname><given-names>SS</given-names></name><collab>Acute Pancreatitis Classification Working Group</collab></person-group><article-title>Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by international consensus</article-title><source>Gut</source><year>2013</year><volume>62</volume><issue>1</issue><fpage>102</fpage><lpage>11</lpage><pub-id pub-id-type="doi">10.1136/gutjnl-2012-302779</pub-id><pub-id pub-id-type="pmid">23100216</pub-id></element-citation></ref><ref id="CR32"><label>32.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>O'Toole</surname><given-names>DM</given-names></name><name><surname>Golden</surname><given-names>AM</given-names></name></person-group><article-title>Evaluating cancer patients for rehabilitation potential</article-title><source>West J Med</source><year>1991</year><volume>155</volume><issue>4</issue><fpage>384</fpage><lpage>7</lpage><pub-id pub-id-type="pmid">1771876</pub-id></element-citation></ref><ref id="CR33"><label>33.</label><mixed-citation publication-type="other">U.S. National Library of Medicine. LiverTox. <ext-link ext-link-type="uri" xlink:href="https://livertox.nlm.nih.gov//Lopinavir.htm">https://livertox.nlm.nih.gov//Lopinavir.htm</ext-link>. Accessed 14 Jan 2018.</mixed-citation></ref><ref id="CR34"><label>34.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Almekhlafi</surname><given-names>GA</given-names></name><name><surname>Albarrak</surname><given-names>MM</given-names></name><name><surname>Mandourah</surname><given-names>Y</given-names></name><name><surname>Hassan</surname><given-names>S</given-names></name><name><surname>Alwan</surname><given-names>A</given-names></name><name><surname>Abudayah</surname><given-names>A</given-names></name><name><surname>Altayyar</surname><given-names>S</given-names></name><name><surname>Mustafa</surname><given-names>M</given-names></name><name><surname>Aldaghestani</surname><given-names>T</given-names></name><name><surname>Alghamedi</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Presentation and outcome of Middle East respiratory syndrome in Saudi intensive care unit patients</article-title><source>Crit Care</source><year>2016</year><volume>20</volume><issue>1</issue><fpage>123</fpage><pub-id pub-id-type="doi">10.1186/s13054-016-1303-8</pub-id><pub-id pub-id-type="pmid">27153800</pub-id></element-citation></ref><ref id="CR35"><label>35.</label><element-citation publication-type="journal"><person-group person-group-type="author"><collab>International Committee of Medical Journal E</collab></person-group><article-title>Uniform requirements for manuscripts submitted to biomedical journals</article-title><source>N Engl J Med</source><year>1997</year><volume>336</volume><issue>4</issue><fpage>309</fpage><lpage>15</lpage><pub-id pub-id-type="doi">10.1056/NEJM199701233360422</pub-id><pub-id pub-id-type="pmid">8995096</pub-id></element-citation></ref><ref id="CR36"><label>36.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Arabi</surname><given-names>Y</given-names></name><name><surname>Deeb</surname><given-names>AM</given-names></name><name><surname>Aqeel</surname><given-names>H</given-names></name><name><surname>Balkhy</surname><given-names>H</given-names></name></person-group><article-title>PubMed-cited research articles on the Middle East respiratory syndrome</article-title><source>Ann Thorac Med</source><year>2016</year><volume>11</volume><issue>2</issue><fpage>112</fpage><lpage>3</lpage><pub-id pub-id-type="doi">10.4103/1817-1737.180024</pub-id><pub-id pub-id-type="pmid">27168858</pub-id></element-citation></ref><ref id="CR37"><label>37.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ippolito</surname><given-names>G</given-names></name><name><surname>Lanini</surname><given-names>S</given-names></name><name><surname>Brouqui</surname><given-names>P</given-names></name><name><surname>Di Caro</surname><given-names>A</given-names></name><name><surname>Vairo</surname><given-names>F</given-names></name><name><surname>Fusco</surname><given-names>FM</given-names></name><name><surname>Krishna</surname><given-names>S</given-names></name><name><surname>Capobianchi</surname><given-names>MR</given-names></name><name><surname>Kyobe-Bosa</surname><given-names>H</given-names></name><name><surname>Puro</surname><given-names>V</given-names></name><etal></etal></person-group><article-title>Non-randomised Ebola trials—lessons for optimal outbreak research</article-title><source>Lancet Infect Dis</source><year>2016</year><volume>16</volume><issue>4</issue><fpage>407</fpage><lpage>8</lpage><pub-id pub-id-type="doi">10.1016/S1473-3099(16)00132-8</pub-id><pub-id pub-id-type="pmid">27036341</pub-id></element-citation></ref><ref id="CR38"><label>38.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Macklin</surname><given-names>R</given-names></name><name><surname>Cowan</surname><given-names>E</given-names></name></person-group><article-title>Conducting research in disease outbreaks</article-title><source>PLoS Negl Trop Dis</source><year>2009</year><volume>3</volume><issue>4</issue><fpage>e335</fpage><pub-id pub-id-type="doi">10.1371/journal.pntd.0000335</pub-id><pub-id pub-id-type="pmid">19399167</pub-id></element-citation></ref><ref id="CR39"><label>39.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schafer</surname><given-names>H</given-names></name><name><surname>Muller</surname><given-names>HH</given-names></name></person-group><article-title>Modification of the sample-size and the schedule of interim analyses in survival trials based on data inspections</article-title><source>Stat Med</source><year>2001</year><volume>20</volume><fpage>3741</fpage><lpage>51</lpage><pub-id pub-id-type="doi">10.1002/sim.1136</pub-id><pub-id pub-id-type="pmid">11782030</pub-id></element-citation></ref></ref-list></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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