Treatment of Middle East respiratory syndrome with a combination of lopinavir/ritonavir and interferon-β1b (MIRACLE trial): statistical analysis plan for a recursive two-stage group sequential randomized controlled trial
Identifieur interne : 000471 ( Pmc/Corpus ); précédent : 000470; suivant : 000472Treatment of Middle East respiratory syndrome with a combination of lopinavir/ritonavir and interferon-β1b (MIRACLE trial): statistical analysis plan for a recursive two-stage group sequential randomized controlled trial
Auteurs : Yaseen M. Arabi ; Ayed Y. Asiri ; Abdullah M. Assiri ; Hani A. Aziz Jokhdar ; Adel Alothman ; Hanan H. Balkhy ; Sameera Aljohani ; Shmeylan Al Harbi ; Suleiman Kojan ; Majed Al Jeraisy ; Ahmad M. Deeb ; Ziad A. Memish ; Sameeh Ghazal ; Sarah Al Faraj ; Fahad Al-Hameed ; Asim Alsaedi ; Yasser Mandourah ; Ghaleb A. Al Mekhlafi ; Nisreen Murad Sherbeeni ; Fatehi Elnour Elzein ; Abdullah Almotairi ; Ali Al Bshabshe ; Ayman Kharaba ; Jesna Jose ; Abdulrahman Al Harthy ; Mohammed Al Sulaiman ; Ahmed Mady ; Robert A. Fowler ; Frederick G. Hayden ; Abdulaziz Al-Dawood ; Mohamed Abdelzaher ; Wail Bajhmom ; Mohamed A. HusseinSource :
- Trials [ 1745-6215 ] ; 2020.
Abstract
The MIRACLE trial (MERS-CoV Infection tReated with A Combination of Lopinavir/ritonavir and intErferon-β1b) investigates the efficacy of a combination therapy of lopinavir/ritonavir and recombinant interferon-β1b provided with standard supportive care, compared to placebo provided with standard supportive care, in hospitalized patients with laboratory-confirmed MERS. The MIRACLE trial is designed as a recursive, two-stage, group sequential, multicenter, placebo-controlled, double-blind randomized controlled trial. The aim of this article is to describe the statistical analysis plan for the MIRACLE trial. The primary outcome is 90-day mortality. The primary analysis will follow the intention-to-treat principle. The MIRACLE trial is the first randomized controlled trial for MERS treatment.
ClinicalTrials.gov,
Url:
DOI: 10.1186/s13063-019-3846-x
PubMed: 31900204
PubMed Central: 6942374
Links to Exploration step
PMC:6942374Le document en format XML
<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): statistical analysis plan for a recursive two-stage group sequential 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 0608 0662</institution-id><institution-id institution-id-type="GRID">grid.412149.b</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, 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 0607 2419</institution-id><institution-id institution-id-type="GRID">grid.416641.0</institution-id><institution>Intensive Care Department,</institution><institution>Ministry of the National Guard - Health Affairs,</institution></institution-wrap>ICU 1425, P.O. Box 22490, Riyadh, 11426 Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Asiri, Ayed Y" sort="Asiri, Ayed Y" uniqKey="Asiri A" first="Ayed Y." last="Asiri">Ayed Y. Asiri</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="GRID">grid.440269.d</institution-id><institution>Prince Mohammed bin Abdulaziz Hospital,</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="Aff4"><institution-wrap><institution-id institution-id-type="GRID">grid.415696.9</institution-id><institution>Infection Prevention and Control, Assistant Deputy Minister, Preventive Health,</institution><institution>Ministry of Health,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Aziz Jokhdar, Hani A" sort="Aziz Jokhdar, Hani A" uniqKey="Aziz Jokhdar H" first="Hani A." last="Aziz Jokhdar">Hani A. 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Al Mekhlafi</name><affiliation><nlm:aff id="Aff19"><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="Aff20"><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="Aff20"><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="Almotairi, Abdullah" sort="Almotairi, Abdullah" uniqKey="Almotairi A" first="Abdullah" last="Almotairi">Abdullah Almotairi</name><affiliation><nlm:aff id="Aff21"><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="Al Bshabshe, Ali" sort="Al Bshabshe, Ali" uniqKey="Al Bshabshe A" first="Ali" last="Al Bshabshe">Ali Al Bshabshe</name><affiliation><nlm:aff id="Aff22">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="Aff23">Department of Critical Care, King Fahad Hospital, Ohoud Hospital, Al-Madinah Al-Monawarah, 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="Aff24"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0608 0662</institution-id><institution-id institution-id-type="GRID">grid.412149.b</institution-id><institution>Department Biostatistics and Bioinformatics,</institution><institution>King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Al Harthy, Abdulrahman" sort="Al Harthy, Abdulrahman" uniqKey="Al Harthy A" first="Abdulrahman" last="Al Harthy">Abdulrahman Al Harthy</name><affiliation><nlm:aff id="Aff25"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0445 6726</institution-id><institution-id institution-id-type="GRID">grid.415998.8</institution-id><institution>Intensive Care Unit,</institution><institution>King Saud Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Al Sulaiman, Mohammed" sort="Al Sulaiman, Mohammed" uniqKey="Al Sulaiman M" first="Mohammed" last="Al 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institution-id-type="GRID">grid.479691.4</institution-id><institution>Department of Anesthesiology and Intensive Care,</institution><institution>Tanta University Hospitals,</institution></institution-wrap>Tanta, Egypt</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="Aff29"><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>Institute of Health Policy Management and Evaluation,</institution><institution>University of Toronto,</institution></institution-wrap>Toronto, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="Aff30"><institution-wrap><institution-id institution-id-type="GRID">grid.416745.5</institution-id><institution>Department of Critical Care Medicine and Department of Medicine,</institution><institution>Sunnybrook Hospital,</institution></institution-wrap>Bayview Avenue, Room D478, Toronto, 2075 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="Aff31"><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>International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC), Division of Infectious Diseases and International Health, Department of Medicine,</institution><institution>University of Virginia School of Medicine,</institution></institution-wrap>Charlottesville, Virginia USA</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 0608 0662</institution-id><institution-id institution-id-type="GRID">grid.412149.b</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, 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 0607 2419</institution-id><institution-id institution-id-type="GRID">grid.416641.0</institution-id><institution>Intensive Care Department,</institution><institution>Ministry of the National Guard - Health Affairs,</institution></institution-wrap>ICU 1425, P.O. Box 22490, Riyadh, 11426 Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Abdelzaher, Mohamed" sort="Abdelzaher, Mohamed" uniqKey="Abdelzaher M" first="Mohamed" last="Abdelzaher">Mohamed Abdelzaher</name><affiliation><nlm:aff id="Aff32">Critical Care Medicine Department, King Abdullah Medical Complex, Jeddah, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff33"><institution-wrap><institution-id institution-id-type="GRID">grid.476980.4</institution-id><institution>Critical Care Medicine Department,</institution><institution>Cairo University Hospital,</institution></institution-wrap>Cairo, Egypt</nlm:aff></affiliation></author><author><name sortKey="Bajhmom, Wail" sort="Bajhmom, Wail" uniqKey="Bajhmom W" first="Wail" last="Bajhmom">Wail Bajhmom</name><affiliation><nlm:aff id="Aff34"><institution-wrap><institution-id institution-id-type="GRID">grid.415696.9</institution-id><institution>Internal Medicine Department,</institution><institution>King Fahad General Hospital, Ministry of Health,</institution></institution-wrap>Jeddah, Saudi Arabia</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="Aff12"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0607 2419</institution-id><institution-id institution-id-type="GRID">grid.416641.0</institution-id><institution>Ministry of the National Guard - Health Affairs,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff24"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0608 0662</institution-id><institution-id institution-id-type="GRID">grid.412149.b</institution-id><institution>Department Biostatistics and Bioinformatics,</institution><institution>King Saud Bin Abdulaziz University for Health Sciences, 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">31900204</idno><idno type="pmc">6942374</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942374</idno><idno type="RBID">PMC:6942374</idno><idno type="doi">10.1186/s13063-019-3846-x</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000471</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000471</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): statistical analysis plan for a recursive two-stage group sequential 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 0608 0662</institution-id><institution-id institution-id-type="GRID">grid.412149.b</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, 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 0607 2419</institution-id><institution-id institution-id-type="GRID">grid.416641.0</institution-id><institution>Intensive Care Department,</institution><institution>Ministry of the National Guard - Health Affairs,</institution></institution-wrap>ICU 1425, P.O. Box 22490, Riyadh, 11426 Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Asiri, Ayed Y" sort="Asiri, Ayed Y" uniqKey="Asiri A" first="Ayed Y." last="Asiri">Ayed Y. Asiri</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="GRID">grid.440269.d</institution-id><institution>Prince Mohammed bin Abdulaziz Hospital,</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="Aff4"><institution-wrap><institution-id institution-id-type="GRID">grid.415696.9</institution-id><institution>Infection Prevention and Control, Assistant Deputy Minister, Preventive Health,</institution><institution>Ministry of Health,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Aziz Jokhdar, Hani A" sort="Aziz Jokhdar, Hani A" uniqKey="Aziz Jokhdar H" first="Hani A." last="Aziz Jokhdar">Hani A. Aziz Jokhdar</name><affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="GRID">grid.415696.9</institution-id><institution>Deputy Minister for Public Health, Ministry of Health,</institution></institution-wrap>Riyadh, Saudi Arabia</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 0608 0662</institution-id><institution-id institution-id-type="GRID">grid.412149.b</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0607 2419</institution-id><institution-id institution-id-type="GRID">grid.416641.0</institution-id><institution>Department of Medicine,</institution><institution>Ministry of the National Guard - Health Affairs,</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 0608 0662</institution-id><institution-id institution-id-type="GRID">grid.412149.b</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, 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 0607 2419</institution-id><institution-id institution-id-type="GRID">grid.416641.0</institution-id><institution>Department of Infection Prevention and Control,</institution><institution>Ministry of the National Guard - Health Affairs,</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 0608 0662</institution-id><institution-id institution-id-type="GRID">grid.412149.b</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff8"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0607 2419</institution-id><institution-id institution-id-type="GRID">grid.416641.0</institution-id><institution>Department of Pathology and Laboratory Medicine,</institution><institution>Ministry of the National Guard - Health Affairs,</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="Aff9"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0608 0662</institution-id><institution-id institution-id-type="GRID">grid.412149.b</institution-id><institution>College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0607 2419</institution-id><institution-id institution-id-type="GRID">grid.416641.0</institution-id><institution>Pharmaceutical Care Department,</institution><institution>Ministry of the National Guard - Health Affairs,</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 0608 0662</institution-id><institution-id institution-id-type="GRID">grid.412149.b</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0607 2419</institution-id><institution-id institution-id-type="GRID">grid.416641.0</institution-id><institution>Department of Medicine,</institution><institution>Ministry of the National Guard - Health Affairs,</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="Aff9"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0608 0662</institution-id><institution-id institution-id-type="GRID">grid.412149.b</institution-id><institution>College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0607 2419</institution-id><institution-id institution-id-type="GRID">grid.416641.0</institution-id><institution>Pharmaceutical Care Department,</institution><institution>Ministry of the National Guard - Health Affairs,</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="Aff11"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0608 0662</institution-id><institution-id institution-id-type="GRID">grid.412149.b</institution-id><institution>King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Research Office,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff12"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0607 2419</institution-id><institution-id institution-id-type="GRID">grid.416641.0</institution-id><institution>Ministry of the National Guard - Health Affairs,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Memish, Ziad A" sort="Memish, Ziad A" uniqKey="Memish Z" first="Ziad A." last="Memish">Ziad A. Memish</name><affiliation><nlm:aff id="Aff13"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1758 7207</institution-id><institution-id institution-id-type="GRID">grid.411335.1</institution-id><institution>Prince Mohammed bin Abdulaziz Hospital, Ministry of Health & College of Medicine,</institution><institution>Alfaisal University,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff14"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 6502</institution-id><institution-id institution-id-type="GRID">grid.189967.8</institution-id><institution>Hubert Department of Global Health,</institution><institution>Rollins School of Public Health, Emory University,</institution></institution-wrap>Atlanta, Georgia USA</nlm:aff></affiliation></author><author><name sortKey="Ghazal, Sameeh" sort="Ghazal, Sameeh" uniqKey="Ghazal S" first="Sameeh" last="Ghazal">Sameeh Ghazal</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="GRID">grid.440269.d</institution-id><institution>Prince Mohammed bin Abdulaziz Hospital,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Al Faraj, Sarah" sort="Al Faraj, Sarah" uniqKey="Al Faraj S" first="Sarah" last="Al Faraj">Sarah Al Faraj</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="GRID">grid.440269.d</institution-id><institution>Prince Mohammed bin Abdulaziz Hospital,</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="Aff15"><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, King Abdullah International Medical Research Center,</institution></institution-wrap>Jeddah, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff16">Intensive Care Department, Ministry of the National Guard - Health Affairs, 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="Aff15"><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, King Abdullah International Medical Research Center,</institution></institution-wrap>Jeddah, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff17">Department of Infection Prevention and Control, Ministry of the National Guard - Health Affairs, 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="Aff18"><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>Military Medical Services, Ministry of Defense,</institution><institution>Prince Sultan Military Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Al Mekhlafi, Ghaleb A" sort="Al Mekhlafi, Ghaleb A" uniqKey="Al Mekhlafi G" first="Ghaleb A." last="Al Mekhlafi">Ghaleb A. Al Mekhlafi</name><affiliation><nlm:aff id="Aff19"><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="Aff20"><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="Aff20"><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="Almotairi, Abdullah" sort="Almotairi, Abdullah" uniqKey="Almotairi A" first="Abdullah" last="Almotairi">Abdullah Almotairi</name><affiliation><nlm:aff id="Aff21"><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="Al Bshabshe, Ali" sort="Al Bshabshe, Ali" uniqKey="Al Bshabshe A" first="Ali" last="Al Bshabshe">Ali Al Bshabshe</name><affiliation><nlm:aff id="Aff22">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="Aff23">Department of Critical Care, King Fahad Hospital, Ohoud Hospital, Al-Madinah Al-Monawarah, 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="Aff24"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0608 0662</institution-id><institution-id institution-id-type="GRID">grid.412149.b</institution-id><institution>Department Biostatistics and Bioinformatics,</institution><institution>King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Al Harthy, Abdulrahman" sort="Al Harthy, Abdulrahman" uniqKey="Al Harthy A" first="Abdulrahman" last="Al Harthy">Abdulrahman Al Harthy</name><affiliation><nlm:aff id="Aff25"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0445 6726</institution-id><institution-id institution-id-type="GRID">grid.415998.8</institution-id><institution>Intensive Care Unit,</institution><institution>King Saud Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Al Sulaiman, Mohammed" sort="Al Sulaiman, Mohammed" uniqKey="Al Sulaiman M" first="Mohammed" last="Al Sulaiman">Mohammed Al Sulaiman</name><affiliation><nlm:aff id="Aff26"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0445 6726</institution-id><institution-id institution-id-type="GRID">grid.415998.8</institution-id><institution>Infectious Disease,</institution><institution>King Saud Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Mady, Ahmed" sort="Mady, Ahmed" uniqKey="Mady A" first="Ahmed" last="Mady">Ahmed Mady</name><affiliation><nlm:aff id="Aff27"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0445 6726</institution-id><institution-id institution-id-type="GRID">grid.415998.8</institution-id><institution>Intensive Care Department,</institution><institution>King Saud Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff28"><institution-wrap><institution-id institution-id-type="GRID">grid.479691.4</institution-id><institution>Department of Anesthesiology and Intensive Care,</institution><institution>Tanta University Hospitals,</institution></institution-wrap>Tanta, Egypt</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="Aff29"><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>Institute of Health Policy Management and Evaluation,</institution><institution>University of Toronto,</institution></institution-wrap>Toronto, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="Aff30"><institution-wrap><institution-id institution-id-type="GRID">grid.416745.5</institution-id><institution>Department of Critical Care Medicine and Department of Medicine,</institution><institution>Sunnybrook Hospital,</institution></institution-wrap>Bayview Avenue, Room D478, Toronto, 2075 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="Aff31"><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>International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC), Division of Infectious Diseases and International Health, Department of Medicine,</institution><institution>University of Virginia School of Medicine,</institution></institution-wrap>Charlottesville, Virginia USA</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 0608 0662</institution-id><institution-id institution-id-type="GRID">grid.412149.b</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, 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 0607 2419</institution-id><institution-id institution-id-type="GRID">grid.416641.0</institution-id><institution>Intensive Care Department,</institution><institution>Ministry of the National Guard - Health Affairs,</institution></institution-wrap>ICU 1425, P.O. Box 22490, Riyadh, 11426 Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Abdelzaher, Mohamed" sort="Abdelzaher, Mohamed" uniqKey="Abdelzaher M" first="Mohamed" last="Abdelzaher">Mohamed Abdelzaher</name><affiliation><nlm:aff id="Aff32">Critical Care Medicine Department, King Abdullah Medical Complex, Jeddah, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff33"><institution-wrap><institution-id institution-id-type="GRID">grid.476980.4</institution-id><institution>Critical Care Medicine Department,</institution><institution>Cairo University Hospital,</institution></institution-wrap>Cairo, Egypt</nlm:aff></affiliation></author><author><name sortKey="Bajhmom, Wail" sort="Bajhmom, Wail" uniqKey="Bajhmom W" first="Wail" last="Bajhmom">Wail Bajhmom</name><affiliation><nlm:aff id="Aff34"><institution-wrap><institution-id institution-id-type="GRID">grid.415696.9</institution-id><institution>Internal Medicine Department,</institution><institution>King Fahad General Hospital, Ministry of Health,</institution></institution-wrap>Jeddah, Saudi Arabia</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="Aff12"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0607 2419</institution-id><institution-id institution-id-type="GRID">grid.416641.0</institution-id><institution>Ministry of the National Guard - Health Affairs,</institution></institution-wrap>Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff24"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0608 0662</institution-id><institution-id institution-id-type="GRID">grid.412149.b</institution-id><institution>Department Biostatistics and Bioinformatics,</institution><institution>King Saud Bin Abdulaziz University for Health Sciences, 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="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Abstract</title><p id="Par1">The MIRACLE trial (MERS-CoV Infection tReated with A Combination of Lopinavir/ritonavir and intErferon-β1b) investigates the efficacy of a combination therapy of lopinavir/ritonavir and recombinant interferon-β1b provided with standard supportive care, compared to placebo provided with standard supportive care, in hospitalized patients with laboratory-confirmed MERS. The MIRACLE trial is designed as a recursive, two-stage, group sequential, multicenter, placebo-controlled, double-blind randomized controlled trial. The aim of this article is to describe the statistical analysis plan for the MIRACLE trial. The primary outcome is 90-day mortality. The primary analysis will follow the intention-to-treat principle. The MIRACLE trial is the first randomized controlled trial for MERS treatment.</p></sec><sec><title>Trial registration</title><p id="Par2">ClinicalTrials.gov, <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT02845843">NCT02845843</ext-link>. Registered on 27 July 2016.</p></sec></div></front><back><div1 type="bibliography"><listBibl><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></biblStruct><biblStruct><analytic><author><name 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Schulz</name></author><author><name sortKey="Montori, V" uniqKey="Montori V">V Montori</name></author><author><name sortKey="Gotzsche, Pc" uniqKey="Gotzsche P">PC Gotzsche</name></author><author><name sortKey="Devereaux, Pj" uniqKey="Devereaux P">PJ Devereaux</name></author><author><name sortKey="Elbourne, D" uniqKey="Elbourne D">D Elbourne</name></author><author><name sortKey="Egger, M" uniqKey="Egger M">M Egger</name></author><author><name sortKey="Altman, Dg" uniqKey="Altman D">DG Altman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schulz, Kf" uniqKey="Schulz K">KF Schulz</name></author><author><name sortKey="Altman, Dg" uniqKey="Altman D">DG Altman</name></author><author><name sortKey="Moher, D" uniqKey="Moher D">D Moher</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Gamble, C" uniqKey="Gamble C">C Gamble</name></author><author><name 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<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">31900204</article-id><article-id pub-id-type="pmc">6942374</article-id><article-id pub-id-type="publisher-id">3846</article-id><article-id pub-id-type="doi">10.1186/s13063-019-3846-x</article-id><article-categories><subj-group subj-group-type="heading"><subject>Update</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): statistical analysis plan for a recursive two-stage group sequential randomized controlled trial</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-5735-6241</contrib-id><name><surname>Arabi</surname><given-names>Yaseen M.</given-names></name><address><email>arabi@ngha.med.sa</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>Asiri</surname><given-names>Ayed Y.</given-names></name><address><email>dr.alasiri@hotmail.com</email></address><xref ref-type="aff" rid="Aff3">3</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="Aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Aziz Jokhdar</surname><given-names>Hani A.</given-names></name><address><email>hjokhdar@moh.gov.sa</email></address><xref ref-type="aff" rid="Aff5">5</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="Aff6">6</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="Aff7">7</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="Aff8">8</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="Aff9">9</xref><xref ref-type="aff" rid="Aff10">10</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="Aff6">6</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="Aff9">9</xref><xref ref-type="aff" rid="Aff10">10</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-3680-7338</contrib-id><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="Aff11">11</xref><xref ref-type="aff" rid="Aff12">12</xref></contrib><contrib contrib-type="author"><name><surname>Memish</surname><given-names>Ziad A.</given-names></name><address><email>zmemish@yahoo.com</email></address><xref ref-type="aff" rid="Aff13">13</xref><xref ref-type="aff" rid="Aff14">14</xref></contrib><contrib contrib-type="author"><name><surname>Ghazal</surname><given-names>Sameeh</given-names></name><address><email>ghazals@pmah.med.sa</email></address><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Al Faraj</surname><given-names>Sarah</given-names></name><address><email>alfarajsa@pmah.med.sa</email></address><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-0231-871X</contrib-id><name><surname>Al-Hameed</surname><given-names>Fahad</given-names></name><address><email>Hameedf@ngha.med.sa</email></address><xref ref-type="aff" rid="Aff15">15</xref><xref ref-type="aff" rid="Aff16">16</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="Aff15">15</xref><xref ref-type="aff" rid="Aff17">17</xref></contrib><contrib contrib-type="author"><name><surname>Mandourah</surname><given-names>Yasser</given-names></name><address><email>Yasser.mandourah@me.com</email></address><xref ref-type="aff" rid="Aff18">18</xref></contrib><contrib contrib-type="author"><name><surname>Al Mekhlafi</surname><given-names>Ghaleb A.</given-names></name><address><email>gmekhlafi@yahoo.com</email></address><xref ref-type="aff" rid="Aff19">19</xref></contrib><contrib contrib-type="author"><name><surname>Sherbeeni</surname><given-names>Nisreen Murad</given-names></name><address><email>nalsherbini@psmmc.med.sa</email></address><xref ref-type="aff" rid="Aff20">20</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="Aff20">20</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="Aff21">21</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="Aff22">22</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="Aff23">23</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="Aff24">24</xref></contrib><contrib contrib-type="author"><name><surname>Al Harthy</surname><given-names>Abdulrahman</given-names></name><address><email>a_almshal@hotmail.com</email></address><xref ref-type="aff" rid="Aff25">25</xref></contrib><contrib contrib-type="author"><name><surname>Al Sulaiman</surname><given-names>Mohammed</given-names></name><address><email>malsulaiman@ksmc.med.sa</email></address><xref ref-type="aff" rid="Aff26">26</xref></contrib><contrib contrib-type="author"><name><surname>Mady</surname><given-names>Ahmed</given-names></name><address><email>afmady@hotmail.com</email></address><xref ref-type="aff" rid="Aff27">27</xref><xref ref-type="aff" rid="Aff28">28</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="Aff29">29</xref><xref ref-type="aff" rid="Aff30">30</xref></contrib><contrib contrib-type="author"><name><surname>Hayden</surname><given-names>Frederick G.</given-names></name><address><email>fgh@virginia.edu</email></address><xref ref-type="aff" rid="Aff31">31</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>Abdelzaher</surname><given-names>Mohamed</given-names></name><address><email>intensivist73@hotmail.com</email></address><xref ref-type="aff" rid="Aff32">32</xref><xref ref-type="aff" rid="Aff33">33</xref></contrib><contrib contrib-type="author"><name><surname>Bajhmom</surname><given-names>Wail</given-names></name><address><email>wbajhmom@moh.gov.sa</email></address><xref ref-type="aff" rid="Aff34">34</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="Aff12">12</xref><xref ref-type="aff" rid="Aff24">24</xref></contrib><contrib contrib-type="author"><collab>and the Saudi Critical Care Trials group</collab></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0608 0662</institution-id><institution-id institution-id-type="GRID">grid.412149.b</institution-id><institution>College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, 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 0607 2419</institution-id><institution-id institution-id-type="GRID">grid.416641.0</institution-id><institution>Intensive Care Department,</institution><institution>Ministry of the National Guard - Health Affairs,</institution></institution-wrap>ICU 1425, P.O. Box 22490, Riyadh, 11426 Saudi Arabia</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="GRID">grid.440269.d</institution-id><institution>Prince Mohammed bin Abdulaziz Hospital,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff4"><label>4</label><institution-wrap><institution-id institution-id-type="GRID">grid.415696.9</institution-id><institution>Infection Prevention and Control, Assistant Deputy Minister, Preventive Health,</institution><institution>Ministry of Health,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff5"><label>5</label><institution-wrap><institution-id institution-id-type="GRID">grid.415696.9</institution-id><institution>Deputy Minister for Public Health, Ministry of Health,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff6"><label>6</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0607 2419</institution-id><institution-id institution-id-type="GRID">grid.416641.0</institution-id><institution>Department of Medicine,</institution><institution>Ministry of the National Guard - Health Affairs,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff7"><label>7</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0607 2419</institution-id><institution-id institution-id-type="GRID">grid.416641.0</institution-id><institution>Department of Infection Prevention and Control,</institution><institution>Ministry of the National Guard - Health Affairs,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff8"><label>8</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0607 2419</institution-id><institution-id institution-id-type="GRID">grid.416641.0</institution-id><institution>Department of Pathology and Laboratory Medicine,</institution><institution>Ministry of the National Guard - Health Affairs,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff9"><label>9</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0608 0662</institution-id><institution-id institution-id-type="GRID">grid.412149.b</institution-id><institution>College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff10"><label>10</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0607 2419</institution-id><institution-id institution-id-type="GRID">grid.416641.0</institution-id><institution>Pharmaceutical Care Department,</institution><institution>Ministry of the National Guard - Health Affairs,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff11"><label>11</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0608 0662</institution-id><institution-id institution-id-type="GRID">grid.412149.b</institution-id><institution>King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Research Office,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff12"><label>12</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0607 2419</institution-id><institution-id institution-id-type="GRID">grid.416641.0</institution-id><institution>Ministry of the National Guard - Health Affairs,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff13"><label>13</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1758 7207</institution-id><institution-id institution-id-type="GRID">grid.411335.1</institution-id><institution>Prince Mohammed bin Abdulaziz Hospital, Ministry of Health & College of Medicine,</institution><institution>Alfaisal University,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff14"><label>14</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 6502</institution-id><institution-id institution-id-type="GRID">grid.189967.8</institution-id><institution>Hubert Department of Global Health,</institution><institution>Rollins School of Public Health, Emory University,</institution></institution-wrap>Atlanta, Georgia USA</aff><aff id="Aff15"><label>15</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, King Abdullah International Medical Research Center,</institution></institution-wrap>Jeddah, Saudi Arabia</aff><aff id="Aff16"><label>16</label>Intensive Care Department, Ministry of the National Guard - Health Affairs, Jeddah, Saudi Arabia</aff><aff id="Aff17"><label>17</label>Department of Infection Prevention and Control, Ministry of the National Guard - Health Affairs, Jeddah, Saudi Arabia</aff><aff id="Aff18"><label>18</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>Military Medical Services, Ministry of Defense,</institution><institution>Prince Sultan Military Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff19"><label>19</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="Aff20"><label>20</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="Aff21"><label>21</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="Aff22"><label>22</label>Department of Critical Care Medicine, King Khalid University, Aseer Central Hospital, Abha, Saudi Arabia</aff><aff id="Aff23"><label>23</label>Department of Critical Care, King Fahad Hospital, Ohoud Hospital, Al-Madinah Al-Monawarah, Saudi Arabia</aff><aff id="Aff24"><label>24</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0608 0662</institution-id><institution-id institution-id-type="GRID">grid.412149.b</institution-id><institution>Department Biostatistics and Bioinformatics,</institution><institution>King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff25"><label>25</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0445 6726</institution-id><institution-id institution-id-type="GRID">grid.415998.8</institution-id><institution>Intensive Care Unit,</institution><institution>King Saud Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff26"><label>26</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0445 6726</institution-id><institution-id institution-id-type="GRID">grid.415998.8</institution-id><institution>Infectious Disease,</institution><institution>King Saud Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff27"><label>27</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0445 6726</institution-id><institution-id institution-id-type="GRID">grid.415998.8</institution-id><institution>Intensive Care Department,</institution><institution>King Saud Medical City,</institution></institution-wrap>Riyadh, Saudi Arabia</aff><aff id="Aff28"><label>28</label><institution-wrap><institution-id institution-id-type="GRID">grid.479691.4</institution-id><institution>Department of Anesthesiology and Intensive Care,</institution><institution>Tanta University Hospitals,</institution></institution-wrap>Tanta, Egypt</aff><aff id="Aff29"><label>29</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>Institute of Health Policy Management and Evaluation,</institution><institution>University of Toronto,</institution></institution-wrap>Toronto, Canada</aff><aff id="Aff30"><label>30</label><institution-wrap><institution-id institution-id-type="GRID">grid.416745.5</institution-id><institution>Department of Critical Care Medicine and Department of Medicine,</institution><institution>Sunnybrook Hospital,</institution></institution-wrap>Bayview Avenue, Room D478, Toronto, 2075 Canada</aff><aff id="Aff31"><label>31</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>International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC), Division of Infectious Diseases and International Health, Department of Medicine,</institution><institution>University of Virginia School of Medicine,</institution></institution-wrap>Charlottesville, Virginia USA</aff><aff id="Aff32"><label>32</label>Critical Care Medicine Department, King Abdullah Medical Complex, Jeddah, Saudi Arabia</aff><aff id="Aff33"><label>33</label><institution-wrap><institution-id institution-id-type="GRID">grid.476980.4</institution-id><institution>Critical Care Medicine Department,</institution><institution>Cairo University Hospital,</institution></institution-wrap>Cairo, Egypt</aff><aff id="Aff34"><label>34</label><institution-wrap><institution-id institution-id-type="GRID">grid.415696.9</institution-id><institution>Internal Medicine Department,</institution><institution>King Fahad General Hospital, Ministry of Health,</institution></institution-wrap>Jeddah, Saudi Arabia</aff></contrib-group><pub-date pub-type="epub"><day>3</day><month>1</month><year>2020</year></pub-date><pub-date pub-type="pmc-release"><day>3</day><month>1</month><year>2020</year></pub-date><pub-date pub-type="collection"><year>2020</year></pub-date><volume>21</volume><elocation-id>8</elocation-id><history><date date-type="received"><day>9</day><month>12</month><year>2018</year></date><date date-type="accepted"><day>24</day><month>10</month><year>2019</year></date></history><permissions><copyright-statement>© The Author(s). 2020</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>Abstract</title><p id="Par1">The MIRACLE trial (MERS-CoV Infection tReated with A Combination of Lopinavir/ritonavir and intErferon-β1b) investigates the efficacy of a combination therapy of lopinavir/ritonavir and recombinant interferon-β1b provided with standard supportive care, compared to placebo provided with standard supportive care, in hospitalized patients with laboratory-confirmed MERS. The MIRACLE trial is designed as a recursive, two-stage, group sequential, multicenter, placebo-controlled, double-blind randomized controlled trial. The aim of this article is to describe the statistical analysis plan for the MIRACLE trial. The primary outcome is 90-day mortality. The primary analysis will follow the intention-to-treat principle. The MIRACLE trial is the first randomized controlled trial for MERS treatment.</p></sec><sec><title>Trial registration</title><p id="Par2">ClinicalTrials.gov, <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT02845843">NCT02845843</ext-link>. Registered on 27 July 2016.</p></sec></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>Coronavirus</kwd><kwd>MERS</kwd><kwd>Antiviral</kwd><kwd>Clinical trial</kwd><kwd>Lopinavir/ritonavir</kwd><kwd>Interferon-β1b</kwd><kwd>Statistical analysis plan</kwd><kwd>Protocol</kwd></kwd-group><funding-group><award-group><funding-source><institution>King Abdullah International Medical Research Center</institution></funding-source><award-id>RC15/142/R</award-id></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2020</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1"><title>Background</title><p id="Par15">Middle East respiratory syndrome (MERS) is a viral respiratory disease caused by the Middle East respiratory syndrome coronavirus (MERS-CoV). MERS cases continue to occur and are often associated with respiratory and multiorgan failure [<xref ref-type="bibr" rid="CR1">1</xref>]. There is no antiviral treatment with proven efficacy at present [<xref ref-type="bibr" rid="CR1">1</xref>, <xref ref-type="bibr" rid="CR2">2</xref>].</p><p id="Par16">The MIRACLE trial (<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 the first randomized controlled trial for MERS treatment. The study protocol has been previously published [<xref ref-type="bibr" rid="CR3">3</xref>].</p><p id="Par17">There are several challenges in a trial for treatment of a disease like MERS: (1) there is not enough information on the effect size of the lopinavir/ritonavir and interferon-β1b provided with standard supportive care compared to placebo provided with standard supportive care to conduct adequate planning for the study sample size; (2) MERS is a sporadic, unpredictable, and rare disease, which makes it difficult to plan a separate pilot study to collect the necessary information needed for the planning of the main trial. To overcome these challenges, we designed the MIRACLE trial as a recursive two-stage adaptive trial, which is a relatively new method for group sequential trials [<xref ref-type="bibr" rid="CR4">4</xref>–<xref ref-type="bibr" rid="CR7">7</xref>]. The approach is based on the conditional error principle, which allows for flexible and continuous adjustment of the trial parameters using data observed during prior stages without inflation of the type I error [<xref ref-type="bibr" rid="CR8">8</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 a situation where recruitment rate is unpredictable and a sudden flux in recruitment of patients could happen at any time. Finally, the design takes advantage of the accumulated information throughout the trial from every single recruited patient as opposed to a traditional two-study approach (pilot followed by the main trial).</p><p id="Par18">In this article, we describe the MIRACLE trial statistical analysis plan (SAP) in advance of trial completion. We identify the procedures to be followed for the primary and secondary analyses for the trial. The SAP was written by the study steering committee members led by the principal investigator, who remains blinded to both group allocation and to study results until after completing patient recruitment, patient follow-up, and completion and locking of the database. The final study report will follow the guidelines of the Consolidated Standards of Reporting Trials (CONSORT) for reporting randomized controlled trials [<xref ref-type="bibr" rid="CR9">9</xref>, <xref ref-type="bibr" rid="CR10">10</xref>].</p><p id="Par19">The trial is being conducted according to the standard requirements of Good Clinical Practice E6 [<xref ref-type="bibr" rid="CR11">11</xref>]. The SAP was developed in accordance with the International Council for Harmonisation guidelines (E9 Statistical principles for clinical trials and E3 clinical study reports guidelines) [<xref ref-type="bibr" rid="CR12">12</xref>, <xref ref-type="bibr" rid="CR13">13</xref>] and with the Guidelines for the Content of Statistical Analysis Plans in Clinical Trials [<xref ref-type="bibr" rid="CR14">14</xref>].</p></sec><sec id="Sec2"><title>Methods</title><sec id="Sec3"><title>Study design</title><p id="Par20">The MIRACLE trial is a recursive, two-stage, group sequential, multicenter, randomized, placebo-controlled, double-blind trial. The trial includes hospitalized patients who are 18 years old or older with laboratory-confirmed MERS in addition to evidence of acute organ dysfunction that is judged related to MERS. Inclusion and exclusion criteria have been detailed in a previously published protocol manuscript [<xref ref-type="bibr" rid="CR3">3</xref>]. Patients are randomized to receive lopinavir/ritonavir and recombinant interferon-β1b or placebo. Randomization is stratified according to center and according to whether the patients require mechanical ventilation (invasive or non-invasive) at the time of enrollment, as mechanical ventilation is a major, but pragmatic, surrogate for severity of illness. The study interventions continue for 14 days or until hospital discharge. Patients are followed up daily until day 28 or hospital discharge and then at day 90.</p></sec><sec id="Sec4"><title>Study population</title><p id="Par21">A CONSORT flow diagram of the trial progress will be constructed (Fig. <xref rid="Fig1" ref-type="fig">1</xref>). The number of randomized patients to each group will be reported as well as the number of randomized patients who received the interventions. We will also report the number of screened patients (defined as all hospitalized patients with MERS) who met the eligibility criteria but were not enrolled and the reasons for non-enrollment.
<fig id="Fig1"><label>Fig. 1</label><caption><p>CONSORT flow chart for the MIRACLE trial</p></caption><graphic xlink:href="13063_2019_3846_Fig1_HTML" id="MO1"></graphic></fig></p><p id="Par22">The <italic>intention-to-treat population</italic> consists of all enrolled patients whether or not they received the allocated intervention, and will be used for the primary analysis. A per-protocol analysis will be conducted for patients who received the allocated interventions (defined by any dose of the study intervention).</p></sec><sec id="Sec5"><title>Data</title><p id="Par23">Baseline characteristics</p><p id="Par24">Baseline characteristics will be presented for the two study groups (Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Table S1) including age, sex, and body mass index, the presence of co-infections, nosocomial versus community-acquired MERS infection, Acute Physiology and Chronic Health Evaluation (APACHE) II scores, Sequential Organ Failure Assessment scores, and the Karnofsky Performance Status Scale score [<xref ref-type="bibr" rid="CR3">3</xref>]. We will report comorbidities and the interventions received before randomization for the patients in each group. We will report baseline laboratory values (international normalization ratio, platelet count, hemoglobin, white blood cell count, lymphocyte count, liver enzymes, glucose, serum amylase, blood urea nitrogen, creatinine, creatine kinase, lactate) and respiratory and vital parameters in addition to the location of the patient at time of randomization.</p></sec><sec id="Sec6"><title>Intervention data</title><p id="Par25">For each group we will report the time of hospital admission to randomization and the time of randomization to the first dose received of the study drugs. We will report the received study intervention and its duration for each group, in addition to the missing or incomplete doses and protocol violations (Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Table S2 and Table S8).</p></sec><sec id="Sec7"><title>Co-interventions</title><p id="Par26">We will compare any use of vasopressors, renal replacement therapy, neuromuscular blockade, mechanical ventilation, extracorporeal membrane oxygenation (ECMO), nitric oxide, prone ventilation, and tracheostomy. We will also compare the use of intravenous immunoglobulin, antiviral therapy, antibiotics, corticosteroids, and statins (Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Table S2).</p></sec><sec id="Sec8"><title>Primary and secondary outcomes</title><p id="Par27">The <italic>primary outcome</italic> is 90-day mortality (Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Table S3). The primary outcome is defined as all-cause mortality after enrollment in the trial within 90 days, as either an inpatient or outpatient.</p><p id="Par28"><italic>Secondary outcomes and subgroups</italic> are defined as presented in Table <xref rid="Tab1" ref-type="table">1</xref> and Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Table S4, and S5).
<table-wrap id="Tab1"><label>Table 1</label><caption><p>Secondary Outcomes in the MIRACLE trial</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Outcome</th><th>Definition</th></tr></thead><tbody><tr><td>28-day mortality</td><td>Death from any cause within 28 days of enrollment</td></tr><tr><td>Hospital mortality</td><td>Death from any cause in the index hospitalization</td></tr><tr><td>ICU mortality</td><td>Death from any cause in index ICU admission.</td></tr><tr><td>Sequential Organ Failure Assessment scores</td><td>SOFA score on study days 0, 3, 7, 14, 21 and 28</td></tr><tr><td>Supplemental oxygen-free days</td><td>Number of days within the first 28 days after enrollment when patients do not receive of supplemental oxygen. Patients who die within 28 days will be assigned the value “0”</td></tr><tr><td>Renal replacement therapy-free days</td><td>Number of days within the first 28 days after enrollment when patients do not receive of renal replacement therapy. Patients who die within 28 days will be assigned the value “0”</td></tr><tr><td>Vasopressor-free days</td><td>Number of days within the first 28 days after enrollment when patients do not receive of vasopressors. Patients who die within 28 days will be assigned the value “0”</td></tr><tr><td>Invasive or non-invasive mechanical ventilation-free days</td><td>Number of days within the first 28 days after enrollment when patients do not receive of mechanical ventilation. Patients who die within 28 days will be assigned the value “0”</td></tr><tr><td>Organ support-free days</td><td>Number of days within the first 28 days after enrollment when patients do not receive of invasive mechanical ventilation, renal replacement therapy and vasopressor. Patients who die within 28 days will be assigned the value “0”</td></tr><tr><td>Extracorporeal circulation support-free days</td><td>Number of days within the first 28 days in which patients are not receiving extracorporeal circulation support. Patients who die within 28 days will be assigned the value “0”</td></tr><tr><td>ICU-free days</td><td>Number of days in which 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”</td></tr><tr><td>Post-randomization hospital length of stay</td><td>Number of days between randomization 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</td></tr><tr><td>Renal replacement therapy at day 90</td><td>Number and percentage of patients on renal replacement therapy at day 90</td></tr><tr><td>Oxygen supply at day 90</td><td>Number and percentage of patients on oxygen supply at day 90</td></tr><tr><td>Non-invasive mechanical ventilation at day 90</td><td>Number and percentage of patients on non-invasive mechanical ventilation at day 90</td></tr><tr><td>Invasive mechanical ventilation at day 90</td><td>Number and percentage of patients on Invasive mechanical ventilation at day 90</td></tr><tr><td colspan="2">Secondary laboratory outcomes</td></tr><tr><td> Viral replication kinetics</td><td>upE and ORF1 cycle thresholds of blood and respiratory samples</td></tr><tr><td> Time to clearance from the lower respiratory tract</td><td>Number of days from randomization to MERS-CoV RNA clearance of respiratory samples 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</td></tr><tr><td colspan="2">Safety outcomes</td></tr><tr><td> Serious adverse event reports (SAE)</td><td>The number and percentage of reported serious adverse events any time during the study period. These SAEs include: acute pancreatitis, severe elevation of Alanine aminotransferase (ALT) to more than five-fold the upper normal limit, anaphylaxis, bleeding diathesis and others</td></tr><tr><td> Adverse Events</td><td>The number and percentage of adverse events graded using the Common Terminology Criteria for Adverse Events, at any time within 28 days after enrollment. The adverse drug reactions include: allergic reactions, gastrointestinal, general nervous system and others. See also Table S6</td></tr><tr><td colspan="2">Functional outcomes</td></tr><tr><td> Karnofsky score</td><td>Karnofsky Performance Status Scale for functional impairment, which is a scale from 100 (indicating “Normal,” no complaints; no evidence of disease) to 0 (indicating death) at day 90</td></tr></tbody></table></table-wrap></p><p id="Par29">In addition, we will compare the physiological parameters among patients treated in the treatment group and the control group.</p></sec><sec id="Sec9"><title>Statistical analysis</title><p id="Par30">All analyses will be performed using SAS 9.4 with specially written code for the analysis of the primary outcome that accounts for the recursive design, as described in Chang [<xref ref-type="bibr" rid="CR4">4</xref>].</p><sec id="Sec10"><title>Data and Safety Monitoring Board and interim analyses</title><p id="Par31">A detailed interim analysis plan is reported in the MIRACLE protocol [<xref ref-type="bibr" rid="CR3">3</xref>]. The trial is designed as a recursive, two-stage, group sequential randomized trial. The first interim analysis will be conducted when 34 subjects (17 per group) have completed 90 days of follow-up. This is about 17.5% of the total sample size needed for the classical design (a classic two-group design requires a total of 194 subjects (97 subjects per group) to have an 80% power at a significance level of 5% using a one-sided <italic>Z</italic> test for difference in proportion to detect 20% absolute risk reduction in 90 days mortality among subjects receiving treatment (20%) compared to a control group (40%)). A Data and Safety Monitoring Board (DSMB) will be convened to review the unblinded data (efficacy and safety) and advise on continuation or termination of the trial. The determination of the stopping boundaries in the first two-stage design was calculated using the conditional power method based on the summing stage-wise <italic>p</italic> values. At the first interim analysis, the DSMB will determine whether the trial should be terminated for futility or not using the following boundaries and their corresponding decisions (Table <xref rid="Tab2" ref-type="table">2</xref>).
<table-wrap id="Tab2"><label>Table 2</label><caption><p>Stopping boundaries in the MIRACLE trial</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Boundary</th><th>Value</th><th>Decision</th></tr></thead><tbody><tr><td>Efficacy sopping boundary (α<sub>1</sub>)</td><td>0</td><td>No stopping for efficacy</td></tr><tr><td>Futility stopping boundary (β<sub>1</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>2</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-foot><p>α1 is the maximum probability threshold under which the trial will be terminated early for efficacy. β1 is the maximum probability threshold above which the trial will be terminated for futility. α2 is the maximum probability threshold (the sum of the stage-wise <italic>p</italic>-values), above which the study will be declared as met its endpoint</p></table-wrap-foot></table-wrap></p></sec><sec id="Sec11"><title>Demographics and clinical characteristics</title><p id="Par32">We will summarize and report the demographics and baseline clinical characteristics using descriptive statistics. As appropriate, the chi-square test or Fisher’s exact test will be used to compare the categorical variables, which will be reported as numbers and percentages. Student’s <italic>t</italic> test or the Mann–Whitney <italic>U</italic> test will be used as appropriate to compare the continuous variables, which will be reported as means and standard deviations or as medians and interquartile ranges.</p></sec><sec id="Sec12"><title>Analysis of adverse events</title><p id="Par33">All adverse events will be grouped using Common Terminology Criteria for Adverse Events (CTCAE) Version 4 of the National Institutes of Health (NIH) (Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Table S6). Adverse events will be grouped into aggregate groups and reported for the entire study period (Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Table S7). All results will be summarized in terms of frequency and percentage and will be compared across study arms using Fisher’s exact test. All results will be declared statistically significant with a <italic>p</italic> value < 0.05.</p></sec><sec id="Sec13"><title>Analysis of the primary outcome and continuous planning of the trial</title><p id="Par34">Let <italic>K</italic> be the number of stages of the current clinical trial needed to complete the trial and <italic>i</italic> ∈ {1, 2} be the index for the two-stage design in the <italic>k</italic><sup><italic>th</italic></sup> stage. Let <italic>r</italic><sub>1<italic>ki</italic></sub> <italic>and r</italic><sub>2<italic>ki</italic></sub> be the proportions of 90 days mortality in the standard of care and treatment group respectively. Then the <italic>Z</italic> test statistic for the difference in proportion can be calculated as follows:
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\begin{document}$$ {\sigma}_{ki}=\sqrt{\left[{r}_{1 ki}\left(1-{r}_{1 ki}\right)+{r}_2\left(1-{r}_{2 ki}\right)\right]/2}, $$\end{document}</tex-math><mml:math id="M4" display="block"><mml:msub><mml:mi>σ</mml:mi><mml:mi mathvariant="italic">ki</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:msqrt><mml:mrow><mml:mfenced close="]" open="["><mml:mrow><mml:msub><mml:mi>r</mml:mi><mml:mrow><mml:mn>1</mml:mn><mml:mi mathvariant="italic">ki</mml:mi></mml:mrow></mml:msub><mml:mfenced close=")" open="("><mml:mrow><mml:mn>1</mml:mn><mml:mo>−</mml:mo><mml:msub><mml:mi>r</mml:mi><mml:mrow><mml:mn>1</mml:mn><mml:mi mathvariant="italic">ki</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:mfenced><mml:mo>+</mml:mo><mml:msub><mml:mi>r</mml:mi><mml:mn>2</mml:mn></mml:msub><mml:mfenced close=")" open="("><mml:mrow><mml:mn>1</mml:mn><mml:mo>−</mml:mo><mml:msub><mml:mi>r</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi mathvariant="italic">ki</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:mfenced></mml:mrow></mml:mfenced><mml:mo>/</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msqrt><mml:mo>,</mml:mo></mml:math><graphic xlink:href="13063_2019_3846_Article_Equb.gif" position="anchor"></graphic></alternatives></disp-formula><disp-formula id="Equc"><alternatives><tex-math id="M5">\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$$ {\delta}_{ki}={r}_{1 ki-}{r}_{2 ki}, $$\end{document}</tex-math><mml:math id="M6" display="block"><mml:msub><mml:mi>δ</mml:mi><mml:mi mathvariant="italic">ki</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mi>r</mml:mi><mml:mrow><mml:mn>1</mml:mn><mml:mi mathvariant="italic">ki</mml:mi><mml:mo>−</mml:mo></mml:mrow></mml:msub><mml:msub><mml:mi>r</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi mathvariant="italic">ki</mml:mi></mml:mrow></mml:msub><mml:mo>,</mml:mo></mml:math><graphic xlink:href="13063_2019_3846_Article_Equc.gif" position="anchor"></graphic></alternatives></disp-formula></p><p id="Par35">where <italic>n</italic><sub><italic>ki</italic></sub> is the sample size per group for the <italic>i</italic><sup><italic>th</italic></sup> two-stage design of the <italic>k</italic><sup><italic>th</italic></sup> stage. In the interim analysis (i.e., at each <italic>i</italic> = 1 of the <italic>k</italic><sup><italic>th</italic></sup> two-stage), the primary outcome will be evaluated, and the trial sample size will be re-estimated for the subsequent stage based on the observed effect size using the following formula assuming a conditional power of 80% (<italic>Pc</italic> = 0.8) to decide if the trial should continue:
<disp-formula id="Equd"><alternatives><tex-math id="M7">\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$$ {n}_{k,2}={\left[\frac{\sqrt{2}{\sigma}_{k1}}{\delta {\delta}_{k1}}\left({\Phi}^{-1}\left(1-{\alpha}_{k,2}+{p}_{k,1}\right)-{\Phi}^{-1}\left(1- Pc\right)\right)\right]}^2. $$\end{document}</tex-math><mml:math id="M8" display="block"><mml:msub><mml:mi>n</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mo>,</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msub><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:msub><mml:mi>σ</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:mrow><mml:mrow><mml:mi>δ</mml:mi><mml:msub><mml:mi>δ</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:mrow></mml:mfrac><mml:mfenced close=")" open="("><mml:mrow><mml:msup><mml:mi mathvariant="normal">Φ</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:msub><mml:mi>α</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mo>,</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>p</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:mrow></mml:mfenced><mml:mo>−</mml:mo><mml:msup><mml:mi mathvariant="normal">Φ</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 mathvariant="italic">Pc</mml:mi></mml:mrow></mml:mfenced></mml:mrow></mml:mfenced></mml:mrow></mml:mfenced><mml:mn>2</mml:mn></mml:msup><mml:mo>.</mml:mo></mml:math><graphic xlink:href="13063_2019_3846_Article_Equd.gif" position="anchor"></graphic></alternatives></disp-formula></p><p id="Par36">Here <italic>α</italic><sub><italic>k</italic>, 2</sub> is the precalculated rejection boundary for efficacy at the second stage of the two-stage design at the <italic>k</italic><sup><italic>th</italic></sup> stage, and <italic>p</italic><sub><italic>k</italic>, 1</sub> is the raw table probability corresponding to the <italic>Z</italic><sub><italic>ki</italic></sub> statistic. At the first interim analysis, should the data suggest that another stage of the two-stage steps is required, we will recalculate the conditional error and new boundaries will be calculated for <italic>K</italic> = 2. Let <italic>β</italic><sub><italic>k</italic> + 1, 1</sub>, <italic>α</italic><sub><italic>k</italic> + 1, 1</sub> be the rejection boundaries for futility and efficacy for the first (<italic>i</italic> = 1) of the two-stage step of the <italic>k</italic><sup><italic>th</italic></sup> + 1 stage. Then the conditional error is:
<disp-formula id="Eque"><alternatives><tex-math id="M9">\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$$ A\left({p}_{k,1}\right)={\alpha}_{k+1,1}+{\alpha}_{k+1,2\kern0.5em }\left({\beta}_{k+1,1}-{\alpha}_{k+1,1}\ \right)-\frac{1}{2}\left({\beta}_{k+1,1}^2-{\alpha}_{k+1,1}^2\right),k=0,1,\dots K, $$\end{document}</tex-math><mml:math id="M10" display="block"><mml:mi>A</mml:mi><mml:mfenced close=")" open="("><mml:msub><mml:mi>p</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:mfenced><mml:mo>=</mml:mo><mml:msub><mml:mi>α</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>α</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mn>2</mml:mn><mml:mspace width="0.5em"></mml:mspace></mml:mrow></mml:msub><mml:mfenced close=")" open="("><mml:mrow><mml:msub><mml:mi>β</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>−</mml:mo><mml:msub><mml:mi>α</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mspace width="0.25em"></mml:mspace></mml:mrow></mml:mfenced><mml:mo>−</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mfenced close=")" open="("><mml:mrow><mml:msubsup><mml:mi>β</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mn>2</mml:mn></mml:msubsup><mml:mo>−</mml:mo><mml:msubsup><mml:mi>α</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mn>2</mml:mn></mml:msubsup></mml:mrow></mml:mfenced><mml:mo>,</mml:mo><mml:mi>k</mml:mi><mml:mo>=</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mo>…</mml:mo><mml:mi>K</mml:mi><mml:mo>,</mml:mo></mml:math><graphic xlink:href="13063_2019_3846_Article_Eque.gif" position="anchor"></graphic></alternatives></disp-formula></p><p id="Par37">where <italic>A</italic>(<italic>p</italic><sub>0, 1</sub>) is the type I error, which is set to 0.05. The new <italic>α</italic><sub><italic>k</italic> + 1, 2</sub> boundary for the <italic>k</italic><sup><italic>t</italic>h</sup> + 1 stage for pre chosen <italic>β</italic><sub><italic>k</italic> + 1, 1</sub>, <italic>α</italic><sub><italic>k</italic> + 1, 1</sub> will be calculated as follows:
<disp-formula id="Equf"><alternatives><tex-math id="M11">\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$$ {\alpha}_{k+1,2}=\frac{A\left({p}_{k,1}\right)+\frac{1}{2}\left({\beta}_{k+1,1}^2-{\alpha}_{k+1,1}^2\right)-{\alpha}_{k+1,1}}{\beta_{k+1,1}-{\alpha}_{k+1,1}\ }. $$\end{document}</tex-math><mml:math id="M12" display="block"><mml:msub><mml:mi>α</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:mi>A</mml:mi><mml:mfenced close=")" open="("><mml:msub><mml:mi>p</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:mfenced><mml:mo>+</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mfenced close=")" open="("><mml:mrow><mml:msubsup><mml:mi>β</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mn>2</mml:mn></mml:msubsup><mml:mo>−</mml:mo><mml:msubsup><mml:mi>α</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mn>2</mml:mn></mml:msubsup></mml:mrow></mml:mfenced><mml:mo>−</mml:mo><mml:msub><mml:mi>α</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:mrow><mml:mrow><mml:msub><mml:mi>β</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>−</mml:mo><mml:msub><mml:mi>α</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mspace width="0.25em"></mml:mspace></mml:mrow></mml:mfrac><mml:mo>.</mml:mo></mml:math><graphic xlink:href="13063_2019_3846_Article_Equf.gif" position="anchor"></graphic></alternatives></disp-formula></p><p id="Par38">At the end of the trial, the treatment will be declared efficacious if the calculated stage-wise ordered <italic>p</italic> value <italic>p</italic><sub><italic>k</italic>, 2</sub> is less than <italic>α</italic><sub><italic>k</italic>, 2</sub>. The adjusted <italic>p</italic> value will be obtained using backward recursion as follows:
<disp-formula id="Equg"><alternatives><tex-math id="M13">\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$$ \left\{\begin{array}{c}{P}_{K_0-1,2}=\left\{\begin{array}{c}t\kern23.5em for\ k=1,\\ {}\ {\alpha}_{k_0,1}+t\left({\beta}_{k_0,1}-{\alpha}_{k_0,1}\right)-\frac{1}{2}\left({\beta^2}_{k_0,1}-{\alpha^2}_{k_0,1}\right)\kern1.5em for\ k=2,\end{array}\right.\\ {}{P}_{i-1,2}={\alpha}_{i,1}+\left({p}_{i,1}+{p}_{i,2}\right)\left({\beta}_{i,1}-{\alpha}_{i,1}\right)-\frac{1}{2}\left({\beta^2}_{i,1}-{\alpha^2}_{i,1}\right)\kern2.75em for\ i=1,\dots, {K}_{0-1}\end{array}\right.\operatorname{} $$\end{document}</tex-math><mml:math id="M14" display="block"><mml:mfenced close="" open="{"><mml:mtable><mml:mtr><mml:mtd><mml:maligngroup></mml:maligngroup><mml:msub><mml:mi>P</mml:mi><mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mn>0</mml:mn></mml:msub><mml:mo>−</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mfenced close="" open="{"><mml:mtable><mml:mtr><mml:mtd><mml:maligngroup></mml:maligngroup><mml:mi>t</mml:mi><mml:mspace width="23.5em"></mml:mspace><mml:mtext mathvariant="italic">for</mml:mtext><mml:mspace width="0.25em"></mml:mspace><mml:mi>k</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:maligngroup></mml:maligngroup><mml:mspace width="0.25em"></mml:mspace><mml:msub><mml:mi>α</mml:mi><mml:mrow><mml:msub><mml:mi>k</mml:mi><mml:mn>0</mml:mn></mml:msub><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:mi>t</mml:mi><mml:mfenced close=")" open="("><mml:mrow><mml:msub><mml:mi>β</mml:mi><mml:mrow><mml:msub><mml:mi>k</mml:mi><mml:mn>0</mml:mn></mml:msub><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>−</mml:mo><mml:msub><mml:mi>α</mml:mi><mml:mrow><mml:msub><mml:mi>k</mml:mi><mml:mn>0</mml:mn></mml:msub><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:mrow></mml:mfenced><mml:mo>−</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mfenced close=")" open="("><mml:mrow><mml:msub><mml:msup><mml:mi>β</mml:mi><mml:mn>2</mml:mn></mml:msup><mml:mrow><mml:msub><mml:mi>k</mml:mi><mml:mn>0</mml:mn></mml:msub><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>−</mml:mo><mml:msub><mml:msup><mml:mi>α</mml:mi><mml:mn>2</mml:mn></mml:msup><mml:mrow><mml:msub><mml:mi>k</mml:mi><mml:mn>0</mml:mn></mml:msub><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:mrow></mml:mfenced><mml:mspace width="1.5em"></mml:mspace><mml:mtext mathvariant="italic">for</mml:mtext><mml:mspace width="0.25em"></mml:mspace><mml:mi>k</mml:mi><mml:mo>=</mml:mo><mml:mn>2</mml:mn><mml:mo>,</mml:mo></mml:mtd></mml:mtr></mml:mtable></mml:mfenced></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:maligngroup></mml:maligngroup><mml:msub><mml:mi>P</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>−</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mi>α</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:mfenced close=")" open="("><mml:mrow><mml:msub><mml:mi>p</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>p</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msub></mml:mrow></mml:mfenced><mml:mfenced close=")" open="("><mml:mrow><mml:msub><mml:mi>β</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>−</mml:mo><mml:msub><mml:mi>α</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:mrow></mml:mfenced><mml:mo>−</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mfenced close=")" open="("><mml:mrow><mml:msub><mml:msup><mml:mi>β</mml:mi><mml:mn>2</mml:mn></mml:msup><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>−</mml:mo><mml:msub><mml:msup><mml:mi>α</mml:mi><mml:mn>2</mml:mn></mml:msup><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:mrow></mml:mfenced><mml:mspace width="2.75em"></mml:mspace><mml:mtext mathvariant="italic">for</mml:mtext><mml:mspace width="0.25em"></mml:mspace><mml:mi>i</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mo>…</mml:mo><mml:mo>,</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>0</mml:mn><mml:mo>−</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:mtd></mml:mtr></mml:mtable></mml:mfenced><mml:mo></mml:mo></mml:math><graphic xlink:href="13063_2019_3846_Article_Equg.gif" position="anchor"></graphic></alternatives></disp-formula></p><p id="Par39">where <italic>K</italic><sub>0</sub> is the total number of two-stage stages, and <italic>t</italic> is the sum of stage-wise raw <italic>p</italic> values. Finally, the adjusted overall 95% one-sided confidence interval will be calculated by:
<disp-formula id="Equh"><alternatives><tex-math id="M15">\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
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\begin{document}$$ \Phi \left(\frac{\delta_{k_0,2}}{\overset{\sim }{\sigma }}\sqrt{\frac{n_{k0,1}}{2}}-{z}_{1-{p}_{k0,1}}\right)+\Phi \left(\frac{\delta_{k_0,2}}{\overset{\sim }{\sigma }}\sqrt{\frac{n_{k0,2}}{2}}-{z}_{1-{p}_{k0,2}}\right)={\alpha}_{k_0,2}, $$\end{document}</tex-math><mml:math id="M24" display="block"><mml:mi mathvariant="normal">Φ</mml:mi><mml:mfenced close=")" open="("><mml:mrow><mml:mfrac><mml:msub><mml:mi>δ</mml:mi><mml:mrow><mml:msub><mml:mi>k</mml:mi><mml:mn>0</mml:mn></mml:msub><mml:mo>,</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msub><mml:mover accent="true"><mml:mi>σ</mml:mi><mml:mo stretchy="true">~</mml:mo></mml:mover></mml:mfrac><mml:msqrt><mml:mfrac><mml:msub><mml:mi>n</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mn>2</mml:mn></mml:mfrac></mml:msqrt><mml:mo>−</mml:mo><mml:msub><mml:mi>z</mml:mi><mml:mrow><mml:mn>1</mml:mn><mml:mo>−</mml:mo><mml:msub><mml:mi>p</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:mrow></mml:msub></mml:mrow></mml:mfenced><mml:mo>+</mml:mo><mml:mi mathvariant="normal">Φ</mml:mi><mml:mfenced close=")" open="("><mml:mrow><mml:mfrac><mml:msub><mml:mi>δ</mml:mi><mml:mrow><mml:msub><mml:mi>k</mml:mi><mml:mn>0</mml:mn></mml:msub><mml:mo>,</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msub><mml:mover accent="true"><mml:mi>σ</mml:mi><mml:mo stretchy="true">~</mml:mo></mml:mover></mml:mfrac><mml:msqrt><mml:mfrac><mml:msub><mml:mi>n</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msub><mml:mn>2</mml:mn></mml:mfrac></mml:msqrt><mml:mo>−</mml:mo><mml:msub><mml:mi>z</mml:mi><mml:mrow><mml:mn>1</mml:mn><mml:mo>−</mml:mo><mml:msub><mml:mi>p</mml:mi><mml:mrow><mml:mi>k</mml:mi><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msub></mml:mrow></mml:msub></mml:mrow></mml:mfenced><mml:mo>=</mml:mo><mml:msub><mml:mi>α</mml:mi><mml:mrow><mml:msub><mml:mi>k</mml:mi><mml:mn>0</mml:mn></mml:msub><mml:mo>,</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msub><mml:mo>,</mml:mo></mml:math><graphic xlink:href="13063_2019_3846_Article_Equi.gif" position="anchor"></graphic></alternatives></disp-formula></p><p id="Par41">where <italic>n</italic><sub><italic>k</italic>0, 1</sub> and <italic>n</italic><sub><italic>k</italic>0, 2</sub> are the sample sizes for the first and second stage of the last <italic>k</italic><sup><italic>th</italic></sup> two-stage design, and <italic>p</italic><sub><italic>k</italic>0, 1</sub>, <italic>p</italic><sub><italic>k</italic>0, 2</sub> are the stage-wise adjusted <italic>p</italic> values.</p><p id="Par42">In order to stay consistent with the method that was used in calculating the boundaries for the trial, we will not account for stratification in the primary outcome analysis. In general, this approach is acceptable and it preserves both type I and type II errors as long as the weighted average of the effect size stays close to the hypothesized effect size [<xref ref-type="bibr" rid="CR15">15</xref>]. Furthermore, as long as the sample size re-estimation at the interim analysis was based on the weighted average of the effect size, the overall power of the trial will be preserved.</p></sec><sec id="Sec14"><title>Secondary analyses of the primary outcome, secondary outcomes, and subgroups</title><p id="Par43">With the exception of the analysis of the primary outcome, all other analyses will be tested using regular statistical methods and will be two-sided. A secondary adjusted 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 will be included as independent variables. Those variables will include at minimum the following: age, community-acquired versus hospital-acquired infection, mechanical ventilation, center, and Sequential Organ Failure Assessment score. Ninety-day 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 (Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Figure S1). Analysis of secondary outcomes will be compared in the intention-to-treat cohort only. Subgroup analyses will be conducted if patient numbers permit (e.g., no fewer than five patients in subgroups of interest) in a priori defined subgroups (Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Table S5). Multivariable logistic regression will be used to report the results of tests of interactions for these subgroups.</p></sec><sec id="Sec15"><title>Handling of missing data</title><p id="Par44">All missing data will be reviewed and characterized in terms of their pattern (e.g., missing completely at random, missing at random, etc.). For missing completely at random, all analyses will be based on a list-wise deletion approach where only observations with complete values will be considered for analysis. For variables with values missing at random, multiple imputation techniques will be utilized to impute the missing values, as suggested by Rubin [<xref ref-type="bibr" rid="CR16">16</xref>].</p></sec><sec id="Sec16"><title>Adjustment multiplicity testing for the secondary analyses</title><p id="Par45">To adjust for multiple testing, we will use the false discovery rate (FDR) as described by Benjamini and Hochberg [<xref ref-type="bibr" rid="CR17">17</xref>]. In this procedure all hypothesis tests will be sorted in ascending order based on their calculated <italic>p</italic> value. All hypothesis tests below an index <italic>K</italic> will be rejected, where <italic>K</italic> is calculated as follows:
<disp-formula id="Equj"><alternatives><tex-math id="M25">\documentclass[12pt]{minimal}
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\begin{document}$$ K=\mathit{\max}\left\{i:p(i)\le \frac{i}{m}.q\right\}, $$\end{document}</tex-math><mml:math id="M26" display="block"><mml:mi>K</mml:mi><mml:mo>=</mml:mo><mml:mo mathvariant="italic">max</mml:mo><mml:mfenced close="}" open="{"><mml:mrow><mml:mi>i</mml:mi><mml:mo>:</mml:mo><mml:mi>p</mml:mi><mml:mfenced close=")" open="("><mml:mi>i</mml:mi></mml:mfenced><mml:mo>≤</mml:mo><mml:mfrac><mml:mi>i</mml:mi><mml:mi>m</mml:mi></mml:mfrac><mml:mo>.</mml:mo><mml:mi>q</mml:mi></mml:mrow></mml:mfenced><mml:mo>,</mml:mo></mml:math><graphic xlink:href="13063_2019_3846_Article_Equj.gif" position="anchor"></graphic></alternatives></disp-formula></p><p id="Par46">where <italic>i</italic> = <italic>m</italic>, … ,1, <italic>m</italic> is the total number of tested hypotheses, and <italic>q</italic> = 0.05.</p><p id="Par47">Additional details about the SAP are available in Additional file <xref rid="MOESM2" ref-type="media">2</xref>.</p></sec></sec></sec><sec id="Sec17"><title>Discussion</title><p id="Par48">The MIRACLE trial investigates the efficacy of a combination therapy of lopinavir/ritonavir and recombinant Interferon-β1b provided with standard supportive care, compared to placebo provided with standard supportive care, in hospitalized patients with laboratory-confirmed MERS.</p><p id="Par49">The first patient was enrolled in November 2016. At present, 14 sites are actively screening for eligible patients. The recruitment rate in the MIRACLE trial has been slow mainly related to the decline in the number of MERS cases in Saudi Arabia. Due to the uncertainty of the efficacy level of the treatment and the recruitment rate, the trial is designed to be a recursive, two-stage, group sequential randomized trial [<xref ref-type="bibr" rid="CR4">4</xref>].</p><p id="Par50">Several methods could be utilized to build an adaptive trial. However, most of these methods would require one to specify a priori the time and type of adjustments that need to take place in the trial. For a disease such as MERS there are many factors that could limit the ability to specify a priori those elements; thus, the recursive two-stage design is a natural choice. This type of design provides enough flexibility to introduce different adjustments while learning from the observed data without inflating the type I error.</p><p id="Par51">Reporting of the SAP to the MIRACLE trial in advance of trial completion will enhance evaluation of the clinical data and support confidence in the final results and the conclusion. Prior specification of the statistical methods and outcomes analysis will facilitate unbiased analyses of these important clinical data.</p><sec id="Sec18"><title>Trial status</title><p id="Par52">Recruitment started in November 2016 and is currently ongoing.</p></sec></sec><sec sec-type="supplementary-material"><title>Supplementary information</title><sec id="Sec19"><p><supplementary-material content-type="local-data" id="MOESM1"><media xlink:href="13063_2019_3846_MOESM1_ESM.docx"><caption><p><bold>Additional file 1: Table S1.</bold> Baseline characteristics of intention-to-treat (ITT) population. <bold>Table S2.</bold> Summary of interventions and co-interventions. <bold>Table S3.</bold> Primary outcome: 90-day mortality. <bold>Table S4.</bold> Secondary outcomes. <bold>Table S5.</bold> Subgroup analyses. <bold>Table S6.</bold> Classification of adverse events in the MIRACLE trial (<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) using the NIH Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. <bold>Table S7.</bold> Summary of adverse events by severity. <bold>Table S8.</bold> Summary of protocol violations. </p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="MOESM2"><media xlink:href="13063_2019_3846_MOESM2_ESM.docx"><caption><p><bold>Additional file 2.</bold> Statistical analysis plan document.</p></caption></media></supplementary-material></p></sec></sec></body><back><glossary><title>Abbreviations</title><def-list><def-item><term>APACHE II</term><def><p id="Par3">Acute Physiology and Chronic Health Evaluation II</p></def></def-item><def-item><term>CONSORT</term><def><p id="Par4">Consolidated Standards of Reporting Trials</p></def></def-item><def-item><term>CTCAE</term><def><p id="Par5">Common Terminology Criteria for Adverse Events</p></def></def-item><def-item><term>DSMB</term><def><p id="Par6">Data and Safety Monitoring Board</p></def></def-item><def-item><term>ECMO</term><def><p id="Par7">Extracorporeal membrane oxygenation</p></def></def-item><def-item><term>MERS</term><def><p id="Par8">Middle East respiratory syndrome</p></def></def-item><def-item><term>MERS-CoV</term><def><p id="Par9">Middle East respiratory syndrome coronavirus</p></def></def-item><def-item><term>MIRACLE trial</term><def><p id="Par10"><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>NIH</term><def><p id="Par11">National Institutes of Health</p></def></def-item><def-item><term>SAP</term><def><p id="Par12">Statistical analysis plan</p></def></def-item><def-item><term>SFDA</term><def><p id="Par13">Saudi Food and Drug Authority</p></def></def-item><def-item><term>TEAE</term><def><p id="Par14">Treatment-emergent adverse event</p></def></def-item></def-list></glossary><fn-group><fn><p><bold>Publisher’s Note</bold></p><p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></fn></fn-group><sec><title>Supplementary information</title><p><bold>Supplementary information</bold> accompanies this paper at 10.1186/s13063-019-3846-x.</p></sec><ack><title>Acknowledgements</title><p>We would like to acknowledge the following Data Safety Monitoring Board (DSMB) Chair and members:</p><p><italic>Greg S Martin, MD, MSc (Chair)</italic></p><p>Professor of Medicine</p><p>Executive Associate Division Director</p><p>Division of Pulmonary, Allergy, Critical Care and Sleep Medicine</p><p>Research Director, Emory Critical Care Center</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>Atlanta, Georgia, USA</p><p><italic>David A Schoenfeld, PhD (Member)</italic></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>Boston, Massachusetts, USA</p><p><italic>Sharon L Walmsley, MSc, MD, FRCPC (Member)</italic></p><p>Senior Scientist, Toronto General Research Institute (TGRI)</p><p>Toronto, Ontario, Canada</p><p><italic>Shannon Carson, MD (Member)</italic></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>Chapel Hill, North Carolina, USA</p></ack><notes notes-type="author-contribution"><title>Authors’ contributions</title><p>YA, AA1, HB, SJ, SH, SK, MJ, AMD, JJ, RAF, FGH, and MAH conceived and designed the plan. YA, AMD, and JJ drafted the manuscript. YA, JJ, and MAH developed the analytical plan. YA, AA, AMA, HAJ, AA1, HB, SJ, SH, SK, MJ, AMD, ZAM, SG, SF, FH, AS, YM, GM, NMS, FEZ, AM, AB, AK, JJ, AH, MS, AM, RAF, FGH, AD, MA, WB, and MAH were involved in trial sites management, critical revision of the manuscript for important intellectual content, and approval of the final version to be published, and they agree to be accountable for all aspects of the work. All authors read and approved the final version of the manuscript.</p></notes><notes notes-type="funding-information"><title>Funding</title><p>The MIRACLE trial is funded by King Abdullah International Medical Research Center, Riyadh, Kingdom of Saudi Arabia. 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.</p></notes><notes notes-type="data-availability"><title>Availability of data and materials</title><p>The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.</p></notes><notes><title>Ethics approval and consent to participate</title><p id="Par53">The MIRACLE study is approved by the Scientific Committee and the Institutional Review Board at the National Guard Health Affairs, Riyadh, Saudi Arabia (RC15/142) and all participating sites and registered at the Saudi Food and Drug Authority (SFDA), Riyadh, Saudi Arabia. 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="Par54">Not applicable.</p></notes><notes notes-type="COI-statement"><title>Competing interests</title><p id="Par55">The authors declare that they have no competing interests. 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