Proactive Prophylaxis With Azithromycin and HydroxyChloroquine in Hospitalised Patients With COVID-19 (ProPAC-COVID): A structured summary of a study protocol for a randomised controlled trial.
Identifieur interne : 001438 ( Main/Corpus ); précédent : 001437; suivant : 001439Proactive Prophylaxis With Azithromycin and HydroxyChloroquine in Hospitalised Patients With COVID-19 (ProPAC-COVID): A structured summary of a study protocol for a randomised controlled trial.
Auteurs : Pradeesh Sivapalan ; Charlotte Suppli Ulrik ; Rasmus Dahlin Bojesen ; Therese Sophie Lapperre ; Josefin Viktoria Eklöf ; Kjell Erik Julius H Kansson ; Andrea Browatzki ; Casper Tidemansen ; Jon Torgny Wilcke ; Julie Janner ; Vibeke Gottlieb ; Howraman Meteran ; Celeste Porsbjerg ; Birgitte Lindegaard Madsen ; Mia Moberg ; Lars Pedersen ; Thomas Lars Benfield ; Jens Dilling Lundgren ; Filip Krag Knop ; Tor Biering-S Rensen ; Muzhda Ghanizada ; Tine Peick Sonne ; Uffe Christian Steinholtz B Dtger ; Sidse Graff Jensen ; Daniel Bech Rasmussen ; Eva Br Ndum ; Oliver Djurhuus Tupper ; Susanne Wiemann S Rensen ; Gitte Alstrup ; Christian Borbjerg Laursen ; Ulla Weinrich M Ller ; Asger Sverrild ; Jens-Ulrik St Hr JensenSource :
- Trials [ 1745-6215 ] ; 2020.
English descriptors
- KwdEn :
- Antiviral Agents (administration & dosage), Antiviral Agents (adverse effects), Azithromycin (administration & dosage), Azithromycin (adverse effects), Betacoronavirus (drug effects), Betacoronavirus (pathogenicity), COVID-19 (MeSH), Coronavirus Infections (diagnosis), Coronavirus Infections (drug therapy), Coronavirus Infections (mortality), Coronavirus Infections (virology), Critical Care (MeSH), Denmark (MeSH), Double-Blind Method (MeSH), Drug Administration Schedule (MeSH), Hospital Mortality (MeSH), Host-Pathogen Interactions (MeSH), Humans (MeSH), Hydroxychloroquine (administration & dosage), Hydroxychloroquine (adverse effects), Inpatients (MeSH), Length of Stay (MeSH), Multicenter Studies as Topic (MeSH), Noninvasive Ventilation (MeSH), Pandemics (MeSH), Patient Admission (MeSH), Pneumonia, Viral (diagnosis), Pneumonia, Viral (drug therapy), Pneumonia, Viral (mortality), Pneumonia, Viral (virology), Randomized Controlled Trials as Topic (MeSH), SARS-CoV-2 (MeSH), Severity of Illness Index (MeSH), Time Factors (MeSH), Treatment Outcome (MeSH).
- MESH :
- chemical , administration & dosage : Antiviral Agents, Azithromycin, Hydroxychloroquine.
- chemical , adverse effects : Antiviral Agents, Azithromycin, Hydroxychloroquine.
- geographic : Denmark.
- diagnosis : Coronavirus Infections, Pneumonia, Viral.
- drug effects : Betacoronavirus.
- drug therapy : Coronavirus Infections, Pneumonia, Viral.
- mortality : Coronavirus Infections, Pneumonia, Viral.
- pathogenicity : Betacoronavirus.
- virology : Coronavirus Infections, Pneumonia, Viral.
- COVID-19, Critical Care, Double-Blind Method, Drug Administration Schedule, Hospital Mortality, Host-Pathogen Interactions, Humans, Inpatients, Length of Stay, Multicenter Studies as Topic, Noninvasive Ventilation, Pandemics, Patient Admission, Randomized Controlled Trials as Topic, SARS-CoV-2, Severity of Illness Index, Time Factors, Treatment Outcome.
Abstract
OBJECTIVES
The aim of this randomised GCP-controlled trial is to clarify whether combination therapy with the antibiotic azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, antiviral efficacy and pre-emptive treatment of supra-infections can shorten hospitalisation duration for patients with COVID-19 (measured as "days alive and out of hospital" as the primary outcome), reduce the risk of non- invasive ventilation, treatment in the intensive care unit and death.
TRIAL DESIGN
This is a multi-centre, randomised, Placebo-controlled, 2-arm ratio 1:1, parallel group double-blind study.
PARTICIPANTS
226 participants are recruited at the trial sites/hospitals, where the study will take place in Denmark: Aalborg, Bispebjerg, Gentofte, Herlev, Hillerød, Hvidovre, Odense and Slagelse hospitals.
INCLUSION CRITERIA
• Patient admitted to Danish emergency departments, respiratory medicine departments or internal medicine departments • Age≥ 18 years • Hospitalized ≤48 hours • Positive COVID-19 test / diagnosis during the hospitalization (confirmed). • Men or non-fertile women. Fertile women* must not be pregnant, i.e. negative pregnancy test must be available at inclusion • Informed consent signed by the patient *Defined as after menarche and until postmenopausal (no menstruation for 12 months) Exclusion criteria: • At the time of recruitment, the patient uses >5 LO2/min (equivalent to 40% FiO2 if measured) • Known intolerance/allergy to azithromycin or hydroxychloroquine or hypersensitivity to quinine or 4-aminoquinoline derivatives • Neurogenic hearing loss • Psoriasis • Retinopathy • Maculopathy • Visual field changes • Breastfeeding • Severe liver diseases other than amoebiasis (INR> 1.5 spontaneously) • Severe gastrointestinal, neurological and hematological disorders (investigator-assessed) • eGFR <45 ml/min/1.73 m2 • Clinically significant cardiac conduction disorders/arrhythmias or prolonged QTc interval (QTc (f) of> 480/470 ms). • Myasthenia gravis • Treatment with digoxin* • Glucose-6-phosphate dehydrogenase deficiency • Porphyria • Hypoglycaemia (Blood glucose at any time since hospitalization of <3.0 mmol/L) • Severe mental illness which significantly impedes cooperation • Severe linguistic problems that significantly hinder cooperation • Treatment with ergot alkaloids *The patient must not be treated with digoxin for the duration of the intervention. For atrial fibrillation/flutter, select according to the Cardiovascular National Treatment Guide (NBV): Calcium antagonist, Beta blocker, direct current (DC) conversion or amiodarone. In case of urgent need for digoxin treatment (contraindication for the aforementioned equal alternatives), the test drug should be paused, and ECG should be taken daily.
INTERVENTION AND COMPARATOR
Control group: The control group will receive the standard treatment + placebo for both types of intervention medication at all times. If part or all the intervention therapy being investigated becomes standard treatment during the study, this may also be offered to the control group. Intervention group: The patients in the intervention group will also receive standard care. Immediately after randomisation to the intervention group, the patient will begin treatment with: Azithromycin: Day 1-3: 500 mg x 1 Day 4-15: 250 mg x 1 If the patient is unable to take the medication orally by themselves, the medication will, if possible, be administered by either stomach-feeding tube, or alternatively, temporary be changed to clarithromycin 500 mg x 2 (this only in agreement with either study coordinator Pradeesh Sivapalan or principal investigator Jens-Ulrik Stæhr Jensen). This will also be done in the control group if necessary. The patient will switch back to azithromycin when possible. Hydroxychloroquine: Furthermore, the patient will be treated with hydroxychloroquine as follows: Day 1-15: 200 mg x 2 MAIN OUTCOMES: • Number of days alive and discharged from hospital within 14 days (summarises both whether the patient is alive and discharged from hospital) ("Days alive and out of hospital") RANDOMISATION: The sponsor (Chronic Obstructive Pulmonary Disease Trial Network, COP:TRIN) generates a randomisation sequence. Randomisation will be in blocks of unknown size and the final allocation will be via an encrypted website (REDCap). There will be stratification for age (>70 years vs. <=70 years), site of recruitment and whether the patient has any of the following chronic lung diseases: COPD, asthma, bronchiectasis, interstitial lung disease (Yes vs. No).
BLINDING (MASKING)
Participants and study personnel will both be blinded, i.e. neither will know which group the participant is allocated to.
NUMBERS TO BE RANDOMISED (SAMPLE SIZE)
This study requires 226 patients randomised 1:1 with 113 in each group.
TRIAL STATUS
Protocol version 1.8, from April 16, 2020. Recruitment is ongoing (first patient recruited April 6, 2020; final patient expected to be recruited October 31, 2020).
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04322396 (registered March 26, 2020) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
DOI: 10.1186/s13063-020-04409-9
PubMed: 32522282
PubMed Central: PMC7284668
Links to Exploration step
pubmed:32522282Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Proactive Prophylaxis With Azithromycin and HydroxyChloroquine in Hospitalised Patients With COVID-19 (ProPAC-COVID): A structured summary of a study protocol for a randomised controlled trial.</title>
<author><name sortKey="Sivapalan, Pradeesh" sort="Sivapalan, Pradeesh" uniqKey="Sivapalan P" first="Pradeesh" last="Sivapalan">Pradeesh Sivapalan</name>
<affiliation><nlm:affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</nlm:affiliation>
</affiliation>
<affiliation><nlm:affiliation>Department of Internal Medicine, Zealand University Hospital, Roskilde, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Ulrik, Charlotte Suppli" sort="Ulrik, Charlotte Suppli" uniqKey="Ulrik C" first="Charlotte Suppli" last="Ulrik">Charlotte Suppli Ulrik</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Bojesen, Rasmus Dahlin" sort="Bojesen, Rasmus Dahlin" uniqKey="Bojesen R" first="Rasmus Dahlin" last="Bojesen">Rasmus Dahlin Bojesen</name>
<affiliation><nlm:affiliation>Department of Surgery, Næstved-Slagelse- Ringsted Hospitals University of Southern Denmark, Slagelse, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Lapperre, Therese Sophie" sort="Lapperre, Therese Sophie" uniqKey="Lapperre T" first="Therese Sophie" last="Lapperre">Therese Sophie Lapperre</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Bispebjerg and Frederiksberg Hospital University of Copenhagen, Copenhagen, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Eklof, Josefin Viktoria" sort="Eklof, Josefin Viktoria" uniqKey="Eklof J" first="Josefin Viktoria" last="Eklöf">Josefin Viktoria Eklöf</name>
<affiliation><nlm:affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="H Kansson, Kjell Erik Julius" sort="H Kansson, Kjell Erik Julius" uniqKey="H Kansson K" first="Kjell Erik Julius" last="H Kansson">Kjell Erik Julius H Kansson</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Browatzki, Andrea" sort="Browatzki, Andrea" uniqKey="Browatzki A" first="Andrea" last="Browatzki">Andrea Browatzki</name>
<affiliation><nlm:affiliation>Department of Respiratory and Infectious Diseases, Nordsjællands Hospital University of Copenhagen, Hillerød, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Tidemansen, Casper" sort="Tidemansen, Casper" uniqKey="Tidemansen C" first="Casper" last="Tidemansen">Casper Tidemansen</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Wilcke, Jon Torgny" sort="Wilcke, Jon Torgny" uniqKey="Wilcke J" first="Jon Torgny" last="Wilcke">Jon Torgny Wilcke</name>
<affiliation><nlm:affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Janner, Julie" sort="Janner, Julie" uniqKey="Janner J" first="Julie" last="Janner">Julie Janner</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Gottlieb, Vibeke" sort="Gottlieb, Vibeke" uniqKey="Gottlieb V" first="Vibeke" last="Gottlieb">Vibeke Gottlieb</name>
<affiliation><nlm:affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Meteran, Howraman" sort="Meteran, Howraman" uniqKey="Meteran H" first="Howraman" last="Meteran">Howraman Meteran</name>
<affiliation><nlm:affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Porsbjerg, Celeste" sort="Porsbjerg, Celeste" uniqKey="Porsbjerg C" first="Celeste" last="Porsbjerg">Celeste Porsbjerg</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Bispebjerg and Frederiksberg Hospital University of Copenhagen, Copenhagen, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Madsen, Birgitte Lindegaard" sort="Madsen, Birgitte Lindegaard" uniqKey="Madsen B" first="Birgitte Lindegaard" last="Madsen">Birgitte Lindegaard Madsen</name>
<affiliation><nlm:affiliation>Department of Respiratory and Infectious Diseases, Nordsjællands Hospital University of Copenhagen, Hillerød, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Moberg, Mia" sort="Moberg, Mia" uniqKey="Moberg M" first="Mia" last="Moberg">Mia Moberg</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Pedersen, Lars" sort="Pedersen, Lars" uniqKey="Pedersen L" first="Lars" last="Pedersen">Lars Pedersen</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Bispebjerg and Frederiksberg Hospital University of Copenhagen, Copenhagen, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Benfield, Thomas Lars" sort="Benfield, Thomas Lars" uniqKey="Benfield T" first="Thomas Lars" last="Benfield">Thomas Lars Benfield</name>
<affiliation><nlm:affiliation>Dep. of Infectious Diseases, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Lundgren, Jens Dilling" sort="Lundgren, Jens Dilling" uniqKey="Lundgren J" first="Jens Dilling" last="Lundgren">Jens Dilling Lundgren</name>
<affiliation><nlm:affiliation>Department of Infectious Diseases, Rigshospitalet University of Copenhagen, Copenhagen, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Knop, Filip Krag" sort="Knop, Filip Krag" uniqKey="Knop F" first="Filip Krag" last="Knop">Filip Krag Knop</name>
<affiliation><nlm:affiliation>Department of Clinical Metabolic Research, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Biering S Rensen, Tor" sort="Biering S Rensen, Tor" uniqKey="Biering S Rensen T" first="Tor" last="Biering-S Rensen">Tor Biering-S Rensen</name>
<affiliation><nlm:affiliation>Department of Cardiology, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Ghanizada, Muzhda" sort="Ghanizada, Muzhda" uniqKey="Ghanizada M" first="Muzhda" last="Ghanizada">Muzhda Ghanizada</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Bispebjerg and Frederiksberg Hospital University of Copenhagen, Copenhagen, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Sonne, Tine Peick" sort="Sonne, Tine Peick" uniqKey="Sonne T" first="Tine Peick" last="Sonne">Tine Peick Sonne</name>
<affiliation><nlm:affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="B Dtger, Uffe Christian Steinholtz" sort="B Dtger, Uffe Christian Steinholtz" uniqKey="B Dtger U" first="Uffe Christian Steinholtz" last="B Dtger">Uffe Christian Steinholtz B Dtger</name>
<affiliation><nlm:affiliation>Department of Internal Medicine, Zealand University Hospital, Roskilde, Denmark.</nlm:affiliation>
</affiliation>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Næstved-Slagelse-Ringsted Hospitals University of Southern Denmark, Slagelse, Denmark.</nlm:affiliation>
</affiliation>
<affiliation><nlm:affiliation>Institute for Regional Health Research University of Southern Denmark, Odense, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Jensen, Sidse Graff" sort="Jensen, Sidse Graff" uniqKey="Jensen S" first="Sidse Graff" last="Jensen">Sidse Graff Jensen</name>
<affiliation><nlm:affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Rasmussen, Daniel Bech" sort="Rasmussen, Daniel Bech" uniqKey="Rasmussen D" first="Daniel Bech" last="Rasmussen">Daniel Bech Rasmussen</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Næstved-Slagelse-Ringsted Hospitals University of Southern Denmark, Slagelse, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Br Ndum, Eva" sort="Br Ndum, Eva" uniqKey="Br Ndum E" first="Eva" last="Br Ndum">Eva Br Ndum</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Tupper, Oliver Djurhuus" sort="Tupper, Oliver Djurhuus" uniqKey="Tupper O" first="Oliver Djurhuus" last="Tupper">Oliver Djurhuus Tupper</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="S Rensen, Susanne Wiemann" sort="S Rensen, Susanne Wiemann" uniqKey="S Rensen S" first="Susanne Wiemann" last="S Rensen">Susanne Wiemann S Rensen</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Alstrup, Gitte" sort="Alstrup, Gitte" uniqKey="Alstrup G" first="Gitte" last="Alstrup">Gitte Alstrup</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Næstved-Slagelse-Ringsted Hospitals University of Southern Denmark, Slagelse, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Laursen, Christian Borbjerg" sort="Laursen, Christian Borbjerg" uniqKey="Laursen C" first="Christian Borbjerg" last="Laursen">Christian Borbjerg Laursen</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Odense University Hospital University of Southern Denmark, Odense, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="M Ller, Ulla Weinrich" sort="M Ller, Ulla Weinrich" uniqKey="M Ller U" first="Ulla Weinrich" last="M Ller">Ulla Weinrich M Ller</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Aalborg University Hospital University of Aalborg, Aalborg, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Sverrild, Asger" sort="Sverrild, Asger" uniqKey="Sverrild A" first="Asger" last="Sverrild">Asger Sverrild</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Bispebjerg and Frederiksberg Hospital University of Copenhagen, Copenhagen, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Jensen, Jens Ulrik St Hr" sort="Jensen, Jens Ulrik St Hr" uniqKey="Jensen J" first="Jens-Ulrik St Hr" last="Jensen">Jens-Ulrik St Hr Jensen</name>
<affiliation><nlm:affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark. jens.ulrik.jensen@regionh.dk.</nlm:affiliation>
</affiliation>
</author>
</titleStmt>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Proactive Prophylaxis With Azithromycin and HydroxyChloroquine in Hospitalised Patients With COVID-19 (ProPAC-COVID): A structured summary of a study protocol for a randomised controlled trial.</title>
<author><name sortKey="Sivapalan, Pradeesh" sort="Sivapalan, Pradeesh" uniqKey="Sivapalan P" first="Pradeesh" last="Sivapalan">Pradeesh Sivapalan</name>
<affiliation><nlm:affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</nlm:affiliation>
</affiliation>
<affiliation><nlm:affiliation>Department of Internal Medicine, Zealand University Hospital, Roskilde, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Ulrik, Charlotte Suppli" sort="Ulrik, Charlotte Suppli" uniqKey="Ulrik C" first="Charlotte Suppli" last="Ulrik">Charlotte Suppli Ulrik</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Bojesen, Rasmus Dahlin" sort="Bojesen, Rasmus Dahlin" uniqKey="Bojesen R" first="Rasmus Dahlin" last="Bojesen">Rasmus Dahlin Bojesen</name>
<affiliation><nlm:affiliation>Department of Surgery, Næstved-Slagelse- Ringsted Hospitals University of Southern Denmark, Slagelse, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Lapperre, Therese Sophie" sort="Lapperre, Therese Sophie" uniqKey="Lapperre T" first="Therese Sophie" last="Lapperre">Therese Sophie Lapperre</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Bispebjerg and Frederiksberg Hospital University of Copenhagen, Copenhagen, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Eklof, Josefin Viktoria" sort="Eklof, Josefin Viktoria" uniqKey="Eklof J" first="Josefin Viktoria" last="Eklöf">Josefin Viktoria Eklöf</name>
<affiliation><nlm:affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="H Kansson, Kjell Erik Julius" sort="H Kansson, Kjell Erik Julius" uniqKey="H Kansson K" first="Kjell Erik Julius" last="H Kansson">Kjell Erik Julius H Kansson</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Browatzki, Andrea" sort="Browatzki, Andrea" uniqKey="Browatzki A" first="Andrea" last="Browatzki">Andrea Browatzki</name>
<affiliation><nlm:affiliation>Department of Respiratory and Infectious Diseases, Nordsjællands Hospital University of Copenhagen, Hillerød, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Tidemansen, Casper" sort="Tidemansen, Casper" uniqKey="Tidemansen C" first="Casper" last="Tidemansen">Casper Tidemansen</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Wilcke, Jon Torgny" sort="Wilcke, Jon Torgny" uniqKey="Wilcke J" first="Jon Torgny" last="Wilcke">Jon Torgny Wilcke</name>
<affiliation><nlm:affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Janner, Julie" sort="Janner, Julie" uniqKey="Janner J" first="Julie" last="Janner">Julie Janner</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Gottlieb, Vibeke" sort="Gottlieb, Vibeke" uniqKey="Gottlieb V" first="Vibeke" last="Gottlieb">Vibeke Gottlieb</name>
<affiliation><nlm:affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Meteran, Howraman" sort="Meteran, Howraman" uniqKey="Meteran H" first="Howraman" last="Meteran">Howraman Meteran</name>
<affiliation><nlm:affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Porsbjerg, Celeste" sort="Porsbjerg, Celeste" uniqKey="Porsbjerg C" first="Celeste" last="Porsbjerg">Celeste Porsbjerg</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Bispebjerg and Frederiksberg Hospital University of Copenhagen, Copenhagen, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Madsen, Birgitte Lindegaard" sort="Madsen, Birgitte Lindegaard" uniqKey="Madsen B" first="Birgitte Lindegaard" last="Madsen">Birgitte Lindegaard Madsen</name>
<affiliation><nlm:affiliation>Department of Respiratory and Infectious Diseases, Nordsjællands Hospital University of Copenhagen, Hillerød, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Moberg, Mia" sort="Moberg, Mia" uniqKey="Moberg M" first="Mia" last="Moberg">Mia Moberg</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Pedersen, Lars" sort="Pedersen, Lars" uniqKey="Pedersen L" first="Lars" last="Pedersen">Lars Pedersen</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Bispebjerg and Frederiksberg Hospital University of Copenhagen, Copenhagen, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Benfield, Thomas Lars" sort="Benfield, Thomas Lars" uniqKey="Benfield T" first="Thomas Lars" last="Benfield">Thomas Lars Benfield</name>
<affiliation><nlm:affiliation>Dep. of Infectious Diseases, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Lundgren, Jens Dilling" sort="Lundgren, Jens Dilling" uniqKey="Lundgren J" first="Jens Dilling" last="Lundgren">Jens Dilling Lundgren</name>
<affiliation><nlm:affiliation>Department of Infectious Diseases, Rigshospitalet University of Copenhagen, Copenhagen, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Knop, Filip Krag" sort="Knop, Filip Krag" uniqKey="Knop F" first="Filip Krag" last="Knop">Filip Krag Knop</name>
<affiliation><nlm:affiliation>Department of Clinical Metabolic Research, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Biering S Rensen, Tor" sort="Biering S Rensen, Tor" uniqKey="Biering S Rensen T" first="Tor" last="Biering-S Rensen">Tor Biering-S Rensen</name>
<affiliation><nlm:affiliation>Department of Cardiology, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Ghanizada, Muzhda" sort="Ghanizada, Muzhda" uniqKey="Ghanizada M" first="Muzhda" last="Ghanizada">Muzhda Ghanizada</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Bispebjerg and Frederiksberg Hospital University of Copenhagen, Copenhagen, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Sonne, Tine Peick" sort="Sonne, Tine Peick" uniqKey="Sonne T" first="Tine Peick" last="Sonne">Tine Peick Sonne</name>
<affiliation><nlm:affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="B Dtger, Uffe Christian Steinholtz" sort="B Dtger, Uffe Christian Steinholtz" uniqKey="B Dtger U" first="Uffe Christian Steinholtz" last="B Dtger">Uffe Christian Steinholtz B Dtger</name>
<affiliation><nlm:affiliation>Department of Internal Medicine, Zealand University Hospital, Roskilde, Denmark.</nlm:affiliation>
</affiliation>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Næstved-Slagelse-Ringsted Hospitals University of Southern Denmark, Slagelse, Denmark.</nlm:affiliation>
</affiliation>
<affiliation><nlm:affiliation>Institute for Regional Health Research University of Southern Denmark, Odense, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Jensen, Sidse Graff" sort="Jensen, Sidse Graff" uniqKey="Jensen S" first="Sidse Graff" last="Jensen">Sidse Graff Jensen</name>
<affiliation><nlm:affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Rasmussen, Daniel Bech" sort="Rasmussen, Daniel Bech" uniqKey="Rasmussen D" first="Daniel Bech" last="Rasmussen">Daniel Bech Rasmussen</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Næstved-Slagelse-Ringsted Hospitals University of Southern Denmark, Slagelse, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Br Ndum, Eva" sort="Br Ndum, Eva" uniqKey="Br Ndum E" first="Eva" last="Br Ndum">Eva Br Ndum</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Tupper, Oliver Djurhuus" sort="Tupper, Oliver Djurhuus" uniqKey="Tupper O" first="Oliver Djurhuus" last="Tupper">Oliver Djurhuus Tupper</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="S Rensen, Susanne Wiemann" sort="S Rensen, Susanne Wiemann" uniqKey="S Rensen S" first="Susanne Wiemann" last="S Rensen">Susanne Wiemann S Rensen</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Alstrup, Gitte" sort="Alstrup, Gitte" uniqKey="Alstrup G" first="Gitte" last="Alstrup">Gitte Alstrup</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Næstved-Slagelse-Ringsted Hospitals University of Southern Denmark, Slagelse, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Laursen, Christian Borbjerg" sort="Laursen, Christian Borbjerg" uniqKey="Laursen C" first="Christian Borbjerg" last="Laursen">Christian Borbjerg Laursen</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Odense University Hospital University of Southern Denmark, Odense, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="M Ller, Ulla Weinrich" sort="M Ller, Ulla Weinrich" uniqKey="M Ller U" first="Ulla Weinrich" last="M Ller">Ulla Weinrich M Ller</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Aalborg University Hospital University of Aalborg, Aalborg, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Sverrild, Asger" sort="Sverrild, Asger" uniqKey="Sverrild A" first="Asger" last="Sverrild">Asger Sverrild</name>
<affiliation><nlm:affiliation>Department of Respiratory Medicine, Bispebjerg and Frederiksberg Hospital University of Copenhagen, Copenhagen, Denmark.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Jensen, Jens Ulrik St Hr" sort="Jensen, Jens Ulrik St Hr" uniqKey="Jensen J" first="Jens-Ulrik St Hr" last="Jensen">Jens-Ulrik St Hr Jensen</name>
<affiliation><nlm:affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark. jens.ulrik.jensen@regionh.dk.</nlm:affiliation>
</affiliation>
</author>
</analytic>
<series><title level="j">Trials</title>
<idno type="eISSN">1745-6215</idno>
<imprint><date when="2020" type="published">2020</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral Agents (administration & dosage)</term>
<term>Antiviral Agents (adverse effects)</term>
<term>Azithromycin (administration & dosage)</term>
<term>Azithromycin (adverse effects)</term>
<term>Betacoronavirus (drug effects)</term>
<term>Betacoronavirus (pathogenicity)</term>
<term>COVID-19 (MeSH)</term>
<term>Coronavirus Infections (diagnosis)</term>
<term>Coronavirus Infections (drug therapy)</term>
<term>Coronavirus Infections (mortality)</term>
<term>Coronavirus Infections (virology)</term>
<term>Critical Care (MeSH)</term>
<term>Denmark (MeSH)</term>
<term>Double-Blind Method (MeSH)</term>
<term>Drug Administration Schedule (MeSH)</term>
<term>Hospital Mortality (MeSH)</term>
<term>Host-Pathogen Interactions (MeSH)</term>
<term>Humans (MeSH)</term>
<term>Hydroxychloroquine (administration & dosage)</term>
<term>Hydroxychloroquine (adverse effects)</term>
<term>Inpatients (MeSH)</term>
<term>Length of Stay (MeSH)</term>
<term>Multicenter Studies as Topic (MeSH)</term>
<term>Noninvasive Ventilation (MeSH)</term>
<term>Pandemics (MeSH)</term>
<term>Patient Admission (MeSH)</term>
<term>Pneumonia, Viral (diagnosis)</term>
<term>Pneumonia, Viral (drug therapy)</term>
<term>Pneumonia, Viral (mortality)</term>
<term>Pneumonia, Viral (virology)</term>
<term>Randomized Controlled Trials as Topic (MeSH)</term>
<term>SARS-CoV-2 (MeSH)</term>
<term>Severity of Illness Index (MeSH)</term>
<term>Time Factors (MeSH)</term>
<term>Treatment Outcome (MeSH)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en"><term>Antiviral Agents</term>
<term>Azithromycin</term>
<term>Hydroxychloroquine</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="adverse effects" xml:lang="en"><term>Antiviral Agents</term>
<term>Azithromycin</term>
<term>Hydroxychloroquine</term>
</keywords>
<keywords scheme="MESH" type="geographic" xml:lang="en"><term>Denmark</term>
</keywords>
<keywords scheme="MESH" qualifier="diagnosis" xml:lang="en"><term>Coronavirus Infections</term>
<term>Pneumonia, Viral</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Betacoronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Coronavirus Infections</term>
<term>Pneumonia, Viral</term>
</keywords>
<keywords scheme="MESH" qualifier="mortality" xml:lang="en"><term>Coronavirus Infections</term>
<term>Pneumonia, Viral</term>
</keywords>
<keywords scheme="MESH" qualifier="pathogenicity" xml:lang="en"><term>Betacoronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Coronavirus Infections</term>
<term>Pneumonia, Viral</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>COVID-19</term>
<term>Critical Care</term>
<term>Double-Blind Method</term>
<term>Drug Administration Schedule</term>
<term>Hospital Mortality</term>
<term>Host-Pathogen Interactions</term>
<term>Humans</term>
<term>Inpatients</term>
<term>Length of Stay</term>
<term>Multicenter Studies as Topic</term>
<term>Noninvasive Ventilation</term>
<term>Pandemics</term>
<term>Patient Admission</term>
<term>Randomized Controlled Trials as Topic</term>
<term>SARS-CoV-2</term>
<term>Severity of Illness Index</term>
<term>Time Factors</term>
<term>Treatment Outcome</term>
</keywords>
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<front><div type="abstract" xml:lang="en"><p><b>OBJECTIVES</b>
</p>
<p>The aim of this randomised GCP-controlled trial is to clarify whether combination therapy with the antibiotic azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, antiviral efficacy and pre-emptive treatment of supra-infections can shorten hospitalisation duration for patients with COVID-19 (measured as "days alive and out of hospital" as the primary outcome), reduce the risk of non- invasive ventilation, treatment in the intensive care unit and death.</p>
</div>
<div type="abstract" xml:lang="en"><p><b>TRIAL DESIGN</b>
</p>
<p>This is a multi-centre, randomised, Placebo-controlled, 2-arm ratio 1:1, parallel group double-blind study.</p>
</div>
<div type="abstract" xml:lang="en"><p><b>PARTICIPANTS</b>
</p>
<p>226 participants are recruited at the trial sites/hospitals, where the study will take place in Denmark: Aalborg, Bispebjerg, Gentofte, Herlev, Hillerød, Hvidovre, Odense and Slagelse hospitals.</p>
</div>
<div type="abstract" xml:lang="en"><p><b>INCLUSION CRITERIA</b>
</p>
<p>• Patient admitted to Danish emergency departments, respiratory medicine departments or internal medicine departments • Age≥ 18 years • Hospitalized ≤48 hours • Positive COVID-19 test / diagnosis during the hospitalization (confirmed). • Men or non-fertile women. Fertile women* must not be pregnant, i.e. negative pregnancy test must be available at inclusion • Informed consent signed by the patient *Defined as after menarche and until postmenopausal (no menstruation for 12 months) Exclusion criteria: • At the time of recruitment, the patient uses >5 LO2/min (equivalent to 40% FiO2 if measured) • Known intolerance/allergy to azithromycin or hydroxychloroquine or hypersensitivity to quinine or 4-aminoquinoline derivatives • Neurogenic hearing loss • Psoriasis • Retinopathy • Maculopathy • Visual field changes • Breastfeeding • Severe liver diseases other than amoebiasis (INR> 1.5 spontaneously) • Severe gastrointestinal, neurological and hematological disorders (investigator-assessed) • eGFR <45 ml/min/1.73 m2 • Clinically significant cardiac conduction disorders/arrhythmias or prolonged QTc interval (QTc (f) of> 480/470 ms). • Myasthenia gravis • Treatment with digoxin* • Glucose-6-phosphate dehydrogenase deficiency • Porphyria • Hypoglycaemia (Blood glucose at any time since hospitalization of <3.0 mmol/L) • Severe mental illness which significantly impedes cooperation • Severe linguistic problems that significantly hinder cooperation • Treatment with ergot alkaloids *The patient must not be treated with digoxin for the duration of the intervention. For atrial fibrillation/flutter, select according to the Cardiovascular National Treatment Guide (NBV): Calcium antagonist, Beta blocker, direct current (DC) conversion or amiodarone. In case of urgent need for digoxin treatment (contraindication for the aforementioned equal alternatives), the test drug should be paused, and ECG should be taken daily.</p>
</div>
<div type="abstract" xml:lang="en"><p><b>INTERVENTION AND COMPARATOR</b>
</p>
<p>Control group: The control group will receive the standard treatment + placebo for both types of intervention medication at all times. If part or all the intervention therapy being investigated becomes standard treatment during the study, this may also be offered to the control group. Intervention group: The patients in the intervention group will also receive standard care. Immediately after randomisation to the intervention group, the patient will begin treatment with: Azithromycin: Day 1-3: 500 mg x 1 Day 4-15: 250 mg x 1 If the patient is unable to take the medication orally by themselves, the medication will, if possible, be administered by either stomach-feeding tube, or alternatively, temporary be changed to clarithromycin 500 mg x 2 (this only in agreement with either study coordinator Pradeesh Sivapalan or principal investigator Jens-Ulrik Stæhr Jensen). This will also be done in the control group if necessary. The patient will switch back to azithromycin when possible. Hydroxychloroquine: Furthermore, the patient will be treated with hydroxychloroquine as follows: Day 1-15: 200 mg x 2 MAIN OUTCOMES: • Number of days alive and discharged from hospital within 14 days (summarises both whether the patient is alive and discharged from hospital) ("Days alive and out of hospital") RANDOMISATION: The sponsor (Chronic Obstructive Pulmonary Disease Trial Network, COP:TRIN) generates a randomisation sequence. Randomisation will be in blocks of unknown size and the final allocation will be via an encrypted website (REDCap). There will be stratification for age (>70 years vs. <=70 years), site of recruitment and whether the patient has any of the following chronic lung diseases: COPD, asthma, bronchiectasis, interstitial lung disease (Yes vs. No).</p>
</div>
<div type="abstract" xml:lang="en"><p><b>BLINDING (MASKING)</b>
</p>
<p>Participants and study personnel will both be blinded, i.e. neither will know which group the participant is allocated to.</p>
</div>
<div type="abstract" xml:lang="en"><p><b>NUMBERS TO BE RANDOMISED (SAMPLE SIZE)</b>
</p>
<p>This study requires 226 patients randomised 1:1 with 113 in each group.</p>
</div>
<div type="abstract" xml:lang="en"><p><b>TRIAL STATUS</b>
</p>
<p>Protocol version 1.8, from April 16, 2020. Recruitment is ongoing (first patient recruited April 6, 2020; final patient expected to be recruited October 31, 2020).</p>
</div>
<div type="abstract" xml:lang="en"><p><b>TRIAL REGISTRATION</b>
</p>
<p>ClinicalTrials.gov Identifier: NCT04322396 (registered March 26, 2020) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).</p>
</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">32522282</PMID>
<DateCompleted><Year>2020</Year>
<Month>06</Month>
<Day>17</Day>
</DateCompleted>
<DateRevised><Year>2020</Year>
<Month>12</Month>
<Day>10</Day>
</DateRevised>
<Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">1745-6215</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>21</Volume>
<Issue>1</Issue>
<PubDate><Year>2020</Year>
<Month>Jun</Month>
<Day>10</Day>
</PubDate>
</JournalIssue>
<Title>Trials</Title>
<ISOAbbreviation>Trials</ISOAbbreviation>
</Journal>
<ArticleTitle>Proactive Prophylaxis With Azithromycin and HydroxyChloroquine in Hospitalised Patients With COVID-19 (ProPAC-COVID): A structured summary of a study protocol for a randomised controlled trial.</ArticleTitle>
<Pagination><MedlinePgn>513</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1186/s13063-020-04409-9</ELocationID>
<Abstract><AbstractText Label="OBJECTIVES" NlmCategory="OBJECTIVE">The aim of this randomised GCP-controlled trial is to clarify whether combination therapy with the antibiotic azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, antiviral efficacy and pre-emptive treatment of supra-infections can shorten hospitalisation duration for patients with COVID-19 (measured as "days alive and out of hospital" as the primary outcome), reduce the risk of non- invasive ventilation, treatment in the intensive care unit and death.</AbstractText>
<AbstractText Label="TRIAL DESIGN" NlmCategory="METHODS">This is a multi-centre, randomised, Placebo-controlled, 2-arm ratio 1:1, parallel group double-blind study.</AbstractText>
<AbstractText Label="PARTICIPANTS" NlmCategory="METHODS">226 participants are recruited at the trial sites/hospitals, where the study will take place in Denmark: Aalborg, Bispebjerg, Gentofte, Herlev, Hillerød, Hvidovre, Odense and Slagelse hospitals.</AbstractText>
<AbstractText Label="INCLUSION CRITERIA" NlmCategory="METHODS">• Patient admitted to Danish emergency departments, respiratory medicine departments or internal medicine departments • Age≥ 18 years • Hospitalized ≤48 hours • Positive COVID-19 test / diagnosis during the hospitalization (confirmed). • Men or non-fertile women. Fertile women* must not be pregnant, i.e. negative pregnancy test must be available at inclusion • Informed consent signed by the patient *Defined as after menarche and until postmenopausal (no menstruation for 12 months) Exclusion criteria: • At the time of recruitment, the patient uses >5 LO2/min (equivalent to 40% FiO2 if measured) • Known intolerance/allergy to azithromycin or hydroxychloroquine or hypersensitivity to quinine or 4-aminoquinoline derivatives • Neurogenic hearing loss • Psoriasis • Retinopathy • Maculopathy • Visual field changes • Breastfeeding • Severe liver diseases other than amoebiasis (INR> 1.5 spontaneously) • Severe gastrointestinal, neurological and hematological disorders (investigator-assessed) • eGFR <45 ml/min/1.73 m2 • Clinically significant cardiac conduction disorders/arrhythmias or prolonged QTc interval (QTc (f) of> 480/470 ms). • Myasthenia gravis • Treatment with digoxin* • Glucose-6-phosphate dehydrogenase deficiency • Porphyria • Hypoglycaemia (Blood glucose at any time since hospitalization of <3.0 mmol/L) • Severe mental illness which significantly impedes cooperation • Severe linguistic problems that significantly hinder cooperation • Treatment with ergot alkaloids *The patient must not be treated with digoxin for the duration of the intervention. For atrial fibrillation/flutter, select according to the Cardiovascular National Treatment Guide (NBV): Calcium antagonist, Beta blocker, direct current (DC) conversion or amiodarone. In case of urgent need for digoxin treatment (contraindication for the aforementioned equal alternatives), the test drug should be paused, and ECG should be taken daily.</AbstractText>
<AbstractText Label="INTERVENTION AND COMPARATOR" NlmCategory="UNASSIGNED">Control group: The control group will receive the standard treatment + placebo for both types of intervention medication at all times. If part or all the intervention therapy being investigated becomes standard treatment during the study, this may also be offered to the control group. Intervention group: The patients in the intervention group will also receive standard care. Immediately after randomisation to the intervention group, the patient will begin treatment with: Azithromycin: Day 1-3: 500 mg x 1 Day 4-15: 250 mg x 1 If the patient is unable to take the medication orally by themselves, the medication will, if possible, be administered by either stomach-feeding tube, or alternatively, temporary be changed to clarithromycin 500 mg x 2 (this only in agreement with either study coordinator Pradeesh Sivapalan or principal investigator Jens-Ulrik Stæhr Jensen). This will also be done in the control group if necessary. The patient will switch back to azithromycin when possible. Hydroxychloroquine: Furthermore, the patient will be treated with hydroxychloroquine as follows: Day 1-15: 200 mg x 2 MAIN OUTCOMES: • Number of days alive and discharged from hospital within 14 days (summarises both whether the patient is alive and discharged from hospital) ("Days alive and out of hospital") RANDOMISATION: The sponsor (Chronic Obstructive Pulmonary Disease Trial Network, COP:TRIN) generates a randomisation sequence. Randomisation will be in blocks of unknown size and the final allocation will be via an encrypted website (REDCap). There will be stratification for age (>70 years vs. <=70 years), site of recruitment and whether the patient has any of the following chronic lung diseases: COPD, asthma, bronchiectasis, interstitial lung disease (Yes vs. No).</AbstractText>
<AbstractText Label="BLINDING (MASKING)" NlmCategory="UNASSIGNED">Participants and study personnel will both be blinded, i.e. neither will know which group the participant is allocated to.</AbstractText>
<AbstractText Label="NUMBERS TO BE RANDOMISED (SAMPLE SIZE)" NlmCategory="UNASSIGNED">This study requires 226 patients randomised 1:1 with 113 in each group.</AbstractText>
<AbstractText Label="TRIAL STATUS" NlmCategory="UNASSIGNED">Protocol version 1.8, from April 16, 2020. Recruitment is ongoing (first patient recruited April 6, 2020; final patient expected to be recruited October 31, 2020).</AbstractText>
<AbstractText Label="TRIAL REGISTRATION" NlmCategory="BACKGROUND">ClinicalTrials.gov Identifier: NCT04322396 (registered March 26, 2020) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).</AbstractText>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Sivapalan</LastName>
<ForeName>Pradeesh</ForeName>
<Initials>P</Initials>
<AffiliationInfo><Affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Internal Medicine, Zealand University Hospital, Roskilde, Denmark.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ulrik</LastName>
<ForeName>Charlotte Suppli</ForeName>
<Initials>CS</Initials>
<AffiliationInfo><Affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Bojesen</LastName>
<ForeName>Rasmus Dahlin</ForeName>
<Initials>RD</Initials>
<AffiliationInfo><Affiliation>Department of Surgery, Næstved-Slagelse- Ringsted Hospitals University of Southern Denmark, Slagelse, Denmark.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Lapperre</LastName>
<ForeName>Therese Sophie</ForeName>
<Initials>TS</Initials>
<AffiliationInfo><Affiliation>Department of Respiratory Medicine, Bispebjerg and Frederiksberg Hospital University of Copenhagen, Copenhagen, Denmark.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Eklöf</LastName>
<ForeName>Josefin Viktoria</ForeName>
<Initials>JV</Initials>
<AffiliationInfo><Affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Håkansson</LastName>
<ForeName>Kjell Erik Julius</ForeName>
<Initials>KEJ</Initials>
<AffiliationInfo><Affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Browatzki</LastName>
<ForeName>Andrea</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Department of Respiratory and Infectious Diseases, Nordsjællands Hospital University of Copenhagen, Hillerød, Denmark.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Tidemansen</LastName>
<ForeName>Casper</ForeName>
<Initials>C</Initials>
<AffiliationInfo><Affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Wilcke</LastName>
<ForeName>Jon Torgny</ForeName>
<Initials>JT</Initials>
<AffiliationInfo><Affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Janner</LastName>
<ForeName>Julie</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Gottlieb</LastName>
<ForeName>Vibeke</ForeName>
<Initials>V</Initials>
<AffiliationInfo><Affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Meteran</LastName>
<ForeName>Howraman</ForeName>
<Initials>H</Initials>
<AffiliationInfo><Affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Porsbjerg</LastName>
<ForeName>Celeste</ForeName>
<Initials>C</Initials>
<AffiliationInfo><Affiliation>Department of Respiratory Medicine, Bispebjerg and Frederiksberg Hospital University of Copenhagen, Copenhagen, Denmark.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Madsen</LastName>
<ForeName>Birgitte Lindegaard</ForeName>
<Initials>BL</Initials>
<AffiliationInfo><Affiliation>Department of Respiratory and Infectious Diseases, Nordsjællands Hospital University of Copenhagen, Hillerød, Denmark.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Moberg</LastName>
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<Author ValidYN="Y"><LastName>Pedersen</LastName>
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<AffiliationInfo><Affiliation>Department of Cardiology, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.</Affiliation>
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<AffiliationInfo><Affiliation>Department of Internal Medicine, Zealand University Hospital, Roskilde, Denmark.</Affiliation>
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<AffiliationInfo><Affiliation>Department of Respiratory Medicine, Næstved-Slagelse-Ringsted Hospitals University of Southern Denmark, Slagelse, Denmark.</Affiliation>
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<AffiliationInfo><Affiliation>Institute for Regional Health Research University of Southern Denmark, Odense, Denmark.</Affiliation>
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<Initials>DB</Initials>
<AffiliationInfo><Affiliation>Department of Respiratory Medicine, Næstved-Slagelse-Ringsted Hospitals University of Southern Denmark, Slagelse, Denmark.</Affiliation>
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<Author ValidYN="Y"><LastName>Brøndum</LastName>
<ForeName>Eva</ForeName>
<Initials>E</Initials>
<AffiliationInfo><Affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</Affiliation>
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<ForeName>Oliver Djurhuus</ForeName>
<Initials>OD</Initials>
<AffiliationInfo><Affiliation>Department of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, Denmark.</Affiliation>
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<ForeName>Gitte</ForeName>
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</Author>
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<ForeName>Christian Borbjerg</ForeName>
<Initials>CB</Initials>
<AffiliationInfo><Affiliation>Department of Respiratory Medicine, Odense University Hospital University of Southern Denmark, Odense, Denmark.</Affiliation>
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</Author>
<Author ValidYN="Y"><LastName>Møller</LastName>
<ForeName>Ulla Weinrich</ForeName>
<Initials>UW</Initials>
<AffiliationInfo><Affiliation>Department of Respiratory Medicine, Aalborg University Hospital University of Aalborg, Aalborg, Denmark.</Affiliation>
</AffiliationInfo>
</Author>
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<ForeName>Asger</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Department of Respiratory Medicine, Bispebjerg and Frederiksberg Hospital University of Copenhagen, Copenhagen, Denmark.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Jensen</LastName>
<ForeName>Jens-Ulrik Stæhr</ForeName>
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<AffiliationInfo><Affiliation>Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark. jens.ulrik.jensen@regionh.dk.</Affiliation>
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</AuthorList>
<Language>eng</Language>
<DataBankList CompleteYN="Y"><DataBank><DataBankName>ClinicalTrials.gov</DataBankName>
<AccessionNumberList><AccessionNumber>NCT04322396</AccessionNumber>
</AccessionNumberList>
</DataBank>
</DataBankList>
<GrantList CompleteYN="Y"><Grant><GrantID>NNF20SA0062834</GrantID>
<Agency>Novo Nordisk Fonden</Agency>
<Country></Country>
</Grant>
</GrantList>
<PublicationTypeList><PublicationType UI="D000078325">Clinical Trial Protocol</PublicationType>
<PublicationType UI="D016422">Letter</PublicationType>
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<ArticleDate DateType="Electronic"><Year>2020</Year>
<Month>06</Month>
<Day>10</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>England</Country>
<MedlineTA>Trials</MedlineTA>
<NlmUniqueID>101263253</NlmUniqueID>
<ISSNLinking>1745-6215</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000998">Antiviral Agents</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>4QWG6N8QKH</RegistryNumber>
<NameOfSubstance UI="D006886">Hydroxychloroquine</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>83905-01-5</RegistryNumber>
<NameOfSubstance UI="D017963">Azithromycin</NameOfSubstance>
</Chemical>
</ChemicalList>
<SupplMeshList><SupplMeshName Type="Protocol" UI="C000705127">COVID-19 drug treatment</SupplMeshName>
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<CitationSubset>IM</CitationSubset>
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<QualifierName UI="Q000009" MajorTopicYN="N">adverse effects</QualifierName>
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<QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName>
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<MeshHeading><DescriptorName UI="D015337" MajorTopicYN="N">Multicenter Studies as Topic</DescriptorName>
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<QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName>
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<MeshHeading><DescriptorName UI="D016032" MajorTopicYN="N">Randomized Controlled Trials as Topic</DescriptorName>
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<Keyword MajorTopicYN="N">azithromycin</Keyword>
<Keyword MajorTopicYN="N">hydroxychloroquine</Keyword>
<Keyword MajorTopicYN="N">protocol</Keyword>
<Keyword MajorTopicYN="N">respiratory infections</Keyword>
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<PubmedData><History><PubMedPubDate PubStatus="received"><Year>2020</Year>
<Month>05</Month>
<Day>07</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="accepted"><Year>2020</Year>
<Month>05</Month>
<Day>14</Day>
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<PubMedPubDate PubStatus="entrez"><Year>2020</Year>
<Month>6</Month>
<Day>12</Day>
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<PubMedPubDate PubStatus="medline"><Year>2020</Year>
<Month>6</Month>
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<Hour>6</Hour>
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<ArticleIdList><ArticleId IdType="pubmed">32522282</ArticleId>
<ArticleId IdType="doi">10.1186/s13063-020-04409-9</ArticleId>
<ArticleId IdType="pii">10.1186/s13063-020-04409-9</ArticleId>
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