Azithromycin and hydroxychloroquine in hospitalised patients with confirmed COVID-19-a randomised double-blinded placebo-controlled trial
MD, PhD Pradeesh Sivapalan, Charlotte Suppli Ulrik, MD Therese Sophie Lapperre, Dahlin Rasmus, Josefin Bojesen, Andrea Eklöf, Jon Torgny Browatzki, Vibeke Wilcke, Kjell Gottlieb, Julius Erik, Casper Håkansson, Oliver Tidemandsen, Howraman Tupper, Christina Marisa Meteran, Eva Bergsøe, Uffe Brøndum, Daniel Bech Bodtger, Sidse Graff Rasmussen, Lars Jensen, Alexander Pedersen, Helene Jordan, Christian Priemé, Ida Elisabeth Søborg, Dorthe Steffensen, Tobias Wirenfeldt Høgsberg, Martin Klausen, Peter Steen, Asger Lange, Muhzda Sverrild, Filip Krag Ghanizada, Tor Knop, Jens D Biering-Sørensen, Jens-Ulrik Staehr Lundgren, Jensen, MD, DMSc Charlotte Suppli Ulrik, PhD ; Rasmus, MD Dahlin Bojesen, PhD Josefin Eklöf, MD, PhD Andrea Browatzki, MD Jon Torgny Wilcke, PhD Vibeke Gottlieb, PhD Kjell Erik, MD Julius Håkansson, MD Casper Tidemandsen, MD Oliver Tupper, PhD Howraman Meteran, MD Christina Bergsøe, BSc Eva Brøndum, RN Uffe Bodtger, PhD ; Daniel, MD Bech Rasmussen, PhD ; Sidse, MD, PhD Graff Jensen, MD Lars Pedersen, PhD Alexander Jordan, BSc Helene Priemé, PhD Christian Søborg, MD, PhD Ida E Steffensen, PhD Dorthe Høgsberg, RN ; Tobias, MSc Wirenfeldt Klausen, PhD Martin Steen Frydland, PhD Peter Lange, MD, DMSc Asger Sverrild, MD, PhD; Muhzda Ghanizada, MD Filip Krag Knop, PhD Tor Biering-Sørensen, PhD, MPH Jens D Lundgren, MD, DMSc Jens-Ulrik Staehr Jensen, Senior Consultant, Research Associate Professor, MD, PhD. Jens-Ulrik Staehr Jensen, Suppli Ulrik, Andrea Bojesen, Howraman Djurhuus Tupper, Uffe Bergsøe, Steinholtz Christian, Daniel Bech Bødtger, Helene Pedersen, Steffensen, Sandbaek Dorthe, Martin Høgsberg, Peter Steen Frydland, Muzhda Sverrild, Jens-Ulrik Ghanizada, Staehr Jensen, Tobias Wirenfeldt Klausen, Jens D Lundgren, MD Andrea Browatzki Senior Consultant, Christian Laursen, Ulla Weinreich
doi:10.1183/13993003.00752-2021)
Azithromycin and hydroxychloroquine in hospitalised patients with confirmed COVID-19 -a randomised doubleblinded placebo-controlled trial by the ProPAC-COVID study group* *A complete list of members in the Proactive Protection with Azithromycin and hydroxy-Chloroquine in Hospitalised Patients With COVID-19 (ProPAC-COVID) Study Group is provided in Supplementary Appendix 3. The ProPAC-COVID study is an initiative by the independent research network COP:TRIN (www.coptrin.dk). The members of the writing group
For the secondary ordinary outcome, we will use a Wilcoxon rank sum test. The primary outcome uses an ordinal severity scale with 8 categories, analyzed using the proportional odds model. The key parameter of interest is the "common odds ratio," which quantifies the shift in the severity distribution resulting from treatment. For an efficacious treatment, an odds ratio greater than 1 quantifies an improvement in disease severity; a value of 2 indicates a bigger improvement than a value of 1.25.
Sample size The power to avoid type II error is 80% (1-β) at a two-sided 5% significance level, using a t-test for the primary outcome, and a group-sequential design allowing for one interim analysis at half target recruitment. This provides a sample size of 226 subjects. All confidence intervals reported will be 95% confidence intervals.
Analysis Software All analyses will be performed using SAS software version 9.4.
DATA ANALYSIS Descriptive analyses -Baseline characteristics at study enrollment (defined as day 1). The following baseline characteristics of the study population will be summarized separately within each randomized group:
Primary objective and outcome The primary outcome is "days alive and out of hospital (DAOH) within 14 days after recruitment" defined as the time from hospital discharge and days without hospitalization up to 14 days from recruitment where the patient is alive. Data for the primary outcome analysis will be presented as mean..
References
Albert, Connett, Bailey, Casaburi, Cooper et al., Azithromycin for prevention of exacerbations of COPD, N Engl J Med
Altenburg, De Graaff, Stienstra, Sloos, Van Haren et al., Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial, JAMA
Altenburg, De Graaff, Stienstra, Sloos, Van Haren et al., Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial, JAMA
Ariti, Cleland, Pocock, Pfeffer, Swedberg et al., Days alive and out of hospital and the patient journey in patients with heart failure: Insights from the candesartan in heart failure: assessment of reduction in mortality and morbidity (CHARM) program, Am Heart J
Bach, Conducted and reported
Beigel, Tomashek, Dodd, Mehta, Zingman et al., Remdesivir for the Treatment of Covid-19 -Final Report, N Engl J Med
Beigelman, Mikols, Gunsten, Cannon, Brody et al., Azithromycin attenuates airway inflammation in a mouse model of viral bronchiolitis, Respir Res
Borba, Val, Sampaio, Alexandre, Melo et al., Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial, JAMA Netw Open
Cantini, Goletti, Petrone, Fard, Niccoli et al., Immune Therapy, or Antiviral Therapy, or Both for COVID-19: A Systematic Review, Drugs
Casadevall, Dragotakes, Johnson, Senefeld, Klassen et al., Convalescent Plasma Use in the United States was inversely correlated with COVID-19 Mortality: Did Convalescent Plasma Hesitancy cost lives? medRxiv
Cavalcanti, Zampieri, Rosa, Azevedo, Veiga et al., Coalition Covid-19 Brazil II. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19, N Engl J Med
Chalmers, Boersma, Lonergan, Jayaram, Crichton et al., Long-term macrolide antibiotics for the treatment of bronchiectasis in adults: an individual participant data meta-analysis, Lancet Respir Med
Chalmers, Crichton, Goeminne, Cao, Humbert et al., Management of hospitalised adults with coronavirus disease 2019 (COVID-19): a European Respiratory Society living guideline
Colson, Rolain, Raoult, Chloroquine for the 2019 novel coronavirus SARS-CoV-2, Int J Antimicrob Agents
Dizziness, Corneal Oedema, Double Vision, Retinopathy, Cramps, Neuropathy, Palsy, Psychosis, Suicidal behaviour. Acute generalized exanthematous pustulosis***, Exfoliative dermatitis, Erythema multiforme, Photosensitivity, Stevens-Johnson syndrome, Toxic epidermal necrolysis. Allergic reactions (including DRESS syndrome), Angioedema. Hearing loss, Macular and retinal degeneration, Maculopathy
Fantini, Chahinian, Yahi, Synergistic antiviral effect of hydroxychloroquine and azithromycin in combination against SARS-CoV-2: What molecular dynamics studies of virus-host interactions reveal, Int J Antimicrob Agents
Fantini, Scala, Chahinian, Yahi, Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection, Int J Antimicrob Agents
Finfer, Bellomo, Why publish statistical analysis plans?, Crit Care Resusc
Freund, Cachanado, Delannoy, Laribi, Yordanov et al., Effect of an Emergency Department Care Bundle on 30-Day Hospital Discharge and Survival Among Elderly Patients With Acute Heart Failure: The ELISABETH Randomized Clinical Trial, JAMA
Gao, Tian, Yang, Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies, Biosci Trends
Gibson, Yang, Upham, Reynolds, Hodge et al., Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial, Lancet
Gielen, Johnston, Edwards, Azithromycin induces anti-viral responses in bronchial epithelial cells, Eur Respir J
Group, Horby, Lim, Emberson, Mafham et al., Dexamethasone in Hospitalized Patients with Covid-19, N Engl J Med
Group, Horby, Mafham, Linsell, Bell et al., Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19, N Engl J Med
Group, Lundgren, Grund, Barkauskas, Holland et al., A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19, N Engl J Med
Hiles, Mcdonald, Guilhermino, Brusselle, Gibson, Does maintenance azithromycin reduce asthma exacerbations? An individual participant data metaanalysis, Eur Respir J
Horby, Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial, Lancet
Kawamura, Ichikado, Takaki, Eguchi, Anan et al., Adjunctive therapy with azithromycin for moderate and severe acute respiratory distress syndrome: a retrospective, propensity score-matching analysis of prospectively collected data at a single center, Int J Antimicrob Agents
Kawamura, Ichikado, Takaki, Eguchi, Anan et al., Adjunctive therapy with azithromycin for moderate and severe acute respiratory distress syndrome: a retrospective, propensity score-matching analysis of prospectively collected data at a single center, Int J Antimicrob Agents
Lee, Silverman, Bargman, The role of antimalarial agents in the treatment of SLE and lupus nephritis, Nat Rev Nephrol
Lee, Silverman, Bargman, The role of antimalarial agents in the treatment of SLE and lupus nephritis, Nat Rev Nephrol
Li, Zu, Deng, Li, Parvatiyar et al., Azithromycin Protects against Zika virus Infection by Upregulating virus-induced Type I and III Interferon Responses, Antimicrob Agents Chemother
Medical, World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects, JAMA
Mehra, Desai, Ruschitzka, Patel, Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis, Lancet
Mercuro, Yen, Shim, Maher, Mccoy et al., Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus Disease 2019 (COVID-19), JAMA Cardiol
Nugroho, Suryantoro, Yuliasih, Rosyid, Asmarawati et al., Optimal use of tocilizumab for severe and critical COVID-19: a systematic review and meta-analysis
O'brien, Fleming, A multiple testing procedure for clinical trials, Biometrics
Pradeesh Sivapalan, Ph, Suppli Ulrik, Sc, Sophie Lapperre et al., Supplemental Appendix 3 -Online Content Proactive protection with azithromycin and hydroxychloroquine in hospitalised patients with COVID-19 (ProPAC-COVID): A randomised clinical trial Authors: The members of the writing group
Roden, Harrington, Poppas, Russo, Considerations for Drug Interactions on QTc in Exploratory COVID-19 Treatment, Circulation
Savarino, Boelaert, Cassone, Majori, Cauda, Effects of chloroquine on viral infections: an old drug against today's diseases?, Lancet Infect Dis
Savarino, Boelaert, Cassone, Majori, Cauda, Effects of chloroquine on viral infections: an old drug against today's diseases?, Lancet Infect Dis
Segal, Clemente, Wu, Wikoff, Gao et al., Randomised, double-blind, placebo-controlled trial with azithromycin selects for anti-inflammatory microbial metabolites in the emphysematous lung, Thorax
Self, Semler, Leither, Casey, Angus et al., Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial, JAMA
Sivapalan, Lapperre, Janner, Laub, Moberg et al., Eosinophil-guided corticosteroid therapy in patients admitted to hospital with COPD exacerbation (CORTICO-COP): a multicentre, randomised, controlled, open-label, non-inferiority trial, Lancet Respir Med
Sivapalan, Lapperre, Janner, Laub, Moberg et al., Eosinophil-guided corticosteroid therapy in patients admitted to hospital with COPD exacerbation (CORTICO-COP): a multicentre, randomised, controlled, open-label, non-inferiority trial, Lancet Respir Med
Sivapalan, Ulrik, Bojesen, Lapperre, Eklof et al., 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, Trials
Sivapalan, Ulrik, Lappere, Eklof, Shaker et al., Proactive prophylaxis with azithromycin and hydroxychloroquine in hospitalized patients with COVID-19 (ProPAC-COVID): a statistical analysis plan, Trials
Svorre, Bach, Med, Respiratory Research Unit, Section of
Uncommon ; Pain, Hepatitis, Oral candidiasis. Dyspnea, Pneumonia, Oedema. Eosinophilia, Leukopenia, Neutropenia. Elevated serum bicarbonate, Hyperchloremia, Hyperglycaemia, Hyperkalaemia, Hypernatremia, Hypokalaemia, Hyponatraemia. Arthritis, Back Pain. Nervousness, Somnolence. Facial oedema, Dermatitis, Photosensitivity. Candidiasis, Infections. Metrorrhagia, Kidney Pain, Testicular
Vincent, Bergeron, Benjannet, Erickson, Rollin et al., Chloroquine is a potent inhibitor of SARS coronavirus infection and spread, Virol J
Vincent, Bergeron, Benjannet, Erickson, Rollin et al., Chloroquine is a potent inhibitor of SARS coronavirus infection and spread, Virol J
Walters, Tan, White, Gibson, Wood-Baker et al., Systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease, Cochrane Database Syst Rev
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'abstract': '<jats:sec><jats:title>Background</jats:title><jats:p>Combining the antibiotic azithromycin '
'and hydroxychloroquine induces airway immunomodulatory effects, with the latter also having '
'<jats:italic>in vitro</jats:italic> antiviral properties. This may improve outcomes in '
'patients hospitalised for coronavirus disease 2019 '
'(COVID-19).</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Placebo-controlled '
'double-blind randomised multicentre trial. Patients aged ≥18\u2005years, admitted to hospital '
'for ≤48\u2005h (not intensive care) with a positive severe acute respiratory syndrome '
'coronavirus 2 (SARS-CoV-2) reverse transcription PCR test were recruited. The intervention '
'was 500\u2005mg daily azithromycin for 3\u2005days followed by 250\u2005mg daily azithromycin '
'for 12\u2005days combined with 200\u2005mg twice-daily hydroxychloroquine for all 15\u2005'
'days. The control group received placebo/placebo. The primary outcome was days alive and '
'discharged from hospital within 14\u2005days '
'(DAOH14).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>After '
'randomisation of 117 patients, at the first planned interim analysis, the data and safety '
'monitoring board recommended stopping enrolment due to futility, based on pre-specified '
'criteria. Consequently, the trial was terminated on 1 February 2021. 61 patients received the '
'combined intervention and 56 patients received placebo. In the intervention group, patients '
'had a median (interquartile range) 9.0 (3–11) DAOH14 <jats:italic>versus</jats:italic> 9.0 '
'(7–10) DAOH14 in the placebo group (p=0.90). The primary safety outcome, death from all '
'causes on day 30, occurred for one patient in the intervention group '
'<jats:italic>versus</jats:italic> two patients receiving placebo (p=0.52), and readmittance '
'or death within 30\u2005days occurred for nine patients in the intervention group '
'<jats:italic>versus</jats:italic> six patients receiving placebo '
'(p=0.57).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>The '
'combination of azithromycin and hydroxychloroquine did not improve survival or length of '
'hospitalisation in patients with COVID-19.</jats:p></jats:sec>',
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'DOI': '10.1038/nrneph.2011.150'},
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'DOI': '10.1001/jama.2013.1937'},
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'first-page': '918',
'DOI': '10.1016/j.ijantimicag.2018.02.009',
'article-title': 'Adjunctive therapy with azithromycin for moderate and severe acute '
'respiratory distress syndrome: a retrospective, propensity '
'score-matching analysis of prospectively collected data at a single '
'center',
'volume': '51',
'author': 'Kawamura',
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'journal-title': 'Int J Antimicrob Agents'},
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'adults: an individual participant data meta-analysis',
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'combination against SARS-CoV-2: what molecular dynamics studies of '
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'systematic review and meta-analysis',
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'mortality: did convalescent plasma hesitancy cost lives? medRxiv 2021; '
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'author': 'Roden',
'year': '2020',
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'hospitalized patients testing positive for coronavirus disease 2019 '
'(COVID-19)',
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'hospital with COPD exacerbation (CORTICO-COP): a multicentre, '
'randomised, controlled, open-label, non-inferiority trial',
'volume': '7',
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'discharge and survival among elderly patients with acute heart failure: '
'the ELISABETH randomised clinical trial',
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'author': 'Freund',
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'[https://doi.org/10.1016/S0140-6736(20)31180-6]. doi: '
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'syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical '
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'volume': '3',
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