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..
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DOI record:
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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 years, admitted to hospital for ≤48 h (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 mg daily azithromycin for 3 days followed by 250 mg daily azithromycin for 12 days combined with 200 mg twice-daily hydroxychloroquine for all 15 days. The control group received placebo/placebo. The primary outcome was days alive and discharged from hospital within 14 days (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 days 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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