Administrative information
Title {1} | Azithromycin added to hydroxychloroquine in patients admitted to intensive care due to coronavirus disease 2019 (COVID-19)—randomised controlled trial AZIQUINE-ICU |
Trial registration {2a and 2b}. | Clinical trials.gov: NCT04339816 Eudra CT number: 2020-001456-18 |
Protocol version {3} | AZIQUINE-ICU 25032020 Version 1.5 |
Funding {4} | The trial is funded by Donatio Intensivistam Endowment Fund www.donatio-intensivistam.cz, VAT No 0907206 Registered under No N1795 by Municipal Court in Prague on 2 April 2020, trial drugs were provided as a kind gift of Zentiva, a.s. and a rapid grant from COVID-19 GAMA-2 scheme of Technology Agency of the Czech Republic |
Author details {5a} | • František Duška, Milada Halačová, Petr Waldauf, Anne Le Roy, Irena Kozáková, Viktor Kubricht, Veronika Řehořová from Dept. of Anaesthesia and Intensive Care Charles University, 3rd Faculty of Medicine and FNKV University Hospital, Prague, Czech Republic • Jakub Bala, Na Bulovce Hospital, Prague, Czech Republic • Martin Balík, Charles University, 1st Faculty of Medicine and VFN University Hospital Prague, Czech Republic • Jan Beneš, Charles University, Medical Faculty and University Hospital Plzen, Czech Republic • Olga Klementová, Medical Faculty, Palacky University and Olomouc University Hospital, Czech Republic • Tomáš Vymazal, Charles University, 2nd Faculty of Medicine, Motol University Hospital, Prague, Czech Republic • Václav Zvoníček, Masaryk University, Medical Faculty and U Svate Anny University Hospital, Brno, Czech Republic • Vladimír Černý from Czech Anaesthesia Clinical Trials and Audit Network and Dept. of Anaesthesia and Intensive Care, Masaryk’s Hospital, Ústí nad Labem, Czech Republic |
Name and contact information for the trial sponsor {5b} | Donatio Intensivistam Endowment Fund VAT No 0907206 Registered under No N1795 by Municipal Court in Prague on 2 April 2020. Address: Hornoměcholupská 40c/1640, 10200 Prague 15, Czech Republic František Duška, MD, PhD, founder Email: frantisek.duska@lf3.cuni.cz Phone: +420608405541 |
Role of sponsor {5c} | This is an investigator-initiated study. Study funders had no role in the study design; collection, management, analysis, and interpretation of data; nor in writing of the report or the decision to submit the report for publication. |
Introduction
Background and rationale {6a}
Objectives {7}
Trial design {8}
Methods: participants, interventions and outcomes
Study setting {9}
Eligibility criteria {10}
Inclusion criteria
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Adult (> 18 years)
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Within 24 h of admission to the intensive care unit
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Proven or suspected COVID-19 infection
Exclusion criteria
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Symptoms of febrile disease for ≥ 1 week at enrolment
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Pregnancy or inability/unwillingness to perform pregnancy test at and 28 days after enrolment
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Treatment limitations in place or moribund patients
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Allergy, intolerance or contraindication to any study drug, such as long QT syndromes, myasthenia gravis, pre-existing maculopathy or retinopathy, allergies or known deficiency of glucose-6-phosphate dehydrogenase
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Known HIV positivity
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Significant liver disease such as cirrhosis Child-Pugh C or active hepatitis B or C
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Known stage IV chronic kidney disease, on dialysis at enrolment or imminent need of it
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Participation in another outcome-based interventional trial within the last 30 days
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Patients taking hydroxychloroquine for other indication than to treat COVID-19
Who will take informed consent? {26a}
Item {26b}
Interventions
Explanation for the choice of comparators {6b}
Intervention description {11a}
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Hydroxychloroquine sulphate 200 mg
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Azithromycin dihydrate 500 mg
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Lactose as placebo
Study group | ||
---|---|---|
HC-A (Intervention) | Azithromycin | Hydroxychloroquine |
HC (ACTIVE COMPARATOR) | Lactose | Hydroxychloroquine |
C (PLACEBO) | Lactose | Lactose |
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Day 1: Patients receive two doses 400 mg of hydroxychloroquine or placebo in 12 h interval and 500 mg of azithromycin or placebo once in 24 h (with the first dose of hydroxychloroquine or placebo)
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Days 2–5: Patients receive two doses 200 mg of hydroxychloroquine or placebo in 12 h interval 250 mg of azithromycin or placebo once in 24 h (with the first dose of hydroxychloroquine or placebo)
Masking
Criteria for discontinuing or modifying allocated interventions {11b}
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Consent withdrawal by study subject
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In case—in the opinion of the investigator—the study procedures are considered unsafe for the study subject or the risks outweigh the potential benefits
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If COVID-19 is negative and believed to be true negative, subjects will be immediately withdrawn from the study and administration study medication will immediately be stopped. Yet, data on adverse events will still be collected and analysed, in accordance with “intention-to-treat” mode of safety analysis
Strategies to improve adherence to interventions {11c}
Relevant concomitant care permitted or prohibited during the trial {11d}
Provisions for post-trial care {30}
Outcomes {12}
Primary outcome
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Composite percentage of patients alive and not on end-of-life pathway who are free of mechanical ventilation at day 14 (see detailed explanation below)
Secondary outcomes
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Composite percentage of patients alive and not on end-of-life pathway who are free of mechanical ventilation at day 14 in the subgroup of patients without the need of mechanical ventilation at baseline
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Length of stay in intensive care unit
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Mortality at day 28 and 90
Tertiary (exploratory) outcomes
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Viral load at day 8 (no. of viral RNA copies/millilitre of blood)
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Proportion of patients alive and with negative rtPCR nasal swab at D14
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Difference of fraction of inspired oxygen (FiO2) between days 0 and 7.
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Difference of respiratory system compliance between days 0 and 7.
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Pharmacokinetic profiles of investigational drugs after oral versus nasogastric administration