Azithromycin Added to Hydrochloroquine in Patients Admitted to Intensive Care With COVID-19: Randomised Controlled Trial

NCT04339816 | Terminated Phase 3

• 2 other identifiers: AZIQUINE-ICU-250320202020-001456-18
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

Trial design: Prospective, multi-centre, randomised, pragmatic, double blind trial Methods: Participants: Adult (\>18 years) within 24 hours of admission to intensive care unit with proven or suspected COVID-19 infection, whether or not mechanically ventilated. Exclusion criteria: symptoms of febrile disease for ≥1 week, treatment limitations in place or moribund patients, allergy or intolerance of any study treatment, incl. long QT syndromes, participation in another outcome-based interventional trial within last 30 days, patients taking Hydrochloroquine for other indication than COVID-19, pregnancy. Interventions: Patients will be randomised in 1:1:1 ratio to receive Hydrochloroquine 800mg orally in two doses followed by 400mg daily in two doses and Azithromycin 500 mg orally in one dose followed by 250 mg in one dose for a total of 5 days (HC-A group) or Hydrochloroquine+ placebo (HC group) or placebo + placebo (C-group) in addition to best standard of care, which may evolve during the trial period but will not differ between groups. Objective: To test the hypothesis that early administration of combination therapy slows disease progression and improves mechanical-ventilation free survival. Outcomes: Primary outcome: Composite percentage of patients alive and not on end-of-life pathway who are free of mechanical ventilation at day 14. Secondary outcomes: 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. ICU-LOS D28 and D 90 mortality (in hospital) Tertiary (exploratory) outcomes: Viral load at D7 of study enrolment (No of viral RNA copies/ml of blood), proportion of patients alive and rtPCR negative from nasal swab at D14, Difference of FiO2 requirement and respiratory system compliance between day 0 and 7. Randomization: In 1:1:1 ratio and stratified according to study centre and patients age (cut-off 70 years) Blinding (masking): Patients, treating clinicians, outcome assessors and data analyst will be blinded to study treatment allocation. Unblinded study pharmacist or research nurse will prepare investigational products.

Conditions

COVID-19; Respiratory Failure

Keywords

covid-19; Azithromycin; Hydroxychloroquine; Respiratory failure; Intensive Care

Outcome Measures

Primary Outcomes (1)

• Proportion of alive patients free off mechanical ventilation

  Composite percentage of patients alive and not on end-of-life pathway who are free of mechanical ventilation at day 14.

  14 days after enrolment

Secondary Outcomes (4)

• Proportion of patients who avoided the need of mechanical ventilation

  14 days

• ICU LOS

  28 days

• Mortality28

  28 days

• Mortality90

  90 days

Study Arms (3)

HC-A group

EXPERIMENTAL

* Day 1: Patients receive two doses 400 mg of Hydrochloroquine in 12 hours interval and 500 mg of Azithromycin once in 24 hours (with the first dose of hydrochloroquine) * Days 2-5: Patients receive two doses 200 mg of Hydrochloroquine in 12 hours interval 250 mg of Azithromycin once in 24 hours (with the first daily dose of hydrochloroquine)

Drug: Azithromycin; Drug: Hydroxychloroquine

HC group

ACTIVE COMPARATOR

* Day 1: Patients receive two doses 400 mg of Hydrochloroquine in 12 hours interval and placebo once in 24 hours (with the first dose of hydrochloroquine) * Days 2-5: Patients receive two doses 200 mg of Hydrochloroquine in 12 hours interval and placebo once in 24 hours (with the first dose of hydrochloroquine)

Drug: Hydroxychloroquine; Drug: Placebo

C group

PLACEBO COMPARATOR

• Day 1-5: Patients receive two doses of placebo in 12 hours interval and 1 extra dose of placebo once in 24 hours

Drug: Placebo

Interventions

Azithromycin DRUG

orally or into nasogastric tube for 5 days

HC-A group

Hydroxychloroquine DRUG

orally or into nasogastric tube for 5 days

HC group; HC-A group

Placebo DRUG

orally or into nasogastric tube for 5 days

Also known as: aqua pro injectione

C group; HC group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult (\>18 years) within 24 hours of admission to intensive care unit with proven or suspected COVID-19 infection. For the purpose of this study, intensive care unit is defined as a facility that allow continuous monitoring of vital functions and oxygen administration . It is expected that most patients will have rtPCR test known within 24 hours of admission to hospital. Nonetheless, if this is not the case (eg. due to overloaded lab facility, lack of supplies) it is possible to randomise a patient based on a strong clinical suspicion of SARS-Cov-2 infection. In case COVID-19 is not confirmed in retrospect, experimental therapy is withdrawn and the study subject is withdrawn from "per protocol" analysis of the primary and secondary outcomes, but remains in "intention-to-treat" cohort for the analysis of safety.

You may not qualify if:

• symptoms of febrile disease for ≥1 week, pregnancy, treatment limitations in place or moribund patients, allergy or intolerance of any study treatment, incl. long QT syndromes, myasthenia gravis, allergies or known deficiency of glucose-6-phosphate dehydrogenase, participation in another outcome-based interventional trial within last 30 days, patients taking Hydrochloroquine for other indication than COVID-19.

Sponsors & Collaborators

• Frantisek Duska, MD, PhD: lead
• Masaryk Hospital Usti nad Labem: collaborator
• University Hospital Pilsen: collaborator
• The Faculty Hospital Na Bulovce: collaborator
• St. Anne's University Hospital Brno, Czech Republic: collaborator
• University Hospital, Motol: collaborator
• General University Hospital, Prague: collaborator
• University Hospital Olomouc: collaborator

Study Sites (1)

František Duška

Prague, Česká Republika, 10034, Czechia

Location

Related Publications (8)

• Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11.

  PMID: 32171076 BACKGROUND

• Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269-271. doi: 10.1038/s41422-020-0282-0. Epub 2020 Feb 4. No abstract available.

  PMID: 32020029 BACKGROUND

• Colson P, Rolain JM, Lagier JC, Brouqui P, Raoult D. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents. 2020 Apr;55(4):105932. doi: 10.1016/j.ijantimicag.2020.105932. Epub 2020 Mar 4. No abstract available.

  PMID: 32145363 BACKGROUND

• Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, Liu X, Zhao L, Dong E, Song C, Zhan S, Lu R, Li H, Tan W, Liu D. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020 Jul 28;71(15):732-739. doi: 10.1093/cid/ciaa237.

  PMID: 32150618 BACKGROUND

• Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Tissot Dupont H, Honore S, Colson P, Chabriere E, La Scola B, Rolain JM, Brouqui P, Raoult D. RETRACTED: Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Jul;56(1):105949. doi: 10.1016/j.ijantimicag.2020.105949. Epub 2020 Mar 20.

  PMID: 32205204 BACKGROUND

• Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 Mar 17;323(11):1061-1069. doi: 10.1001/jama.2020.1585.

  PMID: 32031570 BACKGROUND

• Arentz M, Yim E, Klaff L, Lokhandwala S, Riedo FX, Chong M, Lee M. Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State. JAMA. 2020 Apr 28;323(16):1612-1614. doi: 10.1001/jama.2020.4326.

  PMID: 32191259 BACKGROUND

• Duska F, Waldauf P, Halacova M, Zvonicek V, Bala J, Balik M, Benes J, Klementova O, Kozakova I, Kubricht V, Le Roy A, Vymazal T, Rehorova V, Cerny V; Czech Anaesthesia Clinical Trials and Audit Network. Azithromycin added to hydroxychloroquine for patients admitted to intensive care due to coronavirus disease 2019 (COVID-19)-protocol of randomised controlled trial AZIQUINE-ICU. Trials. 2020 Jul 8;21(1):631. doi: 10.1186/s13063-020-04566-x.

  PMID: 32641163 DERIVED

MeSH Terms

Conditions

COVID-19; Respiratory Insufficiency

Interventions

Azithromycin; Hydroxychloroquine

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals; Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: Visually unrecognisable IP or placebo will be prepared by dedicated unblinded study pharmacist and handed over to care provider immediately before administration
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Dr

Model Details: Prospective, multi-centre, randomised, pragmatic, double blind trial

Study Record Dates

• First Submitted: April 6, 2020
• First Posted: April 9, 2020
• Study Start: May 13, 2020
• Primary Completion: November 4, 2020
• Study Completion: November 4, 2020
• Last Updated: November 6, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: within 6 months of study completion

Locations

CZ (1)