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

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ClinicalTrials.gov Identifier: NCT04339816
Recruitment Status : Not yet recruiting
First Posted : April 9, 2020
Last Update Posted : April 13, 2020
Sponsor:
Collaborators:
Masaryk Hospital Usti nad Labem
University Hospital Pilsen
The Faculty Hospital Na Bulovce
St. Anne's University Hospital Brno, Czech Republic
University Hospital, Motol
General University Hospital, Prague
University Hospital Olomouc
Information provided by (Responsible Party):
Frantisek Duska, MD, PhD, Charles University, Czech Republic

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.


Condition or disease Intervention/treatment Phase
COVID-19 Respiratory Failure Drug: Azithromycin Drug: Hydroxychloroquine Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 240 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Prospective, multi-centre, randomised, pragmatic, double blind trial
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Masking Description: Visually unrecognisable IP or placebo will be prepared by dedicated unblinded study pharmacist and handed over to care provider immediately before administration
Primary Purpose: Treatment
Official Title: Azithromycin Added to Hydrochloroquine in Patients Admitted to Intensive Care Due to Coronavirus Disease 2019 (COVID-19)- Randomised Controlled Trial
Estimated Study Start Date : April 20, 2020
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : June 30, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: HC-A group
  • 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
orally or into nasogastric tube for 5 days

Drug: Hydroxychloroquine
orally or into nasogastric tube for 5 days

Active Comparator: HC group
  • 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
orally or into nasogastric tube for 5 days

Drug: Placebo
orally or into nasogastric tube for 5 days
Other Name: aqua pro injectione

Placebo Comparator: C group
• 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
orally or into nasogastric tube for 5 days
Other Name: aqua pro injectione




Primary Outcome Measures :
  1. Proportion of alive patients free off mechanical ventilation [ Time Frame: 14 days after enrolment ]
    Composite percentage of patients alive and not on end-of-life pathway who are free of mechanical ventilation at day 14.


Secondary Outcome Measures :
  1. Proportion of patients who avoided the need of mechanical ventilation [ Time Frame: 14 days ]
    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.

  2. ICU LOS [ Time Frame: 28 days ]
    Length of stay in intensive care unit

  3. Mortality28 [ Time Frame: 28 days ]
    Proportion of patients who died by day 28

  4. Mortality90 [ Time Frame: 90 days ]
    Proportion of patients who died by day 90



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.
Publications:

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Responsible Party: Frantisek Duska, MD, PhD, Dr, Charles University, Czech Republic
ClinicalTrials.gov Identifier: NCT04339816    
Other Study ID Numbers: AZIQUINE-ICU-25032020
2020-001456-18 ( EudraCT Number )
First Posted: April 9, 2020    Key Record Dates
Last Update Posted: April 13, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Deidentified record-level data will be shared in a public database
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: within 6 months of study completion
URL: http://mendeley.com

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Frantisek Duska, MD, PhD, Charles University, Czech Republic:
covid-19
Azithromycin
Hydroxychloroquine
Respiratory failure
Intensive Care
Additional relevant MeSH terms:
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Respiratory Insufficiency
Respiration Disorders
Respiratory Tract Diseases
Azithromycin
Hydroxychloroquine
Anti-Bacterial Agents
Anti-Infective Agents
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents