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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 08; 21(1):631.T

Abstract

BACKGROUND

Novel coronavirus SARS-CoV-2 is known to be susceptible in vitro to exposure to hydroxychloroquine and its effect has been found to be potentiated by azithromycin. We hypothesise that early administration of hydroxychloroquine alone or in combination with azithromycin can prevent respiratory deterioration in patients admitted to intensive care due to rapidly progressive COVID-19 infection.

METHODS

Design: Prospective, multi-centre, double-blind, randomised, controlled trial (RCT).

PARTICIPANTS

Adult (> 18 years) within 24 h of admission to the intensive care unit with proven or suspected COVID-19 infection, whether or not mechanically ventilated. Exclusion criteria include duration symptoms of febrile disease for ≥ 1 week, treatment limitations in place or moribund patients, allergy or intolerance of any study treatment, and pregnancy.

INTERVENTIONS

Patients will be randomised in 1:1:1 ratio to receive Hydroxychloroquine 800 mg orally in two doses followed by 400 mg 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 hydroxychloroquine + placebo (HC group) or placebo + placebo (C-group) in addition to the best standard of care, which may evolve during the trial period but will not differ between groups. Primary outcome is the composite percentage of patients alive and not on end-of-life pathway who are free of mechanical ventilation at day 14.

SECONDARY OUTCOMES

The percentage of patients who were prevented from needing intubation until day 14, ICU length of stay, and mortality (in hospital) at day 28 and 90.

DISCUSSION

Although both investigational drugs are often administered off label to patients with severe COVID-19, at present, there is no data from RCTs on their safety and efficacy. In vitro and observational trial suggests their potential to limit viral replication and the damage to lungs as the most common reason for ICU admission. Therefore, patients most likely to benefit from the treatment are those with severe but early disease. This trial is designed and powered to investigate whether the treatment in this cohort of patients leads to improved clinical patient-centred outcomes, such as mechanical ventilation-free survival.

TRIAL REGISTRATION

Clinical trials.gov: NCT04339816 (Registered on 9 April 2020, amended on 22 June 2020); Eudra CT number: 2020-001456-18 (Registered on 29 March 2020).

Authors+Show Affiliations

Department of Anaesthesia and Intensive Care, Charles University, 3rd Faculty of Medicine and FNKV University Hospital, Prague, Czech Republic. frantisek.duska@lf3.cuni.cz.Department of Anaesthesia and Intensive Care, Charles University, 3rd Faculty of Medicine and FNKV University Hospital, Prague, Czech Republic.Department of Anaesthesia and Intensive Care, Charles University, 3rd Faculty of Medicine and FNKV University Hospital, Prague, Czech Republic.Masaryk University, Medical Faculty and U Svate Anny University Hospital, Brno, Czech Republic.Na Bulovce Hospital, Prague, Czech Republic.Charles University, 1st Faculty of Medicine and VFN University Hospital Prague, Prague, Czech Republic.Charles University, Medical Faculty and University Hospital Plzen, Pilsen, Czech Republic.Medical Faculty, Palacky University and Olomouc University Hospital, Olomouc, Czech Republic.Department of Anaesthesia and Intensive Care, Charles University, 3rd Faculty of Medicine and FNKV University Hospital, Prague, Czech Republic.Department of Anaesthesia and Intensive Care, Charles University, 3rd Faculty of Medicine and FNKV University Hospital, Prague, Czech Republic.Department of Anaesthesia and Intensive Care, Charles University, 3rd Faculty of Medicine and FNKV University Hospital, Prague, Czech Republic.Charles University, 2nd Faculty of Medicine, Motol University Hospital, Prague, Czech Republic.Department of Anaesthesia and Intensive Care, Charles University, 3rd Faculty of Medicine and FNKV University Hospital, Prague, Czech Republic.Czech Anaesthesia Clinical Trials and Audit Network and Department of Anaesthesia and Intensive Care, Masaryk's Hospital, Ústí nad Labem, Czech Republic.No affiliation info available

Pub Type(s)

Clinical Trial Protocol
Journal Article
Multicenter Study

Language

eng

PubMed ID

32641163

Citation

Duška, František, et al. "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, vol. 21, no. 1, 2020, p. 631.
Duška F, Waldauf P, Halačová M, et al. 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;21(1):631.
Duška, F., Waldauf, P., Halačová, M., Zvoníček, V., Bala, J., Balík, M., Beneš, J., Klementová, O., Kozáková, I., Kubricht, V., Le Roy, A., Vymazal, T., Řehořová, V., & Černý, V. (2020). 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, 21(1), 631. https://doi.org/10.1186/s13063-020-04566-x
Duška F, et al. 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. PubMed PMID: 32641163.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Azithromycin added to hydroxychloroquine for patients admitted to intensive care due to coronavirus disease 2019 (COVID-19)-protocol of randomised controlled trial AZIQUINE-ICU. AU - Duška,František, AU - Waldauf,Petr, AU - Halačová,Milada, AU - Zvoníček,Václav, AU - Bala,Jakub, AU - Balík,Martin, AU - Beneš,Jan, AU - Klementová,Olga, AU - Kozáková,Irena, AU - Kubricht,Viktor, AU - Le Roy,Anne, AU - Vymazal,Tomáš, AU - Řehořová,Veronika, AU - Černý,Vladimír, AU - ,, Y1 - 2020/07/08/ PY - 2020/04/15/received PY - 2020/06/29/accepted PY - 2020/7/10/entrez PY - 2020/7/10/pubmed PY - 2020/7/15/medline KW - Azithromycin KW - COVID-19 KW - Hydroxychloroquine KW - Novel coronavirus KW - Respiratory failure KW - SARS-CoV-2 SP - 631 EP - 631 JF - Trials JO - Trials VL - 21 IS - 1 N2 - BACKGROUND: Novel coronavirus SARS-CoV-2 is known to be susceptible in vitro to exposure to hydroxychloroquine and its effect has been found to be potentiated by azithromycin. We hypothesise that early administration of hydroxychloroquine alone or in combination with azithromycin can prevent respiratory deterioration in patients admitted to intensive care due to rapidly progressive COVID-19 infection. METHODS: Design: Prospective, multi-centre, double-blind, randomised, controlled trial (RCT). PARTICIPANTS: Adult (> 18 years) within 24 h of admission to the intensive care unit with proven or suspected COVID-19 infection, whether or not mechanically ventilated. Exclusion criteria include duration symptoms of febrile disease for ≥ 1 week, treatment limitations in place or moribund patients, allergy or intolerance of any study treatment, and pregnancy. INTERVENTIONS: Patients will be randomised in 1:1:1 ratio to receive Hydroxychloroquine 800 mg orally in two doses followed by 400 mg 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 hydroxychloroquine + placebo (HC group) or placebo + placebo (C-group) in addition to the best standard of care, which may evolve during the trial period but will not differ between groups. Primary outcome is the composite percentage of patients alive and not on end-of-life pathway who are free of mechanical ventilation at day 14. SECONDARY OUTCOMES: The percentage of patients who were prevented from needing intubation until day 14, ICU length of stay, and mortality (in hospital) at day 28 and 90. DISCUSSION: Although both investigational drugs are often administered off label to patients with severe COVID-19, at present, there is no data from RCTs on their safety and efficacy. In vitro and observational trial suggests their potential to limit viral replication and the damage to lungs as the most common reason for ICU admission. Therefore, patients most likely to benefit from the treatment are those with severe but early disease. This trial is designed and powered to investigate whether the treatment in this cohort of patients leads to improved clinical patient-centred outcomes, such as mechanical ventilation-free survival. TRIAL REGISTRATION: Clinical trials.gov: NCT04339816 (Registered on 9 April 2020, amended on 22 June 2020); Eudra CT number: 2020-001456-18 (Registered on 29 March 2020). SN - 1745-6215 UR - https://www.unboundmedicine.com/medline/citation/32641163/Azithromycin_added_to_hydroxychloroquine_for_patients_admitted_to_intensive_care_due_to_coronavirus_disease_2019__COVID_19__protocol_of_randomised_controlled_trial_AZIQUINE_ICU_ L2 - https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-020-04566-x DB - PRIME DP - Unbound Medicine ER -