Azithromycin Added to Hydrochloroquine in Patients Admitted to Intensive Care Due to Coronavirus Disease 2019 (COVID-19)- Randomised Controlled Trial

Introduction Background and objectives. In early 2020 novel Coronavirus disease (COVID-19) begun to spread from Asia to Europe and beyond forcing WHO to declare global pandemic. Infected patients shed the virus for a median of 20 days. Up to 10% of COVID-19 infected patients develop a severe form of disease requiring intensive care admission and some of them die. SARS-Cov2 is encapsulated positive strand RNA virus that uses ACE-2 of type 2 pneumocytes as binding sites. It has been hypothesised (Gattinoni 2020 ICM editorial) that initial hypoxemia caused by loss of primary injury to pulmonary vasculature leads to hyperventilation and patients self-inflicted lung injury predominantly in lung areas of increase stress and strain. In turn, later during the course of the disease, ARDS develops with a typical restrictive pattern of a stiff, wet and recruitable lung. At presents there is no evidence-based causative treatment of SARS-CoV-2 and there is a burning need of randomised-controlled trials to find effective therapeutic strategies intervention.

Explanation of rationale: Chloroquine has been used for malaria treatment and chemoprophylaxis, and hydroxychloroquine is used for treatment of rheumatoid arthritis, systemic lupus erythematosus and porphyrias. Both drugs have in-vitro activity against SARS-CoV, SARS-CoV-2, and other coronaviruses, with hydroxychloroquine having relatively higher potency against SARS-CoV-2 known to be susceptible in vitro to exposure to Hydrochloroquine. At the moment clinical trials are ongoing to test clinical efficacy in pre- and post-exposure prophylaxis in SARS-CoV-2. In one highly cited French non-randomised observational study by Gautret et. al., a significant reduction of virus carriage has been observed in patients co-incidentally treated by Azithromycin in addition to Hydrochloroquine as a part of initial empirical therapy of community-acquired pneumonia. Azithromycin is a macrolide antibiotic, which binds to the 50S subunit of the bacterial ribosome, thus inhibiting translation of mRNA. The positive-sense RNA viruses and indeed all genes defined as positive-sense can be directly accessed by host ribosomes to immediately form proteins and the effects of Azithromycin on this process are not known. No data are available at present on the clinical efficacy of Hydrochloroquine alone or in combination with Azithromycin and it is likely that any treatment affecting virus replication would only be effective if administered early, before overt ARDS develops.

In the light of this, the investigators designed a trial in which a hypothesis is tested, that early administation of hydrochlorochine alone or in combination with azithromycin can prevent respiratory deterioration in patients admitted to intensive care due to rapidly progressive COVID-19 infection.

Methods Trial design: Prospective, multi-centre, randomised, pragmatic, double blind trial Participants: Eligibility criteria for participants: 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.

Settings and locations: Central study site is FNKV University Hospital Prague, updated list of participating centres is listed in the appendix.