Direct antivirals working against the novel coronavirus: azithromycin (DAWn-AZITHRO), a randomized, multicenter, open-label, adaptive, proof-of-concept clinical trial of new antivirals working against SARS-CoV-2—azithromycin trial

Abstract

Background The rapid emergence and the high disease burden of the novel coronavirus SARS-CoV-2 have created a medical need for readily available drugs that can decrease viral replication or blunt the hyperinflammatory state leading to severe COVID-19 disease. Azithromycin is a macrolide antibiotic, known for its immunomodulatory properties. It has shown antiviral effect specifically against SARS-CoV-2 in vitro and acts on cytokine signaling pathways that have been implicated in COVID-19. Methods DAWn-AZITHRO is a randomized, open-label, phase 2 proof-of-concept, multicenter clinical trial, evaluating the safety and efficacy of azithromycin for treating hospitalized patients with COVID-19. It is part of a series of trials testing promising interventions for COVID-19, running in parallel and grouped under the name DAWn-studies. Patients hospitalized on dedicated COVID wards are eligible for study inclusion when they are symptomatic (i.e., clinical or radiological signs) and have been diagnosed with COVID-19 within the last 72 h through PCR (nasopharyngeal swab or bronchoalveolar lavage) or chest CT scan showing typical features of COVID-19 and without alternate diagnosis. Patients are block-randomized (9 patients) with a 2:1 allocation to receive azithromycin plus standard of care versus standard of care alone. Standard of care is mostly supportive, but may comprise hydroxychloroquine, up to the treating physician’s discretion and depending on local policy and national health regulations. The treatment group receives azithromycin qd 500 mg during the first 5 consecutive days after inclusion. The trial will include 284 patients and recruits from 15 centers across Belgium. The primary outcome is time from admission (day 0) to life discharge or to sustained clinical improvement, defined as an improvement of two points on the WHO 7-category ordinal scale sustained for at least 3 days. Discussion The trial investigates the urgent and still unmet global need for drugs that may impact the disease course of COVID-19. It will either provide support or else justify the discouragement of the current widespread, uncontrolled use of azithromycin in patients with COVID-19. The analogous design of other parallel trials of the DAWN consortium will amplify the chance of identifying successful treatment strategies and allow comparison of treatment effects within an identical clinical context. Trial registration EU Clinical trials register EudraCT Nb 2020-001614-38. Registered on 22 April 2020

The Role of Dysbiosis in Critically Ill Patients With COVID-19 and Acute Respiratory Distress Syndrome

“…Similar results were obtained from a large observational study (115,116). Another RCT on the use of azithromycin in hospitalized patients with COVID-19 is currently ongoing (117).…”

Itraconazole for COVID-19: Preclinical Studies and a Proof-of-Concept Pilot Clinical Study

“…We thus designed a pilot proof-of-concept clinical trial and did not communicate the in vitro findings to avoid a potential rush on the drug. As we anticipated that insights in the clinical management would evolve rapidly, we opted for a flexible trial design that is also used for the evaluation of other antiviral strategies [11][12][13].…”

“…The protocol was approved by the institutional Ethics Committee and by the Belgian Federal Agency for Medicines and Health Products (EudraCT 2020-001243-15). The trial was part of the DAWn clinical studies [11][12][13]. An independent Data Safety Monitoring Board (DSMB) reviewed trial safety outcomes.…”

Azithromycin for treatment of hospitalised COVID-19 patients: a randomised, multicentre, open-label clinical trial (DAWn-AZITHRO)

“…DAWn-Azithro was an open-label, randomised, adaptive clinical trial conducted in 15 Belgian hospitals and coordinated by University Hospitals Leuven, to assess if azithromycin added to standard of care could shorten time to discharge or clinical improvement in hospitalised COVID-19 patients. The study protocol and statistical analysis plan are available in the appendix , and have been published previously [ 2 ]. The study was approved by a central Ethics Committee (Comité d'Éthique Hospitalo-Facultaire de Liège) and the Federal Agency for Medicines and Health Products, and registered in the EU Clinical Trial Register (EudraCT: 2020-001614-38A).…”

“…The high disease burden and the rapid spread of the SARS-CoV-2 pandemic immediately directed the search for disease-modifying agents towards the repurposing of existing molecules. The Belgian Direct Antivirals Working against the novel Coronavirus studies were a parallel series of proof-of-concept trials, assessing several treatment strategies for hospitalised patients with COVID-19: itraconazole [ 1 ], azithromycin [ 2 ], anakinra combined with intensified anticoagulation [ 3 ], and convalescent plasma [ 4 ].…”