Early Start of Oral Clarithromycin Is Associated with Better Outcome in COVID-19 of Moderate Severity: The ACHIEVE Open-Label Single-Arm Trial

Tsiakos, Konstantinos; Tsakiris, Antonios; Tsibris, Georgios; Voutsinas, Pantazis-Michael; Panagopoulos, Periklis; Kosmidou, Maria; Petrakis, Vasileios; Gravvani, Areti; Gkavogianni, Theologia; Klouras, Eleftherios; Katrini, Konstantina; Koufargyris, Panagiotis; Rapti, Iro; Karageorgos, Athanassios; Vrentzos, Emmanouil; Damoulari, Christina; Zarkada, Vagia; Sidiropoulou, Chrysanthi; Artemi, Sofia; Ioannidis, Anastasios; Papapostolou, Androniki; Michelakis, Evangelos; Georgiopoulou, Maria; Myrodia, Dimitra-Melia; Tsiamalos, Panteleimon; Syrigos, Konstantinos; Chrysos, George; Nitsotolis, Thomas; Milionis, Haralampos; Poulakou, Garyphallia; Giamarellos-Bourboulis, Evangelos J.

INTRODUCTION: The anti-inflammatory effect of macrolides prompted the study of oral clarithromycin in moderate COVID-19. METHODS: An open-label non-randomized trial in 90 patients with COVID-19 of moderate severity was conducted between May and October 2020. The primary endpoint was defined at the end of treatment (EOT) as no need for hospital re-admission and no progression into lower respiratory tract infection (LRTI) for patients with upper respiratory tract infection and as at least 50% decrease of the respiratory symptoms score without progression into severe respiratory failure (SRF) for patients with LRTI. Viral load, biomarkers, the function of mononuclear cells and safety were assessed. RESULTS: The primary endpoint was attained in 86.7% of patients treated with clarithromycin (95% CIs 78.1–92.2%); this was 91.7% and 81.4% among patients starting clarithromycin the first 5 days from symptoms onset or later (odds ratio after multivariate analysis 6.62; p 0.030). The responses were better for patients infected by non-B1.1 variants. Clarithromycin use was associated with decreases in circulating C-reactive protein, tumour necrosis factor-alpha and interleukin (IL)-6; by increase of production of interferon-gamma and decrease of production of interleukin-6 by mononuclear cells; and by suppression of SARS-CoV-2 viral load. No safety concerns were reported. CONCLUSIONS: Early clarithromycin treatment provides most of the clinical improvement in moderate COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04398004 SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40121-021-00505-8.