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Background: SARS-CoV-2 binding to ACE2 is potentially associated with severe pneumonia due to COVID-19. The aim of the study was to test whether Mas-receptor activation by 20-hydroxyecdysone (BIO101) could restore the Renin-Angiotensin System equilibrium and limit the frequency of respiratory failure and mortality in adults hospitalized with severe COVID-19., Methods: Double-blind, randomized, placebo-controlled phase 2/3 trial. Randomization: 1:1 oral BIO101 (350 mg BID) or placebo, up to 28 days or until an endpoint was reached. Primary endpoint: mortality or respiratory failure requiring high-flow oxygen, mechanical ventilation, or extra-corporeal membrane oxygenation. Key secondary endpoint: hospital discharge following recovery (ClinicalTrials.gov Number, NCT04472728)., Findings: Due to low recruitment the planned sample size of 310 was not reached and 238 patients were randomized between August 26, 2020 and March 8, 2022. In the modified ITT population (233 patients; 126 BIO101 and 107 placebo), respiratory failure or early death by day 28 was 11.4% lower in the BIO101 (13.5%) than in the placebo (24.3%) group, (p = 0.0426). At day 28, proportions of patients discharged following recovery were 80.1%, and 70.9% in the BIO101 and placebo group respectively, (adjusted difference 11.0%, 95% CI [-0.4%, 22.4%], p = 0.0586). Hazard Ratio for time to death over 90 days: 0.554 (95% CI [0.285, 1.077]), a 44.6% mortality reduction in the BIO101 group (not statistically significant). Treatment emergent adverse events of respiratory failure were more frequent in the placebo group., Interpretation: BIO101 significantly reduced the risk of death or respiratory failure supporting its use in adults hospitalized with severe respiratory symptoms due to COVID-19., Funding: Biophytis., Competing Interests: Biophytis declares that potential commercial interests had no impact on the scientific conduct of the study nor on the analysis/interpretation of data. Cendrine Tourette, Luis Esmeraldino, Pierre Jean Dilda, René Lafont, Serge Camelo, Sandrine Rabut, Waly Dioh, Rob van Maanen and Stanislas veillet are Biophytis company employees, Anait Azbekyan Samuel Agus and Mounia Chabane are former Biophytis company employees. Jean Mariani is emeritus professor at Sorbonne University and consultant for Biophytis, Richard Kay is a consultant for Biophytis. Alpesh Amin, MD declares that as principal investigator or co-investigator of clinical trials sponsored by NIH/NIAID, NeuroRx Pharma, Pulmotect, Blade Therapeutics, Novartis, Takeda, Humanigen, Eli Lilly, PTC Therapeutics, OctaPharma, Fulcrum Therapeutics, Alexion, BioPhysitis its institution received payments and that he personnally received consultant fees from BMS, Pfizer, BI, Portola, Sunovion, Mylan, Salix, Alexion, AstraZeneca, Novartis, Nabriva, Paratek, Bayer, Tetraphase, Achogen LaJolla, Ferring, Seres, Spero, Eli Lilly, Gilead, Millenium, HeartRite, Aseptiscope, and Sprightly; but that these relationships were unrelated to the current work. Shaheen Islam, MD declares that he received grants or was in contract as a principal or sub investigator from the following companies:–Pliant therapeutics: INTEGRIS-ARDS, drug (PLN74809) Covid -trial 2021 (PI).—CytoDyn, Inc.: CD12-COVID 19 Drug: Leronlimab COVID trial 2020 (PI). -Pluristem Ltd.: PLX-COV-01. Drug PLX-PAD, COVID Trial 2020 (Sub-I).—Edesa Biotech Inc.: EB05-04-2020. Drug: EB05 COVID Trial 2020 (Sub-I). Fabiano Ramos, MD declares that its institution: Hospital São Lucas da Pontíficia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil received financial resources to conduct the study from Biophytis. Brian Snyder, MD declares that he receives research funding from Biophytis as part of the present clinical trial. Moreover, he declares that he received grants or has contracts with Behring, and Rheonix as part of COVID research studies. None of the other investigators declare any relationship related to the current work., (© 2023 The Author(s).)