Efficacy and Safety of Molnupiravir for the Treatment of Non-Hospitalized Adults With Mild COVID-19: A Randomized, Open-Label, Parallel-Group Phase 3 Trial

Abstract

Background: Molnupiravir is an oral prodrug with antiviral activity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Molnupiravir was initially developed for Influenza treatment, is being repurposed for the treatment of COVID-19. This study evaluates the efficacy and safety of molnupiravir in addition to the standard-of-care (SOC) for the treatment of non-hospitalized patients with mild COVID-19. 

Methods: In this phase 3, randomized, open-label, parallel-group study, 1220 patients with laboratory-confirmed (RT-PCR positive) SARS-CoV-2 infection were enrolled across 16 centres in India and 7.3% (90/1220) patients were with one risk factor (i.e. hypertension, diabetes mellitus, obesity, hypothyroidism, hyperthyroidism) presenting a risk for progression to severe COVID-19. Non-hospitalized adults with mild COVID-19 were randomized to receive either molnupiravir 800 mg (200 mg x 4 capsules administered orally every 12 hours for 5 days) with SOC or SOC alone and followed up at day 5 (end of treatment, and days 10, 14 and 28. Standard of care was provided as per the clinical guidance for management of adult COVID-19 patients by the Government of India or as per the Investigator’s discretion. The primary endpoint was the rate of hospitalization of patients from randomization till day 14. Secondary endpoints included rate of hospitalization of patients from randomization up to day 28; clinical improvement (2-point decrease in 11- point WHO Clinical Progression Scale) at days 5, 10, and 14; SARS-CoV-2 RT-PCR negativity at the end of treatment; and mortality rate at day 14 and day 28. The study is registered with the Clinical Trials Registry of India, CTRI/2021/07/034588. 

Findings: Between July 01, 2021 and August 24, 2021, 1220 patients were randomly assigned to receive molnupiravir + SOC (n = 610) or SOC alone (n = 610) and considered for the intent-to-treat (ITT) analysis. No patient met the hospitalization-defined criteria during the 14-day duration as well as till day 28. Clinical improvement was observed significantly earlier in patients of molnupiravir + SOC group as compared to the SOC alone group at the end of treatment day 5 (29.0% vs 5.6%), and further at day 10 (67.4% vs 31.6%) and day 14 (89.0% vs 79.5%) in the ITT population (p < 0.001 for all). The median time to clinical improvement was 10 days in molnupiravir + SOC group vs. 14 days in SOC alone group (p< 0.001). Significantly higher proportion of patients in the molnupiravir + SOC group were associated with RT-PCR negativity as compared to SOC alone at day 5 (81.5% vs. 17.4%), day 10 (89.8% vs. 46.4%,), and day 14 (93.1% vs 83.1%) (p < 0.0001 for all). Mean viral load at day 5 was 4.8 in the molnupiravir + SOC vs. 21.8 in the SOC alone group (p < 0.001). There were no serious adverse events or deaths reported in the study till day 28. 

Interpretation: The addition of molnupiravir to the SOC for treatment of patients with mild COVID-19 was associated with significant clinical improvement and improved RT-PCR negativity rate with no additional safety concerns.

Trial Registration Details: The study is registered with the Clinical Trials Registry of India, CTRI/2021/07/034588.

Funding Information: Funded by Aurobindo Pharma Limited.

Declaration of Interests: DR, MN, CK, VN are employed by the Aurobindo Pharma Limited, India the study sponsor, to perform the study. All other authors declare no competing interests.

Ethics Approval Statement: The study was done in accordance with ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines and applicable local laws and regulations. All sites received approval for the study conduct from the authorised institutional review board/ethics committee. All participants (or their legally authorised representatives) provided written informed consent.

Keywords: molnupiravir, efficacy, safety, COVID-19, mild, non-hospitalized, randomized