Molnupiravir Treatment for COVID-19 in People at Higher Risk in the Community: Outcomes from the PANORAMIC Randomised Controlled Trial at Three and Six Months

Abstract

Objectives: Treating COVID-19 infection with antiviral drugs may reduce the longer-term impact of the illness, but no randomised controlled trials have yet reported on the effectiveness of molnupiravir on longer term outcomes. The main objective of the current research is to investigate the effects of molnupiravir for COVID-19 at 3- and 6-months post-randomisation.

Design: Participants in this open-label controlled trial were followed up at 3- and 6-months. Bayesian analyses were used to estimate the probability of superiority (odds ratio <1 for dichotomous outcomes).

Setting: Primary healthcare.

Participants: Participants were aged ≥50, or ≥18 years with comorbidities, and unwell ≤5 days with confirmed COVID-19 in the community.

Interventions: Participants were randomised to usual care or usual care plus molnupiravir (800mg twice daily for 5 days).

Main Outcome Measures: Participant ratings of wellness, experiencing any severe or persistent symptom, health and social care use, health-related quality of life (measured by the EQ-5D-5L), time off work, and hospitalisation.

Results: Between December 8, 2021, and April 27, 2022, 25,784 participants were randomised to molnupiravir plus usual care (n=12,821) or usual care alone (n=12,963). Long-term follow-up data were available for 23,008 (89.2%), and 99.1% had at least one prior dose of a SARS-CoV-2 vaccine. A range of symptoms were reduced in severity and health-related quality of life (measured by the EQ-5D-5L) improved in the molnupiravir group at 3- and 6- months. Ratings of wellness, experiencing any severe symptom, and health care use had high probabilities of superiority with molnupiravir treatment, but low probability of being clinically meaningful. There were statistically significant differences in persistence of any symptom (8.5% vs 11%, Number Needed to Treat (NNT) = 67)) at 6 months, and reported time off work at 3 months (17‧9% vs 22 ‧4%)  and 6 months (4‧4% vs 5‧4%; NNT= 100). There remained no difference in hospitalisations at long term follow-up.  
Conclusions: Molnupiravir for acute COVID-19 helped patients feel better, experience fewer and less severe COVID-19 associated symptoms, access health care less often, and take less time off work at 6-months. However, the absolute differences are small with potentially high estimated numbers needed to treat.

Trial Registration: ISRCTN30448031.

Funding: National Institute of Health and Care ResearchNIHR135366.

Declaration of Interest: JSN-V-T was seconded to the Department of Health and Social Care, England (DHSC) from October 2017 to March 2022. The views expressed in this paper are those of its authors and not necessarily those of DHSC or its agencies. In Spring 2023, he completed one, 3-hour, paid consultancy assignment for MSD on a subject unrelated to COVID-19. He has given two paid lectures for Gilead who also manufacture COVID-19 treatments in 2022-23, and one paid lecture for AstraZeneca in 2022, who manufacture COVID-19 vaccines. He consults occasionally for Moderna (2023 onwards) who manufacture COVID-19 vaccines. D.M.L has received personal fees from Gilead for an educational video and from Merck for a roundtable discussion, speaker fees from Biotest, Takeda and Astra-Zeneca and support to attend a conference from Octapharma. D.M.L. also holds research grants from GSK and Bristol Myers Squibb and has received consultancy fees from GSK paid to his institution, all outside the current work.

Ethical Approval: The UK Medicines and Healthcare products Regulatory Agency and the South Central- Berkshire Research Ethics Committee approved the trial protocol. Online informed consent was obtained from all participants. Patients were not involved in the design, or conduct, or reporting, or dissemination plans of our research. The authors vouch for the accuracy and completeness of the data and for fidelity to the protocol. An independent Trial Steering Committee (TSC) and Data Monitoring and Safety Committee (DMSC) provide trial oversight.

Keywords: SARS-CoV-2, Primary Care, COVID-19, Randomized controlled trial, Long term follow-up