A Phase 2a, Randomized, Placebo-Controlled Human Challenge Trial to Evaluate the Efficacy and Safety of Molnupiravir in Healthy Participants Inoculated with Respiratory Syncytial Virus

Abstract

Introduction: Human respiratory syncytial virus (RSV) infections can result in hospitalization and/or death among vulnerable populations. Molnupiravir is a prodrug of ß-D-N4-hydroxycytidine, which has broad-spectrum preclinical activity against RNA viruses. We conducted a pilot trial evaluating molnupiravir for RSV infection.

Methods: Double-blind, placebo-controlled, phase 2a human challenge study in healthy adults (≥ 18 to ≤ 55 years old). Eligible participants were randomized 1:1:1 to molnupiravir prophylaxis (5 days, 800 mg twice daily; followed by placebo), molnupiravir treatment (5 days, 800 mg twice daily; started on day 5, unless triggered earlier by positive PCR test; preceded and followed by placebo), or placebo. Study intervention was administered for 11 days, from day -1 (evening), prior to inoculation with RSV on day 0 (morning). For 10 days, quarantined participants reported symptoms thrice daily and underwent nasal wash sample collection twice daily. Primary efficacy endpoints (assessed by quantitative viral culture on plaque assay) were peak viral load (PVL) in all participants (for prophylaxis) and area under the viral-load time curve (VL-AUC) in participants with confirmed infection (for treatment). Adverse events were assessed from day 0 to day 28.

Results: Forty participants each were randomized to prophylaxis and placebo and 36 to treatment. Molnupiravir was not statistically significant from placebo in either primary endpoint: with prophylaxis, the difference in mean log₁₀ PVL was - 0.29 plaque-forming units (PFU)/ml (90% CI - 1.16, 0.58; p = 0.578), and with treatment, the difference in mean log₁₀ VL-AUC was - 2.69 day*PFU/ml (90% CI - 6.17, 0.79; p = 0.201). Molnupiravir treatment resulted in significantly faster symptom resolution: 6.0 days versus 8.5 days with placebo (hazard ratio: 2.24 [95% CI: 0.99, 5.07]; p = 0.0459). Adverse event rates were comparable between arms.

Conclusions: Although the primary endpoints were not met, modest, non-significant benefits with molnupiravir treatment were seen across virologic endpoints, along with significantly faster symptom resolution.

Clinical trial registration: ClinicalTrials.gov NCT05559905.

Keywords: Antiviral; Clinical trial; Efficacy; Human challenge; Molnupiravir; RSV; hVCM.

Fig. 1

CONSORT diagram indicating the flow of participants through the trial. ^aAll randomized participants were inoculated with RSV. FAS full analysis set (defined as all randomized participants who received both the RSV inoculation and ≥ 1 dose of study intervention), FAS-I full analysis set-infected (defined as all participants in the FAS population who had confirmed RSV infection), MOV molnupiravir

Fig. 2

Mean (standard error) viral load and total clinical symptoms for A molnupiravir prophylaxis in the FAS analysis population and B molnupiravir triggered treatment in the FAS-I analysis population. For treatment, the number of participants with data available became less as time progressed, resulting in greater variability in the depicted mean results for viral load by qRT-PCR and in total symptom score, after day 7. The lower limits of quantification were 3.24 log₁₀ copies/ml in the qRT-PCR assay and 2 log₁₀ PFU/ml in the plaque assay. n number of participants in the FAS primary analysis population (prophylaxis) or FAS-I primary analysis population (treatment)

Fig. 3

Kaplan–Meier curves of time to symptom resolution from initial administration of study intervention in the FAS-I analysis population of the molnupiravir treatment arm (n = 23) versus the placebo arm (n = 26). Participants without confirmed symptom resolution by the end of the trial were censored at their last date of symptom scoring