Effectiveness of oral and inhaled repurposed and antiviral pharmaceutical treatments for acute SARS-CoV-2 in outpatient settings: a systematic review of 124 randomized trials.

BACKGROUND

Outpatient therapeutics for SARS-CoV-2 remain critical to reducing disease severity, preventing hospitalization, and mitigating long-term complications, yet evidence across trials has been fragmented and evolving.

OBJECTIVE

To systematically identify and evaluate the effectiveness of oral or inhaled pharmaceutical treatments, including repurposed and antiviral therapies, for acute SARS-CoV-2 infection in adult patients managed in outpatient settings.

METHODS

Comprehensive peer-reviewed searches were conducted in several databases for studies published by March 2024. We included randomized controlled trials evaluating oral or inhaled therapeutics administered to adults with acute SARS-CoV-2 infection in outpatient settings and excluded non-randomized and observational studies. Outcomes of interest included severe clinical outcomes. Random-effects meta-analyses were performed where feasible.

RESULTS

A total of 124 randomized controlled trials evaluating 137 therapeutics across 35 countries were included. Most interventions were repurposed agents (n = 88), with 33 antiviral and three combination regimens. Molnupiravir shortened time to recovery and reduced hospitalization in a subgroup pool of unvaccinated, higher-risk outpatients (OR 0.68, 95% CI 0.52-0.89), although this effect attenuated when mostly vaccinated patients was included (OR 0.83, 95% CI 0.58-1.19). Inhaled budesonide and metformin showed modest or setting-specific benefits, while most repurposed drugs, including fluvoxamine, ivermectin, and hydroxychloroquine, had no consistent clinical impact. Safety profiles were class-typical with no new signals identified.

CONCLUSIONS

Most repurposed and antiviral therapies evaluated in outpatient COVID-19 trials showed no consistent benefit for severe clinical outcomes. Modest or setting-specific effects were observed for inhaled budesonide, metformin, and molnupiravir, with molnupiravir's effect on hospitalization most evident in unvaccinated, higher-risk outpatients and unreplicated for mortality.

CLINICAL TRIAL NUMBER: Not applicable.