Background: During pandemics, early outpatient treatments reduce the health system burden. Randomized controlled trials (RCTs) in COVID-19 outpatients have tested therapeutic agents, but no RCT or systematic review has been conducted comparing the efficacy of the main outpatient treatment classes to each other. We aimed in this systematic review of outpatient RCTs in COVID-19 to compare hospitalisation rate reductions with four classes of treatment: convalescent plasma, monoclonal antibodies, small molecule antivirals and repurposed drugs.
Methods: We conducted a systematic review and meta-analysis of all COVID-19 outpatient RCTs that included the endpoint of progression to hospitalisation. We assembled, from multiple published and preprint databases, participant characteristics, hospitalisations, resolution of symptoms and mortality from January 2020 to May 21, 2023. The risk of bias from COVID-NMA was incorporated into the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. We measured heterogeneity with I 2 . Meta-analysis by a random or fixed effect model dependent on significant heterogeneity (I 2 >50%) was performed. The protocol was registered in PROSPERO, CRD42022369181.
Findings: The search identified 281 studies of which 54 RCTs for 30 diverse interventions were included in the final analysis. These trials, performed largely in unvaccinated cohorts during pre-Omicron waves, focused on populations with at least one COVID-19 hospitalisation risk factor. Grouping by class, monoclonal antibodies (OR=0.31 [95% CI=0.24-0.40]) had highest efficacy, followed by COVID-19 convalescent plasma (CCP) (OR=0.69 [95% CI=0.53 to 0.90]) and small molecule antivirals (OR=0.78 [95% CI=0.48-1.33]) for hospital reduction. Repurposed drugs (OR=0.82 [95% CI-0.72-0.93]) had lower efficacy.
Interpretation: Inasmuch as omicron sublineages (XBB and BQ.1.1) are now resistant to monoclonal antibodies, oral antivirals are the preferred treatment in outpatients where available, but intravenous interventions from convalescent plasma to remdesivir are also effective and necessary in constrained medical resource settings or for acute and chronic COVID-19 in the immunocompromised.
Funding: US Department of Defense and National Institute of Health.
Research in context: Evidence before this study: We systematically searched the published and preprint data bases for outpatient randomized clinical trials of treatment of COVID-19 disease with hospitalisation as an endpoint. Previous systematic reviews and meta-analyses have confined the reviews to specific classes such as convalescent plasma, monoclonal antibodies, small molecule antivirals or repurposed drugs. Few comparisons have been made between these therapeutic classes. The trials took place both in the pre-vaccination and the vaccination era, spanning periods with dominance of different COVID variants. We sought to compare efficacy between the four classes of treatments listed above when used in outpatient COVID-19 patients as shown in randomized, placebo-controlled trials.
Added value of this study: This systematic review and meta-analysis brings together trials that assessed hospitalisation rates in diverse COVID-19 outpatient populations varying in age and comorbidities, permitting us to assess the efficacy of interventions both within and across therapeutic classes. While heterogeneity exists within and between these intervention classes, the meta-analysis can be placed in context of trial diverse populations over variant time periods of the pandemic. At present most of the world population has either had COVID-19 or been vaccinated with a high seropositivity rate, indicating that future placebo-controlled trials will be limited because of the sample sizes required to document hospitalisation outcomes.
Implications of all the available evidence: Numerous diverse therapeutic tools need to be ready for a resilient response to changing SARS-CoV-2 variants in both immunocompetent and immunocompromised COVID-19 outpatient populations. To date few head-to-head randomized controlled trials (RCTs) has compared treatment options for COVID-19 outpatients, making comparisons and treatment choices difficult. This systematic review compares outcomes among RCTs of outpatient therapy for COVID-19, taking into account time between onset of symptoms and treatment administration. We found that small-chemical antivirals, convalescent plasma and monoclonal antibodies had comparable efficacy between classes and amongst interventions within the four classes. Monoclonals have lost efficacy with viral mutation, and chemical antivirals have contraindications and adverse events, while intravenous interventions like convalescent plasma or remdesivir remain resilient options for the immunocompromised, and, in the case of CCP, in resource constrained settings with limited availability of oral drugs.