Hydroxychloroquine/chloroquine for the treatment of hospitalized patients with COVID-19: An individual participant data meta-analysis (preprint)

Background Results: from observational studies and randomized clinical trials (RCTs) have led to the consensus that hydroxychloroquine (HCQ) and chloroquine (CQ) are not effective for COVID-19 prevention or treatment. Pooling individual participant data, including unanalyzed data from trials terminated early, enables more detailed investigation of the efficacy and safety of HCQ/CQ among subgroups of hospitalized patients. Methods We searched ClinicalTrials.gov in May and June 2020 for US-based RCTs evaluating HCQ/CQ in hospitalized COVID-19 patients in which the outcomes defined in this study were recorded or could be extrapolated. The primary outcome was a 7-point ordinal scale measured between day 28 and 35 post enrollment; comparisons used proportional odds ratios. Harmonized de-identified data were collected via a common template spreadsheet sent to each principal investigator. The data were analyzed by fitting a prespecified Bayesian ordinal regression model and standardizing the resulting predictions. Results Eight of 19 trials met eligibility criteria and agreed to participate. Patient-level data were available from 770 participants (412 HCQ/CQ vs 358 control). Baseline characteristics were similar between groups. We did not find evidence of a difference in COVID-19 ordinal scores between days 28 and 35 post-enrollment in the pooled patient population (odds ratio, 0.97; 95% credible interval, 0.76-1.24; higher favors HCQ/CQ), and found no convincing evidence of meaningful treatment effect heterogeneity among prespecified subgroups. Adverse event and serious adverse event rates were numerically higher with HCQ/CQ vs control (0.39 vs 0.29 and 0.13 vs 0.09 per patient, respectively). Conclusions The findings of this individual participant data meta-analysis reinforce those of individual RCTs that HCQ/CQ is not efficacious for treatment of COVID-19 in hospitalized patients.

Real-World Effectiveness and Tolerability of Monoclonal Antibodies for Ambulatory Patients with Early COVID-19 (preprint)

ImportanceInterventions to reduce hospitalization of patients with COVID-19 are urgently needed. Randomized trials for efficacy suggest that anti-SARS-CoV2 neutralizing monoclonal antibodies (MAb) may reduce medically-attended visits and hospitalization but effectiveness has not been confirmed in a real-world setting. ObjectiveEstimate the effectiveness of MAb infusion in a real-world cohort of ambulatory patients with early symptomatic COVID-19 at high risk for hospitalization. DesignQuasi-experimental observational cohort study using target trial emulation and causal inference methodology in pre-and post-implementation groups. SettingInfusion centers and urgent care clinics within an integrated healthcare system in the United States Participants13,534 high-risk adult outpatients with symptomatic, laboratory-confirmed COVID-19 within 7 days of symptom onset. ExposuresA single intravenous infusion of either bamlanivimab 700 mg or casirivimab/imdevimab 1200 mg/1200 mg. Main Outcomes and MeasuresThe primary outcome was emergency department visit or hospitalization within 14 days of positive test. Patients who received MAb infusion were compared to contemporaneous controls using inverse probability of treatment weighting, and to a pre-implementation cohort using propensity-weighted interrupted time series analysis. An exploratory analysis compared effectiveness of casirivimab/imdevimab and bamlanivimab. Results7404 patients who would have been MAb-eligible were identified in a pre-implementation cohort (July 1-November 27, 2020). In the post-implementation period (November 28, 2020-January 28, 2021), 594 received MAb treatment and 5536 MAb-eligible patients did not. Among Mab recipients, 479 (80.6%) received bamlanivimab and 115 (19.4%) casirivimab/imdevimab. The primary outcome occurred in 75 (12.6%) MAb recipients, 1018 (18.4%) contemporaneous controls, and 1525 (20.6%) patients in the pre-implementation cohort. MAb treatment was associated with fewer subsequent emergency department visits and hospitalizations (odds ratio estimating the average treatment effect 0.69, 95% CI 0.60-0.79). After implementation, propensity-weighted probability of emergency department visit or hospitalization decreased by 0.7% per day (95% CI 0.03-0.10%, p<0.001). Overall, 7 (1.2%) MAb patients experienced an adverse event; two (0.3%) were considered serious. In the exploratory analysis, the effect of casirivimab/imdevimab versus bamlanivimab was not significant (OR 0.52, 95% CI 0.17-1.63, p=0.26). Conclusions and RelevanceMAb treatment of high-risk ambulatory patients with early COVID-19 was well-tolerated and effective at preventing the need for subsequent medically-attended care. Key Points SectionO_ST_ABSQuestionC_ST_ABSWhat is the real-world effectiveness of COVID-19 monoclonal neutralizing antibody (MAb) infusions in high-risk, ambulatory patients? Findings594 high-risk, early-symptomatic adults with COVID-19 treated with MAb infusion were compared to 5536 contemporaneous controls using inverse probability of treatment weighting, and to 7404 patients in a pre-implementation cohort using propensity-weighted interrupted time series analysis. MAb treatment was associated with fewer subsequent emergency department visits and hospitalizations (odds ratio 0.69 (95% CI 0.60-0.79). After MAb implementation the probability of emergency department visit or hospitalization decreased by 0.7% per day, 95% CI 0.03-0.10%, p<0.001). MeaningMonoclonal antibody infusion within seven days of symptom onset in high-risk ambulatory adults with COVID-19 appears to prevent subsequent emergency department visits and hospitalization. Further evaluation of the differences between specific Mab products is warranted.