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Launching a comparative effectiveness adaptive platform trial of monoclonal antibodies for COVID-19 in 21 days.

ABSTRACT: Outpatient treatments that limit progression to severe coronavirus disease 2019 (COVID-19) are of vital importance to optimise patient outcomes and public health. Monoclonal antibodies (mAb) demonstrated ability to decrease hospitalizations in randomized, clinical trials. However, there are many barriers to mAb treatment such as patient access and clinician education. There are no data comparing efficacy or safety of available mAbs. We sought to rapidly launch an adaptive platform trial with the goals of enhancing access to treatment, regardless of geography and socioeconomic status, and evaluating comparative efficacy and safety of available mAbs. Within 21 days from idea genesis, we allocated mAb treatment to all patients within the context of this clinical trial. Within 2 months, we closed the gap of the likelihood of receiving mAb, conditional on background positivity rate, between Black and White patients (Black patients 0.238; White patients 0.241). We describe trial infrastructure, lessons learned, and future directions for a culture of learning while doing.

SUBMITTER: McCreary EK

PROVIDER: S-EPMC8654455 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Launching a comparative effectiveness adaptive platform trial of monoclonal antibodies for COVID-19 in 21 days.

McCreary Erin K EK Bariola J Ryan JR Minnier Tami T Wadas Richard J RJ Shovel Judith A JA Albin Debbie D Marroquin Oscar C OC Schmidhofer Mark M Wisniewski Mary Kay MK Nace David A DA Sullivan Colleen C Axe Meredith M Meyers Russell R Khadem Tina T Garrard William W Collins Kevin K Wells Alan A Bart Robert D RD Linstrum Kelsey K Montgomery Stephanie K SK Haidar Ghady G Snyder Graham M GM McVerry Bryan J BJ Seymour Christopher W CW Yealy Donald M DM Huang David T DT Angus Derek C DC

Contemporary clinical trials 20211209

Outpatient treatments that limit progression to severe coronavirus disease 2019 (COVID-19) are of vital importance to optimise patient outcomes and public health. Monoclonal antibodies (mAb) demonstrated ability to decrease hospitalizations in randomized, clinical trials. However, there are many barriers to mAb treatment such as patient access and clinician education. There are no data comparing efficacy or safety of available mAbs. We sought to rapidly launch an adaptive platform trial with the ...[more]

PMID: 34896293

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Project description:BackgroundMonoclonal antibodies (mAb) that neutralize SARS-CoV-2 decrease hospitalization and death compared to placebo in patients with mild to moderate COVID-19; however, comparative effectiveness is unknown. We report the comparative effectiveness of bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab.MethodsA learning health system platform trial in a U.S. health system enrolled patients meeting mAb Emergency Use Authorization criteria. An electronic health record-embedded application linked local mAb inventory to patient encounters and provided random mAb allocation. Primary outcome was hospital-free days to day 28. Primary analysis was a Bayesian model adjusting for treatment location, age, sex, and time. Inferiority was defined as 99% posterior probability of an odds ratio < 1. Equivalence was defined as 95% posterior probability the odds ratio is within a given bound.FindingsBetween March 10 and June 25, 2021, 1935 patients received treatment. Median hospital-free days were 28 (IQR 28, 28) for each mAb. Mortality was 0.8% (1/128), 0.8% (7/885), and 0.7% (6/922) for bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab, respectively. Relative to casirivimab-imdevimab (n = 922), median adjusted odds ratios were 0.58 (95% credible interval [CI] 0.30-1.16) and 0.94 (95% CI 0.72-1.24) for bamlanivimab (n = 128) and bamlanivimab-etesevimab (n = 885), respectively. These odds ratios yielded 91% and 94% probabilities of inferiority of bamlanivimab versus bamlanivimab-etesevimab and casirivimab-imdevimab, and an 86% probability of equivalence between bamlanivimab-etesevimab and casirivimab-imdevimab.InterpretationAmong patients with mild to moderate COVID-19, bamlanivimab-etesevimab or casirivimab-imdevimab treatment resulted in 86% probability of equivalence. No treatment met prespecified criteria for statistical equivalence. Median hospital-free days to day 28 were 28 (IQR 28, 28) for each mAb.Funding and registrationThis work received no external funding. The U.S. government provided the reported mAb. This trial is registered at ClinicalTrials.gov, NCT04790786.

Project description:Antiviral drugs likely remain effective against the SARS-CoV-2 Omicron variant, while monoclonal antibody (mAb) therapies have experienced drops in neutralizing ability. This systematic review and network meta-analysis aims to estimate the comparative effectiveness of antivirals and mAb therapies for treating COVID-19 patients infected with Omicron, capturing primarily acute outcomes. We searched multiple databases from July 4 to July 19, 2022, with updates through November 4, 2022. Studies comparing the effectiveness of antivirals or mAb to either nonuser controls or other treatments were included. Risk of bias was assessed using the Cochrane RoB 2 and ROBINS-I tools. Data extraction and verification involved five independent researchers. Among 39 studies (727,893 individuals with COVID-19, including 38 nonrandomized trials), nirmatrelvir/ritonavir and sotrovimab were associated with lower risks of mortality (HR = 0.317, 95% credible intervals [CrI] = 0.144-0.678; HR = 0.176, 95%CrI = 0.052-0.527) and hospitalization (HR = 0.479, 95%CrI = 0.319-0.711; HR = 0.489, 95%CrI = 0.293-0.797) compared with nonuser controls. Remdesivir users were associated with a lower risk of hospitalization (HR = 0.367, 95%CrI = 0.147-0.868) but not mortality. Molnupiravir and bebtelovimab showed no significant benefits for these outcomes. In conclusion, among individuals infected with COVID-19 during the Omicron wave, mortality risk was lower with nirmatrelvir/ritonavir or sotrovimab use, whereas hospitalization was reduced with nirmatrelvir/ritonavir, remdesivir, or sotrovimab. Sotrovimab and nirmatrelvir/ritonavir were effective against Omicron B.1.1.529/BA.1 and BA.2/BA.4/BA.5 subvariants, respectively. A key limitation is that findings rely on data from the last search and may be impacted by potential changes in mortality risk due to immune evasion by emerging variants, highlighting the need for ongoing randomized trials across variants and populations. TRIAL REGISTRATION: The study was registered on PROSPERO, CRD42022351508.

Project description:BackgroundTreatment guidelines and U.S. Food and Drug Administration emergency use authorizations (EUAs) of monoclonal antibodies (mAbs) for treatment of high-risk outpatients with mild to moderate COVID-19 changed frequently as different SARS-CoV-2 variants emerged.ObjectiveTo evaluate whether early outpatient treatment with mAbs, overall and by mAb product, presumed SARS-CoV-2 variant, and immunocompromised status, is associated with reduced risk for hospitalization or death at 28 days.DesignHypothetical pragmatic randomized trial from observational data comparing mAb-treated patients with a propensity score-matched, nontreated control group.SettingLarge U.S. health care system.ParticipantsHigh-risk outpatients eligible for mAb treatment under any EUA with a positive SARS-CoV-2 test result from 8 December 2020 to 31 August 2022.InterventionSingle-dose intravenous mAb treatment with bamlanivimab, bamlanivimab-etesevimab, sotrovimab, bebtelovimab, or intravenous or subcutaneous casirivimab-imdevimab administered within 2 days of a positive SARS-CoV-2 test result.MeasurementsThe primary outcome was hospitalization or death at 28 days among treated patients versus a nontreated control group (no treatment or treatment ≥3 days after SARS-CoV-2 test date).ResultsThe risk for hospitalization or death at 28 days was 4.6% in 2571 treated patients and 7.6% in 5135 nontreated control patients (risk ratio [RR], 0.61 [95% CI, 0.50 to 0.74]). In sensitivity analyses, the corresponding RRs for 1- and 3-day treatment grace periods were 0.59 and 0.49, respectively. In subgroup analyses, those receiving mAbs when the Alpha and Delta variants were presumed to be predominant had estimated RRs of 0.55 and 0.53, respectively, compared with 0.71 for the Omicron variant period. Relative risk estimates for individual mAb products all suggested lower risk for hospitalization or death. Among immunocompromised patients, the RR was 0.45 (CI, 0.28 to 0.71).LimitationsObservational study design, SARS-CoV-2 variant presumed by date rather than genotyping, no data on symptom severity, and partial data on vaccination status.ConclusionEarly mAb treatment among outpatients with COVID-19 is associated with lower risk for hospitalization or death for various mAb products and SARS-CoV-2 variants.Primary funding sourceNone.

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Launching a comparative effectiveness adaptive platform trial of monoclonal antibodies for COVID-19 in 21 days.

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Launching a comparative effectiveness adaptive platform trial of monoclonal antibodies for COVID-19 in 21 days.

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