A 3-month clofazimine-rifapentine-containing regimen for drug-susceptible tuberculosis versus standard of care (Clo-Fast): a randomised, open-label, phase 2c clinical trial.

Background: Based on results from preclinical and clinical studies, a five-drug combination of isoniazid, rifapentine, pyrazinamide, ethambutol, and clofazimine was identified with treatment shortening potential for drug-susceptible tuberculosis; the Clo-Fast trial aimed to determine the efficacy and safety of this regimen. We compared 3 months of isoniazid, rifapentine, pyrazinamide, ethambutol, and clofazimine, administered with a clofazimine loading dose, to the standard 6 month regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol in drug-susceptible tuberculosis.

Methods: Clo-Fast was a phase 2c open-label trial recruiting participants at six sites in five countries.

Risks for sudden cardiac and undetermined cause of death among people with HIV in the REPRIEVE primary cardiovascular prevention trial.

Objective: People with HIV (PWH) are at increased risk of sudden cardiac death (SCD) but the mechanisms are unclear limiting prevention efforts. We leveraged the global REPRIEVE trial with carefully adjudicated atherosclerotic cardiovascular disease (ASCVD) outcomes to determine cardiac, behavioral, and HIV-specific risks associated with SCD and assess potential similarities to undetermined deaths (UDD).

Design/methods: REPRIEVE included 7769 PWH with low-to-moderate traditional ASCVD risk without known ASCVD randomized to pitavastatin vs.

Summary measures in non-inferiority clinical trials with a time-to-event outcome: an empirical comparison of power.

Background: Time-to-event data is commonly used in non-inferiority clinical trials. While the hazard ratio is a popular summary measure in this context, the difference in restricted mean survival time has been theoretically shown to increase power and interpretability. This study aimed to empirically compare the power of the hazard ratio, difference in survival and difference in restricted mean survival time for non-inferiority clinical trials with a time-to-event outcome recently published in key clinical journals.

Estimands for clinical endpoints in tuberculosis treatment randomized controlled trials: a retrospective application in a completed trial.

Background: Randomized trials for the treatment of tuberculosis (TB) rely on a composite primary outcome to capture unfavorable treatment responses. However, variability between trials in the outcome definition and estimation methods complicates across-trial comparisons and hinders the advancement of treatment guidelines. The International Council for Harmonization (ICH) provides international regulatory standards for clinical trials.

An evaluation of confidence intervals for a cumulative proportion to enable decisions at interim reviews of single-arm trials.

Background: Clinical trials often include interim analyses of the proportion of participants experiencing an event by a fixed time-point. A pre-specified proportion excluded from a corresponding confidence interval (CI) may lead an independent monitoring committee to recommend stopping the trial. Frequently this cumulative proportion is estimated by the Kaplan-Meier estimator with a Wald approximate CI, which may have coverage issues with small samples.

Estimands for clinical endpoints in Tuberculosis treatment randomized controlled trials: a retrospective application in a completed trial.

Background: Randomized trials for the treatment of tuberculosis (TB) rely on a composite primary outcome to capture unfavorable treatment responses. However, variability between trials in the outcome definition and estimation methods complicates across-trial comparisons and hinders the advancement of treatment guidelines. The International Council for Harmonization (ICH) provides international regulatory standards for clinical trials.

Prevalence and Correlates of Electrocardiographic Abnormalities in Adults With HIV: Insights From the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE).

Background: People with HIV (PWH) are at increased risk of cardiovasvular disease (CVD) and sudden cardiac death. Previous work has suggested an association between HIV infection and electrocardiographic (ECG) abnormalities. There are limited data on the burden of ECG abnormalities among PWH in a multiracial, multiethnic globally representative population.

Counterfactual mediation analysis in the multistate model framework for surrogate and clinical time-to-event outcomes in randomized controlled trials.

In cancer randomized controlled trials, surrogate endpoints are frequently time-to-event endpoints, subject to the competing risk from the time-to-event clinical outcome. In this context, we introduce a counterfactual-based mediation analysis for a causal assessment of surrogacy. We use a multistate model for risk prediction to account for both direct transitions towards the clinical outcome and indirect transitions through the surrogate outcome.

Treatment Effect Measures for Culture Conversion Endpoints in Phase IIb Tuberculosis Treatment Trials.

Phase IIb trials of tuberculosis therapy rely on early biomarkers of treatment effect. Despite limited predictive ability for clinical outcomes, culture conversion, the event in which an individual previously culture positive for Mycobacterium tuberculosis yields a negative culture after initiating treatment, is a commonly used endpoint. Lack of consensus on how to define the outcome and corresponding measure of treatment effect complicates interpretation and limits between-trial comparisons.

Multivariate meta-analysis model for the difference in restricted mean survival times.

In randomized controlled trials (RCTs) with time-to-event outcomes, the difference in restricted mean survival times (RMSTD) offers an absolute measure of the treatment effect on the time scale. Computation of the RMSTD relies on the choice of a time horizon, $\tau$. In a meta-analysis, varying follow-up durations may lead to the exclusion of RCTs with follow-up shorter than $\tau$.

Design analysis indicates Potential overestimation of treatment effects in randomized controlled trials supporting Food and Drug Administration cancer drug approvals.

Objective: Statistical significance drives interpretation of randomized controlled trials (RCTs). We examined the type S error risk-claiming a new drug is falsely beneficial-and exaggeration ratio-how estimated effects differ from true effects-to re-emphasize direction and magnitude of treatment effects.

Study Design And Setting: We systematically reviewed RCTs supporting Food and Drug Administration (FDA) approval of cancer drugs between 2007 and 2016.

Design of non-inferiority randomized trials using the difference in restricted mean survival times.

Background/aims Non-inferiority trials with time-to-event outcomes are becoming increasingly common. Designing non-inferiority trials is challenging, in particular, they require very large sample sizes. We hypothesized that the difference in restricted mean survival time, an alternative to the hazard ratio, could lead to smaller required sample sizes.