Examining the bias-efficiency tradeoff from incorporation of nonconcurrent controls in platform trials: A simulation study example from the adaptive COVID-19 treatment trial.

Background: Platform trials typically feature a shared control arm and multiple experimental treatment arms. Staggered entry and exit of arms splits the control group into two cohorts: those randomized during the same period in which the experimental arm was open (concurrent controls) and those randomized outside that period (nonconcurrent controls). Combining these control groups may offer increased statistical power but can lead to bias if analyses do not account for time trends in the response variable.

PET/CT guided tuberculosis treatment shortening: a randomized trial.

Six months of chemotherapy using current agents is standard of care for pulmonary, drug-sensitive tuberculosis (TB), even though some are believed to be cured more rapidly and others require longer therapy. Understanding what factors determine the length of treatment required for durable cure in individual patients would allow individualization of treatment durations, provide better clinical tools to determine the of appropriate duration of new regimens, as well as reduce the cost of large Phase III studies to determine the optimal combinations to use in TB control programs. We conducted a randomized clinical trial in South Africa and China that recruited 704 participants with newly diagnosed, drug-sensitive pulmonary tuberculosis and stratified them based on radiographic disease characteristics as assessed by FDG PET/CT scan readers.

Group sequential designs for clinical trials when the maximum sample size is uncertain.

Motivated by the experience of COVID-19 trials, we consider clinical trials in the setting of an emerging disease in which the uncertainty of natural disease course and potential treatment effects makes advance specification of a sample size challenging. One approach to such a challenge is to use a group sequential design to allow the trial to stop on the basis of interim analysis results as soon as a conclusion regarding the effectiveness of the treatment under investigation can be reached. As such a trial may be halted before a formal stopping boundary is reached, we consider the final analysis under such a scenario, proposing alternative methods for when the decision to halt the trial is made with or without knowledge of interim analysis results.

SARS-CoV-2 RNA and Nucleocapsid Antigen Are Blood Biomarkers Associated With Severe Disease Outcomes That Improve in Response to Remdesivir.

Background: Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter Adaptive COVID-19 Treatment Trial 1, which randomized patients to remdesivir or placebo.

Methods: Longitudinal specimens collected during hospitalization from a substudy of 642 patients with COVID-19 were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers.

Effects of remdesivir in patients hospitalised with COVID-19: a systematic review and individual patient data meta-analysis of randomised controlled trials.

Background: Interpretation of the evidence from randomised controlled trials (RCTs) of remdesivir in patients treated in hospital for COVID-19 is conflicting. We aimed to assess the benefits and harms of remdesivir compared with placebo or usual care in these patients, and whether treatment effects differed between prespecified patient subgroups.

Methods: For this systematic review and meta-analysis, we searched PubMed, Embase, the Cochrane COVID-19 trial registry, ClinicalTrials.

Design of an observational multi-country cohort study to assess immunogenicity of multiple vaccine platforms (InVITE).

In response to the COVID-19 pandemic, COVID-19 vaccines have been developed, and the World Health Oraganization (WHO) has granted emergency use listing to multiple vaccines. Studies of vaccine immunogenicity data from implementing COVID-19 vaccines by national immunization programs in single studies spanning multiple countries and continents are limited but critically needed to answer public health questions on vaccines, such as comparing immune responses to different vaccines and among different populations.

Subgroup Analyses: Subpar or Sublime?

Subgroup Analyses: Subpar or Sublime?This animated video explores some of the potential pitfalls of performing subgroup analyses in randomized controlled trials and explains how to approach potential findings with caution.

Noninferiority testing with censoring when the event rate is low.

The PREDICT TB trial tests noninferiority of an abbreviated treatment regimen (arm A) vs a conventional treatment regimen (arm C). Treatment trials of drug-susceptible tuberculosis are expected to have low event rates (ie, relapse probabilities around 3-5%). We examine the question of what is the "best" way to test for noninferiority in a setting with low event rates.

Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial.

Background: Baricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.

Methods: In this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site).

Data and Safety Monitoring Board Monitoring of Clinical Trials for Early Efficacy.

DSMB Monitoring of Clinical Trials for Early EfficacyIn this article in the DSMB mini-series, Dodd and Proschan review the clinical, ethical, and statistical issues that confront a DSMB when trial data suggest that the treatment under test is highly efficacious. Examples of such trials are reviewed.

Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial.

Background: Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19.

Methods: We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA).

Deconstructing the Treatment Effect of Remdesivir in the Adaptive Coronavirus Disease 2019 (COVID-19) Treatment Trial-1: Implications for Critical Care Resource Utilization.

Background: The Adaptive Coronavirus Disease 2019 (COVID-19) Treatment Trial-1 (ACTT-1) found that remdesivir therapy hastened recovery in patients hospitalized with COVID-19, but the pathway for this improvement was not explored. We investigated how the dynamics of clinical progression changed along 4 pathways: recovery, improvement in respiratory therapy requirement, deterioration in respiratory therapy requirement, and death.

Methods: We analyzed trajectories of daily ordinal severity scores reflecting oxygen requirements of 1051 patients hospitalized with COVID-19 who participated in ACTT-1.

Remdesivir for the Prevention of Invasive Mechanical Ventilation or Death in Coronavirus Disease 2019 (COVID-19): A Post Hoc Analysis of the Adaptive COVID-19 Treatment Trial-1 Cohort Data.

This post hoc analysis of the Adaptive Coronavirus Disease 2019 (COVID-19) Treatment Trial-1 (ACTT-1) shows a treatment effect of remdesivir (RDV) on progression to invasive mechanical ventilation (IMV) or death. Additionally, we create a risk profile that better predicts progression than baseline oxygen requirement alone. The highest risk group derives the greatest treatment effect from RDV.

Study protocol for a phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for HIV-associated tuberculous meningitis [LASER-TBM].

Tuberculous meningitis (TBM) is the most lethal form of tuberculosis with a mortality of ~50% in those co-infected with HIV-1. Current antibiotic regimens are based on those known to be effective in pulmonary TB and do not account for the differing ability of the drugs to penetrate the central nervous system (CNS). The host immune response drives pathology in TBM, yet effective host-directed therapies are scarce.

Monitoring Immune Activation with Whole-Body Fluorodeoxyglucose-Positron-Emission Tomography in Simian Immunodeficiency Virus-Infected Rhesus Macaques.

This study aimed to assess immune activation in tissues by measuring glucose metabolism with F-fluorodeoxyglucose (FDG) and investigate the associations of various peripheral markers of disease progression with initiation and interruption of combination antiretroviral therapy in SIV-infected rhesus macaques (). Mixed-effect linear models revealed a significant inverse association of peripheral blood CD4 T cell counts ( < 0.01) and a direct association of plasma viral load ( < 0.