Publications by authors named "Michael A Proschan"

The first Adaptive COVID-19 Treatment Trial (ACTT-1) showed that remdesivir improved COVID-19 recovery time compared with placebo in hospitalized adults. The secondary outcome of mortality was almost significant overall (p = 0.07) and highly significant for people receiving supplemental oxygen at enrollment (p = 0.

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Article Synopsis
  • The COVID-19 pandemic underscored the importance of efficient randomized clinical trials, and the Multiplatform Randomized Clinical Trial (mpRCT) utilized Bayesian methods for quicker decisions regarding drug efficacy and futility compared to traditional approaches.
  • Bayesian methods involve translating prior beliefs about a treatment's effectiveness into hypothetical data, which are then combined with actual trial data to derive conclusions.
  • The study found that the Bayesian efficacy boundary in the mpRCT closely aligns with the frequentist Pocock boundary, suggesting that the methods may yield similar outcomes in monitoring trial efficacy and futility.
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Designing clinical trials for emerging infectious diseases such as COVID-19 is challenging because information needed for proper planning may be lacking. Pre-specified adaptive designs can be attractive options, but what happens if a trial with no such design needs to be modified? For example, unexpectedly high efficacy (approximately 95%) in two COVID-19 vaccine trials might cause investigators in other COVID-19 vaccine trials to increase the number of interim analyses to allow earlier stopping for efficacy. If such a decision is based solely on external data, there are no issues, but what if internal trial data by arm are also examined? Fortunately, the conditional error principle of Müller and Schäfer (2004) can be used to ensure no inflation of the type 1 error rate, even if no interim analyses were planned.

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Rare events can sometime arise in clinical development of treatments. For example, CYPIDES was a single-arm study of the CYP11A1 inhibitor ODM-208 to treat metastatic prostate cancer. Preclinical testing of the compound identified elevated thyroid-stimulating hormone (TSH) and bilirubin in rats and dogs.

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Background: Toxoplasmic encephalitis (TE) is a life-threatening complication of people with human immunodeficiency virus (PWH) with severe immunodeficiency, especially those with a CD4 T-cell count <100 cells/µL. Following a clinical response to anti- therapy, and immune reconstitution after initiation of combination antiretroviral therapy (ART), anti- therapy can be discontinued with a low risk of relapse.

Methods: To better understand the evolution of magnetic resonance imaging (MRI)-defined TE lesions in PWH receiving ART, we undertook a retrospective study of PWH initially seen at the National Institutes of Health between 2001 and 2012, who had at least 2 serial MRI scans.

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SARS-CoV-2 mRNA booster vaccines provide protection from severe disease, eliciting strong immunity that is further boosted by previous infection. However, it is unclear whether these immune responses are affected by the interval between infection and vaccination. Over a 2-month period, we evaluated antibody and B cell responses to a third-dose mRNA vaccine in 66 individuals with different infection histories.

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SARS-CoV-2 mRNA booster vaccines provide protection from severe disease, eliciting strong immunity that is further boosted by previous infection. However, it is unclear whether these immune responses are affected by the interval between infection and vaccination. Over a two-month period, we evaluated antibody and B-cell responses to a third dose mRNA vaccine in 66 individuals with different infection histories.

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Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV). However, eradication of the virus in individuals with HIV has not been possible to date. Given that HIV suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication.

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Hung et al. (2007) considered the problem of controlling the type I error rate for a primary and secondary endpoint in a clinical trial using a gatekeeping approach in which the secondary endpoint is tested only if the primary endpoint crosses its monitoring boundary. They considered a two-look trial and showed by simulation that the naive method of testing the secondary endpoint at full level α at the time the primary endpoint reaches statistical significance does not control the familywise error rate at level α.

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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.

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Benkeser et al. present a very informative paper evaluating the efficiency gains of covariate adjustment in settings with binary, ordinal, and time-to-event outcomes. The adjustment method focuses on estimating the marginal treatment effect averaged over the covariate distribution in both arms combined.

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The first table in many articles reporting results of a randomized clinical trial compares baseline factors across arms. Results that appear inconsistent with chance trigger suspicion, and in one case, accusation and confirmation of data falsification. We confirm theoretically results of simulation analyses showing that inconsistency with chance is extremely difficult to prove in the absence of any information about correlations between baseline covariates.

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Article Synopsis
  • Adaptive designs (ADs) allow for planned modifications during clinical trials without affecting the validity of the overall results, but there is a need for clearer reporting practices.
  • The Adaptive designs CONSORT Extension (ACE) guideline was created to improve how randomized trials using ADs are documented, involving input from global experts in the field.
  • The ACE guideline includes checklists with new and modified items to ensure comprehensive reporting, ultimately aiming to enhance the transparency and reproducibility of AD trials, thereby benefiting future research and practice.
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Adaptive designs (ADs) allow pre-planned changes to an ongoing trial without compromising the validity of conclusions and it is essential to distinguish pre-planned from unplanned changes that may also occur. The reporting of ADs in randomised trials is inconsistent and needs improving. Incompletely reported AD randomised trials are difficult to reproduce and are hard to interpret and synthesise.

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Multiple comparison adjustments have a long history, yet confusion remains about which procedures control type 1 error rate in a strong sense and how to show this. Part of the confusion stems from a powerful technique called the closed testing principle, whose statement is deceptively simple, but is sometimes misinterpreted. This primer presents a straightforward way to think about multiplicity adjustment.

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Despite the substantial clinical benefits of antiretroviral therapy (ART), complete eradication of HIV has not been possible. The gastrointestinal tract and associated lymphoid tissues may play an important role in the pathogenesis of HIV infection. The integrin αβ facilitates homing of T lymphocytes to the gut by binding to the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed on venules in gut-associated lymphoid tissue.

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As randomization methods use more information in more complex ways to assign patients to treatments, analysis of the resulting data becomes challenging. The treatment assignment vector and outcome vector become correlated whenever randomization probabilities depend on data correlated with outcomes. One straightforward analysis method is a re-randomization test that fixes outcome data and creates a reference distribution for the test statistic by repeatedly re-randomizing according to the same randomization method used in the trial.

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Background: Adequate reporting of adaptive designs (ADs) maximises their potential benefits in the conduct of clinical trials. Transparent reporting can help address some obstacles and concerns relating to the use of ADs. Currently, there are deficiencies in the reporting of AD trials.

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Despite substantial clinical benefits, complete eradication of HIV has not been possible using antiretroviral therapy (ART) alone. Strategies that can either eliminate persistent viral reservoirs or boost host immunity to prevent rebound of virus from these reservoirs after discontinuation of ART are needed; one possibility is therapeutic vaccination. We report the results of a randomized, placebo-controlled trial of a therapeutic vaccine regimen in patients in whom ART was initiated during the early stage of HIV infection and whose immune system was anticipated to be relatively intact.

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Despite the best efforts of investigators, problems forcing design changes can occur in clinical trials. Changes are usually relatively minor, but sometimes not. The primary endpoint or analysis may need to be revised, for example.

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Background And Aims: Multi-arm, multi-stage trials have recently gained attention as a means to improve the efficiency of the clinical trials process. Many designs have been proposed, but few explicitly consider the inherent issue of multiplicity and the associated type I error rate inflation. It is our aim to propose a straightforward design that controls family-wise error rate while still providing improved efficiency.

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Background: The discovery of potent and broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) has made passive immunization a potential strategy for the prevention and treatment of HIV infection. We sought to determine whether passive administration of VRC01, a bNAb targeting the HIV CD4-binding site, can safely prevent or delay plasma viral rebound after the discontinuation of antiretroviral therapy (ART).

Methods: We conducted two open-label trials (AIDS Clinical Trials Group [ACTG] A5340 and National Institutes of Health [NIH] 15-I-0140) of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of VRC01 in persons with HIV infection who were undergoing interruption of ART.

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