The precision interventions for severe and/or exacerbation-prone asthma (PrecISE) adaptive platform trial: statistical considerations

Ivanova, Anastasia; Israel, Elliot; LaVange, Lisa M.; Peters, Michael C.; Denlinger, Loren C.; Moore, Wendy C.; Bacharier, Leonard B.; Marquis, Miriam; Gotman, Nathan; Kosorok, Michael R.; Tomlinson, Chalmer; Mauger, David T.; Georas, Steve N.; Wright, Rosalind J.; Noël, Patricia; Rosner, Gary L.; Akuthota, Praveen; Billheimer, Dean; Bleecker, Eugene R.; Cardet, Juan Carlos; Castro, Mario; DiMango, Emily; Erzurum, Serpil C.; Fahy, John V.; Fajt, Merritt L.; Gaston, Benjamin; Holguín, Fernando; Jain, Sonia; Kenyon, Nicholas J.; Krishnan, Jerry A.; Kraft, Monica; Kumar, Rajesh; Liu, Mark C.; Ly, Ngoc P.; Moy, James N.; Phipatanakul, Wanda; Ross, Kristie; Smith, Lewis J.; Szefler, Stanley J.; Teague, W. Gerald; Wechsler, Michael E.; Wenzel, Sally E.; White, Steven R.

doi:10.1080/10543406.2020.1821705

Cited by 12 publications

(14 citation statements)

References 27 publications

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“…Randomisation at every step is weighted (initially in a 2:1 ratio) so that patients in the biomarker subgroup targeted by a particular intervention are more likely to receive that intervention, and definitions of the biomarker-defined subgroups are updated over time as trial data accumulate. 85 This approach allows for detection of drug effects in subgroups not anticipated to benefit from the drug as well as confirmation of non-responders, which are essential for targeted treatments. At the conclusion of this phase 2 signal-finding trial, novel therapies demonstrating efficacy across three dimensions of asthma severity (lung function, symptom control, and exacerbations), and the optimally defined disease subtype that each therapy should target, will be identified for further study in a phase 3 confirmatory trial.…”

Section: Clinical Trials To Advance Precision Medicinementioning

confidence: 99%

Advancing precision medicine for acute respiratory distress syndrome

Beitler

Thompson

Baron

et al. 2022

The Lancet Respiratory Medicine

108

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Acute respiratory distress syndrome (ARDS) is a heterogeneous clinical syndrome. Understanding of the complex pathways involved in lung injury pathogenesis, resolution, and repair has grown considerably in recent decades. Nevertheless, to date, only therapies targeting ventilation-induced lung injury have consistently proven beneficial, and despite these gains, ARDS morbidity and mortality remain high. Many candidate therapies with promise in preclinical studies have been ineffective in human trials, probably at least in part due to clinical and biological heterogeneity that modifies treatment responsiveness in human ARDS. A precision medicine approach to ARDS seeks to better account for this heterogeneity by matching therapies to subgroups of patients that are anticipated to be most likely to benefit, which initially might be identified in part by assessing for heterogeneity of treatment effect in clinical trials. In October 2019, the US National Heart, Lung, and Blood Institute convened a workshop of multidisciplinary experts to explore research opportunities and challenges for accelerating precision medicine in ARDS. Topics of discussion included the rationale and challenges for a precision medicine approach in ARDS, the roles of preclinical ARDS models in precision medicine, essential features of cohort studies to advance precision medicine, and novel approaches to clinical trials to support development and validation of a precision medicine strategy. In this Position Paper, we summarise workshop discussions, recommendations, and unresolved questions for advancing precision medicine in ARDS. Although the workshop took place before the COVID-19 pandemic began, the pandemic has highlighted the urgent need for precision therapies for ARDS as the global scientific community grapples with many of the key concepts, innovations, and challenges discussed at this workshop.

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Section: Clinical Trials To Advance Precision Medicinementioning

confidence: 99%

Advancing precision medicine for acute respiratory distress syndrome

Beitler

Thompson

Baron

et al. 2022

The Lancet Respiratory Medicine

108

View full text Add to dashboard Cite

show abstract

“…We will perform post hoc analyses to see whether we can identify other biomarkers that define responder subject subgroups. In Ivanova et al, 5 we consider the statistical implications of upfront adaptive assignment versus unbiased assignment in more detail.…”

Section: Upfront Assignment To Interventions Based On Phenotypic Biomarkersmentioning

confidence: 99%

“…To make the trial adaptive in this regard, we strove to introduce early futility analysis. Furthermore, we set moderately wide boundaries in these analyses (please see Statistical Analysis Publication 5 ). We recognized that setting wider futility boundaries may result in a higher likelihood of discontinuing ''effective'' therapies, and therefore tried to balance this consideration against our goals of testing multiple interventions.…”

Section: Early Futility Analysis and Futility Boundariesmentioning

confidence: 99%

PrecISE: Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment

Israel

Denlinger

Bacharier

et al. 2021

Journal of Allergy and Clinical Immunology

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“…Indeed, the discovery of distinct molecular phenotypes in asthma has motivated a shift in clinical trials toward endotype-based strategies (reviewed [ 15 ]). The PrecISE study (Precision Interventions for Severe and/or Exacerbation-prone Asthma) [ 16 ] is one such example, where six different treatments are now being tested across severe asthma phenotypes defined on the basis of variations in blood eosinophils, IL-6 levels in plasma, fractional exhaled nitric oxide, and genotypes in an adaptive Phase 2 clinical trial. These treatments target a variety of inflammatory mechanisms and include a tyrosine kinase inhibitor, anti-IL-6, a Janus kinase 1-selective inhibitor, medium-chain triglycerides, a modulator of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and Broncho-Vaxom; an endotoxin-low lyophilised extract from eight major respiratory bacterial pathogens.…”

Section: Gene Expression Signatures Reveal Immunophenotypes Biomarkers and Avenues For Therapeutic Interventionmentioning

confidence: 99%

Unlocking immune-mediated disease mechanisms with transcriptomics

Jong

Bosco

2021

Biochemical Society Transactions

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The transcriptome represents the entire set of RNA transcripts expressed in a cell, reflecting both the underlying genetic and epigenetic landscape and environmental influences, providing a comprehensive view of functional cellular states at any given time. Recent technological advances now enable the study of the transcriptome at the resolution of individual cells, providing exciting opportunities to characterise cellular and molecular events that underpin immune-medicated diseases. Here, we draw on recent examples from the literature to highlight the application of advanced bioinformatics tools to extract mechanistic insight and disease biology from bulk and single-cell transcriptomic profiles. Key considerations for the use of available analysis techniques are presented throughout.

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The precision interventions for severe and/or exacerbation-prone asthma (PrecISE) adaptive platform trial: statistical considerations

Cited by 12 publications

References 27 publications

Advancing precision medicine for acute respiratory distress syndrome

Advancing precision medicine for acute respiratory distress syndrome

PrecISE: Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment

Unlocking immune-mediated disease mechanisms with transcriptomics

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