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

Abstract

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.

Keywords: Severe asthma; adaptive design; biomarkers; clinical trial; master protocol; platform trial; precision medicine; therapy.

Figure 1.. PrecISE Study Structure.

See Section IV – Protocol Design and Analytic Scheme.

Figure 2.. Futility Analysis, Biomarker Adaptation, and Study Analysis for an Intervention in PrecISE.

Patients are characterized, and their biomarker characteristics are determined and assigned during the run-in (see text). Based on these biomarker characteristics (Table II) they are preferentially (but not exclusively) assigned to interventions and placebos throughout their participation in the trial (Figure 1). As seen in Figure 2, patients within the target biomarker subgroup (green band) and those outside the target subgroup (orange band) are assigned to each intervention. After an intervention has accumulated 60 patients within the target biomarker subgroup (green band) and 30 subjects outside the biomarker subgroup (orange band), a futility analysis is performed restricted to the within-target 60 patients (see text). If the intervention is dropped for futility, all patients still receiving that intervention are assigned to alternative interventions. If the intervention is not dropped for futility, subgroups are refined and subjects within and outside the newly refined biomarker thresholds are enrolled and evaluated as outlined with an additional scheduled refinement as shown. When 150 patients are enrolled within the varying refined subgroups a final efficacy analysis is performed restricted to the 150 patients within the refined subgroups.