The general structure of this Adaptive Platform Trial (APT) consists of a 30-day Screening Period, a 12-week Platform Treatment Period, and a 4-week Safety Follow-up. The trial begins with 3 open platform cohorts (it is possible for 1 of the cohorts to begin sooner than the others, as necessary). Importantly, the integration of multi-modal biomarker assessments within the DOD PTSD APT allows for defining future cohorts based on to-be-determined biomarker signatures in a multi stage approach. Initial testing in non-biomarker-defined cohorts will be referred to as main stage testing, while testing in biomarker-defined cohorts will occur within biomarker extensions.~Initially viewed as a 3-arm trial versus control, the adaptive platform trial will continue enrollment until decisions are made to stop all of the cohorts. At quarterly interim analyses, unblinded data will be reviewed by an independent, firewalled Independent Statistical Analysis Committee (ISAC) and a Data Safety Monitoring Board (DSMB). At each interim analysis, the possible cohort-level decisions that could be made include stopping enrollment to a cohort for futility, anticipated success, or for reaching the maximum sample size. New cohorts for investigation can be added at any time. The DSMB may recommend stopping a cohort for safety reasons.~Candidate biomarker data will be retrospectively analyzed after each cohort has completed main stage testing, and cohort testing may be re-initiated for prospective evaluation of the treatment in a subject population enriched (eg, either only biomarker positive or only biomarker negative subjects would be enrolled) or stratified based on biomarker status. In addition, candidate biomarkers (which may also be characterized or validated externally to the DOD PTSD APT) may be used to stratify randomization across cohorts or as a prospective enrichment strategy at the initiation of a cohort. Exploratory biomarker data will be evaluated throughout the trial to identify additional candidate biomarkers for testing within the APT, or to inform candidate drug selection for additional cohorts.
This is a Phase 2 randomized, double-blinded, placebo-controlled study that will evaluate multiple potential pharmacotherapeutic interventions for PTSD utilizing an adaptive platform trial design. Subjects are randomized among the multiple cohorts in the study and the resulting randomization enables sharing/pooling of control subjects, where all interventions may be compared to a common control (placebo). This master protocol describes the default procedures and analyses for all cohorts; treatment-specific procedures will be described in the Master Protocol cohort-specific appendices. Individual cohorts may have additional eligibility requirements or safety and efficacy procedures.