Integrating biological treatment mechanisms into randomized clinical trials: Design of PROGrESS (PROlonGed ExpoSure and Sertraline Trial).

Increased emphasis on mechanisms of treatment effectiveness, biomarker predictors, and objective indicators of treatment response has sparked interest in integrated, translational treatment outcomes trials. The PROlonGed ExpoSure and Sertraline Trial (PROGrESS) is one such randomized controlled trial (RCT) focused on a key question in clinical management of posttraumatic stress disorder (PTSD) - the comparative and combined effectiveness of medication and psychotherapy. PROGrESS employs a state of the art trial design to examine psychotherapy and medication effects across three conditions: 1) Prolonged Exposure (PE) plus pill placebo, 2) Sertraline (SERT) plus Enhanced Medication Management (EMM), and 3) Combined treatment (PE/SERT). Innovative measures will capture potential biomarker predictors and indicators of treatment response within and across these three treatment conditions in Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) service members and veterans with PTSD. Assessments include clinician-rated measures, self-report outcome measures, saliva for salivary cortisol and cortisol response to awakening at six assessment points, blood at baseline and week 24 for genetic and genomic analysis, as well as resting state connectivity and emotion processing and regulation using functional Magnetic Resonance Imaging (fMRI) paradigms in a subsample of veterans. Accordingly, the current study is designed to provide pragmatic clinical direction for the delivery of PTSD treatment through its primary outcomes in an effectiveness design, and will also provide informative results to elucidate underlying mechanisms and biomarkers involved in PTSD treatment response.