Department of Defense PTSD Adaptive Platform Trial - Master Protocol

A Phase 2, Multi-center, Multi-arm, Randomized, Placebo-controlled, Double-blind, Adaptive Platform Study to Evaluate the Safety, Tolerability, and Efficacy of Potential Pharmacotherapeutic Interventions in Active-Duty Service Members and Veterans With PTSD

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. Participants are randomized among the multiple cohorts in the study and the resulting randomization enables sharing/pooling of control participants, 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, safety and efficacy procedures, or endpoints, which will be described in corresponding intervention-specific clinicaltrials.gov records.

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" participants 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. For information specific to each intervention included in this platform trial, please refer to the corresponding, separate, clinicaltrials.gov record.

Multiple interventions will be tested in this adaptive platform trial and each will be described in Master Protocol cohort-specific platform appendices.

The overall 2-stage randomization scheme will be implemented by an unblinded statistician who is otherwise uninvolved in study operations. Participants will be assigned a study number at Screening (Subject ID). In the first stage of randomization, eligible participants who complete screening will be randomly assigned to an open platform cohort for which they are eligible (both site PIs and participants are aware of the cohort assignment) and, within that cohort, the second stage of randomization is to intervention vs placebo (double-blind) using Interactive Response Technology (IRT). For this APT, participant assignment to a cohort will not be blinded. The tablets/capsules used in the cohorts may not be visually similar between cohorts and blinding to cohort assignment is not necessary to avoid bias. However, within each cohort, participants, site personnel, contract research personnel and the sponsor will be blind to treatment assignment (intervention vs. placebo).

Fluoxetine will be administered at 10 to 60 mg daily. The initial dose for all participants will be 10 mg daily for 1 week, then increased to 20 mg daily for 2 weeks, then increased to 40 mg daily for 2 weeks, then increased to 60 mg daily for the remainder of the trial. One reduction in dose due to tolerability will be allowed. When a participant's dose is decreased due to tolerability, the dose will not be increased.

A matching placebo will be administered at 10 to 60 mg daily in the same regimen as the intervention.

Vilazodone HCl will be administered at 10 mg once daily for 7 days, followed by 20 mg for 7 days, followed by 40 mg for the remainder of the trial. There must be a minimum of 7 days between dosage increases. One reduction in dose due to tolerability will be allowed. After Week 8, dose reduction for tolerability is allowed, but dose increase is not allowed.

A matching placebo will be administered at 10 to 40 mg daily in the same regimen as the intervention.

Absolute change in the Clinician-Administered PTSD Scale-5-Revised (CAPS-5-R) Past Month total score at Week 12 (Final/ET Visit).

A change in PTSD symptom severity from baseline as measured by CAPS-5-R Past Month. The range of the scale is 0-200. The higher the score at baseline, the worse the PTSD severity. The larger the decrease in score from baseline, the better the outcome.

Incidence of new or worsening suicidal thoughts or behaviors as measured by change in Columbia Suicide Severity Rating Scale (C-SSRS) score from baseline.

The C-SSRS is an assessment of suicidal ideation and behavior in clinical and research settings. The C-SSRS consists of 16 questions that ask about suicidal ideation and behaviors (the first 10 questions comprise the ideation subscale and the last 6 comprise the behavior subscale). This 5-item subscale ranges from a minimum of 0 (corresponding to no suicidal ideation) to a maximum of 5 (representing active suicidal ideation with plan and intent).

The TEAEs recorded during the study will be summarized by system organ class, preferred term, and treatment group. Adverse events and medical history will be coded using the most current version of MedDRA.

The TEAEs recorded during the study will be summarized by system organ class, preferred term, and treatment group. Adverse events and medical history will be coded using the most current version of MedDRA.

The SAEs recorded during the study will be summarized by system organ class, preferred term, and treatment group. Adverse events and medical history will be coded using the most current version of MedDRA.

The SAEs recorded during the study will be summarized by system organ class, preferred term, and treatment group. Adverse events and medical history will be coded using the most current version of MedDRA.

A relative change in PTSD symptom severity from baseline as measured by CAPS-5-R Past Month. The range of the scale is 0-200. The higher the score at baseline, the worse the PTSD severity. The larger the decrease in score from baseline, the better the outcome.

Participants who have undergone or plans to undergo gender reassignment surgery are not eligible. Participants who are currently undergoing stable hormone replacement therapy are eligible for inclusion in the study.

Inclusion Criteria: A participant must meet all the following criteria to be eligible to participate in this study: Provides written informed consent and HIPAA authorization. Is male or female, ≥18 and <65 years of age at screening. Meets Diagnostic and Statistical Manual for Mental Disorders, 5th edition (DSM-5) criteria for PTSD according to CAPS-5-R, Past Month assessment. Is at least 3 months post the index trauma at screening. Has a CAPS-5-R, Past Month total score of ≥26 at Screening. If the Baseline visit is >30 days after Screening, the CAPS-5-R assessment will be repeated at the Baseline visit to verify continued eligibility. Note: The CAPS-5 scoring grid will be used to score answers and to calculate the total score to determine eligibility. Is currently serving, or has previously served, in a branch of the US military service (eg, Air Force, Army, Navy, Marine Corps, and Coast Guard including Reserves and National Guard). Agrees to consistently use an acceptable method of birth control as defined in Section 7.4.2 (required for both males and females who are of reproductive potential and sexually active with partners of the opposite sex) throughout the duration of participants' active involvement in the study and for at least 30 days after the last dose of study treatment or as specified in the assigned cohort appendix (Table 3). For females of reproductive potential, acceptable birth control methods are defined as: hormonal contraceptives, intrauterine device, or double barrier contraception (ie, condom + diaphragm, condom or diaphragm + spermicidal gel or foam). Hormonal contraceptives must have been started at least 2 months prior to the Baseline visit. In addition, agrees to no egg donation or in vitro fertilization procedures for the duration of the study and for at least 30 days after the last dose of study treatment or as specified in the assigned cohort appendix (Table 3). Non-reproductive potential for females is defined by a post-menopausal or surgically sterile status. Post-menopause is defined as 1 year without menses; if in question, a FSH of >40 U/mL, per central laboratory testing must be documented. Surgical sterility (hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) must be documented. Females of reproductive potential must have a negative pregnancy test at the screening (serum) and baseline (urine) visits. For males, adequate birth control methods will be defined as the use of double barrier contraception (eg, condom + diaphragm, condom or diaphragm + spermicidal gel or foam). In addition, male participants must agree not to donate sperm for the duration of the study and for at least 30 days after the last dose of study treatment or as specified in the assigned cohort appendix (Table 3). Non-reproductive potential for males is defined as surgical sterility (ie, vasectomy) at least 3 months prior to screening. Is able and willing to participate in study assessments and undergo blood draws. Is willing to undergo MRI eg, is not claustrophobic, and has no contraindications to MRI. Is fluent in English, both spoken and written. Exclusion Criteria: A participant who meets any of the following criteria will not be eligible to participate in this trial: Is pregnant or breastfeeding at the Screening or Baseline visits, or desires pregnancy during the study. Is at risk for suicide based on any of the following: Had any suicidal ideation or behavior (including preparatory behavior) that required psychiatric hospitalization for stabilization in the 3 months prior to screening. Had more than 2 actual suicide attempts within the last 3 years, not including interrupted or aborted attempts, preparatory acts or behaviors, or non-suicidal self-injurious behavior (as per C SSRS response). Has any history of an acute exacerbation of suicidal ideation and/or intent and/or a suicide-related psychiatric hospitalization following initiation of a medication (eg, SSRI). Is taking any prohibited medication per Section 8.5.1 or cohort-specific appendix restrictions (Table 3) or is unable/unwilling to discontinue medications. Participants must agree to a washout period of at least 2 weeks or 5 half-lives, whichever is longer, prior to the first dose of study treatment. In the 3 months prior to Baseline, has initiated or terminated individual or group PTSD specific psychotherapy (eg, Eye Movement Desensitization & Reprocessing, Prolonged Exposure, Cognitive Processing Therapy, Stress Inoculation Training, Present Centered Therapy), or therapy is anticipated to conclude during the study. Completion of ≤2 sessions in the prior 3 months with no plans to continue is not exclusionary. Participants in stable trauma-focused or non-trauma focused therapy must agree to continue treatment for the duration of participation in the study. Has undergone or plans to undergo gender reassignment surgery. Note: participants who are currently undergoing stable hormone replacement therapy are eligible for inclusion in the study. Meets DSM-5 (American Psychiatric Association 2013) criteria for moderate (≥4 symptoms) or severe (≥6 symptoms) AUD or other SUDs, including cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, or stimulants within 3 months of screening. Nicotine use disorder is allowed. Has a positive screen for illicit drug use (not including cannabis) or recent heavy alcohol consumption (as indicated by GGT outside of normal range) at Screening and the Baseline visits. Has a lifetime history or current experience of psychotic features, as defined by the Mini International Neuropsychiatric Interview (MINI) Psychotic Disorders and Mood Disorders with Psychotic Features screening questions. Dissociative symptoms of PTSD are not exclusionary. Has a current diagnosis of OSA considered not well-managed (AHI >5) with C-, Bi-, or V PAP. Participants who have AHI >5 at Screening with the WatchPAT One may re-screen prior to Baseline or provide a note from their physician stating that their CPAP machine readings are <5. Has a history of neoplastic disease in the last 5 years, except for basal cell carcinoma or non-metastatic squamous cell carcinoma of the skin that been adequately treated. Has any clinically significant abnormal findings on the 12-lead ECG at the Screening or Baseline visits, as determined by the central rater. Has clinically significant abnormal laboratory results at the Screening visit that indicate inadequate renal function: serum creatinine >1.5 mg/dL OR estimated creatinine clearance of <50 mL/min calculated by the Cockcroft and Gault formula). Has clinically significant abnormal laboratory results at the Screening visit that indicate impaired liver function: ALT or AST >2 × ULN and/or total bilirubin level >1.5 × ULN prolonged PT >1.2 × ULN participants previously diagnosed with Gilbert's syndrome are allowed. Has a prior history of drug induced liver injury characterized by ALT or AST >3 × ULN AND total bilirubin level >2 × ULN without cholestasis (ie, Alkaline Phosphatase <2 × ULN); this is generally referred to as Hy's Law. Has any other abnormal laboratory result at the Screening visit that could impact the participant's safety or participation in the study, as determined by the Site PI. Has any other concurrent psychiatric or medical condition that would impact the participant's safety, ability to appropriately complete evaluations, or participation in the study, as determined by the Site PI. Does not have a permanent address and will not have a stable method of contact (eg, no cell phone) over the duration of the study. Is currently involved in litigation, medical evaluation for disability benefits or damages, or benefit examination related to the PTSD diagnosis. Has participated in any interventional clinical trial or treatment with any investigational drug or other investigational intervention within 3 months or 5 half-lives, whichever is longer, of screening. Note: previous participation in an observational study is permitted. Note: Participants who are enrolled in this APT, and who are eligible for re randomization, are permitted to remain in the study and receive alternative cohort intervention following a 2-week or 5 half-lives washout period, whichever is longer. Is unavailable for the duration of the trial, unlikely to be compliant with the protocol, or deemed by the Site PI to be unsuitable for participation in the trial for any reason.