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, Veterans, and Non-Veteran Civilians 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 available 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). The master protocol describes the default procedures and analyses for all cohorts; treatment-specific eligibility requirements, safety and efficacy procedures, or endpoints are described in the cohort-specific appendices and reflected in the intervention-specific clinicaltrials.gov records.

The general structure of the M-PACT consists of a 30-day Screening Period, a 12-week Treatment Period, and a 4-week Safety Follow-up. The trial will include up to 5 open 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 M-PACT 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 designed as up to 5-arms versus control, the adaptive platform trial will continue enrollment until decisions are made to stop all cohorts. Interim analyses will be conducted at approximately quarterly intervals, beginning after at least 40 participants have been randomized and at least 10 participants have completed the End of Study (EOS) visit. At each interim analyses, unblinded data will be reviewed by an independent, firewalled ISAC and a DSMB. The possible cohort-level decisions that could be made by the prespecified adaptive plan include stopping enrollment to a cohort for futility, stopping enrollment to a cohort for anticipated success, or stopping enrollment to a cohort for reaching the maximum sample size. For cohort-specific interventions intending to pursue a labeling claim (which will be clearly stated in the cohort-specific appendix before cohort initiation), early stopping for success will not be considered. New cohorts for investigation can be added at any time. The DSMB may recommend stopping any 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 participant population enriched (e.g., 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 M-PACT) 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 M-PACT.

For information specific to each intervention included in this platform trial, please refer to the below corresponding, separate, clinicaltrials.gov records:

Vilazodone NCT05948579; Fluoxetine NCT05948553; Daridorexant NCT05948540; SLS-002 NCT06816433.

Parties interested in having their intervention considered for testing within the M-PACT should email partners@gcaresearch.org

Inclusion Criteria: An individual must meet all the following criteria to be eligible to participate in this study:

1. Is willing and able to provide written informed consent.

2. ≥18 and <65 years of age at Screening.

3. Meets DSM-5 criteria for PTSD according to CAPS-5-R, Past Month assessment at Screening and Baseline.

4. The index trauma must have occurred more than 3 months prior to Screening.

5. Has a CAPS-5-R, Past Month total score of ≥26 at Screening and Baseline. Note: The CAPS-5 scoring grid will be used to score answers and to calculate the total score to determine eligibility.

6. Participants must be able to read, speak, and understand English sufficiently to complete the CAPS-5, which is the primary efficacy endpoint and is administered by trained Centralized Assessors.

7. Agrees to consistently use an acceptable method of birth control (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' involvement in the study and for a minimum of 30 days after the last dose of study intervention or longer, as specified in the assigned cohort-specific appendices.

   1. For females of reproductive potential, acceptable birth control methods are defined as: hormonal contraceptives, intrauterine device, or double barrier contraception (ie, male condom and diaphragm, male condom or diaphragm with 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 harvesting for the duration of the study and for at least 30 days after the last dose of study intervention or as specified in the assigned cohort-specific appendices.
   2. Non-reproductive potential for females is defined by a post-menopausal (12 consecutive months without menses or surgically sterile). If in question, an FSH of >40 U/mL, per central laboratory testing must be documented. Surgical sterility (hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) must be documented.
   3. Females of reproductive potential must have a negative pregnancy test at the Screening (serum) Visit and Baseline (urine) Visit.
   4. For males, adequate birth control methods will be defined as the use of double barrier contraception (e.g., male condom and diaphragm, male condom or diaphragm with 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 intervention or as specified in the assigned cohort-specific appendices.
   5. Non-reproductive potential for males is defined as surgical sterility (i.e., vasectomy) at least 3 months prior to Baseline.

8. Is able and willing to participate in study assessments and undergo blood draws.

9. For participants who consent to the optional MRI: willingness to undergo MRI, e.g., is not claustrophobic, and has no contraindications to MRI.

Exclusion Criteria: An individual who meets any of the following criteria will not be eligible to participate in this trial:

1. Is pregnant or breastfeeding at the Screening or Baseline Visits or planning pregnancy during the study.

2. Is at risk for suicide based on any of the following:

   1. Had any suicidal ideation or behavior (including preparatory behavior) that required psychiatric hospitalization in the 3 months prior to screening.
   2. 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).
   3. Has any history of suicidal ideation and/or intent following initiation of a medication used for psychiatric symptoms or disorders.
   4. Has any history of suicide-related hospitalization following initiation of a medication used for psychiatric symptoms or disorders.

3. Is taking any prohibited medication or cohort-specific restrictions (see cohort-specific appendices), is unable/unwilling to discontinue medications, or in the PI's judgment, cannot discontinue medications. Participants must agree to a washout period of at least 14 days or 5 half-lives, whichever is longer, prior to the first dose of study intervention. Note, the half-life of the parent drug (not metabolites) should be used in this calculation.

4. In the 3 months prior to the Baseline Visit, has initiated or terminated individual or group PTSD specific psychotherapy (e.g., 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.

5. Has undergone or plans to undergo sex reassignment surgery. Note: participants who are currently undergoing stable hormone replacement therapy are eligible for inclusion in the study.

6. Meets DSM-5 (American Psychiatric Association 2013) criteria for moderate or severe AUD or other SUDs, including cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, or stimulants within 3 months of screening. Nicotine use disorder is allowed.

7. Has a positive screen for illicit drugs (excluding cannabis) or positive alcohol screen (either positive on qualitative test or above .04% on a quantitative test) at the Baseline Visit.

   1. If the urine drug screen is positive at Screening (excluding cannabis), the participant will not immediately be excluded from participation in the study. The urine drug screen must be repeated at Baseline after at least 7 days since the initial test. If the urine drug screen is positive at Baseline (excluding cannabis), then the participant will be discontinued from the study.
   2. If the urine alcohol screen is positive at Screening, the participant will not immediately be excluded from participation in the study. If the urine alcohol screen is also positive at Baseline, then the participant will be discontinued from the study.

8. Has a lifetime history or current symptoms of psychotic features, as determined by the MINI Psychotic Disorders and Mood Disorders with Psychotic Features screening questions.

9. Has a history of neoplastic disease or completion of treatment in the last 5 years, except for treated basal cell or squamous cell carcinoma of the skin.

10. Has any clinically significant abnormal findings on the 12-lead ECG at the Screening Visit or Baseline Visit, such as:

    1. Abnormal heart rhythm (such as atrial fibrillation, ventricular fibrillation, or torsade de pointes)
    2. ECG with a QTc interval >450 msec for males or >470 msec for females (QT interval corrected with Fridericia correction [QTcF]) At Screening, eligibility will be based on the central ECG reading. At Baseline, eligibility will be based on the local ECG reading by a site investigator.

11. Has abnormal laboratory results at the Screening Visit:

    1. serum creatinine >1.5 mg/dL OR
    2. estimated creatinine clearance of <50 mL/min calculated by the Cockcroft and Gault formula.

12. Has clinically significant abnormal laboratory results at the Screening Visit that indicate impaired liver function:

    1. ALT or AST >2 × ULN
    2. total bilirubin level >1.5 × ULN (unless previously known Gilbert syndrome)
    3. prolonged prothrombin time >1.5 × ULN

13. 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, ALP <2 × ULN).

14. Has any other clinically significant laboratory result at Screening that could impact the participant's safety or participation in the study, as determined by the Site PI.

15. 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.

16. Does not have a stable method of contact over the duration of the study.

17. 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 within 3 months of screening is permitted.

    Note: Participants who are enrolled in the M-PACT, and who are eligible for re randomization, are permitted to remain in the study and receive alternative cohort intervention following a 14-day or 5 half-lives washout period, whichever is longer. The half-life of the parent drug (not metabolites) should be used in this calculation.

18. 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.

19. Systolic blood pressure >140 mm Hg and/or diastolic blood pressure >90 mm Hg or Systolic blood pressure <90 mm Hg and/or diastolic blood pressure <50 mm Hg.