Department of Defense PTSD Adaptive Platform Trial - Master Protocol

Inclusion Criteria: A participant 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 Diagnostic and Statistical Manual for Mental Disorders, 5th edition (DSM-5)criteria for PTSD according to CAPS-5-R, Past Month assessment at Screening andBaseline.

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: TheCAPS-5 scoring grid will be used to score answers and to calculate the total scoreto determine eligibility.

6. Is currently serving, or has previously served, in a branch of the US militaryservice (ie, Air Force, Army, Navy, Marine Corps, and Coast Guard including Reservesand National Guard).

7. Agrees to consistently use an acceptable method of birth control as defined inSection 7.4.2 (required for both males and females who are of reproductive potentialand sexually active with partners of the opposite sex) throughout the duration ofparticipants' involvement in the study and for a minimum of 30 days after the lastdose of study intervention or longer, as specified in the assigned cohort-specificappendices.

8. For females of reproductive potential, acceptable birth control methods aredefined as: hormonal contraceptives, intrauterine device, or double barriercontraception (ie, male condom and diaphragm, male condom or diaphragm withspermicidal gel or foam). Hormonal contraceptives must have been started atleast 2 months prior to the Baseline visit. In addition, agrees to no eggdonation or harvesting for the duration of the study and for at least 30 daysafter the last dose of study treatment or as specified in the assignedcohort-specific appendices.

9. Non-reproductive potential for females is defined by a post-menopausal (12consecutive months without menses or surgically sterile). If in question, anFollicle-stimulating hormone (FSH) of >40 U/mL, per central laboratory testingmust be documented. Surgical sterility (hysterectomy, bilateral oophorectomy,or bilateral tubal ligation) must be documented.

10. Females of reproductive potential must have a negative pregnancy test at thescreening (serum) and baseline (urine) visits.

11. For males, adequate birth control methods will be defined as the use of doublebarrier contraception (eg, male condom and diaphragm, male condom or diaphragmwith spermicidal gel or foam). In addition, male participants must agree not todonate sperm for the duration of the study and for at least 30 days after thelast dose of study treatment or as specified in the assigned cohort-specificappendices.

12. Non-reproductive potential for males is defined as surgical sterility (ie,vasectomy) at least 3 months prior to baseline.

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

14. Is willing to undergo magnetic resonance imaging (MRI) eg, is not claustrophobic,has no contraindications to MRI.

Exclusion Criteria: A participant 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 planningpregnancy during the study.

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

3. Had any suicidal ideation or behavior (including preparatory behavior) thatrequired psychiatric hospitalization in the 3 months prior to screening.

4. Had more than 2 actual suicide attempts within the last 3 years, not includinginterrupted or aborted attempts, preparatory acts or behaviors, or non-suicidalself-injurious behavior (as per C-SSRS response).

5. Has any history of suicidal ideation and/or intent following initiation of amedication used for psychiatric symptoms or disorders.

6. Has any history of suicide-related hospitalization following initiation of amedication used for psychiatric symptoms or disorders.

7. Is taking any prohibited medication per Section 8.5.1 or cohort-specificrestrictions (see cohort-specific appendices), is unable/unwilling to discontinuemedications, or in the PI's judgement, cannot discontinue medications. Subjects mustagree 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 parentdrug (not metabolites) should be used in this calculation.

8. In the 3 months prior to the Baseline visit, has initiated or terminated individualor group PTSD specific psychotherapy (eg, Eye Movement Desensitization &Reprocessing, Prolonged Exposure, Cognitive Processing Therapy, Stress InoculationTraining, Present Centered Therapy), or therapy is anticipated to conclude duringthe study. Completion of ≤2 sessions in the prior 3 months with no plans to continueis not exclusionary. Participants in stable trauma-focused or non-trauma focusedtherapy must agree to continue treatment for the duration of participation in thestudy.

9. Has undergone or plans to undergo gender reassignment surgery. Note: participantswho are currently undergoing stable hormone replacement therapy are eligible forinclusion in the study.

10. Meets DSM-5 (American Psychiatric Association 2013) criteria for moderate or severealcohol use disorder (AUD) or other substance use disorders (SUDs), includingcannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, orstimulants within 3 months of screening. Nicotine use disorder is allowed.

11. Has a positive screen for illicit drugs (excluding cannabis) or recent heavy alcoholconsumption (as possibly indicated by an elevated gamma-glutamyl transferase (GGT)or an elevated aspartate aminotransferase (AST) to alanine aminotransferase (ALT)ratio - to be interpreted in the context of other clinical information) at theBaseline visit.

12. Has a lifetime history or current symptoms of psychotic features, as determined bythe Mini International Neuropsychiatric Interview (MINI) Psychotic Disorders andMood Disorders with Psychotic Features screening questions.

13. Has a current diagnosis of obstructive sleep apnea (OSA) considered not well-managed (AHI ≥5) with C-, Bi-, or V PAP. Participants who have AHI ≥5 at Screening with theOSA screening device may repeat the OSA assessment prior to the Baseline visit orprovide documentation from a physician stating that their C-, Bi-, or V-PAP machineAHI readings are <5.

14. 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.

15. Has any clinically significant abnormal findings on the 12-lead electrocardiogram (ECG) at the Screening or Baseline visits, such as:.

16. Abnormal heart rhythm (such as atrial fibrillation, ventricular fibrillation,or torsade de pointes)

17. ECG with a QTc interval >450 msec for males or >470 msec for females (QTinterval corrected with Fridericia correction [QTcF]).At Screening, eligibilitywill be based on the central ECG reading. At baseline, eligibility will bebased on the local ECG reading by a qualified site investigator.

18. Has abnormal laboratory results at the Screening visit:

19. serum creatinine >1.5 mg/dL OR

20. estimated creatinine clearance of <50 mL/min calculated by the Cockcroft andGault formula).

21. Has clinically significant abnormal laboratory results at the Screening visit thatindicate impaired liver function:

22. ALT or AST >2 × ULN

23. total bilirubin level >1.5 × ULN (unless previously known Gilbert syndrome)

24. prolonged prothrombin time >1.5 × ULN

25. Has a prior history of drug induced liver injury characterized by ALT or AST >3 ×upper limit of normal (ULN) AND total bilirubin level >2 × ULN without cholestasis (ie, Alkaline Phosphatase <2 × ULN).

26. Has any other clinically significant laboratory result at Screening that couldimpact the participant's safety or participation in the study, as determined by theSite PI.

27. Has any other concurrent psychiatric or medical condition that would impact theparticipant's safety, ability to appropriately complete evaluations, orparticipation in the study, as determined by the Site PI.

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

29. Is currently involved in litigation, medical evaluation for disability benefits ordamages, or benefit examination related to the PTSD diagnosis.

30. Has participated in any interventional clinical trial or treatment with anyinvestigational drug or other investigational intervention within 3 months or 5half-lives, whichever is longer, of screening. Note: Previous participation in an observational study is permitted. Note: Subjects who are enrolled in the M-PACT, and who are eligible for rerandomization, are permitted to remain in the study and receive alternative cohortintervention 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 thiscalculation.

31. Is unavailable for the duration of the trial, unlikely to be compliant with theprotocol, or deemed by the Site PI to be unsuitable for participation in the trialfor any reason.

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