Study Comparing Two Versus Three Active MDMA-assisted Sessions in U.S. Military Veterans With Chronic PTSD

Study Overview
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Brief Summary
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This open-label, randomized study will assess the comparative effectiveness of two versus three active MDMA-assisted sessions in U.S. military veterans with at least moderate chronic PTSD treated in an outpatient VA treatment clinic.

Detailed Description
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This open-label, randomized study will assess the comparative effectiveness of two versus three active MDMA-assisted therapy sessions in U.S. military veterans with at least moderate chronic PTSD treated in an outpatient VA treatment clinic. The study will be conducted in up to 60 participants. Prior to the randomized portion of the study, each therapist pair team will treat one participant under the 3-session model, and one participant under the 2-session model. In total, 8 participants will be treated under this proof of principle therapist training lead-in. A 120 mg dose of MDMA, followed by a supplemental dose (60 mg) unless contraindicated, is administered during the treatment period with manualized psychotherapy in 2 or 3 open-label monthly Experimental Sessions. This   8-12-week Treatment Period includes three Preparatory Sessions prior to the first MDMA-assisted session. During the treatment period, each Experimental Session is followed by three Integrative Sessions of non-drug therapy. The Primary Outcome measure, the change in CAPS-5 from Baseline, is assessed by a centralized, blinded Independent Rater (IR) pool at post-treatment for each group.

Official Title
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A Phase 2, Open-Label, Randomized Comparative Effectiveness Study for MDMA-Assisted Psychotherapy in U.S. Veterans With Chronic PTSD

Conditions
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PTSD

Intervention / Treatment
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* Drug: Midomafetamine
* Behavioral: Psychotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are at least 18 years old. Are fluent in speaking and reading the predominantly used or recognized language of the study site. Are able to swallow pills. Agree to have study visits recorded, including Experimental Sessions, Independent Rater assessments, and non-drug psychotherapy sessions. Must provide a contact (relative, spouse, close friend or other caregiver) who is willing and able to be reached by the investigators in the event of a participant becoming suicidal or unreachable. Must agree to inform the investigators within 48 hours of any medical conditions and procedures. If of childbearing potential, must have a negative pregnancy test at study entry and prior to each Experimental Session, and must agree to use adequate birth control through 10 days after the last Experimental Session. Must not participate in any other interventional clinical trials during the duration of the study. Must be willing to remain overnight at the study site after each Experimental Session and be driven home after, and commit to medication dosing, therapy, and study procedures. At baseline, have moderate PTSD diagnosis. Exclusion Criteria: Are not able to give adequate informed consent. Have uncontrolled hypertension. Have a marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 milliseconds [ms] corrected by Bazett's formula). Have a history of additional risk factors for Torsade de pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome). Have evidence or history of significant medical disorders. Have symptomatic liver disease. Have history of hyponatremia or hyperthermia. Weigh less than 48 kilograms (kg). Are pregnant or nursing, or are of childbearing potential and are not practicing an effective means of birth control. Are abusing illegal drugs.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Two sessions of MDMA-assisted therapy<br>Two experimental sessions of MDMA-assisted therapy | Drug: Midomafetamine<br>* Administration of MDMA<br>* Other names: MDMA;Behavioral: Psychotherapy<br>* Standardized non-directive psychotherapy performed by therapist team<br>|
| Active Comparator: Three sessions of MDMA-assisted therapy<br>Three experimental sessions of MDMA-assisted therapy | Drug: Midomafetamine<br>* Administration of MDMA<br>* Other names: MDMA;Behavioral: Psychotherapy<br>* Standardized non-directive psychotherapy performed by therapist team<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in CAPS-5 Total Severity Score from Baseline to Visit 12 for 2 Session Group | The Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV) is a clinician administered and scored assessment of PTSD symptoms via structured interview based upon PTSD diagnosis in DSM-IV. It contains symptom subscales, a CAPS-IV total severity score, and a diagnostic score. The total severity score is a sum of symptom frequency and intensity scores for the subscales B (re-experiencing), C (avoidance) and D (hypervigilance) and ranges from 0 to 136, with higher scores indicating greater severity of PTSD symptoms. The dichotomous diagnostic score is based upon meeting each of five criteria, including index trauma, presence or absence of Criteria B, C, D described above, duration of symptoms and distress and is scored as meeting versus not meeting criteria for diagnosis. | Baseline - 3 months from enrollment | 
| Change in CAPS-5 Total Severity Score from Baseline to Visit 16 for 3 Session Group | The Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV) is a clinician administered and scored assessment of PTSD symptoms via structured interview based upon PTSD diagnosis in DSM-IV. It contains symptom subscales, a CAPS-IV total severity score, and a diagnostic score. The total severity score is a sum of symptom frequency and intensity scores for the subscales B (re-experiencing), C (avoidance) and D (hypervigilance) and ranges from 0 to 136, with higher scores indicating greater severity of PTSD symptoms. The dichotomous diagnostic score is based upon meeting each of five criteria, including index trauma, presence or absence of Criteria B, C, D described above, duration of symptoms and distress and is scored as meeting versus not meeting criteria for diagnosis. | Baseline - 4 months from enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Sheehan Disability Scale (SDS) from Baseline to Visit 12 for 2 Session Group | Sheehan Disability Scale (SDS) total score, a measure of clinician-rated functional impairment. The items indicate degree of impairment in the domains of work/school, social life, and home life, with response options based on an eleven-point scale (0=not at all to 10=extremely), and five verbal tags (not at all, mildly, moderately, markedly, extremely). | Baseline - 3 months from enrollment | 
| Change in Sheehan Disability Scale (SDS) from Baseline to Visit 16 for 3 Session Group | Sheehan Disability Scale (SDS) total score, a measure of clinician-rated functional impairment. The items indicate degree of impairment in the domains of work/school, social life, and home life, with response options based on an eleven-point scale (0=not at all to 10=extremely), and five verbal tags (not at all, mildly, moderately, markedly, extremely). | Baseline - 4 months from enrollment |