A Multi-Site Open-Label Extension Study of MDMA-Assisted Psychotherapy for PTSD

Study Overview
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Brief Summary
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This multi-site open-label study assesses the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in participants who were enrolled in a parent study for treatment of posttraumatic stress disorder (PTSD). The study will be conducted in up to N ≈ 100 participants. Participants will receive a flexible dose of MDMA, followed by a supplemental dose, unless contraindicated, during the Treatment Period with manualized psychotherapy in three monthly Experimental Sessions. This  12-week Treatment Period is preceded by three Preparatory Sessions. During the Treatment Period, each Experimental Session is followed by three Integrative Sessions of non-drug psychotherapy. The Primary Outcome measure is the change in PTSD Checklist (PCL-5) for the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) from Visit 3 is assessed at Visit 16. This study will compare the effects of three manualized Experimental Sessions of psychotherapy assisted by flexible doses of MDMA. Initial doses per Experimental Session include 80 mg or 120 mg of MDMA compounded with mannitol and magnesium stearate alone (mannitol and magnesium stearate), followed 1.5 to 2 hours later by a supplemental dose (40 or 60 mg). Total amounts of MDMA to be administered per Experimental Session range from 80 mg to 180 mg.

Detailed Description
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PTSD is a serious debilitating disorder that negatively impacts a person's daily life. PTSD is a stress-related psychiatric condition that may occur following a traumatic event such as war, disaster, sexual abuse, violence, terrorism, and accidents. PTSD negatively impacts a person's daily life, resulting in relationship difficulties, difficulty in finding and maintaining a job, reduced cognitive and psychosocial functioning, substance abuse, high-cost healthcare use, and increased depression and suicide risk. Available PTSD treatments, including medications and therapy, effectively treat only a fraction of people who try them for adequate dose and duration. People with PTSD can be treated with psychotherapies and pharmacotherapies. In the past decade, there has been a growing amount of research into medications and other methods that may augment the effectiveness of psychotherapy for PTSD 3,4-methylenedioxymethamphetamine (MDMA) is a drug that releases serotonin, norepinephrine and dopamine in the brain and indirectly increases levels of the neurohormones oxytocin, arginine vasopressin and cortisol. The combined neurobiological effects of MDMA increase compassion, reduce defenses and fear of emotional injury, and enhance communication and introspection. MDMA produces anxiolytic and prosocial effects, which counteract avoidance and hyperarousal in the context of therapy. A combined treatment of MDMA and psychotherapy may be especially useful for treating PTSD. This multi-site, open-label safety extension study assesses the efficacy and safety of MDMA-assisted psychotherapy versus psychotherapy in participants diagnosed with PTSD. The study will be conducted in N ≈ 100 participants. Participants who were randomized to the placebo arm in the two parent Phase 3 trials of MDMA-assisted psychotherapy and who meet all other entry criteria will be eligible and invited to participate in this open-label safety extension study. In addition, participants in the parent Phase 3 trials whose study participation was affected by COVID-19 pandemic or other unforeseen circumstances, and were unable to complete the study may participate in this open-label study. The treatment consists of a flexible dose of MDMA (80 or 120 mg), followed by a supplemental dose (40 or 60 mg) unless contraindicated, administered with manualized psychotherapy in three open-label approximately monthly Experimental Sessions. During Experimental Session 1, participants will receive an initial dose of 80 mg of MDMA, followed by a supplemental dose of 40 mg. During Experimental Sessions 2 and 3, participants will receive an initial dose of 80 or 120 mg of MDMA, followed by a supplemental dose of 40 or 60 mg. This Treatment Period is preceded by three Preparatory Sessions. During the Treatment Period, each Experimental Session is followed by three Integrative Sessions of non-drug psychotherapy. Experimental Sessions are followed by an overnight stay. The Primary Outcome measure, the change in PCL-5 (PTSD Checklist for DSM-5) from Visit 3 is assessed at Visit 16.

Official Title
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A Multi-Site Open-Label Safety Extension Study of Manualized MDMA-Assisted Psychotherapy for the Treatment of Participants With Posttraumatic Stress Disorder

Conditions
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PTSD

Intervention / Treatment
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* Drug: Midomafetamine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Were previously enrolled in a parent study and (meet one of the following): At time of unblinding, their treatment assignment was to the placebo arm; or, Did not begin Experimental Sessions due to the COVID-19 global pandemic or other unforeseen circumstances; Completed fewer than three Experimental Sessions prior to Study Termination due to the COVID-19 global pandemic or other unforeseen circumstances. Are considered in good standing with the study site at which they enrolled in a parent study; if, in the opinion of the investigator, therapy team, and Medical Monitor, the participant was compliant with protocol requirements, even if they were unable to complete all study visits. 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 Agree to the following lifestyle modifications: comply with requirements for fasting and refraining from certain medications prior to Experimental Sessions. 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. 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MDMA-assisted therapy<br>Three open-label sessions of MDMA-assisted therapy with flexible dose of MDMA (80 or 120 mg) and optional supplemental dose of (40 or 60 mg), 1.5 to 2 hours later | Drug: Midomafetamine<br>* Three sessions of MDMA-assisted therapy with flexible dose of MDMA from 80 to 120 mg and optional supplemental dose half that of initial dose 1.5 to 2 hours later<br>* Other names: MDMA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline to Visit 16 in PCL-5 total score | The PCL-5 is a 20-item self-report questionnaire in which respondents indicate the presence and severity of PTSD symptoms, derived from the symptoms of PTSD per DSM-5. Participants indicate how much distress they have experienced in the last 2 weeks due to symptoms such as Repeated, disturbing memories, thoughts, or images of a stressful experience from the past, Trouble remembering important parts of a stressful experience from the past, and Feeling irritable or having angry outbursts on a five-point Likert-type scale (1=Not at all to 5=Extremely), with lower scores indicating less PTSD symptoms. | Baseline enrollment to approximately 18 weeks later (Visit 16 occurs 24 to 32 days after Experimental Session 3) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline to Visit 16 in Sheehan Disability Scale (SDS) total score | The SDS is a self-report assessment of functional impairment. The reporting period for the SDS refers to the past month. 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), with higher scores indicating greater functional impairment. | Baseline enrollment to approximately 18 weeks later (Visit 16 occurs 24 to 32 days after Experimental Session 3) |