A Multi-Site Open-Label Extension Study of MDMA-Assisted Psychotherapy for 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 either of 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 study. In addition, participants in the parent Phase 3 trials who were unable to complete the study due to the COVID-19 pandemic or other unforeseen circumstances may participate in this study.

The treatment consists of an initial dose of midomafetamine HCl (80 or 120 mg), followed by a supplemental dose (40 or 60 mg) unless contraindicated, administered with manualized psychotherapy in three open-label Experimental Sessions each spaced approximately one month apart. During Experimental Session 1, participants will receive an initial dose of 80 mg of midomafetamine HCl, 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 midomafetamine HCl, 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, with the exception of a subset of participants who will be invited to participate in a sub-study to assess the feasibility of Experimental Sessions without overnight stay. The primary study endpoint is the change from baseline in PCL-5 (PTSD Checklist for DSM-5) scores from Visit 3 to Visit 16.

• Midomafetamine HCl (Drug), also known as 3,4-methylenedioxymethamphetamine, MDMA HCl, midomafetamine, MDMA: Initial doses per Experimental Session include 80 mg or 120 mg midomafetamine HCl, followed 1.5 to 2 hours later by a supplemental dose unless tolerability issues emerge. For an initial dose of 80 mg, a 40 mg supplemental dose will be used. For an initial dose of 120 mg, a 60 mg supplemental dose will be used. Total amounts of midomafetamine HCl to be administered per Experimental Session range from 80 mg to 180 mg.

Primary outcomes

• Change From Baseline to Visit 16 in PCL-5 Total Score [Baseline enrollment to approximately 18 weeks later (Visit 16 occurs 24 to 32 days after Experimental Session 3)]: The Post Traumatic Stress Disorder Checklist for DSM-5 (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 (0=Not at all to 4=Extremely). The total severity score can range from 0 to 80 and lower scores indicate less PTSD symptoms.

Secondary outcomes

• Change From Baseline to Visit 16 in Sheehan Disability Scale (SDS) Total Score [Baseline enrollment to approximately 18 weeks later (Visit 16 occurs 24 to 32 days after Experimental Session 3)]: 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.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Were previously enrolled in a parent study and (meet one of the following):

  1. At time of unblinding, their treatment assignment was to the placebo arm; or,
  2. Did not begin Experimental Sessions due to the COVID-19 global pandemic or other unforeseen circumstances;
  3. 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 \[ms\] in males and >460 ms in females corrected by Fridericia 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, such as myocardial infarction, cerebrovascular accident, or aneurysm
* Have symptomatic liver disease
* Have recent 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
* Have an active illicit or prescription drug substance use disorder within 12 months

Participant flow

Outcome results

• Change From Baseline to Visit 16 in PCL-5 Total Score (Primary), Least squares mean, score on a scale: MDMA-assisted Therapy -14.92 (-18.05 to -11.79)
• Change From Baseline to Visit 16 in Sheehan Disability Scale (SDS) Total Score (Secondary), Least squares mean, score on a scale: MDMA-assisted Therapy -4.10 (-5.95 to -2.25)

Adverse events

Time frame: From baseline to end of follow up (approximately 18 weeks)

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2023-03-15)
• Statistical Analysis Plan (PDF, 2021-04-13)
• Informed Consent Form (PDF, 2023-05-04)