A Multi-Site Phase 3 Study of MDMA-Assisted Psychotherapy for PTSD (MAPP1)

A Randomized, Double-Blind, Placebo-Controlled, Multi-Site Phase 3 Study of the Efficacy and Safety of Manualized MDMA-Assisted Psychotherapy for the Treatment of Severe Posttraumatic Stress Disorder

This multi-site double-blind, placebo-controlled randomized Phase 3 study assesses the efficacy and safety of MDMA-assisted therapy versus placebo with therapy in participants diagnosed with at least severe PTSD. The study will be conducted in up to N ≈ 100 participants. Participants will be randomized to receive a flexible dose of MDMA or placebo, followed by a supplemental half-dose, unless contraindicated, during the Treatment Period with manualized therapy 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.

Study Overview

• Status: Completed
• Conditions: Posttraumatic Stress Disorder
• Intervention / Treatment: Behavioral: Therapy; Drug: Midomafetamine; Drug: Placebo

Detailed Description

Posttraumatic stress disorder (PTSD) is a stress-related psychiatric condition that may occur following a traumatic event such as war, disaster, sexual abuse, violence, terrorism, or accidents. PTSD can negatively impact 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) induces serotonin release and has been shown to enhance fear memory extinction, modulate fear memory reconsolidation, and bolster social behavior in animal models. Pooled analysis of six Phase 2 trials of MDMA-assisted therapy for PTSD have now shown promising safety and efficacy findings.

This multi-site, double-blind, randomized Phase 3 study assessed the efficacy and safety of MDMA-assisted therapy versus placebo with therapy in participants diagnosed with at least severe PTSD. The study will be conducted in N ≈ 100 participants. Participants will be enrolled in one of two groups at a 1:1 ratio. A flexible dose of MDMA or placebo, followed by a supplemental half-dose unless contraindicated, is administered during the Treatment Period with manualized therapy 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. Initial doses per Experimental Session include 80 mg or 120 mg of MDMA or placebo followed 1.5 to 2 hours later by a supplemental half-dose (40 or 60 mg). Total amounts of MDMA to be administered per Experimental Session range from 80 mg to 180 mg.

The Primary Outcome measure is change in Clinician Administered PTSD Scale for DSM-V (CAPS-5) from Baseline to Primary Endpoint (18 weeks post-Baseline). Drug safety will be assessed by measuring blood pressure, heart rate and body temperature during experimental sessions, collecting adverse events and measuring suicidal thoughts or behaviors with the Columbia Suicide Severity Rating Scale (adapted C-SSRS).

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5R 5H3
      • Providence Health Center
  • Quebec
    • Montreal, Quebec, Canada, H2W1Y9
      • Dr. Simon Amar, Inc.
• Israel
  • Be'er Ya'akov, Israel
    • Assaf Harofeh Research Fund
  • Tel HaShomer, Israel
    • Sheba Fund for Health Services and Research
• United States
  • California
    • North Hollywood, California, United States, 91601
      • New School Research LLT
    • San Francisco, California, United States, 94114
      • San Francisco Insight and Integration Center
    • San Francisco, California, United States, 94122
      • University of California San Francisco
  • Colorado
    • Boulder, Colorado, United States, 80302
      • Aguazul-Blue Water Inc.
    • Fort Collins, Colorado, United States, 80525
      • Wholeness Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70123
      • Ray Worthy Psychiatry LLC
  • Massachusetts
    • Boston, Massachusetts, United States, 02446
      • Trauma Research Foundation
  • New York
    • New York, New York, United States, 10016
      • New York University
    • New York, New York, United States, 10024
      • New York Private Practice
  • South Carolina
    • Mount Pleasant, South Carolina, United States, 29464
      • Zen Therapeutic Solutions, LLC
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • University of Wisconsin At Madison

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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, meet DSM-5 criteria for current severe PTSD

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MDMA-assisted therapy; Administration of 80 or 120 mg MDMA (with a supplemental dose offered 1.5 to 2 hours later of 40 or 60 mg MDMA respectively) in combination with therapy during 3 experimental sessions scheduled 3-5 weeks apart.	Behavioral: Therapy; Non-directive therapy performed by therapist team; Other Names: Manualized therapy; Drug: Midomafetamine; Administration of 80 to 120 mg MDMA during three sessions of MDMA-assisted therapy followed by a supplemental dose of 40 or 60 mg MDMA offered 1.5/2 hrs after the initial dose, respectively.; Other Names: MDMA; 3,4-methylenedioxymethamphetamine
Placebo Comparator: Placebo with therapy; Administration of inactive placebo in combination with therapy during 3 experimental sessions scheduled 3-5 weeks apart	Behavioral: Therapy; Non-directive therapy performed by therapist team; Other Names: Manualized therapy; Drug: Placebo; Administration of placebo during three experimental sessions; Other Names: Inactive placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Primary Endpoint in Clinician Administered PTSD Scale for DSM-V (CAPS-5)	The Clinician-Administered PTSD Scale for DSM-V (CAPS-5) is a clinician administered and scored assessment of PTSD symptoms via structured interview based upon PTSD diagnosis in DSM-5. 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.	Baseline to 18 weeks post enrollment confirmation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Primary Endpoint in Sheehan Disability Scale (SDS) Total Score	The Sheehan Disability Scale (SDS) is a clinician-rated assessment of functional impairment that was adapted for the purposes of this study to limit missing item-level data as per the FDA requirements and included use of the three-item mean as the total score and imputation of work-related impairment. The SDS is a 3-item scale measuring the severity of disability in the domains of work, family life/home responsibilities and social/leisure activities, with each item scored on a ten-point Likert scale from 0 ('not at all impaired') to 10 ('very severely impaired'). The SDS total score was the mean of the 3 item responses. The SDS total score ranged from 0 to 10, with higher scores indicating greater functional impairment.	Baseline to 18 weeks post enrollment confirmation

Collaborators and Investigators

• Sponsor: Lykos Therapeutics
• Investigators: Study Director: Michael Mithoefer, MD, MAPS Public Benefit Corp.

Publications and helpful links

General Publications

• Mitchell JM, Bogenschutz M, Lilienstein A, Harrison C, Kleiman S, Parker-Guilbert K, Ot'alora G M, Garas W, Paleos C, Gorman I, Nicholas C, Mithoefer M, Carlin S, Poulter B, Mithoefer A, Quevedo S, Wells G, Klaire SS, van der Kolk B, Tzarfaty K, Amiaz R, Worthy R, Shannon S, Woolley JD, Marta C, Gelfand Y, Hapke E, Amar S, Wallach Y, Brown R, Hamilton S, Wang JB, Coker A, Matthews R, de Boer A, Yazar-Klosinski B, Emerson A, Doblin R. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med. 2021 Jun;27(6):1025-1033. doi: 10.1038/s41591-021-01336-3. Epub 2021 May 10.

Helpful Links

• Recruitment Website: Sites with IRB approval to use this tool: Charleston, Boulder, Fort Collins, New Orleans, San Francisco (two sites), Madison, New York (two sites), Boston, Vancouver and Montreal.

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2018
• Primary Completion (Actual): August 11, 2020
• Study Completion (Actual): August 21, 2020

Study Registration Dates

• First Submitted: May 14, 2018
• First Submitted That Met QC Criteria: May 24, 2018
• First Posted (Actual): May 25, 2018

Study Record Updates

• Last Update Posted (Estimated): January 24, 2024
• Last Update Submitted That Met QC Criteria: January 22, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Trauma and Stressor Related Disorders; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Hallucinogens; Adrenergic Uptake Inhibitors; N-Methyl-3,4-methylenedioxyamphetamine
• Other Study ID Numbers: MAPP1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will share outcome data appearing in any published reports upon request.
• IPD Sharing Time Frame: Data and study-related documents will be available when the database has been locked and data has been unblinded.
• IPD Sharing Access Criteria: Interested persons should correspond with the central contact for the multisite study.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No