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

• ClinicalTrials.gov Identifier: NCT03537014
• Recruitment Status: Active, not recruiting
• First Posted: May 25, 2018
• Last Update Posted: April 13, 2020
• Sponsor: Multidisciplinary Association for Psychedelic Studies
• Information provided by (Responsible Party): Multidisciplinary Association for Psychedelic Studies

Study Description

Brief Summary:

This multi-site double-blind, placebo-controlled randomized Phase 3 study assesses the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy versus psychotherapy with placebo in participants diagnosed with at least severe posttraumatic stress disorder (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 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 change in Clinician Administered PTSD Scale for DSM 5 (CAPS-5) from Baseline. Exploratory measures will address specific symptoms or behavior that is sometimes related to PTSD. 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 (CSSRS). This study will compare the effects of three manualized Experimental Sessions of psychotherapy assisted by flexible doses of MDMA versus placebo. Initial doses per Experimental Session include 80 mg or 120 mg of MDMA compounded with mannitol and magnesium stearate or placebo alone (mannitol and magnesium stearate), 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.

Condition or disease	Intervention/treatment	Phase
Posttraumatic Stress Disorder	Behavioral: Psychotherapy; Drug: MDMA; Drug: Placebo	Phase 3

Detailed Description:

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, double-blind, randomized Phase 3 study assesses the efficacy and safety of MDMA-assisted psychotherapy versus psychotherapy with placebo control in participants diagnosed with at least severe posttraumatic stress disorder (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 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 change in Clinician Administered PTSD Scale for DSM 5 (CAPS-5) from Baseline. Exploratory measures will address specific symptoms, or behavior that is sometimes related to PTSD. 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 (CSSRS). This study will compare the effects of three manualized Experimental Sessions of psychotherapy supported by assisted by flexible doses of MDMA versus placebo. Initial doses per Experimental Session include 80 mg or 120 mg of MDMA compounded with mannitol and magnesium stearate or placebo alone (mannitol and magnesium stearate), 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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized, double-blind between group comparison of change in PTSD symptoms
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Masking Description: Use of separate databases for outcome measures and safety data. Assessment made by pool of independent raters. Randomization will be managed via an Interactive Web Randomization System (IWRS) based on a centralized randomization schedule developed by an independent third-party vendor to maintain blinding.
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: November 29, 2018
• Estimated Primary Completion Date: June 10, 2020
• Estimated Study Completion Date: June 18, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: MDMA; Administration of 80 or 120 mg MDMA in combination with psychotherapy and a supplemental dose offered 1.5/2 hrs later of 40 or 60 mg MDMA respectively.	Behavioral: Psychotherapy; Standardized non-directive psychotherapy performed by therapist team; Other Name: Manualized MDMA-assisted psychotherapy; Drug: MDMA; Administration of 80 to 120 mg MDMA during three sessions of MDMA-assisted psychotherapy followed by a supplemental dose of 40 or 60 mg MDMA offered 1.5/2 hrs after the initial dose, respectively.; Other Name: 3,4-methylenedioxymethamphetamine
Placebo Comparator: Placebo; Administration of inactive placebo in combination with psychotherapy	Behavioral: Psychotherapy; Standardized non-directive psychotherapy performed by therapist team; Other Name: Manualized MDMA-assisted psychotherapy; Drug: Placebo; Administration of placebo during three sessions of MDMA-assisted psychotherapy; Other Name: Inactive placebo

Outcome Measures

Primary Outcome Measures :

1. Change from Baseline in Clinician-Administered PTSD for DSM 5 [ Time Frame: 18 weeks post baseline post enrollment confirmation ]
   Global severity Scores on the CAPS-5, a measure of PTSD symptoms

Secondary Outcome Measures :

1. Change from Baseline in Sheehan Disability Scale (SDS) total score [ Time Frame: 18 weeks post enrollment confirmation ]
   Sheehan Disability Scale (SDS) total score, a measure of clinician-rated functional impairment.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

New School Research LLT

North Hollywood, California, United States, 91601

San Francisco Insight and Integration Center

San Francisco, California, United States, 94114

University of California San Francisco

San Francisco, California, United States, 94122

United States, Colorado

Aguazul-Blue Water Inc.

Boulder, Colorado, United States, 80302

Wholeness Center

Fort Collins, Colorado, United States, 80525

United States, Louisiana

Ray Worthy Psychiatry LLC

New Orleans, Louisiana, United States, 70123

United States, Massachusetts

Trauma Research Foundation

Boston, Massachusetts, United States, 02446

United States, New York

New York University

New York, New York, United States, 10016

New York Private Practice

New York, New York, United States, 10024

United States, South Carolina

Zen Therapeutic Solutions, LLC

Mount Pleasant, South Carolina, United States, 29464

United States, Wisconsin

University of Wisconsin at Madison

Madison, Wisconsin, United States, 53705

Canada, British Columbia

Providence Health Center

Vancouver, British Columbia, Canada, V5R 5H3

Canada, Quebec

Dr. Simon Amar, Inc.

Montreal, Quebec, Canada, H2W1Y9

Israel

Assaf Harofeh Research Fund

Beer Yaakov, Israel

Sheba Fund for Health Services and Research

Tel HaShomer, Israel

Sponsors and Collaborators

Multidisciplinary Association for Psychedelic Studies

Investigators

• Study Director: Michael Mithoefer, MD; MAPS Public Benefit Corp.

More Information

Additional Information:

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. 

• Responsible Party: Multidisciplinary Association for Psychedelic Studies
• ClinicalTrials.gov Identifier: NCT03537014
• Other Study ID Numbers: MAPP1
• First Posted: May 25, 2018
• Last Update Posted: April 13, 2020
• Last Verified: January 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: We will share outcome data appearing in any published reports upon request.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: Data and study-related documents will be available when the database has been locked and data has been unblinded.
• Access Criteria: Interested persons should correspond with the central contact for the multisite study.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Trauma and Stressor Related Disorders; Mental Disorders; N-Methyl-3,4-methylenedioxyamphetamine; Hallucinogens; Physiological Effects of Drugs; Psychotropic Drugs; Serotonin Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Adrenergic Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Adrenergic Agents