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

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ClinicalTrials.gov Identifier: NCT03537014
Recruitment Status : Completed
First Posted : May 25, 2018
Results First Posted : September 16, 2021
Last Update Posted : November 11, 2021
Sponsor:
Information provided by (Responsible Party):
Multidisciplinary Association for Psychedelic Studies

Brief Summary:
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.

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

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).

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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
Actual Primary Completion Date : August 21, 2020
Actual Study Completion Date : August 21, 2020

Resource links provided by the National Library of Medicine


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 Name: Manualized MDMA-assisted therapy

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 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 Name: Manualized MDMA-assisted therapy

Drug: Placebo
Administration of placebo during three sessions of MDMA-assisted psychotherapy
Other Name: Inactive placebo




Primary Outcome Measures :
  1. Change From Baseline to Primary Endpoint in Clinician Administered PTSD Scale for DSM-V (CAPS-5) [ Time Frame: Baseline to 18 weeks post enrollment confirmation ]
    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.


Secondary Outcome Measures :
  1. Change From Baseline to Primary Endpoint in Sheehan Disability Scale (SDS) Total Score [ Time Frame: Baseline to 18 weeks post enrollment confirmation ]
    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.



Information from the National Library of Medicine

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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03537014


Locations
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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
Be'er Ya'akov, Israel
Sheba Fund for Health Services and Research
Tel HaShomer, Israel
Sponsors and Collaborators
Multidisciplinary Association for Psychedelic Studies
Investigators
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Study Director: Michael Mithoefer, MD MAPS Public Benefit Corp.
  Study Documents (Full-Text)

Documents provided by Multidisciplinary Association for Psychedelic Studies:
Study Protocol  [PDF] May 22, 2020
Statistical Analysis Plan  [PDF] May 22, 2020
Informed Consent Form  [PDF] June 12, 2020

Additional Information:
Publications of Results:
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Responsible Party: Multidisciplinary Association for Psychedelic Studies
ClinicalTrials.gov Identifier: NCT03537014    
Other Study ID Numbers: MAPP1
First Posted: May 25, 2018    Key Record Dates
Results First Posted: September 16, 2021
Last Update Posted: November 11, 2021
Last Verified: November 2021
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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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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