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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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

Tracking Information
First Submitted Date  ICMJE May 14, 2018
First Posted Date  ICMJE May 25, 2018
Results First Submitted Date  ICMJE August 18, 2021
Results First Posted Date  ICMJE September 16, 2021
Last Update Posted Date November 11, 2021
Actual Study Start Date  ICMJE November 29, 2018
Actual Primary Completion Date August 21, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 18, 2021)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: May 24, 2018)
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
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 18, 2021)
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.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 24, 2018)
  • Change from Baseline in Beck Depression Inventory II (BDI-II) [ Time Frame: 18 weeks post enrollment confirmation ]
    Assesses self-reported depression symptoms
  • Systolic Blood pressure (SBP) [ Time Frame: 4 weeks after enrollment ]
    Systolic blood pressure assessed 1.5 to 2 hours after initial MDMA/placebo dose during first of three experimental sessions
  • Systolic Blood pressure (SBP) [ Time Frame: 8 weeks after enrollment ]
    Systolic blood pressure assessed 1.5 to 2 hours after initial MDMA/placebo dose during second of three experimental sessions
  • Systolic Blood pressure (SBP) [ Time Frame: 12 weeks after enrollment ]
    Systolic blood pressure assessed 1.5 to 2 hours after initial MDMA/placebo dose during third of three experimental sessions
  • Diastolic blood pressure (DBP) [ Time Frame: 4 weeks after enrollment ]
    Diastolic blood pressure assessed 1.5 to 2 hours after initial MDMA dose during first of three experimental sessions
  • Diastolic blood pressure (DBP) [ Time Frame: 8 weeks after enrollment ]
    Diastolic blood pressure assessed 1.5 to 2 hours after initial MDMA/placebo dose during second of three experimental sessions
  • Diastolic blood pressure (DBP) [ Time Frame: 12 weeks after enrollment ]
    Diastolic blood pressure assessed 1.5 to 2 hours after initial MDMA/placebo dose during third of three experimental sessions
  • Pulse [ Time Frame: 4 weeks after enrollment ]
    Pulse assessed 1.5 to 2 hours after initial dose of MDMA or placebo during first of three experimental sessions
  • Pulse [ Time Frame: 8 weeks after enrollment ]
    Pulse assessed 1.5 to 2 hours after initial dose of MDMA or placebo during second of three experimental sessions
  • Pulse [ Time Frame: 12 weeks after enrollment ]
    Pulse assessed 1.5 to 2 hours after initial dose of MDMA or placebo during third of three experimental sessions
  • Body temperature (BT) [ Time Frame: 4 weeks after enrollment ]
    BT assessed 1.5 to 2 hours after initial dose of MDMA or placebo during first of three experimental sessions.
  • Body temperature (BT) [ Time Frame: 8 weeks after enrollment ]
    BT assessed 1.5 to 2 hours after initial dose of MDMA or placebo during second of three experimental sessions.
  • Body temperature (BT) [ Time Frame: 12 weeks after enrollment ]
    BT assessed 1.5 to 2 hours after initial dose of MDMA or placebo during third of three experimental sessions.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Multi-Site Phase 3 Study of MDMA-Assisted Psychotherapy for PTSD (MAPP1)
Official Title  ICMJE 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
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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
Condition  ICMJE Posttraumatic Stress Disorder
Intervention  ICMJE
  • 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
  • Drug: Placebo
    Administration of placebo during three sessions of MDMA-assisted psychotherapy
    Other Name: Inactive placebo
Study Arms  ICMJE
  • 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.
    Interventions:
    • Behavioral: Therapy
    • Drug: MDMA
  • Placebo Comparator: Placebo with therapy
    Administration of inactive placebo in combination with therapy during 3 experimental sessions scheduled 3-5 weeks apart
    Interventions:
    • Behavioral: Therapy
    • Drug: Placebo
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 24, 2018)
100
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE August 21, 2020
Actual Primary Completion Date August 21, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   Israel,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03537014
Other Study ID Numbers  ICMJE MAPP1
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: We will share outcome data appearing in any published reports upon request.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: 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.
Responsible Party Multidisciplinary Association for Psychedelic Studies
Study Sponsor  ICMJE Multidisciplinary Association for Psychedelic Studies
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Michael Mithoefer, MD MAPS Public Benefit Corp.
PRS Account Multidisciplinary Association for Psychedelic Studies
Verification Date November 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP