MDMA-assisted Therapy Versus Cognitive Processing Therapy for Veterans With Severe Posttraumatic Stress Disorder

Study Overview
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Brief Summary
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In partnership with the Veterans Affairs (VA) Palo Alto Health Care System and Stanford University, this study aims to evaluate clinical outcomes, assess implementation feasibility, and health economics of MDMA-assisted therapy in the treatment of posttraumatic stress disorder (PTSD). Through a randomized comparison of MDMA-assisted therapy versus Cognitive Processing Therapy (CPT), a VA gold standard treatment for PTSD, the proposed study will set the stage for understanding the potential use and application of MDMA-assisted therapy for PTSD within the VA system.

Detailed Description
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Posttraumatic stress disorder (PTSD) is a serious debilitating disorder that negatively impacts a person's daily life, and can result in diminished cognitive and psychosocial functioning, fractured relationships, inability to maintain employment, substance use disorders, high-cost healthcare utilization, increased depression, and suicide risk. People who suffer from PTSD relive their traumatic experience(s) through nightmares and flashbacks, have difficulty sleeping, and feel detached or estranged. Symptoms can be severe and long lasting. Many available PTSD treatments, including medications and therapy, effectively treat only a fraction of people who try them. This indicates a need to assess treatments targeting durable remission of PTSD. An extensive list of medications, namely antipsychotics, anxiolytics, antidepressants, and sleep aids, are frequently prescribed off-label but are minimally effective in reducing PTSD symptoms. MDMA-assisted therapy is a novel treatment package that combines psychotherapeutic techniques with the administration of MDMA as a pharmacological adjunct intended to enhance certain aspects of therapy. The subjective effects of MDMA create a productive psychological state that enhances the therapeutic process. The Multidisciplinary Association for Psychedelic Studies (MAPS) is a non-profit research and educational organization working as a clinical trial sponsor to obtain approval for the prescription use of 3,4-methylenedioxymethamphetamine (MDMA) as an adjunct to therapy in patients with treatment-resistant PTSD. Data from a series of Phase 2 and Phase 3 studies of MDMA-assisted therapy conducted by MAPS provide preliminary evidence that chronic PTSD, independent of cause, is treatable with up to three sessions of MDMA-assisted therapy and associated non-drug preparatory and integrative therapy sessions. Cognitive Processing Therapy (CPT) is a cognitively-oriented approach to treating PTSD developed in the late 1980's by Dr. Patricia Resick. Significant research on CPT has been conducted in the VA system nationally. Across a number of studies, a meta-analysis found the number of subjects that no longer meet PTSD criteria after receiving a full course of CPT ranged from 30% to 97%, and 51% of subjects receiving CPT achieved loss of diagnosis compared to waitlist, self-help booklets, and treatment as usual control groups. There are various task forces and active efforts to deploy CPT more broadly in the VA. The comparison of CPT and MDMA-assisted therapy for treatment of PTSD is very timely given the tremendous need to treat PTSD throughout the VA system, making this comparison all the more pertinent. PTSD carries a high public burden, both economically and socially, by increased healthcare utilization, use of social services, lost wages, and disability payments. Given the chronicity of PTSD, low treatment compliance evidenced by high dropouts, and limited recovery with current medications contributing to serious outcomes, PTSD patients exhibit an unmet medical need. Currently, the VA serves approximately nine million Veterans and the conservative estimate of those with PTSD is 25%, or over two million Veterans. The potential importance and benefits of this novel treatment to Veterans, doctors, researchers, and the VA system cannot be underestimated. The clinical effectiveness, implementation evaluation, and economic assessment conducted in this study will provide critical information and understanding of the feasibility of utilization in the VA system.

Official Title
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A Randomized Trial to Compare MDMA-assisted Therapy (MDMA-AT) Versus Cognitive Processing Therapy (CPT), a VA Standard-of-care Psychotherapy for PTSD, for the Treatment of Severe Posttraumatic Stress Disorder

Conditions
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PTSD

Intervention / Treatment
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* Drug: MDMA
* Behavioral: Cognitive Processing Therapy
* Behavioral: MDMA-assisted Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants are eligible to be included in the study only if all of the following criteria apply: Are at least 18 years at the time of signing the informed consent. Are a U.S Military Veteran Are receiving services from VA Palo Alto Healthcare System, VA San Francisco Healthcare System, or VA NorCal Healthcare System Are fluent in speaking and reading in English Agree to have study visits audio and/or video recorded Able to identify appropriate support person(s) to stay with the participant on the evenings of the Experimental Sessions. Meet DSM-5 criteria for current severe PTSD with a symptom duration of at least 6 months. Have severe PTSD symptoms in the last month. Body weight of at least 48 kilograms (kg). Is not pregnant, planning to get pregnant, or breastfeeding Capable of giving signed informed consent Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Have a history of any medical condition that could make receiving a sympathomimetic drug harmful Have current unstable medical illness Have cardiac conditions, including uncontrolled hypertension, prolonged QTc interval, and other cardiac conditions Have received Electroconvulsive Therapy (ECT), ketamine-assisted therapy, or used ketamine within 12 weeks of enrollment Have an active alcohol or substance use disorder Have current serious suicide risk Unable or unwilling to stop or safely taper off prohibited medications Have used Ecstasy more than 10 times within the last 10 years Currently enrolled in any clinical study Have a history of or current psychotic disorders, bipolar disorder type I, or severe personality disorders Lack social support, or lack a stable living situation Previous participation in a MAPS-sponsored MDMA clinical trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a randomized study. Participants will be 1:1 randomized to receive either MDMA or CPT.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MDMA-assisted therapy (MDMA-AT)<br>This arm consists of three, 90-minute, non-drug Preparatory Sessions and a  12-week Treatment Period comprised of three Experimental Sessions with MDMA (  8 hours), each followed by three 90-minute, non-drug Integration Sessions. Participants will receive 60mg MDMA HCl for first Experimental Session and 60mg or 120mg MDMA HCl for following Experimental Sessions. During each Experimental Session, participants will have the option of receiving a supplemental dose of 40mg or 60mg MDMA HCl 1.5-2 hours after the initial dose. Participants will have the option to crossover to the CPT arm 6 months after all study visits are completed. | Drug: MDMA<br>* Participants will receive a flexible divided-dose of MDMA HCl plus therapy at three Experimental Sessions, as well as non-drug Preparatory and Integration Sessions<br>Behavioral: MDMA-assisted Therapy<br>* Participants assigned to MDMA and d-amphetamine will undergo a therapeutic approach, which is detailed in the MDMA-Assisted Therapy Treatment Manual and administered by MAPS-trained therapists. In brief, this therapy is guided by the subject's own recollections of traumatic events. The subject and two therapists provide a comfortable and supportive environment and allow the subject to guide the discussion. Subjects are encouraged to experience and express fear, anger, and grief with less likelihood of feeling overwhelmed by these emotions. MDMA seems to engender internal awareness that even painful feelings that arise are an important part of the therapeutic process. In addition, feelings of empathy, love, and deep appreciation often emerge, along with a clearer perspective of the trauma as a past event, a more accurate perspective about its significance, and a heightened awareness of the support and safety that exists in the present.<br>|
| Experimental: Cognitive processing therapy<br>This arm consists of one, 60-minute, introductory meeting with the therapist followed by a  12-week Treatment Period comprised of 12 1-hour CPT sessions with three optional additional sessions, each approximately one week apart. Participants will have the option to crossover to the MDMA-AT arm 6 months after all study visits are completed. | Behavioral: Cognitive Processing Therapy<br>* Participants will receive 12-16 sessions of Cognitive Processing Therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Clinician Administered PTSD Scale (CAPS-5) Total Severity Score | The Primary Outcome measure will be the change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) Total Severity Score from Baseline to 4 months post-baseline assessed by a blinded study staff rater. 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. | From Baseline to approximately 4 months post-baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Quality of Life Enjoyment and Satisfaction Questionnaire | The secondary outcome measure will be the change in the8.6.2.2 Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF), assessed by a blinded study staff rater. The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) is a self-report measure designed to enable investigators to easily obtain sensitive measures of the degree of enjoyment and satisfaction experienced by subjects in various areas of daily functioning. The summary scores were found to be reliable and valid measures of these dimensions in a group of depressed outpatients. The Q-LES-Q measures were related to, but not redundant with, measures of overall severity of illness or severity of depression within this sample. These findings suggest that the Q-LES-Q measures may be sensitive to important differences among depressed patients that are not detected by the measures usually employed. | From Baseline to approximately 4 months post-baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDMA-assisted Therapy, Cognitive Processing Therapy, Veterans, Posttraumatic stress disorder, Quality of Life