Posttraumatic Stress Disorder
Conditions
Brief summary
The goal of this clinical trial is to learn if MDMA-assisted therapy is safe and effective in people with at least severe PTSD. The main question it aims to answer is: Do three sessions of MDMA-assisted therapy reduce PTSD symptoms? Researchers will compare three sessions of MDMA-assisted therapy with an initial dose of 80 to 120 mg to three sessions of placebo with therapy. Participants will undergo three preparatory sessions without any study drug, followed by three MDMA-assisted therapy or placebo with therapy sessions. Each medication session will be followed by three integrative therapy sessions without study drug.
Detailed description
This multi-site, double-blind, placebo-controlled, randomized Phase 3 study will assess 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 randomized to one of two groups at a 1:1 ratio. An initial dose of midomafetamine HCl 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 midomafetamine HCl or placebo followed 1.5 to 2 hours later by a supplemental half-dose (40 or 60 mg). Total amounts of midomafetamine HCl to be administered per Experimental Session range from 80 mg to 180 mg. The primary endpoint is change from baseline in Clinician Administered PTSD Scale for DSM-V (CAPS-5) to 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).
Interventions
BEHAVIORALTherapy
Non-directive therapy performed by therapist team
Administration of 80 to 120 mg midomafetamine HCl, followed by a supplemental dose 1.5 to 2 hrs later of 40 or 60 mg midomafetamine HCl, respectively, during three experimental sessions
DRUGPlacebo
Administration of placebo during three experimental sessions
Sponsors
Lykos Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, 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.
Intervention model description
Randomized, double-blind, between-group comparison of change in PTSD symptoms
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 \[ms\] in males and \>460 ms in females 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, such as myocardial infarction, cerebrovascular accident, or aneurysm * 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 * Have an active illicit or prescription drug use disorder * Have used Ecstasy (material represented as containing MDMA) more than 10 times within the last 10 years or at least once within 6 months of the first Experimental Session; or have previously participated in a MAPS-sponsored MDMA clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Primary Endpoint in Clinician Administered PTSD Scale for DSM-V (CAPS-5) | Baseline to 18 weeks post enrollment confirmation | The CAPS-5 is a 30-item semi-structured interview assessing PTSD in the past month through diagnostic and symptom severity scores anchored to a DSM-5 defined traumatic event. The CAPS-5 produces a Total Severity Score based on severity of PTSD domains described in the DSM-5, as well as a categorical rating indicating whether a participant meets PTSD diagnostic criteria. CAPS-5 Total Symptom Severity scores range from 0 to 80 with higher values indicating greater symptom severity. CAPS-5 assigns PTSD diagnosis as being present or absent. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Primary Endpoint in Sheehan Disability Scale (SDS) Total Score | 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. |
Countries
Canada, Israel, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MDMA-assisted Therapy 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.
Psychotherapy: Standardized non-directive psychotherapy performed by therapist team
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. | 46 |
| Placebo With Therapy Administration of inactive placebo in combination with psychotherapy
Psychotherapy: Standardized non-directive psychotherapy performed by therapist team
Placebo: Administration of placebo during three sessions of MDMA-assisted psychotherapy | 44 |
| Total | 90 |
Baseline characteristics
| Characteristic | Placebo With Therapy | Total | MDMA-assisted Therapy |
|---|---|---|---|
| Age, Continuous | 38.19 years STANDARD_DEVIATION 10.36 | 40.93 years STANDARD_DEVIATION 11.95 | 43.55 years STANDARD_DEVIATION 12.86 |
| Body mass index | 24.8 kg/m^2 STANDARD_DEVIATION 4.2 | 25.4 kg/m^2 STANDARD_DEVIATION 4.5 | 26.0 kg/m^2 STANDARD_DEVIATION 4.8 |
| Dissociative subtype of PTSD | 13 Participants | 19 Participants | 6 Participants |
| Duration of PTSD | 13.3 years STANDARD_DEVIATION 11.4 | 14.0 years STANDARD_DEVIATION 11.5 | 14.8 years STANDARD_DEVIATION 11.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 8 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants | 81 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 7 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 8 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 30 Participants | 69 Participants | 39 Participants |
| Sex: Female, Male Female | 32 Participants | 59 Participants | 27 Participants |
| Sex: Female, Male Male | 12 Participants | 31 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 0 / 44 |
| other Total, other adverse events | 46 / 46 | 44 / 44 |
| serious Total, serious adverse events | 0 / 46 | 2 / 44 |
Outcome results
Primary
Change From Baseline to Primary Endpoint in Clinician Administered PTSD Scale for DSM-V (CAPS-5)
The CAPS-5 is a 30-item semi-structured interview assessing PTSD in the past month through diagnostic and symptom severity scores anchored to a DSM-5 defined traumatic event. The CAPS-5 produces a Total Severity Score based on severity of PTSD domains described in the DSM-5, as well as a categorical rating indicating whether a participant meets PTSD diagnostic criteria. CAPS-5 Total Symptom Severity scores range from 0 to 80 with higher values indicating greater symptom severity. CAPS-5 assigns PTSD diagnosis as being present or absent.
Time frame: Baseline to 18 weeks post enrollment confirmation
Population: Modified intention-to-treat
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MDMA-assisted Therapy | Change From Baseline to Primary Endpoint in Clinician Administered PTSD Scale for DSM-V (CAPS-5) | -24.5 score on a scale |
| Placebo With Therapy | Change From Baseline to Primary Endpoint in Clinician Administered PTSD Scale for DSM-V (CAPS-5) | -12.64 score on a scale |
Secondary
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.
Time frame: Baseline to 18 weeks post enrollment confirmation
Population: Modified intention-to-treat
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MDMA-assisted Therapy | Change From Baseline to Primary Endpoint in Sheehan Disability Scale (SDS) Total Score | -3.15 score on a scale |
| Placebo With Therapy | Change From Baseline to Primary Endpoint in Sheehan Disability Scale (SDS) Total Score | -1.79 score on a scale |