The overall objective of this study is to use standard clinical measures to explore the safety and effects of open-label manualized MDMA-assisted psychotherapy with a flexible dose of MDMA in participants with severe PTSD, and to serve as an…
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Brief title
Condition
- Psychiatric and behavioural symptoms NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of this study is to evaluate the effect of MDMA-assisted
psychotherapy on PTSD, as measured by the estimand of change in CAPS-5 Total
Severity Score from Baseline (Visit 3) to 13 weeks post Baseline (Visit 14).
The primary and key secondary endpoint analyses will be based on the mITT
analysis set. Change from Visit 3 (Baseline) in CAPS-5 Total Severity Scores to
Visit 14 (Primary Endpoint) will be analyzed with least squares means from a
Mixed-Effect Repeated Measures model (MMRM). The mITT analysis set will include
all participants who receive IP in at least one Experimental Session and have
at least one follow-up CAPS-5 assessment.
The Primary Outcome measure, the change in CAPS-5 from Baseline (V3), is
assessed by a centralized Independent Rater (IR) pool at 13 weeks post Baseline
(V14). The CAPS-5 is also administered as an exploratory measure after
Treatment 1 (V8). The IR pool will be blinded to visit number and number of
treatments received and will not have access to data collected by the sites
during the active treatment period.
Secondary outcome
The secondary objective is to evaluate the effectiveness of MDMA-assisted
psychotherapy for PTSD in clinician-rated functional impairment, as measured by
the mean change in Sheehan Disability Scale (SDS) item scores from Visit 3
(Baseline) to Visit 14 (13 weeks post Baseline).
Safety Objective
The overall safety objective is to assess severity, incidence and frequency of
AEs, AEs of Special Interest (AESIs), and Serious Adverse Events (SAEs),
concomitant medication use, suicidal ideation and behavior, and vital signs to
support the package insert for MDMA-assisted psychotherapy. The following
safety objectives will evaluate the safety of MDMA-assisted psychotherapy:
1. Assess incidence of AEs during Experimental Sessions that may be indicative
of a medical complication of the Investigational Product (IP), such as clinical
signs and symptoms of chest pain, shortness of breath, or neurological symptoms
or any other signs or symptoms that prompt additional vital sign measurements.
2. Assess incidence of AEs by severity.
3. Assess incidence of Treatment Emergent AEs (TEAEs) by severity.
4. Assess incidence of TEAEs by severity taken during an Experimental Session
and through 2 days after IP administration.
5. Assess incidence of AESIs, defined as AEs specified in the protocol related
to cardiac function and abuse liability.
6. Assess incidence of AEs by severity categorized as leading to
discontinuation of IP, resulting in death or hospitalization, and continuing at
Study Termination.
7. Assess incidence of SAEs.
8. Assess incidence of psychiatric concomitant medications taken during an
Experimental Session and through 2 days after IP administration.
9. Assess incidence of any psychiatric concomitant medications taken during the
Treatment Period.
10. Assess incidence of serious suicidal ideation and positive suicidal
behavior assessed with the Columbia Suicide Severity Rating Scale (C-SSRS).
11. Assess mean changes in blood pressure, heart rate, and body temperature
from pre-IP administration to end of each Experimental Session.
Exploratory Objectives: These objectives may be explored to characterize
participants receiving MDMA-assisted psychotherapy to support the primary
objective:
1. Explore the effect of presence of secondary traumatic stressors (LEC-5) on
the CAPS-5 Total Severity analyses
2. Explore changes within-participants in PTSD symptom clusters of
re-experiencing, avoidance, negative alterations in cognition and mood, and
hyperarousal, as measured by changes in CAPS-5 subscale scores from Visit 3
(Baseline) to Visit 14 (13 weeks post Baseline)
3. Explore the effect of adverse childhood experiences (ACE) on the CAPS-5
Total Severity analyses
4. Explore changes in:
• Dissociative symptoms associated with PTSD (DSP-I)
• Depression (BDI-II)
• Chronic pain (CPGS)
• Quality of life (EQ-5D-5L)
• Self-compassion (SCS)
• Addictive behaviors including: alcohol use (AUDIT), drug use (DUDIT), and
nicotine use (SRNU)
• Eating habits (EAT-26)
• Healthcare utilization (UFEC)
• Subjective effect (SE)
fMRI Sub-Study Objectives and Evaluation:
To explore possible biological correlates of treatment outcomes obtained from
MDMA-assisted psychotherapy among participants with PTSD.
- To investigate pre-post effects of MDMA-assisted psychotherapy on brain
function and connectivity as measured by functional magnetic resonance imaging
(fMRI) and magnetic resonance spectroscopy (MRS), including response to
trauma-unrelated emotional stimuli (emotional faces), response to trauma
symptom provocation (personal trauma narrative). The outcome variables will be
compared between timepoints (Baseline scan V 4.1 and post-treatment scan V
14.1).
- To examine the relationship between fMRI outcome variables and the primary
outcome variable, namely change in CAPS-5 Total Severity Score from Baseline
(Visit 3) to 13 weeks post Baseline (Visit 14).
Background summary
PTSD is a serious, debilitating disorder that negatively impacts a person*s
daily life. MDMA has been shown to reduce defenses and fear of emotional
injury, enhance communication, and increase empathy. MDMA may enhance fear
extinction learning in humans. These subjective effects of MDMA create a
productive psychological state that enhances the therapeutic process for the
treatment of PTSD and other anxiety disorders. This novel treatment package
consists of up to three Experimental Sessions spaced a month apart of
psychotherapy combined with a flexible dose of MDMA, along with non-drug
preparatory and integrative psychotherapy. This study design is supported by
data from an international series of Phase 2 pilot studies of MDMA-assisted
psychotherapy conducted by the sponsor that provide preliminary evidence that
chronic PTSD, independent of cause, is treatable with two to three sessions of
MDMA-assisted psychotherapy and associated non-drug preparatory and integrative
psychotherapy sessions. The results from multiple independent studies in Phase
2 efficacy analyses demonstrate superiority of MDMA-assisted psychotherapy over
psychotherapy with placebo or low dose MDMA. The acceptable risk-benefit safety
ratio in early trials justifies further study.
This open-label, lead-in Phase 2 study is intended to gather supportive data on
the safety and effectiveness of manualized MDMA-assisted psychotherapy as a
treatment for PTSD. The Primary Outcome measure, the change in Clinician
Administered PTSD Scale for DSM-5 (CAPS-5) from Baseline to V14, evaluates
changes in PTSD symptom severity and is assessed by a centralized Independent
Rater (IR) pool in this study and in planned Phase 3 clinical trials. This will
be the first study of MDMA-assisted psychotherapy in Europe using the CAPS-5 as
a primary outcome measure to confirm assumptions made for statistical power
calculations using the Clinician-Administered PTSD Scale for DSM-4 (CAPS-4)
which support planned Phase 3 clinical trials. This study will gather
supportive data on the safety and effectiveness of manualized MDMA-assisted
psychotherapy as a treatment for PTSD and provide clinical supervision to
planned Phase 3 therapy teams. This study will also be the first multi-site
study of MDMA-assisted psychotherapy for PTSD in Europe and will explore
reproducibility of findings from FDA-regulated trials in a multi-site format to
further confirm the Phase 3 study design.
In addition, the fMRI Sub-Study will explore possible biological correlates of
treatment outcomes obtained from MDMA-assisted psychotherapy among participants
with PTSD. The sub-study will investigate pre-post effects of MDMA-assisted
psychotherapy on brain function and connectivity as measured by functional
magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS),
including response to trauma-unrelated emotional stimuli (emotional faces),
response to trauma symptom provocation (personal trauma narrative).
Study objective
The overall objective of this study is to use standard clinical measures to
explore the safety and effects of open-label manualized MDMA-assisted
psychotherapy with a flexible dose of MDMA in participants with severe PTSD,
and to serve as an opportunity for supervision of therapy teams selected to
conduct Phase 3 MDMA-assisted psychotherapy research.
The primary objective of this study is to evaluate the effect of MDMA-assisted
psychotherapy on PTSD, as measured by the estimand of change in CAPS-5 Total
Severity Score from Baseline (Visit 3) to 13 weeks post Baseline (Visit 14).
The secondary objective is to evaluate the effect of MDMA-assisted
psychotherapy for PTSD in clinician-rated functional impairment, as measured by
the mean change in Sheehan Disability Scale (SDS) item scores from Visit 3
(Baseline) to 13 weeks post Baseline (Visit 14).
The overall safety objective is to assess severity, incidence and frequency of
AEs, AEs of Special Interest (AESIs), and Serious Adverse Events (SAEs),
concomitant medication use, suicidal ideation and behavior, and vital signs to
support the package insert for MDMA-assisted psychotherapy. The safety
objectives will evaluate the safety of MDMA-assisted psychotherapy.
In addition, the fMRI Sub-Study will explore possible biological correlates of
treatment outcomes obtained from MDMA-assisted psychotherapy among participants
with PTSD:
- To investigate pre-post effects of MDMA-assisted psychotherapy on brain
function and connectivity as measured by functional magnetic resonance imaging
(fMRI) and magnetic resonance spectroscopy (MRS), including response to
trauma-unrelated emotional stimuli (emotional faces), response to trauma
symptom provocation (personal trauma narrative). The outcome variables will be
compared between timepoints (Baseline scan V 4.1 and post-treatment scan V
14.1).
- To examine the relationship between fMRI outcome variables and the primary
outcome variable, namely change in CAPS-5 Total Severity Score from Baseline
(Visit 3) to 13 weeks post Baseline (Visit 14).
Study design
An Open-Label, Phase 2, Multicenter Feasibility Study of Manualized
MDMA-Assisted Psychotherapy with an optional fMRI sub-study Assessing Changes
in Brain Activity in Subjects with Post-Traumatic Stress Disorder
Intervention
The treatment consists of a flexible dose of MDMA, followed by a supplemental
half-dose unless contraindicated, administered with manualized psychotherapy in
two open-label Experimental Sessions spaced a month apart. This ~8-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. Experimental Sessions are followed by an
overnight stay.
Initial doses per Experimental Session include 80 mg or 120 mg MDMA, followed
1.5 to 2 hours later by a supplemental half-dose (40 mg or 60 mg). Total
amounts of MDMA to be administered per Experimental Session range from 80 mg to
180 mg. MDMA dose ranges proposed in this study have been safely used in
previous Phase 2 studies sponsored by MAPS (Protocol section 5.5). Procedures
for MDMA-assisted psychotherapy will remain the same across all sessions and
all procedures regardless of dose received. Experimental Sessions must be at
least 8 hours long, measured from 30 minutes prior to IP administration.
For each participant, the study will consist of:
- Screening Period: phone screen, informed consent, eligibility assessment, and
enrollment of eligible participants
- Preparatory Period with Enrollment Confirmation: medication tapering,
Preparatory Sessions and Baseline assessments leading to Enrollment Confirmation
- Treatment Period: two Experimental Sessions spaced a month apart and
associated Integrative Sessions over ~8 weeks plus one CAPS-5 assessment
- Follow-up Period and Study Termination: ~4 weeks with no study visits,
followed by Primary Outcome CAPS-5 and Study Termination visit
- MRI: 2 visits for baseline scan Visit 4.1 and post-treatment scan Visit 14.1
Study burden and risks
During Screening, throughout MDMA-assisted psychotherapy, and during assessment
of study measures, participants will be asked to think about and discuss their
thoughts and emotions relating to the traumatic event or events. They may
experience intense emotional responses or suicidal ideation as a result of
recalling and speaking about this material. Even in a therapeutic context,
thinking about and discussing the trauma, symptoms related to the trauma or the
effects of PTSD on life function can produce distress and exacerbate suicidal
ideation during and immediately after psychotherapy sessions. Psychotherapy is
conducted as part of this study, and people undergoing psychotherapy are
expected to confront unpleasant thoughts, feelings and memories in the process.
Because psychotherapy is an integral part of the research study design, the
potential distress arising from psychotherapy is unavoidable.
Therapy teams will provide emotional support to participants during any
psychological distress.
The therapy team will minimize risks by carefully evaluating all participants
to determine if there is a current risk of suicidal behavior. Participants with
a history of suicide attempts will not be excluded unless significant risk of
suicidal behavior is present at the time of screening.
Blood draws and a full medical examination, including a physical examination,
ECG, 1-minute rhythm strip, and laboratory tests, are required to establish
eligibility for the study. Temporary discomfort, inflammation, or infection
could arise as a result of sampling blood at the punctured vein. Submitting to
a full medical examination may also cause discomfort or psychological distress.
fMRI: taking brain scans is associated with a loud thumping noise, participants
will be given hearing protection. Besides possible discomfort, there are no
known harmful side-effects associated with temporary exposure to the strong
magnetic field used by MRI scanners.
Tine van Dethstraat 83
Leiden 2331CD
NL
Tine van Dethstraat 83
Leiden 2331CD
NL
Listed location countries
Age
Inclusion criteria
1. Are at least 18 years old
2. Are fluent in speaking and reading the predominantly used or recognized
language of the study site
3. Are able to swallow pills
4. Agree to have study visits video-recorded, including Experimental Sessions,
Independent Rater assessments, and non-drug psychotherapy sessions
5. Must provide a contact (relative, spouse, close friend or other support
person) who is willing and able to be reached by the investigators in the event
of a participant becoming suicidal or unreachable
6. Must agree to inform the investigators within 48 hours of any medical
treatments and procedures
7. 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. Adequate
birth control methods include intrauterine device (IUD), injected or implanted
hormonal methods, abstinence, oral hormones plus a barrier contraception,
vasectomized sole partner or double barrier contraception. Two forms of
contraception are required with any barrier method or oral hormones (i.e.
condom plus diaphragm, condom or diaphragm plus spermicide, oral hormonal
contraceptives plus spermicide or condom). Not of childbearing potential is
defined as permanent sterilization, postmenopausal, or assigned male at birth.
8. Agree to the following lifestyle modifications (described in more detail in
Section 4.3 Lifestyle Modifications): comply with requirements for fasting and
refraining from certain medications prior to Experimental Sessions, not
participate in any other interventional clinical trials during the duration of
the study, remain overnight at the study site after each Experimental Session
and be driven home after, and commit to medication dosing, therapy, and study
procedures
9. At Screening, meet DSM-5 criteria for current PTSD with a symptom duration
of 6 months or longer
10. At Screening, have at least severe PTSD symptoms in the last month based on
PCL-5 total score of 50 or greater
11. At Screening, may have well-controlled hypertension that has been
successfully treated with anti-hypertensive medicines, if they pass additional
screening to rule out underlying cardiovascular disease
12. At Screening, may have asymptomatic Hepatitis C virus (HCV) that has
previously undergone evaluation and treatment as needed
13. At Baseline, have a confirmed diagnosis of PTSD per CAPS-5 and at least
severe symptoms in the last month constituting a CAPS-5 Total Severity Score of
35 or greater.
14. Absence of Traumatic Brain Injury
15. Absence of metal implants or metal fragments in the body
16. PTSD must be of non-dissociative sub-type
17. Absence of claustrophobia
18. Absence of tattoos in the head/neck or permanent eye makeup
Exclusion criteria
1. Are not able to give adequate informed consent
2. Are currently engaged in compensation litigation whereby financial gain
would be achieved from prolonged symptoms of PTSD or any other psychiatric
disorders
3. Are likely, in the investigator*s opinion and via observation during the
Preparatory Period, to be re-exposed to their index trauma or other significant
trauma, lack social support, or lack a stable living situation
4. 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
5. Have any current problem which, in the opinion of the investigator or
Medical Monitor, might interfere with participation, Psychiatric History, 1.
Have received Electroconvulsive Therapy (ECT) within 12 weeks of enrollment
2. Have a history of, or a current primary psychotic disorder, bipolar
affective disorder type 1 assessed via MINI or dissociative identity disorder
assessed via DDIS
3. Have Dissociative Subtype of PTSD assessed via CAPS-5
4. Have a current eating disorder with active purging assessed via MINI
5. Have current major depressive disorder with psychotic features assessed via
MINI
6. Meet DSM-5 criteria for current substance use disorder for alcohol or
substance use disorder other than caffeine or nicotine assessed via MINI,
AUDIT, DUDIT, drug test, and blood %carbohydrate-deficient transferrin (%CDT)
7.Have current Personality Disorders (paranoid, schizoid, antisocial,
borderline, histrionic, narcissistic, avoidant, dependent,
obsessive-compulsive) assessed via CIPD. Diagnoses will be confirmed via
clinical interview
8. Any participant presenting current serious suicide risk, as determined
through psychiatric interview, responses to C-SSRS, and clinical judgment of
the investigator will be excluded; however, history of suicide attempts is not
an exclusion. Any participant who is likely to require hospitalization related
to suicidal ideation and behavior, in the judgment of the investigator, will
not be enrolled
9. Would present a serious risk to others as established through clinical
interview and contact with treating psychiatrist
10. Require ongoing concomitant therapy with a psychiatric medication with
exceptions described in Section 12.0: Concomitant Medications., Medical
History, 1. Have evidence on clinical examination or history of significant
(controlled or uncontrolled) hematological, endocrine, cerebrovascular,
traumatic brain injury (TBI) with residual neurological signs or symptoms on
the physical exam, cardiovascular, coronary artery disease (using the New York
Heart Association criteria) cerebral or peripheral vascular disease, pulmonary,
renal, hepatic disease with abnormal liver enzymes (outside of the normal
clinical range), gastrointestinal, immunocompromising, or neurological disease,
including seizure disorder, or any other medical disorder judged by the
investigator to significantly increase the risk of MDMA administration
(participants with hypothyroidism who are on adequate and stable thyroid
replacement will not be excluded). Note: if participants present with a history
of glaucoma, enrollment would be allowed only with the approval of their
ophthalmologist
2. Have uncontrolled hypertension using the standard criteria of the American
Heart Association (values of 140/90 milligrams of Mercury [mmHg] or higher
assessed on three separate occasions)
3. 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). Abnormal ECG (including sinus bradycardia of less than 50 beats per
minute, sinus tachycardia of more than 100 beats per minute or prolonged QTc of
more than 450 ms in males and 460 ms in females).
4. Have a history of additional risk factors for Torsade de pointes (e.g.,
heart failure, hypokalemia, family history of Long QT Syndrome)
5. Require use of concomitant medications that prolong the QT/QTc interval
during Experimental Sessions. Refer to Section 12.0 Concomitant Medications.
6. Have symptomatic liver disease
7. Have history of hyponatremia (defined as outside of the normal range of 135
to 145 mmol/L) or hyperthermia
8. Weigh less than 48 kilograms (kg)
9. Are pregnant or nursing or are of childbearing potential and are not
practicing an effective means of birth control.
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-001718-13-NL |
| CCMO | NL67928.058.18 |