Transcript MAPS MP-7 Protocol Review

Berra Yazar-Klosinski
Kamila Novak
Site
 Principal Investigator: Nasser Shuriquie MD
 Co-therapists: Tayseer Shawash MD, Mona Al-Nsour PhD,
Malak Talep abu Hdaib
CRO
 Regional Manager: Kamila Novak
 Clinical Research Associate: Doaa Al-Faqih
Sponsor
 Clinical Program Manager: Amy Emerson
 Clinical Research Associate: Berra Yazar-Klosinski, PhD
 Executive Director: Rick Doblin, PhD
 Medical Monitor: Michael Mithoefer, MD
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MDMA-assisted psychotherapy for chronic, treatmentresistant PTSD
◦ Explore safety and efficacy
◦ Determine effect size for this subject population
◦ Assess if investigators and participants accurately guess MDMA
dose condition
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Primary Objective
◦ Assess changes in PTSD symptoms via CAPS* score at baseline
and end of Stage 1
* CAPS = Clinician Administered PTSD Scale
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Assess:
o Before and after Stage 1 in all dose conditions
 Quality of life by GAF*
 Symptoms of depression by BDI-II** scores
o After open-label lead-in (CAPS, GAF, BDI-II)
o After Stage 2 cross over (CAPS, GAF, BDI-II)
o At the the 12 month follow-up (CAPS, GAF, BDI-II)
* GAF = Global Assessment of Functioning
** BDI-II = Beck Depression Inventory - II
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Primary efficacy measure: CAPS
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CAPS interviews determined to have
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CAPS has been translated into Arabic for first time for
the study
◦ Measures overall PTSD severity
◦ Covers 4 symptom clusters
◦ Evaluates frequency and intensity dimensions of each symptom
cluster
◦ Measures impact of symptoms on social and occupational
functioning
◦ Good internal consistency
◦ Concurrent validity
◦ Test/retest reliability
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GAF
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BDI-II
◦ Measures Quality of life
◦ General function
◦ Scores from 0 to 100
 100 = superior function
 0 = serious risk of causing harm to self or others
◦ 21-item measure of depressive symptoms
◦ Self-report: completed by subject
◦ Previous studies used and validated in Arabic
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To monitor and assure safety of participants by
assessing:
◦ Psychological distress with SUD* during each experimental
session
◦ Vital signs during each experimental session
◦ Suicidality with C-SSRS**
 Before, during and after experimental sessions
◦ Adverse Events (AEs), Serious Adverse Events (SAEs) and
Spontaneously Reported Reactions
* SUD = Subjective Units of Distress
** C-SSRS = Columbia Suicide Severity Rating Scale
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Subjective Units of Distress Scale (SUD)
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Vital signs
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Current degree of distress according to subject
Single item
Self-report: completed by subject
Measured every 60-90 minutes during experimental session
◦ More frequent measures if one of following thresholds are exceeded:
 160 mmHg systolic BP
 110 mm Hg diastolic BP
 110 bpm heart rate
◦ Blood pressure
 Measured every 30 minutes during experimental session
◦ Heart rate
 Measured every 30 minutes during experimental session
◦ Body temperature
 Measured every 60-90 minutes during experimental session
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C-SSRS
◦ Measure of suicidal behavior
◦ Detects potential suicidal thoughts or behaviors during a
clinical trial
 Face to face interview
 Over the telephone
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Adverse Events (AEs) and spontaneously reported
reactions
◦ Collected during experimental sessions and for 7 days after
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Serious adverse events (SAEs)
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Concomitant Medications
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The Reactions to Research Participation Questionnaire
(RRPQ)
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Assesses participant’s experience as a research subject
Reasons for consenting to be a research participant
Perceived freedom to take part in the study
Self-report: completed by subject
Translated to Arabic for the study
Belief of condition assignment
◦ Subject, investigators and Independent Rater try to guess
condition assignment during Stage 1
◦ How certain they are is also recorded
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Patients: 12 people
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Recruitment:
◦ Chronic, treatment-resistant PTSD (CAPS ≥ 50 at baseline)
◦ At least 18 years old
◦ Hospital database
◦ Letters of referral
 To psychiatrists or psychotherapists
◦ Word of mouth
◦ Iraqi refugees
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Meet DSM IV criteria for current PTSD
◦ 6 months or longer
CAPS score of 50 or higher
◦ Indicating moderate to severe PTSD
At least one unsuccessful attempt at treatment
◦ With medication (SSRI, SNRI, mirtazapine, MAOI) or psychotherapy
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At least 18 years old
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Willing to commit to medication dosing, experimental sessions,
follow-up sessions and complete evaluation instruments
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Willing to refrain from taking psychiatric medications during study
◦ Except gabapentin for pain control
◦ Discontinue only after consultation with prescribing physician
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Agree not to change type or frequency of current psychotherapy or
outside therapist until after 3rd experimental session
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For one week preceding experimental session, refrain from:
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Any herbal supplement
Any nonprescription medications (exept NSAIDs or Acetaminophen)
Any prescription medications (except birth control, thyroid hormones)
Get approval from research team for additional exceptions
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Evening before experimental session after 24:00 (midnight)
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Refrain from the use of any psychoactive drug (except nicotine or
caffeine), within 24 hours of each MDMA session
◦ Nothing by mouth except alcohol-free liquids
◦ no use of nicotine and caffeine 1 hour before and 3 hours after MDMA
administration
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Willing to remain overnight at study site after each experimental
session until after integrative session next morning
Willing to be driven home the morning after the experimental
sessions, after integrative session, either by a driver arranged by the
subject, or by site personnel or taxi
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Willing to be contacted via telephone on a daily basis by one of the
investigators for a week after each experimental session
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If female subject able to bear children
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Literate, proficient in speaking and reading Arabic, able to
effectively communicate with therapists and other site personnel
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Willing not to participate in any other clinical trials during the
duration of this study, including the follow-up period
◦ Willing to have pregnancy tests
◦ Use effective form of birth control
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Pregnant or nursing
◦ Women of child bearing potential who are not practicing an
effective means of birth control (including abstinence)
History of, or current:
◦ Primary psychotic disorder
◦ Bipolar affective disorder type 1
◦ Dissociative identity disorder
◦ Borderline personality disorder
◦ Eating disorder with active purging
Evidence or history of significant:
◦ Hematological, Endocrine, Cerebrovascular, Cardiovascular
◦ Coronary, Pulmonary, Renal, Gastrointestinal
◦ Immunocompromising, Neurological disease, Seizure disorder
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Hypertension, peripheral vascular disease
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Hepatic disease (with or without abnormal liver enzymes)
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History of hyponatremia or hyperthermia
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Weigh less than 48 kg
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Have used “Ecstasy” (illicit drug preparations that may contain
MDMA)
◦ > 5 times total, or
◦ Within last 6 months
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Serious suicide risk, or likely to require hospitalization during study
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Require ongoing concomitant therapy with psychiatric drug
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Meet DSM-IV criteria for substance abuse within last 60 days
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Not able to give adequate informed consent
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Current problem or history of substance abuse which might interfere
with participation in the protocol
◦ E.g. SSRIs, SNRIs, MAOIs
◦ Not including caffeine and nicotine
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This is a randomized, double-blind, dose comparison study with:
◦ Open-label lead-in section
◦ Randomized, blinded arm (Stage 1)
◦ Open-label partial cross-over arm: only Active Placebo subjects
cross over (Stage 2)
Open-label lead-in: training on the treatment method (2 subjects)
◦ Similar to Stage 1 (3 prep sessions)
◦ Similar to Stage 2 (open-label, full dose)
◦ 1st subject: 3 experimental sessions complete with video
◦ 2nd subject: 2 experimental sessions complete with video
◦ Sponsor reviews data for adherence: 3 out of 5 sessions above
◦ After approval, then proceed with Stage 1
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Stage 1: blinded assignment to two dose conditions
◦ 40 mg (active placebo dose)+ optional 20 mg supplement (3 subjects)
◦ 125 mg (full dose) + optional 62.5 mg supplement (7 subjects)
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Web-based randomization
◦ detailed instructions in Study Reference Manual
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Participants are randomized at least 24 hours before first
experimental session
Stage 2: open-label full dose condition
◦ 125mg (full dose) + optional 62.5 mg supplement (8 subjects)
Preparatory
Sessions
Screening
Visit 1
Enroll
Baseline
Evaluation
Ind. Rater
2
3
Approximately
1 week apart
Experimental
Session 1
4
Randomize
5
3-5 weeks after V1
and 3 prep sessions
Experimental
Session 1
5
6
Experimental
Session 2
Integrative Sessions
Integrative
session 1
day after
7 day phone
follow up
9
7
8
Approximately
1 week apart
3-5 weeks after Exp
session 1 and 3
integrative sessions
Experimental
Session 2
9
10
Experimental
Session 3
Integrative Sessions
Integrative
session 1
day post
7 day phone
follow up
13
11
12
Approximately
1 week apart
3-5 weeks after Exp
session 2 and 3
integrative sessions
Experimental
Session 3
13
14
Outcome,
unblinding and
possible enrollment
in Stage 2
Integrative sessions
Integrative
session 1
day post
7 day phone
follow up
17
15
16
Approximately
1 week apart
Outcome
Ind. Rater
2 months after
Exp session 3
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Only Active Placebo subjects eligible
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Course and schedule is similar to Stage 1 & lead-in
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Confirm informed consent & willingness to continue
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Confirm eligibility criteria
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1 preparatory psychotherapy session – V18
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All Stage 2 subjects will receive full dose MDMA
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Dropouts will not be replaced, max 3 subjects
Final Experimental
Session
(Stage 1 or Stage 2)
Long Term
Follow-up
Evaluation
1 year
Memory aids
Psychiatric medications
Outcome
Ind. Rater
2 months after
Exp session 3
(Stage 1 or Stage 2)
Outcome
Ind. Rater
12 months after final
Exp session
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Screening Visits
◦ Completed during 1 month prior to Visit 1
◦ Collect psychiatric & medical history
◦ Complete physical exams, clinical labs
◦ Review previous medical records or talk with treating physician if
needed to clarify medical history
◦ Review Inclusion Exclusion
◦ Schedule Independent Rater Baseline Screening
Discussion:
What is the best way to communicate and provide information about
subjects between the Rater and the Investigator?
How to complete and share source records
Video recording
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Preprinted Source Records for visits are provided
Source cover sheets and checklists are provided to the Independent
Rater
◦ Independent Rater Checklist
◦ Checklists and outcome measure results will be sent over in
packets at the time each subject is enrolled or progresses to Stage
2 and/or Follow-up
Completed Outcome Measures are the source for independent rater
assessments
The source will be used to complete CRFs. The CRFs will be
monitored and entered into the MAPS database
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Tool for subject to record adverse events and
safety information during the 10 months after the
final Independent Rater assessment
Memory Aids will not be collected
◦ Info may be collected by phone or in person
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The Memory Aids are designed to help the subject
recall
◦ any AEs/SAEs and medications associated with these
◦ If and when they started psychiatric medications
Long Term Follow-up and Study
Termination
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Subjects complete the 2 month outcome measures following the
final experimental session and enter long term follow up.
◦ Complete RRPQ right before follow-up period
◦ Give a memory aid card to help with safety collection during the
10 month period until termination
At 12 months after the final experimental session they will be
contacted to have final outcome measures completed and a final
visit with the therapists
◦ Subjects can withdraw consent at any time
◦ Investigators can withdraw a subject in his/her clinical
judgment if:
 The safety of the study subject is impacted
 The subject cannot comply with the protocol
 Due to contraindications
◦ Withdrawn subjects in Stage 1 will be replaced
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If a subject terminates from treatment and does not
withdraw consent they should be followed for safety
and proceed to follow up visits as applicable
◦ Complete the next integrative session(s) and complete final
outcome measure as appropriate
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Inform Randomization Monitor of withdrawal via
email
Replacement subjects will receive new Enrollment
Code