MP-7 Investigator MeetingJanuary 31, 2011

Berra Yazar-KlosinskiKamila Novak

Site Principal Investigator: Nasser Shuriquie MD Co-therapists: Tayseer Shawash MD, Mona Al-Nsour PhD,

Malak Talep abu HdaibCRO Regional Manager: Kamila Novak Clinical Research Associate: Doaa Al-FaqihSponsor Clinical Program Manager: Amy Emerson Clinical Research Associate: Berra Yazar-Klosinski, PhD Executive Director: Rick Doblin, PhD Medical Monitor: Michael Mithoefer, MD

MP-7 Team

MDMA-assisted psychotherapy for chronic, treatment-resistant PTSD◦ Explore safety and efficacy◦ Determine effect size for this subject population◦ Assess if investigators and participants accurately guess MDMA

dose condition

Primary Objective◦ Assess changes in PTSD symptoms via CAPS* score at baseline

and end of Stage 1

* CAPS = Clinician Administered PTSD Scale

Objectives

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

Secondary Objectives

Primary efficacy measure: CAPS◦ 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

CAPS interviews determined to have◦ Good internal consistency◦ Concurrent validity◦ Test/retest reliability

CAPS has been translated into Arabic for first time for the study

Efficacy Variables- Outcome Measures

GAF◦ Measures Quality of life◦ General function◦ Scores from 0 to 100

100 = superior function 0 = serious risk of causing harm to self or others

BDI-II◦ 21-item measure of depressive symptoms◦ Self-report: completed by subject◦ Previous studies used and validated in Arabic

Efficacy Variables- Outcome Measures

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

Safety Objectives

Subjective Units of Distress Scale (SUD) ◦ Current degree of distress according to subject ◦ Single item◦ Self-report: completed by subject◦ Measured every 60-90 minutes during experimental session

Vital signs◦ 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

Safety Variables

C-SSRS◦ Measure of suicidal behavior◦ Detects potential suicidal thoughts or behaviors during a

clinical trial Face to face interview Over the telephone

Adverse Events (AEs) and spontaneously reported reactions◦ Collected during experimental sessions and for 7 days

after

Serious adverse events (SAEs)

Concomitant Medications

Safety Variables

The Reactions to Research Participation Questionnaire (RRPQ) ◦ 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

Process Measures

Patients: 12 people◦ Chronic, treatment-resistant PTSD (CAPS ≥ 50 at

baseline)◦ At least 18 years old

Recruitment:◦ Hospital database◦ Letters of referral

To psychiatrists or psychotherapists◦ Word of mouth◦ Iraqi refugees

Patient Population and Recruitment

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

At least 18 years old

Willing to commit to medication dosing, experimental sessions, follow-up sessions and complete evaluation instruments

Willing to refrain from taking psychiatric medications during study◦ Except gabapentin for pain control◦ Discontinue only after consultation with prescribing physician

Inclusion Criteria

Agree not to change type or frequency of current psychotherapy or outside therapist until after 3rd experimental session

For one week preceding experimental session, refrain from:◦ 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

Evening before experimental session after 24:00 (midnight)◦ Nothing by mouth except alcohol-free liquids

Refrain from the use of any psychoactive drug (except nicotine or caffeine), within 24 hours of each MDMA session◦ no use of nicotine and caffeine 1 hour before and 3 hours after MDMA

administration

Inclusion Criteria

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

Willing to be contacted via telephone on a daily basis by one of the investigators for a week after each experimental session

If female subject able to bear children◦ Willing to have pregnancy tests◦ Use effective form of birth control

Literate, proficient in speaking and reading Arabic, able to effectively communicate with therapists and other site personnel

Willing not to participate in any other clinical trials during the duration of this study, including the follow-up period

Inclusion Criteria

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

Exclusion Criteria

Hypertension, peripheral vascular disease

Hepatic disease (with or without abnormal liver enzymes)

History of hyponatremia or hyperthermia

Weigh less than 48 kg

Have used “Ecstasy” (illicit drug preparations that may contain MDMA) ◦ > 5 times total, or◦ Within last 6 months

Serious suicide risk, or likely to require hospitalization during study

Exclusion Criteria

Require ongoing concomitant therapy with psychiatric drug◦ E.g. SSRIs, SNRIs, MAOIs

Meet DSM-IV criteria for substance abuse within last 60 days◦ Not including caffeine and nicotine

Not able to give adequate informed consent

Current problem or history of substance abuse which might interfere with participation in the protocol

Exclusion Criteria

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

Study Design

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)

Web-based randomization◦ detailed instructions in Study Reference Manual

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)

Randomization

MP-7 Flowchart- Exp Session 1

Screening

Experimental Session 1

Preparatory Sessions

Approximately 1 week apart

RandomizeVisit 1Enroll 2 4 53

Baseline Evaluation Ind. Rater

3-5 weeks after V1 and 3 prep sessions

5

Experimental Session 1

Experimental Session 2

7 day phone follow up

Integrative session 1 day after6 7 8

9

Integrative Sessions

Approximately 1 week apart

MP-7 Flowchart- Exp Session 2

3-5 weeks after Exp session 1 and 3

integrative sessions

9

7 day phone follow up

10 11 1213

Experimental Session 2

Experimental Session 3

Integrative session 1 day post

Integrative Sessions

Approximately 1 week apart

MP-7 Flowchart- Exp Session 3

3-5 weeks after Exp session 2 and 3

integrative sessions

13

7 day phone follow up

Integrative sessions

14 15 16

Outcome Ind. Rater2 months afterExp session 3

17

Outcome, unblinding and possible enrollment in Stage 2

Experimental Session 3

Approximately 1 week apart

MP-7 Flowchart- End of Stage 1

Integrative session 1 day post

Only Active Placebo subjects eligible

Course and schedule is similar to Stage 1 & lead-in

Confirm informed consent & willingness to continue

Confirm eligibility criteria

1 preparatory psychotherapy session – V18

All Stage 2 subjects will receive full dose MDMA

Dropouts will not be replaced, max 3 subjects

Stage 2 – Open Label Crossover

MP-7 Flowchart- Long Term Follow Up

Memory aidsPsychiatric medications

Final Experimental Session (Stage 1 or Stage 2)

Long Term Follow-up Evaluation

Outcome Ind. Rater2 months afterExp session 3(Stage 1 or Stage 2)

1 year

Outcome Ind. Rater12 months after final Exp session

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 recordsVideo recording

Screening

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

Study Procedures and Source records

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

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

Memory Aid Card

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

Long Term Follow-up and Study Termination

◦ 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

Early Termination

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

Inform Randomization Monitor of withdrawal via email

Replacement subjects will receive new Enrollment Code

Withdrawal of Subjects from Trial and Replacement Procedures