Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619001334190p
Ethics application status
Not yet submitted
Date submitted
20/08/2019
Date registered
30/09/2019
Date last updated
Type of registration
Prospectively registered

Titles & IDs
Public title
The Effect of 3, 4-Methylenedioxymethamphetamine (MDMA)-assisted therapy on Mood and Anxiety symptoms in advanced-stage Cancer Study
Scientific title
A double-blinded randomised controlled trial of low-dose vs standard dose MDMA in MDMA-assisted therapy for treatment of mood and anxiety symptoms in advanced-stage cancer patients
Secondary ID [1] 298990 0
Nil Known
Universal Trial Number (UTN)
U1111-1238-8911
Trial acronym
EMMAC Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Depression symptoms 313993 0
Anxiety symptoms 313994 0
Advanced-stage cancer 313996 0
Condition category
Condition code
Mental Health 312383 312383 0 0
Anxiety
Mental Health 312384 312384 0 0
Depression
Cancer 312385 312385 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Standard dose 3, 4-Methylenedioxymethamphetamine (MDMA) in the context of MDMA-assisted therapy.

Single session - 125mg oral dose with an optional supplemental 62.5mg oral dose 1.5 to 2.5 hours later. The optional supplemental dose controls for inter-participant differences in dose-response. The optional supplemental dose will be offered to the participants 1.5 to 2.5 hours after the initial dose. Participants will have the option to accept or decline the supplemental dose based on whether they feel there has been a subjective adequate effect. They can discuss this choice with the therapy team. The team will withhold the supplemental dose if there is a contraindication - this includes a heart rate outside of the acceptable range, blood pressure outside of the acceptable range, concerns regarding mental state and any other concerns regarding tolerability.

Dosing will occur in a comfortable clinical setting with a qualified observer (physician, psychologist or nurse) with the participant for at least 6 hours post-dosing. The mode of administration will be oral capsules. All doses will be administered with 200mls water after a 2 hour fast. All dosing will be directly observed by a study clinician.

Extension study - After evaluation of the primary endpoint at 4 weeks, patients who have <20% improvement in Hospital Anxiety and Depression Scale (HADS) score compared with baseline/randomisation visit, will be eligible to receive a second open-label standard-dose of MDMA-assisted therapy (single session 125 mg + 62.5 mg optional supplemental dose). Therapy procedures for the extension study including timing and number of sessions will be identical to those of the initial dosing process.

Therapy:
Participants will undergo supportive therapy on days preceding and subsequent to dosing – specifically they will receive one hour at acceptance to the trial, one hour on the day before dosing, four hours at the time of dosing, one hour the day after dosing and one hour at a follow up session approximately 7 days post-dosing. There will also be additional availability of the therapists to the participants during the trial period as needed. Additional therapist input will be based on mental state assessment (presence of distress, worsening anxiety or depressive symptoms), this process of assessment may be based on clinician review during follow up or initiated by the patient.

Therapy will proceed as per the study manual, this will be based on a pre-existing manual for MDMA-assisted therapy for anxiety associated with life-threatening illness ('A Manual for MDMA-Assisted Psychotherapy in the Treatment of Anxiety Associated with a Life-Threatening Illness', Phillip E Wolfson MD and Michael Mithoefer MD, Version 1:9 April 2015, research sponsor: Multidisciplinary Association for Psychedelic Studies). Therapy sessions are expected to include a review of the participant’s existential anxieties in the light of their impending death, review of any unfinished business, review of their important relationships and review of their accomplishments and regrets. A supportive approach will be taken to any difficult/anxiety-laden material such as past trauma. Introducing material will be led by the patient unless the patient is appearing to be avoiding major issues or needing support in finding a useful focus for their experience.

With regards to the therapists, in addition to clinical competence as a health professional, training is planned in the form of workshops with role play and discussion. Discussion will include therapeutic optimism/neutrality, spiritual neutrality and acceptance of diverse beliefs, thorough acquaintance with the effects of MDMA and familiarity with the use of music/art materials which will be available in the sessions. The development of our therapy manual so that it is owned by the therapists involved will be the backbone of the training.

Attendance to therapy sessions will be monitored. We will also be recording all sessions for content analysis. Each participant is unique and will be processing their own material with the active supportive presence of the therapists. Effectiveness of the preliminary sessions will be monitored by the self-report non-verbal responses on the set and setting questionnaire. This is expected to reveal the degree of therapeutic alliance and trust in the therapists, setting and set prior to dosing.
Intervention code [1] 315257 0
Treatment: Drugs
Intervention code [2] 315258 0
Behaviour
Comparator / control treatment
Low dose 3, 4-Methylenedioxymethamphetamine (MDMA) in the context of MDMA-assisted therapy.

Single session - 25mg oral dose with an optional supplemental 12.5mg oral dose 1.5 to 2.5 hours later.The optional supplemental dose controls for inter-participant differences in dose-response. The optional supplemental dose will be offered to the participants 1.5 to 2.5 hours after the initial dose. Participants will have the option to accept or decline the supplemental dose based on whether they feel there has been a subjective adequate effect. They can discuss this choice with the therapy team. The team will withhold the supplemental dose if there is a contraindication - this includes a heart rate outside of the acceptable range, blood pressure outside of the acceptable range, concerns regarding mental state and any other concerns regarding tolerability.

Dosing will occur in a comfortable clinical setting with a qualified observer (physician, psychologist or nurse) with the participant for at least 6 hours post-dosing. The mode of administration will be oral capsules. All doses will be administered with 200mls water after a 2 hour fast. All dosing will be directly observed by a study clinician.

Extension study - After evaluation of the primary endpoint at 4 weeks, patients who have <20% improvement in Hospital Anxiety and Depression Scale (HADS) score compared with baseline/randomisation visit, will be eligible to receive a open-label standard-dose of MDMA-assisted therapy (single session 125 mg + 62.5 mg optional supplemental dose). Therapy procedures for the extension study including timing and number of sessions will be identical to those of the initial dosing process.


Therapy:
Participants will undergo supportive therapy on days preceding and subsequent to dosing – specifically they will receive one hour at acceptance to the trial, one hour on the day before dosing, four hours at the time of dosing, one hour the day after dosing and one hour at a follow up session approximately 7 days post-dosing. There will also be additional availability of the therapists to the participants during the trial period as needed. Additional therapist input will be based on mental state assessment (presence of distress, worsening anxiety or depressive symptoms), this process of assessment may be based on clinician review during follow up or initiated by the patient.

Therapy will proceed as per the study manual, this will be based on a pre-existing manual for MDMA-assisted therapy for anxiety associated with life-threatening illness ('A Manual for MDMA-Assisted Psychotherapy in the Treatment of Anxiety Associated with a Life-Threatening Illness', Phillip E Wolfson MD and Michael Mithoefer MD, Version 1:9 April 2015, research sponsor: Multidisciplinary Association for Psychedelic Studies). Therapy sessions are expected to include a review of the participant’s existential anxieties in the light of their impending death, review of any unfinished business, review of their important relationships and review of their accomplishments and regrets. A supportive approach will be taken to any difficult/anxiety-laden material such as past trauma. Introducing material will be led by the patient unless the patient is appearing to be avoiding major issues or needing support in finding a useful focus for their experience.

With regards to the therapists, in addition to clinical competence as a health professional, training is planned in the form of workshops with role play and discussion. Discussion will include therapeutic optimism/neutrality, spiritual neutrality and acceptance of diverse beliefs, thorough acquaintance with the effects of MDMA and familiarity with the use of music/art materials which will be available in the sessions. The development of our therapy manual so that it is owned by the therapists involved will be the backbone of the training.

Attendance to therapy sessions will be monitored. We will also be recording all sessions for content analysis. Each participant is unique and will be processing their own material with the active supportive presence of the therapists. Effectiveness of the preliminary sessions will be monitored by the self-report non-verbal responses on the set and setting questionnaire. This is expected to reveal the degree of therapeutic alliance and trust in the therapists, setting and set prior to dosing.
Control group
Dose comparison

Outcomes
Primary outcome [1] 321023 0
Change in anxiety and depressive symptoms measured using the Hospital Anxiety and Depression Scale
Timepoint [1] 321023 0
Day 28 (+/- 3 days) post-dosing of MDMA
Secondary outcome [1] 373708 0
Change in Brief Pain Inventory-Short Form (BPI-SF) score.
Timepoint [1] 373708 0
Day 28 (+/- 3 days) post-dosing of MDMA
Secondary outcome [2] 373709 0
Change in International Palliative Outcomes Scale (IPOS) score
Timepoint [2] 373709 0
Day 28 (+/- 3 days) post-dosing of MDMA
Secondary outcome [3] 373710 0
Change in Kessler Psychological Distress Scale (K10) score
Timepoint [3] 373710 0
Day 28 (+/- 3 days) post-dosing of MDMA
Secondary outcome [4] 373711 0
Change in Mystical Experiences Questionnaire (MEQ30) score
Timepoint [4] 373711 0
7 hours post-dosing of MDMA and day 28 (+/- 3 days) post-dosing of MDMA
Secondary outcome [5] 373712 0
Change in FACIT Sp-12 score
Timepoint [5] 373712 0
Day 28 (+/- 3 days) post-dosing of MDMA
Secondary outcome [6] 373713 0
Change in Death Attitudes Profile Revised (ADP-R) score
Timepoint [6] 373713 0
Day 28 (+/- 3 days) post-dosing of MDMA
Secondary outcome [7] 373714 0
Change in Personality Traits (NEO-FFI) scores
Timepoint [7] 373714 0
Day 28 (+/- 3 days) post-dosing of MDMA
Secondary outcome [8] 374008 0
Adverse events including nausea, teeth-clenching, muscle cramps, blurred vision, chills and excessive sweating.

Adverse events will be identified by participant report.
Timepoint [8] 374008 0
Any adverse events reported between dosing and day 28 (+/-3 days) post-dosing.
Secondary outcome [9] 374678 0
Suicidality assessed by Columbia-suicide severity rating scale (C-SSRS)
Timepoint [9] 374678 0
7 hours post-dosing, 2 days post-dosing, 4 days post-dosing, 8 days post-dosing, 15 days post-dosing and day 28 (+/- 3 days) post-dosing

Eligibility
Key inclusion criteria
1. Diagnosed with life-threatening cancer, which can be ongoing or in remission, but with a possibility of recurrence.
2. Prognosis of at least 3 months life expectancy from the time of screening
3. DSM-5 diagnosis of a depressive disorder, an anxiety disorder; and/or an adjustment disorder/stress reaction.
4. HADS total score >11 and K-10 score >25
5. Are at least 18 years old
6. Must be willing for the investigators to communicate directly with their medical team (oncologist, GP, palliative care physician, etc).
7. Are willing to refrain from starting any new psychiatric medication and/or psychotherapy during the study period.
8. Willing to follow restrictions and guidelines concerning consumption of food, beverages, and nicotine the night before and just prior to MDMA dosing.
9. Agree to have transportation other than driving themselves to where they are staying on the day of MDMA dosing.
10. Are willing to be contacted via telephone for all necessary telephone contacts.
11. Must have a negative pregnancy test if able to bear children, and agree to use an effective form of birth control if of child-bearing potential.
12. Must provide a contact in the event of a participant becoming suicidal
13. Are proficient in speaking and reading English.
14. Agree to not use any medications on the prohibited medications list during the course of the study.
15. Normal hepatic and renal function
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Are pregnant or nursing, or if a woman who can have children, those who are not practicing an effective means of birth control.
2. Weigh less than 48 kg
3. Are using illegal drugs
4. Are unable to give adequate informed consent
5. Upon review of past and current drugs/medication must not be on a medication that is exclusionary, or has been off an exclusionary drug for the requisite washout period (see appendix).
6. Upon review of medical or psychiatric history must not have any current or past diagnosis that would be considered a risk to participation in the study.
7. Are not receiving chemotherapy or other systemic cancer treatment.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Doses will be individually packaged and numbered in appropriately labelled containers. Doses will be allocated to specific patients based on their subject number. Randomization of dosing will be based on a computer-generated random code (double-blind).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization of dosing will be based on a computer-generated random code.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
n=24 is a convenience sample. There is no published data using MDMA in this patient population to permit formal statistical power calculations however a recently completed but unpublished MDMA study in this population enrolled n=18 (NCT02427568)

Data will be listed and analysed using counts and/or summary statistics where appropriate. A detailed SAP will be created and signed off prior to database finalization.

Primary Analysis
Comparison of difference of HADS total scores (end of trial visit minus Randomisation visit) using independent sample t-tests (or non-parametric alternative) to test for significance between dose groups, with p value set at 0.05.

Secondary Analyses
Comparison of difference of scores (end of trial visit minus Randomisation visit) for the following scales, using independent sample t-tests (or non-parametric alternative): HADS anxiety subscale, HADS depression subscale, Pain (BPI-SF), distress (K-10), International Palliative Outcomes Scale (IPOS), Mystical experiences questionnaire (MEQ30), FACIT Sp-12 (Spirituality), Death Attitudes Profile Revised (ADP-R) and Openness personality trait score Personality traits (NEO-FFI)

Extension study
Efficacy and pharmacodynamic data obtained after the open-label extension study dosing will be compared with both Randomisation visit and end of primary trial visit data. The influence of a second MDMA-assisted therapy session on rating scale scores will be compared between groups who received low-dose vs standard-dose MDMA-assisted therapy on Day 1.

Safety data (AEs, vital signs, safety lab tests, C-SSRS scores) will be listed and summarized by MDMA dose group. All adverse events recorded during the study will be summarised by system organ class, severity (based on CTC grades), type of adverse event, and relation to the study treatment by treatment arm. Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and tabulated by type of adverse event and treatment group.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/01/2020
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
24
Accrual to date
Final
Recruitment outside Australia
Country [1] 21758 0
New Zealand
State/province [1] 21758 0

Funding & Sponsors
Funding source category [1] 303529 0
University
Name [1] 303529 0
University of Otago
Country [1] 303529 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
362 Leith St, North Dunedin, Dunedin 9016
Country
New Zealand
Secondary sponsor category [1] 303594 0
None
Name [1] 303594 0
Address [1] 303594 0
Country [1] 303594 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 304056 0
Health and Disability Ethics Committee
Ethics committee address [1] 304056 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 304056 0
New Zealand
Date submitted for ethics approval [1] 304056 0
01/10/2019
Approval date [1] 304056 0
Ethics approval number [1] 304056 0

Summary
Brief summary
EMMAC is a randomised controlled trial studying the effects of MDMA-assisted therapy on mood and anxiety symptoms in advanced-stage cancer patients. Standard dose MDMA (125.5mg + optional 62.5mg) will be compared to low dose MDMA (25mg + optional 12.5mg) with both being given as a single dose. On the basis of MDMA pharmacology and recent research showing promising results with the use of psilocybin to reduce anxiety and depression in patients with advanced-stage cancer (Grob et al., 2011, Griffiths et al., 2016, Ross et al., 2016) we hypothesise that MDMA may have the potential to achieve similar positive mental health outcomes with reduced psychological risk given the differences in psychopharmacological effects.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 95670 0
Prof Paul Glue
Address 95670 0
University of Otago,
362 Leith St, North Dunedin,
Dunedin 9016
Country 95670 0
New Zealand
Phone 95670 0
+64 21 243 3372
Fax 95670 0
Email 95670 0
Paul.glue@otago.ac.nz
Contact person for public queries
Name 95671 0
Prof Paul Glue
Address 95671 0
University of Otago,
362 Leith St, North Dunedin,
Dunedin 9016
Country 95671 0
New Zealand
Phone 95671 0
+64 3 474 0999
Fax 95671 0
Email 95671 0
Paul.glue@otago.ac.nz
Contact person for scientific queries
Name 95672 0
Prof Paul Glue
Address 95672 0
University of Otago,
362 Leith St, North Dunedin,
Dunedin 9016
Country 95672 0
New Zealand
Phone 95672 0
+64 3 474 0999
Fax 95672 0
Email 95672 0
Paul.glue@otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the individual participant data collected during the trial after de-identification
When will data be available (start and end dates)?
Available immediately following publication with no end date determined
Available to whom?
Case-by-case basis at the discretion of the primary sponsor
Available for what types of analyses?
Any purpose
How or where can data be obtained?
Access subject to approval by Principal Investigator - can be contacted at Paul.glue@otago.ac.nz


What supporting documents are/will be available?

TypeCitationLinkEmailOther DetailsAttachment
Study protocol  Paul.glue@otago.ac.nz
Statistical analysis plan  Paul.glue@otago.ac.nz
Informed consent form  Paul.glue@otago.ac.nz
Clinical study report  Paul.glue@otago.ac.nz
Ethical approval  Paul.glue@otago.ac.nz
Analytic code  Paul.glue@otago.ac.nz


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.