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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]

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

Anxiety symptoms

Advanced-stage cancer

Condition category

Condition code

Mental Health

Anxiety

Mental Health

Depression

Cancer

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]

Treatment: Drugs

Intervention code [2]

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]

Change in anxiety and depressive symptoms measured using the Hospital Anxiety and Depression Scale

Timepoint [1]

Day 28 (+/- 3 days) post-dosing of MDMA

Secondary outcome [1]

Change in Brief Pain Inventory-Short Form (BPI-SF) score.

Timepoint [1]

Day 28 (+/- 3 days) post-dosing of MDMA

Secondary outcome [2]

Change in International Palliative Outcomes Scale (IPOS) score

Timepoint [2]

Day 28 (+/- 3 days) post-dosing of MDMA

Secondary outcome [3]

Change in Kessler Psychological Distress Scale (K10) score

Timepoint [3]

Day 28 (+/- 3 days) post-dosing of MDMA

Secondary outcome [4]

Change in Mystical Experiences Questionnaire (MEQ30) score

Timepoint [4]

7 hours post-dosing of MDMA and day 28 (+/- 3 days) post-dosing of MDMA

Secondary outcome [5]

Change in FACIT Sp-12 score

Timepoint [5]

Day 28 (+/- 3 days) post-dosing of MDMA

Secondary outcome [6]

Change in Death Attitudes Profile Revised (ADP-R) score

Timepoint [6]

Day 28 (+/- 3 days) post-dosing of MDMA

Secondary outcome [7]

Change in Personality Traits (NEO-FFI) scores

Timepoint [7]

Day 28 (+/- 3 days) post-dosing of MDMA

Secondary outcome [8]

Adverse events including nausea, teeth-clenching, muscle cramps, blurred vision, chills and excessive sweating.

Adverse events will be identified by participant report.

Timepoint [8]

Any adverse events reported between dosing and day 28 (+/-3 days) post-dosing.

Secondary outcome [9]

Suicidality assessed by Columbia-suicide severity rating scale (C-SSRS)

Timepoint [9]

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?

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

Accrual to date

Final

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Funding & Sponsors

Funding source category [1]

University

Name [1]

University of Otago

Address [1]

University of Otago
362 Leith St, North Dunedin,
Dunedin 9016

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Not yet submitted

Ethics committee name [1]

Health and Disability Ethics Committee

Ethics committee address [1]

Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

01/10/2019

Approval date [1]

Ethics approval number [1]

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

Prof Paul Glue

Address

University of Otago,
362 Leith St, North Dunedin,
Dunedin 9016

Country

New Zealand

Phone

+64 21 243 3372

Fax

Paul.glue@otago.ac.nz

Contact person for public queries

Name

Prof Paul Glue

Address

University of Otago,
362 Leith St, North Dunedin,
Dunedin 9016

Country

New Zealand

Phone

+64 3 474 0999

Fax

Paul.glue@otago.ac.nz

Contact person for scientific queries

Name

Prof Paul Glue

Address

University of Otago,
362 Leith St, North Dunedin,
Dunedin 9016

Country

New Zealand

Phone

+64 3 474 0999

Fax

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?

Type	Citation	Link	Email	Other Details	Attachment
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.

Trial Review

Documents added manually

Documents added automatically