Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619001334190
Ethics application status
Approved
Date submitted
20/08/2019
Date registered
30/09/2019
Date last updated
27/10/2023
Date data sharing statement initially provided
30/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of 3, 4-Methylenedioxymethamphetamine (MDMA)-assisted therapy on Mood and Anxiety symptoms in patients with advanced-stage Cancer Study (EMMAC Study)
Scientific title
A double-blind, randomised trial of methylphenidate-assisted versus MDMA-assisted therapy for 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
Single dose 3, 4-Methylenedioxymethamphetamine (MDMA) in the context of MDMA-assisted therapy.

Participants will undergo a single session of MDMA assisted-therapy. Participants will receive a 120mg oral dose. If meeting criteria, an optional supplemental 60mg oral dose will be offered after 2 hours to control for inter-participant differences in dose-response. Blood pressure and pulse rate will be measured at 2 hours, if the BP is <160 and HR <110 and/or stabilising/trending down after re-assessing at 5min intervals and both therapists are in agreement, then the supplemental dose will be made available to the participant. Participants will have the option to accept or decline the supplemental dose based on whether they feel there has been a subjective adequate effect. This choice can be discussed with the therapists.

Participants will undergo 8 hours of supervised medication-assisted therapy in a comfortable non-clinical environment, with a therapeutic approach guided by the Aotearoa/New Zealand Manual for MDMA-assisted therapy treatment of depression and anxiety in the context of advanced-stage cancer.

For each medication-assisted therapy session, participants will undergo 2 x 90-minute therapeutic support sessions in the week preceding (e.g. to prepare for dosing, cover psychoeducational topics, explore important issues that may arise during the dosing session). Participants will also undergo 1 x 90-minute therapeutic support session the day after dosing (eg. for debrief, integration of experience, explore spiritual/other changes experienced after dosing).

The MAPS model for MDMA-assisted therapy will be followed - two therapists will be present with the participant for all pre and post MDMA-assisted therapy sessions and will both be present for 8 hours on the dosing day. All psychotherapists will have a professional qualification in either counselling, social work, psychotherapy, psychology, nursing or medicine, or equivalent experience and have formal training and supervision with MAPS.

Sessions will be audio and video recorded for qualitative analysis and to assess therapist adherence to the therapy manual.
Intervention code [1] 315257 0
Treatment: Drugs
Intervention code [2] 315258 0
Behaviour
Comparator / control treatment
Methylphenidate as psychoactive control in the context of medication-assisted therapy.

Participants will undergo a single session of medication assisted-therapy. Participants will receive a 20mg oral dose of methylphenidate. If meeting criteria, an optional supplemental 10mg oral dose will be offered after 2 hours to control for inter-participant differences in dose-response. Blood pressure and pulse rate will be measured at 2 hours, if the BP is <160 and HR <110 and/or stabilising/trending down after re-assessing at 5min intervals and both therapists are in agreement, then the supplemental dose will be made available to the participant. Participants will have the option to accept or decline the supplemental dose based on whether they feel there has been a subjective adequate effect. This choice can be discussed with the therapists.

Participants will undergo 8 hours of supervised medication-assisted therapy in a comfortable non-clinical environment, with a therapeutic approach guided by the Aotearoa/New Zealand Manual for MDMA-assisted therapy treatment of depression and anxiety in the context of advanced-stage cancer.

For each medication-assisted therapy session, participants will undergo 2 x 90-minute therapeutic support sessions in the week preceding (e.g. to prepare for dosing, cover psychoeducational topics, explore important issues that may arise during the dosing session). Participants will also undergo 1 x 90-minute therapeutic support session the day after dosing (eg. for debrief, integration of experience, explore spiritual/other changes experienced after dosing).

The MAPS model for MDMA-assisted therapy will be followed - two therapists will be present with the participant for all pre and post medication-assisted therapy sessions and will both be present for 8 hours on the dosing day. All psychotherapists will have a professional qualification in either counselling, social work, psychotherapy, psychology, nursing or medicine, or equivalent experience and have formal training and supervision with MAPS.

Sessions will be audio and video recorded for qualitative analysis and to assess therapist adherence to the therapy manual.
Control group
Active

Outcomes
Primary outcome [1] 321023 0
Change from baseline score of Montgomery Asberg Depression Scale
Timepoint [1] 321023 0
Day 28 (+/- 3 days) post-dosing of MDMA or methylphenidate
Secondary outcome [1] 373709 0
Change in International Palliative Outcomes Scale (IPOS) score
Timepoint [1] 373709 0
Day 28 (+/- 3 days) post-dosing of MDMA or methylphenidate
Secondary outcome [2] 373711 0
Change in Mystical Experiences Questionnaire (MEQ30) score
Timepoint [2] 373711 0
Day 28 (+/- 3 days) post-dosing of MDMA or methylphenidate
Secondary outcome [3] 373712 0
Change in FACIT Sp-12 score
Timepoint [3] 373712 0
Day 28 (+/- 3 days) post-dosing of MDMA or methylphenidate
Secondary outcome [4] 373713 0
Change in Death Attitudes Profile Revised (ADP-R) score
Timepoint [4] 373713 0
Day 28 (+/- 3 days) post-dosing of MDMA or methylphenidate
Secondary outcome [5] 373714 0
Big Five Inventory - 2 (BFI-2) scores
Timepoint [5] 373714 0
Day 28 (+/- 3 days) post-dosing of MDMA or methylphenidate
Secondary outcome [6] 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 [6] 374008 0
Any adverse events reported between dosing and day 28 (+/-3 days) post-dosing.
Secondary outcome [7] 374678 0
Suicidality assessed by Columbia-suicide severity rating scale (C-SSRS)
Timepoint [7] 374678 0
7 hours post-dosing, 1 day post-dosing, 3 days post-dosing (+/- 2 days), 7 days post-dosing (+/-2 days), 14 days post-dosing (+/-2 days) and day 28 (+/- 3 days) post-dosing
Secondary outcome [8] 380118 0
Change from baseline in Hospital Anxiety and Depression Scale
Timepoint [8] 380118 0
Day 28 (+/- 3 days) post-dosing of MDMA or methylphenidate
Secondary outcome [9] 405265 0
Change in Hamilton Anxiety Rating Scale (HAM-A)
Timepoint [9] 405265 0
Day 28 (+/- 3 days) post-dosing of MDMA or methylphenidate
Secondary outcome [10] 405268 0
Change in Australian Karnofsky Performance Score (AKPS)
Timepoint [10] 405268 0
Day 28 (+/- 3 days) post-dosing of MDMA or methylphenidate
Secondary outcome [11] 428247 0
Hua Oranga score (in participants identifying as Maori)
Timepoint [11] 428247 0
Secondary outcome [12] 428248 0
Hua Oranga score (in participants identifying as Maori)
Timepoint [12] 428248 0
Day 28 (+/-3 days) post-dosing of MDMA or methylphenidate
Secondary outcome [13] 428249 0
Watts Connectedness Scale (WCS)
Timepoint [13] 428249 0
Day 28 (+/-3 days) post-dosing of MDMA or methylphenidate
Secondary outcome [14] 428250 0
Watts Connectedness Scale (WCS)
Timepoint [14] 428250 0
Day 28 (+/- 3 days) post-dosing of MDMA or methylphenidate
Secondary outcome [15] 428251 0
Demoralisation Scale-II (DS-II)
Timepoint [15] 428251 0
Day 28 (+/- 3 days) post-dosing of MDMA or methylphenidate
Secondary outcome [16] 428252 0
Demoralisation Scale-II (DS-II)
Timepoint [16] 428252 0
Day 28 (+/- 3 days) post-dosing of MDMA or methylphenidate

Eligibility
Key inclusion criteria
1. Diagnosed with advanced-stage cancer (stage 3 or 4).
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. MADRS score > 15 and HAM-A score > 12
5. Are at least 18 years old
6. Are able to swallow pills
7. The participant agrees to have study visits recorded
8. Must agree to inform the investigators within 48 hours of any medical conditions and procedures
9. Must be willing for the investigators to communicate directly with their medical team (oncologist, GP, palliative care physician, etc).
10. Agree to refrain from starting any new psychiatric medication and/or psychotherapy during the study period.
11. Willing to follow restrictions and guidelines concerning consumption of food, beverages, including caffeine and nicotine the night before and just prior to medication dosing.
12. Agree to have transportation other than driving themselves to where they are staying on the day of medication dosing.
13. Are able and willing to be contacted via telephone for all necessary telephone contacts.
14. Must have a negative pregnancy test if able to become pregnant, and agree to use an effective form of contraception for 10 days following the last experimental session if of child-bearing potential (Effective forms of contraception include: IUD, injected, implanted, intravaginal, or transdermal hormonal methods, abstinence, oral hormones plus barrier contraception, vasectomized sole partner, or double barrier contraception. Two forms of contraception are required with any barrier method or oral hormones. Not of childbearing potential is defined as permanent sterilization, postmenopausal, or assigned male at birth.).
15. Must provide a contact/support person in the event of the participant being unreachable by study staff or in the event of severe emergent distress or suicidality.
16. Are proficient in speaking and reading English.
17. Agree to not use any medications on the prohibited medications list during the study.
18. Agree to the lifestyle modifications illustrated below, comply with requirements for fasting, refrain from certain medications prior to Experimental Sessions, not participate in any other interventional clinical trials during the duration of the study, remain at the study site after each Experimental Session until cleared to be driven home after, and commit to medication dosing, therapy, and study procedures.

All participants must agree to the following lifestyle modifications at enrollment and throughout the duration of the study. Participants are eligible to enroll in the study if they:

• Are willing to commit to medication dosing, therapy sessions, follow-up sessions, completing evaluation instruments, and all necessary telephone contact.
• Agree to not participate in any other interventional clinical trials during the duration of this study.

Leading up to Experimental Sessions

• Agree to take nothing by mouth except alcohol-free liquids after 12:00 A.M. (midnight) the evening before each Experimental Session.
• Refrain from the use of any psychoactive medication not approved by the research team from Baseline through Study Termination.
• Agree not to use caffeine or nicotine for 2 hours before and at least 6 hours after the initial dose during each Experimental Session.
• Are willing to comply with medication requirements per protocol. Medications will only be discontinued after enrollment per clinical judgment of the site physician in consultation with the prescribing physician.
• Are on a stable dose of allowable opiates for 2 weeks leading up to the Experimental Session as determined by the study physician.. During this period and throughout the study, the participant will be allowed to take their usual pain medication if needed for breakthough pain.
• Agree that, for 1 week preceding each Experimental Session to refrain from:
o Taking any herbal supplement (except with prior approval of the research team).
o Taking any nonprescription medications (with the exception of non-steroidal anti-inflammatory medications or acetaminophen/paracetamol unless with prior approval of the research team).
o Taking any prescription medications (with the exception of birth control, thyroid hormones, or other medications approved by the research team).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pregnancy or lactation
2. BMI < 15
3. Recent or current use of illicit drugs including methamphetamine, heroin, and synthetic cannabinoids. Other non-prescribed drugs will prompt exclusion at the discretion of the study physician
4. Unable to give adequate informed consent
5. Upon review of past and current drugs/medication must not be taking a medication that is exclusionary (see Study Reference Manual), or has stopped taking an exclusionary drug for less than the requisite washout period (see Study Reference Manual)
6. Liver function test >3 times the upper limit of normal or creatinine clearance <30 mL/min
7. Upon review of medical or psychiatric history must not have any current or past diagnosis that would be considered a risk for participation in the study. Any participant presenting current serious suicide risk, as determined through psychiatric interview, responses to C-SSRS, and clinical judgement of the investigator will be excluded; however, history of suicide attempts is not, in itself, exclusionary. Any participant who is likely to require hospitalization related to suicidal ideation and behaviour, in the judgement of the Study physician will not be enrolled. Any participant presenting with the following on the Baseline C-SSRS will be excluded:
- Suicidal ideation score of >4 within the last month, at a frequency of once a week or more
- Suicidal ideation score of 5 within the last 6 months
- Any suicidal behaviour, including suicide attempts or preparatory acts, within the last 6 months. Participants with non-suicidal self-injurious behaviour may be included if approved by the Study physician

8. Have a history of any medical condition that could make receiving a sympathomimetic drug harmful because of increases in blood pressure and heart rate. This includes, but is not limited to, a history of myocardial infarction, cerebrovascular accident, or aneurysm. Participants with other mild, stable chronic medical problems may be enrolled if the site physician, CI, and Study physician agree the condition would not significantly increase the risk of MDMA administration or be likely to produce significant symptoms during the study that could interfere with study participation or be confused with side effects of the IMP. Examples of stable medical conditions that could be allowed include, but are not limited to diabetes mellitus (Type 2), human immunodeficiency virus (HIV) infection, gastroesophageal reflux disease (GERD), etc. Any medical disorder judged by the investigator to significantly increase the risk of MDMA administration by any mechanism would require exclusion.
9. Have uncontrolled essential 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).
10. Have a history of ventricular arrhythmia at any time, other than occasional premature atrial contractions (PACs) or premature ventricular contractions (PVCs) in the absence of ischemic heart disease.
11. Have Wolff-Parkinson-White syndrome or any other accessory pathway that has not been successfully eliminated by ablation.
12. Have a history of arrhythmia, other than occasional PACs or PVCs in the absence of ischemic heart disease, within 12 months of screening. Participants with a history of atrial fibrillation, atrial tachycardia, atrial flutter or paroxysmal supraventricular tachycardia or any other arrhythmia associated with a bypass tract may be enrolled only if they have been successfully treated with ablation and have not had recurrent arrhythmia for at least one year off all antiarrhythmic drugs, and confirmed by a cardiologist.
13. Have a marked Baseline prolongation of QT/QTc interval e.g., repeated demonstration of a QTc interval >450 milliseconds (ms) in males and >460 ms in females. For transgender or non-binary participants, QTc interval will be evaluated based on sex assigned at birth, unless the participant has been on hormonal treatment for 5 or more years. Have a history of additional risk factors for Torsade de pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
14. Require use of concomitant medications that prolong the QT/QTc interval during Experimental Sessions. Refer to Section 8.2
15. Have any current problem which, in the opinion of the investigator or Study physician, might interfere with participation

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.

Enclosed treatment assignments will be serially numbered in opaque, sealed envelopes and opened sequentially after the participant’s name and other details have been written on the appropriate envelope
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation to treatment group will be stratified by clinical site and gender. A computer-generated randomisation schedule will be used to assign subjects to treatments in a 1:1 ratio using blocks of 4.

Randomization will be managed via an Interactive Web Randomization System (IWRS) based on a centralized randomization schedule developed by an independent third-party vendor to maintain blinding.
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
Study size justification:
Wolfson’s 2020 paper on use of MDMA in anxious patients with Life Threatening Illness (mainly terminal cancer) reported a mean difference of 14.7 (SD = 14) in Spielberger Trait Anxiety Index, with n=13 treated with MDMA and 5 treated with placebo. Based on these findings and with 16 subjects in each arm, we calculate that there is 82% power to detect a difference between treatment arms, alpha = 0.05.

Statistical methods/analysis:
Data will be analysed using the Statistical Package for Social Scientists (SPSS version 14).

Analyses of primary and all secondary efficacy endpoints will be based on the Full Analysis Set (FAS) defined according to the Intention to Treat (ITT) principle. Safety analysis will be performed for the safety analysis population.

Demographic and other baseline data (including disease characteristics) will be listed in detail. Qualitative data (e.g. KS performance status) and quantitative (e.g. weight) will be summarized by appropriate descriptive statistics for each treatment group.

Change in MADRS from pre-dose to Day 28 will be assessed with a Mixed Model Repeated Measures (MMRM) method, with treatment, time and the interaction of treatment with time as fixed effects, subject as random effect and baseline MADRS as covariates. The least square mean differences between MDMA and active placebo will be presented along with a 95% confidence interval. The same approach will be undertaken for secondary and exploratory outcome scales. We also plan to include a prespecified interim analysis into the SAP. Unblinded data would be reviewed by a statistician not involved with the EMMAC study, to assist in resizing the study, if necessary. A detailed statistical analysis plan (SAP) will be developed and finalized separate from this protocol.

AEs will be categorised using NIH/NCI CTC V3.0 (http://evs.nci.nih.gov/ftp1/CTCAE/About.html). AEs will be summarised by number of participants having an AE by system organ class and preferred term and treatment group. Any other information collected (e.g. severity or relationship to study treatment) will be listed and summarised by treatment group as appropriate. AEs which result in death, discontinuation or treatment delay will be presented by treatment group. Data from other tests (e.g. vital signs, ECG) will be listed along with any other information collected, as appropriate. Any statistical tests performed to explore the data will be used to highlight comparisons between treatment groups.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/02/2022
Actual
31/07/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
32
Accrual to date
1
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
Funding source category [2] 315010 0
Other
Name [2] 315010 0
Individual donor
Country [2] 315010 0
United States of America
Funding source category [3] 315011 0
Charities/Societies/Foundations
Name [3] 315011 0
Multidisciplinary Association for Psychedelic Studies (MAPS)
Country [3] 315011 0
United States of America
Funding source category [4] 315104 0
Other
Name [4] 315104 0
Individual donor
Country [4] 315104 0
United States of America
Funding source category [5] 315105 0
Charities/Societies/Foundations
Name [5] 315105 0
Multidisciplinary Association for Psychedelic Studies (MAPS)
Country [5] 315105 0
United States of America
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
University
Name [1] 303594 0
University of Auckland
Address [1] 303594 0
The University of Auckland
Private Bag 92019
Auckland 1142
New Zealand
Country [1] 303594 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304056 0
Health and Disability Ethics Committee
Ethics committee address [1] 304056 0
Ethics committee country [1] 304056 0
New Zealand
Date submitted for ethics approval [1] 304056 0
19/04/2021
Approval date [1] 304056 0
22/09/2021
Ethics approval number [1] 304056 0
21/NTB/105

Summary
Brief summary
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
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
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?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
4125Study protocol  Paul.glue@otago.ac.nz
4126Statistical analysis plan  Paul.glue@otago.ac.nz
4127Informed consent form  Paul.glue@otago.ac.nz
4128Clinical study report  Paul.glue@otago.ac.nz
4129Ethical approval  Paul.glue@otago.ac.nz
4159Analytic code  Paul.glue@otago.ac.nz



Results publications and other study-related documents

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