Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000478617
Ethics application status
Approved
Date submitted
27/04/2023
Date registered
11/05/2023
Date last updated
20/05/2024
Date data sharing statement initially provided
11/05/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A feasibility study of Psychedelic Microdosing-Assisted Meaning Centred Psychotherapy in advanced stage cancer patients (PAM Trial)
Scientific title
A feasibility study of Psychedelic Microdosing-Assisted Meaning Centred Psychotherapy in advanced stage cancer patients (PAM Trial)
Secondary ID [1] 309546 0
none
Universal Trial Number (UTN)
U1111-1278-8619
Trial acronym
PAM Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Stage IV Solid Organ Malignancy 329832 0
End-of-life distress 329833 0
Condition category
Condition code
Cancer 326733 326733 0 0
Any cancer
Mental Health 326734 326734 0 0
Anxiety
Mental Health 326735 326735 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Psychedelic-microdose plus Meaning-Centred Psychotherapy (PA–MCP)

Lysergic acid diethylamide (LSD) microdose, starting at 8 mcg (titration protocol) taken 2 times a week for 6 weeks + 1 day, totaling 13 doses. LSD will be dissolved in pharmaceutical solvent to create single use vials each containing up to 15 mcg base LSD equivalent. Doses will be extracted from the vial using a single-use syringe, and administered sublingually.

Implementation of the titration protocol is based on participant response, the dose will be reduced by half (if reported to be too much) initially, and then will change by 1 mcg per dose, with a minimum dose of 4 mcg and maximum dose of 12 mcg. A mix of supervised and unsupervised monitored administration.

Participants will also receive 7 weekly 1-hour sessions of MCP on days 1, 8, 15, 22 and 29, 36, 43 (+/- 1 day), notwithstanding the potential need for break weeks (see below). The MCP sessions will be conducted at either the research clinic site or via Zoom (in the case the participant is too unwell to travel) by a registered psychologist who has been trained and has expertise in delivering MCP.

MCP is an existential therapeutic approach that combines didactic components with experiential exercises to facilitate participants’ understanding and connection to various sources of meaning (Breitbart et al., 2010). The goal of MCP is to have patients understand the concept of meaning and its importance in life, particularly as one faces the ultimate limitation of an impending death. The proposed study will follow the manualised and previously validated 7-week protocol for IMCP in patients with stage IV solid tumour cancers (Breitbart et al., 2018)

The schedule and process of dosing is tied to MCP treatment. Dosing will occur in clinic when participants attend each MCP session i.e., days 1, 8, 15, 22, 29, 35, 43 (+/- 1 day). On dosing days between MCP sessions, i.e., days 4, 11, 18, 25, 32, 39 (+/- 1 day), doses will be self-administered at home. This dosing pattern will be repeated for a total of 13 occasions over a 43-day period on days 1, 4, 8, 11, 15, 18, 22, 25, 29, 32, 35, 39, 43 (+/- 1 day). All doses will be administered by 2pm at the latest to minimize potential disruptions to sleep.

Participants have a maximum of 7x break-weeks available where they can take a one week break from MCP and medication dosing and would resume participation of the protocol the following week. These may be necessary if a participant is unwell due to their cancer, or cancer treatment, or has other medical commitments.

Data will be collected on participant attendance to MCP sessions, and we will keep track of doses taken using a mix of logging in clinic (by study staff) and by participants via the completion of their 'dose day questionnaire'. Furthermore, MCP treatment fidelity (30% of the total MCP sessions) will be assessed by an appropriately trained member of the study team.
Intervention code [1] 325971 0
Treatment: Drugs
Comparator / control treatment
Meaning-Centred Psychotherapy (MCP) plus placebo

Participants will receive 7 weekly 1-hour sessions of MCP by a registered psychologist as with the intervention arm but will receive a vial containing an inert liquid (i,e, water/saline) instead of the active LSD. These vials will be identical in appearance to the active LSD and will be administered in the same way. Participants will extract their dose from the vial using a single-use syringe and administer it sublingually.
Control group
Placebo

Outcomes
Primary outcome [1] 334596 0
Feasibility: Feasibility measures will include adherence to medication regimen, attendance at MCP sessions, MCP treatment fidelity, and participant recruitment and attrition rates.
1. Adherence to medication regimen: defined as a percentage of doses administered
2. Attendance at MCP sessions: defined as a percentage of sessions attended
3. Utilisation of break-weeks: defined as percentage of participants who used at least one break-week, and average number of break-weeks used per participant
4. Participant recruitment: percentage of consented participants randomised
5. Attrition: number of dropouts following randomisation

All data relevant to feasibility outcomes will be recorded by study staff or by the participant (dose day questionnaires) in the online Research Electronic Data Capture (REDCap) tool.
Timepoint [1] 334596 0
All feasibility measures will be assessed at the end of trial.
Primary outcome [2] 334597 0
Acceptability will be assessed using open-ended questions in the electronic questionnaires completed by participants on dosing days and using semi-structured qualitative interviews conducted by a member of the research team. Questions will ask participants about their experience of taking medication, attending MCP sessions, and completing the study measures. These interviews will last between 30 and 60 minutes and will be audio-recorded and transcribed for analysis.

Completeness of data will also be used as an indicator of acceptability of completing study measures, via an audit of study records.
Timepoint [2] 334597 0
Open-ended questions will be answered by participants twice weekly during the 7-week intervention period, aligning with dosing days 1, 4, 8, 11, 15, 18, 22, 25, 29, 32, 35, 39, 43 (+/- 1 day).

Semi-structured qualitative interviews will be conducted at the 1 and 6-month follow-up phone-call.

Data completeness will be assessed at end-of-trial.
Primary outcome [3] 334598 0
Safety

Monitoring of vital signs including heart rate and blood pressure using a digital blood pressure monitor.

Symptoms of serotonin syndrome will also be checked, by physical examination - looking for diaphoresis, shiver/tremor and agitation. Should any of these be positive and/or body temperature be >38 °C (using a thermometer) then induced clonus will be checked. These will be documented as AEs.

Recording of adverse effects by participant self-report in the dose day questionnaire, using an open-text response format, in the study app (integrated with the electronic survey tool, REDCap). For example, participants may report feeling jittery or having impaired concentration.

ECG collected on the screening and last study visit (treatment 7).
Timepoint [3] 334598 0
Monitoring of vital signs including heart rate and blood pressure at regular intervals over 6 hours (0, 30, 120, 240, 360 mins post dosing) following the first dose of LSD/placebo and at each clinic visit before and after dosing (120 mins post dose).

Symptoms of serotonin syndrome will be checked 120 mins after dosing in-clinic.

Recording of adverse effects on all dosing days (1, 4, 8, 11, 15, 18, 22, 25, 29, 32, 35, 39, 43 (+/- 1 day)).

ECG collected on the screening and last study visit (treatment 7).
Secondary outcome [1] 421337 0
Sense of meaning: Assessed using the Personal Meaning Index of the Life Attitude Profile – Revised.
Timepoint [1] 421337 0
Baseline (pre-intervention), at treatment sessions 4 and 7, and at 1 and 6-month follow-up.

Please note, due to potential participant utilization of break-weeks treatment sessions 4 and 7 may or may not be 4 and 7 weeks post trial commencement.
Secondary outcome [2] 421338 0
Quality of Life - Functional Assessment of Cancer Therapy – General
Timepoint [2] 421338 0
Baseline (pre-intervention), at treatment sessions 4 and 7, and at 1 and 6-month follow-up.
Secondary outcome [3] 421339 0
Spiritual well-being - Functional Assessment of Chronic Illness Therapy – Spiritual Well-Being-12 item scale (FACIT Sp-12)
Timepoint [3] 421339 0
Baseline (pre-intervention), at treatment sessions 4 and 7, and at 1 and 6-month follow-up.
Secondary outcome [4] 421340 0
Anxiety and Depression using DASS-21 and HADS
Timepoint [4] 421340 0
Baseline (pre-intervention), at treatment sessions 4 and 7, and at 1 and 6-month follow-up.
Secondary outcome [5] 421341 0
Te Whare Tapa Wha mental health outcome - Hua Oranga (participant, whanau and treating clinicians)
Timepoint [5] 421341 0
At baseline (pre-intervention) and end-of-treatment period (treatment session 7)
Secondary outcome [6] 421342 0
Demoralisation - Demoralization Scale
Timepoint [6] 421342 0
Baseline (pre-intervention), at treatment sessions 4 and 7, and at 1 and 6-month follow-up.
Secondary outcome [7] 421343 0
Attitudes towards death - Schedule of Attitudes toward Hastened Death (SAHD)
Timepoint [7] 421343 0
Baseline (pre-intervention), at treatment sessions 4 and 7, and at 1 and 6-month follow-up.
Secondary outcome [8] 421344 0
Symptom load using the Palliative Care Outcomes Collaboration Symptom Assessment Scale (PCOC-SAS)
Timepoint [8] 421344 0
Baseline (pre-intervention) and at every treatment session, 2, 3, 4, 5, 6, and 7.
Secondary outcome [9] 421345 0
Pain using the Brief Pain Inventory - Short Form (BPI-SF)
Timepoint [9] 421345 0
At baseline (pre-intervention), and treatment sessions 4 and 7.
Secondary outcome [10] 421346 0
Openness using the The Big Five Inventory-2 Extra Short Form (BFI-2-XS)
Timepoint [10] 421346 0
Baseline (pre-intervention), at treatment sessions 4 and 7, and at 1 and 6-month follow-up.
Secondary outcome [11] 421347 0
Sense of Connectedness using the Watts Connectedness Scale (WCS)
Timepoint [11] 421347 0
Baseline (pre-intervention), at treatment sessions 4 and 7, and at 1 and 6-month follow-up.
Secondary outcome [12] 421348 0
Expectancy using the Treatment Expectancy Questionnaire (TEX-Q)
Timepoint [12] 421348 0
At baseline (pre-intervention) and end-of-treatment (treatment session 7).
Secondary outcome [13] 421349 0
Therapeutic Alliance using the Working Alliance Inventory Short Form (participant and therapist)
Timepoint [13] 421349 0
At baseline (pre-intervention) and end-of-treatment (treatment session 7).

Eligibility
Key inclusion criteria
- Diagnosis with an incurable stage IV solid organ malignancy.
- Prognosis of at least 6 months life expectancy from the time of screening.
- A score 4 or higher on the distress thermometer.
- Agree to have study visits video and/or audio recorded.
- Agree to inform the Investigators within 48 hours of any medical conditions and procedures being undertaken.
- Willing for the Investigators to communicate directly with their medical team to determine medical suitability for study participation (oncologist, GP, palliative care physician, etc).
- Agree to refrain from starting any new psychiatric medication and/or psychotherapy during the study period.
- Agree to have transportation other than driving themselves to where they are staying on the days of medication dosing.
- Able and willing to be contacted via telephone for all necessary telephone contacts.
- Agree to use an effective form of contraception if of child-bearing potential for the duration of medication dosing.
- Must provide a contact/support person in the event of the being unreachable by study staff or in the event of severe distress or suicidality.
- Proficient in speaking and reading English.
- Agree to not use any medications on the prohibited medications list during the course of the study.
- Agree not to take any herbal supplement for the duration of medication dosing (except with prior approval of the research team).
Minimum age
25 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Currently participating in a clinical trial of a systemic anti-cancer treatment
- Pregnancy or lactating.
- BMI < 18.5.
- Diagnosis of cerebral metastases.
- Karnofsky performance scores below 50 or other physical limitations that preclude participation in weekly psychotherapy and microdosing of LSD.
- Upon review of psychiatric history (i.e., responses to the relevant modules of MINI (Standard version 7.0.2)), participants must not have any current or past diagnosis that would be considered a risk to participation in the study:
- Lifetime history of schizophrenia or other psychotic disorders, or bipolar I or II disorder assessed through participant interview.
- Or a current diagnosis of PTSD, panic disorder, agoraphobia, OCD, anorexia, and bulimia.

- Liver function test >3 times the upper limit of normal or creatinine clearance <30 mL/min.
- Have a history of any medical condition that could make receiving a sympathomimetic drug harmful because of potential 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 LSD 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 LSD administration by any mechanism would require exclusion.
- Blood pressure not exceeding 160 mmHg (systolic) and 90 mmHg (diastolic) (measured at three time-points).
- Current serious suicide risk, as determined through psychiatric interview, responses to The Columbia-Suicide Severity Rating Scale (C-SSRS), and clinical judgement of the investigator, however, history of suicide attempts is not an exclusion. Any participant who is likely to require hospitalization related to suicidal ideation and behaviour, in the judgement of the investigator, will not be enrolled. Any participant presenting with the following on the Baseline C-SSRS will be excluded:
- Suicidal ideation score of 4 or greater within the last month of the assessment at a frequency of once a week or more;
- Suicidal ideation score of 5 within the last 6 months of the assessment;
- Any suicidal behaviour, including suicide attempts or preparatory acts, within the last 6 months of the assessment. Participants with non-suicidal self-injurious behaviour may be included if approved by the Study Physician.

- Any lifetime history of psychedelic microdosing; defined as repeated low-dose psychedelic usage for more than a week at a time.
- Use of a psychedelic within the last year.
- Recent or current use of illicit drugs including methamphetamine, heroin and synthetic cannabis. Other non-prescribed drugs will prompt exclusion at the discretion of the study physician.
- Current THC usage will prompt exclusion if the participant does not agree to cease. However, CBD is permitted, and usage will be recorded.

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)
A biostatistician will perform randomisation of the allocation of participants to the interventions.

The active and placebo interventions will be matched in appearance. Only the statistician and pharmacist members of the research team will know the identity of the drugs to be administered. These team members will not interact with study participants and will not be present during any drug administration sessions. To ensure allocation concealment when a participant is entered into the trial, they will then be allocated by a blinded investigator to the first available code on the randomisation sequence list.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The biostatistician will generate a randomisation code list and participants will be randomised in randomly permuted blocks of two and four with stratification used to give separate lists for Maori and non-Maori.
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
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety
Statistical methods / analysis
Baseline measures will be presented for each treatment group using summary statistics, with frequencies and percentages for categorical variables and appropriate measure of average and spread for continuous variables.
Data on quantitative primary outcome measures for feasibility, acceptability, and safety for Maori and non-Maori participants will also be presented using descriptive statistics, including: recruitment rates, attrition, adherence to medication and MCP, adverse effects, MCP treatment fidelity, and feasibility of outcome data collection.
Changes in secondary outcome measures over the study period will be assessed using generalised linear mixed models (GLMMs) with main effects of treatment (PA-MCP versus Placebo-MCP) and time (T0 – T9, see below), treatment-by-time interactions and subject level random effects to model longitudinal trajectories whilst accounting for correlations between repeated measures within subjects.
Qualitative interviews will be analysed using Thematic Analysis, a systematic process for identifying patterns in qualitative data (Braun & Clarke, 2013).

Timepoint Zero (T0) = Screening
Timepoint 1 (T1) = MCP treatment session 1
Timepoint 2 (T2) = MCP treatment session 2
Timepoint 3 (T3) = MCP treatment session 3
Timepoint 4 (T4) = MCP treatment session 4
Timepoint 5 (T5) = MCP treatment session 5
Timepoint 6 (T6) = MCP treatment session 6
Timepoint 7 (T7) = MCP treatment session 7
Timepoint 8 (T8) = 1 month follow-up
Timepoint 9 (T9) = 6 month follow-up

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/06/2023
Actual
4/10/2023
Date of last participant enrolment
Anticipated
3/12/2024
Actual
Date of last data collection
Anticipated
3/06/2025
Actual
Sample size
Target
40
Accrual to date
8
Final
Recruitment outside Australia
Country [1] 25418 0
New Zealand
State/province [1] 25418 0
Auckland

Funding & Sponsors
Funding source category [1] 313736 0
Government body
Name [1] 313736 0
Health Research Council
Country [1] 313736 0
New Zealand
Funding source category [2] 313737 0
Commercial sector/Industry
Name [2] 313737 0
MindBio Therapeutics Ltd
Country [2] 313737 0
Australia
Primary sponsor type
University
Name
The University of Auckland
Address
22-30 Park Avenue, Grafton, Auckland 1023
Country
New Zealand
Secondary sponsor category [1] 315552 0
None
Name [1] 315552 0
Address [1] 315552 0
Country [1] 315552 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312908 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 312908 0
133 Molesworth Street
Thorndon
Wellington 6011
Ethics committee country [1] 312908 0
New Zealand
Date submitted for ethics approval [1] 312908 0
28/06/2022
Approval date [1] 312908 0
14/07/2022
Ethics approval number [1] 312908 0
2022 FULL 13074

Summary
Brief summary
Psychedelic compounds have shown clinically significant effects in the treatment of psychological distress in patients with advanced stage cancer. Given the challenges of delivering timely and effective intervention in the advanced cancer context, it is possible that an alternative, more pragmatic, approach lies in psychedelic ‘microdosing’. Microdosing refers to repeated administration of psychedelics such as LSD or psilocybin in doses around the threshold for overtly altering perception. The purpose of this study is to evaluate the feasibility of conducting a full-scale randomised controlled trial comparing Psychedelic-Microdose Assisted – Meaning-Centred Psychotherapy (PA–MCP) to standard Meaning-Centred Psychotherapy (MCP) in people who have a life-threatening cancer diagnosis and symptoms of anxiety and/or depression. Although MCP is a well-established psychotherapeutic treatment in advanced cancer populations (Breitbart et al., 2010; Breitbart et al., 2012), to date, there has been no research that investigates whether the efficacy and effectiveness of this therapy might be improved if delivered alongside a standardised microdose regimen of a psychedelic compound. Participants with advanced stage cancer and symptoms of anxiety and/or depression (N=40; 20 Maori, 20 non-Maori) will be randomised under double-blind conditions to receive MCP alongside repeated doses of either an LSD microdose (PA–MCP) or inactive placebo. The feasibility, acceptability and safety of this intervention and physiological and psychological measures will be recorded at baseline and after completion of each session of MCP and at a one month and six-month follow-up. Our findings will enable a rigorous evaluation of the feasibility of a larger randomised controlled trial and provide initial indication of potential benefits of psychedelic microdosing for psychological distress in advanced stage cancer patients.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 126298 0
Dr Lisa Reynolds
Address 126298 0
Department of Psychological Medicine, The University of Auckland, 22-30 Park Avenue, Grafton, Auckland 1023
Country 126298 0
New Zealand
Phone 126298 0
+64 93737599
Fax 126298 0
Email 126298 0
l.reynolds@auckland.ac.nz
Contact person for public queries
Name 126299 0
Dr Lisa Reynolds
Address 126299 0
Department of Psychological Medicine, The University of Auckland, 22-30 Park Avenue, Grafton, Auckland 1023
Country 126299 0
New Zealand
Phone 126299 0
+64 93737599
Fax 126299 0
Email 126299 0
l.reynolds@auckland.ac.nz
Contact person for scientific queries
Name 126300 0
Dr Lisa Reynolds
Address 126300 0
Department of Psychological Medicine, The University of Auckland, 22-30 Park Avenue, Grafton, Auckland 1023
Country 126300 0
New Zealand
Phone 126300 0
+64 93737599
Fax 126300 0
Email 126300 0
l.reynolds@auckland.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 participant de-identified and/or anonymised participant data (i.e. data which can be adequately de-identified, protecting the privacy of the participants). However as noted those who request access must provide a methodologically sound proposal, and access will be confirmed on a case by case basis at the discretion of the Sponsor.
When will data be available (start and end dates)?
Following publication, no end date determined.
Available to whom?
Collaborators / companies / researchers who provide a methodologically sound proposal on a case by case basis at the discretion of the Sponsor. The Sponsor must be satisfied that appropriate Data and Tissue Management Plans are in place and that ethical approval for use has been obtained in accordance with local laws and regulations.
Available for what types of analyses?
Ethically sound future research and / or to be added to data from other sources to form larger datasets.
How or where can data be obtained?
Contact Principal Investigator Dr Lisa Reynolds - l.reynolds@auckland.ac.nz


What supporting documents are/will be available?

No Supporting Document Provided



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