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Trial registered on ANZCTR


Registration number
ACTRN12619001225101
Ethics application status
Approved
Date submitted
1/08/2019
Date registered
5/09/2019
Date last updated
2/09/2024
Date data sharing statement initially provided
5/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Psilocybin-assisted psychotherapy for the treatment of depression and anxiety associated with life-threatening illness
Scientific title
Psilocybin-assisted psychotherapy for the treatment of depression and anxiety associated with life-threatening illness
Secondary ID [1] 298907 0
Nil known
Universal Trial Number (UTN)
U1111-1237-8914
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Depression in terminal illness (any palliative condition including malignant and non-malignant terminal illnesses) 313882 0
Anxiety in terminal illness (any palliative condition including malignant and non-malignan terminal illnesses) 313883 0
Condition category
Condition code
Mental Health 312296 312296 0 0
Anxiety
Mental Health 312297 312297 0 0
Depression
Cancer 312298 312298 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Psilocybin assisted psychotherapy

The study aim is to investigate the efficacy of psilocybin plus psychotherapy (before during and after the psilocybin dose sessions) in the treatment of depression and/or anxiety associated with having a terminal illness
-Materials used - 25 mg Psilocybin (active dose) - oral capsule, single dose supervised administration with drug packaging return
- 100mg Niacin (active placebo) - oral capsule, single dose supervised administration
11 sessions of psychotherapy (including two dose days) will take place across the two parts of the study
Preparatory psychotherapy - 3 sessions before dose 1
Integrative/preparatory psychotherapy - 3 sessions after dose 1 and before dose 2
Integrative psychotherapy - 3 session post dose 2
Psychotherapy session frequency varies - initially, the first 3 psychotherapy sessions and dose day occur within the first 14 days of baseline and another session occurs the day following the first dose. Following this, psychotherapy occurs approximately every 3rd week until the second dose, and again every 3 weeks following the second dose - if additional sessions are required, this is arranged and documented.
**There is a psychotherapy session the DAY BEFORE each dose day to ensure that the participant is adequately prepared, and another psychotherapy session the DAY AFTER the dose session to ensure the participant has an opportunity to integrate their experiences.

PART 1 = RCT (Baseline - 6-7 weeks post dose one)
Dose day 1 = EITHER 25mg psilocybin OR 100mg Niacin (active placebo)

PART 2 = Open label (commences 6-7 weeks following dose 1 which is at the same time as the completion of the RCT arm- Participants are followed up for 26 weeks post dose 2/open label dose)
Dose day 2 = Psilocybin 25mg for all participants.

Follow-up continues to 26 weeks weeks post dose two.

The psychotherapy component is largely informed by meaning centred psychotherapy approaches for palliative care patients, plus Johnson, Richards & Griffiths (2008) ‘Human Hallucinogen Research: Guidelines for Safety’, which incorporates safeguards and protocol guidelines to include the importance of ‘set and setting’ for participants. In addition, anxiety management strategies will be employed in preparatory sessions. Prepratory psychotherapy sessions include obtaining a developmental history and formulation, psychoeducation about potential effects of psilocybin, anxiety management and meaning centered psychotherapy. Integrative psychotherapy occurs post dose sessions and includes integrating experiences of the participant on their dose day and worked through using components of meaning centered psychotherapy. Dose days occur over several hours and are largely monitoring/supporting the participant through their experience. Integrative work may commence towards the end of the dose day but are largely confined to the sessions following the dose day (not on the dose day itself).
Treatment fidelty will be monitored by use of session checklists, and audit of video/audio material obtained during sessions.
PROCEDURES
Post screening and upon being deemed eligible, participants are given baseline measures including a semi-structured interview, and commence preparatory psychotherapy (minimum 3 x sessions) before commencing their first psilocybin assisted psychotherapy dose day. Post the first dose day (two in total), there is further integrative psychotherapy sessions and preparation for dose two. Post dose two, integrative psychotherapy sessions are conducted. Measures assessing depression, anxiety, death anxiety, quality of life, spiritual wellbeing, demoralisation and mystical experiences (and other areas) are given throughout various time points in the study.
Psychotherapy sessions will last up to 2 hrs, with the dose day lasting up to 8 hours.
Clinically trained healthcare professionals (psychologists, social workers, psychiatrists) with a minimum of 3 years (average 8 yrs) experience working in psycho-oncology and palliative care are providing the psychedelic assisted psychotherapy. All clinicians have knowledge of the potential effects of psilocybin and altered states of consciousness as well as clinical parameters requiring escalation of care in the event of adverse events. All have current training in ICH-GCP.
Most psychotherapy sessions will be delivered face to face but in extenuating circumstances, may be delivered by phone or internet video chat (such as Skype or zoom). All sessions are delivered individually to participants with two therapists present at all times.
All psychotherapy and psilocybin dose sessions will be delivered onsite at St. Vincent’s Hospital Melbourne. The treatment room is not a usual medical consulting room, rather, a spacious room specifically designed for the trial to emulate a living room environment whereby a relaxed and comforting atmosphere is created for the participant.
Participants are able to choose the music playlist that they would prefer for the psilocybin dose sessions.
Intervention code [1] 315183 0
Treatment: Drugs
Intervention code [2] 315184 0
Treatment: Other
Comparator / control treatment
Placebo = Niacin 100mg (to provide a flushing response in RCT part of the study) oral capsule.
Control group
Placebo

Outcomes
Primary outcome [1] 320936 0
Changes in depressive and anxiety symptoms as measured on the HADS
Timepoint [1] 320936 0
Baseline, The day after Dose 1, 3 weeks post Dose 1, 7 weeks post dose 1 (1 day before dose 2)- PRIMARY TIMEPOINT, The day after Dose 2, 3 weeks post Dose 2, 7 weeks post Dose 2.
Primary outcome [2] 320937 0
Changes in anxiety symptoms as measures on the STAI
Timepoint [2] 320937 0
Baseline The day after Dose 1 3 weeks post Dose 1 7 weeks post dose 1 (1 day before dose 2), PRIMARY TIMEPOINT The day after Dose 2 3 weeks post Dose 2 7 weeks post Dose 2 (FOR SENSITIVITY ANALYSES)
Primary outcome [3] 321207 0
Changes in depressive symptoms as measured on the BDI
Timepoint [3] 321207 0
Baseline The day after Dose 1 3 weeks post Dose 1 7 weeks post dose 1 (1 day before dose 2), PRIMARY TIMEPOINT The day after Dose 2 3 weeks post Dose 2 7 weeks post Dose 2 (FOR SENSITIVITY ANALYSES)
Secondary outcome [1] 373415 0
Changes in death anxiety as measured on the DAP-R and qualitative interview (SEMI STRUCTURED INTERVIEW, FACE TO FACE, ONE TO ONE, AUDIO RECORDED, TRANSCRIBED,- QUALITATIVE ANALYSIS WILL BE CONDUCTED WITH GROUNDED THEORY OVERTONES)
Timepoint [1] 373415 0
Baseline
The day after Dose 1
3 weeks post Dose 1
7 weeks post dose 1 (1 day before dose 2),
The day after Dose 2
3 weeks post Dose 2
7 weeks post Dose 2
26 weeks post Dose 2
Secondary outcome [2] 426178 0
WHO-QOL-Bref (abbreivated 26 item version) to assess changes to overall quality of life of participants before, during and after psilocybin assisted psychothearpy treatment.
Timepoint [2] 426178 0
Baseline The day after Dose 1 3 weeks post Dose 1 7 weeks post dose 1 (1 day before dose 2), The day after Dose 2 3 weeks post Dose 2 7 weeks post Dose 2, 26 weeks post dose 2
Secondary outcome [3] 426179 0
MEQ - Mystical Experiences Questionnaire - to assess the mystical type experiences occasioned by psilocybin during dose day
Timepoint [3] 426179 0
Dose day 1, dose day 2
Secondary outcome [4] 426180 0
PEQ - Persisting effects questionnaire which assess persisting effects/changes in attitudes, mood, bheaviour and spiritual type experiences as a result of psilocybin experiences.
Timepoint [4] 426180 0
3 weeks post dose 1, 7 weeks post dose 1 (day before dose day 2). 3 weeks post dose 2, 7 weeks post dose 2, 26 weeks post dose 2
Secondary outcome [5] 426181 0
HADS - Hospital Anxiety and Depression Scale (depression and anxiety subscales) to assess anxiety and depression in a medically unwell cohort,

AT 26 WEEKS POST DOSE 2
Timepoint [5] 426181 0
26 weeks post dose 2
Secondary outcome [6] 426182 0
STAI - State and Trait Anxiety Inventory - to assess both state and trait anxiety in participants AT 26 WEEKS POST DOSE 2.
Timepoint [6] 426182 0
26 weeks post dose 2
Secondary outcome [7] 426183 0
BDI - Beck Depression Inventory - Assesses frequency and intensity of depressive symptoms AT 26 WEEKS POST DOSE 2
Timepoint [7] 426183 0
26 weeks post dose 2

Eligibility
Key inclusion criteria
Adults aged between 18-85 years with a life - threatening illness, under the care of a specialist physician; proficient in English (funds available for this research would preclude access to translators to enable non-English speaking participants); Experiencing psychological distress that was precipitate or augmented by their life-threatening illness; AKPS of 50 or above (or if participant is immobile but deemed physically well enough to participate by the study doctor and their treating physician, scores lower than 50; upon receipt of medial clearance from the potential participants primary treating physician and being screened by the study doctor and being deemed eligible.
Examples of eligible conditions include metastatic malignant diseases, end stage respiratory disease, end stage renal failure, incurable but indolent cancers that have a high likelihood of returning.
Minimum age
18 Years
Maximum age
85 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Diseases with major CNS involvement
Hepatic dysfunction
Known paraneoplastic syndrome or ectopic hormone production
Uncontrolled cardiovascular condtions, unstable angina, atrial fibrillation, TIA
Patients who are respirator dependent or intubated.
A diagnosis of epilepsy or known previous seizure activity
Renal insufficiency
Insulin dependent diabetes
Females who are pregnant, nursing, or attempting to become pregnant
Patients taking SSRI or SNRI (participant may be eligible if they would like to wean and cease under supervision and if deemed safe to do so)
Participants taking medications including:
Rifamycin, rifampin, rifabutin, rifapentine, carbamazepine, phenytoin, phenobarbital, nevirapine, efavirenz, paclitaxol, St John's Wort, - all HIV protease inhibitors, itraconazole, ketoconazole, erythromycin, clarithromycin, troleandomycin.
PSYCHIATRIC - Severity of depression or anxiety symptoms that would warrant immediate hospitalisation (including acute suicidality); current or past history of psychosis/psychotic disorder, current or past history of bipolar disorder; first degree relative with psychosis or bipolar disorder; current or past history of alcohol or substance dependence (excluding caffeine or nicotine) in the past 5 years; Axis II conditions that may not e compatible with the treatment protocol (determined by clinical interview).

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)
central randomisation by pharmacy
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
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
Following the RCT double blinded phase, the trial will move into an open label extension phase with followup.
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
Phase 1 (RCT phase): for continuous outcomes with baseline measurement, for the primary outcome measures (HADS-D and HADS-A and sensitivity measures BDI, GRIDHAMD,, STAI-S, HAMS-A) and secondary outcome measures (DAP-R, WHO-QoL_Bref, DS-II, HAI and FACIT-SWB will be analysed using an appropriate marginal mean model containing exposure, time and time/exposure interaction, run over the four assessment times (baseline, day 1 post dose 1, 3 weeks post dose 1, and 6-7 weeks post dose 1). Robust standard errors and a within group exchangeable correlation structure will be used in the first instance. Regression diagnostics will assess fit and guide choice of correlation structure. Results will be presented both numerically and graphically. Clinically meaningful change will be assessed by comparing the predicted mean between group difference at week 6-7 post dose 1.
Between group difference for mean MEQ (day 1) will be analysed using a linear regression model with robust standard errors. PEQ outcomes will be assessed using the marginal mean model to estimate between group and within group differences across week 3 and week 7.

Phase 2 (OPEN LABEL phase): for continuous outcomes with baseline measurement, for both primary outcome measures (HADS-D and HADS-A and sensitivity measures BDI, GRID-HAMD,, STAI-S, HAMS-A) and secondary outcome measures (DAP-R, WHO-QoL_Bref, DS-II, HAI and FACIT-SWB will be analysed using marginal mean model will be used to assess change within randomisation group over the same outcomes as phase 1 with time zero set as phase 1 week 6-7 post dose 1 (which is also 1 day prior to open label dose). Model covariates will be the same as those used in the phase 1 analysis. The focus is on change within exposure groups defined for phase 1. That is for the phase 1 active arm and whether there is evidence of outcome change after a second dose; and for the phase 1 control arm whether there is evidence for a change in mean score from baseline (phase 1 6-7 weeks post dose 1) and whether the magnitude is clinically meaningful (greater than 50% reduction post-pre mean score).
Between group difference for mean MEQ (day 1) will be analysed using linear regression model with robust standard errors. PEQ outcomes will be assessed using the marginal mean model to estimate between group and within group difference across week 3 and week 7.

Treatment effects will be presented as point estimates and associated 95% confidence limits. If interaction is identified presentation will be appropriately stratified.
Hypothesis test p-values will be reported only for primary outcomes and for these outcomes we will report 95% confidence limits adjusted for multiplicity (see section on type I error above)
The distributional assumptions informing the primary analysis model will be checked using scatter and partial regression plots. Independence of errors will be tested using a Durbin-Watson test. Homoscedasticity will be visually checked using a plot of standardised residuals against predicted values. Normality of residuals will be examined via a histogram or Q-Q plot. If distribution assumptions for the primary analysis model are not met then a suitable transformation will be sought.

Qualitative interviews will be analysed using thematic analysis with grounded theory overtones.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
27/09/2019
Actual
23/01/2020
Date of last participant enrolment
Anticipated
31/08/2022
Actual
22/02/2023
Date of last data collection
Anticipated
31/10/2023
Actual
24/10/2023
Sample size
Target
35
Accrual to date
Final
35
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 27389 0
3065 - Fitzroy

Funding & Sponsors
Funding source category [1] 303455 0
Hospital
Name [1] 303455 0
St. Vincent's Hospital Melbourne
Country [1] 303455 0
Australia
Funding source category [2] 303457 0
Charities/Societies/Foundations
Name [2] 303457 0
PRISM
Country [2] 303457 0
Australia
Funding source category [3] 303458 0
Other Collaborative groups
Name [3] 303458 0
Usona Institute
Country [3] 303458 0
United States of America
Primary sponsor type
Hospital
Name
St. Vincent's Hospital Melbourne
Address
41 Victoria Parade
Fitzroy 3065 VIC
Country
Australia
Secondary sponsor category [1] 303511 0
None
Name [1] 303511 0
Address [1] 303511 0
Country [1] 303511 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303985 0
St. Vincent's Hospital Melbourne Human Research Ethics Committee
Ethics committee address [1] 303985 0
Ethics committee country [1] 303985 0
Australia
Date submitted for ethics approval [1] 303985 0
22/08/2018
Approval date [1] 303985 0
07/09/2018
Ethics approval number [1] 303985 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 95462 0
Dr Margaret Ross
Address 95462 0
St. Vincent's Hospital Melbourne
Psychosocial Cancer Care
41 Victoria Parade
Fitzroy 3065 VIC
Country 95462 0
Australia
Phone 95462 0
+61 3 9231 2211
Fax 95462 0
Email 95462 0
margaret.ross@svha.org.au
Contact person for public queries
Name 95463 0
Virginia Francis
Address 95463 0
St. Vincent's Hospital Melbourne
Psychosocial Cancer Care
41 Victoria Parade
Fitzroy 3065 VIC
Country 95463 0
Australia
Phone 95463 0
+61 3 9231 2211
Fax 95463 0
Email 95463 0
virginia.francis@svha.org.au
Contact person for scientific queries
Name 95464 0
Margaret Ross
Address 95464 0
St. Vincent's Hospital Melbourne
Psychosocial Cancer Care
41 Victoria Parade
Fitzroy 3065 VIC
Country 95464 0
Australia
Phone 95464 0
+61 3 9231 2211
Fax 95464 0
Email 95464 0
margaret.ross@svha.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
We are in non-disclosure agreements with our collaborators and will be sharing safety and efficacy data (de-identified) with those collaborators only.


What supporting documents are/will be available?

No Supporting Document Provided



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.