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Trial registered on ANZCTR


Registration number
ACTRN12621001097831
Ethics application status
Approved
Date submitted
12/07/2021
Date registered
18/08/2021
Date last updated
18/08/2021
Date data sharing statement initially provided
18/08/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A study of psilocybin-assisted psychotherapy for treatment-resistant depression (TRD)
Scientific title
An open-label study of the efficacy and feasibility of psilocybin-assisted psychotherapy for treatment-resistant depression (TRD)
Secondary ID [1] 304677 0
Nil known
Universal Trial Number (UTN)
U1111-1267-6357
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Treatment Resistant Depression (TRD) 322647 0
Condition category
Condition code
Mental Health 320263 320263 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Psilocybin-assisted psychotherapy
The treatment being tested in this trial is psilocybin-assisted psychotherapy. This treatment includes both a drug and psychotherapy component. The drug component of the treatment consists of two 25 mg doses of psilocybin administered in the context of a psychotherapy session, called a 'dosing session'. There will also be 9 non-drug psychotherapy sessions. The total duration of the intervention will be 12 weeks.

Dosing sessions
During each dosing session, the participant will be administered 25mg of psilocybin (oral, capsule), under the supervision of a team of two therapists. Participants will be encouraged to focus on their internal experience and will be provided with eyeshades and headphones with a preselected playlist of music. Therapists will remain present throughout the session to provide occasional guidance and support, as necessary. These sessions are conducted at Swinburne University, Hawthorn campus, in a designated dosing room that has been furnished to create a relaxing, comfortable, living-room-like environment. Sessions will last approximately 6-8 hours. The two dosing sessions will be spaced 6 weeks apart, with the second session being optional.

Non-drug psychotherapy sessions
There will be a total of 9 non-drug psychotherapy session. Before the first dosing session there will be 3 preparatory psychotherapy (PP) sessions, spaced out across 3 weeks. Following each dosing session (regardless of whether participants opt-in to the second dose) there will be 3 integrative psychotherapy (IP) session (total of 6). IP 1 occurs day after dose 1, IP 2 occurs 7-14 days after dose 1, IP 3 occurs within 7 days prior to dose 2. IP 6 occurs day after dose 2, and IP 7 and IP 8 occur within 7-21 days after dose 2.

PP sessions will focus on building a relationship between therapist and participant, discussing the common effects of the psilocybin, and teaching relevant skills such as anxiety management. IP sessions will focus on discussing the participant's experience during the dosing session and integrating any insights or changes in perspective into their daily life. All non-drug psychotherapy sessions will be 60-90 minutes and take place at either Swinburne University, Hawthorn campus or Millswyn Clinic in South Yarra.

Therapists
All psychotherapy sessions will be conducted by two trained therapists (psychiatrists, psychologists, psychotherapists), one of whom has medical training. All therapists have undergone specialist training in delivering this treatment, facilitated by experts in the field.

Safety
Participant heart rate and blood pressure will be monitored throughout the dosing session to ensure they remain within a safe range. Rescue medications (benzodiazepines) will also be on hand in the event of an adverse psychological reaction that does not respond to other therapeutic tactics.

Adherence and Fidelity
Intervention adherence will be monitored through attrition rates and opt-in rates for the second dose. Treatment fidelity will also be monitored. All dosing session will be video recorded and an independent expert will review excerpts and provide feedback to the psychotherapists where necessary.
Intervention code [1] 321046 0
Treatment: Drugs
Intervention code [2] 321047 0
Treatment: Other
Intervention code [3] 321345 0
Behaviour
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 328125 0
Change in depression, measured using the 16-item Quick Inventory of Depressive Symptomatology (QIDS) - self-rated.
Timepoint [1] 328125 0
Baseline, 1 day pre-, 1 day post-, and 3 weeks post- dose 1 and 2
Primary outcome [2] 328126 0
Long-term change in depression, measured using the 16-item Quick Inventory of Depressive Symptomatology (QIDS) - self-rated.
Timepoint [2] 328126 0
Baseline and 20 weeks post-dose 2
Secondary outcome [1] 397967 0
Changes in quality of life, measured using the World Health Organisation Quality of Life Scale - Abbreviated version (WHO-Qol-Bref)
Timepoint [1] 397967 0
Baseline, 3 week post-dose 1 and 2, and 20 weeks post-dose 2
Secondary outcome [2] 397968 0
Changes in anxiety, measured using the Generalised Anxiety Disorder 7-item scale (GAD-7)
Timepoint [2] 397968 0
Baseline, 3 weeks post-dose 1 and 2, and 20 weeks post-dose 2
Secondary outcome [3] 397969 0
Changes in self-efficacy, measured using the Revised Self-Efficacy Scale
Timepoint [3] 397969 0
Baseline and 20 weeks post-dose 2
Secondary outcome [4] 397970 0
Changes in cognitive function, measured using a subset of the MATRICs cognitive test battery
Timepoint [4] 397970 0
Baseline, 3 weeks and 20 weeks post-dose 2
Secondary outcome [5] 397971 0
Changes in cognitive function, measured using the Trail Making Test

Timepoint [5] 397971 0
Baseline, 1 day, 3 weeks and 20 weeks post-dose 2
Secondary outcome [6] 397972 0
Changes in cognitive function, measured using the Stroop colour-word interference task

Timepoint [6] 397972 0
Baseline, 1 day, 3 weeks and 20 weeks post-dose 2
Secondary outcome [7] 397973 0
Changes in cognitive function, measured using the Brixton Spatial Anticipation Test
Timepoint [7] 397973 0
Baseline, 1 day, 3 weeks and 20 weeks post-dose 2

Secondary outcome [8] 397974 0
Changes in self-reported cognitive flexibility, measured using the Cognitive Flexibility Scale
Timepoint [8] 397974 0
Baseline, 1 day, 3 weeks and 20 weeks post-dose 2
Secondary outcome [9] 397975 0
Changes in convergent thinking, measured using the Remote Associates Task
Timepoint [9] 397975 0
Baseline, 1 day, 3 weeks and 20 weeks post-dose 2
Secondary outcome [10] 397976 0
Changes in divergent thinking, measured using the Alternative Uses Task
Timepoint [10] 397976 0
Baseline, 1 day, 3 weeks and 20 weeks post-dose 2
Secondary outcome [11] 397977 0
Changes in empathy measured using the Multifaceted Empathy Test (MET)
Timepoint [11] 397977 0
Baseline, 3 weeks post-dose 2, and 20 weeks post-dose 2
Secondary outcome [12] 397978 0
Changes in self-reported social functioning measured using the Social Adaptation Self-Evaluation Scale (SASS)
Timepoint [12] 397978 0
Baseline, 3 weeks post-dose 1, 3 weeks post-dose 2, and 20 weeks post-dose 2
Secondary outcome [13] 397979 0
Changes in facial affect perception measured using the Dynamic Emotional Expression Recognition Task (DEER-T)
Timepoint [13] 397979 0
Baseline, 3 weeks post-dose 2, and 20 weeks post-dose 2
Secondary outcome [14] 399219 0
Changes in functional brain activity during an implicit face affect recognition task, measured using fMRI
Timepoint [14] 399219 0
Baseline and 20 weeks post-dose 2
Secondary outcome [15] 399220 0
Changes in participant resting state functional brain activity, measured using fMRI
Timepoint [15] 399220 0
Baseline and 20 weeks post-dose 2
Secondary outcome [16] 399221 0
Participant mindset prior to the dosing sessions, assessed with the Mind(SET) questionnaire
Timepoint [16] 399221 0
Approximately 1-hour prior to dose administration (both doses)
Secondary outcome [17] 399222 0
Subjective ratings of the acute psychedelic experiences, assessed using the Mystical Experiences Questionnaire (MEQ)
Timepoint [17] 399222 0
Approximately 6 hours post dose administration (both doses)
Secondary outcome [18] 399223 0
Subjective ratings of the acute psychedelic experiences, assessed using the 11 Dimension Altered States of Consciousness (11D-ASC)
Timepoint [18] 399223 0
Approximately 6 hours post dose administration (both doses)
Secondary outcome [19] 399224 0
Subjective ratings of the acute psychedelic experiences, assessed using the Emotional Breakthrough Inventory (EBI)
Timepoint [19] 399224 0
Approximately 6 hours post dose administration (both doses)
Secondary outcome [20] 399225 0
Subjective ratings of the acute psychedelic experiences, assessed using the Psychological Insight Questionnaire (PIQ)
Timepoint [20] 399225 0
1-day post dose 1 and 2
Secondary outcome [21] 399226 0
Subjective ratings of the acute psychedelic experiences, assessed using the Fresh Experiences Scale (FES)
Timepoint [21] 399226 0
1-day post dose 1 and 2
Secondary outcome [22] 399227 0
Subjective ratings of the acute psychedelic experiences, assessed using the Reliable Experiences Scale (RES)
Timepoint [22] 399227 0
1-day post dose 1 and 2

Secondary outcome [23] 399228 0
Lasting subjective effects, measured with the Watts Connectedness Scale
Timepoint [23] 399228 0
Baseline and 20 weeks post-dose 2
Secondary outcome [24] 399229 0
Lasting subjective effects, measured with the Persisting Effects Questionnaire (PEQ)
Timepoint [24] 399229 0
20 weeks post-dose 2
Secondary outcome [25] 399230 0
Lasting subjective effects, measured with the Fresh Experiences Scale (FES)
Timepoint [25] 399230 0
Baseline and 20 weeks post-dose 2
Secondary outcome [26] 399231 0
Lasting subjective effects, measured with the Reliable Experiences Scale (RES)
Timepoint [26] 399231 0
20 weeks post-dose 2
Secondary outcome [27] 399232 0
Lasting subjective effects, measured with the Relational Type, Range, Intensity, Proximity Scale (R-TRIPS)
Timepoint [27] 399232 0
Baseline and 20 weeks post-dose 2
Secondary outcome [28] 399233 0
Changes in blood BDNF levels, measured by obtaining a 40ml blood sample from the cubital fossa region using a vacutainer system with appropriate tubes
Timepoint [28] 399233 0
Baseline, 1 day, 3 weeks and 20 weeks post-dose 2
Secondary outcome [29] 399234 0
Participant’s subjective experience and perspectives about their depression pre- and post-treatment, assessed using a 60-minute, audio-recorded, one-on-one, semi-structured qualitative interview, with interview questions devised for the purposes of this study.
Timepoint [29] 399234 0
Baseline, 3 weeks and 20 weeks post-dose 2
Secondary outcome [30] 399235 0
Recruitment rate assessed by audit of study database
Timepoint [30] 399235 0
Outcome assessed at the end of screening
Secondary outcome [31] 399236 0
Attrition rate assessed by audit of study database
Timepoint [31] 399236 0
Outcome assessed at the end of the trial
Secondary outcome [32] 399237 0
Percentage of participants who opt-in to the second dosing session, as determined by audit of study database
Timepoint [32] 399237 0
Outcome assessed at the end of the trial
Secondary outcome [33] 399238 0
Adverse events identified by (prompted or unprompted) participant reporting and will be classified according to the definitions produced by the Therapeutic Goods Association (TGA)
Timepoint [33] 399238 0
Prompted adverse event reporting will occur at baseline, 1 day pre-, 1 hour pre-, 6 hours post-, 1 day post-, and 3 weeks post-dose 1 and 2, and 20 weeks post-dose 2
Secondary outcome [34] 399239 0
Changes to the big five personality traits measured using the Ten Item Personality Inventory (TIPI)
Timepoint [34] 399239 0
Baseline and 20 weeks post-dose 2
Secondary outcome [35] 399240 0
Changes in experiential avoidance, measured using the Brief Experiential Avoidance Questionnaire (BEAQ)
Timepoint [35] 399240 0
Baseline, 3 weeks post-dose 1 and 2, and 20 weeks post-dose 2

Eligibility
Key inclusion criteria
1. Adults experiencing treatment-resistant unipolar depression, under the care of a psychiatrist, psychologist, physician, or GP.
2. Proficient in English.
3. Experiencing severe depression as diagnosed by a trial therapist, with use of a clinical interview and the Montgomery –Asberg Depression Rating Scale (MADRS). Only participants with scores above 30 on the MADRS will be eligible for participation.
4. Experiencing depression that has not responded to two or more separate pharmacological interventions during the current depressive episode.
5. Treating medical doctor can confirm patient has safely tapered and washed-out current antidepressant pharmacotherapy prior to baseline assessment.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Containdicated medical conditions including: cardiovascular conditions, major CNS disease, hepatic dysfunction, hypercalcaemia risk, epilepsy/seizures, renal insuffiency, diabetes, hypothyroidism.
2. Females who are pregnant, breastfeeding, attempting to conceive or not using effective means of contraception
3. Weight <40kg
4. Taking a contraindicated medication that cannot be ceased for an appropriate length of time during the trial (may include opioids, metabolic inducers or inhibitors, drugs with a low therapeutic index, and antidepressant medications)
5. MRI contraindications
6. Any significant, uncorrected visual impairments. This is necessary as some of the cognitive and social processing tasks require visual inspection of stimuli.
7. Extremely severe depression/anxiety/suicidality symptoms warranting immediate hospitalisation, as determined by the screening psychiatrist in a clinical interview.
8. Current, past history or 1st degree relative with schizophrenia, psychotic disorder (unless induced by substance or medical condition), or Bipolar I/II, as determined by the screening psychiatrist in a clinical interview.
9. Current or past (5 year) history of alcohol of substance use disorder (excluding caffeine and nicotine), as determined by the screening psychiatrist in a clinical interview and with the use of the DAST-10 and AUDIT.
10. Current Dissociative disorder, Anorexia Nervosa, Bulimia Nervosa or other condition judged to be incompatible with establishment of rapport of safe psilocybin administration as determined by the screening psychiatrist.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Sample size was based upon the primary outcome measure of QIDS score. Using QIDS as the primary outcome, Carhart-Harris et al. (2018) established marked reductions in depressive symptoms at 1-week (Cohen's d = 2.2) and 5-weeks post treatment (Cohen's d = 2.3). Using an effect size of d=2 and 1% significance will require N=9 completers at 26 weeks to achieve 95% power. This calculation is for a single-arm design (2-sided) assuming a Wilcoxon Signed Rank Test. This sample size is also sufficient to detect large correlations (r=0.7) between change scores with 5% significance and 80% power. Based upon these calculations we aim to enrol 15 participants to ensure that we still have adequate power with an expected attrition rate of 20% in this trial.

Demographic and clinical data will be represented by descriptive statistics.
A binary logistic repeated measures mixed model analysis will be used for baseline comparisons, testing for a 50% reduction in depressive symptoms. After any transformations required to make assumptions of normality valid, general repeated measures mixed model analyses will also be conducted for the secondary measures, in order to determine any significant changes during and after treatment. The effects of the 2-dose option will be tested at the same time, using interaction effects for the number of doses across time.
Spearman rank correlations will be used to test for correlations between changes in depressive symptoms and changes in the secondary measures.
All statistical analyses will be two-sided and pre-specified in a formal statistical analysis plan prior to trial completion. Textual data will be subject to thematic analysis.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 309044 0
University
Name [1] 309044 0
Swinburne University of Technology
Address [1] 309044 0
John St, Hawthorn VIC 3122
Country [1] 309044 0
Australia
Funding source category [2] 309089 0
Hospital
Name [2] 309089 0
St Vincent's Hospital Melbourne
Address [2] 309089 0
41 Victoria Parade, Fitzroy VIC 3065
Country [2] 309089 0
Australia
Funding source category [3] 309090 0
Charities/Societies/Foundations
Name [3] 309090 0
The Barbara dicker Brain Sciences Foundation
Address [3] 309090 0
John St, Hawthorn VIC 3122
Country [3] 309090 0
Australia
Funding source category [4] 309091 0
Other
Name [4] 309091 0
Usona Institute
Address [4] 309091 0
2780 Woods Hollow Rd, Madison, WI 53711, United States
Country [4] 309091 0
United States of America
Primary sponsor type
University
Name
Swinburne University of Technology
Address
John St, Hawthorn VIC 3122
Country
Australia
Secondary sponsor category [1] 309981 0
None
Name [1] 309981 0
Address [1] 309981 0
Country [1] 309981 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308922 0
Swinburne University Human Research Ethics Committee
Ethics committee address [1] 308922 0
John St, Hawthorn VIC 3122
Ethics committee country [1] 308922 0
Australia
Date submitted for ethics approval [1] 308922 0
04/10/2019
Approval date [1] 308922 0
12/05/2020
Ethics approval number [1] 308922 0

Summary
Brief summary
This open-label trial will investigate feasibility and efficacy of psilocybin-assisted psychotherapy for treatment-resistant depression.

Individuals will be thoroughly screened to ensure they meet all eligibility criteria before entering the trial. All participants will receive the trial treatment. The treatment consists of two psilocybin dosing sessions (second dose optional), preceded by 3 preparatory psychotherapy sessions and followed by 3 integrative psychotherapy sessions. Participants will be under the care of a specialist team of two psychotherapists throughout the intervention.

Participants will undergo multiple assessment sessions throughout the trial and there will be a long-term follow up assessment 20 weeks after the second dose. Where possible, assessments will be conducted via online surveys. Some assessments need to take place at the study site; these will be at baseline, 1 day, 3 weeks, and 20 weeks after dose 2. Assessments include questionnaires, cognitive and social processing tasks, fMRI scans, blood samples, and semi-structured interviews.

It is predicted that this treatment will be effective in reducing symptoms of depression in those with treatment resistant depression.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 112350 0
Prof Susan Rossell
Address 112350 0
Centre for Mental Health
Department of Psychological Sciences
Swinburne University of Technology
John St, Hawthorn VIC 3122
Country 112350 0
Australia
Phone 112350 0
+61 3 9214 8173
Fax 112350 0
Email 112350 0
srossell@swin.edu.au
Contact person for public queries
Name 112351 0
Prof Susan Rossell
Address 112351 0
Centre for Mental Health
Department of Psychological Sciences
Swinburne University of Technology
John St, Hawthorn VIC 3122
Country 112351 0
Australia
Phone 112351 0
+61 3 9214 8173
Fax 112351 0
Email 112351 0
srossell@swin.edu.au
Contact person for scientific queries
Name 112352 0
Prof Susan Rossell
Address 112352 0
Centre for Mental Health
Department of Psychological Sciences
Swinburne University of Technology
John St, Hawthorn VIC 3122
Country 112352 0
Australia
Phone 112352 0
+61 3 9214 8173
Fax 112352 0
Email 112352 0
srossell@swin.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-indentified individual participant data will be available for all study outcomes, however some demographic information may be witheld to protect participant confidentiality given the small sample size.
When will data be available (start and end dates)?
Start: Immediately following the publication of the long-term follow-up results
End: 5 years after the completion of data collection
Available to whom?
Data will be made available on a 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 (Susan Rossell; srossell@swin.edu.au)
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Informed consent form
Clinical study report
Ethical approval
Analytic code
How or where can supporting documents be obtained?
Type [1] 12471 0
Study protocol
Citation [1] 12471 0
Link [1] 12471 0
Email [1] 12471 0
srossell@swin.edu.au
Other [1] 12471 0
Attachment [1] 12471 0
Type [2] 12472 0
Statistical analysis plan
Citation [2] 12472 0
Link [2] 12472 0
Email [2] 12472 0
srossell@swin.edu.au
Other [2] 12472 0
Attachment [2] 12472 0
Type [3] 12473 0
Informed consent form
Citation [3] 12473 0
Link [3] 12473 0
Email [3] 12473 0
srossell@swin.edu.au
Other [3] 12473 0
Attachment [3] 12473 0
Type [4] 12474 0
Clinical study report
Citation [4] 12474 0
Link [4] 12474 0
Email [4] 12474 0
srossell@swin.edu.au
Other [4] 12474 0
Attachment [4] 12474 0
Type [5] 12475 0
Ethical approval
Citation [5] 12475 0
Link [5] 12475 0
Email [5] 12475 0
srossell@swin.edu.au
Other [5] 12475 0
Attachment [5] 12475 0
Type [6] 12476 0
Analytic code
Citation [6] 12476 0
Link [6] 12476 0
Email [6] 12476 0
srossell@swin.edu.au
Other [6] 12476 0
Attachment [6] 12476 0
Summary results
No Results