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Trial registered on ANZCTR


Registration number
ACTRN12623000667617
Ethics application status
Approved
Date submitted
22/05/2023
Date registered
21/06/2023
Date last updated
3/10/2023
Date data sharing statement initially provided
21/06/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Swinburne Three-dose Psilocybin Assisted Psychotherapy (3PAP): a clinical trial of 2 vs 3 doses of psilocybin-assisted psychotherapy vs psychotherapy with placebo for Treatment-Resistant Depression
Scientific title
Efficacy and safety of two versus three high dose psilocybin-assisted therapy sessions in comparison to a placebo for treatment resistant major depressive disorder (TR-MDD): A double blind, 3-arm Phase 2b randomised controlled trial
Secondary ID [1] 309698 0
None
Universal Trial Number (UTN)
U1111-1292-8443
Trial acronym
3PAP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Treatment-Resistant Depression 330077 0
Condition category
Condition code
Mental Health 326974 326974 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
There will be two intervention arms and one control arm.
Arm 1: 3 dose-sessions of 25 mg oral psilocybin + psychotherapy
Arm 2: 2 dose-sessions of 25 mg oral psilocybin + psychotherapy, followed by 1 dose-session of oral inactive placebo + psychotherapy
Arm 3 (control): 3 dose-sessions of oral inactive placebo + psychotherapy
Each dose session will be 6-8 hours in length, and will occur at the following time points:
1: 1 week post baseline;
2: 5 weeks post baseline;
3: 18 weeks post baseline.
Administration of psilocybin and inactive placebo will be by oral tablet with neutral excipient, and will occur under direct supervision of a medical practitioner at the study site.
All psychotherapy associated with the intervention will be administered face-to-face by a trained co-therapist dyad consisting of one medically-trained health professional (psychiatrist, psychiatry registrar, GP, or physician) and one psychologist. Psychotherapy will involve 2 Preparatory Sessions prior to Dose Session 1, at which time participants will be provided with information relating to psilocybin and its psychotropic effects. Supportive psychotherapy provided on-site during Dose Sessions will consist of non-directive psychological support within the context of a largely non-interventional approach. Each Dose Session will be followed by 3 Integration Sessions, during which participants will be invited to discuss their experience during the Dose Session, and engage in analysis and meaning-making to consolidate any therapeutic outcomes accrued during the experience.
Intervention code [1] 326137 0
Treatment: Other
Comparator / control treatment
3 dose-sessions of oral inactive placebo, each with 6-8 hours of psychotherapy plus preparatory and integrative psychotherapy as per active treatment arms.
Control group
Placebo

Outcomes
Primary outcome [1] 334814 0
To determine if two dosing sessions of psilocybin-assisted psychotherapy (PAP) significantly reduces depressive symptoms compared to psychotherapy with placebo: i) immediately after the second dosing session (week 5), and ii) at short-term follow-up 3-months after the second dosing session (week 17) using the clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS) in comparison to baseline (week 0).
Timepoint [1] 334814 0
Weeks 5 and 17 after baseline measure
Secondary outcome [1] 422150 0
Long-term sustainability of change on the MADRS in response to two-dose PAP.
Timepoint [1] 422150 0
6 and 12 months after 2nd dosing session.
Secondary outcome [2] 422151 0
Comparison of three-dose PAP versus two-dose PAP versus psychotherapy with placebo on depression as determined using the MADRS.
Timepoint [2] 422151 0
6 and 12 months after 2nd dosing session.
Secondary outcome [3] 422152 0
Changes in participant anxiety (Generalized Anxiety Disorder 7-item: GAD-7) compared to psychotherapy with placebo.
Timepoint [3] 422152 0
17 weeks after baseline measures.
Secondary outcome [4] 422153 0
Changes in participant quality of life (Assessment of Quality of Life – 8 Dimensions: AQOL-8D) compared to psychotherapy with placebo.
Timepoint [4] 422153 0
17 weeks after baseline measures.
Secondary outcome [5] 423000 0
Changes in participant employment status (World Health Organization Health and Performance Questionnaire: HPQ) compared to psychotherapy with placebo.
Timepoint [5] 423000 0
17 weeks after baseline measures.
Secondary outcome [6] 423001 0
Changes in participant cognitive function (using a brief battery) compared to psychotherapy with placebo.
Timepoint [6] 423001 0
17 weeks after baseline measures.
Secondary outcome [7] 423002 0
Perceptions of individuals with TR-MDD in terms of their recovery in relation to PAP (Recovery Assessment Scale – Domains and Stages: RAS-DS).
Timepoint [7] 423002 0
17 weeks after baseline measures.
Secondary outcome [8] 423003 0
Self-reported changes on the Beck Depression Inventory II (BDI-II).
Timepoint [8] 423003 0
Every 4 weeks after baseline measures until the final face-to-face assessment at 12 months after baseline.

Eligibility
Key inclusion criteria
- Adults aged 18 to 65 years.
- Those currently experiencing major depressive disorder (DSM-5) as determined by the SCID-5.
- Those with current moderate to severe depression according to the MADRS.
- Treatment-resistance using criteria adapted from current literature of research in major depression.
- Under the care of a psychiatrist, psychologist, physician, or GP.
- Proficiency in English.
- Safe tapering and wash-out of current antidepressant pharmacotherapy prior to baseline assessment, as confirmed by treating GP, psychiatrist, or physician.
- Abstinence from illicit or extra-medical drug and alcohol use for at least 2 days prior to each dose session.
- Participants who agree to have their drug dosing sessions recorded to video for treatment fidelity and clinical supervision within the study team.
- Participants who are able to swallow tablets.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Key General Medical Exclusion Criteria:
- Patients in treatment in another clinical trial involving an investigational product.
- Any disorder with known CNS involvement, or other major CNS disease.
- Hepatic dysfunction.
- Known conditions putting participant at risk for hypercalcaemia,
- Cardiovascular conditions: uncontrolled hypertension, angina, a clinically significant ECG abnormality (e.g., atrial fibrillation), TIA in the last 6 months, stroke, or cerebrovascular disease, peripheral or pulmonary vascular disease.
- A diagnosis of epilepsy or previous seizures.
- Renal insufficiency.
- Insulin-dependent diabetes.
- Females who are pregnant or nursing or are trying to get pregnant, or become pregnant during the study.
- Current hypothyroidism.
- Weight less than 40 kg.
- Contraindicated medication (SSRIs, SNRIs, MAOIs), and either 1) do not wish to be tapered off this medication, or 2) it is deemed by trial psychiatrists or the participant’s usual treatment team that tapering the participant off their current medication would be inappropriate.
- Use of any illicit or extra-medical drugs or alcohol within the 2 days prior to each psilocybin dosing.
- Current use of any potent metabolic inducers or inhibitors
- Significant, uncorrected visual impairments (to ensure that they can read all study material).

Key Psychiatric Exclusion Criteria:
- Current or past history of meeting DSM-5 criteria for Schizophrenia, Psychotic Disorder (unless substance-induced or due to a medical condition), Bipolar I or II Disorder, or Mania.
- First degree relative with diagnosed Schizophrenia, Psychotic Disorder (unless substance-induced or due to a medical condition), Bipolar I or II Disorder or Mania.
- Currently meets DSM-5 criteria for Dissociative Disorder, Anorexia Nervosa, Bulimia Nervosa, or any psychiatric conditions judged to be incompatible with establishment of rapport or safe exposure to psilocybin.
- Unable to give adequate informed consent.

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)
Participants will be randomly allocated to one of the three arms after eligibility is confirmed post screening and before baseline. Allocation will be performed and verified via an independent biostatistician who holds the allocation schedule and is off-site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomised permuted blocking with participants stratified by scores on the MADRS at screening, and sex.
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
Efficacy
Statistical methods / analysis
We will recruit 160 patients. Preliminary power calculations indicate that, assuming a standardised effect size of at least 0.5, this study would be well powered to detect treatment effects of psilocybin vs placebo at both randomisations, with 100% power for inactive placebo versus 2-dose randomisation and 80% power for the third active dose versus inactive placebo randomisation. Some uncertainty regarding the power to detect differences in the efficacy of two vs three doses remains, given an absence of prior research comparing these two treatment regimens. This power calculation was based on a further assumption that there would be 15% attrition. The literature has shown that attrition is typically between 9-12% for trials of this nature, thus 15% is a conservative estimate.

Baseline values for the three arms will be compared using chi-squared tests of association for categorical variables (or Fisher’s exact test for small samples) and univariate ANOVA tests (or Kruskal-Wallis tests) for continuous variables. Any significant clinical differences are unlikely, due to the random allocation of participants across conditions. Such analyses will however be critical in determining the possible covariates for the primary and secondary analysis.
While the attrition rate is not expected to vary by arm, we will identify key predictors of attrition status (i.e. demographic/baseline characteristics) and test for differences across arms. Assuming the data are missing at random, several procedures offer effective methods to control for attrition. Maximum likelihood models allow the use of all available data, reducing bias and increasing power. We will confirm these results using multiple imputation procedures that utilise the expectation-maximisation (EM) algorithm with bootstrap estimates of standard error.

Descriptive statistics will be used to summarise assessments of recruitment (including successful screening), complaisance, drop-out and intervention completion across the three arms. For both primary outcomes and secondary outcomes, summary raw scores will be presented at each assessment time both numerically and graphically.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
3/07/2023
Actual
14/08/2023
Date of last participant enrolment
Anticipated
28/06/2024
Actual
Date of last data collection
Anticipated
30/06/2025
Actual
Sample size
Target
160
Accrual to date
5
Final
Recruitment in Australia
Recruitment state(s)
QLD,TAS,VIC

Funding & Sponsors
Funding source category [1] 313892 0
Commercial sector/Industry
Name [1] 313892 0
Woke Pharmaceuticals
Country [1] 313892 0
Australia
Primary sponsor type
University
Name
Swinburne University of Technology, Hawthorn
Address
John Street
Hawthorn, Vic 3122.
Country
Australia
Secondary sponsor category [1] 315742 0
None
Name [1] 315742 0
Address [1] 315742 0
Country [1] 315742 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313039 0
Swinburne University Human Research Ethics Committee
Ethics committee address [1] 313039 0
John Street,
Hawthorn, Vic 3122.
Ethics committee country [1] 313039 0
Australia
Date submitted for ethics approval [1] 313039 0
25/11/2022
Approval date [1] 313039 0
16/02/2023
Ethics approval number [1] 313039 0
20236919-13556

Summary
Brief summary
This is a 3-arm study using psilocybin-assisted psychotherapy. A randomised controlled, multi-arm design will be used with the same control group all the way through the 57 weeks of the study. Potential participants will be screened to ensure suitability for trial inclusion, and 160 participants will be accepted into the trial upon completion of informed consent. The schedule for all participants will consist of two courses of therapy separated by 4 weeks, each course is comprised of a dosing session plus preparatory and post-integrative psychotherapy sessions with a co-therapist dyad that will generally consist of one female and one male therapist. After the 3-month face to face follow-up session, a third course of therapy (preparatory, dosing, post-integrative) will occur. Participants randomly allocated to the treatment arm will receive an active dose of psilocybin during the first two dosing sessions. Participants in the treatment arm will then be randomly re-allocated to receive either active psilocybin (Arm 1) or an inactive placebo (Arm 2) for the third and final dosing session. Participants allocated to the control group (Arm 3) will receive an in-active placebo at all three dosing sessions. Self-report follow-up assessments will be conducted for all participants every 4 weeks after the first dose-session until 12 months after the second dosing session. Face to face follow-up sessions will occur at 3 months, 6 months and 12 months after the second dosing sessions.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 126774 0
Prof Susan Rossell
Address 126774 0
Centre for Mental Health,
Department of Psychology,
Swinburne University of Technology,
John Street,
Hawthorn, Vic, 3122
Country 126774 0
Australia
Phone 126774 0
+61 3 9214 8173
Fax 126774 0
Email 126774 0
srossell@swin.edu.au
Contact person for public queries
Name 126775 0
Prof Susan Rossell
Address 126775 0
Centre for Mental Health,
Department of Psychology,
Swinburne University of Technology,
John Street,
Hawthorn, Vic, 3122
Country 126775 0
Australia
Phone 126775 0
+61 3 9214 8173
Fax 126775 0
Email 126775 0
srossell@swin.edu.au
Contact person for scientific queries
Name 126776 0
Prof Susan Rossell
Address 126776 0
Centre for Mental Health,
Department of Psychology,
Swinburne University of Technology,
John Street,
Hawthorn, Vic, 3122
Country 126776 0
Australia
Phone 126776 0
+61 3 9214 8173
Fax 126776 0
Email 126776 0
srossell@swin.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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.