Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001358831
Ethics application status
Approved
Date submitted
26/08/2021
Date registered
8/10/2021
Date last updated
15/10/2023
Date data sharing statement initially provided
8/10/2021
Date results information initially provided
15/10/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Psilocybin-assisted psychotherapy for Generalised Anxiety Disorder
Scientific title
Safety and efficacy of psilocybin-assisted psychotherapy for Generalised Anxiety Disorder [Psi-GAD-1]: a randomised triple-blind active-placebo-controlled trial
Secondary ID [1] 305067 0
None
Universal Trial Number (UTN)
U1111-1271-0466
Trial acronym
Psi-GAD-1
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Generalised Anxiety Disorder 323273 0
Condition category
Condition code
Mental Health 320847 320847 0 0
Anxiety

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Psilocybin-assisted Psychotherapy
This will be the first clinical trial to investigate the use of psilocybin-assisted-psychotherapy in the treatment of Generalised Anxiety Disorder. The intervention is a combined pharmacological and psychological treatment.

Dosing sessions
The experimental drug is psilocybin, taken orally. There will be two dosing sessions approximately 3 weeks apart. Dose 1 = 25mg psilocybin; Dose 2 = 25 or 30mg psilocybin. Doses will be maintained at 25mg across both sessions unless the participant exhibits limited acute subjective response during the first session (as determined by acute effects questionnaires) without substantial adverse effects, in which case the dose will be increased to 30mg for the second session. A range of extra-pharmacological parameters are specified to optimise safety and efficacy.

Psychotherapy
The psychotherapy is conducted by qualified and experienced mental healthcare therapists who have also undergone an extensive trial-specific psychedelic therapist training program with supervised practice. All psychotherapy and dosing sessions will take part at BrainPark, Monash University, within comfortably furnished and aesthetically pleasing rooms. The psychological treatment comprises preparatory psychotherapy, dosing support, and integrative psychotherapy.
*Preparatory psychotherapy includes a range of approaches supporting safe and effective dosing sessions, and sustained outcomes. 3-to-5 x 90-minute sessions will take place approximately weekly preceding the first dosing session.
*Dosing session support occurs on the day of psilocybin administration, and is based on best-practice in psychedelic therapies, including a range of approaches that support safe and effective administration and sustained outcomes. 2 x 8-hour sessions will take place three weeks apart.
*Integrative psychotherapy includes a range of approaches supporting sustained outcomes. Three integration psychotherapy sessions follow each dosing session, with one session the day after dosing and subsequent sessions approximately weekly thereafter. 6 x 90-minute sessions in total.

Safety
Participant heart rate, blood pressure, and general symptomology will be monitored throughout the dosing session. Rescue medications will also be on hand should certain adverse events not respond to other psychological support.

Treatment Fidelity
All dosing sessions will be video recorded and an independent expert will review excerpts for therapeutic supervision. Adherence to all sessions and any deviation from protocol will be documented.
Intervention code [1] 321461 0
Treatment: Drugs
Intervention code [2] 321462 0
Treatment: Other
Comparator / control treatment
Diphenhydramine-assisted psychotherapy is the active comparator. Dose 1 = 75mg diphenhydramine; Dose 2 = 75 or 100mg diphenhydramine. Administered orally, and in conjunction with preparatory and integrative psychotherapy, defined above. Doses will be maintained at 75mg across both sessions unless the participant exhibits limited acute subjective response during the first session (as determined by acute effects questionnaires) without substantial adverse effects, in which case the dose will be increased to 100mg for the second session.
Control group
Active

Outcomes
Primary outcome [1] 328647 0
Change in Hamilton Anxiety Ratings Scale (HAM-A). The HAM-A is a gold standard clinician-rated instrument that comprises 14 items measuring both psychological and physiological aspects of anxiety on a rating scale of 0 (not present) to 4 (very severe).
Timepoint [1] 328647 0
Baseline, Week 11
Secondary outcome [1] 399806 0
Frequency of Adverse Events and Serious Adverse Events associated with participation in the trial, as measured using trial AE/SAE report forms that follow the CTCAE v5.
Timepoint [1] 399806 0
At conclusion of the study
Secondary outcome [2] 399807 0
Change in suicidality, as assessed using the Ultra Brief Checklist for Suicidality (UBCS)
Timepoint [2] 399807 0
Baseline; weekly (weeks 7-16); three-weekly (weeks 16-23)
Secondary outcome [3] 399808 0
Proportion of participants who complete both dosing sessions and Primary Endpoint assessment, according to audit of study records
Timepoint [3] 399808 0
At conclusion of the study
Secondary outcome [4] 399809 0
Change in anxiety severity assessed using Generalized Anxiety Disorder 7-item Scale (GAD-7)
Timepoint [4] 399809 0
Baseline, week 11, week 23
Secondary outcome [5] 399810 0
Change in Hamilton Anxiety Ratings Scale (HAM-A)
Timepoint [5] 399810 0
Baseline, week 23
Secondary outcome [6] 399811 0
Rates of clinical response as assessed by change in HAM-A
Timepoint [6] 399811 0
Baseline, week 11, week 23
Secondary outcome [7] 399812 0
Rates of clinical remission as assessed by change in HAM-A
Timepoint [7] 399812 0
Baseline, week 11, week 23
Secondary outcome [8] 399813 0
Change in disability, assessed using Sheehan Disability Scale (SDS)
Timepoint [8] 399813 0
Baseline, week 11, week 23
Secondary outcome [9] 399814 0
Change in quality of life, assessed using Personal Wellbeing Inventory (PWI)
Timepoint [9] 399814 0
Baseline, week 11, week 23
Secondary outcome [10] 399815 0
Change in symptoms of depression, assessed using the Quick Inventory of Depression (QIDS-SR)
Timepoint [10] 399815 0
Baseline, week 11, week 23
Secondary outcome [11] 399816 0
Change in symptoms of social anxiety, assessed using the Mini-Social Phobia Inventory (Mini-SPIN)
Timepoint [11] 399816 0
Baseline, week 11, week 23
Secondary outcome [12] 399817 0
Change in symptoms of agoraphobia, assessed using the Agoraphobia Dimensional Scale (AG-D)
Timepoint [12] 399817 0
Baseline, week 11, week 23
Secondary outcome [13] 399818 0
Change in symptoms of panic disorder, assessed using the Panic Disorder Severity Scale - Self Rated (PDSS-SR)
Timepoint [13] 399818 0
Baseline, week 11, week 23
Secondary outcome [14] 399819 0
Change in alcohol misuse, assessed using the Alcohol Use Disorders Identification Test (AUDIT)
Timepoint [14] 399819 0
Baseline, week 11, week 23
Secondary outcome [15] 399820 0
Change in drug misuse, assessed using the Drug Use Disorders Identification Test (DUDIT)
Timepoint [15] 399820 0
Baseline, week 11, week 23
Secondary outcome [16] 399821 0
Change in tobacco misuse, assessed using the self-reported number of cigarettes smoked
Timepoint [16] 399821 0
Baseline, week 11, week 23
Secondary outcome [17] 399822 0
Acceptability of the intervention, assessed using the Acceptability of Intervention Measure (AIM)
Timepoint [17] 399822 0
Week 8
Secondary outcome [18] 399823 0
Appropriateness of the intervention, assessed using the Intervention Appropriateness Measure (IAM)
Timepoint [18] 399823 0
Week 8
Secondary outcome [19] 399824 0
Feasibility of the intervention, assessed using the Feasibility of Intervention Measure (FIM)
Timepoint [19] 399824 0
Week 8

Eligibility
Key inclusion criteria
*Adults experiencing severe GAD.
*Proficiency in English.
*Provide a contact (relative, spouse, close friend or other Support Person) who can transport and provide support to participant following two or three experimental sessions.
*Taper and cease of certain excluded medications is deemed appropriate, agreeable, and under supportive care, and successful following confirmation of preliminary enrolment. Note, prospective participants are not required to taper and cease prior to preliminary enrolment.
*Agree to all study-related requirements.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
*Contraindicated medical conditions including cardiovascular conditions, major CNS disease, hepatic dysfunction, hypercalcaemia risk, epilepsy/seizures, renal insufficiency, diabetes, and hypothyroidism.
*Weigh less than 48 kilograms or BMI < 17.
*Are pregnant or nursing, or able to become pregnant and are not practicing permanent or double-barrier birth control methods.
*Taking a contraindicated medication that cannot be ceased for an appropriate length of time during the trial.
*Extremely severe depression, anxiety, suicidality or other psychiatric symptoms that would warrant hospitalisation, as determined by the screening psychiatrist in a clinical interview.
*Current or past history of meeting DSM-5 criteria for certain excluded psychiatric indications.

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)
An unblinded Randomisation Monitor who is external to trial staff will generate a randomisation list and label all medication containers. Trial staff will be blinded, and allocate participants based on participant number and numbered medication containers.
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
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Power analysis was based on anxiety endpoints from a number of comparable psilocybin-assisted psychotherapy studies, and used an effect size of d = 1.0 . Taking into account a possible 10% attrition rate (Mitchell et al., 2021), and being conservative with effect size estimates (which were based on samples with moderate to severe secondary anxiety, while the present trial addresses severe primary anxiety), a final sample of n = 36 per group (for a total of 72 participants) was selected. After accounting for attrition, this allows for 95% power to detect an effect of d = 0.9, and 80% power to detect an effect of d = 0.7.

Baseline characteristics will be tabulated by using the appropriate summary statistics. Data will be analysed according to the intention-to-treat (ITT) principle and also as per protocol (PP). Once the first 30 participants have completed Primary Endpoint, an interim analysis will be conducted to assess group means and effect sizes for the primary endpoint, frequency of AEs, suicidality severity scores, and retention across both dosing sessions. Due to inadequate power, the interim analysis will not involve significant testing. Predetermined rules will be specified to terminate the trial early for futility, safety concerns, or substantial efficacy.

The HAM-A score at Primary Endpoint (week 11) will be analysed using regression, with treatment group included in the model. Sensitivity of results to missing outcome data will use multiple imputation with chained equations. Sensitivity analysis will also be undertaken to adjust for baseline imbalances.

Binary endpoints will use log-binomial regression or exact logistic regression to approximate these values if the number in either arm is fewer than 5. Change scores will be analysed using regression. Where an outcome has two or more measures of change scores (baseline to week 11 and baseline to week 23) repeated measures analysis will be undertaken. For skewed data, estimated differences between medians and their 95% CIs will be computed via quantile regression.

Qualitative interview transcripts will be thematically analysed.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
10/01/2022
Actual
2/05/2022
Date of last participant enrolment
Anticipated
12/09/2023
Actual
9/10/2023
Date of last data collection
Anticipated
20/02/2027
Actual
Sample size
Target
72
Accrual to date
Final
72
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 309466 0
Commercial sector/Industry
Name [1] 309466 0
Incannex Healthcare Ltd
Country [1] 309466 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Wellington Rd,
Clayton, Victoria 3800
Country
Australia
Secondary sponsor category [1] 310439 0
None
Name [1] 310439 0
None
Address [1] 310439 0
None
Country [1] 310439 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309255 0
Monash University Human Research Ethics Committee (MUHREC)
Ethics committee address [1] 309255 0
Room 111, Chancellery Building D, 26
Sports Walk, Clayton Campus, Research Office,
Monash University VIC 3800
Ethics committee country [1] 309255 0
Australia
Date submitted for ethics approval [1] 309255 0
09/08/2021
Approval date [1] 309255 0
26/10/2021
Ethics approval number [1] 309255 0

Summary
Brief summary
Psilocybin-assisted psychotherapy has demonstrated excellent safety and efficacy in the treatment of depression, substance use disorders, and mental ill-health related to terminal illness. Many patients in these trials have reported rapid, large, and persistent decreases in symptoms of anxiety, suggesting utility in treating anxiety disorders with psilocybin-assisted psychotherapy. However, the impact of this treatment for people with GAD is unknown. In this study, we will complete a randomised controlled trial to test a 7 week (2 dose) psilocybin-assisted psychotherapy for the treatment of GAD. 72 individuals will be randomly assigned to receive two doses either psilocybin (25mg or 30mg, oral) or placebo (diphenhydramine, 75mg or 100mg, oral) with three weeks between doses. All participants will receive psychotherapy before, during, and after dosing sessions. A variety of measures will test for safety and efficacy of the treatment. The primary outcome measure investigates change in clinician-rated symptoms of anxiety. A range of secondary and exploratory measures probe changes in disability, quality of life, comorbid psychiatric and addictive symptoms, baseline and acute predictors, as well as participant-rated acceptability, appropriateness and feasibility of the treatment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 113510 0
Dr Paul Liknaitzky
Address 113510 0
Monash University
770 Blackburn Rd,
Clayton, Victoria, 3168
Country 113510 0
Australia
Phone 113510 0
+61 3 9905 2038
Fax 113510 0
Email 113510 0
[email protected]
Contact person for public queries
Name 113511 0
Dr Paul Liknaitzky
Address 113511 0
Monash University
770 Blackburn Rd,
Clayton, Victoria, 3168
Country 113511 0
Australia
Phone 113511 0
+61 3 9905 2038
Fax 113511 0
Email 113511 0
[email protected]
Contact person for scientific queries
Name 113512 0
Dr Paul Liknaitzky
Address 113512 0
Monash University
770 Blackburn Rd,
Clayton, Victoria, 3168
Country 113512 0
Australia
Phone 113512 0
+61 3 9905 2038
Fax 113512 0
Email 113512 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
In this investigator-initiated trial (Sponsor: Monash University), a data-sharing arrangement is in place between the Sponsor and the Funder.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
12916Statistical analysis plan  [email protected]
12917Clinical study report  [email protected]



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Plain language summaryNo Study not complete

Documents added automatically
No additional documents have been identified.