Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001004651
Ethics application status
Approved
Date submitted
4/07/2023
Date registered
14/09/2023
Date last updated
11/01/2024
Date data sharing statement initially provided
14/09/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluating the management of treatment resistant depression with psychedelic (psilocybin) assisted psychotherapy (EMPACT)
Scientific title
Evaluating the efficacy of psilocybin-assisted psychotherapy in treatment resistant depression (EMPACT): A randomised, double blinded, 4 arm parallel adaptive trial
Secondary ID [1] 309244 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
EMPACT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Treatment Resistant Depression 329400 0
Condition category
Condition code
Mental Health 326344 326344 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study is a randomised, double blinded, 4 arm parallel adaptive trial comparing the efficacy and safety of psychedelic (psilocybin) assisted psychotherapy (PAP) in people with treatment resistant depression, with an active comparator medication, dexamfetamine.

The multi-arm adaptive design will compare three different psilocybin regimens to a control. All participants will engage in identical study procedures and therapy sessions, only the drug used within the groups will be varied.

Within the 4 arms:
Arm A is the control arm with Dexamfetamine administered in all three treatment sessions.
Arm B and C include combined therapies of either Dexamfetamine or Psilocybin across the three treatment sessions.
Arm D is the active arm with Psilocybin administered in all three treatment sessions.
only.

Each medication session will involve either a single dose of 25mg of psilocybin or 7.5mg of dexamfetamine (depending on treatment arm) via an oral tablet, up to 3 times, 2-4 weeks apart.

At the start of the study, participants will be randomly assigned by chance through a computer-generated sequence to one of four groups (arms) and neither the participant nor any member of the treating team will know what group the participant has been allocated to, or what medication will be given during the sessions.

The first 50 participants will be equally randomised to the initial 4 treatment arms in a 1:1:1:1 ratio. From then on, response adaptive randomisation (RAR) with control protection favouring the best performing arms will be used, with the probability of allocation to the remaining arms reassessed every 20 additional participants. Arms can be stopped for efficacy or futility at each interim analysis until the trial itself is stopped, or the maximum sample size of 130 (evaluable) participants is reached.

Psychedelic assisted psychotherapy refers to the integration of the administration of a psychedelic drug with a specific form of trauma-informed psychological support/therapy. The aim of psychological support is to provide the participant with psychoeducation, develop therapeutic alliance and support strategies, establish trust and psychological safety, minimise anxiety, and support participants in staying with their emerging experience while maintaining safety, for both the participant and therapist. The therapists conducting these sessions are health/healing professionals (doctor, psychiatrist, psychologist, psychotherapist, counsellor, nurse) trained in the administration of psychedelic assisted psychotherapy.

Therapy sessions common across all groups will involve several components:

Preparation sessions:
Within three weeks prior to the first medication session there will be two separate preparation sessions, at a minimum of four days apart. These sessions will be conducted either remotely via video conference or in person, with an experienced therapist who will be supporting the participant throughout the program. These two sessions will each take approximately 1-2 hours and will be scheduled as per the therapist’s assessment of the participants needs.

Preparation 1:
- Alliance development and formulation: the primary aims of the initial session will be the development of a therapeutic alliance, build trust and safety between the study therapists and the participant.
- Listening to participant’s narrative of depression and treatment history to understand patterns of psychological inflexibility that are most prominent and ability to observe experience e.g., using mindfulness skills.
- Clarify participant intentions for the medication session, anxieties and hopes for the experience.
- Discuss ethical considerations and participant choices around use of touch, grounding techniques, and preferences such as music playlist, utilising eye mask, what can arise during a medication session, expectations and concerns and previous experience, media awareness or knowledge of psychedelic therapy.
- Psychoeducation around psychological and physiological effects of psilocybin, who will be present, and the integration process. Preparing social support and integration for after the dosing session. Support person should be informed of the nature of the study.
- Introduce Acceptance and Commitment Therapy (ACT), concept of psychological flexibility and observing experience with curiosity and openness, rather than avoidance.
- Grounding exercises and scripts for difficult experience, information on non-ordinary states of consciousness, based on the study manual.

Preparation 2:
- Therapist continues to build trust and rapport with participant.
- More explicitly focussed on ACT principles as they apply to the therapy process.
- Collaboratively set intentions for the medicine session.
- Discuss common experiences in psilocybin session including transpersonal, spiritual aspects and approaching difficult and intense experiences with openness and curiosity.
- Collaborate on the use of various grounding exercises i.e., breathing techniques, sense of touch.
- Practical guidance and safety instructions, including departure requirements with a nominated companion.

Medication sessions:
There will be three medication sessions conducted in person between two and four weeks apart. Each session will last up to 8 hours and will be conducted with each individual participant separately. Prior to the participant’s arrival, the room will be prepared such that it provides a safe, warm, private atmosphere with the provision for music, eye shades, gentle lighting, and the ability for the participant to lie down with an appropriate blanket and pillow.
The participant will be allowed sufficient time to meet any additional medical / nursing staff who are going to be involved in the session and to understand everyone’s roles.

Prior to commencement of the session the participant’s blood pressure, pulse and temperature will be checked to make sure these are within the acceptable/normal range. If the participant is of childbearing potential, they will be asked to perform a urine pregnancy test. A negative sample is required before medication administration.

There will be a brief review of the expectations for the day along with an orientation to the space. Therapists will review participant consent and intentions for the medication session, and the techniques that the participant can use to deal with distress during a session (including asking for support and focusing on the breath). Participants will have the opportunity to trial and make comfortable the headphones/music and eyeshades used for the session prior to taking the medication. Therapists check in again with the participant around consent for supportive physical contact, as well as assuring participant they can say no to these interventions without offending therapists.

Participants are required to stay at the clinic for the full duration of the treatment session after ingesting the medication. Clear commitment from participants is required during the trial consenting processes to stay in the study facility, even if they feel well and want to leave, until cleared to leave by study staff.

For each dose administration, the participant will be given a single capsule of either psilocybin 25 mg or dexamfetamine 7.5mg, depending on the randomised treatment arm. After the participant has been cleared to proceed with the dosing session, the administration of the blinded substance will be carried out by a study doctor and registered nurse (or two registered nurses) and recorded into a study specific register. Both the participant and the treating study team will not know what medication is administered during the session. The capsule will be offered to the participant with a full cup of water and the ingestion of the capsule will be supervised by study personnel to ensure compliance. Administration of medication and completion of session will be documented within the treatment cycle timepoint data form.

The participant’s blood pressure and heart rate will be monitored every 30 minutes during the first two hours and hourly afterwards until up to 3 hours (or longer if there is any indication or elevation on initial readings) by a medical practitioner or nurse who will be onsite for all sessions. In the unlikely event that more serious medical complications occur which require intensive medical attention, an ambulance will be called via 000.

Interaction within the session: The therapist/s in attendance will adopt an approach of attentiveness but non-intrusiveness. Interaction should be predominantly supportive and not be specifically psychotherapeutic. The therapist/s can check on how the participant is going at the time of vital sign monitoring but otherwise typically respond only to the participant rather than initiating contact, unless the participant is showing signs of significant emotional distress. If the participant demonstrates an interest in talking, the therapist should respond in a supportive manner and after a short time gently redirect the participant towards an inward-directed focus. More dialogue is expected towards the end of the session.

End of session: The effects of the medication will be expected to have markedly diminished by between six and seven hours. The therapists will assess whether the participant is ready to leave based on assessment of their mental state, vital signs, observation of coordination and steadiness of gait and whether the participant reports any lingering effects of the medication. The participant must leave with a nominated companion and is required to have either this same companion or another nominated companion with them for the rest of the day.

Integration sessions:
The participant will engage in an in-person integration session within 5 – 10 days of each dosing session. An additional 4th integration session will follow within two weeks of the third final dosing session. Each integration session will take approximately 1-2 hours.
The purpose of the integration sessions is to support the participant in their ability to reflect on the medication sessions and to help them to reach insights that may have been developed. The primary activity of the therapists in these sessions is to ask open-ended questions to elicit insights that the participant may have come to. The therapist may identify elements of the participant’s narrative consistent with ACT principles and help them to understand their experience in this context. The integration sessions may also involve an exploration of values and how these may have evolved through the process of the treatment sessions. There may be some discussion of how the insights the participant has come to, and changes in their values, may be reflected in alterations they may make in specific day-to-day behaviours. An ACT framework will be used to guide this process.

The overall duration of the intervention, involving the preparation, medication and integration sessions, is approximately 12 weeks.
Intervention code [1] 325682 0
Treatment: Drugs
Intervention code [2] 325684 0
Behaviour
Comparator / control treatment
7.5mg of Dexamfetamine will be used as the comparator/control treatment. The control arm of the study is Arm A, with dexamfetamine administered in all three treatment sessions.
Dexamfetamine is widely used in psychiatry in the treatment of ADHD and occasionally in depression, and as such has an established track record of safe use. Dexamfetamine in single doses is likely to produce transient euphoria and a meaningful alteration in mental state that is likely to provide a valid control and significant blinding.

For each dose administration, the participant will be given a single capsule of either psilocybin 25mg or dexamfetamine 7.5mg, depending on the randomised treatment arm. The administration of the blinded substance will be carried out by a study doctor and registered nurse (or two registered nurses) and recorded into a study specific register. Both the participant and the treating study team will not know what medication is administered during the session. The capsule will be offered to the participant with a full cup of water and the ingestion of the capsule will be supervised by study personnel to ensure compliance.

Administration of medication and completion of session will be documented within the treatment cycle timepoint data form.
Control group
Active

Outcomes
Primary outcome [1] 334200 0
Continuous scores on the Hamilton Depression Scale (HAM-D)
Timepoint [1] 334200 0
From baseline compared to post cycle 1, post cycle 2, post cycle 3 and then 1, 3 and 6 months post the third cycle.
Secondary outcome [1] 419808 0
Any change in depressive symptoms and remission rates as assessed using the HAM-D.
Timepoint [1] 419808 0
Baseline compared to 1, 3 and 6 months post the third/final PAP cycle
Secondary outcome [2] 419809 0
The emergence of unipolar depression symptoms will be measured with the Bipolar Depression Rating Scale (BDRS) items 16-20.
Timepoint [2] 419809 0
Baseline compared to study timepoints: Post PAP cycle 1, Post PAP cycle 2, Post PAP cycle 3, and 1, 3 and 6 months post the third/final PAP cycle
Secondary outcome [3] 419810 0
Overall clinical outcomes of Patient Global Impression, Improvement (PGI-I) scale
Timepoint [3] 419810 0
Baseline compared to study timepoints: Post PAP cycle 1, Post PAP cycle 2, Post PAP cycle 3, and 1, 3 and 6 months post the third/final PAP cycle
Secondary outcome [4] 419811 0
Self-reported depression and anxiety symptoms via the Inventory for Depression and Anxiety Symptoms, expanded version (IDAS-II)
Timepoint [4] 419811 0
Baseline compared to study timepoints: Post PAP cycle 1, Post PAP cycle 2, Post PAP cycle 3, and 1, 3 and 6 months post the third/final PAP cycle
Secondary outcome [5] 419812 0
Assess suicidal symptoms via the Columbia-Suicide Severity Rating Scale (C-SSRS)
Timepoint [5] 419812 0
Baseline compared to study timepoints: Post PAP cycle 1, Post PAP cycle 2, Post PAP cycle 3, and 1, 3 and 6 months post the third/final PAP cycle
Secondary outcome [6] 419813 0
Quality of life / functioning: WHO-DAS 2.0 (12 items) will be used to assess functioning across six domains (Cognition, Mobility, Self-care, Getting along, Life activities and Participation)
Timepoint [6] 419813 0
Baseline compared to study timepoints: Post PAP cycle 2 and 1 month post the third/final PAP cycle
Secondary outcome [7] 419814 0
Assessment of Quality of Life-8D (AQoL-8D) to assess health related quality of life
Timepoint [7] 419814 0
Baseline compared to study timepoints: 1 and 6 months post the third/final PAP cycle
Secondary outcome [8] 419815 0
The Mystical Experience Questionnaire (MEQ30) to assess different experiential aspects of psilocybin. It consists of 30 items which provides scale scores for the four factors of mystical experiences: 1. Mystical (15 items); 2. Positive Mood (6 items); 3. Transcendence of Time and Space (6 items); 4. Ineffability (3 items)
Timepoint [8] 419815 0
Baseline compared to study timepoints: 1 and 6 months post the third/final PAP cycle
Secondary outcome [9] 419816 0
Adverse effect questionnaire – this will ask about expected side effects of PAP
Examples of known/possible adverse events:

1 Changes to eyesight/perception – e.g., objects moving, brighter colours than usual, visual hallucinations

2 Changes to hearing/perception of sound – e.g., sounds louder or quieter than usual, auditory hallucinations

3 Anxiety

4 Intermittent racing heartbeat

5 Nausea

6 Headache
Timepoint [9] 419816 0
Post PAP cycle 1, Post PAP cycle 2, Post PAP cycle 3, and 1 month post the third/final PAP cycle
Secondary outcome [10] 419817 0
Assessing symptoms related to past trauma via Screen for Post-Traumatic Stress Symptoms (SPTSS)
Timepoint [10] 419817 0
Baseline compared to study timepoints: Post PAP cycle 2 and 1 month post the third/final PAP cycle
Secondary outcome [11] 424158 0
Assessing symptoms related to past trauma via Trauma History Questionnaire.
Timepoint [11] 424158 0
Baseline compared to study timepoints: Post PAP cycle 2 and 1 month post the third/final PAP cycle
Secondary outcome [12] 424159 0
Overall clinical outcomes of Patient Global Impression, Severity (PGI-S) scale
Timepoint [12] 424159 0
Baseline compared to study timepoints: Post PAP cycle 1, Post PAP cycle 2, Post PAP cycle 3, and 1, 3 and 6 months post the third/final PAP cycle
Secondary outcome [13] 424160 0
Overall person’s interest/willingness to engage in PAP in the future.
Timepoint [13] 424160 0
Post PAP cycle 1, Post PAP cycle 2, Post PAP cycle 3, and 1 month post the third/final PAP cycle
Secondary outcome [14] 424161 0
Cognitive Safety Screen Battery - Processing Speed

Symbol Search assessment conducted via Inquisit (millisecond scripts)
Timepoint [14] 424161 0
Baseline compared to 1 month post the third/final PAP cycle
Secondary outcome [15] 424162 0
Cognitive Safety Screen Battery - Sustained Attention

0 Back and 1 Back assessment conducted via Inquisit (millisecond scripts)
Timepoint [15] 424162 0
Baseline compared to 1 month post the third/final PAP cycle
Secondary outcome [16] 424163 0
Cognitive Safety Screen Battery - Working Memory

2 Back and 3 Back assessment conducted via Inquisit (millisecond scripts)
Timepoint [16] 424163 0
Baseline compared to 1 month post the third/final PAP cycle
Secondary outcome [17] 424164 0
Cognitive Safety Screen Battery - Visuospatial Memory

Dot Memory assessment conducted via Inquisit (millisecond scripts)
Timepoint [17] 424164 0
Baseline compared to 1 month post the third/final PAP cycle
Secondary outcome [18] 424165 0
Cognitive Safety Screen Battery - Verbal Memory (episodic)

List Learning assessment conducted via Inquisit (millisecond scripts)
Timepoint [18] 424165 0
Baseline compared to 1 month post the third/final PAP cycle
Secondary outcome [19] 424166 0
Cognitive Safety Screen Battery - Cognitive Flexibility

Wisconsin Card Sorting assessment conducted via Inquisit (millisecond scripts)
Timepoint [19] 424166 0
Baseline compared to 1 month post the third/final PAP cycle
Secondary outcome [20] 424288 0
A custom battery of inflammatory markers will be collected via blood sample at two timepoints. The analysis of these biomarkers is to investigate whether they can predict response to treatment and all measures will be assessed as a composite secondary outcome.
Samples will be analysed using a proprietary 15 biomarker array that includes, but is not limited to, C-reactive protein, Myeloperoxidase, IL-1 beta, TNF alpha and IL-6. The effects of these potential biomarkers on change in the primary outcome will be modelled with linear regression analyses.
Timepoint [20] 424288 0
Prior to treatment (baseline) and again one month post the the third/final PAP cycle
Secondary outcome [21] 430540 0
Mentalization Imbalances Scale (MIS) to assess multiple dimensions of one’s own and others’ mental states, providing a lens into specific predispositions or imbalances in mentalizing capabilities (dimensions: self, others, cognitive, affective, external and automatic).
Timepoint [21] 430540 0
Secondary outcome [22] 430541 0
Mentalization Imbalances Scale (MIS) to assess multiple dimensions of one’s own and others’ mental states, providing a lens into specific predispositions or imbalances in mentalizing capabilities (dimensions: self, others, cognitive, affective, external and automatic).
Timepoint [22] 430541 0
Prior to treatment at preparation session 1 and after treatment at the final integration session.
Secondary outcome [23] 430542 0
Metacognitive Self-Assessment Scale (MSAS) employs a five-point Likert scale to assess the individual’s self-perception of their five principal metacognitive capabilities (monitoring, differentiation, integration, decentring and mastery)
Timepoint [23] 430542 0
Prior to treatment at preparation session 1 and after treatment at the final integration session.
Secondary outcome [24] 430543 0
Metacognitive Self-Assessment Scale (MSAS) employs a five-point Likert scale to assess the individual’s self-perception of their five principal metacognitive capabilities (monitoring, differentiation, integration, decentring and mastery)
Timepoint [24] 430543 0
Before treatment at baseline and after treatment at the 3-month follow up.

Eligibility
Key inclusion criteria
• Diagnosis of a major depressive episode (MDE) in accordance with the Mini International Neuropsychiatric Interview (MINI)

• Treatment resistant symptoms at Stage II of the Thase and Rush classification: a failure to tolerate minimum of two trials of antidepressant medication at minimum effective therapeutic dose for at least 6 weeks (no exclusion for greater degrees of treatment resistance)

• Moderate – severe depressive symptoms: HAM-D score of >17 (moderate – severe depression)

• Demonstrated capacity to give informed consent

• Willingness and capacity (as judged on assessment by study clinicians) to engage in the therapeutic elements of the study protocol
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Participants who are not able to give adequate informed consent.

• Current or previously diagnosed psychotic disorder, schizophrenia or bipolar disorder

• Immediate family member with a diagnosed psychotic disorder

• Significant history of mania.

• History of serious suicide attempts in recent years requiring hospitalisation as judged by a study psychiatrist at initial assessment to impact on safety of participation.

• Psychiatric condition judged to be incompatible with establishment of rapport with therapy team and/or safe exposure to psilocybin, e.g., diagnosis of borderline personality disorder.

• Medically significant condition reviewed as unsuitable for the study due to safety reasons, as reviewed by the study investigator. Such as:
o Unstable diabetes
o Moderate – severe hepatic failure
o Moderate – severe renal failure
o Severe cardiovascular disease

• Participants presenting with abnormal QT interval prolongation at screening or with a history of this (QTc at screening above 440ms for men and above 470ms for women)

• Have a history of ventricular arrhythmia at any time, other than occasional premature ventricular contractions (PVCs) in the absence of ischemic heart disease.

• Have Wolff-Parkinson-White syndrome or any other accessory pathway that has not been successfully eliminated by ablation.

• Epilepsy

• Moderate to severe previous or current head injury/Traumatic Brain Injury (TBI).

• Have a history of stroke or Transient Ischemic Attack (TIA).

• Current drug or alcohol dependence: Moderate (not in early remission in the 3 months prior to enrolment; meets 5 of 11 diagnostic criteria per DSM-5) or severe alcohol or drug use disorder within the 12 months prior to enrolment (meets at least 6 of 11 diagnostic criteria per DSM-5)

• Positive pregnancy test at screening or during the study, women who are planning a pregnancy and/or women who are nursing/breastfeeding.

• Participants who do not agree to use an acceptable contraceptive method throughout their participation in the study, if applicable.

• Nicotine dependence that would disallow an individual to be nicotine free for the 7-10 hours during the dosing period.

• Recreational use in last 12 months of psychedelic substances or a history of regular psychedelic use

• No email access/ability or no willingness to engage in follow up by electronic questionnaires

• Use of contraindicated medication (outlined further below) including MAOI, SSRI or SNRI: SSRI/SNRI withdrawal for at least one week (4 weeks for fluoxetine), 2 weeks for irreversible MAOI

• Use within 5 half-lives of any other serotonin-enhancing medication

• Participants with significant difficulties in English comprehension or communication such as to prevent completion of study materials.

• BMI <17 or >42

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 study group via an "off-site" central clinical trial management system, using simple randomisation techniques i.e. using a randomisation table created by computer software (i.e. computerised sequence generation).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The first 50 participants will be equally randomised to the initial 4 treatment arms by a professional biostatistician employing random non-stratified permuted blocks in a 1:1:1:1 ratio. From then on, response adaptive randomisation (RAR) with control protection favouring the best performing arms will be used, with the probability of allocation to the remaining arms reassessed every 20 additional participants until the trial is stopped, or the maximum sample size of 130 (evaluable) participants is reached.
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/efficacy
Statistical methods / analysis
SAMPLE SIZE

Modelling of the adaptive design and estimation of sample size: To assess the properties of the design, we ran 10,000 simulations for a series of scenarios based on mean reduction in HAM-D scores (baseline minus end of one month follow up) chosen as the primary outcome:

1. all means at 5 (null hypothesis);
2. means at 5, 8, 10, 12 for the 4 arms / groups A-D, A equals control, increasing reduction
3. means at 5, 8, 11, 14 (each dose is more effective than the lesser one by 3 points);
4. means at 5, 5, 5, 10 (only D is effective);
5. means at 5, 5, 10, 10 (only C and D are effective);
6. mean change of 5, 10, 10, 10 (all 3 active groups are equally effective).

Max sample size is 130 evaluable participants in these simulations; first interim after 50 participants and every 20 additional participants thereafter.

The means listed here represent mean reductions in HAM-D scores where 3 is generally accepted as a minimum clinically meaningful difference. An estimated improvement of 5 in the comparator group has been extrapolated from previous trials of ours in people with depression that is resistant to antidepressant treatment. A mean of 10 for any experimental arm corresponds to a difference of 5 compared with the control arm.

Under scenario 1., i.e. the null hypothesis, the probability of declaring a regimen effective is the false error rate; it is well controlled at the 2.5% level. The design has at least 80% power to detect a shift in 5 in the HAM-D reduction compared with control for the high dose group in all scenarios and power greater than or equal to 95% for bigger effect size. In all scenarios, the average sample size is less than or equal to 117 participants, but a large reduction can occur when all treatments are either poor or effective (scenario 1. and 6.). The probability of stopping early for efficacy increases if we have more efficacious regimens. The same stands for futility with poor regimens. The simulations above are based on a standard linear regression model with the group indicators as only covariates, the model being fitted the Bayesian way. In reality, we may adjust for the baseline HAM-D score, which is typically recommended. In this situation, there is a small efficiency gain in using ANCOVA, since the required sample size to detect any effect is reduced by a factor (1-p2) where p is the correlation between the baseline HAM-D score and the HAM-D score at 1 month. Here p=0.4 is small, so the adjustment is minor and may offset the loss to follow-up if it’s slightly higher than anticipated.

Note: On the basis of the modelling above, and to allow for a 7% attrition rate, we aim to recruit up to 140 participants

STATISTICAL ANALYSIS

The analysis will be based on the intention to treat principle using Bayesian methodology. Unless specified otherwise, all models used will be fitted using Bayesian methods via the R libraries INLA or rstanarm that can accommodate common parametric models. The primary endpoint, the HAM-D reduction at 1 month will be analysed using ANCOVA. A summary of the posterior distribution of the treatment effect per am (e.g. mean or median) will be reported with 95% credible intervals, all provided by INLA or rstanarm. Other continuous endpoints (e.g. C-SSRS, WHO-DAS scores) will be analysed similarly. Binary outcomes will be analysed using logistic regression following the same logic. Repeated measurements of quality of life or cognition will be analysed using mixed linear models. Should a frequentist technique be used, a bootstrap approach will be used to correct p-values impacted by the adaptations performed along the way. To allow for more fine-grained analysis of changes in specific symptoms variables, analyses of the detailed symptom data in in the IDAS-II will be conducted using multiple-group latent change score models. Latent change score models enable direct comparison of treatment effects between randomised groups, as well as quantification of variance in response to treatment within groups, such that individual differences in treatment response can be evaluated. The continuous outcome measures can be specified as single-indicator latent variables (i.e., factors) to remove measurement error, increase statistical power, and enable estimation in small samples. Analyses will be conducted on symptom components (i.e., suicidality, insomnia) and measures of cognitive function with high specificity and statistical power to detect meaningful clinical change in circumscribed clinical domains. Bayesian will allow us to deal adequately with relatively small sample size and missing data. Side effect rates and interest in returning for future PAP treatment will be descriptively presented.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
5/02/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/10/2028
Actual
Sample size
Target
140
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,VIC

Funding & Sponsors
Funding source category [1] 313435 0
Government body
Name [1] 313435 0
Australian Department of Health and Aged Care -Medical Research Future Fund
Country [1] 313435 0
Australia
Funding source category [2] 313437 0
University
Name [2] 313437 0
The Australian National University
Country [2] 313437 0
Australia
Funding source category [3] 313438 0
Other Collaborative groups
Name [3] 313438 0
Mynd Life Sciences
Country [3] 313438 0
Canada
Primary sponsor type
University
Name
The Australian National University
Address
ANU College of Health and Medicine
School of Medicine and Psychology
Room 1.27 Florey Building
54 Mills Road,
Canberra ACT 2601
Canberra ACT
Country
Australia
Secondary sponsor category [1] 315209 0
None
Name [1] 315209 0
Address [1] 315209 0
Country [1] 315209 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312643 0
ACT Health
Ethics committee address [1] 312643 0
PO Box 11
Woden, ACT 2606
Ethics committee country [1] 312643 0
Australia
Date submitted for ethics approval [1] 312643 0
09/02/2023
Approval date [1] 312643 0
12/04/2023
Ethics approval number [1] 312643 0
2023.ETH.00030

Summary
Brief summary
The purpose of this study is to explore the therapeutic benefits, tolerability and acceptability of psychedelic therapy using psilocybin and its potential to improve symptoms of treatment resistant depression (TRD), depression in people which has not resolved with a number of courses of standard treatment. Prior research has suggested that this type of treatment may have significant antidepressant effects, but we require further evidence to fully understand the therapeutic value, benefits, and risk of psilocybin in a treatment setting.

The design includes an adaptive, dose finding, single phase 2b clinical trial exploring the efficacy and safety of psilocybin assisted psychotherapy (PAP) in the treatment of people diagnosed with treatment resistant major depressive disorder (TRD). If successful, this will lead to the conduct of a subsequent multi-site phase 3 trial to report findings of the therapeutic value, benefits and risks of psilocybin for the treatment of mental health conditions, including the size of effect, the quality of evidence and the relevance to real-world use in Australia.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 125398 0
Prof Paul Fitzgerald
Address 125398 0
School of Medicine and Psychology
ANU College of Health and Medicine
The Australian National University,
Room 1.27, Florey Building, 54 Mills Road,
Canberra ACT 2601
Country 125398 0
Australia
Phone 125398 0
+61 2 6125 2622
Fax 125398 0
Email 125398 0
paul.fitzgerald@anu.edu.au
Contact person for public queries
Name 125399 0
Ms Jillian Bethwaite
Address 125399 0
Monarch Mental Health Group
Level 4, 131 York Street
Sydney 2000
Country 125399 0
Australia
Phone 125399 0
+61 1300 867 888
Fax 125399 0
Email 125399 0
jillian.bethwaite@anu.edu.au
Contact person for scientific queries
Name 125400 0
Prof Paul Fitzgerald
Address 125400 0
School of Medicine and Psychology
ANU College of Health and Medicine
The Australian National University,
Room 1.27, Florey Building, 54 Mills Road,
Canberra ACT 2601
Country 125400 0
Australia
Phone 125400 0
+61 2 6125 2622
Fax 125400 0
Email 125400 0
paul.fitzgerald@anu.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-identified self-report and outcome data
When will data be available (start and end dates)?
Beginning 3 months following main results publication, with no end date determined.
Available to whom?
Data collected for the study will be made available to other researchers
Available for what types of analyses?
For future research projects
How or where can data be obtained?
Via a data repository yet to be determined. Until determined, Prof Fitzgerald can be contacted via email regarding individual participant data:

Paul.Fitzgerald@anu.edu.au


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.