The Safety and Efficacy of Psilocybin in Participants with Treatment Resistant Depression (P-TRD)

A recent open label study of the effects of psilocybin in participants with
treatment resistant depression (TRD) showed rapid significant decrease of
depressive symptoms after treatment with psilocybin coupled with psychological
support. Over 40% of participants sustained response at 3 months. In this
study, the aim is to assess effectiveness of 3 different doses of psilocybin (1
mg, 10 mg, and 25 mg) in TRD, with the lowest dose assumed to be in effect a
placebo.

The primary objective of this study is to evaluate the efficacy of psilocybin
(25 mg or 10 mg) compared to 1 mg, administered under supportive conditions to
adult participants with TRD, in improving depressive symptoms, as assessed by
the change in the Montgomery Asberg Depression Rating Scale (MADRS) total score
from Baseline. Baseline is defined as the assessment score obtained on Day 1.
The primary timepoint is Week 3; this variable will be analysed for the change
from Baseline to Day 1, and Weeks 1, 3, 6, 9, and 12.
The secondary objectives are:
* To assess the efficacy of psilocybin compared to 1 mg psilocybin on:
o Proportion of participants with response defined as a * 50% decrease in
MADRS total score from Baseline to Week 3. This will also be assessed at Day 1
and at Weeks 1, 6, 9, and 12.
o The proportion of participants who have a sustained response at Week 12.
Sustained response is defined as the proportion of patients fulfilling response
criteria at any visit up to and including Week 3, that also fulfills response
criteria at all subsequent visits up to and including Week 12. Response is
defined as * 50% decrease in MADRS total score from Baseline.
* To evaluate the safety and tolerability of psilocybin in participants with
TRD based on adverse events (AEs), changes in vital signs, and suicidal
ideation/behaviour (measured using the Columbia-Suicide Severity Rating Scale
[C SSRS]) score at all visits.
The exploratory objectives are:
* To evaluate the effects of psilocybin on quality of life and wellbeing,
functioning and associated disability, cognitive function, and anxiety compared
to 1 mg psilocybin on:
outcomes as possible predictors of response.
The main purpose of this study is to allow COMPASS to determine the optimal
dose of psilocybin, either 10 mg or 25 mg. The intent of the primary efficacy
analysis is to demonstrate superiority of at least one therapeutic dose of
psilocybin (10 mg or 25 mg) versus the 1 mg psilocybin via the following
objectives.
The primary objective of this study is to evaluate the efficacy of psilocybin
(25 mg or 10 mg) compared to 1 mg, administered under supportive conditions to
adult participants with TRD, in improving depressive symptoms, as assessed by
the change in the Montgomery Asberg Depression Rating Scale (MADRS) total score
from Baseline. Baseline is defined as the assessment score obtained on Day 1.
The primary timepoint is Week 3; this variable will be analysed for the change
from Baseline to Day 1, and Weeks 1, 3, 6, 9, and 12.
The secondary objectives are:
* To assess the efficacy of psilocybin compared to 1 mg psilocybin on:
o Proportion of participants with response defined as a * 50% decrease in
MADRS total score from Baseline to Week 3. This will also be assessed at Day 1
and at Weeks 1, 6, 9, and 12.
o The proportion of participants who have a sustained response at Week 12.
Sustained response is defined as the proportion of patients fulfilling response
criteria at any visit up to and including Week 3, that also fulfills response
criteria at all subsequent visits up to and including Week 12. Response is
defined as * 50% decrease in MADRS total score from Baseline.
* To evaluate the safety and tolerability of psilocybin in participants with
TRD based on adverse events (AEs), changes in vital signs, and suicidal
ideation/behaviour (measured using the Columbia-Suicide Severity Rating Scale
[C SSRS]) score at all visits.
The exploratory objectives are:
* To evaluate the effects of psilocybin on quality of life and wellbeing,
functioning and associated disability, cognitive function, and anxiety compared
to 1 mg psilocybin on:
o Quality of life in participant EuroQoL (EQ) 5 dimension 3 level scale
(EQ 5D 3L) score change from Baseline to Week 3. This will also be assessed at
Week 12.
o Quality of life in caregiver EQ 5D 3L score change from Baseline to Week
3. This will also be assessed at Week 12. This assessment is not mandatory.
o Functioning and associated disability in the Sheehan Disability Scale
(SDS) score change from Baseline to Week 3. This will be also assessed at Week
12.
o Cognitive function as measured by the Digit Symbol Substitution Test
(DSST) score change from Baseline to Week 3. This will also be assessed at Day
1 and Week 12.
o Level of anxiety as measured using the change in Generalised Anxiety
Disorder 7 item Scale (GAD 7) total score change from Baseline to Week 3. This
will also be assessed at Week 12.
o Participant determined level of depression as measured using the change
in Quick Inventory of Depressive Symptomatology Self Rated (QIDS SR 16) total
score from Baseline to Week 3. This will also be assessed at Day 1, and Weeks
1, 2, 6, 9, and 12.
o Psychosocial functioning and predictor of response duratbility as
measured using the change in Work and Social Adjustment Scale (WSAS) from
Baseline to Week 3. This will also be assessed at Week 12.
o To evaluate the impact of different psilocybin doses on real life
functional activity estimated from passive data streams collected on a mobile
app on participants* mobile phones. The data collected from the participant*s
phone will include:
* Number of and time of phone calls/e mails/texts (content will not be
collected)
* Gestures used (taps, swipes, other)
* Gyroscope (orientation) of the phone (the way the phone is pointing)
* Acceleration of the phone (sudden movements of the phone)
* Keystroke patterns with characters redacted
* Location information from the GPS
* The app also maintains a histogram of daily words that the participant types
on their phone. These words will be stripped from their context and syntax,
thus preventing the content of any particular message from being deciphered.
o The Positive and Negative Affect Schedule, Five Dimension Altered States
of Consciousness questionnaire, 2a receptor polymorphism test and the Scale to
Assess Therapeutic Relationship (Clinician and Patient version, STAR C and STAR
P, respectively) will be assessed for correlation with the primary and
secondary outcomes as possible predictors of response.

This is a Phase 2, international multicentre, randomised, fixed dose, double
blind trial. The study population will include adult men and women, 18 years of
age and older, with TRD. Participants with TRD are defined as those who meet
the Diagnostic and Statistical Manual of Mental Disorders (5th Edition; DSM 5)
diagnostic criteria for single or recurrent episode of major depressive
disorder (MDD) without psychotic features which have failed to respond to an
adequate dose and duration of 2, 3, or 4 pharmacological treatments for the
current episode; if single episode MDD, the duration of the current episode
must be at least 3 months but not more than 2 years. Augmentation counts as a
second treatment, provided it is approved for the adjunctive treatment of MDD
in that country..
Participants will be outpatients and will be recruited primarily through
referrals from general practitioners and specialised psychiatric services.
The majority of participants will have no prior exposure to psilocybin or so
called magic mushrooms; however, to reflect the prevalence of experience in
general population, we will allow up to 10% of participants with prior
recreational experience with psilocybin or magic mushrooms. Past exposure to
psilocybin has to be more than 12 months prior to Screening and not during the
current depressive episode. This will be constrained by the centralised
randomisation process, Interactive Web based Response System.
After signing the informed consent form (ICF), participants will be assessed
for their eligibility with the Mini International Neuropsychiatric Interview
(MINI), the Hamilton Depression Rating Scale (HAM D 17), the Massachusetts
General Hospital Antidepressant Treatment History Response Questionnaire
(MGH-ATRQ), the C SSRS, and McLean Screening Instrument for Borderline
Personality Disorder. Those who meet the eligibility criteria will enter the
screening period, which will last between 3 and 6 weeks. At the initial
Screening visit (V1), the participant will also be evaluated with the QIDS SR
16, and the Adult Self Report Scale. Additionally, a medical history, an
electrocardiogram (ECG), blood tests, and vital signs will be obtained.
During the screening period, participants who are on antidepressant medications
will be expected to complete the taper at least 2 weeks prior to Baseline (V2).
Participants will be given a choice of the tapering rate. During the tapering
period all participants will be supported by the study clinician.
Once a patient completes all V1 assessments and all screening data is entered
into the Electronic Data Capture (EDC), the Medical Monitor (MM) and Clinical
Assessment Technologies Team (CAT) will review data entered and issue approval,
if the patient is eligible. Once approval is issued, the patient should then be
invited for a screening V1a visit. The V1a visit is the point at which the
patient begins tapering off their antidepressant and/or antipsychotic
medications, if appropriate. The patient must complete the taper within the
first 4 weeks of this period, prior to 2 weeks completely off antidepressant
and/or antipsychotic medications, before Baseline V2. The tapering period used
in the study is set at the industry standard for depression trials.
The designated study team member will be in frequent contact with the
participants to monitor for withdrawal and worsening of depression symptoms.
Participants will be assessed for suicidality with the C SSRS at each
contact/visit.
The participant will meet with a therapist for a minimum of 3 visits during
screening. These are safety sessions and will cover what to expect during the
psilocybin session. The therapist and the participant will review
psychoeducational materials provided at the time of enrolment.
All participants will be evaluated for safety at the clinic weekly for a
minimum of 3 weeks prior to psilocybin administration to ensure safe
discontinuation of current antidepressant therapy required by the protocol.
Participants* companions (friends or family members) will be educated about the
signs of worsening of depression and suicidality, and instructed on ways to
contact the study team in case of significant worsening of depression. Any
safety assessment visits during the screening period will be called V1a, V1b,
etc. During these visits, the C SSRS and any changes in medications since the
previous visit will be obtained in addition to other assessments at the study
clinician*s discretion.
The day before psilocybin session, the participants will undergo a baseline
assessment (3 to 6 weeks after initial Screening [V1]) that will consist of the
HAM D 17, MADRS, QIDS SR 16, C SSRS, SDS, GAD 7, DSST, EQ 5D 3L (administered
to both participant and caregiver [the latter is not mandatory]), WSAS, vital
signs, urinalysis, urine drug screen, and urine pregnancy test (only for women
of childbearing potential). Both the therapist and the participant will be
asked to fill out a therapeutic alliance evaluation questionnaire, STAR C and
STAR P, respectively. After baseline data is entered into EDC, the CAT team
will complete a final review to ensure the participant*s continued
eligilblilty. Participants cannot be progressed to V3 until this approval is
received.
The psilocybin administration session (V3, Day 0) will last approximately 6
hours and will be supported by a trained therapist. Psilocybin session may be
video recorded for training and adherence monitoring. A full description of the
activities of the psilocybin administration session is found in the Therapist
Manual. After the acute effects of the psilocybin pass, participants will be
evaluated for safety and accompanied home. On Day 1 (V4), the day following
psilocybin administration, participants will be seen in person for a safety
check, assessment of suicidality, and to discuss their experience during the
psilocybin session. All sessions between the therapist and the participant may
be audio recorded for adherence monitoring and quality assurance. Audio and
video recording of the sessions are subject to participant consent.
Participants who do not consent to either or all recordings will not be
excluded from the study.
All participants will be asked to remain off their antidepressant medications
for at least 3 weeks following the psilocybin session until the primary
endpoint assessment, or longer. Rescue medications are allowed as noted in the
protocol. Participants who restart their antidepressant medications during the
first 3 weeks after the psilocybin treatment administration will be assessed
for reasons of resuming their medications and followed until 12 weeks post
psilocybin administration.
The treatment period will determine the optimal therapeutic dose; 216
participants will be randomised in a 1:1:1 ratio to receive 1 mg psilocybin, 10
mg psilocybin, or 25 mg psilocybin.
Participants will be seen at the clinic for Screening (V1 plus a minimum of 3
safety visits), Baseline (V2, Day 1), Day 0 (V3, Dosing), Day 1 (V4), Week 1
(V5), Week 2 (V6), Week 3 (V7), and Week 12 (V10). Participants will also be
contacted for follow up at Week 6 (V8) and Week 9 (V9). The MADRS will be done
by telephone and the other assessments will be done electronically.
Participants are seen at the clinic for safety visits between the initial
Screening (V1) and the Baseline (V2) visit, and the visits will be labelled
V1a, V1b, V1c, etc.

216 patients will be randomized in a 1:1:1 ratio to 25 mg, 10 mg, or 1 mg of
psilocybin.

Side effects associated with psilocybin:
Over 1000 psilocybin sessions have conducted in modern scientific studies in
patients and healthy volunteers. Hundreds of patients were treated with
psilocybin in the 1950s and 60s and millions of people have taken psilocybin in
the form of magic mushrooms in recreational settings.
The most common acute side-effects associated with psilocybin are anxiety and
nausea. In addition, psilocybin can raise blood pressure and heart rate but not
to dangerous levels.

It is not uncommon to feel anxious after being given the drug but with proper
support and guidance, these effects are short-lived. Developing a relationship
of trust in the patients* therapist and feeling safe and relaxed in the
surroundings can minimise the feeling of being anxious in psilocybin sessions.
The participants will receive psilocybin in a calm environment, have eye-shades
and listen to relaxing music playing quietly for most of the drug experience.
The participants will be fully supported by a psychiatrist and
psychologist/therapist and other members of the research team, who will be
specially trained and competent in dealing with any problems that might arise.

So-called *flashbacks* or a sense of re-experiencing psychedelic drug effects
when no drug has been taken, have been described in scientific literature but
have not been reported in modern research studies with psilocybin.

It is possible that the participants* depression may fail to respond to the
study medication they receive in this trial and even deteriorate further. The
site will be in frequent contact with the participants throughout the study to
record their mood.


Below is a summary of the frequency of effects with psilocybin:

Common (over 50%):
1) Visual and other sensory distortions, feeling of unreality & changed sense
of time
2) Anxiety at the onset of the drug effects
3) Increased heart rate and blood pressure

Less common (about 10-40%):
1) Nausea
2) Dizziness, blurred vision, drowsiness & sleepiness
3) Headache
5) Temporary suspiciousness

Rare (< 10%):
1) *Flashbacks*, or hallucinogen-induced persistent perceptual disorder
(HIPPD). This adverse effect is seen rarely following recreational use and has
not been reported in scientific studies done under supportive clinical
conditions
2) Worsening of mental state after the drug experience (very rare and was not
seen in similar studies).

Possible risks from Blood Sampling
The risks of taking blood include fainting and pain, bruising, swelling, or
tenderness where the needle was inserted. These discomforts are generally brief
and temporary.
Very rarely there can be some inflammation of the vein, infection, formation of
blood clots (thrombosis) or permanent nerve injury.

Possible risks from Electrocardiogram (ECG)
Skin irritation from the ECG electrode pads or pain when removing the pads are
possible side effects.