Clinical trial NCT03775200
Conditions: Treatment Resistant Depression
Sponsor: COMPASS Pathways
Start date: 2019-03-01; Completion date: 2021-09-27
Enrollment: 233 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The Safety and Efficacy of Psilocybin in Participants with Treatment Resistant Depression

Detailed description:
The Safety and Efficacy of Psilocybin in Participants with Treatment Resistant Depression - a dose-ranging study

Arms: arm 1: Low dose Psilocybin arm 2: Medium dose Psilocybin arm 3: High dose Psilocybin
Interventions: intervention 1: Psilocybin
Intervention descriptions: intervention 1: Dose-finding

Protocol documents:
Prot_000.pdf: 
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THE SAFETY AND EFFICACY OF PSILOCYBIN IN 
PARTICIPANTS WITH TREATMENT-RESISTANT DEPRESSION 
(P-TRD) 
DRUG: 
Psilocybin 
3-[2-(Dimethylamino)ethyl]-1H-indol-4-yl 
dihydrogen phosphate 
STUDY NUMBER: 
COMP 001 
 
CLINICAL PHASE 
2 
 
EudraCT NUMBER: 
2017-003288-36 
 
SPONSOR: 
COMPASS Pathways, Ltd 
16 Old Bailey 
London, England, UK EC4M 7EG 
 
ORIGINAL PROTOCOL 
DATE: 
11 Oct 2017 
 
VERSION NUMBER: 
V4.0 
 
VERSION DATE: 
22 Jul 2019 
 


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CLINICAL PROTOCOL APPROVAL FORM 
Protocol Title: The Safety and Efficacy of Psilocybin in Participants with Treatment-Resistant 
Depression (P-TRD) 
Study No: COMP 001 
Original Protocol Date: 11 Oct 2017 
Protocol Version No: v4.0 
Protocol Version Date: 22 Jul 2019 
This study protocol was reviewed and approved by the sponsor. The information 
contained in this protocol is consistent with: 
• The current risk-benefit evaluation of the investigational product. 
• The moral, ethical and scientific principles governing clinical research as set out in 
the Declaration of Helsinki, and principles of Good Clinical Practices (GCP) as 
described in the Code of Federal Regulations (CFR) 21 CFR parts 50, 54, 56 and 312 
and according to applicable local requirements. 
The investigator will be supplied with details of any significant or new findings, 
including adverse events, relating to treatment with the investigational product. 
 
Sponsor Approval: 
 
Signature: 
 
 
Date: 
 
Name (print): 
Ekaterina Malievskaia, MD MScPH 
 
 
 
 
 
 
 
 
Title: 
Co-Founder, Head of Research and 
Development 
COMPASS Pathways 
 
 
 
 
 
 
25 July 2019


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STUDY NUMBER COMP 001 
THE SAFETY AND EFFICACY OF PSILOCYBIN IN 
PARTICIPANTS WITH TREATMENT-RESISTANT DEPRESSION 
(P-TRD) 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
The information contained in this protocol and all other information relevant to 
psilocybin are the confidential and proprietary information of COMPASS Pathways, Ltd 
(COMPASS), and except as may be required by federal, state or local laws or regulation, 
may not be disclosed to others without prior written permission of COMPASS. 
I have read the protocol, including all appendices, and I agree that it contains all the 
necessary information for me and my staff to conduct this study as described. I will 
conduct this study as outlined herein, in accordance with the regulations stated in the 
Code of Federal Regulations (CFR) for Good Clinical Practices (GCP) and International 
Conference on Harmonisation (ICH) guidelines, and will make a reasonable effort to 
complete the study within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by COMPASS or specified 
designees. I will discuss the material with them to ensure that they are fully informed 
about psilocybin and the study. 
 
 
 
Principal Investigator Name (printed)  
Signature 
 
 
Date) 
 
Site Number 
 
 
 


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SUMMARY OF CHANGES 
The changes made to the prior version of the protocol, dated 11 Oct 2017, in Version 4.0, 
dated 22 Jul 2019, are summarised in a standalone document.  
 
 


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STUDY SUMMARY 
Title:  
The Safety and Efficacy of Psilocybin in Participants with Treatment-Resistant 
Depression (P-TRD) 
EudraCT 
Number: 
2017-003288-36/ 
Clinical Phase: 
2 
Rationale: 
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. 
Target 
Population: 
TRD 
Number of 
Participants: 
216 participants 
Objectives:  
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: 


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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. 
Study Design: 
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) 


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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 


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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. 
Eligibility 
Criteria: 
Inclusion Criteria 
Participants meeting all the following inclusion criteria at Screening (V1) should be 
considered for admission into the study 
1. Signed ICF. 
2. 18 years of age or older at Screening (V1). 


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3. At least moderate MDD (single or recurrent episode as informed by DSM-5; if 
single episode, duration of ≥ 3 months and ≤ 2 years) based on medical records, 
clinical assessment and documented completion of the version 7.0.2 MINI. 
4. HAM-D-17 (17-item) score ≥ 18 at Screening (V1) and at Baseline (V2).  
5. Failure to respond to an adequate dose and duration of 2, 3, or 4 pharmacological 
treatment for the current episode as determined through the MGH-ATRQ and 
using the supplementary advice on additional antidepressants not included in 
MGH-ATRQ (Appendix III). Augmentation with an add-on treatment counts as 
a second treatment, provided it is approved for the adjunctive treatment of MDD 
in that country.  
6. McLean Screening Instrument for Borderline Personality Disorder < 7 at 
Screening (V1). 
7. Have successfully discontinued all antidepressant medications at least 2 weeks 
prior to Baseline (V2). 
8. Ability to complete all protocol required assessment tools without any assistance 
or alteration to the copyrighted assessments, and to comply with all study visits.  
Exclusion Criteria 
Participants meeting any of the following exclusion criteria at Screening (V1) will 
not be enrolled in the study. 
Psychiatric Exclusion Criteria: 
1. Current or past history of schizophrenia, psychotic disorder (unless substance 
induced or due to a medical condition), bipolar disorder, delusional disorder, 
paranoid personality disorder, schizoaffective disorder, borderline personality 
disorder, or any serious psychiatric comorbidity as assessed by medical history 
and a structured clinical interview (version 7.0.2 MINI). 
2. Prior electroconvulsive therapy and/or ketamine for current episode. 
3. Current cognitive behavioural therapy (CBT) that will not remain stable for the 
duration of the study. CBT cannot be initiated within 21 days of baseline.  
4. Current (within the last year) alcohol or substance abuse as informed by DSM-5 
at Screening (V1). 
5. Significant suicide risk as defined by (1) suicidal ideation as endorsed on items 4 
or 5 on the C-SSRS within the past year, at Screening or at Baseline, or; 
(2) suicidal behaviors within the past year, or; (3) clinical assessment of 
significant suicidal risk during subject interview. 
6. Depression secondary to other severe medical conditions.  
7. Other personal circumstances and behaviour judged to be incompatible with 
establishment of rapport or safe exposure to psilocybin, including exposure to 
psilocybin within the past year and use of psychedelics, such as ayahuasca, 
during the current depressive episode. 
General Medical Exclusion Criteria:  
8. Women who are pregnant, nursing, or planning a pregnancy. Participants who 
are sexually active must agree to use a highly effective contraceptive method 
throughout their participation in the study. Women of child bearing potential 
must have a negative urine pregnancy test at Screening (V1) and Baseline (V2). 


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9. Cardiovascular conditions: recent stroke (< 1 year from signing of ICF), recent 
myocardial infarction (< 1 year from signing of ICF), hypertension (blood 
pressure > 140/90 mmHg) or clinically significant arrhythmia within 1 year of 
signing the ICF. 
10. Uncontrolled insulin-dependent diabetes. 
11. Seizure disorder.  
12. Positive urine drug screen for illicit drugs or drugs of abuse at V1 and/or V2. 
Any positive urine drug test will be reviewed with participants to determine the 
pattern of use and eligibility will be determined at the investigator’s discretion in 
conjunction with the medical monitor.  
13. Current enrolment in any investigational drug or device study or participation in 
such within 30 days of Screening (V1). 
14. Current enrolment in an interventional study for depression or participation in 
such within 30 days of Screening (V1).  
15. Abnormal and clinically significant results on the physical examination, vital 
signs, ECG, or laboratory tests at Screening (V1).  
16. Any other clinically significant cardiovascular, pulmonary, gastrointestinal, 
hepatic, renal or any other major concurrent illness that, in the opinion of the 
investigator, may interfere with the interpretation of the study results or 
constitute a health risk for the participant if he/she takes part in the study. 
Investigational 
Product(s): 
Single 5-capsule oral psilocybin dose:  
o 
25 mg treatment: 5 × 5 mg capsules  
o 
10 mg treatment: 2 × 5 mg capsules and 3 × placebo capsules 
o 
1 mg treatment: 1 × 1 mg capsule and 4 × placebo capsules 
Primary 
Endpoint:  
The primary endpoint is the change in MADRS total score from Baseline (Day -1) to 
3 weeks post psilocybin.  
Secondary 
Endpoints: 
The secondary endpoints are: 
• 
The proportion of participants with a response (defined as a ≥ 50% improvement 
in MADRS total score from Baseline) at Week 3 post psilocybin. 
• 
The proportion of participants with remission (defined as a MADRS total score 
≤ 10) at Week 3 post psilocybin.  
• 
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. 
• 
Time to event measures: restart antidepressant medication for any reason, restart 
medication for continuing depressive symptoms, and relapse from a previously 
recovered state (clinical judgement, supported by the QIDS-SR-16). Participants 
who withdraw from the study will be censored from the time to event analysis. 
Exploratory 
Endpoints: 
The exploratory endpoints are: 


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• 
Change from Baseline in the following: 
o 
Participant EQ-5D-3L at Week 3 
o 
Caregiver EQ-5D-3L at Week 3 (this assessment is not mandatory) 
o 
SDS at Week 3 
o 
DSST at Week 3 
o 
GAD-7 at Week 3 
o 
QIDS-SR-16 at Week 3 
o 
WSAS at Week 3 
o 
Measures derived from smart phone usage via the Mindstrong app. 
Efficacy and 
Outcome 
Measures: 
• 
MADRS 
• 
QIDS-SR-16  
• 
SDS 
• 
GAD-7 
• 
DSST 
• 
EQ-5D-3L (participant and caregiver, the latter is not mandatory) 
• 
WSAS 
Safety 
Assessments 
• 
ECG 
• 
Vital signs  
• 
Blood test including liver function tests  
• 
Suicide risk as assessed by the C-SSRS 
• 
AEs and Serious AEs  
Statistical 
Procedures 
Analysis Sets 
The Safety Population will consist of all randomised participants who receive study 
treatment, regardless of whether or not treated. This population will be used for all 
summaries of participant accountability, demographic and baseline data, and safety 
information, including AE incidence.  
The Full Analysis Set (FAS) will consist of all participants randomised who also 
receive the dose of investigational product (IP). 
The modified intention-to-treat population will consist of all participants in the FAS 
that have at least 1 post dose assessment.  
The Per Protocol (PP) population will consist of all participants in the FAS who do 
not have a major protocol deviation. Major protocol deviations will be reviewed and 
determined prior to unblinding. The PP population will be used for supportive 
sensitivity analyses.  
Sample Size Determination  
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 
based on the change from Baseline in MADRS score at Week 3.  


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For this primary analysis, a sample size of 216 randomised participants (72:72:72) 
will provide 90% power at the alpha = 0.05 level to detect a 6-point difference in 
average MADRS total score between the optimal therapeutic dose of psilocybin and 
1 mg psilocybin, assuming the common standard deviation is 11.0.  
It is assumed that up to 90% of randomised participants may not have prior 
psychedelic experience. The power for this post hoc subgroup is approximately 86%, 
if the maximum number of participants to have prior psychedelic experience were 
10% of randomised participants. 
Primary and Secondary Efficacy Analyses 
The primary efficacy endpoint (change from Baseline in MADRS total score at 
Week 3) will be evaluated with a mixed-effects model for repeated measures 
analysis. The model will include treatment, visit, study site, prior psychedelic 
experience, treatment-by-visit interaction, participant as a random effect, and 
baseline MADRS total score. Comparison of the psilocybin optimal dose versus 1 mg 
psilocybin will be performed at the 0.05 testing level. A sensitivity analysis will be 
performed on the primary mixed model repeated measures model adding treatment 
by study site or country interaction into the model. If it is significant (at the 10% 
level), then further investigations of sites will be performed. 
The 4 secondary efficacy endpoints that are dichotomous variables (proportion of 
participants who are responders, remitters, and sustained responders) will be analysed 
using the Cochran-Mantel-Haenszel chi-square test, stratified by country, to compare 
the psilocybin optimal therapeutic dose versus 1 mg psilocybin. A stepdown 
procedure to correct for multiplicity will be employed.  
Time-to-event measures will be evaluated using Kaplan-Meier methods. 
Response and remission rates will be summarised at each visit.  
Exploratory Analyses 
Change from Baseline in continuous efficacy measures, including the QIDS-SR-16 
scale and GAD-7 total scores at each point, will be analysed based on last 
observation carried forward data using an analysis of covariance model, with 
treatment and study site as factors, and the respective baseline score as the covariate. 
The exploratory analyses for quality of life and wellbeing, functioning and associated 
disability, cognitive function, and anxiety are not hierarchical; there will be no 
correction for multiplicity in these analyses.  
Scores for all efficacy endpoints, including dimension scores of the EQ-5D-3L and 
the EQ visual analogue scale, will be summarised over time using descriptive 
statistics for all visits during the observation period.  
The covariate selection process will be addressed in the Statistical Analysis Plan to 
be approved before any analyses are undertaken.  
Continuous behavior sampling will be tested with the Mindstrong application 
technology in a subgroup of smart phone users consented to this part of the study. 
Participants who do not consent to the app installation, or don’t have a smart phone, 
will not be excluded from the study. Following the installation of the Mindstrong app 
on the participant’s smart phone, the app will begin to collect data from the smart 
phone and periodically send these data back to the secure database. The participant 
does not need to do anything at this stage, except use their phone as they normally 
do. As explained above personal data from mobile phone usuage will be analysed in a 
sub-group of consenting participants.  


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The correlation between sensor data, keyboard behavior, or voice and speech metrics 
will be assessed for correlation with standard clinical assessments and the ability of 
app features to identify impending relapse before clinical change is apparent with 
traditional ratings. The goal of these exploratory assessments is to identify mobile use 
patterns (app features) predictive of clinically significant mood changes that will 
have an impact on care and treatment outcomes.  
Safety Analysis 
Safety analyses will be performed using data from the Safety Population. Safety will 
be evaluated based on AEs, vital signs, clinical laboratory assessments, and ECG 
findings. A Data and Safety Monitoring Board (DSMB) will periodically review and 
evaluate the accumulated study data for participant safety, study conduct and 
progress and when appropriate, efficacy. 


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TABLE OF CONTENTS 
CLINICAL PROTOCOL APPROVAL FORM .............................................................2 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT ...................................3 
SUMMARY OF CHANGES .............................................................................................4 
STUDY SUMMARY ..........................................................................................................5 
TABLE OF CONTENTS ................................................................................................14 
LIST OF TABLES ...........................................................................................................17 
LIST OF ABBREVIATIONS .........................................................................................18 
INTRODUCTION AND RATIONALE .........................................................................21 
1.1 
Background ..........................................................................................................21 
1.2 
Study Rationale ....................................................................................................21 
1.2.1 
Pharmacokinetics ...........................................................................................22 
1.2.2 
Preclinical Pharmacology ..............................................................................22 
1.2.3 
Clinical Adverse Event Profile ......................................................................23 
1.2.4 
Potential Risk to Foetal Development ..........................................................23 
1.2.5 
Dosing Regimen ..............................................................................................23 
2 
STUDY OBJECTIVES ............................................................................................24 
2.1 
Primary .................................................................................................................24 
2.2 
Secondary..............................................................................................................24 
2.3 
Exploratory ...........................................................................................................24 
3 
STUDY ENDPOINTS ..............................................................................................27 
3.1 
Primary .................................................................................................................27 
3.2 
Secondary..............................................................................................................27 
3.3 
Exploratory ...........................................................................................................27 
3.4 
Efficacy and Outcome Measures ........................................................................28 
4 
STUDY PLAN ...........................................................................................................29 
4.1 
Study Design .........................................................................................................29 
4.2 
Study Schematic ...................................................................................................32 
4.3 
Schedule of Assessments ......................................................................................33 
5 
POPULATION ..........................................................................................................37 
5.1 
Number of Participants .......................................................................................37 
5.2 
Inclusion Criteria .................................................................................................37 
5.3 
Exclusion Criteria ................................................................................................37 
5.4 
Participant Screening ..........................................................................................39 
5.5 
Deviation from Inclusion/Exclusion Criteria ....................................................39 
6 
STUDY CONDUCT ..................................................................................................40 
6.1 
General Instructions ............................................................................................40 
6.2 
Study Procedures by Time Point ........................................................................40 
6.2.1 
Screening Period ............................................................................................40 
6.2.2 
Baseline Visit – Visit 2 – Day -1 ....................................................................41 
6.2.3 
Visit 3 – Day 0 – Psilocybin Session ..............................................................43 
6.2.4 
Visit 4 – Day 1 Postdosing .............................................................................43 
6.2.5 
Visit 5 – 1 Week Postdosing ..........................................................................44 


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6.2.6 
Visit 6 – 2 Weeks Postdosing .........................................................................44 
6.2.7 
Visit 7 – 3 Weeks Postdosing .........................................................................45 
6.2.8 
Visit 8 – 6 Weeks Postdosing .........................................................................45 
6.2.9 
Visit 9 – 9 Weeks Postdosing .........................................................................46 
6.2.10 
Visit 10 – 12 Weeks Postdosing – End of Study ..........................................46 
6.3 
Premature Discontinuation .................................................................................47 
7 
DESCRIPTION OF STUDY PROCEDURES .......................................................48 
7.1 
Efficacy Assessments ...........................................................................................48 
7.1.1 
Montgomery-Asberg Depression Rating Scale ...........................................48 
7.1.2 
Quick Inventory of Depressive Symptomatology........................................48 
7.1.3 
Sheehan Disability Scale ................................................................................48 
7.1.4 
Generalised Anxiety Disorder scale .............................................................48 
7.1.5 
Digit Symbol Substitution Test .....................................................................49 
7.1.6 
EuroQoL-5-dimension 3-level Scale .............................................................49 
7.1.7 
Work and Social Adjustment Scale ..............................................................49 
7.2 
Safety Assessments ...............................................................................................50 
7.2.1 
Columbia-Suicide Severity Rating Scale .....................................................50 
7.2.2 
Vital Signs .......................................................................................................50 
7.2.3 
Electrocardiogram .........................................................................................50 
7.2.4 
Clinical Laboratory Tests..............................................................................51 
7.2.5 
Adverse Events ...............................................................................................51 
7.3 
Other Assessment Instruments ...........................................................................52 
7.3.1 
Hamilton Depression Rating Scale – 17-item ..............................................52 
7.3.2 
Mini International Neuropsychiatric Interview ..........................................52 
7.3.3 
Massachusetts General Hospital-Antidepressant Treatment 
History Questionnaire ...................................................................................52 
7.3.4 
McLean Screening Instrument for Borderline Personality 
Disorder ..........................................................................................................52 
7.3.5 
Adult Self-Report Scale .................................................................................53 
7.3.6 
Scale to Assess Therapeutic Relationships – Patient and Clinician 
Version ............................................................................................................53 
7.3.7 
Five Dimension Altered States of Consciousness Questionnaire ...............53 
7.3.8 
The Positive and Negative Affect Schedule .................................................53 
7.3.9 
Emotional Breakthrough Inventory .............................................................54 
7.3.10 
Mindstrong application .................................................................................54 
7.4 
Protocol Deviations ..............................................................................................55 
8 
INVESTIGATIONAL PRODUCT MANAGEMENT ..........................................56 
8.1 
Description ............................................................................................................56 
8.1.1 
Formulation ....................................................................................................56 
8.1.2 
Storage ............................................................................................................56 
8.2 
Packaging and Blinding .......................................................................................56 
8.3 
Dose and Administration .....................................................................................57 
8.4 
Accountability ......................................................................................................58 
8.5 
Concomitant Therapy ..........................................................................................58 
8.5.1 
Permissible Medications ................................................................................58 


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8.5.2 
Definition of Women of Childbearing Potential and/or Acceptable 
Contraceptive Methods .................................................................................59 
8.5.3 
Prohibited Medications .................................................................................60 
8.5.4 
Rescue Medication .........................................................................................60 
8.6 
Compliance ...........................................................................................................61 
9 
ADVERSE EVENTS ................................................................................................62 
9.1 
Documenting Adverse Events .............................................................................62 
9.2 
Assessment of Intensity........................................................................................63 
9.3 
Assessment of Causality ......................................................................................64 
9.4 
Action Taken Regarding Investigational Product ............................................64 
9.5 
Other Action Taken for Event ............................................................................64 
9.6 
Adverse Event Outcome ......................................................................................65 
9.7 
Clinical Laboratory Changes ..............................................................................65 
9.8 
Overdose ...............................................................................................................65 
9.9 
Adverse Events of Special Interest .....................................................................66 
9.10 
Adverse Event Follow-up ....................................................................................67 
10 SERIOUS ADVERSE EVENTS ..............................................................................68 
10.1 
Definition of Serious Adverse Event ..................................................................68 
10.2 
Reporting Serious Adverse Events .....................................................................69 
11 STATISTICS .............................................................................................................72 
11.1 
General Procedures .............................................................................................72 
11.2 
Sample Size ...........................................................................................................72 
11.3 
Statistical Methods ...............................................................................................72 
11.3.1 
Efficacy and Outcome Measures ..................................................................73 
11.3.2 
Analysis of Efficacy ........................................................................................73 
11.3.3 
Multiplicity .....................................................................................................74 
11.3.4 
Analysis of Safety ...........................................................................................75 
11.3.5 
Demographic and Baseline Characteristics .................................................76 
11.4 
Interim Analysis ...................................................................................................76 
12 ETHICS AND RESPONSIBILITIES .....................................................................77 
12.1 
Good Clinical Practice .........................................................................................77 
12.2 
Data and Safety Monitoring Board ....................................................................77 
12.3 
Steering Committee .............................................................................................77 
12.4 
Institutional Review Board/Independent Ethics Committee ...........................77 
12.5 
Informed Consent ................................................................................................77 
12.6 
Exposure in Utero During Clinical Studies .......................................................77 
12.7 
Records Management ..........................................................................................78 
12.8 
Source Documentation.........................................................................................78 
12.9 
Study Files and Record Retention ......................................................................78 
13 AUDITING AND MONITORING ..........................................................................80 
14 AMENDMENTS .......................................................................................................81 
15 STUDY REPORT AND PUBLICATIONS ............................................................82 
16 STUDY DISCONTINUATION ...............................................................................83 
17 CONFIDENTIALITY ..............................................................................................84 
18 REFERENCES .........................................................................................................85 


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19 APPENDICES ...........................................................................................................89 
19.1 
APPENDIX I – Names of Study Personnel........................................................89 
19.2 
APPENDIX II – Declaration of Helsinki ...........................................................90 
19.3 
APPENDIX III – MGH-ATRQ – Additional Detail Regarding the 
Assessment of Previous Antidepressant Treatment..........................................95 
 
LIST OF TABLES 
Table 8.1 
Details of Investigational Product ..........................................................56 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
5D-ASC 
Five Dimension Altered States of Conscniousness questionnaire 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ASRS 
Adult Self-Report Scale 
AST 
aspartate aminotransferase 
bpm 
beats per minute 
CBT 
cognitive behavioural therapy 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
COMPASS 
COMPASS Pathways, Ltd 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
DSMB 
Data and Safety Monitoring Board 
EBI 
Emotional Breakthrough Inventory 
EC50 
half-maximal effective concentration 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EIU 
Exposure In Utero 
EOS 
End of Study 
EQ 
Euro QoL 
EQ-5D-3L 
Euro QoL-5 dimension-3 level 
EQ VAS 
Euro QoL visual analog scale 
ET 
early termination 
FAS 
full analysis set 
GAD-7 
Generalised Anxiety Disorder Scale 
GCP 
Good Clinical Practices 
h 
hours 
HAM-D-17 
Hamilton Depression Rating Scale 
HDPE 
high density polyethylene 
IB 
Investigator’s Brochure 


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Abbreviation 
Definition 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IP 
investigational product 
IRB 
Institutional Review Board 
IV 
intravenous 
IWRS 
Interactive Web-based Response System 
kg 
kilogram 
L 
litres 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MDD 
major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MGH-ATRQ 
Massachusetts General Hospital Antidepressant Treatment History Questionnaire 
min 
minute 
MINI 
Mini International Neuropsychiatric Interview 
mL 
millilitre 
mmHg 
millimetres of mercury 
MSI-BPD 
McLean Screening Instrument for Borderline Personality Disorder 
ng 
nanogram 
PANAS 
Positive and Negative Affect Schedule 
PP 
per protocol (analysis population) 
PRN 
pro re nata, as needed 
PS 
Prescreen 
PT 
Preferred Term 
P-TRD 
psilocybin for treatment-resistant depression 
QIDS 
Quick Inventory of Depressive Symptoms 
QIDS-SR-16 
Quick Inventory of Depressive Symptomatology – Self-Rated 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SDS 
Sheehan Disability Scale 
STAR-C 
Scale to Assess Therapeutic Relationship – Clinician version 


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Abbreviation 
Definition 
STAR-P 
Scale to Assess Therapeutic Relationship – Patient version 
TRD 
treatment-resistant depression 
UK 
United Kingdom 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analog scale 
Worldwide 
Worldwide Clinical Trials, Inc. 
WSAS 
Work and Social Adjustment Scale 


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INTRODUCTION AND RATIONALE 
The following is a summary of the information found in the current Investigator’s 
Brochure (IB).5  
1.1 
Background 
Psilocybin belongs to a class of drugs referred to as psychedelics (‘mind-manifesting’). 
Specifically, psilocybin is considered a 5-hydroxytryptaminergic (serotonergic) 
psychedelic, along with other tryptamines such as dimethyltryptamine (DMT), ergolines 
such as lysergic acid diethylamide (LSD), and phenethylamines such as mescaline. 
Psilocybin was first isolated from psilocybe mushrooms by Hofmann in 1957, and later 
synthesised by him in 1958.24 Psilocybin has been used in psychiatric research and in 
psychodynamic orientated psychotherapy from the early to mid-1960s up until it became 
a Schedule 1 substance in the United States (US) in 1970, and until the 1980s in 
Germany.24,25 Research on the effects of psilocybin resumed in the mid-1990s, and it is 
currently the preferred compound for use in clinical research of 5-hydroxytryptaminergic 
psychedelics,3,10,15 because it has a shorter duration of action and suffers from less 
notoriety and stigma than other similar drugs.  
1.2 
Study Rationale 
Carhart-Harris conducted an open-label feasibility study in 12 patients (6 men and 
6 women) with moderate-to-severe, unipolar, treatment-resistant major depression 
(ISRCTN 14426797).2 Each patient received 2 oral doses of psilocybin (10 mg and 
25 mg, 7 days apart) in a supportive setting. There was no control group. Psychological 
support was provided before, during, and after each session. The primary outcome 
measure was patient-reported intensity of psilocybin’s effects. Patients were monitored 
for adverse events (AEs) during the dosing sessions and at subsequent clinic and remote 
follow-ups. Depressive symptoms were assessed using the 16-item Quick Inventory of 
Depressive Symptoms (QIDS); QIDS scores were obtained from week 1 to the 3 months 
following dosing. Psilocybin's acute psychedelic effects were detectable 30 to 60 minutes 
(min) after dosing, peaked 2 to 3 hours (h) after dosing, and subsided at least 6 h after 
dosing. Mean self-rated intensity (on a scale of 0-1) was 0.51 (standard deviation [SD] 
0.36) for the low-dose session and 0.75 (SD 0.27) for the high-dose session. Compared to 
Baseline, depressive symptoms were markedly reduced 1 week (means QIDS 
difference -11.8, 95% confidence interval (CI) -9.15 to -14.35, p=0.002, Hedges’ g=3.1) 
and 3 months (-9.2, 95% CI -5.69 to -12.71, p=0.003, Hedges’ g=2) after high-dose 
treatment. Marked and sustained improvements in anxiety and anhedonia were also 
noted. Psilocybin was well tolerated and no serious or unexpected AEs were reported. 
The AEs noted were transient anxiety (12/12 patients, 100%) during psilocybin onset, 
transient confusion or thought disorder (9/12 patients, 75%), mild transient nausea 
(4/12 patients, 33%), and transient headache (4/12 patients, 33%).  
This study provides preliminary support for the safety and efficacy of psilocybin for 
treatment-resistant depression and motivates further trials, with more rigorous designs, to 


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better examine the therapeutic potential of this approach. In this study, the aim is to 
assess effectiveness of 2 doses of psilocybin (10 mg and 25 mg) in treatment-resistant 
depression (TRD) as compared to 1 mg psilocybin. 
1.2.1 
Pharmacokinetics 
Psilocybin is detectable in plasma 20 to 40 min after oral administration of 0.224 mg/kg 
(10-20 mg total dose).13 Orally ingested psilocybin is metabolised (dephosphorylated) in 
the liver, and primarily transformed into the active hydroxy metabolite, psilocin. 
Psilocybin is detectable in plasma 30 min after administration,13,16,20,24 and psilocin is 
detectable in plasma 15 to 50 min after oral administration of 0.2 mg/kg psilocybin. 
Therefore, psilocybin is essentially a prodrug and psilocin represents the 
pharmacologically active agent in systemic circulation. The elimination half-life of 
psilocybin is 50 min.20 Psilocin’s half-life ranges between 2 and 3 h, and is detectable 6 h 
after oral administration.13,20 Hasler et al.13 and Lindenblatt et al.20 reported similar but 
not identical findings, with peak levels of psilocin appearing between 80 to 105 min and 
psilocin half-life ranging between 2.25 h for 0.2 mg/kg and 2.7 h for 0.22 mg/kg. The 
majority, 80%, of psilocin in plasma was found to be in a conjugated form. Both psilocin 
(at 90-97%) and psilocybin (3-10%) are detectable in human urine, unmodified (only 
3-10%) and particularly conjugated with glucuronic acid.14 The majority of psilocin 
recovered in urine is excreted within 3 h after oral administration and is completely 
eliminated from the body within 24 h.14 
1.2.2 
Preclinical Pharmacology 
Psilocybin and its active metabolite psilocin directly affect a number of 5-HT receptor 
subtypes without directly affecting other neurotransmitter systems.  
Human psilocybin research has confirmed the importance of 5-HT2A stimulation for the 
psychedelic effects of psilocybin and psilocin as the effects can be blocked by a 5-HT2A 
receptor antagonist.37 Reviews of the pharmacology of psilocybin is provided by Passie, 
and more current knowledge and perspective by Tyls et al.24,36 
When assessed for potential effects on the human-ether-à-go-go related gene channel 
psilocybin was shown to be without significant effects when tested up to concentrations 
of 1 mM. 
Although the literature on the effect of psilocin at the 5-HT2B is somewhat contradictory, 
the most recent publication by Rickli et al. indicates that the half-maximal effective 
concentration (EC50) for activation of the 5-HT2B receptor is greater than 20 μM.27 That 
concentration would generally be considered to be pharmacologically inactive in vivo 
because plasma concentrations would never reach 20 μM or greater after a single 
administration of psilocin. Brown et al. indicate that the maximal plasma concentration 
achieved after a single dose of 0.45 mg/kg in normal humans would not reach 200 nM 
(0.2 μM).1 In any event, all studies suggest that chronic activation of the 5-HT2B is 
necessary in order to invoke cardiac valvulopathy, and with a single administration there 


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should be no concern for that effect. With the EC50 reported by Rickli et al, even multiple 
administrations of psilocin would not be expected to be harmful. The valvulopathy 
induced by Fen-phen, or ergoline type anti-Parkinson agents, involved daily 
administration of the drugs over a significant period of time. Thus, there is no expectation 
that single use of psilocybin will be problematic. 
1.2.3 
Clinical Adverse Event Profile 
The use of psilocybin in psychotherapy have been reported since the 1960’s, but these 
studies suffer from a lack of experimental control and standardised assessments. Owing 
to the absence of adequate control groups, and use of follow-up measurements with 
vague criteria for therapeutic outcomes, the studies do not clearly distinguish between the 
drug or the therapeutic engagement itself that produced the reported beneficial effect.  
The safety of psilocybin should be considered in terms of benefit and risk. Within the 
context of psilocybin administration in a controlled setting, a participant may report 
visual or auditory disturbances, feelings of unreality, altered sense of time, and other 
changes in mood or affect amongst other neuropsychiatric observations which have been 
previously described (see Table 4.1 of the current Psilocybin IB).5 These effects are both 
expected, and may be a necessary component of therapeutic response. Investigators must 
follow regulatory guidance under 21 CFR 312.32(a) for AE reporting which addresses 
untoward medical occurrences associated with the use of a drug in humans, whether or 
not considered drug related. An AE can be any unfavourable and unintended sign (eg, an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of 
a drug, without any judgment about causality.  
1.2.4 
Potential Risk to Foetal Development 
Reproductive toxicology studies have not been performed to establish risk to the fetus; 
however, the results of Ames test, the human lymphocyte micronucleus assay and the in 
vivo rat micronucleus study clearly indicate no potential for genotoxicity with psilocybin. 
It is recommended to prevent or eliminate such risk, if any, women should not be 
pregnant or lactating and should be using an effective method of birth control when using 
psilocybin.  
1.2.5 
Dosing Regimen 
Carhart-Harris successfully evaluated 2 oral doses of psilocybin (10 mg and 25 mg) 
administered 7 days apart to patients with unipolar TRD; minimal AEs were reported in 
this study.2 Work by the Griffiths group showed that under supportive conditions, 
psilocybin at doses of 20 to 30 mg/70 kg can dose-dependently occasion mystical-type 
experiences.11 
Therefore, this study will evaluate 3 single psilocybin doses (1 mg, 10 mg, or 25 mg 
psilocybin) under supportive conditions in this study.  


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2 STUDY OBJECTIVES 
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 optimal therapeutic dose of psilocybin (10 mg or 
25 mg) versus the 1 mg psilocybin via the following objectives. 
2.1 
Primary 
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.  
2.2 
Secondary 
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 AEs, changes in vital signs, and suicidal ideation/behaviour (measured using the 
Columbia-Suicide Severity Rating Scale [C-SSRS]) score at all visits. 
2.3 
Exploratory  
The exploratory objectives are: 
o 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: 


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▪ 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. This assessment is not mandatory. 
▪ Quality of life in caregiver EQ-5D-3L score change from Baseline to Week 3. 
This will also be assessed at Week 12. 
▪ 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. 
▪ 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. 
▪ 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. 
▪ 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 Screening, 
Day 1, and Weeks 1, 2, 6, 9, and 12. 
▪ Psychosocial functioning and predictor of response durability 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.  
▪ 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 


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• 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. 
▪ Positive and Negative Affect Schedule (PANAS), Five Dimension Altered 
States of Consciousness Questionnaire (5D-ASC), 2a receptor polymorphism 
test and 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. 


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3 STUDY ENDPOINTS  
3.1 
Primary 
The primary endpoint is the change in MADRS total score from Baseline (Day -1) to 
3 weeks post psilocybin.  
3.2 
Secondary 
The secondary endpoints are: 
o The proportion of participants with a response (defined as a ≥ 50% improvement 
in MADRS total score from Baseline) at Week 3 after the psilocybin session. 
o The proportion of participants with remission (defined as a MADRS total score 
≤ 10) at Week 3 post psilocybin.  
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. 
o Time to event measures: restart antidepressant medication for any reason, restart 
medication for continuing depressive symptoms, and relapse from a previously 
recovered state (clinical judgement, supported by the QIDS-SR-16). Participants 
who withdraw from the study will be censored from the time to event analysis. 
3.3 
Exploratory 
The exploratory endpoints are: 
o Change from Baseline in the following: 
▪ Participant EQ-5D-3L at Week 3 
▪ Caregiver EQ-5D-3L at Week 3 (this assessment is not mandatory) 
▪ SDS at Week 3 
▪ DSST at Week 3 
▪ GAD-7 at Week 3 
▪ QIDS-SR-16 at Week 3 
▪ WSAS at Week 3 


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▪ Measures derived from smart phone usage via the Mindstrong app 
3.4 
Efficacy and Outcome Measures 
Measures of interest include: 
o MADRS 
o SDS 
o QIDS-SR-16  
o GAD-7 
o DSST 
o EQ-5D-3L (participant and caregiver [latter is not mandatory]) 
o WSAS 


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4 STUDY PLAN 
4.1 
Study Design 
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 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 (IWRS). 
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 (MSI-BPD). 
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 (ASRS). 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. 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. 
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 


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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. 
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 (friend or 
family member) 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 participant will meet with a therapist for a minimum of 3 visits during screening. 
These are called 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. 
The day before the 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 
eligibility. Participants cannot be progressed to V3 until this approval is received. 
The psilocybin administration session (V3, Day 0) will last approximately 6 h and will be 
supported by a trained therapist. Psilocybin sessions 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.  


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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 Section 8.5.4. 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. 
The study schematic is presented in Section 4.2 and the schedule of assessments is 
presented in Section 4.3.


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4.2 
Study Schematic 
 
 
Abbreviations: D = day; EoS = End of Study; V = Visit 
 
Randomisation 
1:1:1
D-1   D0    D1
Week 3
Week 12
3-6 weeks
Screening (V1)
D-1: Baseline (V2)
D0: Psilocybin Session (V3)
D1 (V4)
Week 1 (V5)
Week 2 (V6)
Week 3 (V7)
Additional 
Weekly 
Visits
(V1b, V1c, 
V1d, V1e, V1f)
Week 6 (V8) 
Week 9 (V9) 
Week 12 (EOS, V10)
25 mg psilocybin
72 subjects
10 mg psilocybin
72 subjects
1 mg psilocybin
72 subjects
Variable
Screening (V1a)


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4.3 
Schedule of Assessments 
 
 
3-6 weeks 
prior to 
Baseline 
 
 
Time Post Psilocybin Session 
 
Screen Visit2 
Screening 
Period 
Baseline 
(Day -1) 
Psilocybin 
Session  
(Day 0) 
Day 1 
Week 1 
Day 7 
Week 2 
Day 14 
Week 3 
Day 21 
Week 6 
Day 42 
Week 9 
Day 63 
Week 12 
Day 84 
(ET) 
Visit 
1 
1a, 1b, 
etc 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Location of Visit1 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Remote 
Remote 
Clinic 
Allowable Window 
 
Weekly 
 
≤ 7 days 
none 
±1 day 
±1 day 
± 1 day 
± 3 days 
± 3 days 
± 7 days 
 
Clinic Assessments and Procedures 
Informed Consent 
✓ 
 
 
 
 
 
 
 
 
 
 
Medical History 
✓ 
 
✓ 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
Criteria 
✓ 
 
✓ 
 
 
 
 
 
 
 
 
MINI 
✓ 
 
 
 
 
 
 
 
 
 
 
HAM-D-17 
✓ 
 
✓ 
 
 
 
 
 
 
 
 
MGH-ATRQ 
✓ 
 
 
 
 
 
 
 
 
 
 
STAR-C 
 
 
✓ 
 
 
 
 
 
 
 
 
C-SSRS3 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Vital signs 
✓ 
 
✓ 
✓ 
✓ 
 
 
 
 
 
 
Weight 
✓ 
 
 
 
 
 
 
 
 
 
 
Height 
✓ 
 
 
 
 
 
 
 
 
 
 
ECG 
✓ 
 
 
 
✓ 
 
 
 
 
 
 
Clinical laboratory 
tests and biomarker4 
✓ 
 
 
 
✓ 
 
 
✓ 
 
 
 
Urinalysis4 
✓ 
 
 
 
✓ 
 
 
 
 
 
 


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3-6 weeks 
prior to 
Baseline 
 
 
Time Post Psilocybin Session 
 
Screen Visit2 
Screening 
Period 
Baseline 
(Day -1) 
Psilocybin 
Session  
(Day 0) 
Day 1 
Week 1 
Day 7 
Week 2 
Day 14 
Week 3 
Day 21 
Week 6 
Day 42 
Week 9 
Day 63 
Week 12 
Day 84 
(ET) 
Visit 
1 
1a, 1b, 
etc 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Location of Visit1 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Remote 
Remote 
Clinic 
Allowable Window 
 
Weekly 
 
≤ 7 days 
none 
±1 day 
±1 day 
± 1 day 
± 3 days 
± 3 days 
± 7 days 
Urine Drug Screen4  
✓ 
 
✓ 
 
 
 
 
 
 
 
 
Urine Pregnancy Test5 
✓ 
 
✓ 
 
 
 
 
 
 
 
 
Documentation of 
Birth Control to be 
used6 
✓ 
 
 
 
 
 
 
 
 
 
 
2a polymorphism 
(optional)  
✓ 
 
 
 
 
 
 
 
 
 
 
Activate/deactivate 
Mindstrong (optional) 
✓ 
 
 
 
 
 
 
 
 
 
✓ 
Provide access to 
psychoeducational 
material (Longboat) 
✓ 
✓9 
 
 
 
 
 
 
 
 
 
Psilocybin dose 
 
 
 
✓10 
 
 
 
 
 
 
 
Prior/Concomitant 
Medications 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
AE/SAE 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Randomisation 
 
 
✓ 
 
 
 
 
 
 
 
 
 
Participant Completed Assessments 
5D-ASC 
 
 
 
✓7 
 
 
 
 
 
 
 
ASRS 
✓ 
 
 
 
 
 
 
 
 
 
 


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3-6 weeks 
prior to 
Baseline 
 
 
Time Post Psilocybin Session 
 
Screen Visit2 
Screening 
Period 
Baseline 
(Day -1) 
Psilocybin 
Session  
(Day 0) 
Day 1 
Week 1 
Day 7 
Week 2 
Day 14 
Week 3 
Day 21 
Week 6 
Day 42 
Week 9 
Day 63 
Week 12 
Day 84 
(ET) 
Visit 
1 
1a, 1b, 
etc 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Location of Visit1 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Remote 
Remote 
Clinic 
Allowable Window 
 
Weekly 
 
≤ 7 days 
none 
±1 day 
±1 day 
± 1 day 
± 3 days 
± 3 days 
± 7 days 
DSST 
 
 
✓ 
 
✓ 
 
 
✓ 
 
 
✓ 
EBI  
 
 
 
 
✓ 
 
 
 
 
 
 
EQ-5D-3L8 
 
 
✓ 
 
 
 
 
✓ 
 
 
✓ 
GAD-7 
 
 
✓ 
 
 
 
 
✓ 
 
 
✓ 
MSI-BPD 
✓ 
 
 
 
 
 
 
 
 
 
 
PANAS 
 
 
✓ 
 
✓ 
 
 
✓ 
 
 
 
QIDS-SR-16 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
SDS 
 
 
✓ 
 
 
 
 
✓ 
 
 
✓ 
STAR-P 
 
 
✓ 
 
 
 
 
 
 
 
 
WSAS 
 
 
✓ 
 
 
 
 
✓ 
 
 
✓ 
 
Remote-rater Assessment 
MADRS 
 
 
✓ 
 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
Abbreviations: 5D-ASC, Five Dimension Altered States of Consciousness Questionnaire; AE, adverse event; ASRS, Adult Self-Report Scale; CRP, C-reactive protein; C-SSRS, Columbia-Suicide 
Severity Rating Scale; DSM-5 Diagnostic and Statiscal Maual of Mental Disorders (5th edtion);DSST, Digit Symbol Substitution Test; EBI, Emotional Breakthrough Inventory; 
ECG, electrocardiogram; EQ-5D, EuroQoL 5-dimension; ET, early termination; GAD-7, Generalised Anxiety Disorder 7; h, hour(s); HAM-D-17, Hamilton Depression Rating Scale; 
MADRS, Montgomery-Asberg Depression Scale; MGH-ATRQ, Massachusetts General Hospital Antidepressant Treatment History Questionnaire; MINI, Mini International Neuropsychiatric 
Interview; MSI-BPD, McLean Screening Instrument for Borderline Personality Disorder; PANAS, Positive and Negative Affect Schedule; QIDS-SR-16, Quick Inventory of Depressive 
Symptomatology-Self-rated; SAE, serious adverse event; SDS, Sheehan Disability Scale; STAR-C, Scale to Assess the Therapeutic Relationship-Clinician; STAR-P, Scale to Assess the Therapeutic 
Relationship-Patient; UK, United Kingdom; VAS, visual analogue scale; WSAS, Work and Social Adjustment Scale 
 
1  On site clinic visits; visits allowed remotely will have the MADRS performed by telpehone and other assessments will be done electronically. 


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2  If additional visits are needed to ensure adequate time for discontinuation of prior antidepressant therapy, visits should occur weekly prior to the psilocybin session (V3). At subsequent screening 
period visits (V1a, V1b, etc), medications taken and any changes in medications since the previous visit and C-SSRS will be obtained, in addition, to other assessments at the study clinician’s 
discretion. Assessments may be performed over several days, but all scales should be completed on the same day.  
3 The “Last 12 Months” version will be administered at Screening and the “Since Last Visit” version will be administered at all other visits.  
4 See Section 7.2.4 for complete list of required tests to be performed.  
5 For women of child-bearing potential only. 
6 Site is to document method of contraception agreed to be used by each participant. 
7 To be administered immediately after the psilocybin session. 
8 The EQ-5D-3L will be administered to both the participant and their caregiver (latter is not mandatory).   
9 Longboat access can be granted at V1 or V1a at the study team’s discretion. 
10 After baseline data is entered into EDC the CAT team will complete a final review to ensure the participant’s continued eligilblilty. Participants cannot complete psilocybin dose at V3 until this 
approval is received.   
11 Screening period visits should not be initiated until initial MM and CAT approval is received. Screening visits are to occur weekly 3-6 weeks prior to Baseline, number of visits is determined by the 
length of the participant’s taper off antidepressant medication. 
 
Instruments (all measures below will be captured electronically): 
5D-ASC – The Five Dimension Altered States of Consciousness Questionnaire measures the acute drug effects. 
ASRS – The Adult Self-Report Scale is a tool to screen for attention deficit hyperactivity disorder. The 6-item screener version will be administered.  
C-SSRS – Columbia-Suicide Severity Rating Scale assesses treatment-emergent suicidal thoughts. This scale should be administered prior to dosing, if possible. 
DSST – The Digit Symbol Substitution Test is a measure of cognition. It consists of a number of digit-symbol pairs, and requires individuals to note the corresponding symbol for a given digit under 
time-limited conditions. This test should be administered at approximately the same time of day each time to minimise the impact of diurnal variation on the results  
EBI – The Emotional Breakthrough Inventory is an 8-item brief measure intended to index the degree to which an individual experiences his/her emotion during a psilocybin session. It is a VAS style 
scale, typically with units from 0 to 100. It is typically rated within 24 h of a psychedelic experience and ideally within 5 h of the 'end' of the psychedelic experience or once acute drug effects have 
significantly subsided. 
EQ-5D-3L – The 3-level EQ-5D version (EQ‑5D‑3L) was introduced by the EuroQoL Group in 1990. The EQ-5D-3L essentially consists of 2 pages: the EQ-5D-3L descriptive system and the EQ 
visual analogue scale (EQ VAS). 
HAM-D-17 – The 17-item Hamilton Depression Rating scale measure the degree of symptom severity in depressed patients.  
GAD-7 – The Generalised Anxiety Disorder scale is a 7-item participant completed scale to assess anxiety in a participant.  
MADRS – the Montgomery-Asberg Depression Scale is a clinician rated outcome measure to assess a participant’s level of depression.  
MSI-BPD – The McLean Screening Instrument for Borderline Personality Disorder is a self-reporting screening tool to determine the presence of DSM-5 borderline personality disorder. 
PANAS - Positive and Negative Affect Schedule measures the acute emotional drug effects.  
QIDS-SR-16 – Quick Inventory of Depressive Symptomatology scale is a participant-rated scale to assess their depression.  
SDS – The Sheehan Disability Scale is a patient-reported outcome measure used to assess functional impairment and associated disability. 
STAR-C and STAR-P –Scale to Assess the Therapeutic Relationship completed by the clinician (STAR-C) and the patient (STAR-P) to assess the therapeutic relationship in community psychiatry with 
good psychometric properties sutiable for both research and routine care.  
WSAS – Work and Social Adjustment Scale is a self-report scale used to assess psychosocial functioning and to predict durability of response to antidepressant treatment. 
 
 
 


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5 POPULATION 
5.1 
Number of Participants 
A total of 216 participants are planned to be enrolled in the study. 
5.2 
Inclusion Criteria 
Participants meeting all the following inclusion criteria at Screening (V1) should be 
considered for admission into the study. 
1. Signed ICF. 
2. 18 years of age or older at Screening (V1). 
3. At least moderate MDD (single or recurrent episode as informed by DSM-5; if single 
episode, duration of ≥ 3 months and ≤ 2 years) based on medical records, clinical 
assessment and documented completion of the version 7.0.2 MINI. 
4. HAM-D-17 (17-item) score ≥ 18 at Screening (V1) and at Baseline (V2).  
5. Failure to respond to an adequate dose and duration of 2, 3, or 4 pharmacological 
treatments for the current episode as determined through the MGH-ATRQ and using 
the supplementary advice on additional antidepressants not included in MGH-ATRQ 
(Appendix III). Augmentation with an add on treatment counts as a second treatment, 
provided it is approved for the adjunctive treatment of MDD in that country. 
6. McLean Screening Instrument for Borderline Personality Disorder < 7 at Screening 
(V1). 
7. Have successfully discontinued all antidepressant medications at least 2 weeks prior 
to Baseline (V2) (see Section 8.5.3). 
8. Ability to complete all protocol required assessment tools without any assistance or 
alteration to the copyrighted assessments, and to comply with all study visits.  
5.3 
Exclusion Criteria 
Participants meeting any of the following exclusion criteria at Screening (V1) will not be 
enrolled in the study. 
Psychiatric Exclusion Criteria: 
1. Current or past history of schizophrenia, psychotic disorder (unless substance induced 
or due to a medical condition), bipolar disorder, delusional disorder, paranoid 
personality disorder, schizoaffective disorder, or borderline personality disorder, or 


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any serious psychiatric comorbidity as assessed by medical history and structured 
clinical interview (version 7.0.2 MINI). 
2. Prior electroconvulsive therapy and/or ketamine for current episode. 
3. Current cognitive behavioural therapy (CBT) that will not remain stable for the 
duration of the study. CBT cannot be initiated within 21 days of Baseline.  
4. Current (within the last year) alcohol or substance abuse as informed by DSM-5 at 
Screening (V1). 
5. Significant suicide risk as defined by (1) suicidal ideation as endorsed on items 4 or 5 
on the C-SSRS within the past year, at Screening or at Baseline, or; (2) suicidal 
behaviors within the past year, or; (3) clinical assessment of significant suicidal risk 
during subject interview.  
6. Depression secondary to other medical conditions.  
7. Other personal circumstances and behaviour judged to be incompatible with 
establishment of rapport or safe exposure to psilocybin, including exposure to 
psilocybin within the past year and use of psychedelics, such as ayahuasca, during the 
current depressive episode.  
General Medical Exclusion Criteria:  
8. Women who are pregnant, nursing, or planning a pregnancy. Participants who are 
sexually active must agree to use a highly effective contraceptive method (as listed in 
Section 8.5.2) throughout their participation in the study. Women of child bearing 
potential must have a negative urine pregnancy test at Screening (V1) and Baseline 
(V2). 
9. Cardiovascular conditions: recent stroke (< 1 year from signing of ICF), recent 
myocardial infarction (< 1 year from signing of ICF), hypertension (blood pressure 
> 140/90 mmHg) or clinically significant arrhythmia within 1 year of signing the ICF. 
10. Uncontrolled insulin-dependent diabetes. 
11. Seizure disorder.  
12. Positive urine drug screen for illicit drugs or drugs of abuse at V1 and/or V2 
(cannabis for medicinal purposes or recreational use is permitted). Any positive urine 
drug test will be reviewed with participants to determine the pattern of use and 
eligibility will be determined at the investigator’s discretion in conjunction with the 
medical monitor.  
13. Current enrolment in any investigational drug or device study or participation in such 
within 30 days of Screening (V1). 


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14. Current enrolment in an interventional study for depression or participation in such 
within 30 days of Screening (V1).  
15. Abnormal and clinically significant results on the physical examination, vital signs, 
ECG, or laboratory tests at Screening (V1).  
16. Any other clinically significant cardiovascular, pulmonary, gastrointestinal, hepatic, 
renal or any other major concurrent illness that, in the opinion of the investigator, 
may interfere with the interpretation of the study results or constitute a health risk for 
the participant if he/she takes part in the study.  
5.4 
Participant Screening 
Participants will be outpatients and will be recruited from general practitioners and 
specialised psychiatric services. Those participants considered eligible for the study will 
be further assessed to confirm eligibility after the participant has signed an ICF. All 
participants will then be seen weekly for at least 3 weeks prior to the Psilocybin Session 
(V3) to ensure the safe discontinuation of current antidepressant therapy required by the 
protocol. Rescreening of participants considered not eligible for the study will be 
allowed. 
5.5 
Deviation from Inclusion/Exclusion Criteria 
No deviations will be permitted from the Inclusion or Exclusion Criteria. The investigator 
may call the Medical Monitor to discuss the eligibility of any given participant.  
 


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6 STUDY CONDUCT 
The procedures to be performed throughout the study are outlined in the Schedule of 
Assessments (Section 4.3). A detailed description of each assessment may be found in 
Section 6.2.  
6.1 
General Instructions 
Participants will be outpatients and will be recruited from general practitioners and 
specialised psychiatric services. Those participants considered eligible for the study will 
be further assessed to confirm eligibility after the participant has signed an ICF.  
6.2 
Study Procedures by Time Point 
6.2.1 
Screening Period 
The participant will be seen initially to evaluate suitability for the study. All participants 
will be seen at the clinic weekly for a minimum of 3 weeks prior to Baseline (V2) to 
ensure safe discontinuation of current antidepressant therapy required by the protocol, 
and to conduct psychoeducation. 
At the initial Screening visit (V1), the following assessments will be performed and 
recorded. These assessments may be performed over several days, but all scales should 
be completed on the same day. All clinician or participant-rated assessments throughout 
the study will be captured electronically. 
o ICF 
o Medical history 
o Prior and current medications; the participant will be tapered from prohibited 
medications (see Section 8.5.3), if any, under the supervision of the study 
clinician 
o Review of inclusion/exclusion criteria (Section 5) 
o MINI version 7.0.2 
o HAM-D-17 
o MGH-ATRQ 
o C-SSRS (Last 12 Months) 
o MSI-BPD 
o ASRS 


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o QIDS-SR-16 
o Vital signs (ie, sitting blood pressure, pulse, body temperature, and respiratory 
rate) 
o Weight 
o Height 
o 12-lead ECG 
o Blood and urine samples for: 
▪ Clinical laboratory tests  
▪ 2a polymorphism (optional) 
▪ Biomarker (C-reactive protein [CRP]) 
▪ Urinalysis 
▪ Urine drug screen 
▪ Urine pregnancy test for all women of childbearing potential 
o Document contraceptive method to be used by the participant 
o If the participant opts to participate in the Mindstrong app, the app will be loaded 
on the participant’s mobile phone and activated 
o All participants will undergo an in-person preparatory session before receiving 
access to a digital study platform (Longboat) for psychoeducation 
Before the participant progresses further in the screening period (ie, before they attend 
Visit 1a), the PI will receive 2 email notifications, 1 from the medical monitor and 1 from 
the CAT group, to confirm eligibility. Once these notifications are received (and the 
participant is deemed eligible), the participant can proceed to the next visit (V1a). 
Patients cannot begin psychoeducation or tapering off their antidepressant medication 
until they attend the clinic for the screening visit V1a. 
At subsequent screening period visits (V1a, V1b, etc), medications taken and any 
changes in medications since the previous visit, and the C-SSRS will be obtained. 
6.2.2 
Baseline Visit – Visit 2 – Day -1 
The Baseline visit (V2) should occur 3 to 6 weeks after initial Screening (V1). At the 
Baseline visit (V2), the participant’s eligibility will be confirmed by reviewing the 


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Inclusion/Exclusion Criteria (Sections 5.2 and 5.3) and updating the medical history. The 
Baseline visit (V2) should occur the day before the anticipated psilocybin session. The 
following procedures will be performed and recorded at the Baseline visit (V2): 
o Remote-rater MADRS 
o HAM-D-17 
o STAR-C 
o C-SSRS (Since Last Visit) 
o SDS 
o STAR-P 
o GAD-7 
o EQ-5D-3L (administered to both participant and caregiver; the latter is not 
mandatory) 
o PANAS 
o DSST 
o QIDS-SR-16 
o WSAS 
o Vital signs (ie, sitting blood pressure, pulse, body temperature, and respiratory 
rate) 
o Urine samples for: 
▪ Urinalysis 
▪ Urine drug screen 
▪ Urine pregnancy test for all women of childbearing potential 
o Medications taken and any changes in medications since the previous visit 
If the participant continues to meet the eligibility criteria, the trained therapist will review 
the psychoeducational material and the anticipated psilocybin session with the 
participant. If the participant remains eligible, randomise the participant to the 
appropriate investigational product (IP) (ie, 1 mg, 10 mg, or 25 mg psilocybin) using the 
IWRS (Section 8.2) and arrange for the participant to return to the study site for IP 


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administration the next day. After baseline data is entered into EDC, the CAT team will 
complete a final review to ensure the participant’s continued eligibility. Participants 
cannot be progressed to V3 until this approval is received. 
6.2.3 
Visit 3 – Day 0 – Psilocybin Session 
The psilocybin session (V3) should occur the day after Baseline visit (V2). In exceptional 
circumstances the participant may visit the clinic ≤ 7 d following the Baseline visit (V2). 
A preparation session with the therapist is always conducted the day before the 
psilocybin session, even if the psilocybin session is not conducted the day after Baseline 
(V2). If the participant is out of the ≤ 7-day window, all baseline assessments are to be 
repeated, except randomisation. At the psilocybin session (the day of IP administration), 
the following are to be obtained: 
o Vital signs (ie, sitting blood pressure, pulse, body temperature, and respiratory 
rate)  
o Administer IP (Section 8.3). The psilocybin session may be video recorded for 
training and adherence monitoring. A full description of the activities of the 
psilocybin session is found in the Therapist Manual. After the acute effects of the 
psilocybin pass, participants will be accompanied home.  
o 5D-ASC 
o C-SSRS (Since Last Visit) 
o QIDS-SR-16 
o Medications taken and any changes in medications since the previous visit 
o AEs and Serious AEs (SAEs) (Sections 9 and 10)  
6.2.4 
Visit 4 – Day 1 Postdosing 
On the day following IP administration, the participant will return to the study site for a 
safety check and to discuss their experience during IP during the psilocybin 
administration session. The following will be obtained at this visit: 
o Remote-rater MADRS 
o C-SSRS (Since Last Visit) 
o Emotional Breakthrough Inventory (EBI)  
o PANAS 
o DSST 


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o QIDS-SR-16 
o Vital signs (ie, sitting blood pressure, pulse, body temperature, and respiratory 
rate) 
o 12-lead ECG 
o Blood samples for clinical laboratory tests and biomarker 
o Medications taken and any changes in medications since the previous visit 
o AE and SAE (Sections 9 and 10) 
Participants will be reminded to remain off any antidepressant medications until after V7. 
6.2.5 
Visit 5 – 1 Week Postdosing 
The participant will visit the clinic 1 week (7 days ± 1 day) following IP administration; 
the following assessments will be obtained at this visit: 
o Remote-rater MADRS 
o C-SSRS (Since Last Visit) 
o QIDS-SR-16 
o Medications taken and any changes in medications since the previous visit 
o AE and SAE (Sections 9 and 10)  
Participants will be reminded to remain off any antidepressant medications until after V7. 
6.2.6 
Visit 6 – 2 Weeks Postdosing 
The participant will visit the clinic 2 weeks (14 days ± 1 day) following IP 
administration; the following assessments will be obtained at this visit: 
o C-SSRS (Since Last Visit) 
o QIDS-SR-16 
o Medications taken and any changes in medications since the previous visit 
o AE and SAE (Sections 9 and 10) 
Participants will be reminded to remain off any antidepressant medications until after V7. 


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6.2.7 
Visit 7 – 3 Weeks Postdosing 
The participant will visit the clinic 3 weeks (21 days ± 1 day) following IP 
administration; the following assessments will be obtained at this visit: 
o Remote-rater MADRS 
o C-SSRS (Since Last Visit) 
o SDS 
o GAD-7 
o EQ-5D-3L (administered to both participant and caregiver [the latter is not 
mandatory]) 
o PANAS 
o DSST 
o QIDS-SR-16 
o WSAS 
o Blood samples for clinical laboratory tests and biomarker  
o Medications taken and any changes in medications since the previous visit 
o AE and SAE (Sections 9 and 10) 
Participants will be reminded to remain off any antidepressant medications until after V7. 
6.2.8 
Visit 8 – 6 Weeks Postdosing 
The participant will be contacted by telephone by site staff or visit the clinic at the 
investigator’s discretion 6 weeks (42 days ± 3 days) following IP administration. All 
clinician or participant-rated assessments throughout the study will be captured 
electronically: 
o Remote-rater MADRS 
o C-SSRS (Since Last Visit) 
o QIDS-SR-16 
o Medications taken and any changes in medications since the previous visit  
o AE and SAE (Sections 9 and 10)  


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6.2.9 
Visit 9 – 9 Weeks Postdosing 
The participant will be contacted by telephone 9 weeks (63 days ± 3 days) following IP 
administration; the following assessments will be obtained: 
o Remote-rater MADRS 
o C-SSRS (Since Last Visit) 
o QIDS-SR-16 
o Medications taken and any changes in medications since the previous visit  
o AE and SAE (Sections 9 and 10) 
6.2.10 
Visit 10 – 12 Weeks Postdosing – End of Study 
The participant will visit the clinic 12 weeks (84 days ± 7 days) following IP 
administration for the End of Study (EOS) visit; this visit is also to be completed if the 
participant is discontinued from the study early (early termination [ET]). The following 
assessments will be obtained at this visit: 
o Remote-rater MADRS 
o C-SSRS (Since Last Visit) 
o SDS 
o GAD-7 
o EQ-5D-3L (administered to both participant and caregiver [the latter is not 
mandatory]) 
o DSST 
o QIDS-SR-16 
o WSAS 
o Deactivate Mindstrong app, if appropriate 
o Medications taken and any changes in medications since the previous visit  
o AEs and SAEs (Sections 9 and 10) 


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6.3 
Premature Discontinuation 
If the participant’s participation in the study is terminated prematurely for any reason, the 
reason for such ET should be documented and the V10 (EOS) procedures should be 
performed as noted in Section 6.2.10. 
A termination electronic Case Report Form (eCRF) page should be completed for every 
participant who is randomised, whether the participant completes the study or not. The 
reason for any ET should be indicated on this form; as much information should be 
provided as possible. The primary reason for a participant discontinuing early should be 
selected from the following standard categories of ET: 
• Screen Failure: Participant does not qualify to participate in the study. 
• Lack of efficacy 
• Adverse Event: Clinical or laboratory events occurred that, in the medical judgment of 
the investigator for the best interest of the participant, are grounds for discontinuation. 
This includes serious and nonserious AEs regardless of relation to the IP. 
• Death: The participant died. 
• Withdrawal of Consent: The participant desired to withdraw from further 
participation in the study in the absence of an investigator-determined medical need 
to withdraw. If the participant gave a reason for withdrawing, it should be recorded in 
the eCRF. 
• Protocol Violation: The participant’s findings or conduct failed to meet the protocol 
entry criteria or failed to adhere to the protocol requirements (eg, drug 
noncompliance, failure to return for defined number of visits). The violation 
necessitated early discontinued from the study. 
• Lost to Follow-Up: The participant stopped coming for visits and study personnel 
were unable to contact the participant. 
• Non-compliance: The participant was non-compliant with study visits or procedures.  
• Other: The participant was discontinued for a reason other than those listed above, 
such termination of study by COMPASS. 


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7 DESCRIPTION OF STUDY PROCEDURES 
7.1 
Efficacy Assessments 
All measures below will be captured electronically. 
7.1.1 
Montgomery-Asberg Depression Rating Scale 
MADRS evaluations will be performed by an independent remote rater who is blinded to 
the participant’s treatment assignment at Baseline, Day 1, and Weeks 1, 3, 6, 9, and 12 
(V2, V4, V5, V7, V8, V9, and V10, respectively). The MADRS is a clinician-rated scale 
measuring depression severity, consisting of 10 items, each scored from 0 (normal) to 
6 (severe), for a total possible score of 60; higher scores denote greater severity.22 The 
structure of the telephone-based interview will be controlled through the use of The 
Structured Interview Guide for the MADRS (SIGMA),41 which provides structured 
probes to ensure standardisation of administration and comprehensive coverage of 
10 questions. 
7.1.2 
Quick Inventory of Depressive Symptomatology 
The 16-item QIDS-SR-16 a self-rated scale designed to assess the severity of depressive 
symptoms in the nine diagnostic symptom domains of a major depressive episodes, 
exclusive of atypical or melancholic symptoms.27 The QIDS-SR-16 is sensitive to change 
with various treatments, demonstrating its utility in research settings. The total score 
ranges from 0 to 27 with 0 representing no depression and 27 representing severe 
depression. The total score is the sum of the 9 symptom domains. The QIDS-SR-16 will 
be collected at every clinic visit or contact with the participant. 
7.1.3 
Sheehan Disability Scale 
The SDS is a brief, 5-item self-report inventory that assesses functional impairment in 
work/school, social life, and family life. The total score ranges from 0 to 30 with 
0 representing no impairment and 30 representing severe impairment. The last two items 
of the scale (Days Lost and Days Unproductive) do not count toward the total score. Each 
domain is rated on a 10-point visual analogue scale (VAS).30 The SDS will be obtained at 
Baseline, and Weeks 3 and 12 (V2, V7, and V10, respectively).  
7.1.4 
Generalised Anxiety Disorder scale 
The GAD-7 is useful in primary care and mental health settings as a screening tool and 
symptom severity measure for the seven most common anxiety disorders.32 Participants 
choose one of 4 severity scores associated problems related to the common anxiety 
disorders and then indicate the degree to which these problems caused functional and/or 
social difficulties. Scores are determined by calculating the values for each column. A 
total score is obtained by the sum of all total column values. The GAD-7 will be obtained 
using the ePRO device at Baseline, and Weeks 3 and 12 (V2, V7, and V10, respectively).  


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7.1.5 
Digit Symbol Substitution Test 
The DSST is a neuropsychological test sensitive to brain damage, dementia, age and 
depression.36 The DSST consists of digit-symbol pairs followed by a list of digits. The 
participant will select the corresponding symbol as fast as possible. The number of 
correct symbols within 90 seconds will be recorded at Baseline, Day 1, and Weeks 3 and 
12 (V2, V4, V7, and V10, respectively). 
7.1.6 
EuroQoL-5-dimension 3-level Scale 
The 3-level EQ-5D version (EQ‑5D‑3L) was introduced by the EuroQoL Group in 
1990.17,35 The EQ-5D-3L essentially consists of 2 pages: the EQ-5D-3L descriptive 
system and the EQ visual analogue scale (EQ VAS).  
The descriptive system comprises five dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, slight 
problems, moderate problems, severe problems and extreme problems. The participant is 
asked to indicate his/her health state by ticking the box next to the most appropriate 
statement in each of the five dimensions. This decision results in a 1-digit number that 
expresses the level selected for that dimension. The digits for the five dimensions can be 
combined into a 5-digit number that describes the participant’s health state. 
The EQ VAS records the participant’s self-rated health on a vertical VAS, where the 
endpoints are labelled ‘The best imaginable health state’ and ‘The worst imaginable 
health state’. The VAS can be used as a quantitative measure of health outcome that 
reflect the participant’s own judgement.  
The EQ-5D-3L will be obtained at Baseline, and Weeks 3 and 12 (V2, V7, and V10, 
respectively). Administration to a caregiver is not mandatory. 
7.1.7 
Work and Social Adjustment Scale 
The WSAS is a 5-item self-report scale used to assess psychosocial functioning and to 
predict durability of response to antidepressant treatment.18 Each of the 5 questions is 
rated on a scale from 0 to 8, where 0 is no impairment and 8 is very severe impairment. A 
WSAS score above 20 appears to suggest moderately severe or worse psychopathology.23 
Scores between 10 and 20 are associated with significant functional impairment but less 
severe clinical symptomatology. Scores below 10 appear to be associated with subclinical 
populations. 
The WSAS will be performed at Baseline and Weeks 3 and 12 (V2, V7, and V10, 
respectively), and will be captured electronically.  


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7.2 
Safety Assessments 
7.2.1 
Columbia-Suicide Severity Rating Scale 
The C-SSRS will be used to assess suicide potential or tendency as a study entry criteria 
and monitored throughout the study. 
The C-SSRS is a semi-structured interview designed to assess the severity and intensity 
of suicidal ideation, suicidal behavior, and nonsuicidal self-injurious behavior over a 
specified time period. The measurement of suicidal ideation is based on 5 “yes” or “no” 
questions with accompanying descriptions arranged in order of increasing severity. If the 
patient answers “yes” to either questions 1 or 2, the intensity of ideation is assessed in 
5 additional questions related to frequency, duration, controllability, deterrents, and 
reasons for the most severe suicidal ideation. Suicidal behavior is assessed by asking 
questions categorizing behaviors into actual, aborted, and interrupted attempts; 
preparatory behavior; and nonsuicidal self-injurious behavior.  
If any item(s) on the C-SSRS are answered “yes”, the primary investigator or physician 
investigator must review the patient’s responses in order to (a) at screening and Baseline 
determine the patient’s study eligibility and potential need for referral to a mental health 
professional, and (b) during the study evaluate the patient’s need for appropriate medical 
management such as a referral to a mental health professional. 
A significant risk of suicide is defined as a “yes” in answer to (a) questions 4 or 5 on the 
suicidal ideation section; or (b) any questions on any item in the suicidal behavior 
section. This must be reported as an SAE and followed up accordingly. Additionally, if a 
patient responds “yes” to any of the suicidal ideation questions 1 through 3, the 
investigator should apply clinical judgment to determine the need for reporting this as an 
AE or SAE and the need for any appropriate referral.  
7.2.2 
Vital Signs  
Blood pressure will be measured supine, after at least 5 min at rest. The three 
measurements should be recorded 1 to 2 min apart, and the results averaged to inform 
eligibility. Respiratory rate, body temperature, and pulse rate will be obtained at 
Screening, Baseline, Day 0, and Day 1 (V1, V2, V3, and V4, respectively).  
7.2.3 
Electrocardiogram  
Standard 12-lead ECGs will be obtained at Screening (V1) and Day 1 (V4). 


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7.2.4 
Clinical Laboratory Tests 
Blood samples will be obtained at Screening (V1), Day 1 (V4), and Week 3 (V7) for the 
following:  
• Haematology: haemoglobin, haematocrit, red blood cell count, mean corpuscular 
haemoglobin, mean corpuscular volume, mean corpuscular haemoglobin 
concentration, white blood cell count (with differential), and platelet count.  
• Chemistry: albumin, alkaline phosphatase, alanine aminotransferase (ALT), amylase, 
aspartate aminotransferase (AST), bicarbonate, bilirubin (direct, indirect, and total), 
calcium, chloride, creatine kinase, creatinine, gammaGT, glucose, lactate 
dehydrogenase, lipase, magnesium, phosphate, potassium, protein-total, sodium, urea 
(blood urea nitrogen), and uric acid.  
• Biomarker: C-reactive protein. 
• Other: 2a polymorphism at Screening (V1) only (optional). 
Urine samples will be obtained at Screening (V1) and Baseline (V2) for the following:   
• Urinalysis: A dipstick urinalysis will be performed for blood, glucose, ketone, 
protein, pH, specific gravity, nitrite, leukocytes, bilirubin, and urobilinogen. 
• Urine Drug Screen: for illicit drugs or drugs of abuse at Screening (V1) and Baseline 
(V2). Results of a positive drug screen will be reviewed by the study clinican for 
pattern of use. 
• Urine Pregnancy Test: a dipstick test in women of childbearing potential at Screening 
(V1) and Baseline (V2).  
Laboratory samples will be analysed by a central laboratory (Eurofins) to ensure 
consistent interpretation of results. Instructions for shipment of samples and review of 
results is provided in the Laboratory Manual. In the event of an unexplained clinically 
significant abnormal laboratory test value, the test should be repeated and followed up 
until it has returned to the normal range and/or an adequate explanation of the 
abnormality is found. 
7.2.5 
Adverse Events 
All AEs occurring after the participant signs the ICF and up to the last study event will be 
recorded. Any AEs occurring before the start of treatment (ie, before the dose of the IP on 
Day 0 [V3]) will be recorded in the medical history. Any AE ongoing at V10 (EOS/ET) 
will be followed until resolution or no longer considered clinically significant by the 
investigator.  


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See Section 9 and 10 for additional information. 
7.3 
Other Assessment Instruments  
7.3.1 
Hamilton Depression Rating Scale – 17-item 
The HAM-D-17 17-item scale is used to measure the degree of symptom severity in 
depressed patients.12 The HAM-D-17 rating will be performed by the investigator using 
the eCOA device at the Screening (V1) and Baseline (V2) only. The total score from this 
assessment will be used as eligibility criteria prior to treatment (minimal total symptom 
score ≥ 18). The Structured Interview Guide for the HAM-D-17 (SIGH-D) will be 
administered.40 This will be captured electronically. 
7.3.2 
Mini International Neuropsychiatric Interview 
The MINI was designed as a brief structured interview for the major Axis I psychiatric 
disorders in DSM-5 and International Classification of Diseases-10. Validation and 
reliability studies have been done comparing the MINI to the Structured Clinical 
Interview for DMS-5 Patient Edition and the Composite International Diagnostic 
Interview (a structured interview developed by the World Health Organization). 
Version 7.0.2 of the MINI will be used for this study. The results of these studies show 
that the MINI has similar reliability and validity properties, but can be administered in a 
much shorter period (mean 18.7 ± 11.6 min, median 15 min) than the above referenced 
instruments. It can be used by clinicians after a brief training session.31 
At Screening (V1), participants will be assessed for MDD, as documented by DSM-5 
criteria, and the lack of other psychiatric diagnoses will be confirmed by use of the 
MINI.31 
7.3.3 
Massachusetts General Hospital-Antidepressant Treatment 
History Questionnaire 
The MGH-ATRQ is a self-rated scale used to determine treatment resistance in major 
depressive disorder.4 The scale examines the efficacy (improvement from 0%, not 
improved at all to 100% completely improved, and adequacy of a treatment. Participants 
are asked by clinician about treatment adherence to each medication trial and examines 
the participants’ antidepressant history to identify pseudo-resistance and treatment 
resistance. The MGH-ATRQ will be collected at Screening (V1) only. This will be 
captured electronically. 
7.3.4 
McLean Screening Instrument for Borderline Personality Disorder  
The MSI-BPD is a commonly used measure to assess for BPD.42 The scale consists of 
10 items based on the DSM-5 BPD criteria; the first 8 items represent the first eight 
criteria in the DSM-5 for BPD diagnosis, while the last two questions assess the paranoia 
and dissociation criteria for BPD. Scores for the MSI-BPD range from 0 to 10, with each 


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item rated as “1” if present and “0” if absent. A score of 7 or higher indicates a likelihood 
for the participant to meet criteria for BPD. The MSI-BPD will be collected at Screening 
(V1) only. This will be captured electronically. 
7.3.5 
Adult Self-Report Scale 
The ASRS is a self-reported questionnaire used to determine the presence of attention 
deficit hyperactivity disorder in adults.19 The screener (6-item) version of the scale will 
be used in this study. The first question concerns inattention and the other 5 questions 
assess hyperactivity-impulsivity. Each question is answered on a 5-point Likert-type 
scale, ranging from “Never” to “Very Often”. This scale will be obtained at Screening 
(V1) only and will be captured electronically. 
7.3.6 
Scale to Assess Therapeutic Relationships – Patient and Clinician 
Version 
The STAR-P and STAR-C is a 12-item measure assessing the therapeutic relationship 
between patient and clinician on three components: Collaboration, Positive Clinician 
Input, and Emotional Difficulties (clinician version)/Non-Supportive Clinician (patient 
version) input.21 The Collaboration subtest reflects a good rapport and a shared 
understanding of goals, mutual understanding, openness, and trust. Positive Clinician 
Input reflects the perception (by the participant) of the clinician to encourage, support, 
and listen to the participant. Emotional Difficulties/Non-Supportive Clinician Input 
reflect problems in the relationship. The range of total scores for both versions is 0–48, 
with a higher score suggesting better therapeutic relationships. Each version of the scale 
takes approximately 5 min to complete. Total scores and subscale totals can be obtained. 
The STAR-P and STAR-C will be collected at Baseline (V2) only. These will be 
captured electronically. 
7.3.7 
Five Dimension Altered States of Consciousness Questionnaire 
The 5D-ASC measures the acute drug effects using 5 primary dimensions and respective 
subdimensions to assess alterations in mood, perception, and experience of self in relation 
to environment and thought disorder. The 5 dimensions include oceanic boundlessness, 
anxious ego dissolution, visionary restructuralization, auditory alterations, and reduction 
of vigilance.6,7,33 This will be administered immediately after the psilocybin session on 
Day 0 (V3). This will be captured electronically. 
7.3.8 
The Positive and Negative Affect Schedule 
The PANAS measures the acute emotional drug effects, and comprises 2 mood scales 
that measure positive and negative affect.38 Participants respond to 20 items using a 
5-point scale that ranges from “slightly or not at all (1)” to “extremely (5)”. A total higher 
score on the positive affect questions indicates more of a positive affect while a lower 
score on the negative affect questions indicates less of a negative affect. This will be 


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administered at Baseline (V2), the day after the psilocybin session (V4), and at Week 3 
(V7). This will be captured electronically. 
7.3.9 
Emotional Breakthrough Inventory  
The EBI is a VAS that describes the intensity and quality of the emotional experience 
following the psilocybin session, developed by the Imperial College London. This is 
collected on Day 1 (V4) electronically.  
7.3.10 
Mindstrong application 
If the participant opts to participate in the Mindstrong portion of the study, an app will be 
activated on the participant’s mobile phone at V1; it will be deactivated at the EOS. 
Mobile data collection: The Mindstrong app will collect data from the participant’s smart 
phone and periodically send these data back to the Mindstrong secure database. The 
participant will not need to do anything to collect these, except use their phone as they 
normally do. The data collected from the participant’s phone will include: 
o Number of and time of phone calls/e-mails/texts (content will not be collected) 
o Location information from the GPS 
o Orientation of the smart phone (the way the phone is pointing) 
o Acceleration of the smart phone (sudden movements of the phone) 
o Keystroke information with characters redacted 
o Gestures used (taps, swipes, other) 
The app may also maintain a list of target words and the participant’s use-frequency of 
these words. These words will be completely stripped from their context, thus preventing 
the content of any particular message from being deciphered. 
The data collection application does NOT collect information on who or what number the 
participant calls or receive calls from. The data collection application does NOT capture 
the content of messages the participant sends or receives in a readable format. No 
personally identifiable information is captured and all other data are encrypted on the 
smartphone before transmission to the Mindstrong data enclave hosted on Amazon Web 
Service’s cloud computers. 
Specifically, the application does NOT collect: 
o Email addresses of the emails that the participant sends or receives 
o Phone numbers of the phone calls that the participant makes or receives 


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o Phone numbers of the text messages that the participant makes or receives 
o Messages sent or received in a readable format 
7.4 
Protocol Deviations 
All protocol deviations will be assessed and documented on a case-by-case basis before 
the database lock, and deviations considered having a serious impact on the efficacy 
results will lead to the relevant participant being excluded from the analysis. 
Protocol deviations will be summarised by centre and grouped into different categories, 
as follows:  
o those who entered the study even though they did not satisfy the entry criteria; 
o those who developed withdrawal criteria during the study but were not 
withdrawn; 
o those who received the wrong treatment or incorrect dose; 
o those who took any prohibited medications during the study. 
 


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8 INVESTIGATIONAL PRODUCT MANAGEMENT 
8.1 
Description 
Information about the IP is provided in Table 8.1. 
Table 8.1 
Details of Investigational Product 
 
Psilocybin 
Psilocybin 
Placebo 
Ingredient 
Psilocybin 
Psilocybin 
placebo 
Manufacturer 
Juniper Pharma Services Ltd,  
8 Orchard Place,  
Nottingham Business Park,  
Nottingham, NG8 6PX, UK 
Dose(s) 
1 mg 
10 mg and 25 mg 
Not applicable 
Route 
Oral 
Oral 
Oral 
Formulation 
Capsule 
Capsule 
Capsule 
Strength(s) 
1 mg 
5 mg 
Not applicable 
8.1.1 
Formulation  
Matching psilocybin capsules, 1 mg and 5 mg, and the matching placebo capsules were 
manufactured by Juniper Pharma Services, Ltd.  
8.1.2 
Storage 
All IP must be kept in a locked area with limited access. The high-density polyethylene 
(HDPE) bottles of IP are to be stored as indicated in the IP Handling Manual. Deviations 
of storage temperature outside this required range should be documented and COMPASS 
or its designee should be notified promptly. Bottles of IP should not be frozen. If any 
component of the IP is damaged, COMPASS or its designee must be notified as soon as 
possible.  
8.2 
Packaging and Blinding 
Psilocybin and placebo capsules were packaged into HDPE containers with 
child-resistant, tamper-evident screw cap lids with a mounted desiccant by Fisher Clinical 
Services UK Ltd (Langhurstwood Road, Horsham, West Sussex, RH12 4QD, UK). Each 
bottle contains 5 capsules for a single dose administration. Labels are affixed on to the 
bottles consistent with regulations in participating countries. Single individual bottles will 
be provided for use by a given participant. Bottles for each participant will be assigned 
according to unique identifiers by IWRS. Refer to the IP Handling Manual for additional 
details. 


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The IWRS will be programmed with blind-breaking instructions. The study blind should 
NOT be broken for a given participant except in a medical emergency where knowledge 
of the dose of IP received would impact treatment of the emergency. If, in the opinion of 
the investigator, it is in the participant's best interest to know the IP assignment, the blind 
may be broken as instructed in the IWRS. COMPASS must be notified before the blind is 
broken unless identification of the IP is required for a medical emergency in which the 
knowledge of the specific blinded IP will affect the immediate management of the 
participant's condition. In this case, COMPASS must be notified within 24 h after 
breaking the blind. The date and reason that the blind was broken must be recorded in the 
source documentation and eCRF, as applicable. 
8.3 
Dose and Administration 
In preparation for dosing on Day 0 (V3), the site will use the IWRS to randomise the 
participant to the appropriate therapy after it is confirmed at Baseline (V2) the participant 
remains eligible to participate in the study; randomisation will be stratified by country. 
Using IWRS, each participant will be assigned 1 treatment bottle containing 5 capsules 
packaged in a double-blind fashion, depending on the randomised treatment arm, the 
bottle will contain 1 of the following: 
o 10 mg treatment bottle: 2 × 5 mg capsules and 3 × placebo capsules 
o 25 mg treatment bottle: 5 × 5 mg capsules 
o 1 mg treatment bottle: 1 × 1 mg capsule and 4 × placebo capsules 
After a light breakfast taken 2 h prior to dosing and under observation of study staff, the 
5-capsule dose is to be swallowed with a full glass of water; due to the number of 
capsules in a dose, additional water may be necessary to swallow the dose. Study staff 
will ensure the entire 5-capsule dose has been swallowed.  
To prepare for the drug experience, the participant will take the IP and lie down on a 
couch in a room with dim lights and a standard playlist of relaxing music playing quietly. 
The trained therapist will be present with the participant at all times. 
The effects of psilocybin usually start about 20 to 30 min after administration, becoming 
most intense in the first 90 to 120 min, and gradually subside in 5 to 6 h. The participants 
will be asked to remain in the room for the duration of the session regardless of the 
intensity of the effects, prefreably lying down and mostly silent unless they have a 
concern or need to communicate a discomfort or seek reassurance from the therapist, or 
use the restroom. The therapist will ‘check-in’ with the participant (ie, ask how the 
participant is doing) in 30- to 60-min intervals postdosing. A light meal and fruit will be 
available for the participant. 
About 5 to 6 h after dosing, trained therapist will discuss the IP administration experience 
with the participant. The participant is to be discharged 6 to 8 h postdosing when, in the 
opinion of the investigator, the acute effects of psilocybin are resolved. The participant 


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will be accompanied home . The site is to be notified that they have returned home safely, 
and in the absence of receiving a phone call, site staff will directly contact the participant.  
8.4 
Accountability 
The investigator must keep an accurate accounting of the number of IP units delivered to 
the site, administered to participants, and returned to COMPASS or its designee during 
and at the completion of the study. The IP must be administered to participants only by 
an appropriately qualified person. The IP is to be used in accordance with the protocol by 
participants who are under the direct supervision of the investigator. Investigators should 
maintain records that document adequately that the participants were administered the IP 
dose specified by the protocol and reconcile all IPs received at the site before final 
disposition. At the end of the study, or as directed, all IP, including unused, partially 
used, and empty containers, will be returned to the sponsor or its designee. 
8.5 
Concomitant Therapy 
All prescription and non-prescription medications (eg, over-the-counter drugs and herbal 
supplements) that participants report taking during the 30 days prior to Screening (V1) 
will be assessed and recorded at that visit. For each medication, documentation should 
list the trade or generic name, the total daily dose including units (or the dose, units and 
scheduled and actual frequency of administration if the medication is not taken daily), the 
route of administration, and the reason for use.  
Concomitant medication refers to all drugs and therapies used from the time the ICF was 
signed through the end of study participation.  
Changes, additions, or discontinuations to medications will be assessed and recorded in 
the eCRF during each study visit. All as-needed (pro re nata, PRN) prescriptions should 
be converted to reflect actual number of pills or dose taken per day. 
8.5.1 
Permissible Medications 
Medications for the management of concurrent anxiety and insomnia, or nonpsychiatric 
medications that have a potential psychotropic effect are permitted within the following 
limitations. From the initial Screen Visit (V1) through final study visit (V10, EOS), 
participants are permitted to use benzodiazepines (up to 2 mg of lorazepam equivalents 
per day for insomnia and anxiety if it is not taken within 12 h before the psilocybin dose. 
Prescription and nonprescription medications with psychoactive properties that are used 
as needed for nonpsychiatric conditions (eg, pseudoephedrine for allergies or cold 
symptoms; zopiclone for sleep disorders) should be used no more than 2 times a week 
and not in the 12 h before any study assessment. Documentation of the use of adjunctive 
anxiolytics, hypnotics, or medication with potential psychotropic properties (including 
over-the-counter preparations) will be obtained at each clinic visit. 


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Therapy considered necessary for the participant’s welfare may be given at the discretion 
of the study clinician. If the permissibility of a specific medication/treatment is in 
question, please contact COMPASS or its designee. 
8.5.2 
Definition of Women of Childbearing Potential and/or Acceptable 
Contraceptive Methods 
A woman is considered of childbearing potential (ie, fertile) following menarche and 
until becoming postmenopasusal unless permanently sterilised (ie, subject had 
hysterectomy, bilateral salpingectomy, or bilateral oophorectomy).  
A woman who is not of childbearing potential is considered to be postmenopausal after at 
least 12 months without menstruation. The following methods of contraception, if used 
properly and used for the duration of the study, are generally considered highly effective:  
o Combined estrogen- and progestogen-containing hormonal contraception 
associated with inhibition of ovulation: 
▪ Oral 
▪ Intravaginal 
▪ Transdermal 
o Progestogen-only hormonal contraception associated with inhibition of ovulation: 
▪ Oral  
▪ Injectable 
▪ Implantable 
o Intrauterine devise 
o Intrauterine hormone-releasing system 
o Bilateral tubal occlusion 
o Vasectomised partner 
o Sexual abstinence 
Periodic abstinence (ie, calendar, symptothermal, or postovulation methods, and tubal 
ligation/occlusion) is not an acceptable form of contraception for this study.   
These methods of contraception also apply to partners of male participants. 


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The investigator and each participant will determine the appropriate method of 
contraception for the participant during the participation in the study. This will be 
documented at Screening (V1). 
If a participant or the partner of a male participant becomes pregnant during the study, the 
investigator will notify COMPASS or Worldwide immediately after the pregnancy is 
confirmed according to Section 12.6.  
8.5.3 
Prohibited Medications 
Participants are to be discontinued from antidepressant and/or antipsychotic medications 
at least 2 weeks prior to Baseline (V2). These medications include the following 
2 classes of the Anatomical Therapeutic Chemical (ATC) Classification System: - NO5A 
Antipsychotics & NO6A Antidepressants. Methylphenidate is also excluded. 
The medical monitor should be contacted if there is any question that a used medication 
is thought to be in one of these classes. These medications are not to be reintroduced to 
the participant until after V7 (Week 3). Participants who require concomitant 
medication(s) specifically for the treatment of depression at any time through the duration 
of the study will be assessed for reasons of resuming their medications and followed until 
12 weeks post psilocybin administration. The study clinician should initiate treatment of 
symptoms of depression per local site practice and may change the venue of therapy (ie, 
outpatient to inpatient) if deemed clinically necessary. The intervention may be a 
combination of somatic (eg, approved antidepressant medication) and nonsomatic 
(various forms psychotherapy, eg, CBT) whose therapeutic intention is remediation of the 
depressive episode. Because the anticipated half-life of psilocybin is approximately 3 h, 
and only 1 administration of test product is permitted, no known issues regarding PK or 
pharmacodynamic interactions are envisioned within approximately 7 days of product 
administration. 
8.5.4 
Rescue Medication 
Rescue medications may be used during and after the psilocybin session. 
The decision to medicate a participant will depend on whether the monitors and 
responsible physician judge that they are capable of maintaining the safety of the patient 
and others without medical intervention. 
• Benzodiazepine anxiolytics is the pharmacological intervention of choice in case of 
acute psychological distress (eg, medications such as lorazepam or alprazolam that 
have a rapid onset, a short time until peak plasma concentration, and a short duration 
of therapeutic action; the oral route is preferable because IV injection procedures may 
further exacerbate the participant’s anxiety). 
• Antipsychotic medications (eg, risperidone) should be available in the event that an 
adverse reaction escalates to unmanageable psychosis.  


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In case of development of acute anxiety or psychotic symptoms requiring 
pharmacological intervention, the participant will be managed appropriately. The 
participant may be discharged from the clinic when, in the opinion of investigator, the 
condition has stabilized. The participant will be accompanied home. The site is to be 
notified by the participant that they have returned home safely, and in the absence of 
receiving a phone call site staff will directly contact the participant.  
Information for how to manage subjects during difficult psychological states are detailed 
in the Therapist Manual.  
8.6 
Compliance 
Administration of IP will be supervised by study personnel to ensure compliance. 
 


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9 ADVERSE EVENTS 
Throughout the course of the study, all AEs will be monitored and recorded on an AE 
eCRF, including the AE’s description, start and end date, seriousness, severity, action 
taken, and relationship to the IP. If AEs occur, the first concern will be the safety of the 
study participants.  
Per ICH E2A: An AE is any untoward medical occurrence in a participant or clinical 
investigation participant administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore be 
any unfavourable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, 
whether considered related to the medicinal product. 
Medical interventions such as surgeries, diagnostic procedures, and therapeutic 
procedures are not AEs but the action taken to treat the medical condition. They should 
be recorded as treatment of the AEs. 
The investigator will promptly notify COMPASS or Worldwide of all SAEs and 
nonserious AEs occurring during the clinical trial so that legal obligations and ethical 
responsibilities towards the safety of participants and the safety of the product under 
clinical investigation are met.  
COMPASS or Worldwide has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a product under clinical 
investigation. COMPASS or Worldwide will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC), and investigators. These will be 
detailed in the safety plan. 
9.1 
Documenting Adverse Events 
AEs occurring from when the participant signs the ICF until the last study event will be 
recorded. Any AEs occurring before the start of treatment (ie, before the dose of the IP on 
Day 0 [V3]) will be recorded in the medical history. Also, the sign, symptom, or disease 
present before starting the treatment period are only considered AEs if they worsen after 
starting the treatment period. Investigators should document all significant illnesses that 
the participant has experienced within 3 months of the Screening visit. Additional 
illnesses present at the time informed consent is given are to be regarded as concomitant 
illnesses. Illnesses first occurring or detected during the study and/or worsening of a 
concomitant illness during the study are to be documented as AEs on the eCRF. 
All clinical laboratory results, vital signs, and ECG results or findings should be 
appraised by the investigator to determine their clinical significance. Isolated abnormal 
clinical laboratory test results, vital sign findings, or ECG findings (ie, not part of a 
reported diagnosis) should be reported as AEs if they are symptomatic, lead to IP 


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discontinuation, require corrective treatment, or constitute an AE in the investigator’s 
clinical judgment. 
At each time point, the investigator will determine whether any AEs have occurred by 
evaluating the participant. AEs may be directly observed, reported spontaneously by the 
participant or by questioning the participant at each time point. Participants should be 
questioned in a general way, without asking about the occurrence of any specific 
symptoms. The investigator must assess all AEs to determine intensity, causality and 
seriousness, in accordance with the definitions in Sections 9.2, 9.3, and 10.1, 
respectively. The investigator’s assessment must be clearly documented in the study 
site’s source documentation with the investigator’s signature.  
Always report the diagnosis as the AE or SAE term. When a diagnosis is unavailable, 
report the primary sign or symptom as the AE or SAE term with additional details 
included in the narrative until the diagnosis becomes available. If the signs and symptoms 
are distinct and do not suggest a common diagnosis, report them as individual entries of 
AE or SAE. 
The investigator should report all AEs on the AE page(s) of the eCRF and source 
documents, regardless of seriousness, severity, and causality. Whenever possible, an AE 
will be reported using a diagnostic term, (eg, “common cold” or “upper respiratory 
infection” rather than “runny nose, cough, mild fever”) and should be described with the 
attributes described in Sections 9.2 and 9.3.  
9.2 
Assessment of Intensity 
Each AE will be classified according to the following criteria: 
 
Mild: 
The AE does not interfere in a significant manner with the 
participant’s normal level of functioning. 
Moderate: 
The AE produces some impairment of functioning, but is not 
hazardous to the participant’s health. 
Severe: 
The AE produces significant impairment of functioning or 
incapacitation and is a definite hazard to the participant’s 
health. 
Severity versus Seriousness: Severity is used to describe the intensity of a specific event 
while the event itself, however, may be of relatively minor medical significance (such as 
severe headache). This is not the same as "seriousness," which is based on 
participant/event outcome at the time of the event. 
When changes in the intensity of an AE occur more frequently than once a day, the 
maximum intensity for the experience should be noted. If the intensity category changes 
over several days, those changes should be recorded separately (with distinct onset dates). 


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9.3 
Assessment of Causality 
Each AE will be assessed as to its relationship to the IP, based on the following criteria. 
Although the attribution by the investigator will be collected for reported events, for 
analytic purposes a temporal association with the use of the IP will be assumed sufficient 
for at least plausible association. 
 
Not related: 
No causal relationship exists between the IP and the AE, but an 
obvious alternative cause exists, eg, the participant’s underlying 
medical condition or concomitant therapy. 
Possibly related: 
A connection with the administration of the IP appears unlikely, 
but cannot be ruled out with certainty. An AE may be 
considered possibly related if or when it meets 2 of the 
following criteria: (1) it follows a reasonable temporal sequence 
from administration of the IP; (2) it could not readily have been 
produced by the participant’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the 
participant; or (3) it follows a known pattern of response to the 
IP. 
Related: 
There is a reasonable/plausible possibility that the AE may have 
been caused by the IP. 
When assessing the relationship to the IP, the following criteria will be considered: 
o Known class effect 
o Biological plausibility 
o Lack of alternative explanation—concomitant drug or disease 
9.4 
Action Taken Regarding Investigational Product 
Dose modifications of IP (ie, dose not changed, drug withdrawn, drug interrupted, or 
dose increased) are not applicable as this is a single dose study.  
o Not Applicable: Participant died, study treatment had been completed prior to 
reaction/event, or reaction/event occurred prior to start of treatment. 
9.5 
Other Action Taken for Event 
1 = None (ie, no treatment was required) 
2 = Medication required (ie, prescription and/or OTC medication was required to treat 
the AE) 


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3 = Hospitalisation or prolongation of hospitalisation required (ie, hospitalisation was 
required or prolonged because of the AE, whether medication was required) 
4 = Other 
9.6 
Adverse Event Outcome 
1 = Recovered/Resolved (ie, the participant fully recovered from the AE with no 
residual effect observed) 
2 = Recovering/Resolving (ie, the AE improved but has not fully resolved) 
3 = Not Recovered/Not Resolved (ie, the AE itself is still present and observable) 
4 = Recovered/Resolved with Sequelae (ie, the residual effects of the AE are still 
present and observable, including sequelae/residual effects) 
5 = Fatal (ie, ‘fatal’ should be used when death is a direct outcome of the AE) 
6 = Unknown 
9.7 
Clinical Laboratory Changes 
Any abnormality in a laboratory value that is new in onset or which has worsened in 
severity or frequency from the baseline condition and meets 1 of the following criteria 
will be recorded on the AE pages of the eCRF: 
o Requires therapeutic intervention or diagnostic tests 
o Leads to discontinuation of IP 
o Has accompanying or inducing symptoms or signs 
o Is judged by the investigator as clinically significant 
Combined elevations of aminotransferases and bilirubin, either serious or nonserious, and 
whether causally related, meeting the criteria of a potential Hy’s Law case (total bilirubin 
level ≥ 2 × upper limit of normal [ULN] with simultaneous ALT or AST ≥ 3 × ULN) 
should always be reported to the sponsor as soon as possible following the procedures 
outlined in Section 10.2 for SAE reporting, with the investigator’s assessment of 
seriousness, causality, and a detailed narrative. 
9.8 
Overdose 
Any instance of overdose (suspected or confirmed) must be communicated to Worldwide 
or a specified designee within 24 h and be fully documented as an AE or SAE if it meets 


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the SAE criteria. Details of any signs or symptoms and their management should be 
recorded including details of any antidote(s) administered. 
9.9 
Adverse Events of Special Interest 
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific 
and medical concern specific to the study drug, for which ongoing monitoring and 
immediate notification by the investigator to the sponsor is required. Such AEs may 
require further investigation to characterise and understand them.  
The following events will be reported as AESI: 
o Euphoric mood 
o Dissociative disorder 
o Hallucination 
o Psychotic disorder 
o Cognitive disorder 
o Disturbance in attention 
o Mood altered 
o Psychomotor skills impaired 
o Inappropriate affect 
o Overdose 
o Intentional product misuse 
The investigator must report to the Sponsor all the above event on the eCRF page within 
24 h of learning about the event regardless of relationship to study drug. 
The report should include the following minimum information: 
o Subject number 
o Event 
o Date/time of onset 
o Duration of the event 
o Dose of drug taken 


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o Severity 
o Outcome 
All AESIs will be followed until resolved or stable. 
9.10 Adverse Event Follow-up 
All AEs will be followed until resolved or stable and the outcome documented on the 
eCRF. 
If the investigator detects an AE in a study participant after the last scheduled follow-up 
visit and considers the event possibly related or related to prior study treatment, the 
investigator should report it to Worldwide. 
 


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10 SERIOUS ADVERSE EVENTS 
10.1 Definition of Serious Adverse Event 
An SAE is any event that meets any of the following criteria: 
o Death 
o Life-threatening 
o Inpatient hospitalisation or prolongation of existing hospitalisation 
o Persistent or significant disability/incapacity 
o Congenital anomaly/birth defect in the offspring of a participant who received 
psilocybin. 
o Other: Important medical events that may not result in death, be life-threatening, 
or require hospitalisation, may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardise the participant and may 
require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such events are: 
▪ Intensive treatment in an emergency room or at home for allergic 
bronchospasm 
▪ Blood dyscrasias or convulsions that do not result in inpatient hospitalisation 
▪ Development of drug dependency or drug abuse 
Definition of Terms 
Life threatening: An AE is life threatening if the participant was at immediate risk of 
death from the event as it occurred; ie, it does not include a reaction that if it had 
occurred in a more serious form might have caused death. For example, drug-induced 
hepatitis that resolved without evidence of hepatic failure would not be considered life 
threatening even though drug-induced hepatitis can be fatal. 
Hospitalisation: AEs requiring hospitalisation should be considered SAEs. 
Hospitalisation for elective surgery or routine clinical procedures that are not the result of 
AEs (eg, elective surgery for a pre-existing condition that has not worsened) need not be 
considered AEs or SAEs. If anything untoward is reported during the procedure, that 
occurrence must be reported as an AE, either 'serious' or 'nonserious' according to the 
usual criteria. 
In general, hospitalisation signifies that the participant has been detained (usually 
involving at least one an overnight stay) at the hospital or emergency ward for 


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observation and/or treatment that would not have been appropriate in the physician's 
office or outpatient setting. When in doubt as to whether 'hospitalisation' occurred or was 
necessary, the AE should be considered serious. 
For deaths, the underlying or immediate cause of death should always be reported as an 
SAE. 
Any serious, untoward event that may occur subsequent to the reporting period that the 
investigator assesses as related to IP should also be reported and managed as an SAE. 
The investigator should follow participants with AEs until the event has resolved or the 
condition has stabilised. In case of unresolved AEs, including significant abnormal 
clinical laboratory values at the end of study assessment, these events will be followed 
until resolution or until they become clinically not relevant.  
Disability/incapacitating: An AE is incapacitating or disabling if the experience results in 
a substantial and/or permanent disruption of the participant's ability to carry out normal 
life functions. 
10.2 Reporting Serious Adverse Events 
Each AE will be assessed to determine whether it meets seriousness criteria 
(Section 10.1). If the AE is considered serious, the investigator should report this event to 
Worldwide and to the IRB/IEC according to its standard operating procedures. 
If the investigator detects an SAE in a study participant after the last scheduled follow-up 
visit, and considers the SAE related or possibly related to this study’s IP administration, 
the investigator should report it to Worldwide. 
The investigator must report to the sponsor all SAEs on the eCRF page within 24 h of 
learning about the event regardless of relationship to IP.  
All information about SAEs will be collected and reported via the SAE form and sent by 
e-mail message or facsimile (contact information will be contained in the investigator site 
file). The investigator should send the initial report within 24 h of becoming aware of the 
SAE. At minimum, the initial report should include the following information: 
o Event 
o Study code 
o Participant number, initials, and date of birth 
o IP 
o Reporter name and contact information 


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If the site experiences a temporary disruption of the eCRF system, a back-up paper SAE 
Report Form will be available for site staff to complete. 
• Site staff will complete the paper SAE report form and e-mail it within 24 h to the 
following address: drugsafety@worldwide.com 
• In cases where the email system is unavailable, site staff will send the SAE by fax 
to: +1-866-387-5539 (US) and +44 208 043 4813 (ROW). 
If notification is made via email or fax, site staff must enter the SAE information into the 
eCRF system as soon as the system becomes available. Should a back-up SAE form be 
used, the original SAE form should be kept at the study site. 
If the SAE has not resolved at the time the investigator submits an initial SAE report, the 
investigator must provide a follow-up report as soon as the event resolves (or upon 
receipt of significant information if the event is still ongoing). Additional follow-up 
information must be reported in the eCRF within 24 h of awareness following 
investigator (or site) awareness of the information. The investigator should not delay 
reporting an SAE in order to obtain additional information. Additional information, when 
available, should be reported per the reporting procedures described above. 
All SAEs shall be followed until resolution, until the condition stabilises, or until the 
participant is lost to follow-up, or otherwise explained. Once the SAE is resolved, the 
corresponding AE eCRF page shall be updated. Additionally, any relevant laboratory test 
reports, consultation reports from other health care professionals, discharge summaries, 
or other information that has been gathered about the event shall be transmitted to the 
sponsor.  
In the case of a “minimum report” (one that solely comprises the information bulleted 
above), a more detailed follow-up report should be sent as soon as more information 
becomes available but no later than 7 calendar days after the date of the initial report. 
Each SAE should be followed up until resolution or stabilisation and for reported deaths, 
the investigator should supply Worldwide and the IRB/IEC with any additional requested 
information (eg, autopsy reports and terminal medical reports). 
The original SAE form should be kept at the study site. The sponsor or its representative 
will be responsible for determining and in turn, reporting SAEs to regulatory authorities 
according to the applicable regulatory requirements. 
All SAEs will be followed until resolved or stable and the outcome documented on the 
eCRF. 
Investigator safety reports will be prepared for suspected unexpected serious adverse 
reactions (those not listed in the IB) according to local regulatory requirements and 
COMPASS/Worldwide policy and are forwarded to investigators as necessary.  


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An investigator who receives an investigator safety report describing an SAE(s) or other 
specific safety information (eg, summary or listing of SAEs) from COMPASS or 
Worldwide will file it with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements. 


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11 STATISTICS 
11.1 General Procedures 
The statistical analysis will be undertaken by Worldwide in collaboration with 
COMPASS. A detailed Statistical Analysis Plan (SAP) will be finalised and signed 
before database lock and before study unblinding. Any deviations from the analyses 
described below will be included in the SAP, which will be included in the clinical study 
report. All statistical testing will be performed at the two-sided alpha 0.05 level unless 
otherwise stated. 
11.2 Sample Size 
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 based on the 
change from Baseline in MADRS score at Week 3. The 3 treatment groups will be 
randomised in a 1:1:1 ratio.  
For this primary analysis, a sample size of 216 randomised participants (72:72:72) will 
provide 90% power at the alpha = 0.05 level to detect a 6-point difference in average 
MADRS total score between the optimal therapeutic dose of psilocybin and 1 mg 
psilocybin, assuming the common SD is 11.0.  
The 6-point difference in average MADRS total score on a group level is supported by 
the pilot study with psilocybin,2 and is within the range of potential differences that have 
been used to power other studies in major depression and TRD. The assumed SD of 11.0 
is based on a review of other studies for this condition. A blinded interim analysis may be 
performed to verify this assumption. 
It is assumed that up to 90% of randomised participants may not have prior psychedelic 
experience. The power for this post hoc subgroup is approximately 86%, if the maximum 
number of participants to have prior psychedelic experience were 10% of randomised 
participants.  
11.3 Statistical Methods 
The Safety Population will consist of all randomised participants who receive study 
treatment, regardless of whether or not treated. This population will be used for all 
summaries of participant accountability, demographic and baseline data, and safety 
information, including AE incidence.  
The Full Analysis Set (FAS) will consist of all participants randomised who also receive 
the dose of IP. 
The modified intention-to-treat population will consist of all participants in the FAS that 
have at least 1 post dose assessment.  


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The Per Protocol (PP) population will consist of all participants in the FAS who do not 
have a major protocol deviation. Major protocol deviations will be reviewed and 
determined prior to unblinding. The PP population will be used for supportive sensitivity 
analyses. 
11.3.1 
Efficacy and Outcome Measures  
• MADRS 
• QIDS-SR-16 
• SDS 
• GAD-7 
• DSST 
• EQ-5D-3L (participant and caregiver; the latter is not mandatory) 
• WSAS 
11.3.2 
Analysis of Efficacy 
The primary efficacy endpoint (change from Baseline in MADRS total score at Week 3) 
will be evaluated with a mixed effects model for repeated measures analysis. The model 
will include treatment, visit, study site, prior psychedelic experience, treatment by visit 
interaction, participant as a random effect, and Baseline MADRS total score. Comparison 
of the psilocybin optimal dose versus 1 mg psilocycbin will be performed at the 0.05 
testing level. A sensitivity analysis will be performed on the primary mixed model 
repeated measures model adding treatment by study site or country interaction into the 
model. If it is significant (at the 10% level), then further investigations of sites will be 
performed. 
The 4 secondary efficacy endpoints that are dichotomous variables (proportion of 
participants who are responders, remitters, and sustained responders) will be analysed 
using the Cochran Mantel Haenszel chi square test, stratified by country, to compare the 
psilocybin optimal therapeutic dose versus 1 mg psilocybin. A stepdown procedure to 
correct for multiplicity will be employed.  
Time-to-event measures will be evaluated using Kaplan-Meier methods.  
Response and remission rates will be summarised at each visit.  
Change from Baseline in continuous efficacy measures, including the QIDS-SR-16 scale 
and GAD-7 total scores at each point, will be analysed based on last observation carried 
forward data using an analysis of covariance model, with treatment and study site as 


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factors, and the respective baseline score as the covariate. The exploratory analyses for 
quality of life and wellbeing, functioning and associated disability, cognitive function, 
and anxiety are not hierarchical; there will be no correction for multiplicity in these 
analyses.  
Scores for all efficacy endpoints, including dimension scores of the EQ-5D-3L and the 
EQ VAS, will be summarised over time using descriptive statistics for all visits during 
the observation period.  
The covariate selection process will be addressed in the SAP to be approved before any 
analyses are undertaken.  
Continuous behavior sampling will be tested with the Mindstrong application technology 
in a subgroup of smart phone users consented to this part of the study. Participants who 
do not consent to the app installation, or don’t have a smart phone, will not be excluded 
from the study. Following the installation of the Mindstrong app on the participant’s 
smart phone, the app will begin to collect data from the smart phone and periodically 
send these data back to the secure database. The participant does not need to do anything 
at this stage, except use their phone as they normally do. As explained above, personal 
data from mobile phone usuage will be analysed in a sub-group of consenting 
participants.  
The correlation between sensor data, keyboard behavior, or voice and speech metrics will 
be assessed for correlation with standard clinical assessments and the ability of app 
features to identify impending relapse before clinical change is apparent with traditional 
ratings. The goal of these exploratory assessments is to identify mobile use patterns (app 
features) predictive of clinically significant mood changes that will have an impact on 
care and treatment outcomes. 
11.3.3 
Multiplicity 
To control the overall Type 1 error rate, the following hierarchical testing method will be 
employed. A sequential test procedure will be applied across the primary and key 
secondary efficacy endpoints, with all testing between 1 mg psilocybin and the optimal 
dose done at the 0.05 level. Thus, in the final analysis, statistical testing will be 
performed at the 0.05 level in a prespecified order, such that testing will not continue 
once non-significance is observed. If a non-significant p-value is observed, the remaining 
endpoints will still have nominal p-values presented but will not be considered 
statistically significant. The pre-specified testing order will be: 
• Primary endpoint, change in MADRS total score from Baseline to 3 Weeks, for 
25 mg versus 1 mg 
• Primary endpoint, change in MADRS total score from Baseline to 3 Weeks, for 
10 mg versus 1 mg 


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• Secondary endpoint, proportion of participants with a response (≥ 50% improvement 
in MADRS total score from Baseline) at Week 3, for 25 mg versus 1 mg 
• Secondary endpoint, proportion of participants with a response (≥ 50% improvement 
in MADRS total score from Baseline) at Week 3, for 10 mg versus 1 mg 
• Secondary endpoint, proportion of participants with remission (MADRS total 
score ≤ 10) at Week 3, for 25 mg versus 1 mg 
• Secondary endpoint, proportion of participants with remission (MADRS total 
score ≤ 10) at Week 3, for 10 mg versus 1 mg 
• Secondary endpoint, proportion of participants who have a sustained response at 
Week 12, for 25 mg versus 1 mg 
• Secondary endpoint, proportion of participants who have a sustained response at 
Week 12, for 10 mg versus 1 mg 
11.3.4 
Analysis of Safety 
Safety analyses will be performed using data from the Safety Population. Safety will be 
evaluated based of AEs, vital signs, clinical laboratory assessments, and ECG findings.  
11.3.4.1 
Columbia-Suicide Severity Rating Scale 
Item scores from the C-SSRS, all visits by randomised treatment, the item scores from 
the version assessing suicidality since the last visit, and all postbaseline visits (V3 to V10, 
inclusive) by treatment will be tabulated. Summary statistics of suicidal ideation and 
suicidal behavior following IP administration will be presented by randomised treatment. 
11.3.4.2 
Adverse Events 
AEs will be coded by Preferred Term (PT) using the Medical Dictionary for Regulatory 
Activities (MedDRA) classification. All reported AEs with onset or worsening after the 
administration of study medication will be included in the analysis. The incidence of AEs 
will be summarised by treatment group, and by severity and relationship to IP. Serious 
AEs and AEs leading to withdrawal from the study will be tabulated. 
A TEAE is defined as any AE that has an onset on or after the dose of IP, or any 
pre-existing condition that has worsened on or after the dose of IP.  
The incidence of TEAEs and treatment-related AEs will also be summarised by 
maximum severity and most-related relationship to IP by MedDRA primary system organ 
class and PT. The summary will include the total number and percentage of participants 
reporting an event. In counting the number of events reported, a continuous event, ie, 
reported more than once and which did not cease, will be counted only once; 


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non-continuous AEs reported several times by the same participant will be counted as 
multiple events. 
11.3.4.3 
Electrocardiographic Data 
The ECG data will be summarised descriptively based on measures of change in each 
ECG parameter from V1 to post-treatment (V4). Frequency tabulations of the 
abnormalities will be provided. ECG variables to be analysed will include heart rate, PR 
interval, QRS interval, QT interval, and corrected QT interval using the following 
correction methods: QT corrected according to Bazett’s formula and QT corrected 
according to Fridericia’s formula. 
11.3.4.4 
Laboratory Data 
Laboratory data (haematology and blood chemistry parameters) will be presented for 
each treatment group using descriptive statistics, including mean and mean change from 
baseline values at each scheduled time point. Shift tables will display numbers of 
participants with normal/abnormal values at Baseline versus post-treatment. The 
frequency of laboratory abnormalities will be tabulated. By-participant data listings will 
flag laboratory values that are outside normal reference ranges or markedly abnormal 
findings. 
11.3.4.5 
Vital Signs 
Changes from Baseline in vital signs, blood pressure (systolic and diastolic), body 
temperature, pulse rate, and respiratory rate, will be summarised for each treatment group 
using descriptive statistics. The last measurement obtained prior to IP administration will 
serve as baseline. The percentage of participants with values outside clinically important 
limits will be summarised. A listing of weight and height at V1 will be provided.  
11.3.5 
Demographic and Baseline Characteristics 
Treatment groups will be compared with respect to participant demographics and 
baseline characteristics will be summarised using descriptive statistics, no formal 
statistical analysis tests will be performed. 
11.4 Interim Analysis 
There may be a blinded interim analysis after approximately 50% of the planned 
216 participants have been randomized and had an opportunity to complete 3 weeks of 
the study post treatment. The purpose of this blinded interim would be to perform an 
assessment of the overall combined (across all treated participants) SD of the change 
from Baseline in the MADRS collected at Week 3. If the SD in this assessment is greater 
than the SD assumed for the study sample size calculation (11.0), then a sample size 
re-estimation may be performed. The sample size re-estimation would not result in a 
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12 ETHICS AND RESPONSIBILITIES 
12.1 Good Clinical Practice 
The study will be performed in accordance with this protocol, US investigational new 
drug (IND) regulations (21 Code of Federal Regulations [CFR] 312), ICH guidelines for 
Good Clinical Practice (GCP), the regulations on electronic records and electronic 
signature (21 CFR 11), and the most recent guidelines of the Declaration of Helsinki 
(Section 19.2). These guidelines are on file at Worldwide. 
The study will also be performed in accordance with any laws and regulations in force in 
the country in which the research is carried out.  
12.2 Data and Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) will periodically review and evaluate the 
accumulated study data for participant safety, study conduct and progress and when 
appropriate, efficacy.  The DSMB will make recommendations concerning the 
continuation, modification or termination of the trial, always ensuring participant safety 
is paramount.  The composition, the frequency of the review, range of decisions 
permitted, and the methods for dissemination of information will be addressed in a 
separate charter. 
12.3 Steering Committee 
A Steering Committee will not be used for this study.  
12.4 Institutional Review Board/Independent Ethics Committee 
Conduct of the study must be approved by an appropriately constituted IRB/ IEC. 
Approval is required for the study protocol, protocol amendments, ICFs, participant 
information sheets, and advertising materials. No IP will be shipped to a site until written 
IRB/IEC authorisation has been received by the sponsor or its representative. 
12.5 Informed Consent 
Participants should be informed that they may withdraw from the study at any time. They 
will receive all information that is required by local regulations and ICH guidelines. The 
principal investigator or a designated representative will provide the sponsor or its 
representative with a copy of the IRB/IEC-approved ICF before the start of the study. 
12.6 Exposure in Utero During Clinical Studies 
Sponsor must be notified of any participant who becomes pregnant within 30 days of 
receiving the IP. Reporting after the follow-up visit or ET is done voluntarily by the 
investigator. 


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Sponsor must be notified of any male participant whose partner becomes pregnant within 
30 days of the participant receiving the IP. Reporting after any follow-up visit or ET is 
done voluntarily by the investigator. 
Although pregnancy is not technically an AE, all pregnancies must be followed to 
conclusion to determine their outcome. This information is important for both drug safety 
and public health concerns. It is the responsibility of the investigator, or designee, to 
report any pregnancy in a participant or the partner of a male participant using the eCRF 
pregnancy within 24 h of becoming aware of the event. Exposure in Utero (EIU) 
Reporting form. Please contact your study monitor to receive the EIU Reporting form 
upon learning of a pregnancy. The investigator should make every effort to follow the 
participant until completion of the pregnancy and complete the EIU Reporting form 
eCRF with complete pregnancy outcome information, including normal delivery and 
induced abortion. The adverse pregnancy outcome, either serious or nonserious, should 
be reported in accordance with study procedures. If the outcome of the pregnancy meets 
the criteria for immediate classification as an SAE (ie, post-partum complications, 
spontaneous or induced abortion, stillbirth, neonatal death, or congenital anomaly, 
including that in an aborted foetus), the investigator should follow the procedures for 
reporting SAEs outlined in Section 10. In the event the eCRF system is unavailable, a 
back-up paper Pregnancy Reporting Form will be available for site staff to complete 
following the reporting guidelines as outlined in Section 10.2. 
For reports of pregnancy in the partner of a male participant, the pregnancy eCRF page 
EIU form (or SAE form if associated with an adverse outcome) should be completed with 
the participant’s randomisation number, initials, and date of birth, and details regarding 
the partner of the male participant should be entered in the narrative section. 
12.7 Records Management 
By signing this protocol, the investigator grants permission to personnel from the 
sponsor, its representatives, and appropriate regulatory authorities, for on-site monitoring 
of all appropriate study documentation, paper and electronic, as well as on-site review of 
the procedures employed in eCRF generation, where clinically appropriate. 
12.8 Source Documentation 
Note that a variety of original documents, data, and records will be considered as source 
documents in this trial. The eCRF itself is not to be used as a source document under any 
circumstances.  
12.9 Study Files and Record Retention 
The investigator must arrange for retention of study records at the site. The nature of the 
records and the duration of the retention period must meet the requirements of the 
relevant regulatory authority. In addition, because this is an international study, the 
retention period must meet the requirements of the most stringent authority. The 


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investigator should take measures to prevent accidental or premature destruction of these 
documents. 


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13 AUDITING AND MONITORING 
This study will be monitored for quality assurance at all stages of its development by the 
clinical research personnel employed by the sponsor or its representative. Monitoring will 
include personal visits and telephone communication to assure that the investigation is 
conducted according to the protocol, standard operating procedures, GCP guidelines, and 
applicable regulatory requirements. Quality control procedures will be applied to each 
stage of data handling to ensure that all data are reliable and have been processed 
correctly. On-site review of eCRFs will include a review of forms for completeness and 
clarity, and consistency with source documents available for each Participant.  
Medical advisors and clinical research associates or assistants may request to witness 
participant evaluations occurring as part of this protocol. The investigator and appropriate 
personnel will be periodically requested to attend meetings/workshops organised by the 
sponsor to assure acceptable protocol execution. The study may be audited by the sponsor 
or by regulatory authorities. If such an audit occurs, the investigator must agree to allow 
access to required Participant records. By signing this protocol, the investigator grants 
permission to personnel from the sponsor, its representatives, and appropriate regulatory 
authorities, for on-site monitoring of all appropriate study documentation, as well as 
on-site review of the procedures employed in eCRF generation, where clinically 
appropriate. 


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14 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study 
participants, may be made only by COMPASS. A protocol change intended to eliminate 
an apparent immediate hazard to participants may be implemented immediately, provided 
the IRB/IEC is notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment. The 
written amendment must be submitted to the IRB/IEC and the investigator must await 
approval before implementing the changes. COMPASS will submit protocol amendments 
to the appropriate regulatory authorities for approval. 
If in the judgment of the IRB/IEC, the investigator, and/or COMPASS, the amendment to 
the protocol substantially changes the study design and/or increases the potential risk to 
the participant and/or has an impact on the participant's involvement as a study 
participant, the currently approved written informed consent form will require similar 
modification. In such cases, informed consent will be renewed for participants enrolled in 
the study before continued participation. 
 


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15 STUDY REPORT AND PUBLICATIONS 
COMPASS is responsible for preparing and providing the appropriate regulatory 
authorities with clinical study reports according to the applicable regulatory 
requirements. 
The publication policy of COMPASS is discussed in the investigator's Clinical Research 
Agreement. 
 


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16 STUDY DISCONTINUATION  
Both COMPASS and the Principal Investigator reserve the right to terminate the study at 
the investigator’s site at any time. Should this be necessary, COMPASS or a specified 
designee will inform the appropriate regulatory authorities of the termination of the study 
and the reasons for its termination, and the Principal Investigator will inform the IRB/IEC 
of the same. In terminating the study, COMPASS and the Principal Investigator will 
assure that adequate consideration is given to the protection of the participants’ interests. 
 


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17 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written 
consent is gained from COMPASS. However, authorised regulatory officials, IRB/IEC 
personnel, COMPASS and its authorised representatives are allowed full access to the 
records. 
Identification of participants and CRFs shall be by initials, screening and treatment 
numbers only. If required, the participant's full name may be made known to an 
authorised regulatory agency or other authorised official. 
 


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Sheehan DV, Alphs LD, Mao L, et al. Comparative validation of the SSTS, the 
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Tylš F, Páleníček T, Horáček J. Psilocybin-summary of knowledge and new 
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Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A, Vogel H, Hell 
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40. 
Williams JB. A structured interview guide for the Hamilton depression rating 
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Williams JB, Kobak KA. Development and reliability of a structured interview 
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19 APPENDICES 
19.1 APPENDIX I – Names of Study Personnel 
Sponsor: 
Ekaterina Malievskaia, MD, MScPH 
Co-Founder, Head of Research and Development 
COMPASS Pathways, Ltd 
16 Old Bailey 
London, England, EC4M 7EG 
UK 
Telephone: +44 (0) 79 2087 6562 (UK) 
+1 (516) 805 3533 (US) 
Medical Monitor: 
Olga Kolotilina, Medical Director, Medical Affairs 
Worldwide Clinical Trials 
Kemerovo, 650065, Russia 
Telephone: +7 906 925 1812 (mobile) 
+7 812 346 8247, #1504 (office) 
+7 812 346 8248 (fax) 
Clinical Research 
Organisations: 
Worldwide Clinical Trials 
3800 Paramount Parkway, Suite 400 
Morrisville, NC 27560 
Telephone: +1 (919) 674 2900 
Central Laboratory: 
Eurofins Central Laboratory B.V. 
Bergschot 71 
4817 PA Breda 
The Netherlands 
Telephone: +31 76 573 75 21 
+31 76 573 77 76 (fax) 
Investigational 
Product Distribution: 
Fisher Clinical Services UK Ltd  
Langhurstwood Road,  
Horsham, West Sussex, RH12 4QD,  
UK 
Telephone: +44 (0) 1403 224308 
 


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19.2 APPENDIX II – Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
 
Ethical Principles 
for 
Medical Research Involving Human Participants 
 
Adopted by the 18th WMA General Assembly 
Helsinki, Finland, June 1964 
and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DS, USA, October 2002 
55th WMA General Assembly, Tokyo, Japan, October 2004 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
and the 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
A. INTRODUCTION 
The World Medical Association has developed the Declaration of Helsinki as a statement 
of ethical principles to provide guidance to physicians and other participants in medical 
research involving human participants. Medical research involving human participants 
includes research on identifiable human material or identifiable data. 


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It is the duty of the physician to promote and safeguard the health of the people. The 
physician’s knowledge and conscience are dedicated to the fulfillment of this duty. 
The Declaration of Geneva of the World Medical Association binds the physician with 
the words, "The health of my participant will be my first consideration," and the 
International Code of Medical Ethics declares that, "A physician shall act only in the 
participant's interest when providing medical care which might have the effect of 
weakening the physical and mental condition of the participant." 
Medical progress is based on research, which ultimately must rest in part on 
experimentation involving human participants. 
In medical research on human participants, considerations related to the well being of the 
human participant should take precedence over the interests of science and society. 
The primary purpose of medical research involving human participants is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the etiology 
and pathogenesis of disease. Even the best-proven prophylactic, diagnostic, and 
therapeutic methods must continuously be challenged through research for their 
effectiveness, efficiency, accessibility and quality. 
In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens. 
Medical research is participant to ethical standards that promote respect for all human 
beings and protect their health and rights. Some research populations are vulnerable and 
need special protection. The particular needs of the economically and medically 
disadvantaged must be recognised. Special attention is also required for those who cannot 
give or refuse consent for themselves, for those who may be participant to giving consent 
under duress, for those who will not benefit personally from the research and for those for 
whom the research is combined with care. 
Research investigators should be aware of the ethical, legal and regulatory requirements 
for research on human participants in their own countries as well as applicable 
international requirements. No national ethical, legal or regulatory requirement should be 
allowed to reduce or eliminate any of the protections for human participants set forth in 
this Declaration. 
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
It is the duty of the physician in medical research to protect the life, health, privacy, and 
dignity of the human participant. 
Medical research involving human participants must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, other 


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relevant sources of information, and on adequate laboratory and, where appropriate, 
animal experimentation. 
Appropriate caution must be exercised in the conduct of research, which may affect the 
environment, and the welfare of animals used for research must be respected. 
The design and performance of each experimental procedure involving human 
participants should be clearly formulated in an experimental protocol. This protocol 
should be submitted for consideration, comment, guidance, and where appropriate, 
approval to a specially appointed ethical review committee, which must be independent 
of the investigator, the sponsor or any other kind of undue influence. This independent 
committee should be in conformity with the laws and regulations of the country in which 
the research experiment is performed. The committee has the right to monitor ongoing 
trials. The researcher has the obligation to provide monitoring information to the 
committee, especially any SAEs. The researcher should also submit to the committee, for 
review, information regarding funding, sponsors, institutional affiliations, other potential 
conflicts of interest and incentives for participants. 
The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that there is compliance with the principles enunciated in 
this Declaration.  
Medical research involving human participants should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person. The 
responsibility for the human participant must always rest with a participant of the 
research, even though the participant has given consent. 
Every medical research project involving human participants should be preceded by 
careful assessment of predictable risks and burdens in comparison with foreseeable 
benefits to the participant or to others. This does not preclude the participation of healthy 
volunteers in medical research. The design of all studies should be publicly available. 
Physicians should abstain from engaging in research projects involving human 
participants unless they are confident that the risks involved have been adequately 
assessed and can be satisfactorily managed. Physicians should cease any investigation if 
the risks are found to outweigh the potential benefits or if there is conclusive proof of 
positive and beneficial results. 
Medical research involving human participants should only be conducted if the 
importance of the objective outweighs the inherent risks and burdens to the participant. 
This is especially important when the human participants are healthy volunteers. 
Medical research is only justified if there is a reasonable likelihood that the populations 
in which the research is carried out stand to benefit from the results of the research. 
The participants must be volunteers and informed participants in the research project. 


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The right of research participants to safeguard their integrity must always be respected. 
Every precaution should be taken to respect the privacy of the participant, the 
confidentiality of the participant’s information and to minimise the impact of the study on 
the participant's physical and mental integrity and on the personality of the participant. 
In any research on human beings, each potential participant must be adequately informed 
of the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and 
the discomfort it may entail. The participant should be informed of the right to abstain 
from participation in the study or to withdraw consent to participate at any time without 
reprisal. After ensuring that the participant has understood the information, the physician 
should then obtain the participant's freely-given informed consent, preferably in writing. 
If the consent cannot be obtained in writing, the non-written consent must be formally 
documented and witnessed. 
When obtaining informed consent for the research project the physician should be 
particularly cautious if the participant is in a dependent relationship with the physician or 
may consent under duress. In that case the informed consent should be obtained by a 
well-informed physician who is not engaged in the investigation and who is completely 
independent of this relationship. 
For a research participant who is legally incompetent, physically or mentally incapable of 
giving consent or is a legally incompetent minor, the investigator must obtain informed 
consent from the legally authorised representative in accordance with applicable law. 
These groups should not be included in research unless the research is necessary to 
promote the health of the population represented and this research cannot instead be 
performed on legally competent persons. 
When a participant deemed legally incompetent, such as a minor child, is able to give 
assent to decisions about participation in research, the investigator must obtain that assent 
in addition to the consent of the legally authorised representative. 
Research on individuals from whom it is not possible to obtain consent, including proxy 
or advance consent, should be done only if the physical/mental condition that prevents 
obtaining informed consent is a necessary characteristic of the research population. The 
specific reasons for involving research participants with a condition that renders them 
unable to give informed consent should be stated in the experimental protocol for 
consideration and approval of the review committee. The protocol should state that 
consent to remain in the research should be obtained as soon as possible from the 
individual or a legally authorised surrogate. 
Both authors and publishers have ethical obligations. In publication of the results of 
research, the investigators are obliged to preserve the accuracy of the results. Negative as 
well as positive results should be published or otherwise publicly available. Sources of 
funding, institutional affiliations and any possible conflicts of interest should be declared 


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in the publication. Reports of experimentation not in accordance with the principles laid 
down in this Declaration should not be accepted for publication. 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED 
WITH MEDICAL CARE 
The physician may combine medical research with medical care, only to the extent that 
the research is justified by its potential prophylactic, diagnostic or therapeutic value. 
When medical research is combined with medical care, additional standards apply to 
protect the participants who are research participants. 
The benefits, risks, burdens and effectiveness of a new method should be tested against 
those of the best current prophylactic, diagnostic, and therapeutic methods. This does not 
exclude the use of placebo, or no treatment, in studies where no proven prophylactic, 
diagnostic or therapeutic method exists. 
At the conclusion of the study, every participant entered into the study should be assured 
of access to the best-proven prophylactic, diagnostic and therapeutic methods identified 
by the study. 
The physician should fully inform the participant which aspects of the care are related to 
the research. The refusal of a participant to participate in a study must never interfere 
with the participant-physician relationship. 
In the treatment of a participant, where proven prophylactic, diagnostic and therapeutic 
methods do not exist or have been ineffective, the physician, with informed consent from 
the participant, must be free to use unproven or new prophylactic, diagnostic and 
therapeutic measures, if in the physician’s judgment it offers hope of saving life, 
re-establishing health or alleviating suffering. Where possible, these measures should be 
made the object of research, designed to evaluate their safety and efficacy. In all cases, 
new information should be recorded and, where appropriate, published. The other 
relevant guidelines of this Declaration should be followed. 
 
 


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19.3 APPENDIX III – MGH-ATRQ – Additional Detail Regarding the 
Assessment of Previous Antidepressant Treatment 
The MGH-ATRQ scale elicits information regarding prior antidepressant use. Additional 
drugs with regulatory approval for use in major depressive disorder in different countries 
are listed at the end of this document. Among these drugs are atypical antipsychotics 
approved for the treatment of major depressive disorder, as adjunctive treatments or as a 
monotherapy. The drug list may not be exhaustive. 
For a drug treatment to be considered appropriate, it must have been administered at a 
dose approved for the treatment of major depressive disorder in the country where the 
study site is located. The minimum duration of treatment must be deemed appropriate by 
the investigator, and as a guidance, 6 to 8 weeks can often be considered as an adequate 
treatment duration. 
Some drugs are occasionally dosed based on therapeutic drug monitoring results. Prior 
use of drugs approved for major depressive disorder using therapeutic drug monitoring 
should be considered an appropriate intervention, if the concentrations are within the 
target range, irrespective of dose, and if the duration is considered adequate. 
Antidepressants, if administered at an adequate dose and duration, can support a 
characterisation of Treatment-Resistant Depression (TRD), in addition to medications 
listed in the Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire (MGH-ATRQ). 
Tri- and tetra-cyclic antidepressants 
Noveril  
 
Dibenzepin  
Prothiaden  
 
Dosulepin  
Gamanil  
 
Lofepramine   
Sintamil  
 
Nitroxazepine 
Insidon  
 
Opipramol 
Asendin  
 
Amoxapine 
Tecipul  
 
Setiptiline 
MAO inhibitors 
Humoryl  
 
Toloxatone  
Celeport  
 
Bifemelane   
Other antidepressants 
Spravato  
 
Esketamine 
Brexanolone  
Zulresso 
Sediel   
 
Tandospirone 


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Atypical antipsychotics 
Abilify  
 
Aripiprazole 
Rexulti  
 
Brexpiprazole 
Zyprexa  
 
Olanzapine 
Seroquel  
 
Quetiapine 
Combination products 
Etafron  
 
Amitriptyline/perphenazine 
Deanxit  
 
Flupentixol/melitracen  
Symbyax  
 
Olanzapine/fluoxetine 
Parmodalin  
 
Tranylcypromine/trifluoperazine 
 

SAP_001.pdf: 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN (SAP) FOR COMP 001 
THE SAFETY AND EFFICACY OF COMP360 IN PARTICIPANTS 
WITH TREATMENT-RESISTANT DEPRESSION (P-TRD) 
DRUG: 
COMP360 
TITLE: 
The Safety and Efficacy of COMP360 in 
Participants with Treatment-Resistant Depression 
(P-TRD) 
CLINICAL PHASE 
IIb 
SPONSOR: 
 
COMPASS Pathfinder Limited  
3rd Floor, 1 Ashley Road 
Altrincham, Cheshire, WA14 2DT, UK 
VERSION NUMBER: 
Final Version 2.0  
VERSION DATE: 
26 October 2021 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information provided in this document is strictly confidential and is available for 
review to Investigators, potential Investigators, appropriate ethics committees and other 
national authorities. No disclosure should take place without the written authorisation from 
the sponsor, except to the extent necessary to obtain informed consent from potential 
participants. 


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Final Version 2.0 26 October 2021  
 
SAP APPROVAL FORM 
Protocol Number: COMP 001 
Title: The Safety and Efficacy of COMP360 in Participants with Treatment-Resistant Depression 
(P-TRD) 
SAP Version and Date: Version 2.0 26 October 2021 
This SAP was reviewed and approved by the sponsor. The information contained in this 
SAP is consistent with: 
• The current risk benefit evaluation of the investigational product. 
• The moral, ethical and scientific principles governing clinical research as set out in 
the Declaration of Helsinki, and principles of Good Clinical Practices (GCP) as 
described in the Code of Federal Regulations (CFR) 21 CFR parts 50, 54, 56 and 
312 and according to applicable local requirements. 
 
Author Details and Signature: 
Signature: 
 
 
Date: 
 
 
Name (print)  
Niccolò Bassani  
 
 
 
 
 
 
 
 
Title: 
Principal Statistician, Worldwide Clinical Trials, Inc. 
 
Approver Details and Signature: 
Signature: 
 
 
Date: 
 
 
Name (print)  
Sunil Mistry  
 
 
 
 
 
 
 
 
Title: 
Director of Statistics, COMPASS Pathfinder Limited 
 
 


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Final Version 2.0 26 October 2021  
 
SUMMARY OF CHANGES 
Updates made from the protocol (Version 4.0, dated 19 July 2019) and changes made to 
the prior version of the SAP (Version 1.0, dated 06 December 2019) are summarised below. 
  
Section 
Revision / Addition 
Rationale 
Protocol Specific Changes (Version 4.0, dated 19 July 2019) 
All sections 
Minor changes were made to the 
objectives and endpoints wording 
from the protocol. These are all listed 
in Appendix I ‘COMPASS Changes to 
COMP 001 Protocol’. 
The rationale for each change is 
detailed in Appendix II (Section 
19.1). 
7 
Analysis Sets were modified as 
follows: 
• 
modified 
Intent-to-Treat 
was 
removed 
• 
Full 
Analysis 
Set 
definition 
updated to match the modified 
Intent-to-Treat definition 
The 
definition 
of 
the 
Safety 
Analysis Set and Full Analysis Set 
in version 1 of the SAP and in the 
Protocol were the same, so this 
change eliminates any redundancy. 
10.3 
Changed 
‘prior 
psychedelic 
experience’ 
wording 
to 
‘prior 
psilocybin experience’.  
To correct for the discrepancy in the 
Statistics section of the protocol 
with the rest of the protocol. The 
correct term to use is ‘prior 
psilocybin experience’ not ‘prior 
psychedelic 
experience’, 
as 
described in the protocol Section 4.1 
(Study Design).  
11 
Removed 
‘prior 
psychedelic 
experience’ from all analysis models. 
Since only 10% of participants will 
have 
had 
prior 
psilocybin 
experience, adding this covariate to 
the analysis was anticipated not to 
have a large impact and thus 
removed from the analysis model. 
11.2 
The analysis of the key secondary 
endpoints has been changed from the 
originally planned Cochran-Mantel-
Haenszel (CMH) procedure to either a 
GLMM (response and remission 
analysis at week 3) or a logistic 
regression (sustained response at week 
12). 
To increase statistical power by 
adjusting for more covariates than a 
stratified CMH would allow and to 
account for the assumed missing 
data mechanism. 


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Section 
Revision / Addition 
Rationale 
 
 
 
11.4.3 
Added EQ-VAS and PANAS as 
endpoints to be statistically analysed 
as well as providing summaries 
This ensures a better assessment of 
these two endpoints. 
11.4.4 
The caregiver EQ-5D-3L scores will 
only be listed and not analysed (this 
was previously in Section 6.12.7) 
As the caregiver EQ-5D-3L was not 
a mandatory assessment and is 
provisional of optional caregiver 
consent. 
11.5 
Removed the analysis to investigate 
the site/country effect 
Due to the sparseness of data, it has 
been agreed to create a simpler by-
country descriptive summary of 
MADRS total scores. 
SAP Specific Changes (Version 1.0, dated 06 December 2019) 
 
SAP is documented in a new format. 
The new format follows COMPASS 
Pathfinder Limited’s SAP template, 
with more detail being provided in 
certain sections for added clarity. 
See Appendix II (Section 19.2) for 
details of where to find sections 
from Version 1.0 in the new format). 
Also includes a list of abbreviations 
and parameters.  
4, 11 
The efficacy analysis methodology 
text has been restructured to align with 
the estimands framework and all 
analyses have been classified using the 
following hierarchy: 
Primary or Secondary Endpoint  
Primary or Secondary Estimand  
Main, Sensitivity or Supplementary 
Analysis (this was previously in 
Section 6.12) 
Version 1.0 had an old structure that 
did not account for estimands. This 
has been rectified and detailed 
explanations of estimands, methods 
and rationale for assumptions are 
provided. 
5 
Added details regarding the study 
design, study schematic and schedule 
of assessments. 
For completeness and to align with 
the protocol. 
6.2 
Added details confirming that the 
interim analysis was not to be 
performed (this was Section 7). 
To provide notification of a decision 
that was made. 


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Section 
Revision / Addition 
Rationale 
6.3 
Added details regarding the Data 
Safety Monitoring Board (DSMB). 
For completeness and to provide 
information. 
8 
Added 
general 
considerations 
including the versions of SAS, 
MedDRA and WHO-DDE to be used. 
Reporting of unscheduled visits has 
been generalised to both pre- and post-
baseline occurrences across domains 
(this was previously in Section 6.2.10). 
For completeness and to provide 
information. 
The 
original 
description 
only 
included post-baseline assessments 
and for a limited set of variables, the 
definition is now broader. 
9.1.1 
Clearer definition for change from 
baseline to include both ‘absolute’ and 
‘percentage’ 
changes 
(this 
was 
previously in Section 6.2.9). 
The original section only defined an 
absolute 
change; 
however, 
percentage change is part of the 
derivation of one key secondary 
endpoint, hence specifying it here 
ensures alignment of derivations. 
9.2.1 
Added details of the categorisation of 
protocol deviations. Also reworded to 
‘important’ rather than ‘major’. 
To reflect the protocol deviation 
handling plan. 
9.2.2, 9.2.3, 
9.2.4, 9.2.5, 
9.2.6 
Added 
details 
concerning 
the 
derivation of baseline variables 
For completeness and to provide 
information. 
9.2.7 
The definition of prior medications has 
been changed to reflect the study 
protocol (this was previously in 
Section 6.9). 
The prior medications definition 
from the protocol includes a cut-off 
of 30 days prior to screening to 
classify a drug as prior.  
9.3.1 
Added sections to explicitly define 
how key secondary endpoints are to be 
derived. 
Previously 
definitions 
were 
scattered in different sections where 
the analysis was detailed, this 
change 
ensures 
they 
are 
all 
centralised in one location. 
9.3.1.4 
Added a definition for MADRS 
relaxed sustained response. 
To better understand the impact on 
MADRS total scores with a more 
flexible definition of sustained 
response. 
9.3.1.5 
Added a definition for MADRS partial 
responder status. 
To better understand the impact on 
MADRS total scores with a less 
strict definition of response.  
9.3.15, 9.3.16 
Added sections to include all study 
instruments collected and to be 
reported. 
EBI and PANAS were not included 
in Version 1.0. 


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Section 
Revision / Addition 
Rationale 
10.1, 10.2, 
11.4.1, 12.1 
Added outputs related to the COVID-
19 pandemic: missed visits or visits 
that were conducted remotely, PDs, 
primary endpoint, and adverse events.  
To better evaluate the impact of 
COVID-19 on study conduct, safety 
and efficacy, 
10.3 
Added ‘Prior psilocybin experience’, 
height and BMI to baseline summaries 
(this was previously in Section 6.7). 
This is to ensure all relevant 
variables are summarised. 
11.3 
Cox regression has been added in the 
analysis of time to event endpoints to 
provide a direct comparison between 
treatment groups. 
The hazard ratio obtained from Cox 
regression model can provide a 
useful metric to better evaluate the 
impact of treatment on participants’ 
depression. 
11.4.2 
Additional responders analysis added. 
To better assess the response to 
treatment. 
11.5 
Added to the list of subgroup 
variables: country, number of failed 
pharmacological treatments for the 
current episode of depression, and 
depression severity at baseline (this 
was previously in Section 6.12.6). 
To better understand the impact of 
baseline variables on the primary 
and key secondary endpoints. 
12.1 
Added 
addition 
adverse 
event 
summary tables (this was previously in 
Section 6.13.1). 
For a more comprehensive analysis 
of safety. 
13.1 
Added section regarding the summary 
and analysis of the biomarker C-
reactive protein (CRP) 
This was omitted from Version 1.0. 
15.1 
Added 
section 
to 
clarify 
that 
Mindstrong app data is not in the scope 
of the current SAP/CSR. 
Since this data will be analysed 
separately, this has been explicitly 
mentioned in this SAP. 
18 
Updated the list of tables, figures and 
listings. Added column headings 
indicating if they are required for 
topline and the source shell number (if 
repeat) (this was previously in Section 
11).  
To reflect the latest shells and 
topline requirements.  


SAP SYNOPSIS 
Protocol Number 
COMP 001  
Title:  
The Safety and Efficacy of COMP360 in Participants with Treatment-Resistant 
Depression (P-TRD) 
EudraCT Number: 
2017-003288-36 
Investigational 
Medicinal Product: 
COMP360 
ClinicalTrials.gov 
Identifier: 
NCT03775200 
Clinical Phase: 
IIb 
Rationale: 
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 three months. In this 
study, the aim is to assess effectiveness of 3 different doses of COMP360 
(COMPASS’ proprietary pharmaceutical-grade synthetic psilocybin formulation 
that has been optimised for stability and purity) - 1 mg, 10 mg, and 25 mg - in 
TRD. 
Number of 
Participants: 
216 
Objectives:  
Primary Objective 
The primary objective of this study is to evaluate the efficacy of COMP360 (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 2, and weeks 1, 3, 6, 9, and 12. 
Secondary Objectives 
The secondary objectives are: 
• 
To assess the efficacy of COMP360 compared to 1 mg COMP360 on: 
• 
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 2 and at weeks 1, 6, 9, and 12. 
• 
The proportion of participants who have a sustained response at week 
12. Sustained response is defined as the proportion of participants 
fulfilling response criteria at any visit up to and including week 3, that 
also fulfils 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 COMP360 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. 


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Exploratory Objectives 
The exploratory objectives are: 
• 
To evaluate the effects of COMP360 on quality of life and wellbeing, 
functioning and associated disability, cognitive function, and anxiety 
compared to 1 mg COMP360 on: 
• 
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. 
• 
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. 
• 
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. 
• 
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 2 and week 12. 
• 
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. 
• 
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 
screening, day 2, and weeks 1, 2, 6, 9, and 12. 
• 
Psychosocial functioning 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. 
• 
To evaluate the impact of different COMP360 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. 


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• 
Positive and Negative Affect Schedule (PANAS), Five Dimension Altered 
States of Consciousness Questionnaire (5D-ASC) and Scale to Assess 
Therapeutic Relationship (Clinician and Patient version, STAR-C and 
STAR-P, respectively) will be assessed for correlation with the primary 
outcome as possible predictors of response. 
Study Design and 
Procedures: 
This is a phase II, 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 
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.  
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 (IWRS). 
After signing the informed consent form (ICF), participants will be assessed for 
their eligibility with the Mini International Neuropsychiatric Interview, version 
7.0.2 (MINI 7.0.2), the 17 item 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 (MSI-BPD). 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 (ASRS). 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 participant 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 participant is eligible. Once approval is issued, the participant 
should then be invited for a screening V1a visit. The V1a visit is the point at 
which the participant begins tapering off their antidepressant and/or antipsychotic 
medications, if appropriate. The participant 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. The tapering period used in the study 
is set at the industry standard for depression trials.  
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 


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COMP360 administration 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 COMP360 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 COMP360 administration 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 eligibility. Participants cannot be progressed to V3 until this approval 
is received.  
The COMP360 administration session (V3, day 1) will last approximately 6 hours 
(h) and will be supported by a trained therapist. After the acute effects of 
COMP360 pass, participants will be evaluated for safety and accompanied home. 
On day 2 (V4), the day following COMP360 administration, participants will be 
seen in person for a safety check, assessment of suicidality, and to discuss their 
experience during the COMP360 administration session.  
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 (plus a minimum of three 
safety visits), baseline (day -1), study drug administration day (day 1), day 2, 
week 1, week 2, week 3, and week 12. Participants will also be contacted for 
follow-up, which can be conducted remotely, at week 6 and week 9. 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 
and the baseline visit. 
Primary Endpoint:  
The primary endpoint is the change in MADRS total score from baseline (day -
1) to 3 weeks post COMP360. 


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Secondary 
Endpoints: 
The secondary endpoints are: 
• 
The proportion of participants with a response (defined as a ≥ 50% 
improvement in MADRS total score from baseline) at week 3 after the 
COMP360 session. 
• 
The proportion of participants with remission (defined as a MADRS total 
score ≤ 10) at week 3 post COMP360. 
• 
The proportion of participants who have a sustained response at week 12. 
Sustained response is defined as the proportion of participants fulfilling 
response criteria at any visit up to and including week 3, that also fulfils 
response criteria at all subsequent visits up to and including week 12. 
Response is defined as ≥ 50% decrease in MADRS total score from baseline. 
• 
Time to event measures: restart antidepressant medication for any reason, 
restart medication for continuing depressive symptoms, and relapse from a 
previously recovered state. Participants who withdraw from the study will be 
censored from the time to event analysis. 
Exploratory 
Endpoints: 
The exploratory endpoints are: 
• 
Change from baseline in the following: 
• 
Participant EQ-5D-3L at week 3 
• 
Caregiver EQ-5D-3L at week 3 (this assessment is not mandatory) 
• 
SDS at week 3 
• 
DSST at week 3 
• 
GAD-7 at week 3 
• 
QIDS-SR-16 at week 3 
• 
WSAS at week 3 
• 
Measures derived from smart phone usage via the Mindstrong app 
Safety Assessments 
• 
ECG 
• 
Vital signs 
• 
Blood test including liver function tests 
• 
Suicide risk as assessed by the C-SSRS 
• 
AEs and Serious AEs 
Estimand 
Framework 
The Hypothetical Strategy will be the primary estimand to best understand the 
clinical effects of COMP360 without the effects of participants taking new 
treatments for depression. Specifically, the primary estimand will be as follows:  
The mean difference (population-level summary) between COMP360 (25 mg or 
10 mg) and COMP360 1 mg (treatment) in participants with TRD, as defined by 
the inclusion/exclusion criteria (population) assessing the change from baseline 
in MADRS total score at week 3 (variable) if new treatment for depression is not 
available post-dose (intercurrent event). 


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The Treatment Policy will be the secondary estimand to understand the clinical 
effects of COMP360 versus inactive control including participants taking new 
treatment for depression if needed in both arms. Specifically, the secondary 
estimand will be as follows:  
The mean difference (population-level summary) between COMP360 (25 mg or 
10 mg) and COMP360 1 mg (treatment) in participants with TRD, as defined by 
the inclusion/exclusion criteria (population) assessing the change from baseline 
in MADRS total score at week 3 (variable) regardless of whether participants 
take new treatment for depression (intercurrent event). 
Sample Size 
Determination 
The intent of the primary efficacy analysis is to demonstrate superiority of at least 
one therapeutic dose of COMP360 (10 mg or 25 mg) versus the 1 mg COMP360 
dose based on the change from baseline in MADRS total score at week 3. The 
three treatment groups will be randomised in a 1:1:1 ratio.  
For this primary analysis, a sample size of 216 randomised participants 
(72:72:72) will provide 90% power at the alpha = 0.05 level to detect a 6-point 
difference in average MADRS total score between the optimal therapeutic dose 
of COMP360 and COMP360 1 mg, assuming the common standard deviation 
(SD) is 11.0.  
It is assumed that up to 90% of randomised participants may not have prior 
psilocybin experience. The power for this post-hoc subgroup is approximately 
86%, if the maximum number of participants to have prior psilocybin experience 
was 10% of randomised participants. 
Analysis Sets 
The Randomised Analysis Set: All randomised participants, whether or not they 
receive study drug. 
The Safety Analysis Set: All randomised participants who receive study drug. 
The Full Analysis Set (FAS): All participants randomised who receive study drug 
and have at least 1 post-dose efficacy assessment.  
The Per-Protocol (PP) Analysis Set: All participants in the FAS who do not have 
a protocol deviation that is thought to significantly affect the integrity of the 
participant’s efficacy data. 
Hypothesis 
The primary efficacy endpoint is the change from baseline in MADRS total score 
at week 3. The primary analysis will be the comparison between COMP360 (25 
mg or 10 mg) versus COMP360 1 mg and will be based on a two-sided hypothesis 
testing approach. The null and alternative hypotheses associated for this 
comparison are: 
H0: µCOMP360 (25 mg or 10 mg) - µCOMP360 1 mg = 0 
H1: µCOMP360 (25 mg or 10 mg) - µCOMP360 1 mg ≠ 0 
Where µCOMP360 (25 mg or 10 mg) and µCOMP360 1 mg represent the mean in change from 
baseline in MADRS total score at week 3 for COMP360 (25 mg or 10 mg) and 
COMP360 1 mg, respectively. 
The null hypothesis is that there is no difference between treatment groups for 
the primary efficacy endpoint and the alternative hypothesis is that there is a 
difference between treatment groups for the primary efficacy endpoint. 


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Primary Endpoint 
Analyses 
The primary efficacy endpoint (change from Baseline in MADRS total score at 
Week 3) will be evaluated with a mixed-effects model for repeated measures 
(MMRM) analysis following multiple imputation of MADRS data. The MMRM 
model will include treatment, visit, study site and treatment-by-visit interaction 
as fixed effects and baseline MADRS total score as a continuous covariate. 
Correlation between repeated observations within a participant will be accounted 
for by specifying an unstructured correlation. Comparison of the COMP360 
optimal dose versus 1 mg COMP360 will be performed at the 0.05 testing level 
and results for each imputation will be pooled to obtain a single treatment effect 
estimate. A sensitivity analysis will be performed on the primary MMRM model 
using a tipping-point approach. A supplementary analysis using Analysis of 
Covariance (ANCOVA) will also be performed following the same multiple 
imputation as for the primary MMRM analysis.  
Key Secondary 
Endpoint Analyses 
The three key secondary efficacy endpoints (proportion of participants who are 
responders, remitters, and sustained responders) will be analysed using either a 
Generalised Linear Mixed Model  (responders and remitters) with the same 
covariates and within-participant correlation structure as the MMRM model for 
the primary endpoint or a logistic regression model (sustained responders) 
including treatment and baseline MADRS total score as covariates, to compare 
the COMP360 optimal therapeutic dose versus 1 mg COMP360. A hierarchical 
procedure to maintain control over type I error will be employed.  


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TABLE OF CONTENTS 
SAP APPROVAL FORM..................................................................................................2 
SUMMARY OF CHANGES .............................................................................................3 
SAP SYNOPSIS .................................................................................................................7 
TABLE OF CONTENTS ................................................................................................14 
LIST OF ABBREVIATIONS .........................................................................................17 
LIST OF PARAMETERS ...............................................................................................19 
1 
INTRODUCTION ....................................................................................................21 
2 
STUDY OBJECTIVES ............................................................................................22 
2.1 
Primary .................................................................................................................22 
2.2 
Secondary..............................................................................................................22 
2.3 
Exploratory ...........................................................................................................22 
3 
STUDY ENDPOINTS ..............................................................................................25 
3.1 
Primary .................................................................................................................25 
3.2 
Secondary..............................................................................................................25 
3.3 
Exploratory ...........................................................................................................25 
3.4 
Safety Assessments ...............................................................................................26 
4 
ESTIMAND FRAMEWORK ..................................................................................27 
4.1 
Primary Endpoint ................................................................................................27 
4.2 
Key Secondary Endpoint .....................................................................................30 
5 
STUDY DESIGN ......................................................................................................33 
5.1 
Study Design .........................................................................................................33 
5.2 
Study Schematic ...................................................................................................35 
5.3 
Schedule of Assessments ......................................................................................36 
5.4 
Hypotheses and Treatment Comparisons ..........................................................40 
5.5 
Multiplicity ...........................................................................................................40 
5.6 
Sample Size Considerations ................................................................................41 
5.7 
Randomisation......................................................................................................41 
6 
PLANNED ANALYSES ...........................................................................................42 
6.1 
Final Analysis .......................................................................................................42 
6.2 
Interim Analysis ...................................................................................................42 
6.3 
Data Safety Monitoring Board (DSMB) ............................................................42 
7 
ANALYSIS SETS .....................................................................................................43 
8 
GENERAL CONSIDERATIONS ...........................................................................44 
9 
DATA DERIVATIONS ............................................................................................45 
9.1 
General ..................................................................................................................45 
9.1.1 
Change from Baseline ....................................................................................45 
9.1.2 
Missing and Partial Dates .............................................................................45 
9.1.3 
Treatment Exposure and Compliance .........................................................45 
9.1.4 
Inexact Values ................................................................................................45 
9.2 
Study Participants ................................................................................................45 
9.2.1 
Protocol Deviations ........................................................................................45 


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9.2.2 
Age Categories ................................................................................................46 
9.2.3 
Body Mass Index (BMI) ................................................................................46 
9.2.4 
Length of Current Depressive Episode ........................................................46 
9.2.5 
Missing Major Depressive Disorder (MDD) Episode Start Dates .............46 
9.2.6 
Prior Psilocybin Experience ..........................................................................47 
9.2.7 
Prior and Concomitant Medications ............................................................47 
9.3 
Efficacy Assessments ...........................................................................................47 
9.3.1 
Montgomery-Asberg Depression Rating Scale Score (MADRS) ...............47 
9.3.2 
Quick Inventory of Depressive Symptomatology (QIDS-SR-16) ..............49 
9.3.3 
European Quality of Life 5-dimension 3-level Scale (EQ-5D-3L) .............50 
9.3.4 
Sheehan Disability Scale (SDS) .....................................................................51 
9.3.5 
Digit Symbol Substitution Test (DSST) .......................................................52 
9.3.6 
Generalised Anxiety Disorder Scale (GAD-7) .............................................52 
9.3.7 
Work and Social Adjustment Scale (WSAS) ...............................................52 
9.3.8 
Mini International Neuropsychiatric Interview ..........................................52 
9.3.9 
Hamilton Depression Rating Scale – 17-Item (HAM-D-17) .......................53 
9.3.10 
The Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire (MGH-ATRQ) ......................................................53 
9.3.11 
McLean Screening Instrument for Borderline Personality 
Disorder (MSI-BPD) ......................................................................................53 
9.3.12 
Adult Self-Report Scale (ASRS) ...................................................................53 
9.3.13 
Scale to Assess Therapeutic Relationships – Patient (STAR-P) and 
Clinician (STAR-C) Versions........................................................................54 
9.3.14 
Five Dimensional Altered States of Consciousness Questionnaire 
(5D-ASC) .........................................................................................................54 
9.3.15 
Emotional Breakthrough Inventory (EBI) ..................................................55 
9.3.16 
The Positive and Negative Affect Schedule (PANAS) ................................55 
9.4 
Safety .....................................................................................................................56 
9.4.1 
Adverse Events ...............................................................................................56 
9.4.2 
Missing / Partial Start / Stop Dates of AEs and Concomitant 
Medications .....................................................................................................57 
9.4.3 
Vital Signs .......................................................................................................58 
9.4.4 
ECG Categorical Intervals ............................................................................58 
9.4.5 
Columbia-Suicide Severity Rating Scale (C-SSRS) ....................................59 
9.4.6 
Sheehan Suicidality Tracking Scale (S-STS) ...............................................59 
9.4.7 
Algorithm to Map Sheehan Suicidality Tracking Scale and 
Columbia-Suicide Severity Rating Scale .....................................................60 
10 STUDY PARTICIPANTS ........................................................................................62 
10.1 
Disposition of Participants ..................................................................................62 
10.2 
Protocol Deviations ..............................................................................................62 
10.3 
Demographic and Baseline Characteristics .......................................................62 
10.4 
Medical History ....................................................................................................63 
10.5 
Prior and Concomitant Medications ..................................................................63 


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10.6 
Treatment Exposure ............................................................................................64 
11 EFFICACY ................................................................................................................65 
11.1 
Primary Efficacy ..................................................................................................65 
11.1.1 
Hypothetical Strategy Estimand (Primary) .................................................65 
11.1.2 
Treatment Policy Estimand (Secondary) .....................................................72 
11.1.3 
Missing data ....................................................................................................72 
11.2 
Key Secondary Efficacy .......................................................................................73 
11.2.1 
Composite Strategy Estimand (Primary) ....................................................73 
11.2.2 
Treatment Policy Estimand (Secondary) .....................................................76 
11.3 
Other Secondary Endpoints ................................................................................77 
11.4 
Exploratory Efficacy ............................................................................................79 
11.4.1 
COVID-19 .......................................................................................................79 
11.4.2 
Additional Responders Analysis ...................................................................79 
11.4.3 
Correlation Analysis ......................................................................................79 
11.4.4 
Exploratory Endpoints ..................................................................................81 
11.5 
Subgroup Analysis: Efficacy ...............................................................................82 
12 SAFETY .....................................................................................................................84 
12.1 
Adverse Events (AEs) ..........................................................................................84 
12.2 
Laboratory Tests ..................................................................................................85 
12.3 
Vital Signs .............................................................................................................87 
12.4 
Electrocardiogram Data ......................................................................................87 
12.5 
C-SSRS ..................................................................................................................87 
12.6 
S-STS .....................................................................................................................88 
13 BIOMARKERS .........................................................................................................89 
13.1 
C-Reactive Protein (CRP) ...................................................................................89 
14 CHANGES FROM THE PROTOCOL-PLANNED ANALYSES .......................90 
15 DATA NOT PRESENTED ......................................................................................91 
15.1 
Mindstrong data ...................................................................................................91 
16 REFERENCES .........................................................................................................92 
17 PROGRAMMING AND DATA PRESENTATION CONVENTIONS...............93 
17.1 
Treatment Labelling ............................................................................................93 
17.2 
Visit Labelling ......................................................................................................93 
17.3 
Baseline Definitions ..............................................................................................94 
17.4 
Study Day, Duration and Time Derivation .......................................................94 
17.5 
Decimal Places ......................................................................................................95 
18 TABLES, FIGURES AND LISTINGS ...................................................................96 
19 APPENDIX ..............................................................................................................114 
19.1 
Appendix I – Changes to COMP 001 Protocol ................................................114 
19.2 
Appendix II – Reference of Section Changes from SAP Version 1 ...............121 
 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ANCOVA 
Analysis of Covariance 
bpm 
beats per minute 
CAT 
Clinical Assessment Technologies 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
COMPASS 
COMPASS Pathfinder Limited 
CRP 
C-Reactive Protein 
CSR 
Clinical Study Report 
dp 
decimal place 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
DSMB 
Data and Safety Monitoring Board 
eCRF 
electronic Case Report Form 
eCTD 
electronic Common Technical Document 
EDC 
Electronic Data Capture 
EOS 
End of Study 
ET 
Early Termination 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GLMM 
Generalised Linear Mixed Model 
HR 
Hazard Ratio 
HRQoL 
Health-Related Quality of Life 
ICF 
Informed Consent Form 
ICH 
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IP 
Independent programming 
IWRS 
Interactive Web-based Response System 
kg 
Kilogram 
l 
Litres 


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Abbreviation 
Definition 
LS 
Least Squares 
MAR 
Missing At Random 
MCMC 
Markov Chain MonteCarlo 
MDD 
Major Depressive Disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
min 
minute(s) 
mg 
Milligram 
mITT 
modified Intent-to-Treat 
MM 
Medical Monitor 
mmHg 
millimetres of mercury  
MMRM 
Mixed Model for Repeated Measures 
MNAR 
Missing Not At Random 
msec 
millisecond(s) 
OR 
Odds Ratio 
PD 
Protocol Deviation 
PP 
Per Protocol 
PT 
Preferred Term 
P-TRD 
Psilocybin for Treatment-Resistant Depression 
QC 
Quality Control 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error 
SOC 
System Organ Class 
TFLs 
Tables, Figures and Listings 
TRD 
Treatment-resistant Depression 
UK 
United Kingdom  
WHO 
World Health Organisation 
Worldwide 
Worldwide Clinical Trials, Inc. 
 


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LIST OF PARAMETERS 
 
Parameter 
Definition 
Efficacy 
5D-ASC 
Five Dimensional - Altered States of Consciousness questionnaire 
ASRS 
Adult Self-Report Scale 
DSST 
Digits Symbol Substitution Test 
EBI 
Emotional Breakthrough Inventory 
EQ-5D-3L 
EuroQoL-5 Dimensions-3 Levels 
EQ VAS 
EuroQoL Visual Analogue Scale 
GAD-7 
Generalised Anxiety Disorder Scale – 7 item 
HAM-D-17 
Hamilton Depression Rating Scale – 17 item 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MGH-ATRQ 
Massachusetts General Hospital-Antidepressant Treatment History Questionnaire 
MINI 7.0.2 
Mini International Neuropsychiatric Interview, Version 7.0.2 
MSI-BPD 
McLean Screening Instrument for Borderline Personality Disorder 
PANAS 
Positive and Negative Affect Schedule 
QIDS-SR-16 
Quick Inventory of Depressive Symptomatology – Self-Rated 16 item 
SDS 
Sheehan Disability Scale 
STAR-C 
Scale to Assess Therapeutic Relationship – Clinician version 
STAR-P 
Scale to Assess Therapeutic Relationship – Patient version 
VAS 
Visual Analogue Scale 
WSAS 
Work and Social Adjustment Scale  
 
 
Study Disposition 
BMI 
Body Mass Index 
 
 
Safety 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
alkaline phosphatase  


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Parameter 
Definition 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
electrocardiogram 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
S-STS 
Sheehan Suicidality Tracking Scale 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
 
 
 
 
 
 


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1 INTRODUCTION 
This statistical analysis plan (SAP) is based on the final protocol (V4.0) dated 19 July 2019. 
The plan covers statistical analysis, tables, figures and listings (TFLs) of the study data to 
investigate the safety and efficacy of COMP360 in participants with treatment-resistant 
depression (TRD). COMP360 is COMPASS Pathfinder Limited’s (COMPASS) 
proprietary pharmaceutical-grade synthetic psilocybin formulation that has been optimised 
for stability and purity. 
The SAP is prepared by Worldwide Clinical Trials, Inc. (Worldwide). The statistical 
analyses and production of the outputs described in the SAP, as well as the quality control 
(QC), will be conducted by Worldwide using SAS® Version 9.4 or later.1 The final 
analyses and outputs will be approved by COMPASS. 
Any statistical analysis details described in this document supersede any description of 
statistical analysis in the protocol. 


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2 STUDY OBJECTIVES 
The main purpose of this study is to allow COMPASS to determine the optimal dose of 
COMP360, either 10 mg or 25 mg. The intent of the primary efficacy analysis is to 
demonstrate superiority of at least one optimal therapeutic dose of COMP360 (10 mg or 
25 mg) versus the 1 mg COMP360 via the following objectives. 
2.1 
Primary 
The primary objective of this study is to evaluate the efficacy of COMP360 (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 2, and weeks 1, 3, 6, 9, and 12. 
2.2 
Secondary 
The secondary objectives are: 
• To assess the efficacy of COMP360 compared to 1 mg COMP360 on: 
• 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 2 and at weeks 
1, 6, 9, and 12. 
• The proportion of participants who have a sustained response at week 12. Sustained 
response is defined as the proportion of participants fulfilling response criteria at 
any visit up to and including week 3, that also fulfils 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 COMP360 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. 
2.3 
Exploratory  
The exploratory objectives are: 
• To evaluate the effects of COMP360 on quality of life and wellbeing, functioning and 
associated disability, cognitive function, and anxiety compared to 1 mg COMP360 on: 


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• Quality of life in participant EuroQoL (EQ) 5 dimensions 3 levels scale (EQ-5D-
3L) score change from baseline to week 3. This will also be assessed at week 12. 
• 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. 
• 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. 
• 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 2 and week 
12. 
• 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. 
• 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 screening, day 2, and weeks 
1, 2, 6, 9, and 12. 
• Psychosocial functioning 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. 
• To evaluate the impact of different COMP360 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 


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• 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. 
• Positive and Negative Affect Schedule (PANAS), Five Dimension Altered States of 
Consciousness Questionnaire (5D-ASC) and Scale to Assess Therapeutic Relationship 
(Clinician and Patient version, STAR-C and STAR-P, respectively) will be assessed 
for correlation with the primary outcome as possible predictors of response. 


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3 STUDY ENDPOINTS  
3.1 
Primary 
The primary endpoint is the change in MADRS total score from baseline (day -1) to 3 
weeks post COMP360. 
3.2 
Secondary 
The secondary endpoints are: 
• The proportion of participants with a response (defined as a ≥ 50% improvement in 
MADRS total score from baseline) at week 3 after the COMP360 session. 
• The proportion of participants with remission (defined as a MADRS total score ≤ 10) 
at week 3 post COMP360. 
• The proportion of participants who have a sustained response at week 12. Sustained 
response is defined as the proportion of participants fulfilling response criteria at any 
visit up to and including week 3, that also fulfils response criteria at all subsequent 
visits up to and including week 12. Response is defined as ≥ 50% decrease in MADRS 
total score from baseline. 
• Time to event measures: restart antidepressant medication for any reason, restart 
medication for continuing depressive symptoms, and relapse from a previously 
recovered state. Participants who withdraw from the study will be censored from the 
time to event analysis. 
3.3 
Exploratory 
The exploratory endpoints are: 
• Change from baseline in the following: 
• Participant EQ-5D-3L at week 3 
• Caregiver EQ-5D-3L at week 3 (this assessment is not mandatory) 
• SDS at week 3 
• DSST at week 3 
• GAD-7 at week 3 


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• QIDS-SR-16 at week 3 
• WSAS at week 3 
• Measures derived from smart phone usage via the Mindstrong app 
3.4 
Safety Assessments 
• Electrocardiogram (ECG) 
• Vital signs 
• Blood test including liver function tests 
• Suicide risk as assessed by the C-SSRS 
• AEs and serious adverse events (SAEs) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4 ESTIMAND FRAMEWORK 
4.1 
Primary Endpoint 
The primary objective is to understand the clinical effects of COMP360 without the effects 
of participants taking new treatment for depression. This is reflected in the trial design, 
where participants are encouraged not to take new treatments for depression for at least 3 
weeks post-dose. However, it would be unethical to preclude the use of any rescue 
medication at any stage during the study. Participants who start antidepressant treatment 
during the first three weeks of the study will be followed up in the study until 12 weeks 
post study drug administration regardless, as will those who initiate new treatments after 
three weeks. To answer this objective, the estimand framework and statistical analyses will 
need to account for whether participants begin new treatments for depression. The 
Hypothetical Strategy best answers this.   
The estimand attributes for the primary endpoint are: 
• Treatment: COMP360 (25 mg or 10 mg) versus COMP360 1 mg 
• Population: Participants with TRD, as defined by the inclusion/exclusion criteria 
• Variable: Change from baseline in MADRS total score at week 3 
• Intercurrent event: Initiation of new treatment for depression post-dose 
• Population-level summary: Mean difference 
The Hypothetical Strategy will be the primary estimand to best understand the clinical 
effects of COMP360 without the effects of participants taking new treatments for 
depression, as outlined above. Specifically, the primary estimand will be as follows:  
The mean difference (population-level summary) between COMP360 (25 mg or 10 mg) 
and COMP360 1 mg (treatment) in participants with TRD, as defined by the 
inclusion/exclusion criteria (population) assessing the change from baseline in MADRS 
total score at week 3 (variable) if new treatment for depression is not available post-dose 
(intercurrent event). 
The Treatment Policy will be the secondary estimand to understand the clinical effects of 
COMP360 including participants taking new treatment for depression if needed. 
Specifically, the secondary estimand will be as follows:  
The mean difference (population-level summary) between COMP360 (25 mg or 10 mg) 
and COMP360 1 mg (treatment) in participants with TRD, as defined by the 
inclusion/exclusion criteria (population) assessing the change from baseline in MADRS 
total score at week 3 (variable) regardless of whether participants take new treatment for 
depression post-dose (intercurrent event). 


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Table 1 below provides further details for each of the above estimands including analysis 
methods, imputation approaches and any planned supplementary/sensitivity analyses. 


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Table 1 Summary of Estimand Framework – Primary Endpoint 
Study Objective 
Study Endpoint 
Estimand 
Analysis Type 
Analysis Details 
To evaluate the efficacy of 
COMP360 (25 mg or 10 
mg) compared to 1 mg, 
administered under 
supportive conditions to 
adult participants with 
TRD, in improving 
depressive symptoms. 
Change in MADRS total 
score from baseline (day -
1) to 3 weeks post 
COMP360. 
Hypothetical Strategy: the mean 
difference between COMP360 
(25 mg or 10 mg) and COMP360 
1 mg in participants with TRD, as 
defined by the 
inclusion/exclusion criteria, 
assessing the change from 
baseline in MADRS total score at 
week 3 if new treatment for 
depression is not available post-
dose. 
Primary 
Missing not at random (MNAR) 
imputation for data after start of new 
treatment for depression and a missing at 
random (MAR) and MNAR imputation 
for data-points after study discontinuation 
and MAR for non-monotone missing data 
+ Mixed Model for Repeated Measures 
(MMRM)  
Sensitivity 
Tipping-point analysis: delta-imputation 
approach (MNAR) for all data imputed in 
the primary analysis + MMRM 
Supplementary 
Primary analysis imputation methods + 
Analysis of Covariance (ANCOVA) 
Treatment Policy: the mean 
difference between COMP360 
(25 mg or 10 mg) and COMP360 
1 mg in participants with TRD, as 
defined by the 
inclusion/exclusion criteria, 
assessing the change from 
baseline in MADRS total score at 
week 3 regardless of whether 
participants take new treatment 
for depression post-dose. 
 
Main 
MAR and MNAR imputation for data-
points after study discontinuation and 
MAR for non-monotone missing data + 
MMRM 
Sensitivity 
1) Tipping-point analysis: delta-
imputation approach (MNAR) for all data 
imputed in the main analysis of this 
estimand + MMRM 
2) MMRM with no imputation for 
missing data 
Supplementary 
Main analysis imputation methods + 
ANCOVA 


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4.2 
Key Secondary Endpoint 
A composite strategy will be adopted to define the primary estimand for the following key 
secondary endpoints: 
• The proportion of participants with a response (defined as a ≥ 50% improvement in 
MADRS total score from baseline) at week 3 after the COMP360 session. 
• The proportion of participants with remission (defined as a MADRS total score ≤ 10) 
at week 3 post COMP360. 
• The proportion of participants who have a sustained response at week 12. Sustained 
response is defined as the proportion of participants fulfilling response criteria at any 
visit up to and including week 3, that also fulfils response criteria at all subsequent 
visits up to and including week 12. Response is defined as ≥ 50% decrease in MADRS 
total score from baseline. 
The formal estimand definition for the first key secondary endpoint (MADRS response at 
week 3) using the Composite Strategy is as follows: 
The odds ratio (population-level summary) between COMP360 (25 mg or 10 mg) and 
COMP360 1 mg (treatment) in participants with TRD, as defined by the 
inclusion/exclusion criteria (population), assessing the MADRS response at week 3 where 
a responder is defined as a participant satisfying the MADRS response criteria who does 
not take new treatment for depression (variable and intercurrent event). 
A similar definition applies for the other two key secondary endpoints. 
A secondary estimand following the Treatment Policy will also be considered, using a 
similar definition as for the primary endpoint. The formal estimand definition for the first 
key secondary endpoint (MADRS response at week 3) using the Treatment Policy strategy 
is as follows: 
The odds ratio (population-level summary) between COMP360 (25 mg or 10 mg) and 
COMP360 1 mg (treatment) in participants with TRD, as defined by the 
inclusion/exclusion criteria (population) assessing the MADRS response at week 3 where 
a responder is defined as a participant satisfying the MADRS response criteria (variable) 
regardless of whether participants take new treatment for depression (intercurrent event). 
All estimands and analyses for the primary and key secondary endpoints are specified in 
Table 2. 


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Table 2 Summary of Estimand Framework – Key Secondary Endpoints 
 
Study Objective 
Study Endpoint 
Estimand 
Analysis Type 
Analysis Details 
To evaluate the efficacy 
of COMP360 (25 mg or 
10 mg) compared to 1 mg, 
administered under 
supportive conditions to 
adult participants with 
TRD, in improving 
depressive symptoms 
The proportion of 
participants with a 
MADRS response 
at week 3 after the 
COMP360 session 
Composite Strategy: the odds ratio between 
COMP360 (25 mg or 10 mg) and COMP360 
1 mg in participants with TRD, as defined 
by the inclusion/exclusion criteria, assessing 
MADRS response at week 3 where a 
responder is defined as a participant 
satisfying the MADRS response criteria who 
does not take new treatment for depression  
Main 
Non-responder imputation for all data-
points after (i) the start of new 
treatment for depression or (ii) study 
discontinuation (lack of efficacy or 
adverse event [AE]), and dichotomised 
MADRS scores from missing at 
random (MAR) imputation (main 
analysis) of Hypothetical Strategy 
estimand for the primary endpoint + 
Generalised Linear Mixed Model 
(GLMM)  
Sensitivity 
- 
Supplementary 
Non-responder/MAR imputation (see 
main analysis) + logistic regression by 
visit 
Treatment Policy: the odds ratio between 
COMP360 (25 mg or 10 mg) and COMP360 
1 mg in participants with TRD, as defined 
by the inclusion/exclusion criteria assessing 
MADRS response at week 3 regardless of 
whether participants take new treatment for 
depression 
Main 
Non-responder imputation for all data-
points after study discontinuation (lack 
of efficacy or AE), and dichotomised 
MADRS scores from MAR imputation 
(main analysis) of the Treatment Policy 
estimand for the primary endpoint + 
GLMM 
Sensitivity 
GLMM with no imputation 
Supplementary 
Non-responder imputation for all data-
points after study discontinuation (lack 
of efficacy or AE), and dichotomised 
MADRS scores from MAR imputation 
(main analysis) of the Treatment Policy 
estimand for the primary endpoint + 
logistic regression by visit   
The proportion of 
participants with 
MADRS 
Composite Strategy: the odds ratio between 
COMP360 (25 mg or 10 mg) and COMP360 
1 mg in participants with TRD, as defined 
Main 
See first secondary endpoint 
Sensitivity 
Supplementary 


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Study Objective 
Study Endpoint 
Estimand 
Analysis Type 
Analysis Details 
remission at week 
3 after the 
COMP360 session 
by the inclusion/exclusion criteria, assessing 
MADRS remission at week 3 where a 
remitter is defined as a participant satisfying 
the MADRS remission criteria who does not 
take new treatment for depression 
Treatment Policy: the odds ratio between 
COMP360 (25 mg or 10 mg) and COMP360 
1 mg in participants with TRD, as defined 
by the inclusion/exclusion criteria assessing 
MADRS remission at week 3 regardless of 
whether participants take new treatment for 
depression 
Main 
See first secondary endpoint 
Sensitivity 
Supplementary 
The proportion of 
participants with 
MADRS sustained 
response at week 
12 after the 
COMP360 session 
Composite Strategy: the odds ratio between 
COMP360 (25 mg or 10 mg) and COMP360 
1 mg in participants with TRD, as defined 
by the inclusion/exclusion criteria, assessing 
MADRS sustained response at week 12 
where a sustained responder is defined as a 
participant satisfying the MADRS sustained 
response criteria who does not take new 
treatment for depression 
Main 
Non-responder imputation for all 
participants that (i) start new treatment 
for depression or (ii) discontinue study 
(lack of efficacy or AE), and 
dichotomised MADRS scores from 
MAR imputation (main analysis) of 
Hypothetical Strategy estimand for the 
primary endpoint + logistic regression 
Sensitivity 
- 
Supplementary 
- 
Treatment Policy: the odds ratio between 
COMP360 (25 mg or 10 mg) and COMP360 
1 mg in participants with TRD, as defined 
by the inclusion/exclusion criteria assessing 
MADRS sustained response at week 12 
regardless of whether participants take new 
treatment for depression 
Main 
Non-responder imputation for all 
participants that discontinue study 
(lack of efficacy or AE), and 
dichotomised MADRS scores from 
MAR imputation (main analysis) of the 
Treatment Policy estimand for the 
primary endpoint + logistic regression  
Sensitivity 
- 
Supplementary 
Observed case analysis – logistic 
regression 
 


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5 STUDY DESIGN 
5.1 
Study Design 
This is a phase IIb, 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 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.  
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 (IWRS). 
After signing the informed consent form (ICF), participants will be assessed for their 
eligibility with the Mini International Neuropsychiatric Interview, version 7.0.2 (MINI 
7.0.2), the 17 item 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 (MSI-BPD). 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 
(ASRS). 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 participant 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 participant 
is eligible. Once approval is issued, the participant should then be invited for a screening 
V1a visit. The V1a visit is the point at which the participant begins tapering off their 
antidepressant and/or antipsychotic medications, if appropriate. The participant 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. The tapering period used 
in the study is set at the industry standard for depression trials.  


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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 COMP360 administration 
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 COMP360 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 COMP360 administration 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 eligibility. 
Participants cannot be progressed to V3 until this approval is received.  
The COMP360 administration session (V3, day 1) will last approximately 6 hours (h) and 
will be supported by a trained therapist. After the acute effects of COMP360 pass, 
participants will be evaluated for safety and accompanied home. On day 2 (V4), the day 
following COMP360 administration, participants will be seen in person for a safety check, 
assessment of suicidality, and to discuss their experience during the COMP360 
administration session.  
Participants will be seen at the clinic for screening (plus a minimum of three safety visits), 
baseline (day -1), study drug administration day (day 1), day 2, week 1, week 2, week 3, 
and week 12. Participants will also be contacted for follow-up, which can be conducted 
remotely, at week 6 and week 9. 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 and the baseline visit. 
The study schematic is presented in Section 5.2 and the schedule of assessments is 
presented in Section 5.3.


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5.2 
Study Schematic 
 
 
 
 
 
 
 
 
 
Abbreviations: D = day; EOS = End of Study; V = Visit 
 
 
 
Variable 
3-6 weeks 
Additional 
Weekly 
Visits 
(V1b, V1c, 
 
D-1  D1      D2 
Week 3 
Week 12 
Randomisation 
1:1:1 
25 mg COMP360 
72 participants 
10 mg COMP360 
72 participants 
1 mg COMP360 
72 participants 
Screening (V1) 
Screening (V1a) 
D-1: Baseline (V2) 
D1: COMP360 Session (V3) 
D2 (V4) 
Week 1 (V5) 
Week 2 (V6) 
Week 3 (V7) 
Week 6 (V8) 
Week 9 (V9)
Week 12 (EOS, V10) 


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5.3 
Schedule of Assessments 
3-6 weeks 
prior to 
Baseline 
Time Post COMP360 
Session 
 
Screen Visit2 
Screening 
Period 
Baseline 
(Day -1) 
COMP360 
session 
(Day 1) 
Day 2 
Week 1 
Day 8 
Week 2 
Day 15 
Week 3 
Day 22 
Week 6 
Day 43 
Week 9 
Day 64 
Week 12 
Day 85 
(ET) 
Visit 
1 
1a, 1b, 
etc 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Location of Visit1 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Remote 
Remote 
Clinic 
Allowable Window 
Weekly 
≤ 7 days 
none 
±1 day 
±1 day 
± 1 day 
± 3 days 
± 3 days 
± 7 days 
Clinic Assessments and Procedures 
Informed Consent 
✓ 
Medical History 
✓ 
✓ 
Inclusion/exclusion 
Criteria 
✓ 
✓ 
MINI 
✓ 
HAM-D-17 
✓ 
✓ 
MGH-ATRQ 
✓ 
STAR-C 
✓ 
C-SSRS3 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Vital signs 
✓ 
✓ 
✓ 
✓ 
Weight 
✓ 
Height 
✓ 
ECG 
✓ 
✓ 
Clinical laboratory 
tests and biomarker4 
✓ 
✓ 
✓ 
Urinalysis4 
✓ 
✓ 


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3-6 weeks 
prior to 
Baseline 
Time Post COMP360 
Session 
Screen Visit2 
Screening 
Period 
Baseline 
(Day -1) 
COMP360 
Session 
(Day 1) 
Day 2 
Week 1 
Day 8 
Week 2 
Day 15 
Week 3 
Day 22 
Week 6 
Day 43 
Week 9 
Day 64 
Week 12 
Day 85 
(ET) 
Visit 
1 
1a, 1b, 
etc 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Location of Visit1 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Remote 
Remote 
Clinic 
Allowable Window 
Weekly 
≤ 7 days 
none 
±1 day 
±1 day 
± 1 day 
± 3 days 
± 3 days 
± 7 days 
Urine Drug Screen4 
✓ 
✓ 
Urine Pregnancy Test5 
✓ 
✓ 
Documentation of 
Birth Control to be 
used6 
✓ 
2a polymorphism 
(optional) 
✓ 
Activate/deactivate 
Mindstrong (optional) 
✓ 
✓ 
Provide 
access 
to
psychoeducational 
material (Longboat) 
✓ 
✓9 
COMP360 dose 
✓10 
Prior/Concomitant 
Medications 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
AE/SAE 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Randomisation 
✓ 
Participant Completed Assessments 
5D-ASC 
✓7 
ASRS 
✓ 


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3-6 weeks 
prior to 
Baseline 
Time Post COMP360 
Session 
Screen Visit2 
Screening 
Period 
Baseline 
(Day -1) 
COMP360 
Session 
(Day 1) 
Day 2 
Week 1 
Day 8 
Week 2 
Day 15 
Week 3 
Day 22 
Week 6 
Day 43 
Week 9 
Day 64 
Week 12 
Day 85 
(ET) 
Visit 
1 
1a, 1b, 
etc 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Location of Visit1 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Remote 
Remote 
Clinic 
Allowable Window 
Weekly 
≤ 7 days 
none 
±1 day 
±1 day 
± 1 day 
± 3 days 
± 3 days 
± 7 days 
DSST 
✓ 
✓ 
✓ 
✓ 
EBI 
✓ 
EQ-5D-3L8 
✓ 
✓ 
✓ 
GAD-7 
✓ 
✓ 
✓ 
MSI-BPD 
✓ 
PANAS 
✓ 
✓ 
✓ 
QIDS-SR-16 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
SDS 
✓ 
✓ 
✓ 
STAR-P 
✓ 
WSAS 
✓ 
✓ 
✓ 
Remote-rater Assessment 
MADRS 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Abbreviations: 5D-ASC, Five Dimension Altered States of Consciousness Questionnaire; AE, adverse event; ASRS, Adult Self-Report Scale; C-SSRS, Columbia-Suicide Severity Rating Scale; DSM-5 
Diagnostic and Statistical Manual of Mental Disorders (5th edition); DSST, Digit Symbol Substitution Test; EBI, Emotional Breakthrough Inventory; 
ECG, electrocardiogram; EQ-5D-3L, EuroQoL 5-Dimension 3-Level; ET, early termination; GAD-7, Generalised Anxiety Disorder scale - 7 item; h, hour(s); HAM-D-17, Hamilton Depression Rating 
scale - 17 item; MADRS, Montgomery-Asberg Depression Scale; MGH-ATRQ, Massachusetts General Hospital Antidepressant Treatment History Questionnaire; MINI, Mini International 
Neuropsychiatric Interview; MSI-BPD, McLean Screening Instrument for Borderline Personality Disorder; PANAS, Positive and Negative Affect Schedule; QIDS-SR-16, Quick Inventory of Depressive 


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Symptomatology-Self-rated; SAE, serious adverse event; SDS, Sheehan Disability Scale; STAR-C, Scale to Assess the Therapeutic Relationship-Clinician; STAR-P, Scale to Assess the Therapeutic 
Relationship-Patient; WSAS, Work and Social Adjustment Scale 
 
1 On site clinic visits; visits allowed remotely will have the MADRS performed by telephone and other assessments will be done electronically. 
2 If additional visits are needed to ensure adequate time for discontinuation of prior antidepressant therapy, visits should occur weekly prior to the COMP360 administration session (V3). At subsequent 
screening  period visits (V1a, V1b, etc), medications taken and any changes in medications since the previous visit and C-SSRS will be obtained, in addition, to other assessments at the study 
clinician’s discretion. Assessments may be performed over several days, but all scales should be completed on the same day. 
3 The “Last 12 Months” version will be administered at screening and the “Since Last Visit” version will be administered at all other visits. 
4 See Protocol Section 7.2.4 for complete list of required tests to be performed. 
5 For women of child-bearing potential only. 
6 Site is to document method of contraception agreed to be used by each participant. 
7 To be administered immediately after the COMP360 administration session. 
8 The EQ-5D-3L will be administered to both the participant and their caregiver (latter is not mandatory). 
9 Longboat access can be granted at V1 or V1a at the study team’s discretion. 
10 After baseline data is entered into EDC the CAT team will complete a final review to ensure the participant’s continued eligibility. Participants cannot complete COMP360 administration at V3 until 
this  approval is received. 
11 Screening period visits should not be initiated until initial MM and CAT approval is received. Screening visits are to occur weekly 3-6 weeks prior to baseline, number of visits is determined by the 
length of the participant’s taper off antidepressant medication. 
 


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5.4 
Hypotheses and Treatment Comparisons 
The primary efficacy endpoint is the change from baseline in MADRS total score at week 
3. The primary analysis will be the comparison between COMP360 (25 mg or 10 mg) 
versus COMP360 1 mg and will be based on a two-sided hypothesis testing approach. The 
null and alternative hypotheses associated for this comparison are: 
H0: µCOMP360 (25 mg or 10 mg) - µCOMP360 1 mg = 0 
H1: µCOMP360 (25 mg or 10 mg) - µCOMP360 1 mg ≠ 0 
Where µCOMP360 (25 mg or 10 mg) and µCOMP360 1 mg represent the mean in change from baseline 
in MADRS total score at week 3 for COMP360 (25 mg or 10 mg) and COMP360 1 mg, 
respectively. 
The null hypothesis is that there is no difference between treatment groups for the primary 
efficacy endpoint and the alternative hypothesis is that there is a difference between 
treatment groups for the primary efficacy endpoint. 
5.5 
Multiplicity 
To control the overall Type I error rate a sequential test procedure will be applied across 
the primary and key secondary efficacy endpoints for both COMP360 doses (25 mg and 
10 mg) following the hierarchy specified below, with all testing done at the 0.05 alpha 
level: 
• Primary endpoint, change in MADRS total score from baseline to week 3 (25 mg vs 1 
mg) 
• Primary endpoint, change in MADRS total score from baseline to week 3 (10 mg vs 1 
mg) 
• Secondary endpoint, proportion of participants with a response (≥50% improvement in 
MADRS total score from baseline) at week 3 (25 mg vs 1 mg) 
• Secondary endpoint, proportion of participants with a response (≥50% improvement in 
MADRS total score from baseline) at week 3 (10 mg vs 1 mg) 
• Secondary endpoint, proportion of participants with remission (MADRS total score 
≤10) at week 3 (25 mg vs 1 mg) 
• Secondary endpoint, proportion of participants with remission (MADRS total score 
≤10) at week 3 (10 mg vs 1 mg) 
• Secondary endpoint, proportion of participants who have a sustained response at week 
12 (25 mg vs 1 mg) 
• Secondary endpoint, proportion of participants who have a sustained response at week 
12 (10 mg vs 1 mg) 


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The above hierarchical procedure will apply only to results from the main analysis of the 
primary study estimand (“Hypothetical Strategy”) and will continue until the first non-
significant test is observed. If a non-significant p-value is observed, the remaining 
endpoints will still have nominal p-values presented but will only be assessed descriptively. 
5.6 
Sample Size Considerations 
The intent of the primary efficacy analysis is to demonstrate superiority of at least one 
therapeutic dose of COMP360 (10 mg or 25 mg) versus the 1 mg COMP360 dose based 
on the change from baseline in MADRS total score at week 3. The three treatment groups 
will be randomised in a 1:1:1 ratio. 
For this primary analysis, a sample size of 216 randomised participants (72:72:72) will 
provide 90% power at the alpha = 0.05 level to detect a 6-point difference in average 
MADRS total score between the optimal therapeutic dose of COMP360 and COMP360 1 
mg, assuming the common standard deviation (SD) is 11.0.  
The 6-point difference in average MADRS total score on a group level is supported by the 
pilot study with psilocybin (non COMP360 formulation)2 and is within the range of 
potential differences that have been used to power other studies in major depression and 
treatment-resistant depression (TRD). The assumed SD of 11.0 is based on a review of 
other studies for this condition. 
It is assumed that up to 90% of randomised participants may not have prior psilocybin 
experience. The power for this post-hoc subgroup is approximately 86%, if the maximum 
number of participants to have prior psilocybin experience was 10% of randomised 
participants. 
5.7 
Randomisation 
Study participants will be randomised at a 1:1:1 ratio to receive either: 
• COMP360 1 mg (72 participants) 
• COMP360 10 mg (72 participants) 
• COMP360 25 mg (72 participants) 
 
 
 
 
 
 
 
 


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6 PLANNED ANALYSES 
6.1 
Final Analysis 
The SAP will be finalised before database lock. Final data analysis will be conducted after 
database lock. The tables, figures and listings planned in this document will be included in 
the final analysis. 
6.2 
Interim Analysis 
The protocol stated there may be a blinded interim analysis after approximately 50% of the 
planned 216 participants had been randomised and had an opportunity to complete three 
weeks of the study after receiving the study drug. The purpose of this blinded interim would 
have been to perform an assessment of the overall combined (across all treated participants) 
SD of the change from baseline in the MADRS collected at week 3. However, upon review, 
it was decided not to perform a blinded interim analysis and to await the final results. 
6.3 
Data Safety Monitoring Board (DSMB) 
An independent DSMB, composed of experts in the management of participants with the 
disease under study and a biostatistician, reviewed selected safety data at predefined 
intervals during the study. The primary purpose of this committee was to review safety 
data for the protection of participant safety. A DSMB Charter defines the primary 
responsibilities of the DSMB, COMPASS, and Worldwide, the purpose and timing of 
meetings, quorum, and voting details. The Charter also provides the procedures for 
confidentiality, communication, and a description of the deliverables that were provided to 
and reviewed by the DSMB. 
The DSMB advised COMPASS and made recommendations regarding continuation of the 
study and modification to the protocol or study procedures in order to protect the 
participants enrolled in the study. 


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7 ANALYSIS SETS 
 
Analysis Set 
Definition 
Randomised Analysis Set 
All randomised participants, whether or not they receive 
study drug. 
Safety Analysis Set 
All randomised participants who receive study drug.  
Outputs based on this analysis set will use the actual 
treatment received by the study participant. 
Full Analysis Set (FAS) 
All participants randomised who receive study drug and 
have at least 1 post-dose efficacy assessment.  
Outputs based on this analysis set will use the treatment 
the study participant was randomised to. 
Per Protocol (PP) Analysis Set  
All participants in the FAS who do not have a protocol 
deviation (PD) that is thought to significantly affect the 
integrity of the participant’s efficacy data.  
 
The Safety Analysis Set will be used for all safety-related evaluations. The Randomised 
and Safety Analysis Sets will be used for study participant-related evaluations. The FAS 
will be used for all efficacy-related evaluations, with the PP Analysis Set being used for 
sensitivity analyses for certain efficacy-related evaluations. Outputs based on the FAS, PP 
and Randomised Analysis Set will use the treatment the study participant was randomised 
to. 
PDs thought to significantly affect the integrity of the particpant’s efficacy data will be 
identified and documented during the blinded data review meeting prior to database lock 
and confirmed at the time of database lock, prior to routine study unblinding. 
 


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8 GENERAL CONSIDERATIONS 
All TFLs will be created using SAS® version 9.4 or later.1  
Listings will be sorted in the following order: treatment group, participant, parameter, and 
visit unless otherwise stated. All data will be listed.  
Participant disposition, baseline/demographics and safety summaries will be presented 
jointly for all treatment arms whereas efficacy analysis and summaries will be split by 
study. 
Unless otherwise specified, “baseline” is defined as the last observed value of the 
parameter of interest prior to dosing for each period. Unless otherwise stated, if baseline 
data is missing no derivation will be performed and baseline will be set to missing. For 
numerical variables, change from baseline will be calculated as the difference between the 
value of interest and the corresponding baseline value.  
Continuous data will be summarised descriptively using N (number of participants in the 
analysis set), n (number of observations), mean, SD, median, minimum and maximum. 
Categorical data will be summarised using frequency counts and percentages.  
The denominator for a percentage will be the total number of participants in the relevant 
treatment group or analysis set, unless otherwise specified (on some occasions, percentages 
may be calculated using the total number of participants with available data at a particular 
visit or time point as the denominator). 
Summaries will be presented by treatment (and overall, where relevant), unless otherwise 
specified. 
Unless otherwise specified, all formal statistical tests will be performed at the 5% two-
sided significance level. 
Unscheduled visits and retests (same visit number assigned) will not be displayed in by-
visit summary tables but will be included in the data listings. 
All individual participant data will be listed. Listings will include scheduled, unscheduled, 
retest and early study discontinuation data. 
All medical histories and AEs will be coded from the actual term using the Medical 
Dictionary for Regulatory Activities (MedDRA) version 23.0 or later.   
All prior and concomitant medications will be coded using the World Health Organization 
Drug Dictionary Enhanced (WHO-DDE) (March 2020 Version or later). 
 
 


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9 DATA DERIVATIONS 
This section describes the derivations required for statistical analysis. Unless otherwise 
stated, variables derived in the source data will not be re-calculated. 
9.1 
General  
9.1.1 
Change from Baseline 
Definition 
Derivation 
Change from baseline  
= 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝– 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣−𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 
Change from baseline (%) 
=ቂ
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝–𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣−𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣
ቃ× 100 
If there is no baseline or post-dose visit value, then both the absolute and percentage change 
from baseline will be set to missing. 
9.1.2 
Missing and Partial Dates 
All rules explained below for partial / missing dates will be followed unless contradicted 
by any other data recorded on the electronic Case Report Form (eCRF). 
All dates presented in the individual participant listings will be as recorded on the eCRF. 
In case of partial eCRF entries, the rules described in Sections 9.2.5 and 9.4.2 will be used 
for date imputation for the purposes of deriving ancillary quantities (e.g. study day, 
duration of an event, etc) but only partial dates will be presented in the listings. 
9.1.3 
Treatment Exposure and Compliance 
Since administration of COMP360 occurs only once, calculations of treatment exposure 
and compliance are not applicable. 
9.1.4 
Inexact Values 
In the case where a variable is recorded as “> x”, “≥ x”, “< x” or “≤ x”, a value of x will 
be taken for analysis purposes. This rule will be applied to continuous laboratory parameter 
values only for summary tables, whereas listings will show the actual value recorded 
(inclusive of the non-numeric symbol). 
9.2 
Study Participants 
9.2.1 
Protocol Deviations 
A PD is any change, divergence or departure from the protocol or investigational plan. PDs 
will be categorised as follows (detailed PD definitions can be found in the protocol 
deviation handling plan: 
1. ‘Important’ from a reporting (TFL/CSR) perspective  


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2. PDs that would exclude the participant from the PP analysis set 
9.2.2 
Age Categories 
The following age categories will be derived: 
• 18-34 years 
• 35-64 years 
• 65-84 years  
• > 84 years 
9.2.3 
Body Mass Index (BMI) 
The BMI will be recalculated at screening using the formula:  
𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 (𝑘𝑘𝑘𝑘) ℎ𝑒𝑒𝑒𝑒𝑒𝑒ℎ𝑡𝑡 (𝑚𝑚)2
⁄
 
BMI will not be calculated for participants enrolled under protocol versions prior to version 
4.0 because height was not planned to be collected at screening for earlier protocol 
versions. 
9.2.4 
Length of Current Depressive Episode 
The length in months of the current depressive episode will be calculated as follows: 
12 × ൤𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑒𝑒𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑−𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑡𝑡ℎ𝑒𝑒 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒
365.25
൨ 
The length of the current depressive episode will also be categorised as follows: 
• < 1 year 
• ≥ 1 year to < 2 years 
• ≥ 2 years 
9.2.5 
Missing Major Depressive Disorder (MDD) Episode Start Dates 
If the month and year for the start date of the current MDD episode are present but the day 
is missing, the diagnosis date will be set to the first day of the relevant month. If only the 
year is recorded the diagnosis date will be set as “01-Jan” for that year. 
This imputation rule will only be implemented to derive the length of the current depressive 
episode (see Section 9.2.4), and the imputed date will not be used elsewhere (ie partial 
dates will be presented in the listings, as recorded). 


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9.2.6 
Prior Psilocybin Experience 
A participant will be considered to have a prior psilocybin experience if they have had a 
prior psychedelic experience that was greater than 12 months prior to screening and that 
this experience was psilocybin (if the experience is missing then this will be considered as 
having a prior psilocybin experience). In addition, the date of the last psilocybin experience 
must have been earlier than the current MDD start date. 
9.2.7 
Prior and Concomitant Medications 
Prior medication refers to any medication that was stopped prior to the start of the 
study/taken during the 30-day period before signing the ICF. Concomitant medication 
refers to the use of any ongoing medication use at the time of the start of the study/all 
medications taken after the ICF has been signed. 
9.3 
Efficacy Assessments 
9.3.1 
Montgomery-Asberg Depression Rating Scale Score (MADRS) 
The MADRS is a clinician rated scale measuring depression severity, consisting of the 
following 10 individual items: 
1. reported sadness 
2. apparent sadness 
3. inner tension 
4. reduced sleep 
5. reduced appetite 
6. concentration difficulties 
7. lassitude 
8. inability to feel 
9. pessimistic thoughts 
10. suicidal thoughts 
Each item has a score ranging from 0 (normal) to 6 (severe), with higher scores denoting 
greater severity. 
MADRS data will be obtained at baseline, day 2 (day 1 according to the study protocol, 
see Section 17.2 for mapping), and weeks 1, 3, 6, 9, and 12. 
9.3.1.1 
Total Score 
The MADRS total score (ranging from 0 – 60) is derived by summing up the scores from 
the 10 individual items.  


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9.3.1.2 
MADRS Responder Status 
A participant is defined as a MADRS responder at a post-baseline visit if they meet the 
following:  
−50% ≤𝑐𝑐ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 (%)  
The derivation of MADRS change from baseline (%) is defined in Section 9.1.1. 
9.3.1.3 
MADRS Remitter Status 
A MADRS remitter is defined as a participant whose MADRS total score value is ≤10 at a 
post-baseline visit. 
9.3.1.4 
MADRS Sustained Response 
A participant is defined as a MADRS sustained responder to treatment if they fulfil the 
MADRS response criteria defined in Section 9.3.1.2 at any visit up to and including week 
3, and also fulfil MADRS response criteria at all subsequent visits up to and including 
week 12. In practice, this means that to be a sustained responder at week 12 a participant 
needs to satisfy the MADRS response criteria at all timepoints from week 3 to week 12. 
The table below summarises the scenarios that would lead to assigning a sustained response 
status at week 12: 
 
Day 2 
Week 1 
Week 3 
Week 6 
Week 9 
Week 12 
O 
O 
O 
O 
O 
O 
O 
X 
O 
O 
O 
O 
X 
O 
O 
O 
O 
O 
X 
X 
O 
O 
O 
O 
     O: Response; X: Non-Response. 
A further relaxed definition of sustained responder is if a participant fulfils the MADRS 
response criteria at any visit up to and including week 3 and also fulfil the response criteria 
at week 12 and at least at one of week 6 or week 9 (where the previous main definition 
requires the participant to qualify as a responder at week 6, 9 and 12 to be classified as 
sustained responder). A similar table to the one presented above for the main sustained 
response definition is displayed below. The key difference between the two tables is that 
the 4 combinations for day 2 to week 3 that make up the previous table are now tripled to 
include the following options for week 6 to 12: 
• Participant is a MADRS responder at all assessments from week 6 to week 12 (first 4 
lines, same as previous table) 
• Participant is a MADRS responder at week 6 and 12 but not at week 9 (lines 5 to 8) 
• Participant is a MADRS responder at week 9 and 12 but not at week 6 (lines 9 to 12) 
 


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Day 2 
Week 1 
Week 3 
Week 6 
Week 9 
Week 12 
O 
O 
O 
O 
O 
O 
O 
X 
O 
O 
O 
O 
X 
O 
O 
O 
O 
O 
X 
X 
O 
O 
O 
O 
O 
O 
O 
O 
X 
O 
O 
X 
O 
O 
X 
O 
X 
O 
O 
O 
X 
O 
X 
X 
O 
O 
X 
O 
O 
O 
O 
X 
O 
O 
O 
X 
O 
X 
O 
O 
X 
O 
O 
X 
O 
O 
X 
X 
O 
X 
O 
O 
     O: Response; X: Non-Response. 
9.3.1.5 
MADRS Partial Responder Status 
A participant is defined as a MADRS partial responder at a post-baseline visit if they 
meet the following:  
−25% ≤𝑐𝑐ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 (%) < −50%  
The derivation of change from baseline (%) is defined in Section 9.1.1. 
9.3.1.6 
Severity Categories 
Baseline MADRS scores will be categorised as indicators of depression severity using the 
following categories3:  
• ≤ 10 = Subthreshold 
• 11 to 19 = Mild 
• 20 to 30 = Moderate 
• ≥ 31 = Severe 
9.3.2 
Quick Inventory of Depressive Symptomatology (QIDS-SR-16) 
The 16-item self-rated scale is designed to assess the severity of depressive symptoms. The 
following 9 symptom domains are used to obtain the total score: 
1. The highest score on any 1 of the 4 sleep items (1-4) 
2. The score on item 5 
3. The highest score on any 1 of the appetite/weight items (6-9) 
4. The score on item 10  
5. The score on item 11  
6. The score on item 12  
7. The score on item 13  


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8. The score on item 14  
9. The highest score on either of the 2 psychomotor items (15 and 16) 
The total score is obtained by summing the 9 symptom scores. The total score ranges from 
0 to 27 with 0 representing no depression and 27 representing severe depression.  
QIDS-SR-16 will be obtained at screening, baseline and all post-baseline timepoints up to 
week 12. 
9.3.3 
European Quality of Life 5-dimension 3-level Scale (EQ-5D-3L) 
The EQ-5D-3L is a multi-attribute instrument used in assessing the health-related quality 
of life (HRQoL) and includes two parts: 
• The EQ-5D descriptive system contains five dimensions: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. Each dimension has three levels: 1 
= no problems, 2 = some problems, 3 = severe problems. The responses to the five EQ-
5D dimensions will be converted into a 5-digit number (eg 12212) called a ‘health 
state’. The health state reflects how good or bad the health state is according to the 
preferences of the general population of a country/region. 
• The EQ visual analogue scale (VAS) records the participant’s self-rated health on a 
vertical VAS, where participants are asked to mark their self-rated health on a scale 
from 0 (‘worst imaginable health state’) to 100 (‘best imaginable health state’). 
In order to convert the health state to a continuous index value, value sets (ie weights 
ranging from 1 for a health state of 11111 to negative values for health states reflective of 
a poor condition such as 33333) will be retrieved from the EuroQoL website4. As suggested 
by EuroQoL, one collection of value sets will be used for all countries in the study, namely 
those for the United Kingdom (UK). The derivation is described in a paper from Dolan et 
al.5 and briefly described below. 
For each dimension of the EQ-5D-3L, two variables are defined: the first one takes values 
of 1 (if the dimension has a value of 2), 2 (if the dimension has a value of 3) and 0 otherwise, 
whereas the second takes a value of 1 if the dimension has a value of 3 and 0 otherwise. In 
addition, an ‘intercept’ is defined, which can either be 0 (if all dimensions have a value of 
1) or 1 otherwise, and a so-called interaction term, which can either be 0 (if no dimension 
has a value of 3) or 1 otherwise (at least one dimension has a value of 3). For each of these 
12 variables a regression coefficient is used to derive the ‘weight’ associated with a given 
5-digit health state. The model coefficients (taken from Table 1 of Dolan paper5) are 
reported in the table below: 
 
Model term 
Regression Coefficient 
Intercept (any dimension > 1) – D1 
0.081 
Mobility (Level 2) - MO 
0.069 


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Model term 
Regression Coefficient 
Self-care (Level 2) - SC 
0.104 
Usual Activities (Level 2) - UA 
0.036 
Pain/Discomfort (Level 2) - PD 
0.123 
Anxiety/Depression (Level 2) - AD 
0.071 
Mobility (Level 3) – MO2 
0.176 
Self-care (Level 3) – SC2 
0.006 
Usual Activities (Level 3) – UA2 
0.022 
Pain/Discomfort (Level 3) – PD2 
0.140 
Anxiety/Depression (Level 3) – AD2 0.094 
Interaction (any dimension = 3) – N3 0.269 
The continuous values are then derived using the following formula: 
EQ-5D-3Li = 1 – D1*β0 - MO*β1 - SC*β2 - UA*β3 - PD*β4 - AD*β5 – MO2*β6 – SC2*β7 
– UA2*β8 – PD2*β9 - AD2*β10 – N3*β11 
Where βj are the coefficients regression from the above table. As an example, a health state 
of 12212 would have an associated continuous value derived as follows: 
- 
The following variables have a value of 0: MO, PD, MO2, SC2, UA2, PD2, AD2, 
N3. Thus, the respective coefficients are irrelevant in the above formula 
- 
The prediction formula simplifies as follows: 
EQ-5D-3Li = 1 – 0.081 - 1*0.104 - 1*0.036 – 1*0.071 = 0.708 
If a component of the EQ-5D-3L was not collected, the 5-digits health state will be recorded 
with ‘-‘ to identify these gaps (e.g. 132-1, implying that the pain/discomfort item was not 
marked) and the continuous score will not be derived and set to missing for analysis 
purposes. 
EQ-5D-3L data will be obtained at baseline, weeks 3 and 12.  
9.3.4 
Sheehan Disability Scale (SDS) 
This brief, 5-item self-report inventory assesses functional impairment in work/school 
(score ranges from 0 to 10), social life (score ranges from 0 to 10), and family life (score 
ranges from 0 to 10). The sum of the above 3 domains scores lead to a total score ranging 
from 0 to 30 with 0 representing no impairment and 30 representing severe impairment. If 
a participant ticks the ‘I have not worked/studied at all during the past week for reasons 
unrelated to the disorder’ box, then no SDS total score can be derived (irrespective of 
whether the work/school item was answered or not) and only the individual answers for 
that participant will only be included in the listings. 
SDS data will be obtained at baseline, weeks 3 and 12. 


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9.3.5 
Digit Symbol Substitution Test (DSST) 
The DSST consists of a look-up table showing pairs of digits and hieroglyphic-like symbols 
and rows of boxes with a digit in the top section and an empty space in the bottom section 
of each box. A participant’s score is the number of correct symbols within the allowed time 
(90 sec).  
The number of correct symbols will be categorised for reporting purposes as follows: ≤29, 
> 29 and ≤ 39, > 39 and ≤ 48 and > 48. 
DSST data will be obtained at baseline, day 2 weeks 3 and 12. 
9.3.6 
Generalised Anxiety Disorder Scale (GAD-7) 
The Generalised Anxiety Disorder (GAD)-7 is a 7 item self-report anxiety questionnaire 
designed to assess the participant’s health status during the previous 2 weeks. Scores of 0, 
1, 2 or 3 are given for experiencing symptoms ‘not at all’, for ‘several days’, for ‘more than 
half the days’ and for ‘nearly every day’, respectively. The scores are then totalled and 
presented from 0 to 21.  
GAD-7 data will be obtained at baseline, weeks 3 and 12. 
9.3.7 
Work and Social Adjustment Scale (WSAS) 
The Work and Social Adjustment Scale (WSAS) is a 5-item self-report scale used to assess 
psychosocial functioning. Each of the 5 questions is rated on a scale from 0 to 8, where 0 
is no impairment and 8 is very severe impairment. The total WSAS score is obtained by 
adding up responses for each individual question, with a range from 0 to 40. A WSAS 
score above 20 appears to suggest moderately severe or worse psychopathology. Scores 
between 10 and 20 are associated with significant functional impairment but less severe 
clinical symptomatology. Scores below 10 appear to be associated with subclinical 
populations. 
WSAS data will be obtained at baseline, weeks 3 and 12. 
9.3.8 
Mini International Neuropsychiatric Interview 
The Mini International Neuropsychiatric Interview (MINI) is the structured psychiatric 
interview of choice for psychiatric evaluation and outcome tracking in clinical 
psychopharmacology trials and epidemiological studies. The MINI is divided into modules 
corresponding to a diagnostic category. The MINI has similar reliability and validity 
properties compared to Structured Clinical Interview for DSM Disorders using Version 5 
of the DSM (SCID-5) and the Composite International Diagnostic Interview (CIDI), a 
structured interview developed by the World Health Organization. In this study, version 
7.0.2 of the MINI will be used. 
MINI data will be obtained at screening only. 


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9.3.9 
Hamilton Depression Rating Scale – 17-Item (HAM-D-17) 
The Hamilton Depression Rating scale (HAM-D) has been used in determining a 
participant’s level of depression before, during, and after treatment. The questionnaire is 
available in both a 17 and 21 item version. In this study, the 17-item version was utilised. 
Nine items are scored on a 5-point scale ranging from 0 to 4, 7 items are scored on a 3-
point scale ranging from 0 to 2, and the remaining item is scored on a 4-point scale ranging 
from 0 to 3. The total score is obtained as the sum of the individual items scores from this 
assessment (values ranging from 0 to 53) and will be used as an eligibility criterion prior 
to treatment (minimal total symptom score ≥ 18). 
HAM-D-17 total scores at baseline will be categorised as moderate (18-23) or severe (≥24) 
depression. 
HAM-D-17 data will be obtained at screening and baseline only. 
9.3.10 
The Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire (MGH-ATRQ) 
The MGH-ATRQ is a self-rated scale used to determine treatment-resistance in major 
depressive disorder (MDD). The MGH-ATRQ defines 6 weeks on an adequate dose of 
antidepressant medication as an adequate duration of treatment. It also provides specific 
operational criteria for adequate dosage for each of the most commonly used 
antidepressants. The ATRQ examines the efficacy using the following categorised ratings:  
<25% improved; 25%-49% improved; 50%-75% improved and >75% improved. A rating 
of 100% is completely improved and a rating of 0% is not improved at all. 
MGH-ATRQ data will be obtained at screening only. 
9.3.11 
McLean Screening Instrument for Borderline Personality Disorder (MSI-
BPD) 
The MSI-BPD is a commonly used measure to assess for BPD. The scale consists of 10 
items based on the DSM-5 BPD criteria; the first 8 items represent the first eight criteria in 
the DSM-5 for BPD diagnosis, while the last two questions assess the paranoia and 
dissociation criteria for BPD. Scores for the MSI-BPD range from 0 to 10, with each item 
rated as “1” if present and “0” if absent. A score of 7 or higher (obtained as the sum of the 
individual items scores) indicates a likelihood for the participant to meet criteria for BPD. 
The MSI-BPD will be obtained at screening only. 
9.3.12 
Adult Self-Report Scale (ASRS) 
The ASRS is a self-reported questionnaire used to determine the presence of attention 
deficit hyperactivity disorder (ADHD) in adults. The screener (6-item) version of the scale 
based on the DSM-5 will be used in this study. The first question concerns inattention and 
the other 5 questions assess hyperactivity-impulsivity. Each question is answered on a 5-


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point Likert-type scale with the following possible outcomes: 0 = “Never”, 1 = “Rarely”, 
2 = “Sometimes”, 3 = “Often” and 4 = “Very Often”. The scoring system follows what 
described in literature6, where the total score is obtained by summing the scores for each 
item, with a total ranging from 0 to 24. 
ASRS data will be obtained at screening only. 
9.3.13 
Scale to Assess Therapeutic Relationships – Patient (STAR-P) and 
Clinician (STAR-C) Versions 
The STAR-P and STAR-C are 12-item measures assessing the therapeutic relationship 
between the participant and therapist on three components: Collaboration, Positive 
Clinician Input, and Emotional Difficulties (clinician version)/Non-Supportive Clinician 
(patient version) input. The Collaboration subtest reflects a good rapport and a shared 
understanding of goals, mutual understanding, openness, and trust. Positive Clinician Input 
reflects the perception (by the participant) of the clinician to encourage, support, and listen 
to the participant. Emotional Difficulties/Non-Supportive Clinician Input reflect problems 
in the relationship. Each of the 12 items are rated on a scale from 0 (never) to 4 (always). 
The total scores are obtained by adding up answers to each item and range between 0 and 
48 for both versions, with a higher score suggesting better therapeutic relationships.  
The STAR-P and STAR-C will be obtained at baseline only. 
9.3.14 
Five Dimensional Altered States of Consciousness Questionnaire (5D-
ASC) 
The 5D-ASC measures the acute drug effects using 5 primary dimensions and respective 
subdimensions to assess alterations in mood, perception, and experience of self in relation 
to environment and thought disorder. The 5 dimensions include oceanic boundlessness, 
anxious ego dissolution, visionary restructuralization, auditory alterations, and reduction 
of vigilance. In addition to these 5 dimensions, the 5D-ASC can be split into 11 subscales, 
as described by Studerus et al.7: experience of unity, spiritual experience, blissful state, 
insightfulness, disembodiment, impaired control and cognition, anxiety, complex imagery, 
elementary imagery, audio-visual synaesthesia and changed meaning of percepts. 
Participants were instructed to respond to the described experiences by placing vertical 
marks on a horizontal VAS 100 millimetres long. The VAS of the altered states of 
consciousness rating scales (OAV and 5D-ASC) are anchored as “No, not more than usual” 
on the left and as “Yes, much more than usual” on the right. The items are scored by 
measuring the millimetres from the low end of the scale to the participant's mark (integers 
from 0–100). Because the low end of the scale indicates a neutral response, the response 
format of these items can be considered as strictly unipolar according to the response 
format typology of Russell and Carroll.7-8 
The mapping of individual items to the 5 dimensions and to the 11 subscales is displayed 
in the table below (the former accounts for 93 out of 94 individual items [item 66 is 
excluded], whereas the latter only accounts for 42 items, as described in the paper from 
Studerus et al.7). Subscales have been ordered and displayed in accordance with the 


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relevant dimension they are included in (apart for the last 2 dimensions for which no 
subscale is defined)9. 
 
Dimension 
Items 
Subscale 
Items 
Oceanic 
Boundlessness 
1, 3, 9, 12, 16, 18, 
26, 34, 35, 36, 40, 
41, 42, 45, 50, 52, 
57, 62, 63, 69, 71, 
73, 81, 86, 87, 91, 94 
Experience of Unity 
18, 34, 41, 42, 52 
Spiritual Experience 
9, 81, 94 
Blissful State 
12, 86, 91 
Insightfulness 
50, 69, 77 
Anxious Ego 
Dissociation 
6, 8, 21, 27, 32, 38, 
43, 44, 46, 47, 53, 
56, 60, 64, 67, 78, 
79, 80, 85, 88, 89 
Disembodiment 
26, 62, 63 
Impaired Control and 
Cognition 
8, 27, 38, 47, 64, 67, 
78 
Anxiety 
32, 43, 44, 46, 56, 89 
Visual 
Restructuralization 
7, 14, 20, 22, 23, 28, 
31, 33, 39, 54, 58, 
70, 72, 75, 77, 82, 
83, 90 
Complex Imagery 
39, 72, 82 
Elementary Imagery 
14, 22, 33 
Audio-Visual 
Synaesthesia 
20, 23, 75 
Changed Meaning of 
Percepts 
28, 31, 54 
Auditory 
Alterations 
4, 5, 11, 13, 19, 25, 
30, 48, 49, 55, 65, 
74, 76, 92, 93 
- 
- 
Reduction of 
Vigilance 
2, 10, 15, 17, 24, 29, 
37, 51, 59, 61, 68, 84 
- 
- 
The overall score for each subscale and dimension is obtained by averaging the score for 
each individual item within that subscale/dimension. 
5D-ASC data will be obtained at day 1 immediately after the COMP360 session. 
9.3.15 
Emotional Breakthrough Inventory (EBI) 
The EBI is an 8-item brief measure intended to index the degree to which an individual 
experiences their emotion during the COMP360 session. It is a VAS, with units from 0 to 
100, typically rated within 24 h of a psychedelic experience and ideally within 5 hours of 
the 'end' of the psychedelic experience or once acute drug effects have significantly 
subsided. An overall EBI score is obtained by averaging individual item responses. 
EBI data will be obtained at day 2 only. 
9.3.16 
The Positive and Negative Affect Schedule (PANAS) 
The PANAS measures the acute emotional drug effects and comprises 2 mood scales that 
measure positive and negative affect. Participants respond to 20 items using a 5-point scale 
that ranges from “very slightly or not at all (1)” to “extremely (5)”. The Positive Affect 
score is obtained by summing up scores for items 1, 3, 5, 9, 10, 12, 14, 16, 17, and 19, 
whereas the Negative Affect score is obtained by summing up the scores for items 2, 4, 6, 


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7, 8, 11, 13, 15, 18, and 20. A total higher score on the positive affect questions (ranging 
from 10 to 50) indicates higher levels of a Positive Affect while a lower score on the 
negative affect questions indicates lower levels of a Negative Affect.  
PANAS data will be obtained at baseline, day 2 and week 3. 
9.4 
Safety 
9.4.1 
Adverse Events 
A treatment-emergent adverse event (TEAE) is defined as any AE that has an onset on or 
after the dose of study drug, or any pre-existing AE condition that has worsened on or after 
the dose of study drug.  
A treatment-related TEAE is defined as an AE reported by the investigator to be possibly 
related or related to the study drug. If an AE has missing relationship, it will be assumed 
to be related to the study drug for analysis purposes. For reporting purposes, a treatment-
related TEAE will be referred to as an adverse drug reaction (ADR) and a serious ADR 
will be referred to as a serious adverse reaction (SAR). 
Maximum severity will be assumed for an AE with missing severity.  
AEs will be categorised by time of onset (day 1, day 2, day 3-8, > day 8) and duration (≤ 1 
day, > 1 and ≤ 2 days, > 2 and ≤ 7 days, >7 days or ongoing). 
Adverse Events of Special Interest (AESI) will be identified as follows: 
 
AESI term 
MedDRA Preferred Terms  
Euphoric mood 
Euphoric mood 
Dissociative disorder 
Dissociative disorder; Dissociative identity disorder; 
Dissociative amnesia; Dissociation; 
Depersonalisation/derealisation disorder 
Hallucination 
Hallucination; Hallucination, auditory; Hallucination, 
synaesthetic; Hallucination, tactile; Hallucination, visual; 
Hallucination, olfactory; Hallucinations, mixed; Somatic 
hallucination 
Psychotic disorder 
Psychotic disorder; Psychotic behaviour; Acute psychosis; 
Hysterical psychosis; Reactive psychosis; Substance-induced 
psychotic disorder; Brief psychotic disorder with marked 
stressors; Brief psychotic disorder without marked stressors; 
Transient psychosis 
Cognitive disorder 
Cognitive disorder 
Disturbance in attention 
Disturbance in attention 
Mood altered 
Mood altered; Depressed mood; Affect lability; Fluctuating 
mood symptoms 
Psychomotor skills impaired 
Psychomotor skills impaired 
Inappropriate affect 
Inappropriate affect 
Overdose 
Overdose 


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AESI term 
MedDRA Preferred Terms  
Intentional product misuse 
Intentional product misuse 
In addition AESIs will include those AEs identified as AESIs by the investigator in the 
eCRF. In the event that the associated preferred term does not feature in the list above then 
they will be assigned an AESI term of “Other”. 
9.4.2 
Missing / Partial Start / Stop Dates of AEs and Concomitant Medications 
Missing and partial start and stop date will be imputed for analysis purposes as detailed 
below. 
Partial or missing stop date will be imputed as follows: 
• If the stop date is completely missing and the event has resolved, or the participant has 
stopped taking the concomitant medication, the stop date will be imputed as the date of 
the participant’s last clinic visit in the study. 
• If only the year is known, and it is equal to the year of the participant’s last clinic visit 
in the study, the stop date will be imputed as the last clinic visit date, otherwise if the 
years differ it will be imputed as “31-Dec”. 
• If the month and year are known, the stop date will be imputed as the last day of that 
month unless the stop date corresponds to the same month as the participant’s last clinic 
visit in which case the date of participant’s last clinic visit in the study will be used 
instead. 
Missing start date will be imputed as follows: 
• If the stop date occurs on or after the dose of study drug or the event / concomitant 
medication is ongoing, the start date will be imputed as the date of the dose of study 
drug.  
• If the stop date occurs before the start of study drug, the start date of the event / 
concomitant medication will be imputed as the participant’s screening date or the stop 
date of the event / concomitant medication whichever the earlier. 
Partial start date (year present, but month and day missing) 
• If the stop date occurs on or after the dose of study drug or the event / concomitant 
medication is ongoing, and the year is the same as the year of dosing the start date will 
be imputed as the date of the dose of study drug. If the year is different from the year 
of dosing “01-Jan” will be used. 
• If the stop date occurs before the dose of study drug, the start date of the event / 
concomitant medication will be imputed as the “01-Jan” of the same year. 
Partial start date (month and year present, but day missing) 


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• If the stop date occurs on or after the dose of study drug or the event / concomitant 
medication is ongoing, the start date will be imputed as the first day of the same month 
and year unless this partial start date is in same month as the dose of study drug in 
which case the date of dose of study drug will be used.  
• If the stop date occurs before the dose of study drug, the start date will be imputed as 
the first day of the month and year of the partial start date. 
If the start time of an AE is missing it will be imputed only in the case where the start date 
corresponds to the date of the dose of study drug. The time will be imputed as the same 
time as the dose of study drug. In all other cases the time will not be imputed. 
9.4.3 
Vital Signs 
Starting with protocol version 4.0, blood pressure measurements were collected as 
triplicate measurements. For analysis purposes replicate measurements (where available) 
have been averaged and the resulting average used in all summaries and listings. 
9.4.3.1 
Vital Signs Ranges of Clinical Importance 
Values outside the following ranges for the vital signs parameters will be considered 
clinically important: 
9.4.4 
ECG Categorical Intervals 
The ECG categorical intervals of interest are: 
• QTcF ≤ 450 msec 
• 450 < QTcF ≤ 480 msec 
• 480 < QTcF ≤ 500 msec 
• QTcF > 500 msec 
• Change from baseline in QTcF interval 
• QTcF interval increases from baseline > 30 and ≤ 60 msec 
• QTcF interval increases from baseline > 60 msec 
Vital sign 
Lower Limit 
Upper Limit 
Systolic blood pressure (mmHg) 
90 mmHg 
160 mmHg 
Diastolic blood pressure (mmHg) 
50 mmHg 
100 mmHg 
Pulse rate (bpm) 
50 bpm 
100 bpm 
Respiration rate (breaths / min) 
11 breaths/min 
20 breaths/min 
Body temperature (℃) 
- 
37.5 ℃ 


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9.4.5 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The following outcomes are C-SSRS categories and have binary responses (yes / no). The 
categories have been re-ordered from the actual scale to facilitate the definition of 
composite endpoints: 
 
Category 1  
Wish to be Dead 
Category 2  
Non-specific Active Suicidal Thoughts 
Category 3  
Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Category 4 
Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Category 5 
Active Suicidal Ideation with Specific Plan and Intent 
Category 6 
Preparatory Acts or Behaviour 
Category 7  
Aborted Attempt 
Category 8 
Interrupted Attempt 
Category 9 
Actual Attempt (non-fatal) 
Category 10 
Completed Suicide 
Suicidal Ideation since baseline – A “yes” answer at any time during double blind treatment 
to any one of the 5 suicidal ideation questions (categories 1-5) on the C-SSRS. 
Suicidal Behaviour since baseline – A “yes” answer at any time during double blind 
treatment to any one of the 5 suicidal behaviour questions (categories 6-10) on the C-SSRS. 
There will be no imputation of missing data for C-SSRS. 
9.4.6 
Sheehan Suicidality Tracking Scale (S-STS) 
The S-STS is a 16-item scale that assesses the seriousness of suicidality phenomena on a 
Likert-type scale (0–4) ranging from “not at all” (0) to “extremely” (4). In addition, 6 extra 
questions are to be completed from the clinician in case a participant does not return for a 
scheduled follow-up visit to identify the reason for the missed appointment. 
At screening, a significant risk of suicide is defined as (a) a score of “3” or “4” on Questions 
2 or 13; or (b) a score of “2” or higher on Questions 1a, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 14 
over the past 13 months.  
A significant risk of suicide during the study is defined as (a) a score of “3” or “4” on 
Questions 2, 3, 4, 5, 6, 7, 8, or 13; or (b) a score of “2” or higher on any of Questions 1a, 
9, 10, 11, 12, 14, 15, 20; or (c) if Question 17 is a “Yes” (suicide results in death).  
Additionally, if a participant responds with a score of “2” or higher on any of Questions 
1a, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 14, or 20, or if any responses to items of concern based on 
clinical judgment, the medical monitor should be contacted to determine need for reporting 
as an AE or SAE. 


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9.4.7 
Algorithm to Map Sheehan Suicidality Tracking Scale and Columbia-
Suicide Severity Rating Scale 
Version 4 of the protocol (dated 22 July 2019) replaced the S-STS with the C-SSRS and 
was finalised when a number of study participants had been already enrolled into the study. 
For analysis purposes these two scales will be mapped to universal categories. Sheehan et 
al. (2014)10 provided detailed instructions on the algorithms they used to map item 
responses from the S-STS and C-SSRS to the FDA Classification Algorithm of Suicide 
Assessment (FDA-CASA) 2012 categories. The table below presents these categories. 
 
FDA-CASA 
2012 CODE 
NUMBER 
FDA-CASA 2012 
CLASSIFICATION 
S-STS MAP TO FDA-
CASA 2012 
C-SSRS MAP TO FDA-
CASA 2012 
1 
Passive suicidal 
ideation 
A positive response to 2 
A "yes" response to item 
1: "Wish to be Dead" 
2 
Active suicidal 
ideation: nonspecific 
(no method, intent, or 
plan) 
A positive response to 3 
AND a negative 
response to 4, 5, 6, and 7 
A "yes" response to item 
2: 'Nonspecific Active 
Suicidal Thoughts" 
3 
Active suicidal 
ideation: method, but 
no intent or plan 
A positive response to 3 
and 4 AND a negative 
response to 5, 6, and 7 
A "yes" response to item 
3: "Active Suicidal 
Ideation With Any 
Methods (no plan) 
Without Intent to Act" 
4 
Active suicidal 
ideation: method and 
intent, but no plan 
A positive response to 3 
and 4 and (6 or 7) and a 
negative response to 5 
A "yes" response to Item 
4: "Active Suicidal 
Ideation With Some 
Intent to Act, Without 
Specific Plan" 
5 
Active suicidal 
ideation: method, 
intent, and plan 
A positive response to 3 
and 4 and (6 or 7) and a 
negative response to 5 
A "yes" response to item 
5: "Active Suicidal 
Ideation With Specific 
Plan and Intent" 
6 
Completed suicide 
A "yes" response to 13 
NA 
7 
Suicide attempt 
A positive response to 
10 or 16 OR a "yes" 
response to 1b 
A "yes" response to 
"Actual Attempt" 
8 
Interrupted suicide 
attempt 
A positive response to 8 
with at least one Level 3 
on 12 
A "yes" response to 
"Interrupted Attempt" 
9 
Aborted suicide 
attempt 
A positive response to 8 
with at least one Level 2 
on 12 
A "yes" response to 
"Aborted Attempt" 
10 
Preparatory acts 
toward imminent 
suicidal behavior"-"not 
counting aborted or 
interrupted attempts 
A positive response to 8 
with at least one Level 1 
on 12 
A "yes" response to 
"Preparatory Acts or 
Behavior" 


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FDA-CASA 
2012 CODE 
NUMBER 
FDA-CASA 2012 
CLASSIFICATION 
S-STS MAP TO FDA-
CASA 2012 
C-SSRS MAP TO FDA-
CASA 2012 
11 
Self-Injurious 
Behavior Without 
Suicidal Intent 
A positive response to 9 
OR a positive response 
to 1a and a negative 
response to 1b 
A "yes" response to "Has 
subject engaged in Non-
Suicidal Self-Injurious 
Behavior?" 
12 
Self-injurious 
behavior, intent 
unknown 
A positive response to 
1a with 1b and 6 and 7 
and 10 unanswered 
NA 
13 
Not enough 
information (fatal) 
A "yes" response to 14 
NA 
14 
Not enough 
information (nonfatal) 
Yes, if question 17 is 
"yes" and FDA-CASA 
2012 code numbers 1-13 
are ALL "no" 
NA 
15 
Other (accidental, 
psychiatric medical), 
no deliberate self-harm 
(A positive or blank 
response to 1 and a 
negative response to 
questions 2, 3, 4, 5, 6, 7, 
8, 9, 10, 13, and 14) OR 
a positive response to 15 
NA 
Abbreviations: C-SSRS, Columbia-Suicide Severity Rating Scale; NA, not applicable; S-STS, 
Sheehan Suicidality Tracking Scale. 


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10 STUDY PARTICIPANTS 
10.1 
Disposition of Participants 
The summaries will be presented for each treatment group and overall. 
The number of participants screened, screen failures, and the number and percentage of 
participants in each analysis set will be summarised by country (including overall category) 
for all screened participants (Table 14.1.1.1). The number and percent of participants who 
completed the study and number and percentage of participants who discontinued from the 
study, with reasons for discontinuation, will be summarised using the Randomised 
Analysis Set (Table 14.1.1.2). The reasons for screen failures will also be tabulated (Table 
14.1.1.3). Reasons for exclusion from the PP Analysis Set will be summarised using the 
FAS (Table 14.1.1.4).  
Participant disposition will be listed by study discontinuations (Listing 16.2.1.1) and 
completers (Listing 16.2.1.2) using the Safety Analysis Set. Participation in each defined 
analysis set, including exclusion from the PP Analysis Set will be listed using the 
Randomised Analysis Set (Listing 16.2.3). Inclusion criteria not met/exclusion criteria met 
at screening and at baseline will be listed for all screened participants (Listing 16.2.4.3 and 
Listing 16.2.4.4). 
A summary of missed visits or visits that were conducted remotely rather than at the clinic 
because of COVID-19 will be presented for the Safety Analysis Set by treatment group 
and overall (Table 14.1.1.5), and a listing created which will also include missed 
assessments, if any (Listing 16.2.1.3). 
10.2 
Protocol Deviations 
The frequency and percentage of participants in each important PD category will be 
summarised and presented for each treatment group and overall using the Safety Analysis 
Set (Table 14.1.1.6). All PDs will be listed using the Safety Analysis Set (Listing 16.2.2.1). 
In addition, a summary table of COVID19-related PDs as well as a separate listing will 
also be presented (Table 14.1.1.7, Listing 16.2.2.2). 
10.3 
Demographic and Baseline Characteristics 
The Safety Analysis Set will be used for all demographic and baseline characteristics-
related evaluations, unless otherwise specified. The summaries will be presented for each 
treatment group and overall. 
Demographic and baseline characteristics (age [years; continuous and by age categories 
(see Section 9.2.2)], gender [male, female], race [White, Black or African American, 
Asian, American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, 


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Other], prior psilocybin experience [yes, no; see Section 9.2.6], height [cm], weight [kg], 
recalculated BMI [kg/m2] (see Section 9.2.3)) will be summarised (Table 14.1.2).  
Other baseline characteristics (number of failed treatments in the current depressive 
episode [2, 3, 4], MADRS severity at baseline [continuous and by severity categories (see 
Section 9.3.1.5)], HAM-D-17 total score, HAM-D-17 severity at baseline (see Section 
9.3.9), MGH-ATRQ [<25% improved, 25-49% improved, 50-75% improved, >75% 
improved], STAR-P total score, STAR-C total score, ASRS total score, MSI-BPD total 
score, length of current depressive episode [years; continuous and by length categories (see 
Section 9.2.4)], 5-HT2A polymorphism and number of lifetime depressive episodes as 
collected in question A6 on the MINI questionnaire) will be summarised (Table 14.1.4.2). 
The MINI version 7.0.2 will be summarised (Table 14.1.4.1) – note this summary will only 
display whether participants meet the criteria for specific modules as displayed on the 
questionnaire cover pages. 
A listing for all demographic and baseline characteristics, and other baseline 
characteristics, including a listing for the MINI version 7.0.2 will be presented (Listing 
16.2.4.1 and Listing 16.2.9.1 – Listing 16.2.9.9). 
Other baseline measurements (Urine Drug Screen and Pregnancy Test) will be listed only 
(Listing 16.2.8.6 and Listing 16.2.8.7). The pregnancy test listing will include results from 
both the urine test and, where this was done, of the serum test. 
10.4 
Medical History  
Medical history collected at screening and baseline will be summarised by primary system 
organ class (SOC) and preferred term (PT) and presented for each treatment group and 
overall using the Safety Analysis Set (Table 14.1.3.1), including both the number and 
percentage of participants with a given medical history item as well as the number of 
occurrences of such item. 
All medical history data will be listed using the Safety Analysis Set (Listing 16.2.4.2). 
10.5 
Prior and Concomitant Medications 
The Safety Analysis Set will be used for all prior and concomitant medication-related 
evaluations, unless otherwise specified. The summaries will be presented for each 
treatment group and overall. 
Prior and concomitant medications will be summarised (Table 14.1.3.2 and Table 
14.1.3.3). In addition, a separate summary will be provided for psychoanaleptic and 
psycholeptic-related concomitant medications by treatment group and by stop date of the 
medication with respect to COMP360 dose (pre-dose/post-dose) (Table 14.1.3.4). 
Prior and concomitant medications will be listed (Listing 16.2.4.5 and Listing 16.2.4.6), 
and a separate listing will also be provided for psychoanaleptic and psycholeptic-related 
medications (Listing 16.2.4.7). 


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10.6 
Treatment Exposure 
Study drug administration will be listed (Listing 16.2.5.1). 


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11 EFFICACY  
The FAS will be used for all efficacy-related evaluations, unless otherwise specified. The 
summaries and analyses will be presented for each treatment group. 
11.1 
Primary Efficacy 
The primary endpoint is the change from baseline in total MADRS score at week 3. 
11.1.1 
Hypothetical Strategy Estimand (Primary) 
11.1.1.1 
Main Analysis 
The main analysis will be conducted, in line with the estimand definition, by imputing data-
points after the start of a new treatment for depression post COMP360 dosing under a 
MNAR mechanism, to hypothesise what would have happened to the MADRS total score 
had new treatment for depression not been available to use. It will be assumed that MADRS 
values will have a strictly monotone increasing pattern defined by a factor c as follows: 
y(t) = y (t-1) + c*y (t-1) 
where y is the MADRS total score data point to be imputed, t is the time of the measurement 
and c will depend on the ordinality of the data-point following the start of the 
antidepressant: 
First data-point  c = x   
Second data-point  c = x/2 
Third data-point  c = x/4 
Fourth data-point  c = x/8 
Fifth data-point  c = x/16 
Sixth data-point  c = x/32 
The value of c to be applied will be confirmed in the blinded data review meeting. For 
illustration purposes c has been assumed as 0.1 in the example below: 
First data-point  c = 0.1   
Second data-point  c = 0.05 
Third data-point  c = 0.025 
Fourth data-point  c = 0.0125 
Fifth data-point  c = 0.0625 
Sixth data-point  c = 0.003125 


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In this example, this means that for the first data point to be imputed the last evaluable 
MADRS total score will be increased by 10%, whereas for the second data point the 
imputation will take the first imputed value and increase it by 5% and so on until all data 
points have been imputed. Should the first data point to be imputed be preceded by one or 
more missing data points, the last available MADRS total score measurement prior to the 
start of new treatment for depression will be used as a starting point. 
The starting value of c for the first data point to impute will be generated 100 times (using 
123 as seed) using a normal distribution with the given c value as the mean and SD = c/5 
(this value for the SD was chosen arbitrarily to ensure a balance between reasonable 
uncertainty and the need for a strictly positive c value without resorting to truncation of 
negative values). The subsequent c values will be derived according to the above specified 
rule and MADRS values will be imputed using the approach described above. 
Using the example of a starting value for c of 0.1, see the table below, where a participant 
is assumed to have started taking medication at week 3, such that records from week 6 
onwards need imputing: 
 
Visit 
Observed 
Imputed 
MADRS 
Total  
Score 
Imputation 1 
(c = 0.1017) 
Imputation 2 
(c = 0.0905) 
… 
Imputation 100 
(c = 0.1032) 
Baseline 
35 
35 
35 
… 
35 
Day 2 
32 
32 
32 
… 
32 
Week 1 
35 
35 
35 
… 
35 
Week 3 
36 
36 
36 
… 
36 
Week 6 
34*** 
39.66 
39.26 
… 
39.72 
Week 9 
15*** 
41.68 
41.03 
… 
41.77 
Week 12 
10*** 
42.73 
41.96 
… 
42.84 
*** Denotes observations obtained after the start of new treatment for depression. 
The timepoint where the new treatment for depression is started will be identified during a 
blinded review of the concomitant medication data. If the date where the new medication 
starts is the same date of a MADRS assessment, that assessment will still be considered 
‘evaluable’ and the above imputation rule applied from the following timepoint. 
Non-monotone missing data and missing data occurring after study discontinuation will be 
imputed under a MAR mechanism, ie assuming that the missing data depend only on the 
observed values from participants with similar baseline covariates and MADRS score 
values profile up to the missing timepoint. However missing data occurring after study 
discontinuation for reasons including (but not limited to) lack of efficacy or AE will be 


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imputed under the MNAR approach described above. This assumption will be evaluated 
during the blinded data review meeting and any additional reasons for study 
discontinuation for which to apply MNAR confirmed.  
SAS PROC MI will be applied to the input dataset containing all the observed MADRS 
total scores at day 2, weeks 1, 3, 6, 9 and 12.  The Markov Chain Monte Carlo (MCMC) 
method will be used for the multiple imputations. One hundred (100) multiple imputed 
datasets will be created. 
A sample SAS code for the MAR imputation is as follows: 
 
proc mi data = <input-dataset> nimpute = 100 seed = 99 out = <output-
dataset>; 
  by trt01pn; 
  var base d2 wk1 wk3 wk6 wk9 wk12; 
  mcmc chain = multiple impute = full initial = em prior = jeffreys; 
run; 
where TRT01PN is the treatment group and d2, wk1, wk3, wk6, wk9 and wk12 are variables 
containing the MADRS total score at baseline, day 2, weeks 1, 3, 6, 9 and 12, respectively. 
The IMPUTE = FULL means that all missing data points will be imputed, whether they 
belong to a monotone missing data pattern or not, and the PRIOR = JEFFREYS specify a 
non-informative prior for the imputation process, so that the posterior distribution used for 
the imputation is largely affected by the observed data themselves. Upon completion of the 
imputation process, all imputed data will be rounded to the closest integer to reflect the 
potential values that could have been observed had the data points not been missing (that 
is, an imputed value of 24.7 is certainly wrong whereas a value of 25 is more plausible), 
and caps will be applied to ensure that the MADRS range (0 to 60) is not exceeded in any 
direction. For each of the multiple imputed data sets, change from baseline in MADRS 
total scores will be calculated at each timepoint. The imputed datasets will be merged with 
the ones obtained for the MNAR imputation of data following start of new treatment for 
depression or study discontinuation due to lack of efficacy or AE, using participant, visit 
and imputation as key variables. In doing so, only imputed values for missing data either 
for participants that never start any new treatment for depression or for missing data prior 
to the start of such treatment will be retained from the MAR imputation step. 
The analysis will be performed using a MMRM model (Table 14.2.1.1). The dependent 
variable will be the change from baseline in MADRS total score at day 2 and weeks 1, 3, 
6, 9 and 12 (visits 4, 5, 7, 8, 9 and 10 respectively). The model will include fixed effects 
for treatment, visit, study site and treatment by visit interaction and baseline MADRS total 
score as a covariate. Should a study site randomise fewer than 5 participants, a pooling-
based approach may be applied for analysis purposes to avoid extreme imbalance in 
treatment assignment within each level of the study site factor in the model.  Details of 
specific pooling occurrences and full rationale will be determined during the blinded data 
review meeting. 
Correlation between repeated observations within a participant will be accounted for by 
specifying an unstructured correlation. If this model does not converge then the following 


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covariance matrices will be used in this particular order until the model converges: 
Toeplitz, first-order autoregressive, and compound symmetry. Analysis will be performed 
for each imputed dataset using PROC MIXED in SAS, and the resulting F-tests will be 
based on using Kenward-Roger’s adjusted degrees of freedom. Model assumptions will be 
examined graphically via inspection of conditional residuals scatterplots (residuals vs 
predicted values), quantile-quantile plots and histograms. If appropriate, alternative 
analyses (eg analysis after data transformation or non-parametric analysis) may be 
performed; these analyses and a detailed motivation for performing them will be detailed 
in the Clinical Study Report (CSR).  
The treatment groups will be compared at all timepoints using a two-sided test at a 5% 
significance level. The sample SAS code below implements the model detailed above with 
an unstructured covariance matrix (TYPE = UN in the REPEATED statement). The code 
assumes that AVISITN has 6 values (one for each visit), and TRT01PN representing 
treatment is coded as 1 = 25 mg COMP360 dose, 2 = 10 mg COMP360 dose and 3 = 1 mg 
COMP360 dose. 
 
ods output estimates = est LSMeans = lsm diffs = diff; 
proc mixed data = <input-dataset> plots (only) = studentpanel(marginal); 
by imputation; 
class subjid trt01pn siteid avisitn; 
model chg = trt01pn siteid avisitn trt01pn*avisitn base / ddfm = kr; 
repeated avisitn / type = un subject = subjid; 
lsmeans trt01pn*avisitn / diff cl; 
estimate "25 mg COMP360 dose vs 1 mg COMP360 dose at visit 3" 
        trt01pn 1 0 -1 trt01pn*avisitn 0 0 1 0 0 0 0 0 0 0 0 0 0 0 -1 0 0 0 / cl;  
estimate "10 mg COMP360 dose vs 1 mg COMP360 dose at visit 3"  
        trt01pn 0 1 -1 trt01pn*avisitn 0 0 0 0 0 0 0 0 1 0 0 0 0 0 -1 0 0 0 / cl;  
run; 
The point estimates (LS means and their differences between treatment arms) and the 
standard error (SE) will be pooled using Rubin’s combination rules11 to incorporate the 
between-imputation with the within-imputation variability and to obtain one single point 
and interval estimate using the PROC MIANALYZE procedure. The below sample SAS 
code implements the pooling across imputations: 
 
proc mianalyze data = <input-dataset>; 
  by trt01pn avisitn; 
  modeleffects estim; 
  stderr sem; 
  ods output parameterestimates = parmest2(keep = parm estimate stderr 
lclmean uclmean probt); 
run; 
where estim and sem are the point estimate and SE from the MMRM analysis for each 
imputed dataset whereas estimate, stderr, lclmean, uclmean, and probt are the final pooled 
point estimate, SE, lower and upper confidence limits, and the p-value for the between 
group comparison. In the above code, the BY statement ensures that the pooling is done 
across imputations within each level of TRT01PN and AVISITN (these variable names 
might change depending on the actual variable used in the analysis).  


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Least squares (LS) means alongside their SE as well as 95% confidence intervals (CIs) for 
each treatment group and timepoint will be displayed; in addition, differences in LS means 
between each dose group and 1 mg COMP360 dose with their SE and 95% CIs as well as 
p-values will also be provided.  
The above analysis will also be repeated for the PP Analysis Set (Table 14.2.1.2).  
The analysis tables for both the FAS and PP Analysis Set will also report descriptive 
summaries obtained using only MADRS data up until the start of new treatment for 
depression after baseline.  
All observed MADRS data will also be listed (Listing 16.2.6.1). 
LS means of change from baseline in total MADRS score at each post-baseline timepoint 
as estimated from this primary analysis will be graphically displayed with their 95% CI for 
each treatment group using both the FAS (Figure 14.2.1.1) and the PP Analysis Set (Figure 
14.2.1.2). Differences (and 95% CIs) in LS means between COMP360 25 or 10 mg and 
the 1 mg dose over time will also be graphically displayed for both the FAS (Figure 
14.2.1.3) and the PP Analysis Set (Figure 14.2.1.4). 
Differences between treatment groups in LS means (and 95% CIs) at week 3 and 12 for 
both treatment groups will also be displayed as a forest plot, including results for both the 
primary and the secondary estimand and main (using both FAS and PP Analysis 
Set)/sensitivity/supplementary analyses, organised as follows (Figure 14.2.2.5): 
• One panel for each treatment (COMP360 25 mg and COMP360 10 mg, both vs 
COMP360 1mg) 
• Primary and secondary estimand analyses results arranged from top to bottom (ordered 
as main/sensitivity/supplementary, where applicable) 
• Point estimates and CIs added as annotation text 
A descriptive summary of percentage change from baseline will also be created for the 
FAS (Table 14.2.1.3) by treatment group and graphically displayed as well (Figure 
14.2.1.5), including only data prior to the start of a new treatment for depression after 
baseline. 
11.1.1.2 
Sensitivity Analysis 
Should the primary analysis display a significant p-value for either of the treatment 
comparisons at week 3 or week 12, a further sensitivity analysis will be performed by 
assuming systematically worse results than what’s been imputed in the primary analysis 
(Section 11.1.1.1). For this purpose, a delta-adjustment approach will be followed, whereby 
a systematic shift will be added to all values of the total MADRS score from the two 
experimental arms imputed according to the rules in Section 11.1.1.1, whereas no shift will 


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be added to the COMP360 1 mg arm, to estimate the treatment effect in a conservative 
scenario. The choice of these delta-values will be based on clinical/practical judgement to 
reflect plausible differences that could have occurred: if a tipping-point, that is a shift that 
leads to a change in the analysis results such as a non-significant p-value, is identified, 
clinical judgement will be further used to ascertain the likelihood of the relevant shift to 
have happened in practice. The larger the shift, the more robust the results from the primary 
analysis will be.  
This delta-adjustment will be applied for all data-points that were imputed for the primary 
analysis apart from non-monotone missing data, ie for the following cases: 
 
Baseline 
Day 2 
Week 1 
Week 3 
Week 6 
Week 9 
Week 12 
X 
X 
X 
X 
X 
X 
X 
O 
X 
X 
X 
X 
X 
X 
 
O 
X 
X 
X 
X 
X 
 
 
O 
X 
X 
X 
X 
 
 
 
O 
X 
X 
X 
 
 
 
 
O 
X 
X 
 
 
 
 
 
O 
X 
X: missing data point/new concomitant treatment for depression;  
O: non-missing data point/no new concomitant treatment for depression.  
Timepoints prior to the latest non-missing data point or the latest data point with no new concomitant 
treatment for depression can either be missing or non-missing. 
The delta-adjustment will be implemented using the following procedure: 
1) Select the shift value 
2) All values, apart from non-monotone missing ones, imputed for the primary 
analysis are ‘adjusted’ by adding a constant shift, consistent between the 25 mg and 
10 mg treatment arms 
3) Step 2) is repeated for all relevant shift values 
As an example, below we’ve taken the example data presented in Section 11.1.1.1 to 
illustrate the MNAR imputation and applied a shift of 2 to all imputed values: 
 
Visit 
Observed 
Imputation 1 (c = 0.1017) 
MADRS 
Total  
Score 
Original 
Imputed 
Values 
Rounded 
Values 
 
Shifted Values 
Baseline 
35 
35 
35 
35 
Day 2 
32 
32 
32 
32 
Week 1 
35 
35 
35 
35 


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Week 3 
36 
36 
36 
36 
Week 6 
34*** 
39.66 
40 
42 
Week 9 
15*** 
41.68 
42 
44 
Week 12 
10*** 
42.73 
43 
45 
*** Denotes observations obtained after the start of new treatment for depression. 
The shifts (or delta) values will be specified as identical for both treatment arms since it is 
reasonable to assume that if a worsening was to happen this would not differ between 
treatment groups. The following positive shifts for the total MADRS score may be 
considered: 2, 4, 6, 8 and 10. For each of these shift values, the same analytical approach 
as the primary efficacy (see Section 11.1.1.1) will be followed, ie a MMRM model will be 
fit by imputation and results pooled using Rubin’s rules. Pooled estimates for the difference 
between COMP360 25 mg/10 mg and COMP360 1 mg in the LS means for the change 
from baseline to week 3 and 12 in the total MADRS score will be presented alongside p-
values for each set of shift values (Table 14.2.1.4).  
Results for the tipping-point analysis for both week 3 and 12 will also be displayed 
graphically (Figure 14.2.1.6), with the shift displayed along the x-axis and the associated 
p-values on the y-axis for each treatment group (COMP360 25 mg and 10 mg), with a 
horizontal reference line at 0.05 (the threshold alpha value), with one panel for each 
timepoint. 
11.1.1.3 
Supplementary Analysis 
In addition to the MMRM model specified for the primary analysis in Section 11.1.1.1, 
ANCOVA models using the change in total MADRS score from baseline as response will 
be fit separately for all visits, using data imputed from the primary analysis. The model 
will include treatment and study site as factors and baseline total MADRS score as 
continuous covariate. As for the primary analysis LS means for each treatment group at 
each timepoint and the difference with the COMP360 1 mg arm will be displayed alongside 
95% CIs and p-values. A sample SAS code to fit such a model is displayed below: 
 
ods output lsmeans = lsm diff = diffs; 
proc mixed data = <input-dataset>; 
  by avisitn imputation; 
  class trt01pn siteid; 
  model chg = trt01pn siteid base; 
  lsmeans trt01pn / diff cl; 
run; 
Estimates from the above model will be combined as for the primary analysis using Rubin’s 
rules (Table 14.2.1.5). 


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11.1.2 
Treatment Policy Estimand (Secondary) 
11.1.2.1 
Main Analysis 
The main analysis of the Treatment Policy estimand will assume a MNAR mechanism for 
missing data after study discontinuation due to lack of efficacy or AE and a MAR 
mechanism for all remaining missing data (both non-monotone and following study 
discontinuation for other reasons) and thus perform an imputation similar to what described 
in Section 11.1.1.1 for the Hypothetical Strategy estimand, using the same example SAS 
code for the MAR part (PROC MI with MCMC statement). 
The imputed datasets will be analysed using the same MMRM model as for the primary 
estimand and the same quantities will be pooled across imputations via Rubin’s rules and 
displayed in a table (Table 14.2.1.6) alongside summary statistics including all observed 
MADRS values. In addition, plots for both the change from baseline in MADRS score 
within each treatment arm as well as differences between treatment arms will be 
graphically displayed for each treatment arm (Figure 14.2.1.7 and Figure 14.2.1.8).  
11.1.2.2 
Sensitivity Analysis 
The first sensitivity analysis will follow the same approach as the sensitivity analysis for 
the Hypothetical Strategy estimand (see Section 11.1.1.2) and will implement a tipping-
point analysis, where a shift will be added to all MNAR/monotone MAR-imputed data in 
the COMP360 25 and 10 mg arms used for the primary analysis as described in Section 
11.2.2.1. Similar quantities will be displayed (Table 14.2.1.7, Figure 14.2.1.9).  
An additional sensitivity analysis will involve a MMRM model with no explicit imputation 
for any missing data (intermittent or discontinuations). Under a MAR assumption, these 
models are known to produce unbiased estimates of the treatment effect (see, for example, 
Panel on Handling Missing Data in Clinical Trials12). The same MMRM model as for the 
primary estimand will be fit and similar quantities displayed (Table 14.2.1.8), and LS 
means over time plotted for all treatment arms (Figure 14.2.1.10). 
11.1.2.3 
Supplementary Analysis 
An ANCOVA model using the same model structure and SAS code as detailed in Section 
11.1.1.3 will be estimated using the multiple imputed data obtained in the main analysis 
for this estimand (Section 11.1.2.1). LS means for each treatment group and the COMP360 
25 mg and 10 mg differences with COMP360 1 mg will be displayed for the change from 
baseline to each post-baseline visit for the total MADRS score alongside 95% CIs and p-
values (Table 14.2.1.9). 
11.1.3 
Missing data 
To better understand the extent of intercurrent events occurrences as well as missing data, 
both due to study discontinuation and non-monotone, a summary by visit will be provided 
displaying the counts and percentages of participants that: 
1) Have started a new treatment for depression 
2) Have missing MADRS data due to study discontinuation 


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3) Have missing MADRS data for any other reason other than study discontinuation 
The above summary (Table 14.2.1.10) will be based on the FAS and displayed both by 
treatment and overall.  
Should a visit be completely missing, and no date be available to compare against the early 
termination date, the planned date of the missed visit will be derived in accordance with 
the study schedule. If this derived date is after the date of study discontinuation the data 
point will be considered as missing due to early termination. 
11.2 
Key Secondary Efficacy 
The key secondary endpoints are: 
• The proportion of participants with response (defined as a ≥50% improvement in 
MADRS total score from baseline) at week 3.  
• The proportion of participants with remission (defined a MADRS total score ≤10) at 
week 3.  
• The proportion of participants who have a sustained response at week 12. Sustained 
response is defined as the proportion of participants fulfilling response criteria at any 
visit up to and including week 3 that also fulfils response criteria at all subsequent visits 
up to and including week 12. Response is defined as ≥ 50% decrease in MADRS total 
score from baseline. 
11.2.1 
Composite Strategy Estimand (Primary) 
11.2.1.1 
Main Analysis 
The main analysis for the key secondary endpoints will be conducted, in accordance with 
the Composite Strategy estimand definition, by imputing any data point from the start of a 
new treatment for depression or after study discontinuation due to lack of efficacy or AE 
as a non-responder or non-remitter. If the date where the new medication starts is the same 
date of a MADRS assessment, that assessment will still be considered ‘evaluable’ and the 
above imputation applied from the following timepoint. Missing MADRS data due to study 
discontinuation other than lack of efficacy or AE for participants that do not start any new 
treatment for depression will be imputed using the same MAR approach as described for 
the main analysis of the Hypothetical Strategy estimand for the primary endpoint (Section 
11.1.1.1) and values will then be dichotomised to derive responder/remitters status.  
The analysis model for the first two key secondary endpoints (proportion of participants 
with response at week 3 and proportion of participants with remission at week 3) will be a 
Generalised Linear Mixed Model (GLMM), with a binomial distribution and a logit link 
function, and it will include fixed effects for treatment, visit, study site and treatment by 
visit interaction, and baseline MADRS total score as covariate. Within-participant 
correlation will be accounted for by using the _RESIDUAL_ option in the RANDOM 
statement to maintain consistency with the primary efficacy analysis (Section 11.1.1.1 ) 


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and similarly an unstructured covariance matrix will be assumed (exploring further options 
using the same approach as for the MMRM should the model fail to converge). Should 
convergence problems arise even with a simpler correlation structure, the model will be 
simplified by removing the study site effect. Sample SAS code to fit the model is displayed 
below: 
 
ods output estimate = <output-dataset>; 
proc glimmix data = data; 
  by imputation; 
  class subjid siteid trt01pn avisitn; 
  model aval = trt01pn avisitn trt01pn*avisitn base siteid / dist = binomial link 
= logit; 
  lsmeans trt01pn*avisitn / diff cl ilink oddsratio; 
  random _residual_ / subject = subjid type = un; 
  estimate "25 mg COMP360 dose vs 1 mg COMP360 dose at visit 3" 
           trt01pn 1 0 -1 trt01pn*avisitn 0 0 1 0 0 0 0 0 0 0 0 0 0 0 -1 0 0 0 / 
cl exp ilink;  
  estimate "10 mg COMP360 dose vs 1 mg COMP360 dose at visit 3"  
           trt01pn 0 1 -1 trt01pn*avisitn 0 0 0 0 0 0 0 0 1 0 0 0 0 0 -1 0 0 0 / 
cl exp ilink; 
run; 
ESTIMATE statements for all other post-baseline timepoints can be derived similar to 
those presented above. The odds ratio (OR) of being a responder (remitter) at all post-
baseline visits will be presented for the comparison of COMP360 25 mg/10 mg vs 
COMP360 1 mg, alongside CIs and p-values. Results will then be pooled across 
imputations using Rubin’s rules to present a single treatment effect estimate. The main 
difference with respect to the pooling across imputation is that the OR is not normally 
distributed, and as such the log-ORs and their SE will be pooled rather than the OR 
themselves. These are stored in the estimate and stderr of the ODS output datasets for 
PROC GLIMMIX. The pooled estimates and the 95% confidence limits can then be 
exponentiated to give the summary measures on the OR scale (whereas the p-value can be 
provided as obtained directly from the combination process). 
This analysis will be performed for the FAS (Table 14.2.2.1.1 for response at all post-
baseline visits and Table 14.2.2.2.1 for remission at all post-baseline visits) and for the PP 
Analysis Set (Table 14.2.2.1.2 for response at all post-baseline visits and Table 14.2.2.2.2 
for remission at all post-baseline visits). ORs over time for the comparison of COMP360 
25mg/10mg vs 1 mg will also be graphically displayed with their 95% CIs for the FAS 
(Figure 14.2.2.1.1 and Figure 14.2.2.2.1 for response and remission, respectively) and the 
PP Analysis Set (Figure 14.2.2.1.2 and Figure 14.2.2.2.2 for response and remission, 
respectively). The proportion of responders and remitters will also be descriptively 
summarised alongside 95% Wald-type asymptotic CIs for all timepoints up to week 12, 
only including records up to the start of new treatment for depression after baseline, and 
graphically displayed via line plots including the estimated 95% CI for the FAS (Figure 
14.2.2.1.3 and Figure 14.2.2.2.3, respectively) and the PP Analysis Set (Figure 14.2.2.1.4 


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and Figure 14.2.2.2.4, respectively). Sample SAS code for the estimation of 95% Wald-
type CIs for proportions is displayed below: 
 
proc freq data = <input-dataset>; 
  by trt01pn avisitn; 
  tables aval / binomial (level = 2 cl = wald); 
run; 
The third (and last) key secondary endpoint (sustained response at week 12) main analysis 
will involve a standard logistic regression model using site and treatment as main effects 
and baseline MADRS total score as a continuous covariate. Every participant that started 
a new treatment for depression or discontinued due to lack of efficacy or AE will be 
regarded as a non-responder under both the standard and relaxed definition and thus 
analysed as such, whereas for participants that discontinued the study for any other reason 
without ever starting new treatment for depression the dichotomised MAR imputed data 
(see Section 11.1.1.1) as obtained for the other two key secondary endpoints will be used 
to derive sustained responder status. 
Similar to the other key secondary endpoints, the OR of having sustained response (vs not 
having it) will be displayed for the relevant pairwise treatment comparisons alongside 95% 
CIs and p-values. Sample SAS code for the logistic regression is as follows: 
 
ods output lsmeans = <output-dataset>; 
proc genmod data = <input-dataset>; 
  by imputation; 
  class trt01pn (ref = '3');   
  model aval = trt01pn base siteid / dist = binomial link = logit; 
  lsmeans trt01pn / diff ilink exp cl; 
run; 
Using the REF = ‘3’ option in the CLASS statement has the effect of ensuring that the ORs 
are then derived using the COMP360 1 mg arm as reference (in the above code it is 
assumed this corresponds to a TRT01PN value of 3). Results will be pooled across 
imputations using Rubin’s rules and the same method described for the other two key 
secondary endpoints. In addition, the proportion of sustained responders will also be 
descriptively summarised for each treatment group alongside Wald-type asymptotic 95% 
CIs, using similar SAS PROC FREQ code to what was presented earlier in this section, 
only including participants that do not start a new treatment for depression after baseline. 
The above analysis will be conducted for the FAS (Table 14.2.2.3.1.1) and the PP Analysis 
Set (Table 14.2.2.3.2), jointly displaying the ORs and the proportions (with their 95% CI). 
The analysis for sustained responders will also be performed using the relaxed definition 
of sustained responders for the FAS only (Table 14.2.2.3.1.2), using the same methods as 
for the main definition.  


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The derived response/remission/sustained response status will be listed as ‘Yes’/’No’ 
values in the same listing as the MADRS total score data (Listing 16.2.6.1), with sustained 
response being available only for week 12. 
Similar to the primary endpoint (see Section 11.1.1.1) a forest plot including all ORs and 
their 95% CIs at week 3 and 12 for the response/remission endpoints and week 12 for the 
sustained response endpoint (only the main definition) for both estimands and all analysis 
methods will be displayed using the same logic (Figures 14.2.2.6.1, 14.2.2.6.2 and 
14.2.2.6.3). 
11.2.1.2 
Sensitivity Analysis 
No sensitivity analysis will be performed. 
11.2.1.3 
Supplementary Analysis 
A supplementary analysis will be performed for the first two key secondary endpoints, 
using a logistic regression model fit separately for each visit using the same imputed data 
considered for the main analysis of this estimand (ie non-responder/remitter imputed) and 
covariates and code similar to the one for the sustained response endpoint discussed in 
Section 11.2.1.1 with the addition of a BY statement to allow for separate model fitting by 
visit and imputation.  
OR and their 95% CI and associated p-values for all post-baseline timepoints will be 
displayed using the FAS only (Table 14.2.2.1.3 and Table 14.2.2.2.3, respectively for the 
two endpoints). 
11.2.2 
Treatment Policy Estimand (Secondary) 
11.2.2.1 
Main Analysis 
The main analysis for the key secondary endpoints will be conducted, in accordance with 
the Treatment Policy estimand definition, by imputing any data point after study 
discontinuation due to lack of efficacy or AE as a non-responder or non-remitter or non-
sustained responder. Missing MADRS data due to study discontinuation other than lack of 
efficacy or AE will be imputed using the same MAR approach as described for the main 
analysis of the Treatment Policy estimand for the primary endpoint (Section 11.1.2.1) and 
values will then be dichotomised to derive responder/remitter/sustained responder status. 
The datasets will be analysed using either the GLMM (responders/remitters) or logistic 
regression (sustained responder, both definitions) analysis model for each imputation, and 
results will then be combined using Rubin’s rules, using a similar approach as described in 
Section 11.2.1.1 . 
OR and their 95% CIs and associated p-values for all post-baseline timepoints will be 
displayed using the FAS only (Table 14.2.2.1.4, Table 14.2.2.2.4 and Table 14.2.2.3.3 
respectively for the three endpoints). Proportion of responders/remitters/sustained 


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responders will also be displayed, using all observed MADRS values irrespective of any 
new treatment for depression started after baseline. 
11.2.2.2 
Sensitivity Analysis 
The responder and remitter endpoints will be analysed using the same analysis model 
described in Section 11.2.1.1 (GLMM), but with no explicit imputation, so that a standard 
GLMM regression model will be fit to derive OR and their 95% CIs (Table 14.2.2.1.5 and 
Table 14.2.2.2.5 respectively for the two endpoints). 
11.2.2.3 
Supplementary Analysis 
The same multiple imputed dataset as for the main analysis will be used for the 
supplementary analysis, where the responder and remitter endpoints will be analysed with 
a by-visit logistic regression model using the same covariates and SAS code as described 
in Section 11.2.1.1 and displaying similar quantities after pooling results across 
imputations using the approach described in Section 11.2.2.1 (Table 14.2.2.1.6 and Table 
14.2.2.2.6). 
The sustained responder endpoint will be analysed using a logistic regression based on all 
observed data and displaying associated OR with 95% CIs and p-values (Table 12.2.2.3.4). 
11.3 
Other Secondary Endpoints 
Time to event measures will be analysed for each treatment group for the following 
parameters: 
• Time to the first of any of the following depressive events from baseline to week 12: 
• Initiation of any antidepressive treatment (first new antidepressant treatment in time 
period only if started for worsening of symptoms or lack of benefit from study 
treatment and not when initiated to prevent relapses and maintain a positive 
response) 
• Hospitalisation due to depression or suicidality 
• Suicide attempt, prevention of an imminent suicide attempt/interrupted 
attempt/aborted attempt, or completed suicide 
• Active suicidal ideation with specific plan according to the C-SSRS (a score of 'yes' 
on question 4 or 5)  
• Worsening in the MADRS clinician rated severity scale: ie a 5-point worsening 
compared to baseline score at any timepoint post-baseline; or a worsening of ≥10 
points (providing the highest score is ≥15) across two or more consecutive visits 
(in this case the first date of the ≥10-point increase will be classed as the event and 
at the final study visit the ≥10-point worsening will qualify as an event without need 
for confirmation at a subsequent visit) 


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• Time to relapse from baseline to week 12 (relapse is defined as participants who 
responded (defined as ≥ 50% reduction on the MADRS at week 3), a worsening of ≥10 
points on the MADRS (providing the highest score is ≥20) across two or more 
consecutive visits (in this case the first date of the ≥10 points increase will be classed 
as the event and at the final study visit the ≥10 points worsening will qualify as an event 
without need for confirmation at a subsequent visit) 
Participants who withdraw from the study or die (for a cause other than suicide) before 
experiencing the event of interest will be censored on the date of their last study visit or on 
the date of their death. The event-free survival curves will be estimated via the Kaplan-
Meier method. 
A sample SAS code to perform the Kaplan-Meier analysis is as follows: 
 
proc lifetest data = <input> method = km; 
  strata trt01pn / diff = control('0') test = logrank; 
  time time*censored(1); 
run; 
 
In addition, a Cox regression model will be fit to both time to event endpoints including 
treatment and baseline MADRS scores (for time to relapse only) as covariates. From this 
model, the hazard ratios (HRs) of COMP360 25mg and 10mg vs COMP360 1mg arm will 
be estimated alongside its 95% CI (derived using the profile likelihood approach) using the 
sample SAS code below: 
 
proc phreg data = <input>; 
  class trt01pn (ref = 'COMP360 1 mg'); 
  model time*censored(1) = base trt01pn; 
  hazardratio trt01pn / cl = pl diff = ref; 
run; 
For each time to event endpoint quartiles of the Kaplan-Meier survival curve alongside 
their 95% CI will be displayed by treatment group, together with the observed minimum 
and maximum time to event occurrence (as measured in days). The HRs and their 95% CI 
will also be presented (Table 14.2.2.4 and Table 14.2.2.5, respectively). Also, Kaplan-
Meier curves for each time to event endpoint will be presented (Figure 14.2.2.3 and Figure 
14.2.2.4, respectively).  
The time to the occurrence of each separate event as analysed above will also be listed 
(Listing 16.2.6.8.1 and Listing 16.2.6.8.2, respectively), and should a participant be 
censored by the time of their study completion this censoring time will be displayed 
instead. 


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11.4 
Exploratory Efficacy 
11.4.1 
COVID-19 
To better evaluate the impact of COVID-19 on the primary endpoint an exploratory 
analysis will be performed where participants that had been dosed before the 
announcement of the first UK lockdown and the first site re-opening after it (29th April 
2020) will be compared to those that were dosed after this date.  
Descriptive summaries by treatment arm will be provided for the MADRS score and its 
change from baseline, with 95% CIs added if the sample size in each treatment arm is 
enough to provide interpretable results (Table 14.2.1.11). 
11.4.2 
Additional Responders Analysis 
An additional analysis will be performed to better assess the response to treatment using 
either data observed prior to the start of a new treatment for depression (in line with the 
Hypothetical Strategy estimand for the primary endpoint) or data as observed, irrespective 
of the start of a new treatment for depression (and allowing missing data after study 
discontinuation), as part of the Treatment Policy estimand.  
For this analysis the following summaries will be presented: 
• Number and frequency of MADRS responders (as defined in Section 9.3.1.2) that are 
not MADRS remitters (so a post-baseline MADRS score > 10) 
• Number and frequency of MADRS partial responders (as defined in Section 9.3.1.5) 
Summaries for each treatment group and post-baseline timepoint will be displayed (Table 
14.2.2.1.7.1 for the Composite Strategy estimand and Table 14.2.2.1.7.2 for the Treatment 
Policy estimand). 
11.4.3 
Correlation Analysis 
Exploratory analyses will be performed to investigate the correlation of the following 
variables with the primary endpoint: 
• PANAS at baseline (Negative Affect and Positive Affect scores separately) 
5D-ASC on day 1 (all five dimensions separately) 
• STAR-C at baseline 
• STAR-P at baseline 
• EBI at day 2 
• C-reactive protein (CRP) at screening 
The correlation with the primary endpoint (change from baseline to week 3 and 12 in the 
total MADRS score) will be analysed using an ANCOVA model with treatment as factor, 
the measurement of the variable at the timepoint listed above as a covariate and their 
interaction to evaluate the presence of unequal slopes. Type III mean squares alongside F-


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tests and p-values for each model effect will be displayed (Table 14.2.1.12). The code for 
the ANCOVA model described in Section 11.1.1.3  can be adapted as follows for this 
analysis: 
 
ods output type3 = anova; 
proc mixed data = <input-dataset> method = type3; 
  by avisitn; 
  class trt01pn; 
  model chg = trt01pn <predictor> trt01pn*<predictor>; 
run; 
For continuous predictors, a scatterplot will also be created, with the relevant predictor 
variable on the x-axis and the primary endpoint on the y-axis, the points color-coded based 
on the treatment received by the participant, the treatment-specific regression lines being 
displayed with the same colours as the symbol markers and an overall Pearson’s correlation 
coefficient, obtained using Fisher’s z transformation, added in the plot area (Figure 
14.2.1.11.1 and Figure 14.2.1.11.2 for week 3 and 12, respectively, one scatterplot per 
page). The correlation will be derived using the following example SAS code: 
 
ods output FisherPearsonCorr = rho; 
proc corr data = <input-dataset> fisher; 
  var chg; 
  with <list-of-predictor-variables>; 
run; 
 
The variable correst from the ODS output dataset will be used in the reporting. 
Three more variables will be added as additional pages to the scatterplot but will not be 
analysed using the ANCOVA model: change from baseline to day 2 in PANAS, change 
from baseline to day 2 and week 3 in CRP (the PANAS has two dimensions, positive and 
negative affect, so there will be 4 additional scatterplots added). The ANCOVA models 
will not be fit for these extra-variables because they were collected after the study drug 
dose and this could cause difficulties in interpreting model results. An example SAS code 
for one plot is as follows: 
 
proc template; 
  define statgraph ScatCurveLegend; 
  begingraph; 
  entrytitle halign = left "Predictor: <predictor-name>"; 
  layout overlay / xaxisopts = (label = "<predictor-name>") 
                   yaxisopts = (label = "Change from Baseline to Week 3 
in Total MADRS Score");  
    scatterplot x = <predictor> y = chg / group = trt01pn name = "scatter" 
markerattrs = (symbol = CircleFilled); 
 
regressionplot x = base y = chg / group = trt01pn name = 
"regression"; 
 
textplot x = x y = y text = text / textattrs = (size = 12); 
    mergedlegend "scatter" "regression" / border = true; 
  endlayout; 
  endgraph; 
  end; 
run; 


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proc sgrender data = <input-dataset> template = ScatCurveLegend; 
run; 
The above code works on the following assumptions: 
• The input dataset has, at a minimum, the trt01pn, chg (change from baseline in 
MADRS) and the <predictor> variable populated for all records (any missing data will 
be excluded from the plot). Only change from baseline to week 3 in MADRS is 
available. 
• The additional variables x, y and text will only be populated for one record in the dataset 
and will contain the coordinates and the text to display Pearson’s correlation coefficient 
in the following form: ‘Pearson’s rho = 0.xxxx’. 
All the above analyses will be performed using the FAS and observed data (ie no 
imputation). 
11.4.4 
Exploratory Endpoints 
The following exploratory endpoints will be analysed in similar way as the primary 
efficacy endpoints, ie using a MMRM with no prior data imputation (see Section 11.1.1.1) 
and displaying estimated LS means alongside their 95% CIs as line plots for each subgroup:  
• Participant EQ-5D-3L total score change from baseline to week 3 and week 12 (Table 
14.2.3.1, Figure 14.2.3.1, Listing 16.2.6.2.1) 
• EQ Visual Analogue Scale change from baseline to week 3 and 12 (Table 14.2.3.2, 
Figure 14.2.3.2, Listing 16.2.6.2.2) 
• SDS total score change from baseline to week 3 and week 12 (Table 14.2.3.3, Figure 
14.2.3.3, Listing 16.2.6.3) 
• GAD-7 total score change from baseline to week 3 and week 12 (Table 14.2.3.4, Figure 
14.2.3.4, Listing 16.2.6.5) 
• QIDS-SR-16 total score change from baseline to every study visit (Table 14.2.3.5, 
Figure 14.2.3.5, Listing 16.2.6.6) 
• WSAS total score change from baseline to week 3 and week 12 (Table 14.2.3.6, Figure 
14.2.3.6, Listing 16.2.6.7) 
• PANAS total score change from baseline to day 2 and week 3 (Table 14.2.3.7, Figure 
14.2.3.7, Listing 16.2.9.10) 
• DSST total score change from baseline to day 2, week 3, and week 12 (Table 14.2.3.8, 
Figure 14.2.3.8, Listing 16.2.6.4) 
All these endpoints will be analysed for the FAS and listed as well (see item list above for 
tables and listings numbers). The Caregiver EQ-5D-3L score, on the other hand, will only 
be listed alongside the participant score since it is not a mandatory assessment and is 
provisional of optional caregiver consent. 


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The DSST will also be summarised by categories of correct symbols at baseline and at each 
post-baseline timepoint as described in Section 9.3.5 (Table 14.2.3.9). 
The following endpoints will also be descriptively summarised by treatment group and 
listed: 
• EBI total score at day 2 (Table 14.2.3.10, Listing 16.2.9.11) 
• 5D-ASC (each dimension and subscale, see Section 9.3.14) at day 1 (Table 14.2.3.11, 
Listing 16.2.9.12) 
11.5 
Subgroup Analysis: Efficacy 
The primary and key secondary endpoints will be descriptively (and, for the primary 
endpoint only, also graphically via profile plots for the change from baseline in MADRS, 
with means and 95% CIs) summarised over time by the subgroups below based on the 
FAS, to explore the heterogeneity of the treatment effect across strata. Subgroups are 
defined as follows: 
• Country (Canada, Czech Republic, Denmark, Germany, Ireland, Netherlands, Portugal, 
Spain, United Kingdom, United States) 
• Gender (Male, Female) 
• Age (18-34, 35-64, 65+) 
• Number of failed pharmacological treatments for the current episode of depression 
(level of treatment resistance) (2, 3, 4 treatments) 
• Depression severity baseline level (HAM-D-17: moderate (18-23), severe (≥24)) 
The table and figure (where applicable) number for each endpoint and subgroup is 
displayed below (when both a table and a figure are needed their numbers are separated by 
a ‘/’): 
 
 
Change in 
MADRS 
Response at 
Week 3 
Remission 
at Week 3 
Sustained 
Response at 
Week 12 
Country 
14.2.1.13/14.2.1.12 
14.2.2.1.8 
14.2.2.2.7 
14.2.2.3.5 
Gender 
14.2.1.14/14.2.1.13 
14.2.2.1.9 
14.2.2.2.8 
14.2.2.3.6 
Age 
14.2.1.15/14.2.1.14 
14.2.2.1.10 
14.2.2.2.9 
14.2.2.3.7 
# of Failed 
Pharmacological 
Treatments 
14.2.1.16/14.2.1.15 
14.2.2.1.11 
14.2.2.2.10 
14.2.2.3.8 
Depression Severity at 
Baseline 
14.2.1.17/14.2.1.17 
14.2.2.1.12 
14.2.2.2.11 
14.2.2.3.9 
A specific category within a subgroup will only be plotted in the associated figure if there 
are at least 10 participants in each treatment arm for that specific subgroup. 


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All summaries, both in the tables and the figures, will follow the Hypothetical Strategy 
estimand, and will only include data collected prior to the start of any new treatment for 
depression after baseline. 


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12 SAFETY 
The Safety Analysis Set will be used for all safety-related evaluations, unless otherwise 
specified. The summaries and analyses will be presented for each treatment group and 
overall. 
12.1 
Adverse Events (AEs) 
An overall summary of AEs, including total number of TEAEs and treatment-emergent 
serious adverse events (TESAEs), ADRs and SARs, severe TEAEs, AESIs, TEAEs and 
TESAEs and ADRs leading to study discontinuation, and TEAEs leading to death will be 
presented (Table 14.3.1.1). 
The following summary tables will be summarised by SOC and PT and sorted by 
alphabetical order for SOC and by total decreasing frequency for PT, including both the 
number of participants with a given event and the number of events. 
• Summary of TEAEs (Table 14.3.1.2) 
• Summary of non-serious TEAEs ≥ 5% (PT for any treatment group ≥ 5%) (Table 
14.3.1.3) 
• Summary of non-Serious TEAEs by worst severity (mild/moderate/severe) (Table 
14.3.1.4) 
• Summary of TEAEs by strongest relationship to study drug (related/not related) (Table 
14.3.1.5) 
• Summary of TEAEs by time of onset (see Section 9.4.1 for categories) (Table 14.3.1.6) 
• Summary of TEAEs by duration (see Section 9.4.1 for categories) (Table 14.3.1.7) 
• Summary of TEAEs by time of onset (see Section 9.4.1 for categories) and duration 
(see Section 9.4.1 for categories) (Table 14.3.1.8) 
• Summary of ADRs by time of onset (see Section 9.4.1 for categories) and duration (see 
Section 9.4.1 for categories) (Table 14.3.1.9) 
• Summary of duration of TEAEs (Table 14.3.1.10) 
• Summary of ADRs (Table 14.3.1.11) 
• Summary of TESAEs (Table 14.3.1.12) 
• Summary of SARs (Table 14.3.1.13) 
• Summary of AESIs (Table 14.3.1.14) 
• Summary of TEAEs leading to study withdrawal (Table 14.3.1.15) 
• Summary of ADRs leading to study withdrawal (Table 14.3.1.16) 
• Summary of COVID-19 related TEAEs (Table 14.3.1.17) 


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For each of the summaries done at the participant level, multiple occurrences of the same 
event within a participant will be counted once in the summaries by SOC and PT; multiple 
occurrences of the same event within a participant will be counted once in the maximum 
intensity category (severe > moderate > mild) and/or maximum study drug relationship 
category (related > not related). If intensity or relationship is found to be missing, the most 
severe occurrence will be imputed for that particular summary. 
These summaries will also present the number of events that occurred: summaries by worst 
severity or strongest relationship will only report the events whose category equals the 
maximum category for a given participant. As an example, should a participant have 2 mild 
and 3 severe AEs, only these latter will be reported in the ‘Severe’ line of the table for the 
overall and appropriate SOC/PT summaries, whereas the 2 mild events will not be 
considered; similarly, if a participant has only mild events all of them will be reported in 
the appropriate ‘Mild’ lines of the display. 
AEs whose end date is not available because the data is genuinely missing will be 
considered as ongoing for analysis purposes. 
All AEs for each participant, including multiple occurrences of the same event, will be 
presented in full in a comprehensive listing including participant number, treatment, 
reported term, SOC, PT, date/time and study day when AE starts/stops, duration (days), 
relationship to treatment, severity, action taken, outcome, seriousness, whether 
concomitant medication started due to TEAE and whether the TEAE leads to study 
discontinuation (Listing 16.2.7.1). Listings will also be provided for participants who 
experience TESAEs (Listing 16.2.7.2), ADRs (Listing 16.2.7.3), AESIs (Listing 16.2.7.4), 
lead to death (Listing 16.2.7.5) and are associated to COVID-19 (Listing 16.2.7.6). 
12.2 
Laboratory Tests 
The full list of parameters and their units (where applicable) are reported in the table below: 
 
Category 
Parameter (Unit) 
Haematology 
Basophils (109/L) 
Basophils/Leukocytes (%) 
Eosinophils (109/L) 
Eosinophils/Leukocytes (%) 
Mean Corpuscular Haemoglobin Concentration (g/L) 
Mean Corpuscular Haemoglobin (pg) 
Mean Corpuscular Volume (fL) 
Erythrocytes (1012/L)) 
Haematocrit (%) 
Haemoglobin (g/L) 
Leukocytes (109/L) 
Lymphocytes (109/L) 
Lymphocytes /Leukocytes (%) 
Monocytes (109/L) 
Monocytes /Leukocytes (%) 


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Category 
Parameter (Unit) 
Neutrophils (109/L) 
Neutrophils/Leukocytes (%) 
Platelets (109/L) 
Chemistry 
Alanine Aminotransferase (ALT) (U/L)  
Albumin (g/L) 
Alkaline Phosphatase (ALP) (U/L) 
Amylase (U/L) 
Aspartate Aminotransferase (AST) (U/L) 
Bicarbonate (mmol/L) 
Bilirubin (direct, indirect, and total) (mg/dL) 
Calcium (mg/dL) 
Chloride (mmol/L) 
Creatine Kinase (U/L) 
Creatinine (mg/dL) 
Gamma Glutamil Transferase (U/L) 
Glucose (mg/dL) 
Lactate Dehydrogenase (U/L) 
Lipase (U/L) 
Magnesium (mG/dL) 
Phosphate (mg/dL) 
Potassium (mmol/L) 
Protein-total (g/L) 
Sodium (mmol/L) 
Urate (mg/dL) 
Urea Nitrogen (mg/dL) 
Urinalysis 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult Blood 
Protein 
Specific Gravity 
Urobilinogen  
pH 
Descriptive statistics of the observed values and change from baseline (continuous data) 
will be presented for each haematology (Table 14.3.4.2) and chemistry (Table 14.3.4.3) 
parameter by visit. Shift tables will display numbers of participants with normal range 
shifts at baseline versus post-treatment day 2 and week 3 (Table 14.3.4.4 and Table 14.3.4.5 
for haematology and chemistry, respectively). 
Listings for haematology, chemistry and urinalysis data (Listing 16.2.8.1, Listing 16.2.8.2 
and Listing 16.2.8.3) will also flag values that are outside normal reference ranges or 
markedly abnormal findings. Laboratory abnormalities will also be listed separately 
(Listing 16.2.8.4). 


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12.3 
Vital Signs 
The full list of parameters and their units (where applicable) are reported below: 
• Systolic blood pressure (mmHg) 
• Diastolic blood pressure (mmHg) 
• Pulse rate (bpm) 
• Respiration Rate (breaths / min) 
• Body temperature (℃) 
Descriptive statistics of the observed values and change from baseline will be presented 
for each parameter by visit (Table 14.3.5.1). The number and percentage of participants 
with values outside clinically important limits, as described in Section 9.4.3 will be 
summarised by visit (Table 14.3.5.2). 
All vital signs data will be listed, which will also include flagged values that are outside 
normal reference ranges or markedly abnormal findings (Listing 16.2.8.8). Clinically 
important vital signs values will also be listed separately (Listing 16.2.8.9). 
12.4 
Electrocardiogram Data 
The full list of parameters and their units (where applicable) are reported below: 
• Heart rate (bpm) 
• PR interval (msec) 
• QRS interval (msec) 
• QT interval (msec) 
• QTcF interval (msec) 
• QTcB interval (msec) 
Descriptive statistics of the observed values and change from baseline will be presented 
for each parameter by visit (Table 14.3.6.1). Shift tables in relation to the overall 
interpretation (Normal, Abnormal Not Clinically Significant (NCS), and Abnormal 
Clinically Significant (CS)) at baseline versus post-treatment day 2 will be presented 
(Table 14.3.6.2). The number and percentage of participants meeting the intervals as 
described in Section 9.4.4 will be summarised by visit (Table 14.3.6.3) and listed (Listing 
16.2.8.11).  
All ECG data will be listed (Listing 16.2.8.10). 
12.5 
C-SSRS 
C-SSRS data will be summarised by visit (Table 14.3.6.4) and listed (Listing 16.2.9.13). 
Conversion to the FDA-CASA 2012 code and categories described in Section 9.4.7 will be 
listed jointly for both the C-SSRS and S-STS (Listing 16.2.9.15). 


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12.6 
S-STS 
S-STS data will be listed only (including the conversion to the FDA-CASA 2012 code and 
categories as described in Section 9.4.7) (Listing 16.2.9.14).


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13 BIOMARKERS 
13.1 
C-Reactive Protein (CRP) 
CRP data and the changes from baseline will be summarised, along with the change from 
baseline being evaluated with a MMRM analysis (model is similar to primary endpoint 
analysis model as described in Section 11.1.1.1) using the Safety Analysis Set (Table 
14.3.4.1). Least Square (LS) means and 95% CIs will be derived from the model for each 
treatment and visit. LS mean differences for COMP360 (25 mg or 10 mg) versus 
COMP360 1 mg will also be provided with 95% CIs for each visit. CRP values will also 
be listed (Listing 16.2.8.5). 


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14 CHANGES FROM THE PROTOCOL-PLANNED ANALYSES 
Below is a list of changes from the protocol-planned analyses: 
• Section 7 (Analysis Sets): The definition of the Safety Analysis Set was updated to 
include all randomised participants that received study drug. Accordingly, the FAS 
definition was updated to include randomised participants that received the drug and 
had at least one post-dose efficacy assessment, thus incorporating the protocol specified 
modified Intent-to-Treat (mITT) population definition (which has thus been removed). 
• Section 11.2 (Key Secondary Efficacy): The analysis of the key secondary endpoints 
has been changed from the originally planned Cochran-Mantel-Haenszel (CMH) 
procedure to either a GLMM (response and remission analysis at week 3) or a logistic 
regression (sustained response at week 12). This was done to increase statistical power 
by adjusting for more covariates than a stratified CMH would allow and to account for 
the assumed missing data mechanism. 
• Section 11.5 (Subgroup Analysis: Efficacy): The analysis of the country effect 
described in Section 11.3.2 of the protocol was simplified to only be a summary of by-
country descriptive statistics of the MADRS score over time due to the sparseness of 
data and the difficulty of interpreting the associated results. 
 
 
 
 
 
 
 
 
 
 
 
 


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15 DATA NOT PRESENTED 
15.1 
Mindstrong data 
Data collected via the Mindstrong app is not in the scope of this SAP and thus details 
related to its handling and reporting will not be provided here. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16 REFERENCES 
 
1. SAS Institute Inc., Cary, NC, 27513, USA 
2. Carhart-Harris RL, Bolstridge M, Rucker J, et al. Psilocybin with psychological 
support for treatment-resistant depression: an open-label feasibility study. Lancet. 
2016; 3(7): 619-627 
3. Muller MJ, Himmerich H, Kienzle B, Szegedi A. Differentiating moderate and severe 
depression using the Montgomery-Asberg depression rating scale (MADRS). J Affect 
Disord 2003 (77): 255-260 
4. https://euroqol.org/eq-5d-instruments/eq-5d-3l-about/valuation/ 
5. Dolan P. Modeling valuations for EuroQol health states. Med Care 1997; 35(11): 1095-
1108. 
6. Ustun B, Adler La, Rudin C, Faraone SV, Spencer TJ, Berglund P, Gruber MJ, Kessler 
RC. The World Health Organization Adult Attention-Deficit/Hyperactivity Disorder 
Self-Report Screening Scale for DSM-5. JAMA Psychiatry 2017; 74(5): 520-526 
7. Studerus E, Gamma A, Vollenweider FX. Psychometric evaluation of the altered states 
of consciousness rating scale (OAV). PLoS One. 2010;5: e12412. 
8. Russell JA, Carroll JM. On the bipolarity of positive and negative affect. Psychol Bull. 
1999; 125:3–30. 
9. Liechti ME, Dolder PC, Schmid Y. Alterations of consciousness and mystical-type 
experiences after acute LSD in humans. Psychopharmacology (Berl). 2017; 234(9): 
1499–1510. 
10. Sheehan DV, Alphs LD, Mao L, et al. Comparative validation of the SSTS, the ISST 
Plus, and the C–SSRS for assessing the suicidal thinking and behavior FDA 2012 
suicidality categories. Innov Clin Neurosci 2014; 11(9-10): 32-46.  
11. Rubin, D.B. (1987), Multiple Imputation for Nonresponse in Surveys, New York: John 
Wiley & Sons, Inc. 
12. National Research Council (US) Panel on Handling Missing Data in Clinical Trials. 
The Prevention and Treatment of Missing Data in Clinical Trials. Washington (DC): 
National Academies Press (US); 2010. PANEL ON HANDLING MISSING DATA IN 
CLINICAL 
TRIALS. 
Available 
from: 
https://www.ncbi.nlm.nih.gov/books/NBK209899/ 
 
 
 


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17 PROGRAMMING AND DATA PRESENTATION 
CONVENTIONS 
17.1 
Treatment Labelling 
 
COMP360 25 mg 
COMP360 10 mg 
COMP360 1 mg 
Overall 
17.2 
Visit Labelling 
To ensure consistency with Clinical Data Interchange Standards Consortium (CDISC) 
standards, the day of drug dosing, defined as day 0 in the Protocol, will be mapped to day 
1. All subsequent visits will then be consistently re-mapped (and henceforth referred to in 
this SAP), as follows: 
 
Protocol Visit        
Analysis Visit 
Output Label 
Screening - Visit 1 
Screening - Visit 1 
Screening 
Screening 
Period 
- 
Visit 
1a/1b/1c/… 
Screening 
Period 
- 
Visit 
1a/1b/1c/… 
Screening a/ Screening 
b/Screening c/… 
Screening Telephone Visit 
Phone Contact Visit 
Phone Contact Visit 
Baseline (day -1) - Visit 2 
Baseline (day -1) - Visit 2 
Baseline or Day -1    
Day 0 - Visit 3 
Day 1 - Visit 3 
Baseline or Day 1a 
Day 1 - Visit 4 
Day 2 - Visit 4 
Day 2 
Week 1/Day 7 - Visit 5 
Week 1/Day 8 - Visit 5 
Week 1 or Day 8 
Week 2/Day 14 - Visit 6 
Week 2/Day 15 - Visit 6 
Week 2 or Day 15 
Week 3/Day 21 - Visit 7 
Week 3/ Day 22 - Visit 7 
Week 3 or Day 22 
Week 4/Day 28 - Visit 7a 
Week 4/Day 29 - Visit 7a 
Week 4 or Day 29 
Week 5/Day 35 - Visit 7b 
Week 4/Day 36 - Visit 7b 
Week 5 or Day 36 
Week 6/Day 42 - Visit 8 
Week 6/Day 43 - Visit 8 
Week 6 or Day 43 
Week 7/Day 49 - Visit 8a 
Week 4/Day 50 - Visit 8a 
Week 7 or Day 50 
Week 8/Day 56 - Visit 8b 
Week 4/Day 57 - Visit 8b 
Week 8 or Day 57 
Week 9/Day 63 - Visit 9 
Week 9/Day 64 - Visit 9 
Week 9 or Day 64 
Week 10/Day 70 - Visit 9a 
Week 10/Day 71 - Visit 9a 
Week 10 or Day 71 
Week 11/Day 77 - Visit 9b 
Week 11/Day 78 - Visit 9b 
Week 11 or Day 78 
Week 12/Day 84 (ET) - Visit 10 
Week 12/Day 85 (ET) - Visit 10 
Week 12 or Day 85 
a Vital signs are collected prior to study drug dosing on day 1 and as such their baseline occurs on day 1 rather than on day -1, as is the 
case for other assessments. 


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Final Version 2.0 26 October 2021 
Visits highlighted in bold only occur in specific countries: Germany (Final Protocol version 4.0, 12 November 2019), Portugal (Final 
Protocol version 4.0, 13 February 2020) and Czech Republic (Final Protocol version 4.3, 26 February 2020). C-SSRS (not for Portugal), 
concomitant medications and AEs will be collected at these extra visits. 
The handling of all assessments occurring out of protocol-specified visit windows or at an 
unplanned timepoint will be agreed at the blinded data review meeting and documented in 
the meeting minutes. 
17.3 
Baseline Definitions 
 
Parameter 
Baseline 
Efficacy 
All 
Day -1 
Safety 
Clinical laboratory 
Screening 
Vital Signs 
Day 1 Pre-dose 
ECGs 
Screening 
C-SSRS 
Day -1 
Biomarker 
CRP 
Screening 
17.4 
Study Day, Duration and Time Derivation 
Study day, defined as the number of days from the dose of study drug, will be derived as 
follows:  
• date of event – date of dose of study drug + 1, for events on or after dose  
• date of event – date of dose of study drug, for events before dose  
Duration of an AE (in days) will be calculated using the following formula: 
[(stop datetime of the AE-start datetime of the AE)/(60×60×24)] 
In cases where the time component of either the start or the stop date is missing the 
following approach will be taken: 
• If the AE start time is missing and the AE occurred after day 1, the duration will be 
calculated assuming the event at started at 00:00:00 AM of that day, otherwise if the 
AE occurred on day 1 the duration will be derived using the datetime of dosing as 
starting point 
• If the AE stop time is missing the duration will be calculated assuming the event 
stopped at 23:59:59 (11:59:59 PM) of that day 
For all time to event analyses, participants not reporting the specified endpoint will be 
censored at the time that the participants were last known not to have experienced the 
endpoint. The last visit is a censoring event, and events that occur after the last visit will 


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Final Version 2.0 26 October 2021 
be disregarded in the statistical analysis. For all endpoints not encompassing death, all 
deaths will be treated as censoring events.  In complex cases where the censoring time of 
the participant is uncertain, the case will be reviewed by the Worldwide Statistician and a 
COMPASS statistician, and a censoring time will be assigned before database lock. 
17.5 
Decimal Places 
Decimal places (dps) for derived data described in Section 9 will be determined by the 
scale of measurement unless otherwise stated. No dps will be displayed if the smallest 
calculated value is ≥ 100; 1 dp will be displayed when the smallest value is within the 
interval (10, 100), with 10 being inclusive; 2 dps will be displayed when the smallest value 
is within (1, 10), with 1 being inclusive; and so on for even smaller scales of measurement.  
Derived data where it is known in advance the result will be an integer for example study 
day, number of days and total scores (for rating scales) will be presented with zero decimal 
places.  
Means, medians, and percentiles will be displayed to one more decimal place than the data, 
dispersion statistics (eg. SD) will have two more dps, and the minimum and maximum will 
be displayed to the same number of dps as reported in the raw data. Percentages will be 
displayed with one dp. No percentage will be displayed for zero-frequency scenarios. 
P-values will be quoted to 3 dps. P-values < 0.001 will be presented as <0.001. Where a P-
value is less than 0.05 attention will be drawn to this fact using the “+” annotation. 


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Final Version 2.0 26 October 2021 
18 TABLES, FIGURES AND LISTINGS 
The following tables includes details of the tables, figures and listings to be included within 
each section of the electronic Common Technical Document (eCTD). The eCTD section 
is shown in bold. The following validation methods maybe used:  
• Independent programming of numbers and manual review of format (IP) 
• Independent programming by statistician of numbers and manual review of format 
(Stat IP) 
• Manual review (MR) 
• Code review (CR) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 
Number 
Table Title 
Validation 
Method 
Topline 
Results 
Shell Number 
(if repeat) 
DSMB 
14.1 
Demographic Data 
14.1.1 
Disposition 
14.1.1.1 
Participant Disposition by Country - All Screened Participants  
IP 
 
 
X 
14.1.1.2 
Participant Disposition, Completions and Early Terminations with 
Reasons – Randomised Analysis Set 
IP 
X 
 
X 
14.1.1.3 
Screen Failures with Reasons – All Screened Participants 
IP 
 
 
 
14.1.1.4 
Reasons for Exclusion from the Per-Protocol Analysis Set – Full Analysis 
Set 
IP 
 
 
 
14.1.1.5 
Visits Impacted Due to COVID-19 – Safety Analysis Set 
IP 
 
 
 
14.1.1.6 
Important Protocol Deviations - Safety Analysis Set 
IP 
 
 
X 
14.1.1.7 
COVID-19 Related Protocol Deviations – Safety Analysis Set 
IP 
 
14.1.1.6 
 
14.1.2 
Demographics 
14.1.2 
Demographics - Safety Analysis Set 
IP 
X 
 
X 
14.1.3 
Baseline Characteristics 
14.1.3.1 
Medical History – Safety Analysis Set 
IP 
 
 
X 
14.1.3.2 
Prior Medications – Safety Analysis Set 
IP 
 
 
X 
14.1.3.3 
Concomitant Medications – Safety Analysis Set 
IP 
 
14.1.3.2 
X 
14.1.3.4 
Psychoanaleptic and Psycholeptic-Related Concomitant Medications – 
Safety Analysis Set 
IP 
X 
14.1.3.2 
 
14.1.4.1 
Mini International Neuropsychiatric Interview (Version 7.0.2) – Safety 
Analysis Set 
IP 
 
 
X 
14.1.4.2 
Other Baseline Assessments – Safety Analysis Set 
IP 
 
 
X 
14.2 
Efficacy Data 
14.2.1 
Primary Efficacy Endpoint 
14.2.1.1 
Primary Endpoint – MMRM for Change from Baseline in Montgomery-
Asberg Depression Rating Scale (MADRS) Total Score (MNAR + MAR 
Imputation, Primary Analysis – Hypothetical Strategy Estimand) - Full 
Analysis Set 
Stat IP 
X 
 
 
14.2.1.2 
Primary Endpoint – MMRM for Change from Baseline in Montgomery-
Asberg Depression Rating Scale (MADRS) Total Score (MNAR + MAR 
Stat IP 
X 
14.2.1.1 
 


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Table 
Number 
Table Title 
Validation 
Method 
Topline 
Results 
Shell Number 
(if repeat) 
DSMB 
Imputation, Primary Analysis – Hypothetical Strategy Estimand) – Per-
Protocol Analysis Set 
14.2.1.3 
Primary Endpoint – Summary of Percentage Change from Baseline in 
Montgomery-Asberg Depression Rating Scale (MADRS) Total Score – 
Full Analysis Set 
IP 
 
 
 
14.2.1.4 
Primary Endpoint - MMRM for Change from Baseline in Montgomery-
Asberg Depression Rating Scale (MADRS) Total Score (Week 3 and 12 
Tipping-Point Analysis – Hypothetical Strategy Estimand) - Full Analysis 
Set 
Stat IP 
X 
 
 
14.2.1.5 
Primary Endpoint – ANCOVA for Change from Baseline in Montgomery-
Asberg Depression Rating Scale (MADRS) Total Score by Visit (MNAR 
+ MAR Imputation, Supplementary Analysis – Hypothetical Strategy 
Estimand) - Full Analysis Set 
Stat IP 
X 
 
 
14.2.1.6 
Primary Endpoint - MMRM for Change from Baseline in Montgomery-
Asberg Depression Rating Scale (MADRS) Total Score (MNAR + MAR 
Imputation, Main Analysis – Treatment Policy Estimand) - Full Analysis 
Set 
Stat IP 
X 
14.2.1.1 
 
14.2.1.7 
Primary Endpoint - MMRM for Change from Baseline in Montgomery-
Asberg Depression Rating Scale (MADRS) Total Score (Week 3 and 12 
Tipping-Point Analysis – Treatment Policy Estimand) - Full Analysis Set 
Stat IP 
X 
14.2.1.4 
 
14.2.1.8 
Primary Endpoint - MMRM for Change from Baseline in Montgomery-
Asberg Depression Rating Scale (MADRS) Total Score (Sensitivity 
Analysis – Treatment Policy Estimand) - Full Analysis Set 
Stat IP 
X 
 
 
14.2.1.9 
Primary Endpoint – ANCOVA for Change from Baseline in Montgomery-
Asberg Depression Rating Scale (MADRS) Total Score by Visit (MNAR 
+ MAR Imputation, Supplementary Analysis – Treatment Policy 
Estimand) - Full Analysis Set 
Stat IP 
X 
14.2.1.5 
 
14.2.1.10 
Summary of Missing Montgomery-Asberg Depression Rating Scale 
(MADRS) Total Scores and New Treatment for Depression – Full 
Analysis Set 
IP 
X 
 
 


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Table 
Number 
Table Title 
Validation 
Method 
Topline 
Results 
Shell Number 
(if repeat) 
DSMB 
14.2.1.11 
Primary Endpoint – Summary of Montgomery-Asberg Depression Rating 
Scale (MADRS) Total Score by Drug Dosing Time in Relation to COVID-
19 Lockdown – Full Analysis Set 
IP 
 
 
 
14.2.1.12 
Primary Endpoint – ANCOVA for Correlation of Change from Baseline to 
Week 3 and 12 in Montgomery-Asberg Depression Rating Scale 
(MADRS) Total Score with Potential Response Predictors – Full Analysis 
Set 
Stat IP 
 
 
 
14.2.1.13 
Primary Endpoint – Summary of Montgomery-Asberg Depression Rating 
Scale (MADRS) Total Score and Change from Baseline by Country – Full 
Analysis Set 
IP 
 
 
 
14.2.1.14 
Primary Endpoint – Summary of Montgomery-Asberg Depression Rating 
Scale (MADRS) Total Score and Change from Baseline by Gender – Full 
Analysis Set 
IP 
 
14.2.1.13 
 
14.2.1.15 
Primary Endpoint – Summary of Montgomery-Asberg Depression Rating 
Scale (MADRS) Total Score and Change from Baseline by Age Group – 
Full Analysis Set 
IP 
 
14.2.1.13 
 
14.2.1.16 
Primary Endpoint – Summary of Montgomery-Asberg Depression Rating 
Scale (MADRS) Total Score and Change from Baseline by Number of 
Failed Pharmacological Treatments for the Current Depressive Episode – 
Full Analysis Set 
IP 
 
14.2.1.13 
 
14.2.1.17 
Primary Endpoint – Summary of Montgomery-Asberg Depression Rating 
Scale (MADRS) Total Score and Change from Baseline by Depression 
Severity at Baseline – Full Analysis Set 
IP 
 
14.2.1.13 
 
14.2.2 
Secondary Efficacy Endpoints 
14.2.2.1.1 
Secondary Endpoint - GLMM for Montgomery-Asberg Depression Rating 
Scale (MADRS) Responders (Non-Responder + MAR Imputation, Main 
Analysis – Composite Strategy Estimand) - Full Analysis Set 
Stat IP 
X 
 
 
14.2.2.1.2 
Secondary Endpoint - GLMM for Montgomery-Asberg Depression Rating 
Scale (MADRS) Responders (Non-Responder + MAR Imputation, Main 
Analysis – Composite Strategy Estimand) – Per-Protocol Analysis Set 
Stat IP 
 
14.2.2.1.1 
 


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Table 
Number 
Table Title 
Validation 
Method 
Topline 
Results 
Shell Number 
(if repeat) 
DSMB 
14.2.2.1.3 
Secondary Endpoint – Logistic Regression for Montgomery-Asberg 
Depression Rating Scale (MADRS) Responders by Visit (Non-Responder 
+ MAR Imputation, Supplementary Analysis – Composite Strategy 
Estimand) - Full Analysis Set 
Stat IP 
 
 
 
14.2.2.1.4 
Secondary Endpoint - GLMM for Montgomery-Asberg Depression Rating 
Scale (MADRS) Responders (Non-Responder + MAR Imputation, Main 
Analysis – Treatment Policy Estimand) - Full Analysis Set 
Stat IP 
 
14.2.2.1.1 
 
14.2.2.1.5 
Secondary Endpoint - GLMM for Montgomery-Asberg Depression Rating 
Scale (MADRS) Responders (Sensitivity Analysis – Treatment Policy 
Estimand) - Full Analysis Set 
Stat IP 
 
 
 
14.2.2.1.6 
Secondary Endpoint – Logistic Regression for Montgomery-Asberg 
Depression Rating Scale (MADRS) Response by Visit (Non-Responder + 
MAR Imputation, Supplementary Analysis– Treatment Policy Estimand) - 
Full Analysis Set 
Stat IP 
 
14.2.2.1.3 
 
14.2.2.1.7.1 
Secondary Endpoint – Response Analysis – Full Analysis Set 
IP 
 
 
 
14.2.2.1.7.2 
Secondary Endpoint – Response Analysis (Observed Cases, Treatment 
Policy Estimand) – Full Analysis Set 
IP 
 
14.2.2.1.7.1 
 
14.2.2.1.8 
Secondary Endpoint – Summary of Montgomery-Asberg Depression 
Rating Scale (MADRS) Responders up to Week 12 by Country – Full 
Analysis Set 
IP 
 
 
 
14.2.2.1.9 
Secondary Endpoint – Summary of Montgomery-Asberg Depression 
Rating Scale (MADRS) Responders up to Week 12 by Gender – Full 
Analysis Set 
IP 
 
14.2.2.1.8 
 
14.2.2.1.10 
Secondary Endpoint – Summary of Montgomery-Asberg Depression 
Rating Scale (MADRS) Responders up to Week 12 by Age Group – Full 
Analysis Set 
IP 
 
14.2.2.1.8 
 
14.2.2.1.11 
Secondary Endpoint – Summary of Montgomery-Asberg Depression 
Rating Scale (MADRS) Responders up to Week 12 by Number of Failed 
Pharmacological Treatments for the Current Depressive Episode – Full 
Analysis Set 
IP 
 
14.2.2.1.8 
 


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Table 
Number 
Table Title 
Validation 
Method 
Topline 
Results 
Shell Number 
(if repeat) 
DSMB 
14.2.2.1.12 
Secondary Endpoint – Summary of Montgomery-Asberg Depression 
Rating Scale (MADRS) Responders up to Week 12 by Depression 
Severity at Baseline – Full Analysis Set 
IP 
 
14.2.2.1.8 
 
14.2.2.2.1 
Secondary Endpoint - GLMM for Montgomery-Asberg Depression Rating 
Scale (MADRS) Remitters (Non-Responder + MAR Imputation, Main 
Analysis – Composite Strategy Estimand) - Full Analysis Set 
Stat IP 
X 
14.2.2.1.1 
 
14.2.2.2.2 
Secondary Endpoint - GLMM for Montgomery-Asberg Depression Rating 
Scale (MADRS) Remitters (Non-Responder +MAR Imputation, Main 
Analysis – Composite Strategy Estimand) – Per-Protocol Analysis Set 
Stat IP 
 
14.2.2.1.1 
 
14.2.2.2.3 
Secondary Endpoint – Logistic Regression for Montgomery-Asberg 
Depression Rating Scale (MADRS) Remitters by Visit (Non-Responder + 
MAR Imputation, Supplementary Analysis – Composite Strategy 
Estimand) - Full Analysis Set 
Stat IP 
 
14.2.2.1.3 
 
14.2.2.2.4 
Secondary Endpoint - GLMM for Montgomery-Asberg Depression Rating 
Scale (MADRS) Remitters (Non-Responder + MAR Imputation, Main 
Analysis – Treatment Policy Estimand) - Full Analysis Set 
Stat IP 
 
14.2.2.1.1 
 
14.2.2.2.5 
Secondary Endpoint - GLMM for Montgomery-Asberg Depression Rating 
Scale (MADRS) Remitters (Sensitivity Analysis – Treatment Policy 
Estimand) - Full Analysis Set 
Stat IP 
 
14.2.2.1.5 
 
14.2.2.2.6 
Secondary Endpoint – Logistic Regression for Montgomery-Asberg 
Depression Rating Scale (MADRS) Remitters by Visit (Non-Responder + 
MAR Imputation, Supplementary Analysis– Treatment Policy Estimand) - 
Full Analysis Set 
Stat IP 
 
14.2.2.1.3 
 
14.2.2.2.7 
Secondary Endpoint – Summary of Montgomery-Asberg Depression 
Rating Scale (MADRS) Remitters up to Week 12 by Country (Composite 
Strategy Estimand) – Full Analysis Set 
IP 
 
14.2.2.1.8 
 
14.2.2.2.8 
Secondary Endpoint – Summary of Montgomery-Asberg Depression 
Rating Scale (MADRS) Remitters up to Week 12 by Gender (Composite 
Strategy Estimand) – Full Analysis Set 
IP 
 
14.2.2.1.8 
 


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Table 
Number 
Table Title 
Validation 
Method 
Topline 
Results 
Shell Number 
(if repeat) 
DSMB 
14.2.2.2.9 
Secondary Endpoint – Summary of Montgomery-Asberg Depression 
Rating Scale (MADRS) Remitters up to Week 12 by Age Group 
(Composite Strategy Estimand) – Full Analysis Set 
IP 
 
14.2.2.1.8 
 
14.2.2.2.10 
Secondary Endpoint – Summary of Montgomery-Asberg Depression 
Rating Scale (MADRS) Remitters up to Week 12 by Number of Failed 
Pharmacological Treatments for the Current Depressive Episode 
(Composite Strategy Estimand) – Full Analysis Set 
IP 
 
14.2.2.1.8 
 
14.2.2.2.11 
Secondary Endpoint – Summary of Montgomery-Asberg Depression 
Rating Scale (MADRS) Remitters up to Week 12 by Depression Severity 
at Baseline (Composite Strategy Estimand) – Full Analysis Set 
IP 
 
14.2.2.1.8 
 
14.2.2.3.1.1 
Secondary Endpoint – Logistic Regression for Montgomery-Asberg 
Depression Rating Scale (MADRS) Sustained Responders at Week 12 
(Non-Responder + MAR Imputation, Main Analysis – Composite Strategy 
Estimand) - Full Analysis Set 
Stat IP 
X 
 
 
14.2.2.3.1.2 
Secondary Endpoint – Logistic Regression for Montgomery-Asberg 
Depression Rating Scale (MADRS) Sustained Responders (Relaxed 
Definition) at Week 12 (Non-Responder + MAR Imputation, Main 
Analysis – Composite Strategy Estimand) - Full Analysis Set 
Stat IP 
X 
14.2.2.3.1.1 
 
14.2.2.3.2 
Secondary Endpoint – Logistic Regression for Montgomery-Asberg 
Depression Rating Scale (MADRS Sustained Responders at Week 12 
(Non-Responder + MAR Imputation, Main Analysis – Composite Strategy 
Estimand) – Per-Protocol Analysis Set 
Stat IP 
 
14.2.2.3.1.1 
 
14.2.2.3.3 
Secondary Endpoint - Logistic Regression for Montgomery-Asberg 
Depression Rating Scale (MADRS) Sustained Responders at Week 12 
(Non-Responder + MAR Imputation, Main Analysis – Treatment Policy 
Estimand) - Full Analysis Set 
Stat IP 
 
14.2.2.3.1.1 
 
14.2.2.3.4 
Secondary Endpoint – Logistic Regression for Montgomery-Asberg 
Depression Rating Scale (MADRS) Sustained Responders at Week 12 
(Observed Cases, Supplementary Analysis – Treatment Policy Estimand) - 
Full Analysis Set 
Stat IP 
 
 
 


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Table 
Number 
Table Title 
Validation 
Method 
Topline 
Results 
Shell Number 
(if repeat) 
DSMB 
14.2.2.3.5 
Secondary Endpoint – Summary of Montgomery-Asberg Depression 
Rating Scale (MADRS) Sustained Responders at Week 12 by Country – 
Full Analysis Set 
IP 
 
 
 
14.2.2.3.6 
Secondary Endpoint – Summary of Montgomery-Asberg Depression 
Rating Scale (MADRS) Sustained Responders at Week 12 by Gender – 
Full Analysis Set 
IP 
 
14.2.2.3.5 
 
14.2.2.3.7 
Secondary Endpoint – Summary of Montgomery-Asberg Depression 
Rating Scale (MADRS) Sustained Responders at Week 12 by Age Group 
– Full Analysis Set 
IP 
 
14.2.2.3.5 
 
14.2.2.3.8 
Secondary Endpoint – Summary of Montgomery-Asberg Depression 
Rating Scale (MADRS) Sustained Responders at Week 12 by Number of 
Failed Pharmacological Treatments for the Current Depressive Episode – 
Full Analysis Set 
IP 
 
14.2.2.3.5 
 
14.2.2.3.9 
Secondary Endpoint – Summary of Montgomery-Asberg Depression 
Rating Scale (MADRS) Sustained Responders at Week 12 by Depression 
Severity at Baseline – Full Analysis Set 
IP 
 
14.2.2.3.5 
 
14.2.2.4 
Secondary Endpoint - Analysis of Time to Depressive Event (days) - Full 
Analysis Set 
Stat IP 
 
 
 
14.2.2.5 
Secondary Endpoint - Analysis of Time to Relapse (days) - Full Analysis 
Set 
Stat IP 
 
 
 
14.2.3 
Exploratory Efficacy Endpoints 
14.2.3.1 
Exploratory Endpoint – MMRM for Change from Baseline in the 
Participant EQ-5D-3L Total Score - Full Analysis Set 
Stat IP 
 
 
 
14.2.3.2 
Exploratory Endpoint – MMRM for Change from Baseline in the 
EuroQoL Visual Analogue Scale (EQ-VAS) – Full Analysis Set 
Stat IP 
 
14.2.3.1 
 
14.2.3.3 
Exploratory Endpoint – MMRM for Change from Baseline in SDS Total 
Score - Full Analysis Set 
Stat IP 
 
14.2.3.1 
 
14.2.3.4 
Exploratory Endpoint – MMRM for Change from Baseline in GAD-7 
Total Score - Full Analysis Set 
Stat IP 
 
14.2.3.1 
 
14.2.3.5 
Exploratory Endpoint – MMRM for Change from Baseline in QIDS-SR-
16 Total Score - Full Analysis Set 
Stat IP 
 
14.2.3.1 
 


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Table 
Number 
Table Title 
Validation 
Method 
Topline 
Results 
Shell Number 
(if repeat) 
DSMB 
14.2.3.6 
Exploratory Endpoint – MMRM for Change from Baseline in WSAS 
Total Score - Full Analysis Set 
Stat IP 
 
14.2.3.1 
 
14.2.3.7 
Exploratory Endpoint – MMRM for Change from Baseline in PANAS 
Positive and Negative Affect Total Scores - Full Analysis Set 
Stat IP 
 
 
 
14.2.3.8 
Exploratory Endpoint – MMRM for Change from Baseline in DSST Total 
Score – Full Analysis Set 
Stat IP 
 
14.2.3.1 
 
14.2.3.9 
Exploratory Endpoint – Summary of Categories of DSST Total Score – 
Full Analysis Set 
IP 
 
14.2.3.1 
 
14.2.3.10 
Exploratory Endpoint – Summary of EBI Total Score – Full Analysis Set 
IP 
 
 
 
14.2.3.11 
Exploratory Endpoint - Summary of 5D-ASC Questionnaire Values – Full 
Analysis Set 
IP 
 
 
 
14.3 
Safety Data 
14.3.1  
Displays of Adverse Events 
14.3.1.1 
Summary of Treatment-Emergent Adverse Event (TEAEs) – Safety 
Analysis Set 
IP 
X 
 
X 
14.3.1.2 
MedDRA Summary of Treatment-Emergent Adverse Events (TEAEs) by 
Primary System Organ Class and Preferred Term – Safety Analysis Set 
IP 
X 
 
X 
14.3.1.3 
MedDRA Summary of Non-Serious Treatment-Emergent Adverse Events 
(TEAEs) with ≥ 5% Incidence by Primary System Organ Class and 
Preferred Term – Safety Analysis Set 
IP 
 
 
 
14.3.1.4 
MedDRA Summary of Treatment-Emergent Adverse Events (TEAEs) by 
Primary System Organ Class, Preferred Term and Worst Severity – Safety 
Analysis Set 
IP 
 
 
X 
14.3.1.5 
MedDRA Summary of Treatment-Emergent Adverse Events (TEAEs) by 
Primary System Organ Class, Preferred Term and Strongest Relationship 
to Study Drug – Safety Analysis Set 
IP 
 
 
X 
14.3.1.6 
MedDRA Summary of Treatment-Emergent Adverse Events (TEAEs) by 
Primary System Organ Class, Preferred Term and Time of Onset – Safety 
Analysis Set 
IP 
 
 
 


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Table 
Number 
Table Title 
Validation 
Method 
Topline 
Results 
Shell Number 
(if repeat) 
DSMB 
14.3.1.7 
MedDRA Summary of Treatment-Emergent Adverse Events (TEAEs) by 
Primary System Organ Class, Preferred Term and Duration of Adverse 
Event – Safety Analysis Set 
IP 
 
 
 
14.3.1.8 
MedDRA Summary of Treatment-Emergent Adverse Events (TEAEs) by 
Primary System Organ Class, Preferred Term, Time of Onset and Duration 
of Adverse Event – Safety Analysis Set 
IP 
 
 
 
14.3.1.9 
MedDRA Summary of Adverse Drug Reactions (ADRs) by Primary 
System Organ Class, Preferred Term, Time of Onset and Duration of 
Adverse Drug Reaction – Safety Analysis Set 
IP 
 
14.3.1.8 
 
14.3.1.10 
MedDRA Summary of Duration of Treatment-Emergent Adverse Events 
(TEAEs) by Primary System Organ Class and Preferred Term – Safety 
Analysis Set 
IP 
 
 
 
14.3.1.11 
MedDRA Summary of Adverse Drug Reactions (ADRs) by Primary 
System Organ Class and Preferred Term – Safety Analysis Set 
IP 
 
14.3.1.2 
 
14.3.1.12 
MedDRA Summary of Treatment-Emergent Serious Adverse Events 
(TESAEs) by Primary System Organ Class and Preferred Term – Safety 
Analysis Set 
IP 
X 
14.3.1.2 
X 
14.3.1.13 
MedDRA Summary of Serious Adverse Reactions (SARs) by Primary 
System Organ Class and Preferred Term – Safety Analysis Set 
IP 
 
14.3.1.2 
 
14.3.1.14 
MedDRA Summary of Treatment-Emergent Adverse Events of Special 
Interest (AESIs) by AESI Term and Preferred Term – Safety Analysis Set 
IP 
 
 
X 
14.3.1.15 
MedDRA Summary of Treatment-Emergent Adverse Events (TEAEs) 
Leading to Study Withdrawal by Primary System Organ Class and 
Preferred Term – Safety Analysis Set 
IP 
 
14.3.1.2 
 
14.3.1.16 
MedDRA Summary of Adverse Drug Reactions (ADRs) Leading to Study 
Withdrawal by Primary System Organ Class and Preferred Term – Safety 
Analysis Set 
IP 
 
14.3.1.2 
 
14.3.1.17 
MedDRA Summary of COVID-19 Related Treatment-Emergent Adverse 
Events (TEAEs) by Primary System Organ Class and Preferred Term – 
Safety Analysis Set 
IP 
 
14.3.1.2 
 
14.3.2  
Listings of Deaths, Other Serious and Significant Adverse Events 


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Table 
Number 
Table Title 
Validation 
Method 
Topline 
Results 
Shell Number 
(if repeat) 
DSMB 
14.3.4  
Laboratory Values 
14.3.4.1 
MMRM for Change from Baseline in C-Reactive Protein (CRP) - Safety 
Analysis Set 
Stat IP 
 
14.2.3.1 
 
14.3.4.2 
Summary Statistics of Observed Values and Change from Baseline in 
Haematology – Safety Analysis Set 
IP 
 
 
X 
14.3.4.3 
Summary Statistics of Observed Values and Change from Baseline in 
Chemistry – Safety Analysis Set 
IP 
 
14.3.4.2 
X 
14.3.4.4 
Normal Range Shifts from Baseline in Haematology Values – Safety 
Analysis Set 
IP 
 
 
X 
14.3.4.5 
Normal Range Shifts from Baseline in Chemistry Values – Safety 
Analysis Set 
IP 
 
14.3.4.4 
X 
14.3.5  
Vital Signs 
14.3.5.1 
Summary Statistics of Observed Values and Change from Baseline in 
Vital Signs by Visit – Safety Analysis Set 
IP 
 
 
X 
14.3.5.2 
Overall Summary of Clinically Important Vital Signs Values – Safety 
Analysis Set 
IP 
 
 
 
14.3.6 
Other Safety 
14.3.6.1 
Summary Statistics of Observed Values and Changes from Baseline to 
Day 2 in ECG Variables – Safety Analysis Set 
IP 
 
14.3.4.2 
X 
14.3.6.2 
ECG Clinical Interpretation – Shift from Baseline to Day 2– Safety 
Analysis Set 
IP 
 
 
X 
14.3.6.3 
Summary of QTc Intervals Categories – Safety Analysis Set 
IP 
 
 
 
14.3.6.4 
Summary of C-SSRS by Visit and Treatment Group – Safety Analysis Set 
IP 
 
 
X 


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Figure 
Number 
Figure Title 
Validation 
Method 
Topline 
Results 
Shell Number 
(if repeat) 
DSMB 
14.2 
Efficacy Data 
14.2.1 
Primary Efficacy Endpoint 
14.2.1.1 
LS Means Profile for Change from Baseline in Montgomery-Asberg 
Depression Rating Scale (MADRS) Total Score (MNAR + MAR 
Imputation, Primary Analysis -- Hypothetical Strategy Estimand) – Full 
Analysis Set 
Stat IP 
X 
 
 
14.2.1.2 
LS Means Profile for Change from Baseline in Montgomery-Asberg 
Depression Rating Scale (MADRS) Total Score (MNAR + MAR 
Imputation, Primary Analysis -- Hypothetical Strategy Estimand) – Per-
Protocol Analysis Set 
Stat IP 
 
14.2.1.1 
 
14.2.1.3 
Differences in LS Means for Change from Baseline in Montgomery-
Asberg Depression Rating Scale (MADRS) Total Score (MNAR + 
MAR Imputation, Primary Analysis -- Hypothetical Strategy Estimand) 
– Full Analysis Set 
Stat IP 
 
 
 
14.2.1.4 
Differences in LS Means for Change from Baseline in Montgomery-
Asberg Depression Rating Scale (MADRS) Total Score (MNAR + 
MAR Imputation, Primary Analysis -- Hypothetical Strategy Estimand) 
– Per-Protocol Analysis Set 
Stat IP 
 
14.2.1.3 
 
14.2.1.5 
Means Profile for Percentage Change from Baseline in Montgomery-
Asberg Depression Rating Scale (MADRS) Total Score (Hypothetical 
Strategy Estimand) – Full Analysis Set 
IP 
 
 
 
14.2.1.6 
Change from Baseline in Montgomery-Asberg Depression Rating Scale 
(MADRS) Total Score (Tipping-Point Analysis at Week 3 and 12 - 
Hypothetical Strategy Estimand) – Full Analysis Set 
Stat IP 
 
 
 
14.2.1.7 
LS Means Profile for Change from Baseline in Montgomery-Asberg 
Depression Rating Scale (MADRS) Total Score (MNAR + MAR 
Imputation, Main Analysis - Treatment Policy Estimand) – Full 
Analysis Set 
Stat IP 
 
14.2.1.1 
 


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Number 
Figure Title 
Validation 
Method 
Topline 
Results 
Shell Number 
(if repeat) 
DSMB 
14.2.1.8 
Differences in LS Means for Change from Baseline in Montgomery-
Asberg Depression Rating Scale (MADRS) Total Score (MNAR + 
MAR Imputation, Main Analysis, Treatment Policy Estimand) – Full 
Analysis Set 
Stat IP 
 
14.2.1.3 
 
14.2.1.9 
Change from Baseline in Montgomery-Asberg Depression Rating Scale 
(MADRS) Total Score (Tipping-Point Analysis at Week 3 and 12 – 
Treatment Policy Estimand) – Full Analysis Set 
Stat IP 
 
14.2.1.6 
 
14.2.1.10 
LS Means Profile for Change from Baseline in Montgomery-Asberg 
Depression Rating Scale (MADRS) Total Score (Sensitivity Analysis, 
Treatment Policy Estimand) – Full Analysis Set 
Stat IP 
 
14.2.1.1 
 
14.2.1.11.1 
Scatterplot of Change from Baseline to Week 3 in Montgomery-Asberg 
Depression Rating Scale (MADRS) Total Score vs Potential Response 
Predictors – Full Analysis Set 
Stat IP 
 
 
 
14.2.1.11.2 
Scatterplot of Change from Baseline to Week 12 in Montgomery-
Asberg Depression Rating Scale (MADRS) Total Score vs Potential 
Response Predictors – Full Analysis Set 
Stat IP 
 
14.2.1.11.1 
 
14.2.1.12 
Means Profile for Change from Baseline in Montgomery-Asberg 
Depression Rating Scale (MADRS) Total Score by Country 
(Hypothetical Strategy Estimand) – Full Analysis Set 
IP 
 
 
 
14.2.1.13 
Means Profile for Change from Baseline in Montgomery-Asberg 
Depression Rating Scale (MADRS) Total Score by Gender 
(Hypothetical Strategy Estimand) – Full Analysis Set 
IP 
 
14.2.1.13 
 
14.2.1.14 
Means Profile for Change from Baseline in Montgomery-Asberg 
Depression Rating Scale (MADRS) Total Score by Age Group 
(Hypothetical Strategy Estimand) – Full Analysis Set 
IP 
 
14.2.1.13 
 
14.2.1.15 
Means Profile for Change from Baseline in Montgomery-Asberg 
Depression Rating Scale (MADRS) Total Score by Number of Failed 
Pharmacological Treatments for the Current Depressive Episode 
(Hypothetical Strategy Estimand) – Full Analysis Set 
IP 
 
14.2.1.13 
 


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Number 
Figure Title 
Validation 
Method 
Topline 
Results 
Shell Number 
(if repeat) 
DSMB 
14.2.1.16 
Means Profile for Change from Baseline in Montgomery-Asberg 
Depression Rating Scale (MADRS) Total Score by Depression Severity 
at Baseline (Hypothetical Strategy Estimand) – Full Analysis Set 
IP 
 
14.2.1.13 
 
14.2.2 
Secondary Efficacy Endpoints 
14.2.2.1.1 
Odds ratios of Montgomery-Asberg Depression Rating Scale 
(MADRS) Responders (Non-Responder + MAR Imputation, Main 
Analysis – Composite Strategy Estimand) – Full Analysis Set 
Stat IP 
 
 
 
14.2.2.1.2 
Odds ratios of Montgomery-Asberg Depression Rating Scale 
(MADRS) Responders (Non-Responder + MAR Imputation, Main 
Analysis – Composite Strategy Estimand) – Per-Protocol Analysis Set 
Stat IP 
 
14.2.2.1.1 
 
14.2.2.1.3 
Proportion of Montgomery-Asberg Depression Rating Scale (MADRS) 
Responders up to Week 12 (Composite Strategy Estimand) – Full 
Analysis Set 
Stat IP 
 
 
 
14.2.2.1.4 
Proportion of Montgomery-Asberg Depression Rating Scale (MADRS) 
Responders up to Week 12 (Composite Strategy Estimand) – Per-
Protocol Analysis Set 
Stat IP 
 
14.2.2.1.3 
 
14.2.2.2.1 
Odds ratios of Montgomery-Asberg Depression Rating Scale 
(MADRS) Remitters (Non-Responder + MAR Imputation, Main 
Analysis – Composite Strategy Estimand) – Full Analysis Set 
Stat IP 
 
14.2.2.1.1 
 
14.2.2.2.2 
Odds ratios of Montgomery-Asberg Depression Rating Scale 
(MADRS) Remitters (Non-Responder + MAR Imputation, Main 
Analysis – Composite Strategy Estimand) – Per-Protocol Analysis Set 
Stat IP 
 
14.2.2.1.1 
 
14.2.2.2.3 
Proportion of Montgomery-Asberg Depression Rating Scale (MADRS) 
Remitters up to Week 12 (Composite Strategy Estimand) – Full 
Analysis Set 
Stat IP 
 
14.2.2.1.3 
 
14.2.2.2.4 
Proportion of Montgomery-Asberg Depression Rating Scale (MADRS) 
Remitters up to Week 12 (Composite Strategy Estimand) – Per-
Protocol Analysis Set 
Stat IP 
 
14.2.2.1.3 
 
14.2.2.3 
Kaplan-Meier Plot of Time to Occurrence of First Depressive Event - 
Full Analysis Set 
Stat IP 
 
 
 
14.2.2.4 
Kaplan-Meier Plot of Time to Relapse - Full Analysis Set 
Stat IP 
 
14.2.2.3 
 


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Number 
Figure Title 
Validation 
Method 
Topline 
Results 
Shell Number 
(if repeat) 
DSMB 
14.2.2.5 
Primary Endpoint - Change from Baseline in Montgomery-Asberg 
Depression Rating Scale (MADRS) Total Score - Forest Plot of Results 
Stat IP 
X 
 
 
14.2.2.6.1 
Key Secondary Endpoint - Montgomery-Asberg Depression Rating 
Scale (MADRS) Response - Forest Plot of Results 
Stat IP 
 
14.2.2.5 
 
14.2.2.6.2 
Key Secondary Endpoint - Montgomery-Asberg Depression Rating 
Scale (MADRS) Remission - Forest Plot of Results 
Stat IP 
 
14.2.2.5 
 
14.2.2.6.3 
Key Secondary Endpoint - Montgomery-Asberg Depression Rating 
Scale (MADRS) Sustained Response - Forest Plot of Results 
Stat IP 
 
14.2.2.5 
 
14.2.3 
Exploratory Efficacy Endpoints 
14.2.3.1 
LS Means Profile for Change from Baseline up to Week 12 in 
Participant EQ-5D-3L Total Score – Full Analysis Set 
Stat IP 
 
 
 
14.2.3.2 
LS Means Profile for Change from Baseline up to Week 12 in EuroQoL 
- Visual Analogue Scale (EQ-VAS) – Full Analysis Set 
Stat IP 
 
14.2.3.1 
 
14.2.3.3 
LS Means Profile for Change from Baseline up to Week 12 in SDS 
Total Score – Full Analysis Set 
Stat IP 
 
14.2.3.1 
 
14.2.3.4 
LS Means Profile for Change from Baseline up to Week 12 in GAD-7 
Total Score – Full Analysis Set 
Stat IP 
 
14.2.3.1 
 
14.2.3.5 
LS Means Profile for Change from Baseline up to Week 12 in QIDS-
SR-16 Total Score – Full Analysis Set 
Stat IP 
 
14.2.3.1 
 
14.2.3.6 
LS Means Profile for Change from Baseline up to Week 12 in WSAS 
Total Score – Full Analysis Set 
Stat IP 
 
14.2.3.1 
 
14.2.3.7 
LS Means Profile for Change from Baseline up to Week 12 in PANAS 
Positive and Negative Affect Total Scores – Full Analysis Set 
Stat IP 
 
 
 
14.2.3.8 
LS Means Profile for Change from Baseline up to Week 12 in DSST 
Total Score – Full Analysis Set 
Stat IP 
 
14.2.3.1 
 


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Listing 
Number 
Listing Title 
Validation 
Method 
Topline 
Results 
Shell Number 
(if repeat) 
DSMB 
16.2  
Participant Data Listings 
16.2.1  
Discontinued Participants 
16.2.1.1  
Details of Study Discontinuations – Safety Analysis Set 
IP 
X 
 
X 
16.2.1.2 
Details of Study Completers – Safety Analysis Set 
IP 
 
 
 
16.2.1.3 
Visits Impacted Due to COVID-19 – Safety Analysis Set 
IP 
 
 
 
16.2.2 
Protocol Deviations 
16.2.2.1 
Protocol Deviations – Safety Analysis Set 
IP 
 
 
X 
16.2.2.2 
COVID-19 Related Protocol Deviations – Safety Analysis Set 
IP 
 
16.2.2.1 
 
16.2.3 
Participants Excluded from The Efficacy Analyses 
16.2.3 
Analysis Sets – Randomised Analysis Set  
IP 
 
 
 
16.2.4  
Demographic Data 
16.2.4.1  
Demographics – Safety Analysis Set 
IP 
 
 
X 
16.2.4.2 
Medical History – Safety Analysis Set 
IP 
 
 
X 
16.2.4.3 
Inclusion Criteria – All Screened Participants 
IP 
 
 
 
16.2.4.4 
Exclusion Criteria – All Screened Participants 
IP 
 
16.2.4.3 
 
16.2.4.5 
Prior Medications – Safety Analysis Set 
IP 
 
 
X 
16.2.4.6 
Concomitant Medications – Safety Analysis Set 
IP 
 
 
X 
16.2.4.7 
Psychoanaleptic and Psycholeptic-Related Concomitant Medications – 
Safety Analysis Set 
IP 
X 
 
 
16.2.5  
Compliance And/Or Drug Concentration Data 
16.2.5  
Study Medication Administration – Safety Analysis Set 
IP 
 
 
X 
16.2.6  
Individual Efficacy Response Data   
16.2.6.1 
Montgomery-Asberg Depression Rating Scale (MADRS) Score - Full 
Analysis Set 
IP 
X 
 
 
16.2.6.2.1 
EQ-5D-3L Descriptive System - Full Analysis Set 
IP 
 
 
 
16.2.6.2.2 
EQ Visual Analogue Scale (VAS) - Full Analysis Set 
IP 
 
 
 
16.2.6.3 
Sheehan Disability Scale (SDS) - Full Analysis Set 
IP 
 
 
 
16.2.6.4 
The Digit Symbol Substitution Test (DSST) - Full Analysis Set 
IP 
 
 
 


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Listing 
Number 
Listing Title 
Validation 
Method 
Topline 
Results 
Shell Number 
(if repeat) 
DSMB 
16.2.6.5 
Generalised Anxiety Disorder Scale (GAD-7) – Full Analysis Set 
IP 
 
 
 
16.2.6.6 
Quick Inventory of Depressive Symptomatology – Self Report – 16 items 
(QIDS SR-16) - Full Analysis Set 
IP 
 
 
 
16.2.6.7 
Work and Social Adjustment Scale (WSAS) - Full Analysis Set 
IP 
 
 
 
16.2.6.8.1 
Time to Depressive Event – Full Analysis Set 
IP 
 
 
 
16.2.6.8.2 
Time to Relapse – Full Analysis Set 
IP 
 
 
 
16.2.7  
Adverse Event Listings 
16.2.7.1 
Treatment-Emergent Adverse Events (TEAEs) – Safety Analysis Set 
IP 
X 
 
X 
16.2.7.2 
Treatment-Emergent Serious Adverse Events (TESAEs) – Safety Analysis 
Set 
IP 
 
 
X 
16.2.7.3 
Adverse Drug Reactions (ADRs) – Safety Analysis Set 
IP 
 
16.2.7.1 
 
16.2.7.4 
Treatment-Emergent Adverse Events of Special Interest (AESIs) – Safety 
Analysis Set 
IP 
 
16.2.7.1 
X 
16.2.7.5 
Deaths – Safety Analysis Set 
IP 
 
 
X 
16.2.7.6 
COVID-19 Related Treatment-Emergent Adverse Events (TEAEs) – Safety 
Analysis Set 
IP 
 
16.2.7.1 
 
16.2.8  
Individual Laboratory Measurements and Other Safety 
16.2.8.1 
Haematology – Safety Analysis Set 
IP 
 
 
X 
16.2.8.2 
Chemistry – Safety Analysis Set 
IP 
 
16.2.8.1 
X 
16.2.8.3 
Urinalysis – Safety Analysis Set 
IP 
 
16.2.8.1 
X 
16.2.8.4 
Clinically Significant Laboratory Values – Safety Analysis Set 
IP 
 
 
X 
16.2.8.5 
C-Reactive Protein – Safety Analysis Set 
IP 
 
16.2.8.1 
 
16.2.8.6 
Urine Drug Screen – Safety Analysis Set 
IP 
 
 
X 
16.2.8.7 
Pregnancy Test – Safety Analysis Set 
IP 
 
 
X 
16.2.8.8 
Vital Signs Data – Safety Analysis Set 
IP 
 
 
X 
16.2.8.9 
Clinically Important Vital Signs Values – Safety Analysis Set 
IP 
 
16.2.8.4 
X 
16.2.8.10 
ECG Data – Safety Analysis Set 
IP 
 
 
X 
16.2.8.11 
Clinically Important ECG Values – Safety Analysis Set 
IP 
 
 
X 
16.2.9 
Other Study Instruments 
16.2.9.1 
Major Depressive Episode – Full Analysis Set 
IP 
 
 
 


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Listing 
Number 
Listing Title 
Validation 
Method 
Topline 
Results 
Shell Number 
(if repeat) 
DSMB 
16.2.9.2 
Mini International Neuropsychiatric Interview (MINI, Version 7.0.2) - Full 
Analysis Set 
IP 
 
 
X 
16.2.9.3 
Hamilton Depression Rating Scale - 17-Item (HAM-D-17) - Full Analysis 
Set 
IP 
 
 
X 
16.2.9.4 
The Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire (MGH-ATRQ) - Full Analysis Set 
IP 
 
 
X 
16.2.9.5 
McLean Screening Instrument for Borderline Personality Disorder (MSI-
BPD) - Full Analysis Set 
IP 
 
 
X 
16.2.9.6 
Adult Self-Report Scale (ASRS) - Full Analysis Set 
IP 
 
 
X 
16.2.9.7 
Scale to Assess Therapeutic Relationships – Patient Version (STAR-P) - 
Full Analysis Set 
IP 
 
 
 
16.2.9.8 
Scale to Assess Therapeutic Relationships – Clinician Version (STAR-C) - 
Full Analysis Set 
IP 
 
16.2.9.7 
 
16.2.9.9 
5-HT2A Polymorphism – Full Analysis Set 
IP 
 
 
 
16.2.9.10 
The Positive and Negative Affect Schedule (PANAS) – Full Analysis Set 
IP 
 
 
 
16.2.9.11 
Emotional Breakthrough Inventory (EBI) - Full Analysis Set 
IP 
 
 
 
16.2.9.12 
Five Dimensions Altered States of Consciousness Questionnaire (5D-ASC) 
– Full Analysis Set 
IP 
 
 
 
16.2.9.13 
Columbia Suicidal Severity Rating Scale (C-SSRS) – Safety Analysis Set 
IP 
 
 
X 
16.2.9.14 
Sheehan Suicidality Tracking Scale (S-STS) – Safety Analysis Set 
IP 
 
 
X 
16.2.9.15 
C-SSRS and S-STS Conversion to FDA-CASA 2012 Codes and Categories 
– Safety Analysis Set 
IP 
 
 
 
 


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Final Version 2.0 26 October 2021 
19 APPENDIX 
19.1 
Appendix I – Changes to COMP 001 Protocol 
COMP 001 PROTOCOL 
COMPARATIVE TABLE 
08-March-2021 
COMP 001 PROTOCOL Objective and Endpoint wording versus STATISTICAL ANALYSIS PLAN (SAP) and CLINICAL STUDY 
REPORT (CSR) Objective and Endpoint wording 
This document will detail the minor changes between the COMP 001 protocol and the final versions of the SAP and CSR, with regards 
to the Objective and Endpoint wording. Note the SAP and CSR are not yet finalised during the time of writing this document as Database 
Lock (DBL) has not occurred. The protocol versions are outlined below. 
• Version 4.0 (22 Jul 2019) 
• Version 4.1 (USA) (13 May 2020) 
• Version 4.0 (Denmark) (14 Aug 2019) 
• Version 4.0 (Germany) (12 Nov 2019) 
• Version 4.0 (Portugal) (13 Feb 2020) 
• Version 4.3 (Czech Republic) (26 Feb 2020) 
• Version 4.1 (United Kingdom) (03 Mar 2020) 
• Version 4.1 (USA - Emory) (13 May 2020) 
• Version 4.2 (USA – Site 212) (05 Nov 20) 
General Changes: 
• Replacing psilocybin with COMP360 as this is COMPASS Pathways’ proprietary formulation name of synthetic psilocybin. 
• Replacing day 1 with day 2 as this complies with the Clinical Data Interchange Standards Consortium (CDISC) requirements of 
there not being a day 0 in a clinical study. So, reference to day 0 and day 1 in the protocol is being replaced with day 1 and day 2.  


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• Replacing capitalised words with non-capitalised words for better sentence flow. 
• Replacing patients with participants to follow consistency with COMPASS Pathways’ choice of wording with regards to referencing 
subjects. 
• Replacing fulfills with fulfils to comply with English (UK) spelling. 
 
Specific Changes: 
• Secondary Endpoints 
• Deleted the wording ‘(clinical judgement, supported by the QIDS-SR-16)’ from the time to event measures endpoint. This 
was an error in the protocol. Further detail on defining this endpoint will be provided in the SAP.  
• Exploratory Objectives 
• Deleted the sentence ‘This assessment is not mandatory’ from the participant EQ-5D-3L objective and added this sentence 
to the caregiver EQ-5D-3L objective. This was an error in the protocol.  
• Amended the last exploratory objective to reflect the correlation of the markers mentioned with the primary outcome only 
and not secondary outcomes. This was an error in the protocol. In addition the ‘2a receptor polymorphism test’ will not be 
assessed for correlation with the primary outcome as it is now out of the scope of the CSR and will be reported separately. 
• Removed ‘and predictor of response durability’ from the exploratory objective regarding the change from baseline in the 
Work and Social Adjustment Scale (WSAS). Although this measure has been found to be a predictor of longer-term 
symptomatic improvement with certain treatments, it is not known if this applies consistently across treatments or replicates 
across studies. 
Summary 
 
Protocol Section Concerned with Wording 
SAP and CSR Amended Wording 
Section 2 STUDY OBJECTIVES 
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 
Section 2 STUDY OBJECTIVES 
The main purpose of this study is to allow COMPASS to determine the 
optimal dose of COMP360, either 10 mg or 25 mg. The intent of the 


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Final Version 2.0 26 October 2021 
Protocol Section Concerned with Wording 
SAP and CSR Amended Wording 
primary efficacy analysis is to demonstrate superiority of at least one 
optimal therapeutic dose of psilocybin (10 mg or 25 mg) versus the 1 
mg psilocybin via the following objectives. 
primary efficacy analysis is to demonstrate superiority of at least one 
optimal therapeutic dose of COMP360 (10 mg or 25 mg) versus the 1 
mg COMP360 via the following objectives. 
Section 2.1 Primary (Primary Objective) 
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. 
Section 2.1 Primary (Primary Objective) 
The primary objective of this study is to evaluate the efficacy of 
COMP360 (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 2, and weeks 1, 3, 6, 9, and 12. 


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Protocol Section Concerned with Wording 
SAP and CSR Amended Wording 
Section 2.2 Secondary (Secondary Objectives) 
The secondary objectives are: 
• 
To assess the efficacy of psilocybin compared to 1 mg psilocybin 
on: 
• 
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. 
• 
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 AEs, changes in vital signs, and suicidal 
ideation/behaviour (measured using the Columbia-Suicide Severity 
Rating Scale [C-SSRS]) score at all visits. 
Section 2.2 Secondary (Secondary Objectives) 
The secondary objectives are: 
• 
To assess the efficacy of COMP360 compared to 1 mg COMP360 
on: 
• 
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 2 and at weeks 1, 6, 9, and 
12. 
• 
The proportion of participants who have a sustained 
response at week 12. Sustained response is defined as the 
proportion of participants fulfilling response criteria at 
any visit up to and including week 3, that also fulfils 
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 COMP360 in participants 
with TRD based on AEs, changes in vital signs, and suicidal 
ideation/behaviour (measured using the Columbia-Suicide Severity 
Rating Scale [C-SSRS]) score at all visits. 
 
Section 2.3 Exploratory (Exploratory Objectives) 
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: 
• 
Quality of life in participant EuroQoL (EQ) 5 dimension 3 
level scale (EQ-5D-3L) score change from Baseline to 
Section 2.3 Exploratory (Exploratory Objectives) 
The exploratory objectives are: 
• 
To evaluate the effects of COMP360 on quality of life and 
wellbeing, functioning and associated disability, cognitive 
function, and anxiety compared to 1 mg COMP360 on: 
• 
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. 


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Week 3. This will also be assessed at Week 12. This 
assessment is not mandatory. 
• 
Quality of life in caregiver EQ-5D-3L score change from 
Baseline to Week 3. This will also be assessed at Week 12. 
• 
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. 
• 
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. 
• 
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. 
• 
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 
Screening, Day 1, and Weeks 1, 2, 6, 9, and 12. 
• 
Psychosocial functioning and predictor of response 
durability 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. 
• 
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) 
• 
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. 
• 
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. 
• 
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 2 and week 12. 
• 
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. 
• 
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 
screening, day 2, and weeks 1, 2, 6, 9, and 12. 
• 
Psychosocial functioning 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. 
• 
To evaluate the impact of different COMP360 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) 


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• 
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. 
• 
Positive and Negative Affect Schedule (PANAS), Five 
Dimension Altered States of Consciousness Questionnaire 
(5D-ASC), 2a receptor polymorphism test and 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. 
• 
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. 
• 
Positive and Negative Affect Schedule (PANAS), Five 
Dimension Altered States of Consciousness Questionnaire 
(5D-ASC) and Scale to Assess Therapeutic Relationship 
(Clinician and Patient version, STAR-C and STAR-P, 
respectively) will be assessed for correlation with the 
primary outcome as possible predictors of response. 
Section 3.1 Primary (Primary Endpoint) 
The primary endpoint is the change in MADRS total score from 
Baseline (Day -1) to 3 weeks post psilocybin. 
Section 3.1 Primary (Primary Endpoint) 
The primary endpoint is the change in MADRS total score from 
baseline (day -1) to 3 weeks post COMP360. 
Section 3.2 Secondary (Secondary Endpoints) 
The secondary endpoints are: 
• 
The proportion of participants with a response (defined as a ≥ 50% 
improvement in MADRS total score from Baseline) at Week 3 after 
the psilocybin session. 
• 
The proportion of participants with remission (defined as a 
MADRS total score ≤ 10) at Week 3 post psilocybin. 
Section 3.2 Secondary (Secondary Endpoints) 
The secondary endpoints are: 
• 
The proportion of participants with a response (defined as a ≥ 50% 
improvement in MADRS total score from baseline) at week 3 after 
the COMP360 session. 
• 
The proportion of participants with remission (defined as a 
MADRS total score ≤ 10) at week 3 post COMP360. 


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• 
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. 
• 
Time to event measures: restart antidepressant medication for any 
reason, restart medication for continuing depressive symptoms, and 
relapse from a previously recovered state (clinical judgement, 
supported by the QIDS-SR-16). Participants who withdraw from 
the study will be censored from the time to event analysis. 
• 
The proportion of participants who have a sustained response at 
week 12. Sustained response is defined as the proportion of 
participants fulfilling response criteria at any visit up to and 
including week 3, that also fulfils response criteria at all subsequent 
visits up to and including week 12. Response is defined as ≥ 50% 
decrease in MADRS total score from baseline. 
• 
Time to event measures: restart antidepressant medication for any 
reason, restart medication for continuing depressive symptoms, and 
relapse from a previously recovered state. Participants who 
withdraw from the study will be censored from the time to event 
analysis. 
Section 3.3 Exploratory (Exploratory Endpoints) 
The exploratory endpoints are: 
• 
Change from Baseline in the following: 
• 
Participant EQ-5D-3L at Week 3 
• 
Caregiver EQ-5D-3L at Week 3 (this assessment is not 
mandatory) 
• 
SDS at Week 3 
• 
DSST at Week 3 
• 
GAD-7 at Week 3 
• 
QIDS-SR-16 at Week 3 
• 
WSAS at Week 3 
• 
Measures derived from smart phone usage via the 
Mindstrong app 
Section 3.3 Exploratory (Exploratory Endpoints) 
The exploratory endpoints are: 
• 
Change from baseline in the following: 
• 
Participant EQ-5D-3L at week 3 
• 
Caregiver EQ-5D-3L at week 3 (this assessment is not 
mandatory) 
• 
SDS at week 3 
• 
DSST at week 3 
• 
GAD-7 at week 3 
• 
QIDS-SR-16 at week 3 
• 
WSAS at week 3 
• 
Measures derived from smart phone usage via the 
Mindstrong app 
 
 


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19.2 
Appendix II – Reference of Section Changes from SAP Version 1 
 
VERSION 2 SAP 
VERSION 1 SAP 
1 INTRODUCTION 
1 INTRODUCTION 
2 STUDY OBJECTIVES 
2 STUDY OBJECTIVES 
3 STUDY ENDPOINTS 
3 ENDPOINTS 
4 ESTIMAND FRAMEWORK 
NA  
5 STUDY DESIGN 
NA 
5.1 Study Design 
NA 
5.2 Study Schematic 
NA 
5.3 Schedule of Assessments 
NA 
5.4 Hypotheses and Treatment Comparisons 
6.12.1 Primary Endpoint  
5.5 Multiplicity 
6.12.8 Multiplicity  
5.6 Sample Size Considerations 
4 SAMPLE SIZE 
5.7 Randomisation 
5 RANDOMISATION 
6 PLANNED ANALYSES 
6 PLANNED ANALYSES  
6.1 Final Analysis 
NA 
6.2 Interim Analysis 
7 INTERIM ANALYSES 
6.3 Data Safety Monitoring Board (DSMB) 
8 
DATA 
SAFETY 
MONITORING 
BOARD 
ANALYSIS 
7 ANALYSIS SETS 
6.1 Analysis Sets 
8 GENERAL CONSIDERATIONS 
6.4 Conventions  
6.2.10 Unscheduled Visits  
9 DATA DERIVATIONS 
NA 
9.1 General 
NA 
9.1.1 Change from Baseline 
6.2.9 Change from Baseline  
9.1.2 Missing and Partial Dates 
6.2.3 Conventions for Missing and Partial Dates  
9.1.3 Treatment Exposure and Compliance 
6.2.4 Exposure to Study Drug  
9.1.4 Inexact Values 
6.2.5 Inexact Values  
9.2 Study Participants 
NA 
9.2.1 Protocol Deviations 
6.6 Protocol Deviations 
9.2.2 Age Categories 
NA  
9.2.3 Body Mass Index (BMI) 
NA  
9.2.4 Length of Current Depressive Episode 
NA  
9.2.5 Missing Major Depressive Disorder (MDD) 
Episode Start Dates 
NA  
9.2.6 Prior and Concomitant Medications 
6.9 Prior and Concomitant Medications  
9.3 Efficacy Assessments 
NA 
9.3.1 Montgomery-Asberg Depression Rating Scale 
Score (MADRS) 
6.3.2 Montgomery-Asberg Depression Rating Scale 
Score  
9.3.1.1 Total Score 
6.3.2 Montgomery-Asberg Depression Rating Scale 
Score  
9.3.1.2 Responder Status 
6.12.4 Analysis of Secondary Efficacy Endpoints  
9.3.1.3 Remitter Status 
6.12.4 Analysis of Secondary Efficacy Endpoints  
9.3.1.4 Sustained Response 
6.12.4 Analysis of Secondary Efficacy Endpoints  
6.3.1 Sustained Response  
9.3.1.5 Partial responder Status 
NA 
9.3.1.6 Severity Categories 
NA 
9.3.2 Quick Inventory of Depressive Symptomatology 
(QIDS-SR-16) 
6.3.3 Quick Inventory of Depressive Symptomatology  
9.3.3 European Quality of Life 5-dimension 3-level Scale 
(EQ-5D-3L) 
6.3.7 European Quality of Life 5-dimension 3-level 
Dimension 3-Level Scale  
9.3.4 Sheehan Disability Scale (SDS) 
6.3.4 Sheehan Disability Scale  
9.3.5 Digit Symbol Substitution Test (DSST) 
6.3.6 Digit Symbol Substitution Test  
9.3.6 Generalised Anxiety Disorder Scale (GAD-7) 
6.3.5 Generalized Anxiety Disorder scale 


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9.3.7 Work and Social Adjustment Scale (WSAS) 
6.3.8 Work and Social Adjustment Scale 
9.3.8 Mini International Neuropsychiatric Interview 
6.3.9 MINI International Neuropsychiatric Interview  
9.3.9 Hamilton Depression Rating Scale (HAM-D-17) 
6.3.10 Hamilton Depression Rating Scale  
9.3.10 
The 
Massachusetts 
General 
Hospital 
Antidepressant 
Treatment 
Response 
Questionnaire 
(MGH-ATRQ) 
6.3.11 
The 
Massachusetts 
General 
Hospital 
Antidepressant Treatment Response Questionnaire 
9.3.11 McLean Screening Instrument for Borderline 
Personality Disorder (MSI-BPD) 
6.3.12 McLean Screening Instrument for Borderline 
Personality Disorder 
9.3.12 Adult Self-Report Scale (ASRS) 
6.3.13 Adult Self-Report Scale  
9.3.13 Scale to Assess Therapeutic Relationships – 
Patient (STAR-P) and Clinician (STAR-C) Version 
6.3.14 Scale to Assess Therapeutic Relationships – 
Patient and Clinician Version  
9.3.14 Five Dimensional Altered States of Consciousness 
Questionnaire (5D-ASC) 
6.3.15 Five Dimension Altered States of Consciousness 
Questionnaire  
9.3.15 Emotional Breakthrough Inventory (EBI) 
6.3.16 Emotional Breakthrough Inventory  
9.3.16 The Positive and Negative Affect Schedule 
(PANAS) 
NA  
9.4 Safety 
NA 
9.4.1 Adverse Events 
6.13.1 Adverse Events  
9.4.2 Missing / Partial Start / Stop Dates of AEs and 
Concomitant Medications 
6.2.3.1 Missing/Partial Start/Stop Date of Adverse Events 
and Concomitant Medications  
9.4.3 Vital Signs 
NA 
9.4.3.1 Vital Signs Ranges of Clinical Importance 
NA 
9.4.4 ECG Categorical Intervals 
6.13.4 Electrocardiogram Data  
9.4.5 Columbia-Suicide Severity Rating Scale (C-SSRS) 
6.2.6 Columbia-Suicide Severity Rating Scale  
9.4.6 Sheehan Suicidality Tracking Scale (S-STS) 
6.2.7 Sheehan Suicidality Tracking Scale  
9.4.7 Algorithm to Map Sheehan Suicidality Tracking 
Scale and Columbia-Suicide Severity Rating Scale 
6.2.8 Algorithm to Map Sheehan Suicidality Tracking 
Scale and Columbia-Suicide Severity Rating Scale  
10 STUDY PARTICIPANTS 
NA 
10.1 Disposition of Participants 
6.5 Subject Disposition  
10.2 Protocol Deviations 
6.6 Protocol Deviations  
10.3 Demographic and Baseline Characteristics 
6.7 Baseline Comparability  
10.4 Medical History 
6.8 Medical History 
10.5 Prior and Concomitant Medications 
6.9 Prior and Concomitant Medications  
10.6 Treatment Exposure 
6.10 Exposure to Study Drug  
11 EFFICACY 
6.12 Efficacy Analyses 
11.1 Primary Efficacy 
6.12.2 Primary Efficacy Analyses 
6.12.3 Sensitivity Analysis  
11.1.1 Hypothetical Strategy Estimand (Primary) 
NA 
11.1.1.1 Main Analysis 
NA 
11.1.1.2 Sensitivity Analysis 
NA 
11.1.1.3 Supplementary Analysis 
NA 
11.1.2 Treatment Policy Estimand (Secondary) 
NA 
11.1.2.1 Main Analysis 
NA 
11.1.2.2 Supplementary Analysis 
NA 
11.1.3 Missing Data 
NA 
11.2 Key Secondary Efficacy 
6.12.4 Analysis of Secondary Efficacy Endpoints  
11.2.1 Composite Strategy Estimand (Primary) 
NA 
11.2.1.1 Main Analysis 
NA 
11.2.1.2 Sensitivity Analysis 
NA 
11.2.1.3 Supplementary Analysis 
NA 
11.2.2 Treatment Policy Estimand (Secondary) 
NA 
11.2.2.1 Main Analysis 
NA 
11.2.2.2 Sensitivity Analysis 
NA 
11.2.2.3 Supplementary Analysis 
NA 
11.3 Other Secondary Endpoints 
6.12.5 Time to event analysis  
11.4 Exploratory Efficacy 
NA 
11.4.1 COVID-19 
NA  


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11.4.2 Additional Responders Analysis 
NA  
11.4.3Correlation Analysis 
NA 
11.4.4 Exploratory Endpoints 
6.12.7 Analysis of Exploratory Endpoints 
11.5 Subgroup Analysis: Efficacy 
6.12.6 Subgroup Analysis  
12 SAFETY 
6.13 Safety Analyses  
12.1 Adverse Events (AEs) 
6.13.1 Adverse Events  
12.2 Laboratory Tests 
6.13.2 Laboratory Data  
12.3 Vital Signs 
6.13.3 Vital Signs 
12.4 Electrocardiogram Data 
6.13.4 Electrocardiogram Data  
12.5 C-SSRS 
NA  
12.6 S-STS 
NA  
13 BIOMARKERS 
NA 
13.1 C-Reactive Protein (CRP) 
NA  
14 CHANGES FROM THE PROTOCOL-PLANNED 
ANALYSES 
9 CHANGES TO PLANNED PROTOCOL ANALYSIS  
15 DATA NOT PRESENTED 
NA 
15.1 Mindstrong Data 
NA  
16 REFERENCES 
10 REFERENCES  
17 PROGRAMMING AND DATA PRESENTATION 
CONVENTIONS 
NA  
17.1 Treatment Labelling 
6.4 Conventions  
17.2 Visit Labelling 
NA  
17.3 Baseline Definitions 
6.2.1 Baseline 
17.4 Study Day, Duration and Time Derivation 
6.2.2 Duration/Study Day  
17.5 Decimal Places 
6.4.1 Decimal Places  
18 TABLES, FIGURES AND LISTINGS 
11 LIST OF TABLES, FIGURES AND LISTINGS 
19 APPENDIX 
NA 
19.1 Appendix I – Changes to COMP 001 Protocol 
NA  
19.2 Appendix II – Reference of Section Changes from 
SAP Version 1 
NA 
NA 
6.2.3.2 Missing Dates of Study Drug Dosing