Clinical trial NCT04739865
Conditions: Treatment Resistant Depression
Sponsor: COMPASS Pathways
Start date: 2020-08-10; Completion date: 2021-10-14
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The Safety and Efficacy of Psilocybin as an Adjunctive Therapy in Participants with Treatment-Resistant Depression

Detailed description:
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 explore effectiveness of 25 mg of psilocybin as an adjunctive therapy in participants with TRD.

Arms: arm 1: 25 mg COMP360 Psilocybin
Interventions: intervention 1: Psilocybin
Intervention descriptions: intervention 1: Open label

Protocol documents:
Prot_000.pdf: 
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Version 1.0 – Final– 11 Sep 2019 
 
THE SAFETY AND EFFICACY OF PSILOCYBIN AS AN 
ADJUNCTIVE THERAPY IN PARTICIPANTS WITH 
TREATMENT-RESISTANT DEPRESSION 
DRUG: 
Psilocybin 
3-[2-(Dimethylamino)ethyl]-1H-indol-4-yl 
dihydrogen phosphate 
STUDY NUMBER: 
COMP003 
 
CLINICAL PHASE: 
2 
 
EudraCT NUMBER: 
2018‐002577‐22  
 
SPONSOR: 
COMPASS Pathways, Ltd 
20 Old Bailey 
London, England, EC4M 7AN, UK 
 
VERSION NUMBER: 
V1.0 
 
VERSION DATE: 
11 Sep 2019 
 
 
 




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STUDY NUMBER COMP003 
THE SAFETY AND EFFICACY OF PSILOCYBIN AS AN 
ADJUNCTIVE THERAPY IN PARTICIPANTS WITH 
TREATMENT-RESISTANT DEPRESSION 
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 the 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use (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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STUDY SUMMARY 
Title:  
The Safety and Efficacy of Psilocybin as an Adjunctive Therapy in 
Participants with Treatment-Resistant Depression 
EudraCT Number: 
 
2018‐002577‐22 
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 explore effectiveness of 25 mg of 
psilocybin as an adjunctive therapy in participants with TRD.  
Target Population: 
TRD 
Number of Participants: 
Approximately 20 participants with simultaneous study drug 
administration to up to six participants 
Objectives:  
The main purpose of this study is to investigate the efficacy of 25 mg 
psilocybin adjunct to serotonergic antidepressants in TRD participants via 
the following objectives. 
Primary Objective 
The primary objective of this study is to explore the efficacy of 25 mg 
psilocybin as an adjunct therapy to antidepressants in improving 
depressive symptoms.  
Secondary Objectives 
The secondary objective is to evaluate the safety and tolerability of 
psilocybin in participants with TRD based on adverse events (AEs), 
changes in vital signs, electrocardiograms (ECGs), clinical laboratory tests 
and suicidal ideation/behavior (measured using the Columbia-Suicide 
Severity Rating Scale [C-SSRS]) score. 
Exploratory Objective 
The exploratory objectives are to evaluate the effects of psilocybin on 
quality of life, wellbeing and anxiety. 
Study Design: 
This is a Phase IIb, international multicenter, fixed-dose, open-label study. 
The study population will include adult men and women, 18 years of age 
or 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; the duration of the current episode must 
be at least 3 months but not more than 2 years.  
Participants will be outpatients and will be recruited primarily through 
referrals from general practitioners and specialised psychiatric services.  
After signing the informed consent form (ICF), participants will be 
assessed for their eligibility with the Mini International Neuropsychiatric 


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Interview, Version 7.0.2 (MINI 7.0.2), the Hamilton Depression Rating 
Scale (17-item; 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. At the initial Screening visit (V1), the 
participant will also be evaluated with the Quick Inventory of Depressive 
Symptomatology – Self Rated - 16 item (QIDS-SR-16). Additionally, a 
medical history, an ECG, blood tests, and vital signs will be obtained.  
Once a participant completes all Screening (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. 
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.  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.  
At Baseline [V2, Day -1], the participants will undergo a baseline 
assessment that will consist of the HAM-D-17, Montgomery-Asberg 
Depression Rating Scale (MADRS), Clinical Global Impression – Severity 
scale (CGI-S) and Improvement scale (CGI-I), QIDS-SR-16, C-SSRS, 
Generalised Anxiety Disorder Scale 7-item Scale (GAD-7), Euro QoL-5 
dimension-3 level (EQ-5D-3L; administered to both participant and 
caregiver [the latter is not mandatory]), Medication Adherence Report 
Scale – 5 item (MARS-5), vital signs, urinalysis, urine drug screen, and 
urine pregnancy test (only for women of childbearing potential). 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. The study drug will be 
administered simultaneously to up to six participants. Blood pressure will 
be monitored continuously during the session.  The 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 clinical 
and self-report assessments, 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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Twenty participants will receive one dose of 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) and Week 3 (V7). Adverse events, serious 
adverse events (SAEs) and concomitant medication and therapies will be 
recorded at all clinic visits. The MADRS will be done by telephone and 
the other assessments will be done electronically. 
Eligibility Criteria: 
Inclusion Criteria 
1. Signed ICF. 
2. 18 years of age or older, depending on country-specific limits, at 
Screening (V1). 
3. At least moderate MDD (single or recurrent episode as informed by 
DSM-5; duration of ≥ 3 months and ≤ 2 years) based on medical 
records, clinical assessment and documented completion of the 
version 7.0.2 MINI. 
4. Hamilton Depression Rating Scale (17-item) score ≥18 at 
Screening (V1) and Baseline (V2, Day-1). 
5. Currently receiving treatment with a selective serotonin reuptake 
inhibitor (SSRI; fluoxetine, fluvoxamine, sertraline, paroxetine, 
citalopram or escitalopram) at, or above, a minimum locally approved 
therapeutic dose for at least 6 weeks before Screening (V1) and 
Baseline (V2, Day -1). Dose changes within the adequate range are 
acceptable. To be defined as an adequate study, adherence of at least 
75% is needed based on participant estimate of percentage of doses 
that were taken. 
6. 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. 
Augmentation with an add on treatment counts as a second treatment, 
provided it is approved for the adjunctive treatment of MDD in that 
country.  
7. McLean Screening Instrument for Borderline Personality Disorder 
<7 at Screening (V1). 
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 
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, as assessed by medical 
history, McLean Screening Instrument for Borderline Personality 
Disorder and a structured clinical interview (version 7.0.2 MINI). 
2. Prior electroconvulsive therapy and/or ketamine for current episode. 


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3. Ongoing use of an antidepressant medication, including augmentation 
or combination therapies, other than a single SSRI at Screening (V1) 
and Baseline (V2, Day -1). Discontinuation from antidepressant 
medications, other than the ongoing SSRI, must have been completed 
2 weeks prior to Baseline visit (V2, Day -1). 
4. Current psychological therapies that will not remain stable within 
21 days of the psilocybin session. Psychological therapies cannot be 
initiated within 21 days of baseline. 
5. Current (within the last year) alcohol or substance use disorder as 
informed by DSM-5 (diagnosed by MINI 7.0.2) at Screening (V1). 
6. 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 participant 
interview. 
7. Depression secondary to other severe medical conditions according to 
clinicians’ judgement.  
8. 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:  
9. Women who are pregnant, nursing or planning a pregnancy. Male and 
female 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, Day -1). 
10. 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. 
11. Uncontrolled or insulin-dependent diabetes. 
12. Seizure disorder.  
13. Positive urine drug screen for illicit drugs or drugs of abuse at 
Screening (V1) and Baseline (V2, Day -1). 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 (MM).  
14. Current enrolment in any investigational drug or device study or 
participation in such within 30 days prior to Screening (V1). 
15. Current enrolment in another clinical study of an investigational 
medical or participation in such within 30 days of Screening (V1).  
16. Abnormal and clinically significant results on the physical 
examination, vital signs, ECG or laboratory tests at Screening (V1).  


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17. 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: 
Single 5-capsule oral psilocybin dose of 25 mg. 
Primary Endpoint:  
The primary endpoint is the change in MADRS total score from Baseline 
(Day -1) to 3 weeks post psilocybin administration. 
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 administration 
• 
The proportion of participants with remission (defined as a MADRS 
total score ≤ 10) at Week 3 post psilocybin administration  
• 
Changes from Baseline in CGI-S score at Week 3 post psilocybin 
administration. 
• 
Incidence of AEs 
• 
Change from Baseline to Day 1 in ECGs, and incidence of clinically 
important changes 
• 
Change from Baseline to Day 1 and to Week 3 in clinical laboratory 
tests, and incidence of clinically important changes 
• 
Change from Baseline to Day 1 in vital signs 
• 
Incidence of changes from Baseline in the C-SSRS at each 
post-Baseline visit 
Exploratory Endpoints: 
• 
Change from Baseline to Week 3 in total scores of: 
▪ 
Participant EQ-5D-3L  
▪ 
Caregiver EQ-5D-3L (this assessment is not mandatory) 
▪ 
GAD-7 
▪ 
QIDS-SR-16 
▪ 
CGI-I 
▪ 
MARS-5 adherence to SSRI 
• 
Change from Baseline to Day 1 in Positive and Negative Affect 
Schedule (PANAS) 
• 
Summary of Five Dimension Altered States of Conscniousness 
questionnaire (5D-ASC) on the day of the psilocybin session (Day 0) 
Efficacy Assessments: 
• 
MADRS 
• 
CGI-S 
• 
CGI-I 
• 
EQ-5D-3L (participant and caregiver, the latter is not mandatory) 
• 
GAD-7 


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• 
QIDS-SR-16 
• 
PANAS 
• 
5D-ASC 
• 
C-SSRS 
Safety Assessments: 
• 
ECG 
• 
Vital signs  
• 
Clinical laboratory tests 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 enrolled participants, 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 enrolled participants who 
receive the dose of investigational product (IP). 
The Per Protocol (PP) Population will consist of all participants in the FAS 
who do not have a major protocol deviation defined as a deviation which 
may significantly affect efficacy for that participant. Major protocol 
deviations will be reviewed and determined prior to database lock.  
Efficacy Analyses 
Since this is a single treatment open-label study, no statistical testing will 
be performed. The FAS and the PP populations will both be used for each 
secondary endpoint, if the two sets are not identical. For each of the 
secondary endpoints (MADRS, CGI-S, C-SSRS), measuring change from 
Baseline to Week 3, summary statistics will be provided. 
Analysis of exploratory endpoints will be detailed in the Statistical 
Analysis Plan (SAP). 
Safety Analyses 
Safety data will be presented for the Safety Population. Safety will be 
evaluated based on AEs, ECGs, clinical laboratory tests, vital signs and 
suicidal ideation/behavior (measured using C-SSRS). 
 


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TABLE OF CONTENTS 
CLINICAL PROTOCOL APPROVAL FORM .............................................................2 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT ...................................3 
STUDY SUMMARY ..........................................................................................................4 
TABLE OF CONTENTS ................................................................................................10 
LIST OF ABBREVIATIONS .........................................................................................13 
1 
INTRODUCTION AND RATIONALE .................................................................15 
1.1 
Background ..........................................................................................................15 
1.2 
Study Rationale ....................................................................................................15 
1.2.1 
Pharmacokinetics ...........................................................................................16 
1.2.2 
Preclinical Pharmacology ..............................................................................16 
1.2.3 
Clinical Adverse Event Profile ......................................................................17 
1.2.4 
Potential Risk to Foetal Development ..........................................................17 
1.2.5 
Dosing Regimen ..............................................................................................17 
2 
STUDY OBJECTIVES ............................................................................................19 
2.1 
Primary .................................................................................................................19 
2.2 
Secondary..............................................................................................................19 
2.3 
Exploratory ...........................................................................................................19 
3 
STUDY ENDPOINTS ..............................................................................................20 
3.1 
Primary .................................................................................................................20 
3.2 
Secondary..............................................................................................................20 
3.3 
Exploratory ...........................................................................................................20 
3.4 
Efficacy and Outcome Measures ........................................................................21 
4 
STUDY PLAN ...........................................................................................................22 
4.1 
Study Design .........................................................................................................22 
4.2 
Study Schematic ...................................................................................................24 
4.3 
Schedule of Assessments ......................................................................................25 
5 
POPULATION ..........................................................................................................28 
5.1 
Number of Participants .......................................................................................28 
5.2 
Inclusion Criteria .................................................................................................28 
5.3 
Exclusion Criteria ................................................................................................29 
5.4 
Participant Screening ..........................................................................................30 
5.5 
Deviation from Inclusion/Exclusion Criteria ....................................................30 
6 
STUDY CONDUCT..................................................................................................31 
6.1 
General Instructions ............................................................................................31 
6.2 
Study Procedures by Time Point ........................................................................31 
6.2.1 
Screening Period – Visit 1 .............................................................................31 
6.2.2 
Baseline Visit – Visit 2 – Day -1 ....................................................................32 
6.2.3 
Visit 3 – Day 0 – Psilocybin Session ..............................................................33 
6.2.4 
Visit 4 – Day 1 Postdosing .............................................................................34 
6.2.5 
Visits 5 and 6 – 1 and 2 Week Postdosing ....................................................35 
6.2.6 
Visit 7 – 3 Weeks Postdosing – End of Study ..............................................35 
6.3 
Premature Discontinuation .................................................................................36 


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7 
DESCRIPTION OF STUDY PROCEDURES .......................................................38 
7.1 
Efficacy Assessments ...........................................................................................38 
7.1.1 
Montgomery-Asberg Depression Rating Scale ...........................................38 
7.1.2 
Clinical Global Impression – Severity Scale ................................................38 
7.1.3 
Clinical Global Impression – Improvement Scale ......................................38 
7.1.4 
Quick Inventory of Depressive Symptomatology – Self Rated – 
16 Item.............................................................................................................38 
7.1.5 
Generalised Anxiety Disorder Scale .............................................................39 
7.1.6 
EuroQoL-5-dimension 3-level Scale .............................................................39 
7.2 
Safety Assessments ...............................................................................................39 
7.2.1 
Columbia-Suicide Severity Rating Scale .....................................................39 
7.2.2 
Vital Signs .......................................................................................................40 
7.2.3 
Electrocardiogram .........................................................................................40 
7.2.4 
Clinical Laboratory Tests..............................................................................40 
7.2.5 
Adverse Events ...............................................................................................41 
7.3 
Other Assessment Instruments ...........................................................................41 
7.3.1 
Hamilton Depression Rating Scale – 17-item ..............................................41 
7.3.2 
Mini International Neuropsychiatric Interview, Version 7.0.2 .................42 
7.3.3 
Massachusetts General Hospital-Antidepressant Treatment 
History Response Questionnaire ..................................................................42 
7.3.4 
McLean Screening Instrument for Borderline Personality 
Disorder ..........................................................................................................42 
7.3.5 
Five Dimension Altered States of Consciousness Questionnaire ...............43 
7.3.6 
The Positive and Negative Affect Schedule .................................................43 
7.3.7 
Medication Adherence Report Scale ............................................................43 
7.4 
Protocol Deviations ..............................................................................................43 
8 
INVESTIGATIONAL PRODUCT MANAGEMENT ..........................................44 
8.1 
Description ............................................................................................................44 
8.1.1 
Formulation ....................................................................................................44 
8.1.2 
Storage ............................................................................................................44 
8.2 
Packaging and Blinding .......................................................................................44 
8.3 
Dose and Administration .....................................................................................45 
8.4 
Accountability ......................................................................................................45 
8.5 
Concomitant Therapy ..........................................................................................46 
8.5.1 
Permissible Medications ................................................................................46 
8.5.2 
Definition of Women of Childbearing Potential and/or Acceptable 
Contraceptive Methods .................................................................................47 
8.5.3 
Prohibited Medications .................................................................................48 
8.5.4 
Rescue Medication .........................................................................................48 
8.6 
Compliance ...........................................................................................................49 
9 
ADVERSE EVENTS ................................................................................................50 
9.1 
Documenting Adverse Events .............................................................................50 
9.2 
Assessment of Intensity........................................................................................51 
9.3 
Assessment of Causality ......................................................................................52 
9.4 
Action Taken Regarding Investigational Product ............................................52 


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9.5 
Other Action Taken for Event ............................................................................53 
9.6 
Adverse Event Outcome ......................................................................................53 
9.7 
Clinical Laboratory Changes ..............................................................................53 
9.8 
Overdose ...............................................................................................................54 
9.9 
Adverse Events of Special Interest .....................................................................54 
9.10 
Adverse Event Follow-up ....................................................................................55 
10 SERIOUS ADVERSE EVENTS ..............................................................................56 
10.1 
Definition of Serious Adverse Event ..................................................................56 
10.2 
Reporting Serious Adverse Events .....................................................................57 
11 STATISTICS .............................................................................................................60 
11.1 
General Procedures .............................................................................................60 
11.2 
Sample Size ...........................................................................................................60 
11.3 
Statistical Methods ...............................................................................................60 
11.3.1 
Efficacy and Outcome Measures ..................................................................60 
11.3.2 
Analysis of Efficacy ........................................................................................61 
11.3.3 
Multiplicity .....................................................................................................61 
11.3.4 
Analysis of Safety ...........................................................................................61 
11.3.5 
Demographic and Baseline Characteristics .................................................62 
11.4 
Interim Analysis ...................................................................................................62 
12 ETHICS AND RESPONSIBILITIES .....................................................................63 
12.1 
Good Clinical Practice .........................................................................................63 
12.2 
Steering Committee .............................................................................................63 
12.3 
Institutional Review Board/Independent Ethics Committee ...........................63 
12.4 
Informed Consent ................................................................................................63 
12.5 
Exposure in Utero During Clinical Studies .......................................................63 
12.6 
Records Management ..........................................................................................64 
12.7 
Source Documentation.........................................................................................64 
12.8 
Study Files and Record Retention ......................................................................64 
13 AUDITING AND MONITORING ..........................................................................65 
14 AMENDMENTS .......................................................................................................66 
15 STUDY REPORT AND PUBLICATIONS ............................................................67 
16 STUDY DISCONTINUATION ...............................................................................68 
17 CONFIDENTIALITY ..............................................................................................69 
18 REFERENCES .........................................................................................................70 
19 APPENDICES ...........................................................................................................73 
19.1 
Appendix I – Names of Study Personnel............................................................73 
19.2 
Appendix II – Declaration of Helsinki ...............................................................74 
19.3 
Appendix III – Massachusetts General Hospital-Antidepressant 
Treatment History Response Questionnaire – Additional Detail 
Regarding the Assessment of Previous Antidepressant Treatment ................79 
 
LIST OF TABLES 
Table 8.1 
Details of Investigational Product ..........................................................44 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
5D-ASC 
Five Dimension Altered States of Consciousness questionnaire 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
CAT 
Clinical Assessment Technologies Team 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression – Improvement scale 
CGI-S 
Clinical Global Impression – Severity scale 
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 
EC50 
half-maximal effective concentration 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture 
EIU 
Exposure In Utero 
EOS 
End of Study 
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 7-item Scale 
GCP 
Good Clinical Practice 
h 
hours 
HAM-D-17 
Hamilton Depression Rating Scale (17-item) 
HDPE 
high-density polyethylene 
IB 
Investigator’s Brochure 
ICF 
informed consent form 


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Abbreviation 
Definition 
ICH 
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IP 
investigational product 
IRB 
Institutional Review Board 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MARS-5 
Medication Adherence Report Scale – 5 item 
MDD 
major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGH-ATRQ 
Massachusetts General Hospital-Antidepressant Treatment Response Questionnaire 
min 
minute 
MINI 7.0.2 
Mini International Neuropsychiatric Interview, Version 7.0.2 
MM 
Medical Monitor 
MSI-BPD 
McLean Screening Instrument for Borderline Personality Disorder 
OTC 
over-the-counter 
PANAS 
Positive and Negative Affect Schedule 
PP 
per protocol (analysis population) 
PT 
preferred term 
QIDS-SR-16 
Quick Inventory of Depressive Symptomatology – Self-Rated - 16 item 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SSRI 
selective serotonin reuptake inhibitor 
TEAE 
treatment-emergent adverse event 
TRD 
treatment-resistant depression 
ULN 
upper limit of normal 
VAS 
visual analog scale 
Worldwide 
Worldwide Clinical Trials, Inc. 


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1 INTRODUCTION AND RATIONALE 
The following is a summary of the information found in the current Investigator’s 
Brochure (IB).7 
1.1 
Background 
Psilocybin belongs to a class of drugs referred to as psychedelics (meaning 
‘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 1958.22 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 US in 1970, and until the 1980s in Germany.22,23 
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,4,10,16 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 (six men and 
six women) with moderate-to-severe, unipolar, treatment-resistant major depression 
(ISRCTN 14426797).3 Each patient received two 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 Quick Inventory of Depressive 
Symptomatology – Self Rated - 16 item (QIDS-SR-16); QIDS-SR-16 scores were 
obtained from Week 1 to 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-SR-16 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%).  


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This study provides further support for the safety and efficacy of psilocybin for 
treatment-resistant depression (TRD) and motivates further studies to better examine the 
therapeutic potential of this approach. In this study, the aim is to explore effectiveness of 
25 mg of psilocybin as an adjunctive therapy in participants with TRD. In addition, there 
is one ongoing study, COMP001, examining the safety and efficacy of psilocybin in 
participants with TRD and one study which has completed the in-clinic phase, 
COMP002, looking at the effects of psilocybin on cognitive and emotional function in 
healthy participants. 
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).14 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 14,17,20,22 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.14,20 Hasler et al.14 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.15 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.15 
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.31 Reviews of the pharmacology of psilocybin is provided by Passie, 
and more current knowledge and perspective by Tylš et al.22,30 
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.24 That 
concentration would generally be considered to be pharmacologically inactive in vivo 


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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 
should be no concern for that effect. With the EC50 reported by Rickli et al.,24 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 1960s, 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).7 These effects are both 
expected, and may be a necessary component of therapeutic response. Investigators must 
follow regulatory guidance under 21 Code of Federal Regulations (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 nursing and should be using an effective method of birth control when 
using psilocybin.  
1.2.5 
Dosing Regimen 
Carhart-Harris successfully evaluated two 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.3 Work by the Griffiths group showed that under supportive conditions, 


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psilocybin at doses of 20 to 30 mg/70 kg can dose-dependently occasion mystical-type 
experiences.11 
This study will evaluate 1 psilocybin dose (25 mg psilocybin) under supportive 
conditions.  


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2 STUDY OBJECTIVES 
The main purpose of this study is to investigate the efficacy of 25 mg psilocybin adjunct 
to serotonergic antidepressants in TRD participants via the following objectives. 
2.1 
Primary 
The primary objective of this study is to explore the efficacy of 25 mg psilocybin as an 
adjunct therapy to antidepressants in improving depressive symptoms. 
2.2 
Secondary 
The secondary objective is to evaluate the safety and tolerability of psilocybin in 
participants with TRD based on AEs, changes in vital signs, electrocardiograms (ECGs), 
clinical laboratory tests and suicidal ideation/behavior (measured using the Columbia-
Suicide Severity Rating Scale [C-SSRS]) score. 
2.3 
Exploratory  
The exploratory objectives are to evaluate the effects of psilocybin on quality of life, 
wellbeing and anxiety. 


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3 STUDY ENDPOINTS  
3.1 
Primary 
The primary endpoint is the change in Montgomery-Asberg Depression Rating Scale 
(MADRS) total score from Baseline (Day -1) to 3 weeks post psilocybin administration. 
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 post psilocybin administration 
o The proportion of participants with remission (defined as a MADRS total score 
≤ 10) at Week 3 post psilocybin administration  
o Changes from Baseline Clinical Global Impression – Severity scale (CGI-S) at 
Week 3 post psilocybin administration  
o Incidence of AEs 
o Change from Baseline to Day 1 in ECGs, and incidence of clinically important 
changes 
o Change from Baseline to Day 1 and to Week 3 in clinical laboratory tests, and 
incidence of clinically important changes 
o Change from Baseline to Day 1 in vital signs 
o Incidence of changes from Baseline in the C-SSRS at each post-Baseline visit 
3.3 
Exploratory 
The exploratory endpoints are: 
o Change from Baseline to Week 3 in total scores of: 
▪ Participant Euro QoL-5 dimension-3 level (EQ-5D-3L) 
▪ Caregiver EQ-5D-3L (this assessment is not mandatory) 
▪ Generalised Anxiety Disorder 7-item Scale (GAD-7)  
▪ QIDS-SR-16  
▪ Clinical Global Impression – Improvement scale (CGI-I) 


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▪ Medication Adherence Report Scale – 5 item (MARS-5) adherence to 
selective serotonin reuptake inhibitor (SSRI) 
o Change from Baseline to Day 1 in Positive and Negative Affect Schedule 
(PANAS) 
o Summary of Five Dimension Altered States of Conscniousness questionnaire 
(5D-ASC) on the day of the psilocybin session (Day 0) 
3.4 
Efficacy and Outcome Measures 
Measures of interest include: 
o MADRS 
o CGI-S 
o CGI-I 
o EQ-5D-3L (participant and caregiver [latter is not mandatory]) 
o GAD-7 
o QIDS-SR-16  
o PANAS 
o 5D-ASC 
o C-SSRS 


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4 STUDY PLAN 
4.1 
Study Design 
This is a Phase IIb, international multicenter, fixed-dose, open-label study. The study 
population will include adult men and women, 18 years of age or 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; the duration of the current episode must be at least 
3 months but not more than 2 years.  
Participants will be outpatients and will be recruited primarily through referrals from 
general practitioners and specialised psychiatric services.  
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 Hamilton Depression Rating Scale (17-item; 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). At the initial Screening visit (V1), the 
participant will also be evaluated with the QIDS-SR-16. Additionally, a medical history, 
an ECG, blood tests, and vital signs will be obtained.  
Once a participant completes all Screening (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. 
All participants will be evaluated for safety at the clinic weekly for a minimum of 
3 weeks prior to psilocybin administration. 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 (≥ 24 h after Screening [V1]; V2, Day -1), the 
participants will undergo a baseline assessment that will consist of the HAM-D-17, 
MADRS, CGI-S, QIDS-SR-16, C-SSRS, GAD-7, EQ-5D-3L (administered to both 
participant and caregiver [the latter is not mandatory]), MARS-5, vital signs, urinalysis, 
urine drug screen, and urine pregnancy test (only for women of childbearing potential). 


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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 
under trained therapist supervision and support. The study drug will be administered 
simultaneously to up to six participants. Blood pressure will be monitored continuously 
during the session. The 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.  
Twenty participants will receive one dose of 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) and Week 3 (V7). Adverse events, serious adverse events (SAEs) and concomitant 
medication will be recorded at all clinic visits. The MADRS will be done by telephone 
and the other assessments will be done electronically.  
Clinicians are advised to continue the prescription of the participant’s baseline SSRI 
(fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram or escitalopram) for the 
duration of the follow-up period, ideally at the same dose. 
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 
                     
 
3 weeks
3 weeks
Screening (V1) 
Day 0 (V3)
Day +1 (V4) 
Week 1 (V5)
Week 2 (V6)  
Week 3 (V7)
Screening (V1a) 
Screening (V1b) 
Day -1 (V2)


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4.3 
Schedule of Assessments 
 
 
 
3 weeks 
prior to 
Baseline 
 
 
Time Post Psilocybin Session 
 
Screening1 
Screening 
Period  
Baseline 
(Day -1) 
Psilocybin 
Session  
(Day 0) 
Day 1 
Week 1 
Day 7 
Week 2 
Day 14 
Week 3 
Day 21 
(EOS/ET) 
Visit 
1 
1a, 1b 
2 
3 
4 
5 
6 
7 
Allowable Window 
- 
Weekly 
+ < 7 days 
none 
None 
±1 day 
±1 day 
± 1 day 
Clinical Assessments and Procedures 
Informed consent 
✓ 
 
 
 
 
 
 
 
Medical history 
✓ 
 
✓ 
 
 
 
 
 
Inclusion/Exclusion Criteria 
✓ 
 
✓ 
 
 
 
 
 
MINI 7.0.2 
✓ 
 
 
 
 
 
 
 
HAM-D-17 
✓ 
 
✓ 
 
 
 
 
 
MGH-ATRQ 
✓ 
 
 
 
 
 
 
 
C-SSRS2 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Vital signs 
✓ 
 
✓ 
✓ 
✓ 
 
 
 
Physical examination, including 
weight and height 
✓ 
 
 
 
 
 
 
 
12-Lead ECG 
✓ 
 
 
 
✓ 
 
 
 
Clinical laboratory tests3 
✓ 
 
 
 
✓ 
 
 
✓ 
Urinalysis3 
✓ 
 
✓ 
 
✓ 
 
 
 
Urine drug screen3  
✓ 
 
✓ 
 
 
 
 
 
Urine pregnancy test4 
✓ 
 
✓ 
 
 
 
 
 


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3 weeks 
prior to 
Baseline 
 
 
Time Post Psilocybin Session 
 
Screening1 
Screening 
Period  
Baseline 
(Day -1) 
Psilocybin 
Session  
(Day 0) 
Day 1 
Week 1 
Day 7 
Week 2 
Day 14 
Week 3 
Day 21 
(EOS/ET) 
Visit 
1 
1a, 1b 
2 
3 
4 
5 
6 
7 
Allowable Window 
- 
Weekly 
+ < 7 days 
none 
None 
±1 day 
±1 day 
± 1 day 
Clinical Assessments and Procedures 
Documentation of contraceptive 
method to be used5 
✓ 
 
 
 
 
 
 
 
CGI-I 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
CGI-S 
 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
MARS-5 
 
 
✓ 
 
 
✓ 
✓ 
✓ 
Psilocybin dose 
 
 
 
✓ 
 
 
 
 
Prior/Concomitant Medications 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
AE/SAEs 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Participant Completed Assessments 
MSI-BPD 
✓ 
 
 
 
 
 
 
 
QIDS-SR-16 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
EQ-5D-3L 
 
 
✓ 
 
 
✓ 
✓ 
✓ 
GAD-7 
 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
PANAS 
 
 
✓ 
 
✓ 
 
 
 
5D-ASC 
 
 
 
✓6 
 
 
 
 
 
Remote-rater Assessment 
MADRS7 
 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
 
Abbreviations: 5D-ASC = Five Dimension Altered States of Consciousness; AE = adverse event; CGI-I = Clinical Global Impression – Improvement; CGI-S = Clinical Global Impression – Severity; 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; EOS = End of Study; EQ-5D-3L = Euro QoL-5 dimension-3 level; ET = early termination; GAD-7 = Generalised Anxiety 
Disorder 7-item Scale; HAM-D-17 = Hamilton Depression Rating Scale (17-item); MINI 7.0.2 = Mini International Neuropsychiatric Interview, Version 7.0.2; MADRS = Montgomery-Asberg 


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Depression Scale; MARS-5 = Medication Adherence Report scale – 5 item; 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; SAE = serious adverse event. 
 
1 Screening (V1) will be performed 3 weeks prior to the Baseline visit (V2, Day -1). 
2 The “Last 12 months” version will be administered at Screening and the “Since Last Visit” version will be administered at all other visits.  
3 See Section 7.2.4 for complete list of required tests to be performed.  
4 For women of child-bearing potential only. 
5 For females of childbearing potential and all males; site is to document method of contraception agreed to be used by each participant. 
6 To be administered immediately after the psilocybin session. 
7 On site clinic visits; visits allowed remotely will have the MADRS performed by telpehone and other assessments will be done electronically. 
 
Instruments (all measures below will be captured electronically): 
5D-ASC – The Five Dimension Altered States of Consciousness questionnaire measures the acute drug effects. 
C-SSRS - Columbia-Suicide Severity Rating Scale. This scale should be administered prior to dosing if possible. 
EQ-5D-3L – The 3-level Euro QoL (EQ)-5D version (EQ‑5D‑3L) was introduced by the EuroQoL Group in 1990. The EQ-5D-3L essentially consists of two 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.  
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 – Self Rated - 16 item is a participant-rated scale to assess their depression. 
MARS-5 – Medication Adherence Report Scale – 5 item, self-report scale measuring adherence to the patients ongoing SSRI antidepressant 
CGI-S – Clinical Global Impression – Severity scale, a clinician-rated measure of depression severity 
CGI-I – Clinical Global Impression – Improvement scale, a clinician-rated measure of improvement 
 


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5 POPULATION 
5.1 
Number of Participants 
A total of 20 participants with simultaneous study drug administration to up to 
6 participants. 
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, depending on country-specific limits, at Screening (V1). 
3. At least moderate MDD (single or recurrent episode as informed by DSM-5; 
duration of ≥ 3 months and ≤ 2 years) based on medical records, clinical 
assessment and documented completion of the version 7.0.2 MINI. 
4. Hamilton Depression Rating Scale (17-item) score ≥18 at Screening (V1) and 
Baseline (V2, Day -1).    
5. Currently receiving treatment with a SSRI (fluoxetine, fluvoxamine, sertraline, 
paroxetine, citalopram or escitalopram) at, or above, a minimum locally approved 
therapeutic dose for at least 6 weeks before Screening (V1) and Baseline (V2, 
Day -1). Dose changes within the adequate range are acceptable. To be defined as 
an adequate study, adherence of at least 75% is needed based on participant 
estimate of percentage of doses that were taken. 
6. 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.  
7. McLean Screening Instrument for Borderline Personality Disorder <7 at Screening 
(V1). 
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.  
 


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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, as 
assessed by medical history, MSI-BPD and a structured clinical interview (version 
7.0.2 MINI). 
2. Prior electroconvulsive therapy and/or ketamine for current episode. 
3. Ongoing use of an antidepressant medication, including augmentation or combination 
therapies, other than a single SSRI at Screening (V1) and Baseline (V2, Day -1). 
Discontinuation from antidepressant medications, other than the ongoing SSRI, must 
have been completed 2 weeks prior to Baseline visit (V2, Day -1). 
4. Current psychological therapies that will not remain stable within 21 days of the 
psilocybin session. Psychological therapies cannot be initiated within 21 days of 
baseline. 
5. Current (within the last year) alcohol or substance use disorder as informed by 
DSM-5 (diagnosed by MINI 7.0.2) at Screening (V1). 
6. 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 participant interview. 
7. Depression secondary to other severe medical conditions according to clinicians’ 
judgement.  
8. Other personal circumstances and behavior 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:  
9. Women who are pregnant, nursing, or planning a pregnancy. Male and female 
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, 
Day -1). 
10. 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. 


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11. Uncontrolled or insulin-dependent diabetes. 
12. Seizure disorder.  
13. Positive urine drug screen for illicit drugs or drugs of abuse at Screening (V1) and 
Baseline (V2, Day -1). 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 MM.  
14. Current enrolment in any investigational drug or device study or participation in such 
within 30 days prior to Screening (V1). 
15. Current enrolment in another clinical study of an investigational medical or 
participation in such within 30 days of Screening (V1).  
16. Abnormal and clinically significant results on the physical examination, vital signs, 
ECG or laboratory tests at Screening (V1).  
17. 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 primarily 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. 
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 MM 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 primarily 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 – Visit 1 
The participant will be seen initially to evaluate suitability for the study.  
At the 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 concomitant medications 
o Review of inclusion/exclusion criteria (Section 5) 
o MINI 7.0.2 
o HAM-D-17 
o MGH-ATRQ 
o C-SSRS (last 12 Months) 
o MSI-BPD 
o QIDS-SR-16 
o Vital signs (ie, sitting blood pressure, pulse, body temperature, and respiratory 
rate) 
o Physical examination, including weight and height 


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o 12-lead ECG 
o Blood and urine samples for: 
▪ Clinical laboratory tests  
▪ Urinalysis 
▪ Urine drug screen 
▪ Urine pregnancy test for all women of childbearing potential 
o Document contraceptive method to be used by the participant 
o AEs and SAEs (Sections 9 and 10) 
Once a participant completes all Screening (V1) assessments and all screening data is 
entered into the EDC, the MM and CAT will review data entered and issue approval, if 
the participant is eligible. 
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 MM 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), 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, Day -1) should occur after Screening (V1) + < 7-Day window. At 
the Baseline visit (V2, Day -1), the participant’s eligibility will be confirmed by 
reviewing the Inclusion/Exclusion Criteria (Sections 5.2 and 5.3) and updating the 
medical history. If the participant is out of the < 7-Day window, all baseline assessments 
are to be repeated. The Baseline visit (V2, Day -1) should occur the day before the 
anticipated psilocybin session. 
The following procedures will be performed and recorded at this visit: 
o MADRS conducted by remotely located, independent raters 
o HAM-D-17 
o CGI-S 


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o MARS-5 
o C-SSRS (Since Last Visit) 
o GAD-7 
o EQ-5D-3L (administered to both participant and caregiver; the latter is not 
mandatory) 
o PANAS 
o QIDS-SR-16 
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 
o AEs and SAEs (Sections 9 and 10) 
If the participant remains eligible, arrange for the participant to return to the study site for 
investigational product (IP) 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 
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, Day -1). If the participant is out of the +≤ 7-day window, all baseline assessments 
are to be repeated. At the psilocybin session (the day of IP administration), the following 
are to be obtained: 
o Vital signs (ie, continuous blood pressure throughout the session, pulse, body 
temperature, and respiratory rate)  


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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 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 MADRS conducted by remotely located, independent raters 
o CGI-S 
o CGI-I 
o C-SSRS (Since Last Visit) 
o GAD-7 
o PANAS 
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 
o Urine sample for urinalysis 
o Medications taken and any changes in medications since the previous visit 
o AEs and SAEs (Sections 9 and 10) 


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6.2.5 
Visits 5 and 6 – 1 and 2 Week Postdosing 
The participant will visit the clinic 1 week (7 days ± 1 day) and 2 weeks 
(14 days ± 1 day) following IP administration; the following assessments will be obtained 
at this visit: 
o MADRS conducted by remotely located, independent raters 
o CGI-S 
o CGI-I 
o MARS-5 
o C-SSRS (Since Last Visit) 
o GAD-7 
o EQ-5D-3L (administered to participant) 
o QIDS-SR-16 
o Medications taken and any changes in medications since the previous visit 
o AEs and SAEs (Sections 9 and 10)  
6.2.6 
Visit 7 – 3 Weeks Postdosing – End of Study 
The participant will visit the clinic 3 weeks (21 days ± 1 day) 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 MADRS conducted by remotely located, independent raters 
o CGI-S 
o CGI-I 
o MARS-5 
o C-SSRS (Since Last Visit) 
o GAD-7 
o EQ-5D-3L (administered to both participant and caregiver [the latter is not 
mandatory]) 


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o QIDS-SR-16 
o Blood samples for clinical laboratory tests 
o Medications taken and any changes in medications since the previous visit 
o AEs and SAEs (Sections 9 and 10) 
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 V7 (EOS) procedures should be 
performed as noted in Section 6.2.6. 
A termination electronic Case Report Form (eCRF) page should be completed for every 
participant who is enrolled, 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.  


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• Other: The participant was discontinued for a reason other than those listed above, 
such termination of study by the sponsor. 


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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 at Baseline 
(Day -1), Day 1 and Weeks 1, 2 and 3 (V2, V4, V5, V6 and V7, 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.21 The structure of the telephone-based interview will be 
controlled through the use of The Structured Interview Guide for the MADRS 
(SIGMA),34 which provides structured probes to ensure standardisation of administration 
and comprehensive coverage of 10 questions. 
7.1.2 
Clinical Global Impression – Severity Scale 
The CGI-S is a 7-point scale that measures the severity of symptoms in patients with 
mental disorders.2,12 It requires the clinician to rate the severity of the patient's illness at 
the time of assessment, relative to the clinician's past experience with patients who have 
the same diagnosis. Ratings range from “normal, not at all ill” (1) to “among the most 
extremely ill patients” (7). This will be obtained at Baseline (Day -1), Day 1, and 
Weeks 1, 2 and 3 (V2, V4, V5, V6 and V7, respectively). 
7.1.3 
Clinical Global Impression – Improvement Scale 
The CGI-I is a 7-point scale that requires the clinician to rate how much the patient’s 
symptoms have improved relative to a baseline state.2,12 Ratings range from “very much 
improved” (1) to “very much worse” (7). This will be obtained at Day 1 and Weeks 1, 2 
and 3 (V4, V5, V6, and V7, respectively). 
7.1.4 
Quick Inventory of Depressive Symptomatology – Self Rated – 
16 Item 
The 16-item QIDS is 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.25 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 nine symptom domains. The QIDS-SR-16 
will be collected at every clinic visit or contact with the participant. 


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7.1.5 
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.27 Participants 
choose one of four severity scores associated with problems related to the common 
anxiety disorders and then indicates 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 with a maximum 
score of 21. The GAD-7 will be obtained using the electronic patient-reported outcome 
(ePRO) device at Baseline (Day -1), Day 1 and Weeks 1, 2 and 3 (V2, V4, V5, V6 and 
V7, 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 
1990.18,29 The EQ-5D-3L essentially consists of two sections: 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 three levels: no problems, 
some 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 visual analog scale 
(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 (Day -1) and Week 3 (V2 and V7, 
respectively). Administration to a caregiver is not mandatory. 
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 
participant answers “yes” to either questions 1 or 2, the intensity of ideation is assessed in 


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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 participant’s responses in order to (a) at Screening and 
Baseline determine the participant’s study eligibility and potential need for referral to a 
mental health professional, and (b) during the study evaluate the participant’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 AE or SAE as appropriate and followed up 
accordingly. Additionally, if a participant 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. 
The C-SSRS will be collected at every clinic visit. 
7.2.2 
Vital Signs  
Respiratory rate, blood pressure, body temperature, and pulse rate will be obtained at 
Screening, Baseline (Day -1), Day 0, and Day 1 (V1, V2, V3, and V4, respectively).  
Blood pressure will be monitored continuously throughout the psilocybin session. At all 
other clinic visits, 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. 
7.2.3 
Electrocardiogram  
Standard 12-lead ECGs will be obtained at Screening (V1) and Day 1 (V4). 
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, gamma-glutamyltransferase, glucose, 


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lactate dehydrogenase, lipase, magnesium, phosphate, potassium, protein-total, 
sodium, urea (blood urea nitrogen), and uric acid.  
Urine samples will be obtained at Screening (V1), Baseline (V2, Day -1) and Day 1 (V4) 
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, Day -1). Results of a positive drug screen will be reviewed by the study clinician 
for pattern of use. 
• Urine Pregnancy Test: a dipstick test in women of childbearing potential at Screening 
(V1) and Baseline (V2, Day -1).  
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 V7 (EOS/ET) 
will be followed until resolution or no longer considered clinically significant by the 
investigator.  
See Sections 9 and 10 for additional information. 
7.3 
Other Assessment Instruments  
7.3.1 
Hamilton Depression Rating Scale – 17-item 
The HAM-D-17, a 17-item scale, is used to measure the degree of symptom severity in 
depressed patients.13 The HAM-D-17 rating will be performed by the investigator using 
the electronic clinical outcome assessment (eCOA) device at the Screening (V1) and 
Baseline (V2, Day -1) 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.33 This will be 
captured electronically. 


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7.3.2 
Mini International Neuropsychiatric Interview, Version 7.0.2 
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 DSM-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.26 
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.26 
7.3.3 
Massachusetts General Hospital-Antidepressant Treatment 
History Response Questionnaire 
The MGH-ATRQ is a self-rated scale used to determine treatment resistance in major 
depressive disorder.5 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 study and examines 
the participants’ antidepressant history to identify pseudo-resistance and treatment 
resistance. 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 are 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. In addition, a list of recently approved antidepressant medications not 
included in MGH-ATRQ will be provided to investigators. 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.35 The scale consists of 
10 items based on the DSM-5 BPD criteria; the first eight 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 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. 


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7.3.5 
Five Dimension Altered States of Consciousness Questionnaire 
The 5D-ASC measures the acute drug effects using five primary dimensions and 
respective subdimensions to assess alterations in mood, perception, and experience of self 
in relation to environment and thought disorder. The five dimensions include: oceanic 
boundlessness, anxious ego dissolution, visionary restructuralization, auditory alterations, 
and reduction of vigilance.8,9,28 This will be administered immediately after the 
psilocybin session on Day 0 (V3). This will be captured electronically. 
7.3.6 
The Positive and Negative Affect Schedule 
The PANAS measures the acute emotional drug effects, and comprises two mood scales 
that measure positive and negative affect.32 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 
administered at Baseline (V2, Day -1) and the day after the psilocybin session (V4) This 
will be captured electronically. 
7.3.7 
Medication Adherence Report Scale 
The MARS-5 is a 5-item self-report scale of medication adherence.6,19 Participants 
respond to five statements regarding how often they engage in non-adherent behaviors in 
relation to their SSRI medication on a 5 point Likert scale (from “always” to “never”). 
The item scores are summed to indicate overall level of adherence. This will be 
administered at Baseline (V2, Day -1) and Weeks 1, 2 and 3 (V5, V6 and V7, 
respectively). 
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 as 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 sites 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 
Ingredient 
Psilocybin 
Manufacturer 
Catalent Pharma Solutions,  
8 Orchard Place,  
Nottingham Business Park,  
Nottingham, NG8 6PX, UK 
Dose 
25 mg 
Route 
Oral 
Formulation 
Capsule 
Strength 
5 mg 
8.1.1 
Formulation  
Matching psilocybin capsules 5 mg are manufactured by Catalent Pharma Solutions, 
Nottingham, UK.  
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 the sponsor 
or its designee should be notified promptly. Bottles of IP should not be frozen. If any 
component of the IP is damaged, the sponsor or its designee must be notified as soon as 
possible.  
8.2 
Packaging and Blinding 
Psilocybin capsules are packaged into HDPE bottles 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 
five 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. Refer to the IP Handling Manual for additional 
details. 


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8.3 
Dose and Administration 
Study drug will be administered simultaneously to up to six participants.  
Each participant will receive 1 x 25 mg treatment bottle containing 5 x 5 mg capsules. 
After a light breakfast taken at least 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 will be provided as 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 or bed 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, a 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 will then 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 account of the number of IP units delivered to the 
site, administered to participants, and returned to the sponsor 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. 


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8.5 
Concomitant Therapy 
All prescription and nonprescription medications (eg, over-the-counter [OTC] 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 and therapies 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 
Participants must have been receiving treatment with a SSRI (fluoxetine, fluvoxamine, 
sertraline, paroxetine, citalopram or escitalopram) at an adequate dose according to local 
recommendations for at least 6 weeks before Screening (V1) and Baseline (V2, Day -1). 
Dose changes within the adequate range are acceptable. We recommend that the 
participant is continued on the SSRI for the duration of the follow-up period of the study, 
ideally at the same dose.  
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 (V7, 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 two 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 
OTC preparations) will be obtained at each clinic visit. 
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 the sponsor or its designee. 


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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, participant 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 the sponsor or Worldwide immediately after the pregnancy is 
confirmed according to Section 12.5.  
8.5.3 
Prohibited Medications 
Participants are to be discontinued from antidepressant and/or antipsychotic medications, 
except the participants SSRI (fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram 
or escitalopram), at least 2 weeks prior to Baseline (V2, Day -1). These medications 
include the following two classes of the Anatomical Therapeutic Chemical (ATC) 
Classification System: NO5A Antipsychotics & NO6A Antidepressants. Methylphenidate 
(ATC Classification System: NO6B Psychostimulants) is also excluded. 
The MM 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, cognitive behavioral therapy whose therapeutic intention is 
remediation of the depressive episode.  
Because the anticipated half-life of psilocybin is approximately 3 h, and only 
one administration of test product is permitted, no known issues regarding 
pharmacokinetic 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 
participant 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 


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of therapeutic action; the oral route is preferable because intravenous (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.  
In case of development of acute anxiety or psychotic symptoms requiring 
pharmacological intervention, the participant will be managed appropriately. Rescue 
medication should be administered according to their respective approved prescribing 
information and dose levels. 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 participants 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 International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (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 the sponsor or Worldwide of all SAEs and 
nonserious AEs occurring during the clinical study so that legal obligations and ethical 
responsibilities towards the safety of participants and the safety of the product under 
clinical investigation are met.  
The sponsor 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. The sponsor 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 


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reported diagnosis) should be reported as AEs if they are symptomatic, lead to IP 
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. 


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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). 
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 two 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. 


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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) 
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 


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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 
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 characterize 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 events on the eCRF page within 
24 h of learning about the event regardless of relationship to study drug. 


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The report should include the following minimum information: 
o Participant number 
o Event 
o Date/time of onset 
o Duration of the event 
o Dose of drug taken 
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 
email 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 identification 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 email 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 the 
sponsor/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 the sponsor 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 the 
sponsor. A detailed Statistical Analysis Plan (SAP) will be finalised and signed before 
database lock. Any deviations from the analyses described below will be included in the 
SAP, which will be included in the clinical study report. 
11.2 Sample Size 
No formal sample size calculations were performed for this study. Approximately 
20 participants are expected to be enrolled in the study. 
11.3 Statistical Methods 
The Safety Population will consist of all enrolled participants, 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 enrolled participants who also receive the 
dose of IP. 
The Per Protocol (PP) population will consist of all participants in the FAS who do not 
have a major protocol deviation defined as a deviation which may significantly affect 
efficacy for that participant. Major protocol deviations will be reviewed and determined 
prior to database lock. 
11.3.1 
Efficacy and Outcome Measures  
• MADRS 
• CGI-S 
• CGI-I 
• EQ-5D-3L (participant and caregiver; the latter is not mandatory) 
• QIDS-SR-16 
• GAD-7 
• PANAS 
• 5D-ASC 
• C-SSRS 


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11.3.2 
Analysis of Efficacy 
Since this is a single treatment open-label study, no statistical testing will be performed. 
The FAS and the PP populations will both be used for each secondary endpoint, if the 
two sets are not identical. For each of the secondary endpoints (MADRS, CGI-S, 
C-SSRS), measuring change from Baseline to Week 3, summary statistics will be 
provided. 
Analysis of exploratory endpoints will be detailed in the SAP. 
11.3.3 
Multiplicity 
Not applicable. 
11.3.4 
Analysis of Safety 
Safety data will be presented for the Safety Population. Safety will be evaluated based on 
AEs, ECGs, clinical laboratory tests, vital signs and suicidal ideation/behavior (measured 
using C-SSRS). 
11.3.4.1 
Columbia-Suicide Severity Rating Scale 
Item scores from the C-SSRS for all visits, the item scores from the version assessing 
suicidality since the last visit, and all postbaseline visits (V3 to V7, inclusive) by 
treatment will be tabulated. Summary statistics of suicidal ideation and suicidal behavior 
following IP administration will be presented. 
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 treatment-emergent adverse event (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; 
non-continuous AEs reported several times by the same participant will be counted as 
multiple events. 


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11.3.4.3 
Electrocardiographic Data 
The ECG data will be summarised descriptively based on measures of change in each 
ECG parameter from Screening (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 Screening (V1) will be 
provided.  
11.3.5 
Demographic and Baseline Characteristics 
Participant demographics and baseline characteristics will be summarised using 
descriptive statistics, no formal statistical analysis tests will be performed. 
11.4 Interim Analysis 
No interim analysis is planned. 


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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 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 (Appendix II). 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 Steering Committee 
A Steering Committee will not be used for this study.  
12.3 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. 
12.4 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. 
12.5 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. 
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 form within 24 h of becoming aware of the event. Exposure in Utero (EIU) 


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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 identification number, initials, and date of birth, and details regarding 
the partner of the male participant should be entered in the narrative section. 
12.6 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. 
12.7 Source Documentation 
Note that a variety of original documents, data, and records will be considered as source 
documents in this study. The eCRF itself is not to be used as a source document under 
any circumstances.  
12.8 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 
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 the sponsor. 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. The sponsor will submit protocol 
amendments to the appropriate regulatory authorities for approval. 
If in the judgment of the IRB/IEC, the investigator, and/or the sponsor, 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 ICF 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 
The sponsor is responsible for preparing and providing the appropriate regulatory 
authorities with clinical study reports according to the applicable regulatory 
requirements. 
The publication policy of the sponsor is discussed in the investigator's Clinical Research 
Agreement. 


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16 STUDY DISCONTINUATION  
Both the sponsor and the Principal Investigator reserve the right to terminate the study at 
the investigator’s site at any time. Should this be necessary, the sponsor 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, the sponsor 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 the sponsor. However, authorised regulatory officials, IRB/IEC 
personnel, the sponsor and its authorised representatives are allowed full access to the 
records. 
Identification of participants and CRFs shall be by initials and participant identification 
number 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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18 REFERENCES 
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Brown RT, Nicholas CR, Cozzi NV, et al. Pharmacokinetics of escalating doses 
of oral psilocybin in healthy adults. Clin Pharmacokinet. 2017;56(12):1543-1554. 
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2. 
Busner J, Targum SD. The clinical global impressions scale: applying a research 
tool in clinical practice. Psychiatry (Edgmont). 2007 Jul;4(7):28-37. 
3. 
Carhart-Harris RL, Bolstridge M, Rucker J, et al. Psilocybin with psychological 
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Carhart-Harris RL, Roseman L, Bolstridge M, et al. Psilocybin for Treatment-
Resistant Depression: fMRI-Measured Brain Mechanisms. Sci Rep 2017; 
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Chandler GM, Iosifescu DV, Pollack MH, Targum SD, Fava M. Validation of the 
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Clatworthy J, Bowskill R, Parham R, Rank T, Scott J, Horne, R. Understanding 
medication non-adherence in bipolar disorders using a Necessity-Concerns 
Framework. J Affect Disord. 2009; 116(1–2):51-55. 
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COMPASS Pathways Limited. Investigator’s Brochure for Psilocybin. 2018. 
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Dittrich A. The standardized psychometric assessment of alter states of 
consciousness (ASCs) in humans. Pharmacopsychiatry. 1998;31(Suppl 2):80-84. 
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Dittrich A, Lamparter D, Maurer M. 5D-ABZ: Fragebogen zur Erfassung 
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questionnaire for the assessment of altered states of consciousness. A short 
introduction]. PSIN Plus Publications. 2006. 
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Gouzoulis-Mayfrank E, Thelen B, Habermeyer E, et al. Psychopathological, 
neuroendocrine and autonomic effects of 3,4-methylenedioxyethylamphetamine 
(MDE), psilocybin and D-methamphetamine in healthy volunteers. Results of an 
experimental double-blind placebo-controlled study. Psychopharmacology (Berl). 
1999b;142(1):41-50. 
11. 
Griffiths RR, Johnson MW, Richards WA, Richards BD, McCann U, Jesse R. 
Psilocybin occasioned mystical-type experiences: immediate and persisting 
dose-related effects. Psychopharmacology (Berl). 2011;218(4):649-665. 
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Guy W (ed). ECDEU Assessment Manual for Psychopharmacology. Rockville, 
MD: US Department of Health, Education, and Welfare Public Health Service 
Alcohol, Drug Abuse, and Mental Health Administration, 1976. 
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Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 
1960;23:56-62. doi:10.1136/jnnp.23.1.56. PMID: 14399272. 


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14. 
Hasler F, Bourquin D, Brenneisen R, Bar T, Vollenweider FX. Determination of 
psilocin and 4-hydroxyindole-3-acetic acid in plasma by HPLC-ECD and 
pharmacokinetic profiles of oral and intravenous psilocybin in man. Pharm Acta 
Helv. 1997;72(3):175-184. 
15. 
Hasler F, Bourquin D, Brenneisen R, Vollenweider FX. Renal excretion profiles 
of psilocin following oral administration of psilocybin: a controlled study in man. 
J Pharm Biomed Anal. 2002;30(2):331-339. 
16. 
Hasler F, Grimberg U, Benz MA, Huber T, Vollenweider FX. Acute 
psychological and physiological effects of psilocybin in healthy humans: a 
double-blind, placebo-controlled dose-effect study. Psychopharmacology (Berl). 
2004;172(2):145-156. 
17. 
Hasler F. Untersuchungen zur Humanpharmakokinetik von Psilocybin. Berne: 
University of Berne (Switzerland). 1997. 
18. 
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the 
new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 
2011;20(10):1727-1736. 
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Horne R. The nature, determinants and effects of medication beliefs in chronic 
illness. 1997. PhD Thesis. University of London. 
20. 
Lindenblatt H, Kramer E, Holzmann-Erens P, Gouzoulis-Mayfrank E, Kovar KA. 
Quantitation of psilocin in human plasma by high-performance liquid 
chromatography and electrochemical detection: comparison of liquid-liquid 
extraction with automated on-line solid-phase extraction. J Chromatogr B Biomed 
Sci Appl. 1998;709(2):255-263. 
21. 
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to 
change. Br J Psychiatry. 1979;134:382-389. 
22. 
Passie T, Seifert J, Schneider U, Emrich HM. The pharmacology of psilocybin. 
Addict Biol. 2002;7(4):357-364. 
23. 
Passie T. A history of the use of psilocybin in psychotherapy. In: Metzner R, 
editor. Sacred mushroom of visions: Teonanácatl: a sourcebook on the psilocybin 
mushroom. Rochester, Vermont: Park Street Press; 2005. p. 113-138. 
24. 
Rickli A, Moning OD, Hoener MC, Liechti ME. Receptor interaction profiles of 
novel psychoactive tryptamines compared with classic hallucinogens. Eur 
Neuropsychopharmacol. 2016;26(8):1327-1337. 
25. 
Rush AJ, Trivedi MH, Ibrahim HM, et al. The 16-item quick inventory of 
depressive symptomatology (QIDS) clinician rating (QIDS-C) and self-report 
(QIDS-SR): a psychometric evaluation in patients with chronic major depression. 
Biol Psychiatry. 2003;54 (5):573-583. 
26. 
Sheehan DV, Giddens JM, Sheehan IS. Status update on the Sheehan-suicidality 
tracking scale (SSTS) 2014. Innov Clin Neurosci. 2014 Sep-Oct;11(9-10):93-140.  


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27. 
Spitzer RL, Kroenke K., Williams, JB, Lowe, B. A brief measure for assessing 
generalized anxiety disorder: the GAD-7. Arch Intern Med. 
2006;166(10):1092-1097. 
28. 
Studerus E, Gamma A, Vollenweider FX. Psychometric evaluation of the altered 
states of consciousness rating scale (OAV). PLoS One. 2010;5(8): e12412. 
29. 
The EuroQol Group. Euroqol-a new faciltiy for the measurement of health–
related quality of life. Health Policy. 1990;16(3):199-208. 
30. 
Tylš F, Páleníček T, Horáček J. Psilocybin-summary of knowledge and new 
perspectives. Eur Neuorpsychopharmcol. 2014 Mar;24(3):342-356. 
31. 
Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A, Vogel H, Hell 
D. Psilocybin induces Schizophrenia-Like Psychosis in Humans via a Serotonin-2 
Agonist Action. Neuroreport. 1998; 9(17):3897-3902. 
32. 
Watson D, Clark LA, and Tellegen A. Development and validation of brief 
measures of positive and negative affect: the PANAS scales. J Pers Soc Psyhchol. 
1988;54(6):1063-1070. 
33. 
Williams JB. A structured interview guide for the Hamilton depression rating 
scale. Arch Gen Psychiatry. 1988;45(8):742-747. 
34. 
Williams JB, Kobak KA. Development and reliability of a structured interview 
guide for the Montgomery-Asberg Depression Rating Scale (SIGMA). Br J 
Psychiatry. 2008;192(1):52-58. 
35. 
Zanarini MC, Vujanovic AA, Parachini EA, Boulanger JL, Frankenburg FR, 
Hennen J. A screening measure for BPD: the McLean Screening Instrument for 
Borderline Personality Disorder (MSI-BPD). J Pers Disord. 2003;17(6):568-573. 


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19 APPENDICES 
19.1 Appendix I – Names of Study Personnel 
Sponsor: 
Hans Eriksson, MD, PhD, MBA 
Chief Medical Officer 
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 
 


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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. 
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 


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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 
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 
studies. 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. 


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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. 
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. 


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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 
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. 
 
 


Protocol 
 
Study Number COMP003 – Psilocybin for TRD (P-TRD) 
Confidential 
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19.3 Appendix III – Massachusetts General Hospital-Antidepressant 
Treatment History Response Questionnaire – Additional Detail 
Regarding the Assessment of Previous Antidepressant Treatment 
The Massachusetts General Hospital-Antidepressant Treatment History Response 
Questionnaire (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 (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 003 
THE SAFETY AND EFFICACY OF COMP360 AS AN ADJUNCTIVE 
THERAPY IN PARTICIPANTS WITH TREATMENT-RESISTANT 
DEPRESSION 
DRUG: 
COMP360 
TITLE: 
The Safety and Efficacy of COMP360 as an 
Adjunctive Therapy in Participants with Treatment-
Resistant Depression 
CLINICAL PHASE 
II 
SPONSOR: 
 
COMPASS Pathfinder Limited  
3rd Floor, 1 Ashley Road 
Altrincham, Cheshire, WA14 2DT, UK 
VERSION NUMBER: 
Final Version 1.0  
VERSION DATE: 
17 November 2021 
AUTHOR 
Niccolo Bassani, PhD (Principal Statistician) 
 
 
 
 
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 1.0 17 November 2021  
 
SAP APPROVAL FORM 
Protocol Number: COMP 003 
Title: The Safety and Efficacy of COMP360 as an Adjunctive Therapy in Participants with 
Treatment-Resistant Depression  
SAP Version and Date: Version 1.0 17 November 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)  
Niccolo’ 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 1.0 17 November 2021  
 
SAP SYNOPSIS 
Protocol Number 
COMP 003  
Title:  
The Safety and Efficacy of COMP360 as an Adjunctive Therapy in Participants 
with Treatment-Resistant Depression 
EudraCT Number: 
2018‐002577‐22 
Investigational 
Product: 
COMP360 
ClinicalTrials.gov 
Identifier: 
NCT04739865 
Clinical Phase: 
II 
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 explore effectiveness of 25 mg COMP360 as an adjunctive therapy 
in participants with TRD. 
Number of 
Participants: 
Approximately 20 participants with simultaneous study drug administration to up 
to six participants 
Objectives:  
The main purpose of this study is to investigate the efficacy of 25 mg COMP360 
adjunct to serotonergic antidepressants in TRD participants via the following 
objectives. 
Primary Objective 
The primary objective of this study is to explore the efficacy of 25 mg COMP360 
as an adjunct therapy to antidepressants in improving depressive symptoms. 
Secondary Objectives 
The secondary objective is to evaluate the safety and tolerability of COMP360 in 
participants with TRD based on adverse events (AEs), changes in vital signs, 
electrocardiograms 
(ECGs), 
clinical 
laboratory 
tests 
and 
suicidal 
ideation/behaviour (measured using the Columbia- Suicide Severity Rating Scale 
[C-SSRS]) score. 
Exploratory Objectives 
The exploratory objectives are to evaluate the effects of COMP360 on quality of 
life, wellbeing and anxiety. 
Study Design and 
Procedures: 
This is a Phase IIb, international multicentre, fixed-dose, open-label study. The 
study population will include adult men and women, 18 years of age or 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 who have failed to respond to an adequate dose and 
duration of 2, 3 or 4 pharmacological treatments for the current episode. The 
duration of the current episode must be at least 3 months but not more than 2 
years. 
Participants will be outpatients and will be recruited primarily through referrals 
from general practitioners and specialised psychiatric services. 


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Final Version 1.0 17 November 2021  
 
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 Hamilton Depression Rating Scale (17-item; 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). At the initial 
Screening visit (V1), the participant will also be evaluated with the Quick 
Inventory of Depressive Symptomatology – Self Rated - 16 item (QIDS-SR-16). 
Additionally, a medical history, an ECG, blood tests, and vital signs will be 
obtained. 
Once a participant completes all Screening (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. 
The participant will meet with a therapist for 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 3 weeks prior 
to COMP360 administration. Any safety assessment visits during the screening 
period will be called V1a, V1b, V1c 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. 
At baseline [V2, day -1], the participants will undergo a baseline assessment that 
will consist of the HAM-D-17, Montgomery-Asberg Depression Rating Scale 
(MADRS), Clinical Global Impression – Severity scale (CGI-S) and 
Improvement scale (CGI-I), QIDS-SR-16, C-SSRS, Generalised Anxiety 
Disorder Scale 7-item Scale (GAD-7), EuroQoL-5 dimension-3 level (EQ-5D-
3L; administered to both participant and caregiver [the latter is not mandatory]), 
vital signs, urinalysis, urine drug screen, and urine pregnancy test (only for 
women of childbearing potential). 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 h 
and will be supported by a trained therapist. The study drug will be administered 
simultaneously to up to six participants. Blood pressure will be monitored 
continuously during the session. The COMP360 administration session may be 
video recorded for training and adherence monitoring. A full description of the 
activities of the COMP360 administration session is found in the Therapist 
Manual. 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 clinical and self-report assessments, and to discuss their 
experience during the COMP360 administration 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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Final Version 1.0 17 November 2021  
 
Twenty participants will receive one dose of 25 mg COMP360. 
Participants will be seen at the clinic for Screening (plus 3 safety visits), baseline 
(day -1), day 1 (dosing), day 2, week 1, week 2 and week 3. AEs, serious adverse 
events (SAEs) and concomitant medication and therapies will be recorded at all 
clinic visits. The MADRS will be done by telephone. 
Clinicians are advised to continue the prescription of the participant’s baseline 
selective serotonin reuptake inhibitor (SSRI) (fluoxetine, fluvoxamine, sertraline, 
paroxetine, citalopram, vilazodone, vortioxetine, or escitalopram) for the 
duration of the follow-up period, ideally at the same dose. 
Primary Endpoint:  
The primary endpoint is the change in MADRS total score from baseline (day -
1) to 3 weeks post COMP360 administration. 
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 
COMP360 administration 
• 
The proportion of participants with remission (defined as a MADRS total 
score ≤ 10) at week 3 post COMP360 administration 
• 
Changes from baseline CGI-S at week 3 post COMP360 administration 
• 
Incidence of AEs 
• 
Change from baseline to day 2 in ECGs, and incidence of clinically important 
changes 
• 
Change from baseline to day 2 and to week 3 in clinical laboratory tests, and 
incidence of clinically important changes 
• 
Change from baseline to day 2 in vital signs 
• 
Incidence of changes from baseline in the C-SSRS at each post-baseline visit 
Exploratory 
Endpoints: 
The exploratory endpoints are: 
• 
Change from baseline to week 3 in total scores of: 
• 
Participant EQ-5D-3L 
• 
Caregiver EQ-5D-3L (this assessment is not mandatory) 
• 
GAD-7 
• 
QIDS-SR-16 
• 
CGI-I 
• 
Change from baseline to day 2 in Positive and Negative Affect Schedule 
(PANAS) 
• 
Summary of Five Dimensional Altered States of Consciousness 
questionnaire (5D-ASC) on the day of the COMP360 administration 
session (day 1) 
Estimand 
Framework 
Due to the lack of a control group and the descriptive nature of the study, no 
estimand will be defined. 
Sample Size 
Determination 
No formal sample size calculations were performed for this study. Approximately 
20 participants are expected to be enrolled in the study. 
Analysis Sets 
The Safety Analysis Set: All participants who receive study drug. 
The Full Analysis Set (FAS): All participants who receive study drug and have 
at least 1 post-dose efficacy assessment. 


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Final Version 1.0 17 November 2021  
 
The Per Protocol (PP) Population: 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 
Since there is only one treatment group, there will be no formal statistical testing 
of any hypothesis. 
Primary Endpoint 
Analyses 
The primary efficacy endpoint (change from baseline in MADRS total score at 
week 3) will be summarised using descriptive statistics for continuous measures 
as well as 95% confidence intervals (CIs). 
Secondary Endpoint 
Analyses 
The proportion of participants who are responders/remitters at week 3 will be 
summarised using counts and percentages and 95% Wald-type CIs based on the 
Normal distribution.  
CGI-S values and their changes from baseline will be summarised using 
descriptive statistics for continuous variables alongside 95% CIs for all 
timepoints up to week 3. In addition, categorical summaries will be provided for 
each CGI-S response option at each relevant timepoint, including 95% Wald-type 
CIs. 
 


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Final Version 1.0 17 November 2021  
 
TABLE OF CONTENTS 
SAP APPROVAL FORM..................................................................................................2 
SAP SYNOPSIS .................................................................................................................3 
TABLE OF CONTENTS ..................................................................................................7 
LIST OF ABBREVIATIONS .........................................................................................10 
LIST OF PARAMETERS ...............................................................................................12 
1 
INTRODUCTION ....................................................................................................14 
2 
STUDY OBJECTIVES ............................................................................................15 
2.1 
Primary .................................................................................................................15 
2.2 
Secondary..............................................................................................................15 
2.3 
Exploratory ...........................................................................................................15 
3 
STUDY ENDPOINTS ..............................................................................................16 
3.1 
Primary .................................................................................................................16 
3.2 
Secondary..............................................................................................................16 
3.3 
Exploratory ...........................................................................................................16 
4 
ESTIMAND FRAMEWORK ..................................................................................17 
5 
STUDY DESIGN ......................................................................................................18 
5.1 
Study Design .........................................................................................................18 
5.2 
Study Schematic ...................................................................................................20 
5.3 
Schedule of Assessments ......................................................................................21 
5.4 
Hypotheses and Treatment Comparisons ..........................................................24 
5.5 
Multiplicity ...........................................................................................................24 
5.6 
Sample Size Considerations ................................................................................24 
5.7 
Randomisation......................................................................................................24 
6 
PLANNED ANALYSES ...........................................................................................25 
6.1 
Final Analysis .......................................................................................................25 
6.2 
Interim Analysis ...................................................................................................25 
7 
ANALYSIS SETS .....................................................................................................26 
8 
GENERAL CONSIDERATIONS ...........................................................................27 
9 
DATA DERIVATIONS ............................................................................................28 
9.1 
General ..................................................................................................................28 
9.1.1 
Change from Baseline ....................................................................................28 
9.1.2 
Missing and Partial Dates .............................................................................28 
9.1.3 
Treatment Exposure and Compliance .........................................................28 
9.1.4 
Inexact Values ................................................................................................28 
9.2 
Study Participants ................................................................................................28 
9.2.1 
Protocol Deviations ........................................................................................28 
9.2.2 
Age Categories ................................................................................................29 
9.2.3 
Body Mass Index (BMI) ................................................................................29 
9.2.4 
Length of Current Depressive Episode ........................................................29 
9.2.5 
Missing Major Depressive Disorder (MDD) Episode Start Dates .............29 
9.2.6 
Prior and Concomitant Medications ............................................................29 
9.3 
Efficacy Assessments ...........................................................................................30 
9.3.1 
Montgomery-Asberg Depression Rating Scale Score (MADRS) ...............30 


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9.3.2 
Quick Inventory of Depressive Symptomatology (QIDS-SR-16) ..............31 
9.3.3 
European Quality of Life 5-dimension 3-level Scale (EQ-5D-3L) .............31 
9.3.4 
Generalised Anxiety Disorder Scale – 7 Item (GAD-7) ..............................33 
9.3.5 
Hamilton Depression Rating Scale – 17 Item (HAM-D-17) .......................33 
9.3.6 
The Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire (MGH-ATRQ) ......................................................33 
9.3.7 
McLean Screening Instrument for Borderline Personality 
Disorder (MSI-BPD) ......................................................................................34 
9.3.8 
5-Dimensional Altered States of Consciousness Questionnaire (5D-
ASC) ................................................................................................................34 
9.3.9 
The Positive and Negative Affect Schedule (PANAS) ................................35 
9.3.10 
Clinical Global Impression – Severity (CGI-S) Scale .................................35 
9.3.11 
Clinical Global Impression – Improvement (CGI-I) Scale ........................36 
9.4 
Safety .....................................................................................................................36 
9.4.1 
Adverse Events ...............................................................................................36 
9.4.2 
Missing / Partial Start / Stop Dates of AEs and Concomitant 
Medications .....................................................................................................37 
9.4.3 
Vital Signs Ranges of Clinical Importance ..................................................38 
9.4.4 
Continuous Vital Signs Collections via Caretaker Device .........................39 
9.4.5 
ECG Categorical Intervals ............................................................................39 
9.4.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) ....................................40 
10 STUDY PARTICIPANTS ........................................................................................41 
10.1 
Disposition of Participants ..................................................................................41 
10.2 
Protocol Deviations ..............................................................................................41 
10.3 
Demographic and Baseline Characteristics .......................................................41 
10.4 
Medical History ....................................................................................................42 
10.5 
Prior and Concomitant Medications ..................................................................42 
10.6 
Treatment Exposure/Compliance and Duration...............................................42 
11 EFFICACY ................................................................................................................43 
11.1 
Primary Efficacy ..................................................................................................43 
11.2 
Secondary Efficacy...............................................................................................43 
11.2.1 
Proportion of MADRS response at week 3 ..................................................43 
11.2.2 
Proportion of MADRS remission at week 3 ................................................44 
11.2.3 
Change from baseline to week 3 in CGI-S ...................................................44 
11.3 
Exploratory Efficacy ............................................................................................44 
12 SAFETY .....................................................................................................................45 
12.1 
Adverse Events (AEs) ..........................................................................................45 
12.2 
Laboratory Tests ..................................................................................................46 
12.3 
Vital Signs .............................................................................................................47 
12.4 
Continuous Vital Signs ........................................................................................48 
12.5 
ECGs .....................................................................................................................48 
12.6 
C-SSRS ..................................................................................................................49 
13 CHANGES FROM THE PROTOCOL-PLANNED ANALYSES .......................50 
14 DATA NOT PRESENTED ......................................................................................51 
15 REFERENCES .........................................................................................................52 


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16 PROGRAMMING AND DATA PRESENTATION CONVENTIONS...............53 
16.1 
Treatment Labelling ............................................................................................53 
16.2 
Visit Labelling ......................................................................................................53 
16.3 
Baseline Definitions ..............................................................................................53 
16.4 
Study Day and Duration Derivation ..................................................................53 
16.5 
Decimal Places ......................................................................................................54 
17 TABLES, FIGURES AND LISTINGS ...................................................................55 
18 APPENDIX ................................................................................................................64 
18.1 
Appendix I: CHANGES TO COMP 003 PROTOCOL ...................................64 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Final Version 1.0 17 November 2021  
 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
bpm 
beats per minute 
CAT 
Clinical Assessment Technologies 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
COMPASS 
COMPASS Pathfinder Limited 
CR 
Code Review 
CS 
Clinically Significant 
dp 
decimal place 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
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 
HR 
Heart Rate 
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 
investigational product 
IProg 
Independent Programming 
kg 
kilogram 
L 
litres 
MAP 
Mean Arterial Pressure 
MDD 
Major Depressive Disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minute(s) 
mg 
milligram 
mITT 
Modified Intent-to-Treat 
MM 
Medical Monitor 


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Final Version 1.0 17 November 2021  
 
Abbreviation 
Definition 
mmHg 
millimetres of mercury  
MR 
Manual Review 
msec 
millisecond(s) 
NCS 
Not Clinically Significant 
PD 
Protocol Deviation 
PP 
Per Protocol 
PT 
Preferred Term 
QC 
Quality Check 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SSRI 
Selective Serotonin Reuptake Inhibitor 
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 
5-Dimensional - Altered States of Consciousness questionnaire 
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical Global Impression - Severity 
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 
VAS 
Visual Analogue Scale 
 
 
Study Disposition 
BMI 
Body Mass Index 
 
 
Safety 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
alkaline phosphatase  
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
electrocardiogram 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 


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Final Version 1.0 17 November 2021  
 
Parameter 
Definition 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 


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Final Version 1.0 17 November 2021  
 
1 INTRODUCTION 
This statistical analysis plan (SAP) is based on the final protocol (V2.2) dated 17 December 
2020. The plan covers statistical analysis, tables, figures and listings of the study data to 
investigate the safety and efficacy of COMP360 as an adjunctive therapy in participants 
with treatment-resistant depression. 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 check 
(QC), will be conducted by Worldwide, using SAS® Version 9.4 or later1. 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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Final Version 1.0 17 November 2021  
 
2 STUDY OBJECTIVES 
The main purpose of this study is to investigate the efficacy of 25 mg COMP360 adjunct 
to serotonergic antidepressants in TRD participants via the following objectives. 
2.1 
Primary 
The primary objective of this study is to explore the efficacy of 25 mg COMP360 as an 
adjunct therapy to antidepressants in improving depressive symptoms. 
2.2 
Secondary 
The secondary objective is to evaluate the safety and tolerability of COMP360 in 
participants with TRD based on adverse events (AEs), changes in vital signs, 
electrocardiograms (ECGs), clinical laboratory tests and suicidal ideation/behaviour 
(measured using the Columbia- Suicide Severity Rating Scale [C-SSRS]) score. 
2.3 
Exploratory  
The exploratory objectives are to evaluate the effects of COMP360 on quality of life, 
wellbeing and anxiety. 
 


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3 STUDY ENDPOINTS  
3.1 
Primary 
The primary endpoint is the change in Montgomery-Asberg Depression Rating Scale 
(MADRS) total score from baseline (day -1) to 3 weeks post COMP360 administration. 
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 post COMP360 administration 
• The proportion of participants with remission (defined as a MADRS total score ≤ 10) 
at week 3 post COMP360 administration 
• Changes from baseline Clinical Global Impression – Severity scale (CGI-S) at week 3 
post COMP360 administration 
• Incidence of AEs 
• Change from baseline to day 2 in ECGs, and incidence of clinically important changes 
• Change from baseline to day 2 and to week 3 in clinical laboratory tests, and incidence 
of clinically important changes 
• Change from baseline to day 2 in vital signs 
• Incidence of changes from baseline in the C-SSRS at each post-baseline visit 
3.3 
Exploratory 
 
The exploratory endpoints are: 
• Change from baseline to week 3 in total scores of: 
• Participant EuroQoL-5 dimension-3 level (EQ-5D-3L) 
• Caregiver EQ-5D-3L (this assessment is not mandatory) 
• Generalised Anxiety Disorder 7-item Scale (GAD-7) 
• QIDS-SR-16 
• Clinical Global Impression – Improvement scale (CGI-I) 
• Change from baseline to day 2 in Positive and Negative Affect Schedule (PANAS) 
• Summary of 5-Dimensional Altered States of Consciousness questionnaire (5D-
ASC) on the day of the COMP360 administration session (day 1) 
 


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4 ESTIMAND FRAMEWORK 
Due to the lack of a control group and the descriptive nature of the study, no estimand will 
be defined. 


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5 STUDY DESIGN 
5.1 
Study Design 
This is a Phase IIb, international multicentre, fixed-dose, open-label study. The study 
population will include adult men and women, 18 years of age or 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, who have failed to 
respond to an adequate dose and duration of 2, 3 or 4 pharmacological treatments for the 
current episode. The duration of the current episode must be at least 3 months but not more 
than 2 years. 
Participants will be outpatients and will be recruited primarily through referrals from 
general practitioners and specialised psychiatric services. 
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 Hamilton Depression Rating Scale (17-item; 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). At the initial Screening visit (V1), the participant will also be 
evaluated with the Quick Inventory of Depressive Symptomatology – Self Rated - 16 item 
(QIDS-SR-16). Additionally, a medical history, an ECG, blood tests, and vital signs will 
be obtained. 
Once a participant completes all Screening (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. 
The participant will meet with a therapist for 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 3 weeks prior to 
COMP360 administration. Any safety assessment visits during the screening period will 
be called V1a, V1b, V1c 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. 
At baseline [V2, day -1], the participants will undergo a baseline assessment that will 
consist of the HAM-D-17, MADRS, CGI-S and CGI-I, QIDS-SR-16, C-SSRS, GAD-7, 
EQ-5D-3L (administered to both participant and caregiver [the latter is not mandatory]), 


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vital signs, urinalysis, urine drug screen, and urine pregnancy test (only for women of 
childbearing potential). 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 h and will be 
supported by a trained therapist. The study drug will be administered simultaneously to up 
to six participants. Blood pressure will be monitored continuously during the session. The 
COMP360 administration session may be video recorded for training and adherence 
monitoring. A full description of the activities of the COMP360 administration session is 
found in the Therapist Manual. 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 clinical and self-report assessments, and to discuss their 
experience during the COMP360 administration 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. 
Twenty participants will receive one dose of 25 mg COMP360. 
Participants will be seen at the clinic for Screening (plus 3 safety visits), baseline (day -1), 
day 1 (dosing), day 2, week 1, week 2 and week 3. AEs, serious adverse events (SAEs) and 
concomitant medication and therapies will be recorded at all clinic visits. The MADRS 
will be done by telephone. 
Clinicians are advised to continue the prescription of the participant’s baseline selective 
serotonin reuptake inhibitor (SSRI) (fluoxetine, fluvoxamine, sertraline, paroxetine, 
citalopram, vilazodone, vortioxetine, or escitalopram) for the duration of the follow-up 
period, ideally at the same dose. 
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 
 
 
 
 
 
 
 
 
 
D=Day V=Visit EOS=End of Study ET=Early Termination 
 
 
 
 
 
Variable 
3 Weeks 
D-1  D1       D2 
Screening (V1) 
Screening (V1a) 
Screening (V1b) 
3 Weeks 
Screening (V1c) 
D-1: Baseline (V2) 
D1: COMP360 Administration Session (V3) 
D2 (V4) 
Week 1 (V5) 
Week 2 (V6) 
Week 3 (EOS/ET V7) 


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5.3 
Schedule of Assessments 
 
3 weeks 
prior to 
Baseline 
Time Post COMP360 Administration Session 
Screening 
Screening 
Period 1 
Baseline 
(Day -1) 
COMP360 
Administration 
Session  
(Day 1) 
 
 
Day 2 
 
Week 1 
Day 8 
 
Week 2 
Day 15 
Week 3 
Day 22 
(EOS/ET) 
Visit 
1 
1a, 1b, 1c 
2 
3 
4 
5 
6 
7 
Allowable Window 
- 
Weekly 
+ ≤ 7 days 
None 
±1 day 
±1 day 
± 1 day 
Clinical Assessments and Procedures 
Informed consent 
✓ 
Medical history 
✓ 
✓ 
Inclusion/Exclusion Criteria 
✓ 
✓ 
MINI 7.0.2 
✓ 
HAM-D-17 
✓ 
✓ 
MGH-ATRQ 
✓ 
C-SSRS2 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Vital signs 
✓ 
✓ 
✓ 
✓ 
Physical examination, 
including weight and height 
✓ 
12-Lead ECG 
✓ 
✓ 
Clinical laboratory tests3 
✓ 
✓ 
✓ 
Urinalysis3 
✓ 
✓ 
✓ 
Urine drug screen3 
✓ 
✓ 
Urine pregnancy test4 
✓ 
✓ 


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3 weeks 
prior to 
Baseline 
Time Post COMP360 Administration Session 
Screening 
Screening 
Period 1 
Baseline 
(Day -1) 
COMP360 
Administration 
Session  
(Day 1) 
 
 
Day 2 
 
Week 1 
Day 8 
 
Week 2 
Day 15 
Week 3 
Day 22 
(EOS/ET) 
Visit 
1 
1a, 1b, 1c 
2 
3 
4 
5 
6 
7 
Allowable Window 
- 
Weekly 
+ ≤ 7 days 
None 
±1 day 
±1 day 
± 1 day 
Clinical Assessments and Procedures 
Documentation of 
contraceptive method to be 
used5 
✓ 
 
 
 
 
 
 
 
CGI-I 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
CGI-S 
 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
COMP360 dose 
 
 
 
✓ 
 
 
 
 
Prior/Concomitant 
Medications 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
AE/SAEs 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Participant Completed Assessments 
MSI-BPD 
✓ 
 
 
 
 
 
 
 
QIDS-SR-16 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
EQ-5D-3L 
 
 
✓ 
 
 
✓ 
✓ 
✓ 
GAD-7 
 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
PANAS 
 
 
✓ 
 
✓ 
 
 
 
5D-ASC 
 
 
 
✓6 
 
 
 
 
Remote-rater Assessment 


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3 weeks 
prior to 
Baseline 
Time Post COMP360 Administration Session 
Screening 
Screening 
Period 1 
Baseline 
(Day -1) 
COMP360 
Administration 
Session  
(Day 1) 
 
 
Day 2 
 
Week 1 
Day 8 
 
Week 2 
Day 15 
Week 3 
Day 22 
(EOS/ET) 
Visit 
1 
1a, 1b, 1c 
2 
3 
4 
5 
6 
7 
Allowable Window 
- 
Weekly 
+ ≤ 7 days 
None 
±1 day 
±1 day 
± 1 day 
MADRS7 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
Abbreviations: 5D-ASC = 5-Dimensional Altered States of Consciousness; AE = adverse event; CGI-I = Clinical Global Impression – Improvement; CGI-S = Clinical Global Impression – Severity; 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; EOS = End of Study; EQ-5D-3L = EuroQoL-5 dimension-3 level; ET = early termination; GAD-7 = 
Generalised Anxiety Disorder Scale - 7 item; HAM-D-17 = Hamilton Depression Rating Scale - 17 item; MINI 7.0.2 = Mini International Neuropsychiatric Interview, Version 
7.0.2; MADRS = Montgomery-Asberg Depression Scale; MGH-ATRQ, Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; 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; SAE = serious adverse event. 
 
1 Screening (V1a) will be performed 3 weeks prior to the Baseline visit (V2, Day -1). 
2 The “Last 12 months” version will be administered at Screening and the “Since Last Visit” version will be administered at all other visits. 
3 See Section 7.2.4 of the study protocol for complete list of required tests to be performed. 
4 For women of child-bearing potential only. 
5 For females of childbearing potential and all males; site is to document method of contraception agreed to be used by each participant. 
6 To be administered immediately after the COMP360 administration session. 
7 On site clinic visits; visits allowed remotely will have the MADRS performed by telephone. 
 


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5.4 
Hypotheses and Treatment Comparisons 
Since there is only one treatment group, there will be no formal statistical testing of any 
hypothesis. In some cases, 95% confidence intervals (CIs) will be reported but these are to 
be interpreted as exploratory. 
5.5 
Multiplicity 
Since there is no formal statistical testing and no p-values reported, no multiplicity 
adjustments are needed for this study. 
5.6 
Sample Size Considerations 
No formal sample size calculations were performed for this study. Approximately 20 
participants are expected to be enrolled in the study. 
5.7 
Randomisation 
Not applicable. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 
No interim analyses are planned. 


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7 ANALYSIS SETS 
 
Analysis Set 
Definition 
Safety Analysis Set 
All participants who receive study drug. 
Full Analysis Set (FAS) 
All participants who receive study drug and have at least 
1 post-baseline efficacy assessment. 
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. 
The Safety Analysis Set will be used for all study participant-related and safety-related 
evaluations. Outputs based on this analysis set will use the actual treatment received by the 
study participant. The FAS will be used for all efficacy-related evaluations, with the PP 
Analysis Set being used for supportive efficacy-related evaluations. Outputs based on these 
analysis sets will use the actual treatment received by the study participant. 
Protocol deviations (PDs) thought to significantly affect the integrity of the particpant’s 
efficacy data will be identified and documented during a data review prior to database lock 
and confirmed at the time of database lock. 


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8 GENERAL CONSIDERATIONS 
All TFLs will be created using SAS® version 9.4 or later1.  
Listings will be sorted in the following order: 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, standard deviation (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 
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 timepoint 
as the denominator). 
Unscheduled visits and retests (same visit number assigned) will not be displayed in by-
visit summary tables and figures but will be included in the data listings. 
All individual participant data will be listed. Listings will include scheduled, unscheduled, 
retest and early 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 
or, in case of partial eCRF entries, completed as per the rules stated in Sections 9.2.5 and 
9.4.2. 
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
⁄
 
9.2.4 
Length of Current Depressive Episode 
The length in months of the current depressive episode will be calculated as follows: 
12 × ൤𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑−𝑠𝑠𝑠𝑠𝑠𝑠𝑟𝑟𝑡𝑡 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 and < 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, in recorded). 
9.2.6 
Prior and Concomitant Medications 
Prior medication refers to any medication that was stopped prior to the start of taking study 
drug/taken during the 30-day period before signing the ICF. Concomitant medication refers 


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to the use of any ongoing medication 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 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 16.2 for mapping), and weeks 1, 2 and 3. 
9.3.1.1 
Total Score 
The MADRS total score is derived by summing up the scores from the 10 items (ranging 
from 0 – 60). 
9.3.1.2 
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 is Section 9.1.1. 
9.3.1.3 
Remitter Status 
A MADRS remitter is defined as a participant whose MADRS total score value is ≤ 10 at 
a post-baseline visit. 


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9.3.1.4 
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. 
9.3.2 
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  
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 3. 
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’). 


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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 website2. As suggested 
by EuroQoL, one collection of value sets will be used for all countries in the study, namely 
those for the United Kingdom. The derivation is described in a paper from Dolan et al.3 
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 paper3) are 
reported in the table below: 
 
Model term 
Regression Coefficient 
Intercept (any dimension > 1) – D1 
0.081 
Mobility (Level 2) - MO 
0.069 
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 


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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 1, 2 and 3.  
9.3.4 
Generalised Anxiety Disorder Scale – 7 Item (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, day 2, weeks 1, 2 and 3. 
9.3.5 
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. 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 first 17 individual items scores from this assessment 
(values ranging from 0 to 53) and will be used as eligibility criteria 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. 
9.3.6 
The Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire (MGH-ATRQ) 
The MGH-ATRQ is a self-rated scale used to determine treatment-resistance in MDD. The 
MGH-ATRQ defines 6 weeks on an adequate dose of antidepressant medication as an 


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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. 
9.3.7 
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. 
9.3.8 
5-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 dissociation, visual restructuralization, auditory alterations, and reduction of 
vigilance. In addition to these 5 dimensions, the 5D-ASC can be split into 11 subscales4: 
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 4-5 
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.4). Subscales have been ordered and displayed in accordance with the 
relevant dimension they are included in (apart for the last 2 dimensions for which no 
subscale is defined)6. 
 


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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 administration 
session. 
9.3.9 
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, 
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, and day 2. 
9.3.10 
Clinical Global Impression – Severity (CGI-S) Scale 
The CGI-S is a 7-point scale that measures the severity of symptoms in patients with mental 
disorders. It requires the clinician to rate the severity of the patient's illness at the time of 
assessment, relative to the clinician's past experience with patients who have the same 


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diagnosis. Ratings range from “normal, not at all ill” (1) to “among the most extremely ill 
patients” (7).  
Participants scoring either 1 or 2 will be classified as responders, whereas all other options 
will classify a participant as ‘non-responder’. If the CGI-S is missing or equal to 0 (= not 
assessed), then the responder status will also be set to missing. 
The CGI-S will be obtained at baseline, day 2, and weeks 1, 2 and 3. 
9.3.11 
Clinical Global Impression – Improvement (CGI-I) Scale 
The CGI-I is a 7-point scale that requires the clinician to rate how much the patient’s 
symptoms have improved relative to a baseline state. Ratings range from “very much 
improved” (1) to “very much worse” (7).  
Participants scoring either 1 or 2 will be classified as responders, whereas all other options 
will classify a participant as ‘non-responder’. If the CGI-I is missing or equal to 0 (= not 
assessed), then the responder status will also be set to missing. 
The CGI-I will be obtained at day 2, and weeks 1, 2 and 3. 
9.4 
Safety 
9.4.1 
Adverse Events 
A treatment-emergent adverse event (TEAE) is defined as any adverse event (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 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). 
 
 
 
 


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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 
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”. 


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• 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) 
• 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 Ranges of Clinical Importance 
The following ranges for the vital signs parameters will be considered clinically important: 
 
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 


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Vital sign 
Lower Limit 
Upper Limit 
Respiration rate (breath / min) 
11 breath/min 
20 breath/min 
Body temperature (℃) 
- 
37.5℃ 
9.4.4 
Continuous Vital Signs Collections via Caretaker Device 
During the COMP360 administration session vital signs will be continuously monitored 
via a device positioned on a participant fingertip that allows real-time measurements of 
blood pressure (systolic, diastolic, and mean arterial) and heart rate (HR).  
For the purposes of this study the individual measurements will be summarised around the 
following specific timepoints: -0.25, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, and 
8 hours post-dose. The values to be summarised for the post-dosing timepoints are values 
that have been measured in the minute from the timepoint itself to the next one, eg for 0.25 
hours (=15 minutes) all measurements occurred between 15 and 16 minutes from the 
dosing will be averaged and used for summary purposes. The pre-dose timepoint -0.25 will 
be derived using a similar approach by taking measurements occurring between 16 and 15 
minutes prior to dosing and averaging them. This measurement will only be displayed in 
the listings. 
In order to define the elapsed hours from dosing for each measurement the difference 
between the timing of each given measurement and the COMP360 dose will be calculated 
in seconds and then converted to minutes as follows: 
Tdiff (min) = Tdiff (sec)/60 
Since the timing of each measurement are recorded on the device using the Eastern time 
zone (UTC-05:00), these will first be converted to match the time zone of each specific site 
(UTC+0 for site 301 and UTC-08:00 for site 302). 
9.4.4.1 
Clinically Relevant Categories 
The following categories for the continuous vital signs parameters will be considered 
clinically relevant: 
 
Parameter 
Clinically Relevant Categories 
Low 
Normal 
High 
High CS 
Systolic blood pressure (mmHg) 
≤ 90 
90 < SBP ≤ 160 
160 < SBP ≤ 180 
> 180 
Diastolic blood pressure (mmHg) 
≤ 50 
50 < DBP ≤ 100 100 < DBP ≤ 110 > 110 
Mean arterial pressure (mmHg) 
  
≤ 135 
> 135 
  
Heart rate (bpm) 
≤ 50 
50 < HR ≤ 100 
100 < HR ≤ 160 
>160 
CS: Clinically Significant. 
9.4.5 
ECG Categorical Intervals 
The ECG categorical intervals of interest are: 


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• QTcF > 450 msec 
• QTcF > 480 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 
9.4.6 
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 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 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. 
The C-SSRS will be obtained at every clinic visit. 


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10 STUDY PARTICIPANTS 
10.1 
Disposition of Participants 
The Safety Analysis Set will be used for all disposition of participant-related evaluations, 
unless otherwise specified. 
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 percentage of participants 
who completed the study and number and percentage of participants who discontinued 
from the study, with reasons for discontinuation, will be summarised (Table 14.1.1.2). 
Reasons for exclusion from the PP Analysis Set will be summarised using the FAS (Table 
14.1.1.3) 
Participant disposition will be listed by 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 (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). 
10.2 
Protocol Deviations 
The frequency and percentage of participants in each important PD category will be 
summarised using the Safety Analysis Set (Table 14.1.1.4). 
All PDs will be listed using the Safety Analysis Set (Listing 16.2.2.1). In addition, a 
separate listing of COVID-19 related PDs will be presented if required (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. 
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, 
Other], ethnicity [Hispanic or Latino, Not Hispanic or Latino], 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], HAM-D-17 total score, MGH-ATRQ [<25% improved, 25-49% 
improved, 50-75% improved, >75% improved], MSI-BPD total score, length of current 
depressive episode (see Section 9.2.4) [months] will be summarised (Table 14.1.4). 


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A listing for all demographic and baseline characteristics, and other baseline characteristics 
will be presented (Listing 16.2.4.1 and Listing 16.2.9.1 – Listing 16.2.9.3). 
Other baseline measurements (urine drug screen and urine pregnancy test) will be listed 
only (Listing 16.2.8.5 and Listing 16.2.8.6). 
10.4 
Medical History  
Medical history collected at screening and baseline will be summarised by primary system 
organ class (SOC) and preferred term (PT) using the Safety Analysis Set (Table 14.1.3.1). 
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. 
Prior and concomitant medications will be summarised (Table 14.1.3.2 and Table 
14.1.3.3). 
Prior and concomitant medications will be listed (Listing 16.2.4.5 and Listing 16.2.4.6). 
10.6 
Treatment Exposure/Compliance and Duration 
COMP360 drug administration will be listed (Listing 16.2.5.1). 
In addition, a summary table (Table 14.1.3.4) and listing (Listing 16.2.5.2) will also be 
created displaying selective serotonin reuptake inhibitor (SSRI) intake after receiving the 
study drug, by selecting records for which CMCLAS = ‘SELECTIVE SEROTONIN 
REUPTAKE INHIBITORS’, including the drug ATC term and dosing (with eventual 
changes in the dosing, if applicable). 
 


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11 EFFICACY  
The FAS will be used for all efficacy-related evaluations, unless otherwise specified. In 
addition, the PP Analysis Set will be used for supportive analyses of the primary efficacy 
endpoint, however, note that if there are no participants excluded from the PP Analysis Set 
no outputs for this population will be produced.  
Since there is only one treatment group, there will be no formal statistical testing of any 
hypothesis. In some cases, 95% CIs will be reported but these are to be interpreted as 
exploratory. 
11.1 
Primary Efficacy 
The primary endpoint is the change from baseline in MADRS total score at week 3. 
MADRS total score values and their changes from baseline at each post-baseline timepoint 
will be descriptively summarised using statistics for continuous variables including 95% 
CIs for the FAS (Table 14.2.1.1) and the PP Analysis Set (Table 14.2.1.2). Both actual 
values and their changes from baseline will also be graphically displayed as line plots for 
the FAS (Figure 14.2.1.1.1 and Figure 14.2.1.2.1, respectively) and the PP Analysis Set 
(Figure 14.2.1.1.2 and Figure 14.2.1.2.2, respectively). 
A summary of percentage change from baseline, including 95% CIs, will also be presented 
(Table 14.2.1.3, Figure 14.2.1.3). 
All observed MADRS data will also be listed (Listing 16.2.6.1). 
11.2 
Secondary Efficacy 
11.2.1 
Proportion of MADRS response at week 3 
The proportion of MADRS responders will be descriptively summarised alongside 95% 
asymptotic CIs for all timepoints up to week 3 (Table 14.2.2.1) and graphically displayed 
via line plots including the estimated 95% CIs (Figure 14.2.2.1). CIs will be Wald-type 
asymptotic intervals based on the Normal approximation to the binomial distribution, 
obtained in SAS as follows: 
 
ods output BinomialCLs = <output-dataset>; 
proc freq data = <input-dataset>; 
by avisitn; 
  tables aval / binomial (level = 2 cl = wald); 
run; 
 
Participant’s status as a responder at each timepoint will be listed (Listing 16.2.6.1). 
 
 


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11.2.2 
Proportion of MADRS remission at week 3 
 
The proportion of MADRS remitters will be descriptively summarised alongside 95% 
asymptotic CIs for all timepoints up to week 3 (Table 14.2.2.2) and graphically displayed 
via line plots including the estimated 95% Wald-type CIs (Figure 14.2.2.2). 
 
Participant’s status as a remitter at each timepoint will be listed (Listing 16.2.6.1). 
11.2.3 
Change from baseline to week 3 in CGI-S 
CGI-S values and their changes from baseline will be descriptively summarised alongside 
95% CIs for all timepoints up to week 3 for the FAS (Table 14.2.2.3) and graphically 
displayed via line plots including the 95% estimated CIs (Figure 14.2.2.3.1 for means and 
Figure 14.2.2.3.2 for mean change from baseline). In addition to continuous summaries, 
CGI-S values will be summarised with counts and percentages for each response option, 
including the number of responders (participants answering either 1 or 2) alongside 95% 
Wald-type CIs (Table 14.2.2.3). 
CGI-S data will be listed (Listing 16.2.6.2.1). 
11.3 
Exploratory Efficacy 
The following exploratory endpoints will be summarised similarly to the primary endpoint 
(ie. including summary of values and their changes from baseline, where applicable): 
• Participant EQ-5D-3L total score change from baseline to weeks 1, 2 and 3 (Table 
14.2.3.1, Listing 16.2.6.3.1) 
• Caregiver EQ-5D-3L total score change from baseline to weeks 1, 2 and 3 (this 
assessment is not mandatory) (Listing 16.2.6.3.1) 
• EQ-VAS change from baseline to week 1, 2 and 3 (Table 14.2.3.2, Listing 16.2.6.3.2) 
• GAD-7 total score change from baseline to day 2 and weeks 1, 2 and 3 (Table 14.2.3.3, 
Listing 16.2.6.4) 
• QIDS-SR-16 score change from baseline to day 2 and weeks 1, 2 and 3 (Table 14.2.3.4, 
Listing 16.2.6.5) 
• PANAS score change from baseline to day 2 (Table 14.2.3.6, Listing 16.2.6.6) 
• 5D-ASC at day 1 (Table 14.2.3.7, Listing 16.2.6.7) 
The CGI-I score at day 2, and weeks 1, 2 and 3 will be summarised with counts and 
percentages for each response option, including the number of responders (participants that 
answered either 1 or 2) alongside 95% Wald-type CIs (Table 14.2.3.5, Listing 16.2.6.2.2). 


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12 SAFETY 
The Safety Analysis Set will be used for all safety-related evaluations, unless specified. 
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 ≥ 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 Duration of TEAEs (Table 14.3.1.9) 
• Summary of ADRs (Table 14.3.1.10) 
• Summary of TESAEs (Table 14.3.1.11) 
• Summary of SARs (Table 14.3.1.12) 
• Summary of AESIs (Table 14.3.1.13) 
• Summary of TEAEs Leading to Study Withdrawal (Table 14.3.1.14) 
• Summary of ADRs Leading to Study Withdrawal (Table 14.3.1.15) 
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. 


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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 reported term, SOC, PT, date and 
study day when AE starts/stops, duration (days), relationship, severity, action taken, 
outcome, seriousness and whether the AE leads to study withdrawal (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) and lead to death (Listing 16.2.7.5). A 
listing of TEAEs associated to COVID-19 (Listing 16.2.7.6) will be provided if there are 
any such events. 
12.2 
Laboratory Tests 
The full list of parameters and their units (where applicable) is 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 (%) 
Neutrophils (109/L) 
Neutrophils/Leukocytes (%) 
Platelets (109/L) 
Chemistry 
Alanine Aminotransferase [ALT] (U/L)  
Albumin (g/L) 


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Category 
Parameter (Unit) 
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 14.3.4.1) and chemistry (Table 14.3.4.2) 
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 14.3.4.3 and Table 14.3.4.4 
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). 
12.3 
Vital Signs 
The full list of parameters and their units (where applicable) is reported below: 
• SBP (mmHg) 


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• DBP (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) and listed (Listing 16.2.8.8). 
All vital signs data will be listed, which will also include flagged values that are outside 
normal reference ranges or markedly abnormal findings (Listing 16.2.8.7). 
12.4 
Continuous Vital Signs 
HR, Mean Arterial Pressure (MAP), SBP and DBP as measured during the COMP360 
dosing session on day 1 will be descriptively summarised at the following timepoints: 0.25, 
0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8 hours post-dose (Table 14.3.5.3) using 
summary statistics for continuous measures. In addition, summaries will be provided 
displaying the number of participants and occurrences of any of the measured vital signs 
at the above timepoints falling within any of the categories described in Section 9.4.4.1 
(Table 14.3.5.4).  
Mean and 95% CIs will also be displayed in a profile plot for each parameter (Figure 
14.3.5.1). 
One listing containing all summarised values (Listing 16.2.8.9) and one only including 
individual values outside the categories described in Section 9.4.4.1 (Listing 16.2.8.10) will 
also be created. 
12.5 
ECGs 
The full list of parameters and their units (where applicable) is reported below: 
• HR (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 (baseline and day 2) (Table 14.3.6.1). Shift tables in relation to 


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the overall interpretation (Normal, Abnormal Not Clinically Significant (NCS), and 
Abnormal Clinically Significant (CS)) from baseline 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 16.2.8.12). 
All ECG data will be listed (Listing 16.2.8.11). 
12.6 
C-SSRS 
C-SSRS data will be summarised by visit (Table 14.3.6.4) and listed (Listing 16.2.9.4). 


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13 CHANGES FROM THE PROTOCOL-PLANNED ANALYSES 
• Section 7 (Analysis Sets): FAS and Safety Analysis Set definitions were changed 
compared to the protocol to be aligned with the definitions provided in the pivotal 
COMP 001 study. The FAS has been defined as similar to a modified Intent-to-Treat 
(mITT), ie treated patients with at least one post-baseline efficacy assessment (the 
protocol definition was closer to the pure ITT definition, including all treated patients) 
whereas the Safety Analysis Set now only includes participants that were treated (the 
protocol definition included all enrolled participants). 
• Section 2 (Study objectives) and Section 3 (Endpoints): Several changes were made to 
objectives and endpoints wording as well as other items in the protocol. These, and 
their rationale, are all listed in Appendix I ‘Changes to COMP 003 Protocol’. 


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14 DATA NOT PRESENTED 
All data available will be reported. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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15 REFERENCES 
 
1. SAS Institute Inc., Cary, NC, 27513, USA 
2. https://euroqol.org/eq-5d-instruments/eq-5d-3l-about/valuation/ 
3. Dolan P. Modeling valuations for EuroQol health states. Med Care 1997; 35(11): 
1095-1108. 
4. Studerus E, Gamma A, Vollenweider FX. Psychometric evaluation of the altered 
states of consciousness rating scale (OAV). PLoS One. 2010;5: e12412. 
5. Russell JA, Carroll JM. On the bipolarity of positive and negative affect. Psychol 
Bull. 1999; 125:3–30. 
6. 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. 


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16 PROGRAMMING AND DATA PRESENTATION 
CONVENTIONS 
16.1 
Treatment Labelling 
 
COMP360 25 mg + SSRI 
16.2 
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/… 
Visit 1a/1b/1c/… 
Baseline (day -1) – Visit 2 
Baseline (day -1) – Visit 2 
Baseline or Day -1 
Day 0 – Visit 3 
Day 1 – Visit 3 
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 
a Continuous vital signs are collected just prior to study drug dosing. 
16.3 
Baseline Definitions 
Baseline is defined as the last non-missing value (either scheduled, unscheduled or 
repeat) before the participant receives study drug. 
 
Parameter 
Baseline 
Efficacy 
All 
Day -1 
Safety 
Clinical Laboratory 
Screening 
Vital Signs (discrete) 
Day -1 
ECGs 
Screening 
C-SSRS 
Day -1 
16.4 
Study Day and Duration Derivation 
Study day, defined as the number of days from the dose of study drug, will be derived as 
follows:  


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• 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 AEs (in days) will be derived as follows: 
• stop date of the event – start date of the event + 1 
16.5 
Decimal Places 
Decimal places (dps) 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 day, 
month, year, number of days and total scores (for rating scales) will be presented with zero 
dps.  
Means, medians and percentiles will be displayed to one more dp 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. 
 


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


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Table 
Number 
Table Title 
Validation 
Method 
Shell Number 
(if repeat) 
14.1  
Demographic Data 
 
 
14.1.1  
Disposition 
 
 
14.1.1.1 
Participant Disposition by Country – All Screened Participants  
IProg 
 
14.1.1.2 
Participant Disposition, Completions and Early Terminations with Reasons – Safety Analysis Set IProg 
 
14.1.1.3 
Reasons for Exclusion from the Per-Protocol Analysis Set – Full Analysis Set 
IProg 
 
14.1.1.4 
Important Protocol Deviations – Safety Analysis Set 
IProg 
 
14.1.2  
Demographics 
 
 
14.1.2 
Demographics - Safety Analysis Set 
IProg 
 
14.1.3 
Baseline Characteristics 
 
 
14.1.3.1 
Medical History – Safety Analysis Set 
IProg 
 
14.1.3.2 
Prior Medications – Safety Analysis Set 
IProg 
 
14.1.3.3 
Concomitant Medications – Safety Analysis Set 
IProg 
 
14.1.3.4 
Concomitant SSRI Treatment – Safety Analysis Set 
IProg 
14.1.3.3 
14.1.4 
Other Baseline Assessments – Safety Analysis Set 
IProg 
 
14.2  
Efficacy Data 
 
 
14.2.1 
Primary Efficacy Endpoint 
 
 
14.2.1.1 
Primary Endpoint – Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Total 
Score and Change from Baseline – Full Analysis Set 
IProg 
 
14.2.1.2 
Primary Endpoint – Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Total 
Score and Change from Baseline – Per-Protocol Analysis Set 
IProg 
14.2.1.1 
14.2.1.3 
Primary Endpoint – Summary of Percentage Change from Baseline in Montgomery-Asberg 
Depression Rating Scale (MADRS) Total Score – Full Analysis Set 
IProg 
 
14.2.2 
Secondary Efficacy Endpoints 
 
 
14.2.2.1 
Secondary Endpoint – Proportion of Montgomery-Asberg Depression Rating Scale (MADRS) 
Responders Over Time – Full Analysis Set 
IProg 
 
14.2.2.2 
Secondary Endpoint - Proportion of Montgomery-Asberg Depression Rating Scale (MADRS) 
Remitters Over Time – Full Analysis Set 
IProg 
14.2.2.1 
14.2.2.3 
Secondary Endpoint – Summary of CGI-S and Change from Baseline – Full Analysis Set 
IProg 
 
14.2.3 
Exploratory Efficacy Endpoints 
 
 
14.2.3.1 
Exploratory Endpoint – Summary of Participant EQ-5D-3L Total Score and Change from 
Baseline – Full Analysis Set 
IProg 
14.2.1.1 


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Table 
Number 
Table Title 
Validation 
Method 
Shell Number 
(if repeat) 
14.2.3.2 
Exploratory Endpoint – Summary of EuroQoL - Visual Analogue Scale (EQ-VAS) and Change 
from Baseline - Full Analysis Set 
IProg 
14.2.1.1 
14.2.3.3 
Exploratory Endpoint – Summary of GAD-7 Total Score and Change from Baseline – Full 
Analysis Set 
IProg 
14.2.1.1 
14.2.3.4 
Exploratory Endpoint – Summary of QIDS-SR-16 Total Score Values and Change from Baseline 
– Full Analysis Set 
IProg 
14.2.1.1 
14.2.3.5 
Exploratory Endpoint – Summary of CGI-I Values– Full Analysis Set 
IProg 
 
14.2.3.6 
Exploratory Endpoint – Summary of PANAS Positive and Negative Affect Scores and Change 
from Baseline – Full Analysis Set 
IProg 
14.2.1.1 
14.2.3.7 
Exploratory Endpoint – Summary of 5D-ASC Questionnaire Values – Full Analysis Set 
IProg 
 
14.3  
Safety Data 
 
 
14.3.1  
Displays of Adverse Events 
 
 
14.3.1.1 
Summary of Treatment-Emergent Adverse Events (TEAEs) – Safety Analysis Set 
IProg 
 
14.3.1.2 
MedDRA Summary of Treatment-Emergent Adverse Events (TEAEs) by Primary System Organ 
Class and Preferred Term – Safety Analysis Set 
IProg 
 
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 
IProg 
14.3.1.2 
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 
IProg 
 
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 
IProg 
 
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 
IProg 
 
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 
IProg 
 
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 
IProg 
 
14.3.1.9 
MedDRA Summary of Duration of Treatment-Emergent Adverse Events (TEAEs) by Primary 
System Organ Class and Preferred Term – Safety Analysis Set 
IProg 
 
14.3.1.10 
MedDRA Summary of Adverse Drug Reactions (ADRs) by Primary System Organ Class and 
Preferred Term – Safety Analysis Set 
IProg 
14.3.1.2 


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Table 
Number 
Table Title 
Validation 
Method 
Shell Number 
(if repeat) 
14.3.1.11 
MedDRA Summary of Treatment-Emergent Serious Adverse Events (TESAEs) by Primary 
System Organ Class and Preferred Term – Safety Analysis Set 
IProg 
14.3.1.2 
14.3.1.12 
MedDRA Summary of Serious Adverse Reactions (SARs) by Primary System Organ Class and 
Preferred Term – Safety Analysis Set 
IProg 
14.3.1.2 
14.3.1.13 
MedDRA Summary of Treatment-Emergent Adverse Events of Special Interest (AESIs) by 
AESI Term and Preferred Term – Safety Analysis Set 
IProg 
 
14.3.1.14 
MedDRA Summary of Treatment-Emergent Adverse Events (TEAEs) Leading to Study 
Withdrawal by Primary System Organ Class and Preferred Term – Safety Analysis Set 
IProg 
14.3.1.2 
14.3.1.15 
MedDRA Summary of Adverse Drug Reactions (ADRs) Leading to Study Withdrawal by 
Primary System Organ Class and Preferred Term – Safety Analysis Set 
IProg 
14.3.1.2 
14.3.2  
Listings of Deaths, Other Serious and Significant Adverse Events 
 
 
14.3.3  
Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events  
 
 
14.3.4  
Laboratory Values 
 
 
14.3.4.1 
Summary Statistics of Observed Values and Change from Baseline in Haematology – Safety 
Analysis Set 
IProg 
 
14.3.4.2 
Summary Statistics of Observed Values and Change from Baseline in Chemistry – Safety 
Analysis Set 
IProg 
14.3.4.1 
14.3.4.3 
Normal Range Shifts from Baseline in Haematology Values – Safety Analysis Set 
IProg 
 
14.3.4.4 
Normal Range Shifts from Baseline in Chemistry Values – Safety Analysis Set 
IProg 
14.3.4.3 
14.3.5  
Vital Signs 
 
 
14.3.5.1 
Summary Statistics of Observed Values and Change from Baseline to Day 2 in Vital Signs – 
Safety Analysis Set 
IProg 
 
14.3.5.2 
Overall Summary of Clinically Important Vital Signs Values – Safety Analysis Set 
IProg 
 
14.3.5.3 
Summary Statistics of Continuous Vital Signs Monitored During the COMP360 Administration 
Session – Safety Analysis Set 
IProg 
 
14.3.5.4 
Summary of Clinically Relevant Categories of Continuous Vital Signs Monitored During the 
COMP360 Administration Session – Safety Analysis Set 
IProg 
 
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 
IProg 
 
14.3.6.2 
ECG Clinical Interpretation – Shift from Baseline to Day 2 – Safety Analysis Set 
IProg 
 


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Table 
Number 
Table Title 
Validation 
Method 
Shell Number 
(if repeat) 
14.3.6.3 
Summary of QTcF Intervals Categories – Safety Analysis Set 
IProg 
 
14.3.6.4 
Summary of C-SSRS by Visit– Safety Analysis Set 
IProg 
 


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Figure 
Number 
Figure Title 
Validation 
Method 
Shell Number 
(if repeat) 
14.2 
Efficacy Data 
 
 
14.2.1 
Primary Efficacy Endpoint 
 
 
14.2.1.1.1 
Primary Endpoint – Montgomery-Asberg Depression Rating Scale (MADRS) Total Score - Full 
Analysis Set 
IProg 
 
14.2.1.1.2 
Primary Endpoint – Montgomery-Asberg Depression Rating Scale (MADRS) Total Score – Per-
Protocol Analysis Set 
IProg 
14.2.1.1.1 
14.2.1.2.1 
Primary Endpoint – Change from Baseline in Montgomery-Asberg Depression Rating Scale 
(MADRS) Total Score - Full Analysis Set 
IProg 
 
14.2.1.2.2 
Primary Endpoint – Change from Baseline in Montgomery-Asberg Depression Rating Scale 
(MADRS) Total Score – Per-Protocol Analysis Set 
IProg 
14.2.1.2.1 
14.2.1.3 
Primary Endpoint – Percentage Change from Baseline in Montgomery-Asberg Depression 
Rating Scale (MADRS) Total Score - Full Analysis Set 
IProg 
14.2.1.2.1 
14.2.2 
Secondary Efficacy Endpoints 
 
 
14.2.2.1 
Secondary Endpoint – Proportion of Montgomery-Asberg Depression Rating Scale (MADRS) 
Responders – Full Analysis Set 
IProg 
 
14.2.2.2 
Secondary Endpoint – Proportion of Montgomery-Asberg Depression Rating Scale (MADRS) 
Remitters – Full Analysis Set 
IProg 
14.2.2.1 
14.2.2.3.1 
Secondary Endpoint – CGI-S – Full Analysis Set 
IProg 
14.2.1.1.1 
14.2.2.3.2 
Secondary Endpoint – Change from Baseline in CGI-S – Full Analysis Set 
IProg 
14.2.1.2.1 
14.3.5 
Vital Signs 
 
 
14.3.5.1 
Continuous Vital Signs Monitored During COMP360 Administration Session, Profile Plot – 
Safety Analysis Set 
IProg 
14.2.1.1.1 
 
 
 


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Listing Number 
Listing Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
16.2  
Participant Data Listings 
 
 
16.2.1  
Discontinued Participants 
 
 
16.2.1.1  
Details of Study Discontinuations – Safety Analysis Set 
IProg 
 
16.2.1.2 
Details of Study Completers – Safety Analysis Set 
IProg 
 
16.2.2 
Protocol Deviations 
 
 
16.2.2.1 
Protocol Deviations – Safety Analysis Set 
IProg 
 
16.2.2.2 
COVID-19 Related Protocol Deviations – Safety Analysis Set 
IProg 
16.2.2.1 
16.2.3 
Participants Excluded from the Efficacy Analyses 
 
 
16.2.3 
Analysis Sets – Safety Analysis Set  
IProg 
 
16.2.4  
Demographic Data 
 
 
16.2.4.1  
Demographics – Safety Analysis Set 
IProg 
 
16.2.4.2 
Medical History – Safety Analysis Set 
IProg 
 
16.2.4.3 
Inclusion Criteria – All Screened Participants 
IProg 
 
16.2.4.4 
Exclusion Criteria – All Screened Participants 
IProg 
 
16.2.4.5 
Prior Medications – Safety Analysis Set 
IProg 
 
16.2.4.6 
Concomitant Medications – Safety Analysis Set 
IProg 
 
16.2.5  
Compliance and / or Drug Concentration Data 
 
 
16.2.5.1  
Study Medication Administration – Safety Analysis Set 
IProg 
 
16.2.5.2 
Ongoing SSRI Treatment – Safety Analysis Set 
IProg 
 
16.2.6  
Individual Efficacy Response Data   
 
 
16.2.6.1 
Montgomery-Asberg Depression Rating Scale (MADRS) Score – Full Analysis Set 
IProg 
 
16.2.6.2.1 
Clinical Global Impression – Severity (CGI-S) – Full Analysis Set 
IProg 
 
16.2.6.2.2 
Clinical Global Impression – Improvement (CGI-I) – Full Analysis Set 
IProg 
 
16.2.6.3.1 
EuroQoL - 5 Dimensions-3 Levels (EQ-5D-3L) Descriptive System - Full Analysis Set 
IProg 
 
16.2.6.3.2 
EuroQoL - Visual Analogue Scale (EQ-VAS) - Full Analysis Set 
IProg 
 
16.2.6.4 
Generalised Anxiety Disorder Scale – 7 Item (GAD-7) – Full Analysis Set 
IProg 
 
16.2.6.5 
Quick Inventory of Depressive Symptomatology – Self Report – 16 items (QIDS SR-
16) - Full Analysis Set 
IProg 
 
16.2.6.6 
The Positive and Negative Affect Schedule (PANAS) – Full Analysis Set 
IProg 
 


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Listing Number 
Listing Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
16.2.6.7 
Five Dimensions Altered States of Consciousness Questionnaire (5D-ASC) – Full 
Analysis Set 
IProg 
 
16.2.7  
Adverse Event Listings 
 
 
16.2.7.1 
Treatment-Emergent Adverse Events (TEAEs) – Safety Analysis Set 
IProg 
 
16.2.7.2 
Treatment-Emergent Serious Adverse Events (TESAEs) – Safety Analysis Set 
IProg 
 
16.2.7.3 
Adverse Drug Reactions (ADRs) – Safety Analysis Set 
IProg 
16.2.7.1 
16.2.7.4 
Adverse Events of Special Interest (AESIs) – Safety Analysis Set 
IProg 
16.2.7.1 
16.2.7.5 
Deaths – Safety Analysis Set 
IProg 
 
16.2.7.6 
COVID-19 Related Treatment-Emergent Adverse Events (TEAEs) – Safety Analysis 
Set 
IProg 
16.2.7.1 
16.2.8  
Individual Laboratory Measurements and Other Safety 
 
 
16.2.8.1 
Haematology – Safety Analysis Set 
IProg 
 
16.2.8.2 
Chemistry – Safety Analysis Set 
IProg 
16.2.8.1 
16.2.8.3 
Urinalysis – Safety Analysis Set 
IProg 
16.2.8.1 
16.2.8.4 
Clinically Significant Laboratory Values – Safety Analysis Set 
IProg 
 
16.2.8.5 
Urine Drug Screen – Safety Analysis Set 
IProg 
 
16.2.8.6 
Pregnancy Test – Safety Analysis Set 
IProg 
 
16.2.8.7 
Vital Signs Data – Safety Analysis Set 
IProg 
 
16.2.8.8 
Clinically Important Vital Signs Values – Safety Analysis Set 
IProg 
16.2.8.4 
16.2.8.9 
Continuous Vital Signs Monitored During COMP360 Administration Session – Safety 
Analysis Set 
IProg 
 
16.2.8.10 
Clinically Important Vital Signs Values During COMP360 Administration Session – 
Safety Analysis Set 
IProg 
16.2.8.9 
16.2.8.11 
ECG Data – Safety Analysis Set 
IProg 
 
16.2.8.12 
Clinically Important ECG Values – Safety Analysis Set 
IProg 
 
16.2.9 
Other Study Instruments 
 
 
16.2.9.1 
Hamilton Depression Rating Scale – 17-Item (HAM-D-17) - Full Analysis Set 
IProg 
 
16.2.9.2.1 
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire 
(MGH-ATRQ) - Full Analysis Set 
IProg 
 


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Listing Number 
Listing Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
16.2.9.2.2 
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire 
(MGH-ATRQ) – Previous Treatments - Full Analysis Set 
IProg 
 
16.2.9.3 
McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD) - Full 
Analysis Set 
IProg 
 
16.2.9.4 
Columbia Suicidal Severity Rating Scale (C-SSRS) – Safety Analysis Set 
IProg 
 


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18 APPENDIX 
18.1 
Appendix I: CHANGES TO COMP 003 PROTOCOL 
COMP 003 PROTOCOL 
COMPARATIVE TABLE 
08-March-2021 
COMP 003 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 003 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 version is 2.2 (17 Dec 2020). 
 
General Changes: 
• Replacing psilocybin with COMP360 as this is COMPASS Pathfinder’s’ 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. 
• Replacing capitalised words with non-capitalised words for better sentence flow. 
• Replacing behavior with behaviour to comply with English (UK) spelling. 
• Correcting spelling errors. 
Summary 
Protocol Section Concerned with Wording 
SAP and CSR Amended Wording 
Section 2 STUDY OBJECTIVES 
The main purpose of this study is to investigate the efficacy of 25 mg 
psilocybin adjunct to serotonergic antidepressants in TRD participants via 
the following objectives. 
Section 2 STUDY OBJECTIVES 
The main purpose of this study is to investigate the efficacy of 25 mg 
COMP360 adjunct to serotonergic antidepressants in TRD participants via 
the following objectives. 
Section 2.1 Primary (Primary Objective) 
The primary objective of this study is to explore the efficacy of 25 mg 
psilocybin as an adjunct therapy to antidepressants in improving depressive 
symptoms. 
Section 2.1 Primary (Primary Objective) 
The primary objective of this study is to explore the efficacy of 25 mg 
COMP360 as an adjunct therapy to antidepressants in improving 
depressive symptoms. 


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Section 2.2 Secondary (Secondary Objectives) 
The secondary objective is to evaluate the safety and tolerability of 
psilocybin in participants with TRD based on AEs, changes in vital signs, 
electrocardiograms (ECGs), clinical laboratory tests and suicidal 
ideation/behavior (measured using the Columbia- Suicide Severity Rating 
Scale [C-SSRS]) score. 
Section 2.2 Secondary (Secondary Objectives) 
The secondary objective is to evaluate the safety and tolerability of 
COMP360 in participants with TRD based on AEs, changes in vital signs, 
electrocardiograms (ECGs), clinical laboratory tests and suicidal 
ideation/behaviour (measured using the Columbia- Suicide Severity 
Rating Scale [C-SSRS]) score. 
Section 2.3 Exploratory (Exploratory Objectives) 
The exploratory objectives are to evaluate the effects of psilocybin on 
quality of life, wellbeing and anxiety. 
Section 2.3 Exploratory (Exploratory Objectives) 
The exploratory objectives are to evaluate the effects of COMP360 on 
quality of life, wellbeing and anxiety. 
Section 3.1 Primary (Primary Endpoint) 
The primary endpoint is the change in Montgomery-Asberg Depression 
Rating Scale (MADRS) total score from Baseline (Day -1) to 3 weeks post 
psilocybin administration. 
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 administration. 
 
 
 
 
 
 
 
 
 
 


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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 post 
psilocybin administration 
• 
The proportion of participants with remission (defined as a MADRS 
total score ≤ 10) at Week 3 post psilocybin administration 
• 
Changes from Baseline Clinical Global Impression - Severity scale 
(CGI-S) at Week 3 post psilocybin administration 
• 
Incidence of AEs 
• 
Change from Baseline to Day 1 in ECGs, and incidence of clinically 
important changes 
• 
Change from Baseline to Day 1 and to Week 3 in clinical laboratory 
tests, and incidence of clinically important changes 
• 
Change from Baseline to Day 1 in vital signs 
• 
Incidence of changes from Baseline in the C-SSRS at each post-
Baseline visit 
(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 
COMP360 administration 
• 
The proportion of participants with remission (defined as a MADRS 
total score ≤ 10) at week 3 post COMP360 administration 
• 
Changes from baseline Clinical Global Impression - Severity scale 
(CGI-S) at week 3 post COMP360 administration 
• 
Incidence of AEs 
• 
Change from baseline to day 2 in ECGs, and incidence of clinically 
important changes 
• 
Change from baseline to day 2 and to week 3 in clinical laboratory 
tests, and incidence of clinically important changes 
• 
Change from baseline to day 2 in vital signs 
• 
Incidence of changes from baseline in the C-SSRS at each post-
baseline visit 
Section 3.3 Exploratory (Exploratory Endpoints) 
The exploratory endpoints are: 
• 
Change from Baseline to Week 3 in total scores of: 
• 
Participant Euro QoL-5 dimension-3 level (EQ-5D-3L) 
• 
Caregiver EQ-5D-3L (this assessment is not mandatory) 
• 
Generalised Anxiety Disorder 7-item Scale (GAD-7) 
• 
QIDS-SR-16 
• 
Clinical Global Impression - Improvement scale (CGI-I) 
• 
Change from Baseline to Day 1 in Positive and Negative 
Affect Schedule (PANAS) 
• 
Summary of Five Dimension Altered States of Conscniousness 
questionnaire (5D-ASC) on the day of the psilocybin session 
(Day 0) 
Section 3.3 Exploratory (Exploratory Endpoints) 
The exploratory endpoints are: 
• 
Change from baseline to week 3 in total scores of: 
• 
Participant Euro QoL-5 dimension-3 level (EQ-5D-3L) 
• 
Caregiver EQ-5D-3L (this assessment is not mandatory) 
• 
Generalised Anxiety Disorder 7-item Scale (GAD-7) 
• 
QIDS-SR-16 
• 
Clinical Global Impression - Improvement scale (CGI-I) 
• 
Change from baseline to day 2 in Positive and Negative Affect 
Schedule (PANAS) 
• 
Summary of Five Dimensional Altered States of 
Consciousness questionnaire (5D-ASC) on the day of the 
COMP360 administration session (day 1)