Clinical trial NCT05414422
Conditions: Treatment Resistant Depression
Keywords: PCN-101 R-ketamine
Sponsor: Perception Neuroscience
Start date: 2022-02-01; Completion date: 2022-11-10
Enrollment: 102 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a double-blind, randomized, placebo-controlled, multicenter study comprised of 3 phases:screening (up to 2 weeks \[Day -15 to Day -2\]), In-Clinic Treatment (Day -1 to Day 2; including double-blind treatment \[Day 1\]), and post-treatment follow-up (7 and 14 days after infusion on Days 8 and 15, respectively). A total of 93 adult subjects with TRD will be randomly allocated in equal cohorts of 31 subjects/arm to the 3 arms of the study in a blinded manner.

Detailed description:

Arms: arm 1: PCN-101 30 mg arm 2: PCN-101 60 mg arm 3: Placebo
Interventions: intervention 1: PCN-101 intervention 2: Placebo
Intervention descriptions: intervention 1: Concentrate for solution for infusion intervention 2: Concentrate for solution for infusion

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
Protocol PCN-101-21 – Protocol Amendment 4, 19 May 2022 
PERCEPTION NEUROSCIENCE 
PROPRIETARY and CONFIDENTIAL 
 
1 
CLINICAL STUDY PROTOCOL 
A RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND STUDY TO ASSESS THE 
SAFETY AND EFFICACY OF INTRAVENOUS PCN-101 IN TREATMENT-RESISTANT 
DEPRESSION 
 
Protocol Number:  
 
PCN-101-21 
 
Study Phase:   
 
2a 
 
EudraCT Number: 
 
2020-005457-25 
 
Sponsor:  
 
 
Perception Neuroscience, Inc.  
 
 
c/o atai Life Sciences, WeWork, 524 Broadway,  
New York, NY 10012 
 
 
Date of Original Protocol: 
16 November 2020 
 
 
Date of Amendment 4:  
19 May 2022 
 
 
 
Confidentiality Statement:   
The information contained in this document is the property of Perception Neuroscience, Inc. (or 
under its control), and therefore provided to you in confidence as an Investigator, potential 
Investigator or consultant for review by you, your staff and an applicable Independent Ethics 
Committee/Institutional Review Board. It is understood that this information will not be disclosed 
to others without written authorization from Perception Neuroscience, Inc., except to the extent 
necessary to obtain informed consent from those persons to whom the drug may be administered. 
 
 
 
NCT: NCT05414422












CONFIDENTIAL 
Protocol PCN-101-21 – Protocol Amendment 4, 19 May 2022 
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7 
TABLE OF FIGURES 
Figure 1 
Study Schema...................................................................................................18 






CONFIDENTIAL 
Protocol PCN-101-21 – Protocol Amendment 4, 19 May 2022 
PERCEPTION NEUROSCIENCE 
PROPRIETARY and CONFIDENTIAL 
 
10 
Objectives 
Estimands 
 
 
 
 
 
 
 
 
 
o 
AEs 
o 
Modified Observer’s Assessment of 
Alertness/Sedation (MOAA/S) 
o 
Clinician-Administered Dissociative States 
Scale (CADSS) 
o 
Brief Psychiatric Rating Scale - Modified 
4 Components (BPRS+) 
o 
5-Dimensional Altered States of 
Consciousness Rating Scale (5D-ASC) 
o 
Columbia Suicide Severity Rating Scale 
(C-SSRS). 
 
Overall Design: 
This is a double-blind, randomized, placebo-controlled, multicenter study comprised of 3 phases: 
screening (up to 2 weeks [Day -15 to Day -2]), In-Clinic Treatment (Day -1 to Day 2; including double-
blind treatment [Day 1]), and post-treatment follow-up (7 and 14 days after infusion on Days 8 and 15, 
respectively). The study consists of 3 arms: placebo, PCN-101 Solution for Injection 30 mg, and PCN-
101 Solution for Injection 60 mg. A total of 93 adult subjects with TRD will be randomly allocated in 
equal cohorts of 31 subjects/arm to the 3 arms of the study in a blinded manner. Randomization will be 
stratified by region (US, EU).  
Subjects will be randomized within 14 days of screening (Visit 1). Subjects will be admitted to the clinic 
the evening prior to study treatment administration (Day -1, Visit 2) and undergo baseline testing to 
ensure continued study eligibility. Study treatments will be infused IV over 40 minutes the next morning 
(Day 1, Visit 2). Starting immediately prior to dosing, subjects will be monitored closely for safety. 
Additionally, the subjects’ alertness, mood, and other psychological parameters will be assessed by 
clinician- and patient completed scales and questionnaires. Subjects will be discharged no earlier than 
24 hours postinfusion and after the final in-clinic assessments have been completed (Day 2, Visit 2). 
Subjects will be asked to return to the clinic approximately 6 days (Day 8, Visit 3) and 13 days (Day 15, 
Visit 4) after discharge to assess the safety and tolerability of the study treatments and to determine the 
durability of the antidepressant effect. 
During the coronavirus disease 2019 (COVID-19) pandemic, the specific guidance from local public 
health and other competent authorities regarding the protection of individuals’ welfare must be applied. If 
subjects cannot attend follow up visits in person because of restrictions arising as a consequence of the 
COVID-19 pandemic, the Investigator must discuss with the Medical Monitor potential mitigation. 
 
Number of Investigators and Study Centers: 
Approximately 20 study centers in the EU and the US are expected to participate in this study. 
 
Number of Subjects: 
The enrollment of 93 subjects is planned. Subjects who do not receive a dose of study treatment on Day 1 
(Visit 2) will be replaced. 
 
Duration of Study: 
The duration of study participation for each subject will be up to 29 days including a screening period, a 
3-day in-clinic visit, and 2 follow-up visits. 


CONFIDENTIAL 
Protocol PCN-101-21 – Protocol Amendment 4, 19 May 2022 
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11 
 
Inclusion Criteria: 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
1. Be capable of giving and give signed informed consent, which includes compliance with the 
requirements and restrictions listed in the Informed Consent Form (ICF) and in this protocol. 
2. Be male or female 18 to 65 years of age inclusive at the time of signing the ICF. 
3. Weigh ≥ 50 kg and have a body mass index (BMI) ≥ 18 and ≤ 35. 
4. Have a diagnosis of recurrent major depressive disorder (MDD) without psychotic features per the 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), confirmed by the 
Mini-International Neuropsychiatric Interview (MINI). 
5. Have an HAM-D total score > 20 at screening and baseline (Day -1). 
6. Have an inadequate response to at least 2 antidepressants in the current episode of depression that 
were each given for ≥ 6 weeks at an adequate dose as defined by the Massachusetts General Hospital 
Antidepressant Response Questionnaire (MGH-ATRQ). 
7. Must be on stable oral antidepressant treatment without a dose change for at least 30 days before 
screening (a missed dose, or reasonable number of missed doses per Investigator’s discretion, in that 
period does not exclude a subject). 
8. A male subject must be medically confirmed sterile for at least 6 months prior to screening or agree to 
use highly effective contraception (see Appendix 5) during the treatment period and for at least 3 
months after the last dose of study treatment and refrain from donating sperm during this period. If a 
male with a partner who is of childbearing potential (OCBP) is included, his partner also needs to use 
highly effective birth control measures. 
9. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the 
following conditions applies: 
• 
Not of childbearing potential (see Appendix 5). 
• 
A subject OCBP who agrees to follow the highly effective contraceptive guidance (see 
Appendix 5) on highly effective birth control measures during the treatment period and for at 
least 3 months after the last dose of study treatment and refrain from donating eggs during this 
period. 
10. Be medically stable on the basis of physical examination, medical history, vital signs, and 12-lead 
ECG performed at screening. If there are abnormalities, the subject may be included only if the 
Investigator judges the abnormalities not to be clinically important. This determination must be 
recorded in the subject's source documents and initialed and dated by the Investigator. 
 
Exclusion Criteria: 
Subjects are excluded from the study if any of the following criteria apply: 
1. History of, or current signs and symptoms of, diseases or conditions that would make participation 
not be in the best interest (eg, compromise the well-being) of the subject or that could prevent, limit, 
or confound the protocol-specified assessments. 
2. History of moderate or severe head trauma (for example, loss of consciousness for more than 
15 minutes) or other neurological disorders (including a diagnosis of epilepsy or has had a seizure in 
the last 6 months), neurodegenerative disorder (Alzheimer’s disease, Parkinson’s disease, multiple 
sclerosis, Huntington’s disease, etc.) or systemic medical diseases that are, in the opinion of the 
Investigator, likely to interfere with the conduct of the study or confound the study assessments. A 
history of febrile seizures in childhood is not exclusionary. 


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Protocol PCN-101-21 – Protocol Amendment 4, 19 May 2022 
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3.
Has a primary DSM-V diagnosis of current (active) MDD with psychotic features, panic disorder,
obsessive compulsive disorder, posttraumatic stress disorder, anorexia nervosa, or bulimia nervosa.
Comorbid anxiety or panic disorder that does not dominate the clinical presentation is acceptable.
4.
Has a current or prior DSM-V diagnosis of a primary psychotic disorder (eg, schizophrenia), bipolar
or related disorders (confirmed by the MINI), intellectual or autism spectrum disorder, or borderline
personality disorder.
5.
Has any significant disease or disorder (eg, cardiovascular, pulmonary, gastrointestinal, hepatic, renal,
neurological, musculoskeletal, endocrine, metabolic, malignant, psychiatric, major physical
impairment) that, in the opinion of the Investigator, may either put the subject at risk because of
participation in the study, influence the results of the study, or affect the subject’s ability to
participate in the study.
6.
Has uncontrolled hypertension, despite medication, at Screening (systolic blood pressure [SBP]
> 160 mm Hg or diastolic blood pressure [DBP] > 90 mm Hg) or any past history of hypertensive
crisis. An abnormal blood pressure value at screening may be repeated once after 10-15 minutes of
relaxation to determine the subject’s eligibility.
7.
Has an abnormal ECG of clinical relevance at screening or baseline (Day -1) including, but not
limited to, the following:
•
QT interval corrected according to Fridericia’s formula (QTcF) interval > 450 msec for male
subjects and >470 msec for female subjects.
•
Evidence of 2nd and 3rd degree atrioventricular block, complete left bundle branch block (LBBB),
or complete right bundle branch block (RBBB).
•
Features of new ischaemia.
•
Arrhythmia (except premature atrial contractions [PACs] and premature ventricular contractions
[PVCs]).
•
Has a history of risk factors including hypokalemia or a family history of Long QT Syndrome.
8.
Has known history of, or positive serology for, human immunodeficiency virus (HIV); has a positive
hepatitis B surface antigen, and/or confirmed current hepatitis C infection (positive hepatitis C virus
[HCV] antibody confirmed with reflex HCV ribonucleic acid [RNA] test). Subjects with a history of
hepatitis B vaccination without a history of hepatitis B are allowed to enroll.
9.
Has a history of malignancy within the 5 years prior to screening (exceptions are squamous and basal
cell carcinomas of the skin and carcinoma in situ of the cervix, or a malignancy that in the opinion of
the Investigator, with concurrence with the Sponsor's Medical Monitor, is considered to have minimal
risk of recurrence).
10. Has homicidal ideation/intent per the Investigator’s clinical judgment; or has suicidal ideation with
some intent to act within 1 month prior to the start of screening per the Investigator’s clinical
judgment or based on the C-SSRS, corresponding to a response of “Yes” on Item 4 (active suicidal
ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific
plan and intent); or a history of suicidal behavior within the past year prior to the start of the
screening/prospective observational phase.
11. Has had major surgery (eg, requiring general or local anesthesia) within the 4 weeks before screening,
or will not have fully recovered from surgery or planned surgery during the time the subject is
expected to participate in the study.
12. Has moderately impaired hepatic function at screening, defined as serum alanine aminotransferase
(ALT) or aspartate aminotransferase (AST) > 2 × upper limit of normal (ULN) or total bilirubin
(TBL) > 2 × ULN.
13. Has received any disallowed therapies as follows (see Section 6.5 for further details):


CONFIDENTIAL 
Protocol PCN-101-21 – Protocol Amendment 4, 19 May 2022 
PERCEPTION NEUROSCIENCE 
PROPRIETARY and CONFIDENTIAL 
 
13 
a. Receipt of a known potent inhibitor of hepatic cytochrome P450 (CYP) 2B6, or CYP3A, 
activity within 1 week or within a period 5 times the drug’s half-life, whichever is longer, 
before the first administration of study drug on Day 1.  
b. Treatment with a disallowed antipsychotic within the past 30 days prior to screening, 
except subjects who are on stable doses of quetiapine, aripiprazole, brexpiprazole, or 
olanzapine prescribed as adjunct treatment for depression (without psychosis) may be 
included in the study. 
c. Any changes in psychotropic medication type or dose within the past 30 days prior to 
screening. 
d. Treatment with monoamine oxidase inhibitors (MAOIs) currently or within the past 
30 days of screening. 
e. Doses of oral contraception should not contain more than 30 micrograms of ethinyl 
estradiol per day. 
f. Refer to Appendix 6 for a list of permitted and prohibited concomitant medications. The 
Medical Monitor should be contacted for any questions regarding concomitant 
medications. 
14. Has initiated psychotherapy (eg, Cognitive Behavior Therapy, Interpersonal Psychotherapy, 
Psychodynamic Psychotherapy other than psycho-education, or acupuncture within the past 90 days 
of screening. Patients planning to initiate individual or group therapy during the study are also not 
eligible. 
15. Has received electroconvulsive therapy, transcranial magnetic stimulation, vagal nerve stimulation, 
deep brain stimulation, or other brain stimulation treatment within the past 4 weeks or currently used 
as either an acute or maintenance treatment of depression. 
16. Has received any investigational product (IP) within 30 days or 5 half-lives prior to dosing with 
PCN-101. 
17. Has a history of substance abuse (drug or alcohol) or dependence (except nicotine or caffeine) within 
the previous 6 months prior to the screening visit.  
• 
Has a positive urine drug screen for ketamine, opiates, cocaine, barbiturates, and/or 
amphetamine/methamphetamine or positive alcohol screen at Screening or Day -1. 
• 
Subjects who have a positive test result at screening due to prescribed opiates or amphetamines 
may be permitted to continue the screening phase if the prohibited medication is discontinued at 
least 1 week or 5 half-lives, whichever is longer, before the first dose of study medication. 
Retesting is not permitted for positive test result(s) from nonprescription use of drugs of abuse. 
18. Has a history of previous nonresponse to ketamine, R-ketamine or S-ketamine, or has received 8 or 
more doses of ketamine, R-ketamine or S-ketamine in their lifetime. 
19. Has a previous history of intolerance to ketamine, R-ketamine, or S-ketamine. 
20. History of abuse of ketamine, R-ketamine, S-ketamine, or phencyclidine. 
21. Subjects should not consume grapefruit, grapefruit juice, or Seville orange -related products for 
72 hours before IP administration and throughout the study. 
22. Has the presence of clinically relevant long-term COVID-19 symptoms. Has current signs or 
symptoms of COVID-19.  
23. COVID-19 vaccination is allowed as long as the doses are administered ≥ 30 days before study drug 
administration; vaccination is not allowed during the course of the study. 




CONFIDENTIAL 
Protocol PCN-101-21 – Protocol Amendment 4, 19 May 2022 
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15 
Populations for Analysis 
Analysis Set 
Description 
Full Analysis Set (FAS) 
The FAS will consist of all randomized subjects who receive at least 1 dose of 
study treatment and have at least 1 postbaseline assessment available. This 
population will serve as the basis for efficacy analysis. Subjects will be 
analyzed according to their randomized treatment. 
Safety Analysis Set 
The Safety Population will consist of all randomized subjects who receive any 
study treatment, even a partial dose. This population will be used for all 
summaries of subject disposition, demographic and baseline data, and safety 
information including AE incidence. Subjects will be analyzed according to 
the treatment they actually received. 
Abbreviations: AE = adverse event; FAS = Full Analysis Set. 
Full details of the efficacy analyses and any further supplementary analyses deemed appropriate, along 
with details on handling of missing data will be provided in the SAP. 
 
Subject Disposition and Demographics 
Subject disposition events (screened, randomized, completed the study, early discontinuation from the 
study along with the reason for discontinuation) as well as the number of subjects in each analysis 
population will be summarized using frequency counts and percentages by treatment groups. 
Efficacy Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
• 
Change from baseline in MADRS 
total score assessed at 24 hours after 
the start of the infusion. 
The primary efficacy estimand will be evaluated in the FAS using a 
mixed effects model for repeated measure (MMRM) analysis with 
observed cases only. The MMRM model will include fixed effects for 
treatment, region, visit, study site and treatment by visit interaction, 
with subject as a random effect and baseline score as a covariate.  
From this analysis the least squares (LS) mean estimates for each 
treatment arm at each visit, along with the standard error and 95% 
confidence intervals (CIs) will be presented separately. The primary 
comparison for the MADRS is the estimate of the treatment 
difference at 24 hours after the start of the infusion. 
Secondary 
• 
Change from baseline in MADRS 
total score at 2 hours, 4 hours, 
7 days, and 14 days after the start of 
the infusion. 
• 
Proportion of subjects with ≥ 50% 
improvement in MADRS total score 
at 24 hours, 7 days, and 14 days 
after start of infusion. 
• 
Proportion of subjects with a 
MADRS total score ≤ 10 at 
24 hours, 7 days, and 14 days after 
start of infusion. 
• 
Changes in HAM‑D on Day 8 and 
Day 15 after start of infusion. 
Observed and change from baseline values in continuous secondary 
endpoints will be summarized descriptively by treatment group. 
Continuous secondary efficacy endpoints assessed at more than 
1 postbaseline visit will be analyzed using an MMRM analysis with 
observed cases only. The MMRM model will include factors for 
treatment, region, visit, study site, and treatment by visit as fixed 
effect; subjects as a random effect; and baseline score as a covariate. 
Categorical secondary endpoints will be summarized by frequency 
counts and percentages and analyzed by a chi-square test between 
each PCN-101 dose versus placebo. 
 


CONFIDENTIAL 
Protocol PCN-101-21 – Protocol Amendment 4, 19 May 2022 
PERCEPTION NEUROSCIENCE 
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16 
Endpoint 
Statistical Analysis Methods 
• 
Change from baseline in 
QIDS-SR-16 by visit. 
• 
Change from baseline in GAD-7 by 
visit. 
• 
Change from baseline in EQ-5D-3L 
by visit. 
• 
Change from baseline in CGI S by 
visit and CGI I (calculated from 
predose CGI S). 
 
Alternate sensitivity analyses will be detailed in the SAP. 
Abbreviations: CI = confidence interval; MMRM = mixed effects model for repeated measure; SAP = Statistical 
Analysis Plan. 
 
Safety Analysis 
All safety analyses will be performed on the Safety Analysis Set. 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA; 
Version 23.0 or higher). Treatment-emergent adverse events (TEAEs) are AEs with onset or worsening 
after the start of study treatment. The AE summaries will be primarily based on TEAEs. The number and 
percentage of subjects with TEAEs will be summarized by treatment group, system organ class, and 
preferred term for all TEAEs, treatment-related TEAEs, serious adverse events (SAEs), serious TEAEs, 
severe TEAEs, TEAEs of special interest, and all TEAEs leading to study drug discontinuation. All 
TEAEs will be further summarized by maximum severity and causality. The TEAEs of special interest 
will be identified in the SAP. 
All AEs will be presented in a by-subject listing. Serious AEs, severe AEs, and AEs leading to study 
discontinuation or death will be presented in separate listings. 
Clinical Laboratory Tests 
Laboratory data will be summarized using descriptive statistics for each parameter, including change from 
baseline at each assessment time by treatment group. Frequency tables or shift tables will be used to 
present the number and percentage of subjects with laboratory values within/outside reference ranges. All 
laboratory data will be present in the listings. A by-subject listing will also be provided for subjects with 
abnormal laboratory results. 
Electrocardiogram  
Descriptive statistics will be used to summarize the observed and change from baseline values of the 
following ECG parameters at each assessment time by treatment group: heart rate, PR interval, QRS 
interval, QT interval, and QTcF. All ECG data will be present in listings. 
Vital Signs  
Vital sign parameters including temperature, pulse/heart rate, respiratory rate, SpO2, and blood pressure 
will be summarized descriptively for both the observed and change from baseline values at each 
assessment time by treatment group. Frequency tabulations will be provided for abnormalities as 
applicable. 
Other Safety Questionnaires and Assessments 
All physical examination results will be listed by subject 


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Protocol PCN-101-21 – Protocol Amendment 4, 19 May 2022 
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17 
Prior and concomitant therapies will be summarized separately and tabulated for each treatment group 
using frequencies and percentages. Percentages will be based on the number of subjects in each treatment 
group. Prior and concomitant medications will be listed by subject. 
For the C-SSRS: suicidal ideation and behavior scores at each assessment time as well as the incidence 
rate of TEAEs will be summarized using frequency counts and percentages by treatment group. 
For the CADSS, BPRS+, 5D-ASC, and MOAA/S: Descriptive statistics of scores and their changes from 
baseline will be summarized at each assessment time by treatment group. 
Pregnancy test and urine drug and alcohol screen will be presented in by-subject listings. 
Other Analyses 
Exploratory analyses may be done if indicated. 
Missing Data 
In general, the missing data which is observed from this study will be assumed to be missing-at-random 
(MAR).  
Since subjects are hospitalized at the time of the primary endpoint, it is anticipated that missing data will 
be infrequent. No imputation will be applied to primary analysis. 
Further details on the handling of missing data will be provided in the SAP. 
  
Interim Analyses 
No interim analysis for efficacy is planned. 
Data Monitoring Committee: 
Because of the short timeframe of the study, there will not be a data monitoring committee. 
 
 




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19 
1.3 
Schedule of Activities 
Procedure 
Visit 1  
Screening  
Day -15 
to -2 
Visit 2 
Baseline  
Day -1 
Visit 2 
In-clinic Dosing 
Day 1 
Visit 2 
Discharge 
Day 2 
Visit 3 
Follow-up 
Day 8 
(±1 Day) 
Visit 4 
Follow-up 
Day 15 
(±1 Day)a 
After Start of Infusionb 
 
 
Predosec 
15 
minc 
40 min 
(EoI) b,c,d 
60 
minc 
2 
hrc 
4 
hrc 
6 
hrc 
24 hrc 
7 daysc 
14 daysc 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
Xe 
Xe 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
Height, weight, and BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
Serum pregnancy test 
(subject OCBP) 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (subject 
OCBP) 
 
X 
 
 
 
 
 
 
 
 
X 
X 
HIV, hepatitis B and C test 
X 
 
 
 
 
 
 
 
 
 
 
 
Laboratory assessmentsf 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
12-Lead ECGg 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
Vital signsh 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Pulse oximetry (SpO2) 
 
 
Continuous from predose to 4 hour postdose 
 
 
 
 
Urine drug/alcohol screeni 
X 
X 
 
 
 
 
 
 
 
 
 
 
Ketamine screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
AE review 
X 
X 
X 
X 
X 
X 


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Protocol PCN-101-21 – Protocol Amendment 4, 19 May 2022 
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Procedure 
Visit 1  
Screening  
Day -15 
to -2 
Visit 2 
Baseline  
Day -1 
Visit 2 
In-clinic Dosing 
Day 1 
Visit 2 
Discharge 
Day 2 
Visit 3 
Follow-up 
Day 8 
(±1 Day) 
Visit 4 
Follow-up 
Day 15 
(±1 Day)a 
After Start of Infusionb 
 
 
Predosec 
15 
minc 
40 min 
(EoI) b,c,d 
60 
minc 
2 
hrc 
4 
hrc 
6 
hrc 
24 hrc 
7 daysc 
14 daysc 
Scales and Questionnaires 
 
 
 
 
 
 
 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
 
 
 
 
 
 
MGH-ATRQ 
X 
 
 
 
 
 
 
 
 
 
 
 
HAM-Dj 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
MADRSj,k 
X 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
QIDS-SR-16 
 
 
X 
 
 
 
 
 
 
Xl 
X 
X 
CGI-Sj 
 
 
Xm 
 
 
 
 
 
 
X 
X 
X 
CGI-Ij 
 
 
 
 
 
 
 
 
 
X 
X 
X 
GAD-7j 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
EQ-5D-3Lj 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
MOAA/S 
 
 
X 
Every 20 min for first 2 hr 
X 
X 
 
 
 
CADSS 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
BPRS+ 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
5D-ASC 
 
 
 
 
 
 
 
 
X 
 
 
 
C-SSRSn 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 


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Procedure 
Visit 1  
Screening  
Day -15 
to -2 
Visit 2 
Baseline  
Day -1 
Visit 2 
In-clinic Dosing 
Day 1 
Visit 2 
Discharge 
Day 2 
Visit 3 
Follow-up 
Day 8 
(±1 Day) 
Visit 4 
Follow-up 
Day 15 
(±1 Day)a 
After Start of Infusionb 
 
 
Predosec 
15 
minc 
40 min 
(EoI) b,c,d 
60 
minc 
2 
hrc 
4 
hrc 
6 
hrc 
24 hrc 
7 daysc 
14 daysc 
Study Administration 
 
 
 
 
 
 
 
 
 
 
 
 
Admission 
 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
Treatment Administration 
 
 
 
40 min 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; BMI = body mass index; BPRS+ = Brief Psychiatric Rating Scale - Modified 4 Components; 
CADSS = Clinician-Administered Dissociative States Scale; CGI-I = Clinical Global Impression - Improvement; CGI-S = Clinical Global Impression - 
Severity; C-SSRS = Columbia Suicide Severity Rating Scale; CRF = case report form; DBP = diastolic blood pressure; 5D-ASC = 5-Dimensional Altered 
States of Consciousness Rating Scale; ECG = electrocardiogram; EQ-5D-3L = European Quality - 5 Dimensions - 3 Levels; EoI = End of Infusion; GAD-
7 = Generalized Anxiety Disorder 7-Item Scale; HAM-D = Hamilton Depression Rating Scale; HIV = human immunodeficiency virus; 
MADRS = Montgomery Åsberg Depression Rating Scale; MGH-ATRQ = Massachusetts General Hospital Antidepressant Response Questionnaire; 
MINI = Mini-International Neuropsychiatric Interview; MOAA/S = Modified Observer’s Assessment of Alertness/Sedation; OCBP = of childbearing 
potential; PK = pharmacokinetic; QIDS-SR-14 = Quick Inventory of Depressive Symptomatology – 14 Items; QIDS-SR-16 = Quick Inventory of Depressive 
Symptomatology – 16 Items; SBP = systolic blood pressure. 
a. Subjects who discontinue the study early will complete Visit 4 assessments and procedures as early termination procedures. 
b. All post-dose timepoints are relative to the start of infusion except for the 40-minute (EoI) timepoint. EoI procedures should occur 40 minutes after the start of 
infusion or at the end of infusion if the infusion continues beyond 40 minutes. 
c. Where activities at a given timepoint coincide, consideration should be given to ensure that the following order of activities is maintained: Efficacy rating 
scales (where more than one efficacy scale is assessed at a timepoint, the order of assessments should be MADRS, CGI-I and CGI-S, QIDS-SR-14/16, 
HAM-D, GAD-7 and EQ5D-3L); 12-lead ECGs; vital signs and pulse oximetry; safety rating scales (order: MOAA/S, CADSS and BPRS+); AE review, 
concomitant medication review, physical exam, and clinical laboratory assessment (including urine pregnancy test and drug/alcohol screen).  
d. Assessments and procedures should be started as close as possible after the EoI. 
e. Check eligibility. 
f. Assess clinical hematology and chemistry tests (non-fasting blood samples will be requested, but both fasting and non-fasting samples are acceptable). 
g. To be collected prior to clinical laboratory assessments. An ECG will be performed after 5 minutes in a supine position, if possible. 


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22 
h. To be collected prior to clinical laboratory assessments. Vital signs will include SBP/DBP, heart rate, respiratory rate, and temperature (tympanic/temporal). 
Blood pressure and pulse measurements should be taken after the subject has been in a supine or semi-supine position in a rested and calm state for at least 
5 minutes. Blood pressure must be recorded using the same arm and position (supine or semi-supine) throughout the study, where possible. Three consecutive 
blood pressure readings will be recorded at intervals of at least 1 minute and the average of the 3 blood pressure readings will be recorded in the CRF. An 
abnormal blood pressure value at screening may be repeated once after 10-15 minutes of relaxation to determine the subject’s eligibility. 
i. Urine drug screen will be conducted by a local laboratory and include alcohol, ketamine, opiates, cocaine, barbiturates, and/or 
amphetamine/methamphetamine. Benzodiazepines are allowed up to 6 hours before the start of the infusion, and if needed as rescue medication. 
j. The HAM-D, MADRS, CGI-S, CGI-I, GAD-7, and EQ-5D-3L should be evaluated by a separate Investigator who is not involved with the assessment of 
safety to avoid functional unblinding.  
k. There are 3 versions of MADRS: 7-day recall, 24-hour recall, and 2-hour recall. For the 2 hour and 4 hour periods, the sleep and appetite items will not be 
assessed; predose scores for these items obtained on the same day will be carried forward. 
l. The QIDS-SR-14, with a 24 hour recall period, will be used on Visit 2 Day 2 assessment due to recall period. 
m. Note: The predose CGI-S will be used as the basis for calculating the CGI-I at Visit 2.  
n. Note: C-SSRS may be evaluated by either efficacy or safety rater. 


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2.0 INTRODUCTION 
As a racemate, ketamine consists of the 2 stereoisomers of R-ketamine and S-ketamine in equal 
proportions. Ketamine is a parenterally administered anesthetic agent that was initially approved 
in the United States (US) in 1970. Since then, it has seen wide use in both adult and pediatric 
populations. S-ketamine was approved in the US and later approved in the European Union (EU) 
in 2019 as the isolated stereoisomer in an intranasal formulation (Spravato™) for the treatment 
of treatment-resistant depression (TRD) in adults. However, this product has shown to have a 
limited therapeutic index, particularly with respect to dissociative side effects including illusions, 
distortions of time and space, derealization, and depersonalization. Further, in a human abuse 
potential study, the scores for “Drug Liking at the Moment” and “Take Drug Again” were 
similar to racemic ketamine, a known drug of abuse, and greater than placebo at both the 
maximum indicated antidepressant dose and 1.3 times this dose (1). Based in part upon these 
findings, the administration of Spravato is limited to the clinic and under the observation of 
medical personnel. 
Perception Neuroscience, Inc. (hereafter referred to as Perception Neuroscience or the Sponsor), 
is developing PCN-101 (R-ketamine) for at-home treatment of TRD. Nonclinical studies suggest 
that R-ketamine could cause less dissociative and psychotomimetic effects at therapeutic doses 
and have a lower potential for misuse compared with S-ketamine or racemic ketamine (2, 3, 4, 5, 
6, 7, 8, 9, 10). 
Both R-ketamine and S-ketamine (and by extension, racemic ketamine) share complex 
pharmacology with receptor-binding studies revealing significant affinity at several receptors and 
ion channels, eg, glutamatergic, cholinergic, sigma, opioid, and hyperpolarization-activated 
cyclic nucleotide-gated channels. R-ketamine and S-ketamine are primarily regarded as 
N-methyl-D-aspartate (NMDA) receptor non-competitive antagonists, with S-ketamine having 
approximately 4 times the binding affinity for the phencyclidine site of this receptor than R-
ketamine. Such pharmacological activity is thought to be the primary driver of the adverse 
psychotomimetic properties seen with ketamine, and S-ketamine is suggested to mainly cause 
these effects. However, data suggest that such NMDA receptor activity is not the only driver of 
antidepressant efficacy. Indeed, nonclinical depression model studies of subanesthetic doses 
(10 mg/kg) in rodents suggest R-ketamine possesses longer acting and more potent effects than 
S-ketamine despite R-ketamine’s lower affinity to the NMDA receptor (2, 3, 5, 7, 9, 11, 12, 13, 
14, 15, 16, 17, 18). Moreover, at doses that had effects in depression models in rodents 
(20 mg/kg), R-ketamine did not cause conditioned place preference (2, 7), a nonclinical test that 
is thought to suggest a clinical risk of substance abuse. However, it should be noted that at a high 
dose (40 mg/kg), R-ketamine did cause conditioned place preference in rodents (19). 


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Overall, the available data support the use of PCN-101 as a potentially better tolerated, 
rapid-acting antidepressant compared with ketamine and S-ketamine, which may support the use 
of PCN-101 outside of a supervised, in-clinic environment. 
2.1 
Study Rationale 
Perception Neuroscience is developing PCN-101 (R-ketamine) for at -home treatment of TRD. 
Evidence from nonclinical depression model studies suggests that R-ketamine may have equal or 
potentially greater efficacy compared with S-ketamine, and both nonclinical and clinical studies 
suggest that R-ketamine may have a more favorable safety profile with a decreased incidence of 
adverse events (AEs) (eg, dissociative, cognitive impairment, and psychotomimetic effects) 
compared with S-ketamine. Based on nonclinical studies, R-ketamine may also have less abuse 
potential than S-ketamine. Overall, the available data support the concept of the use of PCN-101 
as a potentially better tolerated, rapidly acting antidepressant compared with ketamine and 
S-ketamine. Protocol PCN-101-21 is a proof-of-concept study to assess efficacy and safety to 
provide evidence that PCN-101 can be developed as a rapidly acting antidepressant for the 
potential treatment of TRD. 
2.2 
Background 
Although racemic ketamine has been extensively used for almost 50 years as an approved 
parenteral anesthetic worldwide, it has not been approved for the indication of TRD because of 
concerns over potential AEs related to repeated dosing, abuse liability, and its intravenous (IV) 
route of administration. S-ketamine, the isolated (S)-enantiomer of racemic ketamine, was 
approved in the US and later approved in the EU in 2019 in an intranasal formulation for the 
treatment of TRD in adults, but the therapeutic index of this product is limited by dissociative 
side effects including illusions, distortions of time and space, derealization, and 
depersonalization limiting it use to the clinic setting. In addition, the potential abuse profile has 
been demonstrated to be similar to that of racemic ketamine. Thus, the search for novel 
ketamine-like agents has been driven by the goal to reduce the side effects seen with ketamine 
and S-ketamine while providing antidepressant efficacy and a convenient route of administration 
to permit the use outside of a supervised clinical setting. 
Perception Neuroscience plans to develop PCN-101 for the treatment of psychiatric conditions. 
The doses of 30 mg and 60 mg to be used in this study were selected based on the results from a 
Phase 1 single-ascending-dose study in healthy volunteers. A detailed description of the 
chemistry, pharmacology, efficacy, and safety of PCN-101 is provided in the current 
Investigator’s Brochure. 
 


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2.3 
Benefit/Risk Assessment 
Due to its 4-fold lower affinity to the receptor, it is hypothesized that R-ketamine may have 
fewer N-methyl-D-aspartate receptor (NMDAR)-related adverse effects compared with racemic 
ketamine or S-ketamine, such as psychotomimetic effects and dissociation. 
 
 
 It has been 
suggested that this action of R-ketamine may play a role in the hallucinogenic effects of racemic 
ketamine and that it may be responsible for the lowering of the seizure threshold seen with 
racemic ketamine. 
Reported AEs from limited academic clinical studies in healthy volunteers evaluating 
R-ketamine subanesthetic doses of up to 1 mg/kg IV as bolus or short infusion or 1.8 mg/kg 
intramuscular included transient increases in blood pressure, emotional changes, illusion, 
sedation, proprioceptive and sensory disturbances, decline in concentration capacity and primary 
memory, blurred vision, altered hearing, and dizziness. Overall, less pronounced 
psychotomimetic and dissociative-like effects were reported with R-ketamine than with 
S-ketamine (20, 21, 22, 23, 24, 25). Results from an open-label pilot study of a single IV 
infusion of R-ketamine (0.5 mg/kg) administered to 7 subjects with TRD suggested that R-
ketamine might produce fast-onset and sustained antidepressant effects with a favorable safety 
profile (35). 
To date, there has been 1 clinical trial that evaluated the safety of PCN-101. The primary 
objective of study PCN-101-02 was to identify an acceptable tolerated dose of PCN-101 in 
healthy subjects and compare this dose to the safety profile of 15 mg S-ketamine, a dose which 
demonstrated a robust antidepressant effect in a published study of TRD patients (36). Dose 
ranging using single ascending doses of PCN-101-02 demonstrated that doses of 
PCN-101 ≤ 150 mg had acceptable safety profiles as single 40-minute IV infusions. A 
comparison of the safety of dose levels of PCN-101 and 15 mg S-ketamine identified 60 mg 
PCN-101 as the dose level most similar to 15 mg S-ketamine in terms of safety profile. Both 
30 mg and 60 mg doses of PCN-101 resulted in fewer transient elevations in mean systemic 
blood pressure, less sedation, fewer psychological or psychotic and dissociative effects, and 
fewer episodes of altered consciousness than 100 mg or 150 mg doses of PCN-101.  
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PCN-101 may be found in the current Investigator’s Brochure. 
There are no identified serious adverse reactions that are considered expected for the purpose of 
expedited regulatory reporting. 


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2.3.1 
Drug Abuse and Dependence 
Ketamine has been reported being used as a drug of abuse. Ketamine dependence and tolerance 
are possible following prolonged administration. Although R-ketamine may have a potential for 
abuse, nonclinical data suggest a lower abuse potential for R-ketamine than that for racemic 
ketamine or S-ketamine due to its pharmacological properties, such as lesser affinity to NMDAR 
and a lack of effects on the dopamine pathway (4, 30, 31, 32). The abuse and dependence 
potential of PCN-101 in humans is unknown and has not yet been studied. 
2.3.2 
Drug-Drug Interactions 
Multiple in vitro studies examining the in vitro drug metabolism and pharmacokinetics of  
PCN-101 have been conducted. For more information, refer to the Investigator’s Brochure. 
 
 
There is a potential for drug-drug interactions with CYP2B6 and CYP3A4 substrates. The 
clinical impact of these DDI’s is thought to be minimal.  
Clinical drug-drug interaction studies have not been performed with PCN-101 to date. 
Concomitant medications should be avoided except for those specifically allowed (see 
Section 6.5). 
2.3.3 
Overdose 
There is no specific antidote for PCN-101 overdose. 




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Objectives 
Estimands 
 
 
 
• 
To assess the proportion of subjects with remission 
(defined as MADRS total score ≤ 10). 
 
• 
To define changes in Hamilton Depression Rating 
Scale (HAM-D). 
• 
Generalized Anxiety Disorder 7-Item (GAD-7). 
• 
Clinical Global Impression - Severity (CGI-S) and 
Clinical Global Impression - Improvement 
(CGI-I). 
• 
Quick Inventory of Depressive Symptomatology - 
16 Items (QIDS-SR-16). 
• 
European Quality - 5 Dimensions - 3 Levels 
(EQ-5D-3L). 
• 
To determine the safety and tolerability of 2 doses 
of PCN-101 administered IV in subjects with TRD 
compared with placebo. 
 
 
 
 
 
 
 
 
 
 
 
 
 
days after start of infusion (Days 8 and 15, 
respectively). 
• 
Proportion of subjects with a MADRS total score 
≤ 10 at 24 hours, 7 days, and 14 days after start of 
infusion (Days 8 and 15, respectively). 
• 
Changes in HAM-D on Day 8 and Day 15 after 
start of infusion. 
• 
Change from baseline in GAD-7 by visit. 
• 
Change from baseline in CGI-S by visit and CGI-I 
(calculated from predose CGI-S). 
• 
Change from baseline in QIDS-SR-16 by visit. 
• 
Change from baseline in EQ-5D-3L by visit. 
 
• 
Safety as assessed by: 
o 
Vital signs 
o 
12-lead electrocardiogram (ECG) 
o 
Oxygen saturation (SpO2) 
o 
Clinical laboratory parameters 
o 
AEs 
o 
Modified Observer’s Assessment of 
Alertness/Sedation (MOAA/S) 
o 
Clinician-Administered Dissociative States 
Scale (CADSS) 
o 
Brief Psychiatric Rating Scale - Modified 
4 Components (BPRS+) 
o 
5-Dimensional Altered States of 
Consciousness Rating Scale (5D-ASC) 
o 
Columbia Suicide Severity Rating Scale 
(C-SSRS). 
Abbreviations: 5D-ASC = 5-Dimensional Altered States of Consciousness Rating Scale; AE = Adverse event; 
BPRS+ = Brief Psychiatric Rating Scale - Modified 4 Components; CADSS = Clinician-Administered 
Dissociative States Scale; CGI-I = Clinical Global Impression - Improvement; CGI-S = Clinical Global 
Impression - Severity; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; 
EQ-5D-3L = European Quality - 5 Dimensions - 3 Levels; FAS = full analysis set; GAD-7 = Generalized 
Anxiety Disorder 7-Item; HAM-D = Hamilton Depression Rating Scale; ICE = intercurrent event; 
IV = intravenous; MADRS = Montgomery Åsberg Depression Rating Scale; MOAA/S = Modified Observer’s 
Assessment of Alertness/Sedation; QIDS-SR-16 = Quick Inventory of Depressive Symptomatology - 16 
Items; SAP = Statistical Analysis Plan; SpO2 = oxygen saturation; TRD = treatment-resistant depression. 


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4.0 STUDY DESIGN 
4.1 
Overall Design 
This is a double-blind, randomized, placebo-controlled, multicenter study comprised of 3 phases: 
screening (up to 2 weeks [Day -15 to Day -2]), In-Clinic Treatment (Day -1 to Day 2; including 
double-blind treatment [Day 1]), and post-treatment follow-up (7 and 14 days after infusion, on 
Days 8 and 15, respectively). The study consists of 3 arms: placebo, PCN-101 Solution for 
Injection 30 mg, and PCN-101 Solution for Injection 60 mg. A total of 93 adult subjects with 
TRD will be randomly allocated in equal cohorts of 31 subjects/arm to the 3 arms of the study in 
a blinded manner. Randomization will be stratified by region (US, EU).  
 
Subjects will be randomized within 14 days of screening (Visit 1). Subjects will be admitted to 
the clinic the evening prior to study treatment administration (Day -1, Visit 2) and undergo 
baseline testing to ensure continued study eligibility. Study treatments will be infused IV over 
40 minutes the next morning (Day 1, Visit 2). Starting immediately prior to dosing, subjects will 
be monitored closely for safety. Additionally, the subjects’ alertness, mood, and other 
psychological parameters will be assessed by clinician- and patient-completed scales and 
questionnaires. Subjects will be discharged no earlier than 24 hours postinfusion and after the 
final in-clinic assessments have been completed (Day 2, Visit 2). Subjects will be asked to return 
to the clinic approximately 6 days (Day 8, Visit 3) and 13 days (Day 15, Visit 4) after discharge 
to assess the safety and tolerability of the study treatments and to determine the durability of the 
antidepressant effect. 
During the coronavirus disease 2019 (COVID-19) pandemic, the specific guidance from local 
public health and other competent authorities regarding the protection of individuals’ welfare 
must be applied. If subjects cannot attend follow up visits in person because of restrictions 
arising as a consequence of the COVID-19 pandemic, the Investigator must discuss with the 
Medical Monitor potential mitigation. 
4.2 
Scientific Rationale for Study Design 
The study population will include adult men and women, ages 18 to 65 years inclusive, who 
meet the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) 
diagnostic criteria for major depressive disorder (MDD) without psychotic features confirmed by 
the Mini-International Neuropsychiatric Interview (MINI). Based on published data from 
racemic ketamine, R-ketamine may have the potential for adverse fetal effects if administered to 
pregnant women. Therefore, female subjects of childbearing potential should be adequately 
protected from becoming pregnant and pregnant women should not be enrolled in clinical studies 
with PCN-101. 


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Two doses (30 mg and 60 mg) of IV PCN-101 will be compared with placebo to determine the 
most effective dose in improving depressive symptoms in subjects with TRD.  
Randomization will be used to minimize the bias in the assignment of subjects to treatment arms 
and to increase the likelihood that known and unknown subject characteristics are evenly 
balanced across treatment arms. This will improve the validity of the statistical comparisons 
among treatment arms. Blinded treatment will be used to reduce any potential bias during the 
collection of data and the analysis of clinical endpoints. 
PCN-101 30 mg and 60 mg will be administered as an IV infusion over 40 minutes. These doses 
are within the range shown to be well-tolerated in a Phase 1 study in healthy volunteers. 
The World Health Organization reports that depression is the leading cause of disability and loss 
of work worldwide, affecting more than 300 million people (26). In severe cases, it can lead to 
suicide, which has become the third leading cause of death in the US with its incidence having 
increased 30% over the past 10 years (27, 28). The prevalence of TRD, generally defined as 
treatment failure with adequate trials of at least 2 antidepressant regimens, remains very high. A 
multicenter European study found that 51% of depressed patients recruited from specialist 
referral centers met such criteria (29). In addition, much of the cost and disability associated with 
depression is accounted for by TRD (30). Finally, it should be noted that many patients with 
MDD continue to have residual symptoms even without meeting the formal diagnosis of TRD, 
thus adding to the unmet burden. 
Primary and secondary endpoints for this study will be to determine the efficacy of 2 doses of IV 
PCN-101 compared with placebo in improving depressive symptoms in subjects with TRD as 
assessed by change from baseline in the MADRS total score. The 10-item clinician-administered 
MADRS was designed to be used in subjects with MDD to measure the overall severity of 
depressive symptoms. The MADRS scale is validated, reliable, and acceptable to regulatory 
health authorities as a primary scale to determine efficacy in major depression. 
Other secondary endpoints for this study will include scales such as: 
• The HAM-D is a multiple-item questionnaire designed to provide an indication of 
depression in adults and used as a guide to evaluate recovery. The questionnaire is 
designed to rate the severity of depression by probing mood, feelings of guilt, suicide 
ideation, insomnia, agitation or retardation, anxiety, weight loss, and somatic symptoms. 
• The QIDS-SR-16, which is a 16-item, self-reported scale of depression that has very 
similar sensitivity to the Inventory of Depressive Symptomatology Self-Report - 30 Items 
and the Hamilton Rating Scale for Depression - 24 Items in detecting changes in 
symptoms of depression. 


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• The GAD-7, which is a self-administered 7-item scale that is used to diagnose anxiety 
and has sensitivity and specificity as a screener for panic, social anxiety, and 
posttraumatic stress disorder. 
• The CGI-S and CGI-I scales, which will allow the assessment of minimal clinically 
important differences using an anchor-based approach calculated from the global 
impressions of the clinician and the subject. 
• The EQ-5D-3L, which will be used by subjects as a widely accepted, self-completion 
instrument to assess health-related quality of life for the domains of mobility, capacity for 
self-care, conduct of usual activities, pain/discomfort, and anxiety/depression. 
Safety evaluations will include: 
• Standard assessments of vital signs, 12-lead ECG, SpO2, clinical hematology and 
chemistry assays, treatment-emergent adverse events (TEAEs), prior and concomitant 
medications, physical examination, height, weight, body mass index (BMI), serum and 
urine pregnancy tests, and urine drug and alcohol screens. 
• The MOAA/S, which will be used to determine if PCN-101 causes the side effect of 
sedation and to what degree. 
• The CADSS, which will be used to assess the alertness or dissociative state of subjects 
administered PCN-101. 
• The BPRS+, which is one of the oldest, most widely used rating scales to measure 
psychotic symptoms and will be used by the study staff to measure psychiatric symptoms 
such as depression, anxiety, hallucinations and unusual behavior. 
• The 5D-ASC, which will be used to assess the quality of acute psychological effects of 
the PCN-101 infusion. 
• The C-SSRS, which will be used to assess the emergence of suicidal ideation. This 
instrument has been used frequently in clinical studies, and it is a standard measure for 
suicidal ideation assessment; its use is in accordance with US Food and Drug 
Administration guidance. 
4.3 
Justification for Dose 
Study PCN-101-02 was a randomized, placebo-controlled, double-blind, single ascending dose 
study of the safety, tolerability, and pharmacokinetics of PCN-101 that included a relative safety 
comparison of PCN-101 and S-ketamine. Healthy subjects were administered a single IV 
infusion of PCN-101 at total doses of 5, 15, 30, 60, 100, and 150 mg or placebo over a 40-minute 
period. The safety and tolerability of PCN-101 at different doses and of 15 mg S-ketamine was 
assessed using reported AEs, changes in hematology and serum chemistry, changes in vital signs 


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and physical examination findings, ECG and pulse oximetry findings, sedation (as measured by 
the MOAA/S), and the development of dissociative or perceptual changes (as measured by the 
CADSS, BPRS, and 5D-ASC).  
The study evaluated 58 healthy subjects. Forty-eight (48) subjects were randomized to 6 dose 
levels of PCN-101 (N=36) or placebo (N=12) in the single-ascending dose portion of the study. 
Ten additional subjects were evaluated in a parallel and cross-over relative safety comparison of 
150 mg PCN-101 (N=10) and 15 mg S-ketamine (N=10). 
The primary objective was to identify an acceptable tolerated dose of PCN-101 and compare this 
dose to the safety profile of 15 mg S-ketamine. Dose ranging using single ascending doses of 
PCN-101-02 demonstrated that doses of PCN-101 ≤ 150 mg had acceptable safety profiles as 
single IV infusions. 
 
 
Both 30 mg and 60 mg doses of PCN-101 resulted 
in fewer transient elevations in mean systemic blood pressure, less sedation, fewer psychological 
or psychotic and dissociative effects, and fewer episodes of altered consciousness than 100 mg or 
150 mg doses of PCN-101. 
Based on the results of study PCN-101-02, 30 mg and 60 mg of PCN-101 were selected to be 
evaluated in this proof-of-concept study. 
4.4 
End of Study Definition 
The duration of the study will be up to 29 days per subject, which includes a screening period, a 
3-day in-clinic visit, and 2 follow-up visits. A subject will be considered to have completed the 
study if he/she has completed all phases of the study including the last visit. 
The end of the study is defined as the date of the last visit of the last subject in the study. 


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5.0 STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
1. Be capable of giving and give signed informed consent, which includes compliance with 
the requirements and restrictions listed in the Informed Consent Form (ICF) and in this 
protocol. 
2. Be male or female 18 to 65 years of age inclusive at the time of signing the ICF. 
3. Weigh ≥ 50 kg and have a BMI ≥ 18 and ≤ 35. 
4. Have a diagnosis of recurrent MDD without psychotic features per the DSM-V, 
confirmed by the MINI. 
5. Have an HAM-D total score > 20 at screening and baseline (Day -1). 
6. Have an inadequate response to at least 2 antidepressants in the current episode of 
depression that were each given for ≥ 6 weeks at an adequate dose as defined by the 
Massachusetts General Hospital Antidepressant Response Questionnaire (MGH-ATRQ). 
7. Must be on stable oral antidepressant treatment without a dose change for at least 30 days 
before screening (a missed dose, or reasonable number of missed doses per Investigator’s 
discretion, in that period does not exclude a subject). 
8. A male subject must be medically confirmed sterile for at least 6 months prior to 
screening or agree to use highly effective contraception (see Appendix 5) during the 
treatment period and for at least 3 months after the last dose of study treatment and 
refrain from donating sperm during this period. If a male with a partner who is of 
childbearing potential (OCBP) is included, his partner also needs to use highly effective 
birth control measures. 
9. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at 
least 1 of the following conditions applies: 
• Not of childbearing potential (see Appendix 5). 
• A subject OCBP who agrees to follow the highly effective contraceptive guidance 
(see Appendix 5) on highly effective birth control measures during the treatment 
period and for at least 3 months after the last dose of study treatment and refrain from 
donating eggs during this period. 


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10. Be medically stable on the basis of physical examination, medical history, vital signs, and 
12-lead ECG performed at screening. If there are abnormalities, the subject may be 
included only if the Investigator judges the abnormalities not to be clinically important. 
This determination must be recorded in the subject's source documents and initialed and 
dated by the Investigator. 
5.2 
Exclusion Criteria  
Subjects are excluded from the study if any of the following criteria apply: 
1. History of, or current signs and symptoms of, diseases or conditions that would make 
participation not be in the best interest (eg, compromise the well-being) of the subject or 
that could prevent, limit, or confound the protocol-specified assessments. 
2. History of moderate or severe head trauma (for example, loss of consciousness for more 
than 15 minutes) or other neurological disorders (including a diagnosis of epilepsy or has 
had a seizure in the last 6 months), neurodegenerative disorder (Alzheimer’s disease, 
Parkinson’s disease, multiple sclerosis, Huntington’s disease, etc.) or systemic medical 
diseases that are, in the opinion of the Investigator, likely to interfere with the conduct of 
the study or confound the study assessments. A history of febrile seizures in childhood is 
not exclusionary. 
3. Has a primary DSM-V diagnosis of current (active) MDD with psychotic features, panic 
disorder, obsessive compulsive disorder, posttraumatic stress disorder, anorexia nervosa, 
or bulimia nervosa. Comorbid anxiety or panic disorder that does not dominate the 
clinical presentation is acceptable. 
4. Has a current or prior DSM-V diagnosis of a primary psychotic disorder (eg, 
schizophrenia), bipolar or related disorders (confirmed by the MINI), intellectual or 
autism spectrum disorder, or borderline personality disorder. 
5. Has any significant disease or disorder (eg, cardiovascular, pulmonary, gastrointestinal, 
hepatic, renal, neurological, musculoskeletal, endocrine, metabolic, malignant, 
psychiatric, major physical impairment) that, in the opinion of the Investigator, may 
either put the subject at risk because of participation in the study, influence the results of 
the study, or affect the subject’s ability to participate in the study. 
6. Has uncontrolled hypertension, despite medication, at Screening (systolic blood pressure 
[SBP] > 160 mm Hg or diastolic blood pressure [DBP] > 90 mm Hg) or any past history 
of hypertensive crisis. An abnormal blood pressure value at screening may be repeated 
once after 10-15 minutes of relaxation to determine the subject’s eligibility. 
7. Has an abnormal ECG of clinical relevance at screening or baseline (Day -1) including, 
but not limited to, the following: 


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•
QT interval corrected according to Fridericia’s formula (QTcF) interval > 450 msec
for male subjects and >470 msec for female subjects.
•
Evidence of 2nd and 3rd degree atrioventricular block, complete left bundle branch
block (LBBB), or complete right bundle branch block (RBBB).
•
Features of new ischaemia.
•
Arrhythmia (except premature atrial contractions [PACs] and premature ventricular
contractions [PVCs]).
•
Has a history of risk factors including hypokalemia or a family history of Long QT
Syndrome.
8. Has known history of, or positive serology for, human immunodeficiency virus (HIV);
has a positive hepatitis B surface antigen, and/or confirmed current hepatitis C infection
(positive hepatitis C virus [HCV] antibody confirmed with reflex HCV ribonucleic acid
[RNA] test). Subjects with a history of hepatitis B vaccination without a history of
hepatitis B are allowed to enroll.
9. Has a history of malignancy within the 5 years prior to screening (exceptions are
squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or a
malignancy that in the opinion of the Investigator, with concurrence with the Sponsor's
Medical Monitor, is considered to have minimal risk of recurrence).
10. Has homicidal ideation/intent per the Investigator’s clinical judgment; or has suicidal
ideation with some intent to act within 1 month prior to the start of screening per the
Investigator’s clinical judgment or based on the C-SSRS, corresponding to a response of
“Yes” on Item 4 (active suicidal ideation with some intent to act, without specific plan) or
Item 5 (active suicidal ideation with specific plan and intent); or a history of suicidal
behavior within the past year prior to the start of the screening/prospective observational
phase.
11. Has had major surgery (eg, requiring general or local anesthesia) within the 4 weeks
before screening, or will not have fully recovered from surgery or planned surgery during
the time the subject is expected to participate in the study.
12. Has moderately impaired hepatic function at screening, defined as serum alanine
aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 × upper limit of normal
(ULN) or total bilirubin (TBL) > 2 × ULN.
13. Has received any disallowed therapies as follows (see Section 6.5 for further details):


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a.  Receipt of a known potent inhibitor of hepatic cytochrome P450 (CYP) 2B6, or 
CYP3A, activity within 1 week or within a period 5 times the drug’s half-life, 
whichever is longer, before the first administration of study drug on Day 1.  
b. Treatment with a disallowed antipsychotic within the past 30 days prior to 
screening, except subjects who are on stable doses of quetiapine, aripiprazole, 
brexpiprazole, or olanzapine prescribed as adjunct treatment for depression 
(without psychosis) may be included in the study. 
c. Any changes in psychotropic medication type or dose within the past 30 days 
prior to screening. 
d. Treatment with monoamine oxidase inhibitors (MAOIs) currently or within the 
past 30 days of screening. 
e. Doses of oral contraception should not contain more than 30 micrograms of 
ethinyl estradiol per day. 
f. Refer to Appendix 6 for a list of permitted and prohibited concomitant 
medications. The Medical Monitor should be contacted for any questions 
regarding concomitant medications. 
14. Has initiated psychotherapy (eg, Cognitive Behavior Therapy, Interpersonal 
Psychotherapy, Psychodynamic Psychotherapy other than psycho-education, or 
acupuncture within the past 90 days of screening. Patients planning to initiate individual 
or group therapy during the study are also not eligible. 
15. Has received electroconvulsive therapy, transcranial magnetic stimulation, vagal nerve 
stimulation, deep brain stimulation, or other brain stimulation treatment within the past 4 
weeks or currently used as either an acute or maintenance treatment of depression. 
16. Has received any IP within 30 days or 5 half-lives prior to dosing with PCN-101. 
17. Has a history of substance abuse (drug or alcohol) or dependence (except nicotine or 
caffeine) within the previous 6 months prior to the screening visit. 
• Has a positive urine drug screen for ketamine, opiates, cocaine, barbiturates, and/or 
amphetamine/methamphetamine or positive alcohol screen at Screening or Day -1. 
• Subjects who have a positive test result at screening due to prescribed opiates or 
amphetamines may be permitted to continue the screening phase if the prohibited 
medication is discontinued at least 1 week or 5 half-lives, whichever is longer, before 
the first dose of study medication. Retesting is not permitted for positive test result(s) 
from nonprescription use of drugs of abuse. 


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18. Has a history of previous nonresponse to ketamine, R-ketamine or S-ketamine, or has 
received 8 or more doses of ketamine, R-ketamine or S-ketamine in their lifetime. 
19. Has a previous history of intolerance to ketamine, R-ketamine, or S-ketamine. 
20. History of abuse of ketamine, R-ketamine, S-ketamine, or phencyclidine. 
21. Subjects should not consume grapefruit, grapefruit juice, or Seville orange related 
products for 72 hours before IP administration and throughout the study. 
22. Has the presence of clinically relevant long-term COVID-19 symptoms. Has current 
signs or symptoms of COVID-19.  
23. COVID-19 vaccination is allowed as long as the doses are administered ≥ 30 days before 
study drug administration; vaccination is not allowed during the course of the study. 
5.3 
Lifestyle Considerations 
No restrictions are required for this study. 
5.3.1 
Meals and Dietary Restrictions 
Subjects should not consume grapefruit, grapefruit juice, or Seville orange-related products for 
72 hours before PCN-101 administration and throughout the study. 
5.3.2 
Caffeine, Alcohol, and Tobacco 
Subjects will abstain from alcohol for 24 hours prior to the start of the infusion of PCN-101 until 
24 hours after dosing has been completed on Day 1. It is recommended that subjects abstain from 
alcohol use for the period of the study.  
Subjects will abstain from using tobacco and nicotine products (except nicotine replacement 
therapies) for 4 hours prior to the start of the infusion of PCN-101 until 4 hours after dosing has 
been completed on Day 1. 
5.3.3 
Activity 
Subjects will abstain from strenuous exercise while in the clinic. Subjects may participate in light 
recreational activities during studies (eg, watching television, reading). 
5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure subjects to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 


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and any serious adverse event (SAE). Screen failure and rescreening information will be entered 
into the study’s Electronic Data Capture System (EDC). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once per the Investigator’s judgement. However, subjects may not be rescreened if 
they did not meet diagnostic criteria, HAM-D minimum score, or had a positive test result(s) 
from nonprescription drugs of abuse on the first screening. Rescreened subjects should not be 
assigned the same subject number as for the initial screening. Rescreened subjects must first be 
registered as screen failures and subsequently registered as rescreens. Once the subject is 
registered as rescreened, a new screening window will begin. For all rescreens, all screening 
procedures, including ICF, must be repeated. Sites should discuss planned rescreens with the 
Medical Monitor prior to rescreening. 


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6.0 STUDY TREATMENT 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a subject according to the study protocol. 
The IP (also referred to as investigational medicinal product [IMP]) is PCN-101 Solution for 
Injection (R-ketamine hydrochloride in sterile water for injection). Subjects will receive 
PCN-101 Solution for Injection at either 30 mg or 60 mg or placebo. 
A placebo control will be used in the study. 
The active ingredient of the study treatment is R-ketamine. The International Union of Pure and 
Applied Chemistry (IUPAC) name is (2R)-2-(2-chlorophenyl)-2-(methylamino) cyclohexan-1-
one. 
Investigational product will be provided in vials. The site pharmacy will prepare 100 mL 
infusion bags containing IP. PCN-101 or placebo will be administered on Day 1 as a single IV 
infusion via an electronic infusion pump over 40 minutes (Table 2). 
IP/IMP dose modifications are not permitted in this study. 
The duration of study participation for each subject will be up to 29 days including a screening 
period, a 3-day in-clinic visit, and 2 follow-up visits. 


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6.1 
Study Treatment(s) Administered 
Table 2 
Study Treatment Details 
Study Treatment Name: 
PCN-101 30 mg 
IUPAC name: (2R)-2-(2-
chlorophenyl)-2-
(methylamino) 
cyclohexan-1-one 
PCN-101 60 mg 
IUPAC name: (2R)-2-(2-
chlorophenyl)-2-
(methylamino) 
cyclohexan-1-one 
Placebo 
 
Dosage Formulation: 
 
Solution for injection 
Solution for injection 
Solution for injection 
Unit Dose 
Strength(s)/Dosage 
Level(s): 
30 mg 
60 mg 
n/a 
Route of Administration  
IV  
IV    
IV 
Dosing Instructions: 
 
Dilution with saline for 
infusion over 
40 minutes, administered 
by site staff in the clinic 
Dilution with saline for 
infusion over 
40 minutes, administered 
by site staff in the clinic 
Dilution with saline for 
infusion over 
40 minutes, administered 
by site staff in the clinic 
Packaging and Labeling 
1 mL extractable study 
treatment will be 
provided in 2 mL vials. 
Each vial will be labeled 
as required per country.  
1 mL extractable study 
treatment will be 
provided in 2 mL vials. 
Each vial will be labeled 
as required per country.  
1 mL extractable study 
treatment will be 
provided in 2 mL vials. 
Each vial will be labeled 
as required per country.  
Abbreviations: IUPAC = International Union of Pure and Applied Chemistry; IV = intravenous. 
6.2 
Preparation/Handling/Storage/Accountability 
1. The Site Qualification Visit will confirm the knowledge and ability of the site staff to handle 
the study treatment in compliance with all local and national regulations regarding controlled 
substances. Before a site begins any work with PCN-101, the study monitor will provide 
training to the staff regarding licensing and registration requirements, record-keeping, and 
procedures for storage and disposal of controlled substances and waste products. 
2. The Investigator or designee must confirm adherence to local regulations for the importation 
of controlled substances. The Investigator or designee must also ensure that appropriate 
temperature conditions have been maintained during transit for all study treatment received, 
and any discrepancies are reported and resolved before use of the study treatment. 
3. Only subjects enrolled in the study may receive study treatment, and only authorized study 
center staff may supply and administer study treatment. All study treatments must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the Investigator and 
authorized study center staff and in compliance with local regulations for controlled 
substances. 


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4. PCN-101 and placebo must not be injected intravenously without dilution. The study
treatment will be diluted with sodium chloride 0.9% United States Pharmacopeia according
to the Pharmacy Manual.
5. The Investigator, institution, or the head of the medical institution (where applicable) is
responsible for study treatment accountability, reconciliation, and record maintenance (ie,
receipt, reconciliation, and final disposition records).
6. Further guidance and information for the final disposition of used and unused study treatment
are provided in the Pharmacy Manual.
The Investigator, a member of the study center staff, or a hospital pharmacist must maintain an 
adequate record of the receipt and distribution of all study medication using a Drug 
Accountability Form. These forms must be available for inspection at any time. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
All subjects will be centrally assigned to randomized study treatment using an Interactive Web 
Response System (IWRS). Before the study is initiated, the log in information and directions for 
the IWRS will be provided to each study center. 
This is a double-blind study with limited access to the randomization code. The investigational 
treatment and placebo will be identical in physical appearance. The treatment each subject will 
receive will not be disclosed to the Investigator, study center staff, subject, Sponsor, or study 
vendors. The treatment codes will be held by the unblinded statistician and will be programmed 
into the IWRS. 
The IWRS will be programmed with blind-breaking instructions. In case of an emergency, the 
Investigator has the sole responsibility for determining if unblinding of a subject’s treatment 
assignment is warranted. Subject safety must always be the first consideration in making such a 
determination. If the Investigator decides that unblinding is warranted, the Investigator should 
make every effort to contact the Sponsor prior to unblinding a subject’s treatment assignment 
unless this could delay emergency treatment of the subject. If a subject’s treatment assignment is 
unblinded, the Sponsor must be notified within 24 hours after breaking the blind. The date and 
reason that the blind was broken must be recorded in the source documentation and case report 
form (CRF), as applicable. 
6.4 
Study Treatment Compliance 
The prescribed dosage, timing, and mode of administration may not be changed, except as 
defined in Section 6.6. Any departures from the intended regimen must be recorded in the 
appropriate CRFs. 


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Noncompliance is defined as receiving less than the full infusion or a deviation from the 
40-minute infusion time. 
6.5 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the subject is receiving at the time of enrollment (within 30 days 
before the screening visit) or receives during the study must be recorded on the CRF along with: 
• Type of drug. 
• Reason for use. 
• Dates of administration including start and end dates. 
• Dosage information including dose and frequency. 
• Route of administration. 
COVID-19 vaccination is allowed as long as the doses are administered ≥ 30 days before the 
administration of study drug. Vaccination is not allowed during the course of the study. 
Concomitant therapies must be recorded throughout the study beginning with the signing of the 
ICF (ie, screening) until the second follow-up visit. Concomitant therapies should also be 
recorded beyond this time only in conjunction with new or worsening AEs or SAEs. For subjects 
who fail screening, concomitant therapies do not need to be recorded unless there is an AE. 
Modification of an effective pre-existing therapy should not be made for the explicit purpose of 
entering a subject into the study. The following medications are prohibited for the duration of the 
study beginning from 1 week (or 5 half-lives, whichever is longer) prior to Baseline (Day -1). If 
applicable, the possible effects of these medications on the efficacy endpoints will be considered 
during the assessment of the evaluable period (see Table 6 in Appendix 6 for further details). 
• Receipt of a known potent inhibitor of hepatic cytochrome P450 (CYP) 2B6, or CYP3A, 
activity within 1 week or within a period 5 times the drug’s half-life, whichever is longer, 
before the first administration of study drug on Day 1.  
• Treatment with a disallowed antipsychotic within the past 30 days prior to screening, 
except subjects who are on stable doses of quetiapine, aripiprazole, brexpiprazole, or 
olanzapine prescribed as adjunct treatment for depression (without psychosis) may be 
included in the study. 
• Any changes in psychotropic medication type or dose within the past 30 days prior to 
screening. 
• Treatment with monoamine oxidase inhibitors (MAOIs) currently or within the past 
30 days of screening. 


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The following medications are restricted for the duration of the study beginning from the date of 
the screening visit until the completion of assessments at Visit 4 (Day 15) or the discontinuation 
visit: 
• Daily doses of benzodiazepine receptor agonists will be limited to 2 mg/day or less of 
lorazepam or equivalents. Benzodiazepines will be prohibited within 6 hours prior to 
dosing. 
Short acting benzodiazepines except clobazam may be used as rescue medication to treat 
intolerable hallucinations/dissociative effects or any other symptoms in the judgement of the 
Investigator.  
Rescue medications may be used for other symptoms including anxiety/agitation, 
nausea/vomiting, dissociation, and blood pressure/hypertension according to the judgement of 
the Investigator. 
Doses of oral contraception should not contain more than 30 micrograms of ethinyl estradiol per 
day. 
Nonpharmacologic therapies must also be recorded throughout the study (eg, special diets, 
exercise regimens, occupational therapy, etc.) and must be recorded in the CRF. In addition, they 
must be stable 4 weeks prior study entry and remain stable throughout the study. 
Patients undergoing regular psychotherapy (ie, at least 90 days duration at the time of Screening) 
are eligible to participate in the study. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.6 
Dose Modification 
IMP/IP dose modification is not permitted during the study. 
6.7 
Treatment after the End of the Study 
Subjects will return to their normal standard of care upon completion of the study. 
 


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7.0 DISCONTINUATION OF STUDY TREATMENT AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Treatment 
If an AE occurs during the administration of study treatment, discontinuation of the infusion may 
occur if the Investigator believes that it is in best interest of the subject. The subject will then be 
withdrawn from the study. 
If a subject who does not meet the enrollment criteria is inadvertently administered study 
treatment, that subject may be discontinued from the study and the Sponsor or Sponsor designee 
must be contacted. An exception may be granted in rare circumstances for which there is a 
compelling reason to allow the subject to continue. In these rare cases, the Investigator must 
obtain documented approval from the Sponsor or Sponsor designee to allow the subject to 
continue in the study. 
Subjects who discontinue study treatment will not be replaced. 
See the Schedule of Activities (Section 1.3) for the data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that need to be completed. 
7.2 
Subject Discontinuation/Withdrawal from the Study 
A subject may withdraw from the study at any time at his/her own request or may be withdrawn 
at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. 
Any female subject who becomes pregnant while participating in the study will be withdrawn 
from the study. 
If the subject withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a subject withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the study center study records. 
See Section 1.3 for data to be collected at the time of study discontinuation and follow-up and for 
any further evaluations that need to be completed. 


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7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study center.  
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The study center must attempt to contact the subject and reschedule the missed visit as 
soon as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should continue 
in the study. 
• Before a subject is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject’s medical record. 
• If the subject continues to be unreachable, he/she will be considered to have withdrawn 
from the study.  
 


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8.0 STUDY ASSESSMENTS AND PROCEDURES 
Investigator or his/her qualified designee must have completed the sponsor specified training for 
each rating scale (where appropriate), before any rating scales are completed, and some 
additional training certification may be required prior to site activation. To maintain the study 
blind, the staff member that completes the efficacy scales should not complete any safety scales, 
except for C-SSRS, or assessment of adverse events for any given subject. Similarly, the staff 
member that completes the safety scales should not complete any efficacy scales for any given 
subject. To ensure consistency, the same staff member (where possible) should complete the 
questionnaires for each subject throughout the study. 
All post-dose timepoints in the Schedule of Activities (Section 1.3) are relative to the start of the 
infusion, except for the 40-minute (end-of-infusion [EoI]) timepoint. EoI procedures should 
occur 40 minutes after the start of infusion or at the end of infusion if the infusion continues 
beyond 40 minutes.  
EoI procedures include 12-lead ECG, vital signs, pulse oximetry, CADSS, and BPRS+. 
MOAA/S continues on 20 minute intervals from the start-of-infusion and AE review will be 
continuous from predose to 4 hours postdose. 
For the EoI, a time window of ± 2 minutes after the 40-minute total time is allowed. Assessments 
and procedures, however, should be started as close as possible after EoI.  
From predose on Day 1 to the end of the study, the highest priority procedures will be performed 
closest to the nominal time. Where activities at a given timepoint coincide, consideration should 
be given to ensure that the following order of activities is maintained. Deviations are not required 
when the actual order differs from the following. 
•
Efficacy rating scales. Where more than one efficacy scale is assessed at a timepoint, the
order of assessments should be MADRS, CGI-I and CGI-S, QIDS-SR-14/16, HAM-D,
GAD-7 and EQ5D-3L.
•
12-lead ECGs
•
Vital signs and pulse oximetry
•
Safety rating scales. Where more than one safety scale is assessed at a timepoint, the
order of assessments should be MOAA/S, CADSS and BPRS+.
•
AE and concomitant medication review.
•
Physical examination
•
Clinical laboratory assessments (including urine pregnancy test and drug/alcohol screen).
Study procedures and their timing are summarized in the Schedule of Activities in Section 1.3. 


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Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the subject should continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
subjects screened and to confirm eligibility or record reasons for screening failure, as applicable.  
Procedures conducted as part of the subject’s routine clinical management (eg, blood count) and 
obtained before signing of the ICF may be utilized for screening or baseline purposes provided 
the procedures met the protocol-specified criteria and were performed within the time frame 
defined in the Schedule of Activities. 
Screening and/or baseline procedures will include: 
• Obtain informed consent. 
• Confirm that the subject meets all eligibility criteria. 
• Record the subject’s demographic information. 
• Perform a physical exam (include recording of the subject’s height, weight, and BMI). 
• Record the subject’s medical history. 
• Conduct screening tests for HIV, hepatitis B, and hepatitis C. 
• Record the subject’s prior and concomitant medications. 
• For subjects OCBP, perform a serum pregnancy test at screening and a urine pregnancy 
test at baseline. 
• Conduct laboratory assessments. 
• Conduct a 12-lead ECG, vital signs, pulse oximetry. 
• Conduct a urine alcohol and drug screen (at a minimum will include ketamine, opiates, 
cocaine, barbiturates, and/or amphetamine/methamphetamine). 
• Review AEs.  
• Perform a MINI version 7.0.2 to assess the 17 most common psychiatric disorders in 
DSM-III-R, DSM-IV, DSM-V, and ICD-10. The MINI is designed as a brief structured 
diagnostic interview to meet the need for a short but accurate structured psychiatric 


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interview for multicenter clinical trials and epidemiology studies and to be used as a first 
step in outcome tracking in non-research clinical settings. The MINI is a structured 
interview in which patients are asked to answer questions “Yes” or “No” (eg, “Were you 
ever depressed or down, or felt sad, empty or hopeless most of the day, nearly every day, 
for two weeks?”). The MINI is designed to map onto diagnoses defined by the DSM-5 
(37). 
•
Perform an MGH-ATRQ, HAM-D, MADRS, and C-SSRS.
8.1 
Efficacy Assessments 
Efficacy assessments will be conducted at the time points listed in the Schedule of Activities in 
Section 1.3.  
8.1.1 
Montgomery Åsberg Depression Rating Scale 
The 10-item MADRS will be administered by the study staff to measure the overall severity of 
depressive symptoms. The MADRS total score will be assessed at screening and baseline (Day 1 
predose). 
•
The primary efficacy endpoint of improvement in the MADRS total score will be
evaluated prior to discharge on Day 2 of Visit 2, 24 hours after the start of the infusion of
study treatment.
•
The MADRS total score will also be assessed at 2 hours, 4 hours, 7 days (on Day 8), and
14 days (on Day 15) after the start of the infusion of PCN-101 to evaluate the secondary
efficacy endpoints of (1) response (defined as ≥ 50% improvement in the MADRS total
score from predose) and (2) remission (defined as MADRS total score ≤ 10) in the
improvement of depressive symptoms in the subjects.
•
While the MADRS is typically used with a 7-day recall period, versions of the MADRS
including 2-hour and 24-hour recall periods will be used in this study. (For the 2 hour and
4 hour periods, the sleep and appetite items will not be assessed; predose scores for these
items obtained on the same day will be carried forward).
8.1.2 
Hamilton Depression Rating Scale 
The Hamilton Depression Rating Scale is a 17-item questionnaire designed to assess a subject’s 
level of depression before, during, and after treatment. The survey is used as a guide to evaluate 
recovery and is based on the clinician's interview with the subject. The HAM-D rates the severity 
of depression by probing mood, feelings of guilt, suicide ideation, insomnia, agitation or 
retardation, anxiety, weight loss, and somatic symptoms. Scoring take about 15 minutes. The 
rater enters a number for each symptom that ranges from 0 (not present) to 4 (extreme 
symptoms). During this study, the questionnaire will be completed at screening, baseline, 
predose on Day 1, at Day 2 discharge, and both follow-up visits.  


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8.1.3 
Quick Inventory of Depressive Symptomatology - Self Report  
Subjects will answer the questions in the QIDS-SR-16, an instrument that is sensitive in 
detecting changes in the symptoms of depression. The 16 items correlate with the 9 DSM-V 
symptom criterion domains that include: 
• Sleep disturbance - initial, middle, and late insomnia or hypersomnia (Questions 1 to 4) 
• Sad mood (Question 5) 
• Decrease/increase in appetite/weight (Questions 6 to 9) 
• Concentration (Question 10) 
• Self-criticism (Question 11) 
• Suicidal ideation (Question 12) 
• Interest (Question 13) 
• Energy/fatigue (Question 14) 
• Psychomotor agitation/retardation (Questions 15 and 16).  
While the QIDS-SR-16 is typically used with a 7-day recall period, the QIDS-SR-14, with a 
24-hour recall period will be used on Day 2. For the 24 hour recall periods, the weight and 
appetite items will not be assessed; predose scores for these items obtained on Day 1 predose 
will be carried forward. The QIDS-SR-16 item version will be used on Day 1 predose and Day 8 
and Day 15 follow-up. 
8.1.4 
Generalized Anxiety Disorder 7-Item Scale 
The GAD-7 is a self-reported questionnaire for the screening and measurement of the severity of 
generalized anxiety disorder. It has sensitivity and specificity as a screener for panic, social 
anxiety, and posttraumatic stress disorder. The GAD-7 is comprised of 7 items that measure the 
severity of various signs of GAD according to reported response categories with assigned points. 
The scores for all 7 items are added together to obtain the total score on which the assessment of 
anxiety is made. 
8.1.5 
Clinical Global Impression 
The CGI rating scales measure symptom severity, treatment response, and the efficacy of 
treatments in studies of patients with mental disorders. The questionnaires require the study staff 
to compare the subjects to typical patients in the clinician’s experience. 
• The CGI-S assesses minimal clinically important differences in treatments with respect to 
the severity of depression symptoms. 


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•
The CGI-I assesses minimal clinically important differences in treatments with respect to
the improvement in depression symptoms.
8.1.6 
European Quality - 5 Dimensions - 3 Levels 
EQ-5D-3L (a questionnaire to assess the health-related quality of life for the domains of 
mobility, capacity for self-care, conduct of usual activities, pain/discomfort, and 
anxiety/depression). 
The EQ-5D-3L is a questionnaire that essentially consists of 2 pages - the EQ-5D descriptive 
system and a visual analog scale (VAS). The descriptive system is comprised of 5 dimensions: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 
3 levels: no problems, some problems, and extreme problems. The subject will be asked to 
indicate his/her health state by marking the box for the most appropriate statement in each of the 
5 dimensions. The VAS records the subject’s self-rated health on a vertical VAS where the 
endpoints are labeled “best imaginable health state” and “worst imaginable health state.” This 
information will be used as a quantitative measure of health outcome. 
8.2 
Safety Assessments 
The planned time points for all safety assessments are provided in the Schedule of Activities in 
Section 1.3. 
8.2.1 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the cardiovascular, 
respiratory, gastrointestinal, and neurological systems. Height and weight will also be measured 
and recorded and BMI will be calculated and recorded at screening. 
8.2.2 
Vital Signs 
Tympanic or temporal temperature, heart rate, blood pressure (SBP/DBP), respiratory rate, and 
SpO2 will be assessed. 
Blood pressure and pulse measurements will be assessed with a completely automated device 
while the subject is supine or semi-supine. Manual techniques will be used only if an automated 
device is not available. Blood pressure and pulse measurements should be preceded by at least 
5 minutes of rest for the subject in a quiet setting without distractions (eg, television, cell 
phones). An abnormal blood pressure value at screening may be repeated once after 5 minutes of 
relaxation to determine the subject’s eligibility. Blood pressure must be recorded using the same 
arm and position (supine or semi-supine) throughout the study, where possible. 
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 
3 blood pressure measurements (3 consecutive blood pressure readings will be recorded at 


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intervals of at least 1 minute). The average of the 3 blood pressure readings will be recorded in 
the CRF. 
A pulse oximeter will be used to measure peripheral capillary oxygen saturation (SpO2) 
continuously from predose until 4-hours postdose. A pulse oximeter will be clipped onto the 
finger or foot of the subject, and light will be sent through the finger or foot and measured on the 
other side. 
8.2.3 
Concomitant Medication Review 
Concomitant medications will be recorded at the timepoints indicated in Section 1.3 and 
throughout the study until the second follow up visit. See Section 6.5 for further details. 
8.2.4 
Electrocardiograms 
12-Lead ECGs will be obtained as outlined in the Schedule of Activities (see Section 1.3) using
an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and
corrected QT (QTc) intervals. If abnormal, the ECG needs to be repeated. All ECGs will be
centrally reviewed by an independent cardiologist blinded to treatment allocation; however,
central review of the baseline (Day -1) ECG is not required prior to dosing on Day 1.
8.2.5 
Clinical Safety Laboratory Assessments 
See Appendix 3 for the list of clinical laboratory tests to be performed and to the Schedule of 
Activities (Section 1.3) for the timing and frequency.  
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those that are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the subject’s condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 15 days after the last dose of study treatment should be repeated until the 
values return to normal or baseline or are no longer considered clinically significant by the 
Investigator or Medical Monitor. 
•
If such values do not return to normal/baseline within a period of time judged reasonable
by the Investigator, the etiology should be identified, and the Sponsor should be notified.
•
All protocol-required laboratory assessments, as defined in Appendix 3, must be
conducted in accordance with the laboratory manual and the Schedule of Activities.
•
If laboratory values from non-protocol specified laboratory assessments performed at the
institution’s local laboratory require a change in subject management or are considered


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clinically significant by the Investigator (eg, SAE, AE, or dose modification), then the 
results must be recorded in the CRF. 
8.2.6 
Modified Observer’s Assessment of Alertness/Sedation 
The MOAA/S will be used to determine if PCN-101 causes the side effect of sedation and to 
what degree. Sedation will be evaluated by the study staff using the MOAA/S. The observer will 
record the subject’s alertness predose, every 20 minutes for first 2 hours postdose, and at 4 and 6 
hours after the start of the infusion. 
8.2.7 
Clinician-Administered Dissociative States Scale 
The CADSS will be used to assess the alertness or dissociative state of subjects administered 
PCN-101. The study staff will evaluate the subject’s degree of dissociation by administering the 
CADSS questionnaire predose; at 40 minutes postdose (at EoI); and at and 2 and4 hours 
postdose. 
8.2.8 
Brief Psychiatric Rating Scale - Modified 4 Components 
The BPRS+ is one of the oldest, most widely used rating scales to measure psychotic symptoms 
and will be used by the study staff to measure psychiatric symptoms such as depression, anxiety, 
hallucinations, and unusual behavior. Only the four-item positive symptom subscale (consisting 
of: suspiciousness, hallucinations, unusual thought content, and conceptual disorganization) will 
be used in the study to assess treatment emergent psychotic symptoms. The questionnaire will be 
administered predose; at 40 minutes postdose (at EoI); and at 2 and 4hours postdose. 
8.2.9 
5-Dimensional Altered States of Consciousness Rating Scale 
The 5D-ASC will be used to assess the quality of any acute psychological effects of the 
PCN-101 infusion. It is a retrospectively assessed questionnaire to measure subjective 
experiences of altered states of consciousness and contains 94 items that are formulated as a 
visual analog scale. The test will be performed 6 hours after the start of the infusion of PCN-101. 
8.2.10 
Suicidal Risk Monitoring 
PCN-101 is being investigated as an antidepressant/central nervous system-active study 
treatment. Although there has been some concern that these types of treatments may be 
associated with an increased risk of suicidal ideation or behavior when given to some subjects 
with MDD, other studies have indicated that ketamine may be associated with a decrease in 
suicidal ideation or behavior. Therefore, the Sponsor considers it important to monitor suicidal 
ideation and behavior and treatment-emergent suicidal ideation and behavior during the study.  
The definitions of behavioral suicidal events used in this scale are based on those used in the 
Columbia-Suicide History Form. Questions are asked on suicidal behavior, suicidal ideation, and 
intensity of ideation. At screening (Visit 1), questions will be in relation to lifetime experiences. 


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Questioning at all subsequent visits (see Section 1.3, Schedule of Activities) will be in relation to 
the last assessment (since last visit). The adult C-SSRS will be used for all subjects. 
The C-SSRS will be administered to subjects at screening, at baseline, and prior to discharge 
from the clinic 24 hours after the infusion of study treatment. The C-SSRS will be administered 
to subjects at follow-up Visit 3 (Day 8) and Visit 4 (Day 15). Note: the C-SSRS may be 
evaluated by either efficacy or safety rater. 
8.3 
Adverse Events 
The definitions of an AE and SAE can be found in Appendix 4. 
AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or study procedures, or that caused the 
subject to discontinue from the study (see Section 7.0). 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information  
All AEs will be collected from the signing of the ICF until the second follow-up visit (Day 15) at 
the time points specified in the Schedule of Activities (Section 1.3). 
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the CRF, 
not the AE section. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours as indicated 
in Appendix 4. The Investigator will submit any updated SAE data to the Sponsor or designee 
within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE information after the conclusion of 
study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the event to be 
reasonably related to the study treatment or study participation, the Investigator must promptly 
notify the Sponsor or designee. 
The method of recording, evaluating, and assessing the causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 4. 


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8.3.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.  
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is given in Appendix 4. 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse Events 
Prompt notification by the Investigator to the Sponsor or designee of an SAE is essential so that 
legal obligations and ethical responsibilities toward the safety of subjects and the safety of a 
study treatment under clinical investigation are met.  
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Independent Ethics Committees (IECs), Independent Review Boards 
(IRBs), and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Sponsor or designee’s policy and forwarded to 
Investigators as necessary. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the Investigator’s Brochure and will notify the IEC/IRB, if appropriate according to 
local requirements. 
8.3.5 
Pregnancy 
Details of all pregnancies in female subjects and, if indicated, female partners of male subjects 
will be collected after the start of study treatment and until the second follow-up visit. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5. Information 
on the status of the mother and child will be forwarded to the Sponsor. Generally, the follow-up 
will be no longer than 6 to 8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 


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Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 
COVID-19 
If a subject tests positive for COVID-19, this should be recorded as either an AE of 
“symptomatic COVID-19 disease” or “asymptomatic COVID-19 disease.” 
Symptoms, signs, and sequelae of COVID-19 should be reported as an AE per the Definitions 
and Procedures for Recording, Evaluating, Follow-up, and Reporting (Appendix 4). Medications 
for the prevention or treatment of COVID-19 should be entered as concomitant medications. 
(Please refer to the EDC Completion Guidelines for further details.) 
8.4 
Treatment of Overdose 
An overdose is unlikely during this study since all treatment will be administered in a clinic 
setting using an infusion pump. However, if the study treatment is administered in less than 
40 minutes due to a pump error, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the subject for any AE/SAE and laboratory abnormalities for at least 
24 hours. 
3. Obtain a plasma sample for pharmacokinetic (PK) analysis as soon as possible and note the 
time from the start of the infusion of study treatment if requested by the Medical Monitor 
(determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the CRF. 
8.5 
Pharmacokinetics 
No assessment of the PK of PCN-101 is planned in this study. 
8.6 
Pharmacodynamics 
Pharmacodynamic parameters will not be evaluated in this study. 
8.7 
Genetics 
Genetics will not be evaluated in this study. 
8.8 
Biomarkers 
Biomarkers will not be evaluated in this study. 


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8.9 
 Health Economics and/or Medical Resource Utilization and Health 
Economics 
Health economic and/or medical resource utilization parameters will not be evaluated in this 
study. 
9.0 STATISTICAL CONSIDERATIONS 
9.1 
General Considerations 
The comprehensive SAP with detailed description of all statistical analyses will be developed 
and finalized before database lock. 
All statistical analyses, including summary tables and data listings will be performed using 
SAS® software (version 9.4 or higher). Continuous endpoints will be summarized using 
descriptive statistics (number of subjects [n], mean, standard deviation [SD], median, minimum 
and maximum). Categorical endpoints will be summarized using frequency counts and 
percentages. All individual subject data will be presented in listings. 
9.2 
Sample Size Determination  
The intent of the primary efficacy analysis is to demonstrate superiority of at least 1 therapeutic 
dose of PCN-101 Solution for Injection (30 mg or 60 mg) versus placebo based on the change in 
the MADRS total score from predose to 24 hours postdose. 
For the primary analysis, a sample size of 93 randomized subjects (31:31:31) will provide 
80% power to detect an 8-point difference between each PCN-101 Solution for Injection dose 
and placebo in the mean change from baseline MADRS total score at 24 hours postdose, using a 
t-test with α = 0.05 (2-tailed) and assuming a common SD of 11. 
Approximately 20 study centers in the EU and US are expected to participate in this study. The 
enrollment of 93 subjects is planned. Subjects who do not receive a dose of study treatment on 
Day 1 (Visit 2) will be replaced. 
9.3 
Populations for Analyses 
For purposes of analysis, the analysis sets in Table 3 are defined.  
Table 3 
Analysis Sets 
Analysis Set 
Description 
Full Analysis 
Set (FAS) 
The FAS will consist of all randomized subjects who receive at least 1 dose of study treatment 
and have at least 1 postbaseline assessment available. This population will serve as the basis for 
efficacy analysis. Subjects will be analyzed according to their randomized treatment. 
Safety 
Analysis Set 
The Safety Population will consist of all randomized subjects who receive any study treatment, 
even a partial dose. This population will be used for all summaries of subject disposition, 


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demographic and baseline data, and safety information including AE incidence. Subjects will be 
analyzed according to the treatment they actually received. 
Abbreviations: AE = adverse event; FAS = Full Analysis Set. 
9.4 
Statistical Analyses 
9.4.1 
Subject Disposition and Demographics 
Subject disposition events (screened, randomized, completed the study, early discontinuation 
from the study along with the reason for discontinuation) as well as the number of subjects in 
each analysis population will be summarized using frequency counts and percentages by 
treatment groups. 
9.4.2 
Efficacy Analyses 
Primary Endpoint 
The change from baseline in MADRS scores will be summarized separately by treatment arm for 
each visit. Associated baseline scores will be taken as the last corresponding measurement prior 
to the first dose of IMP in the treatment period (i.e., Visit 2, predose). 
The primary endpoint of change from baseline MADRS total score at 24 hours post start of 
infusion will be evaluated using a mixed effects model for repeated measure (MMRM) analysis 
with observed cases only. The MMRM model will include fixed effects for treatment group, 
region, visit, study site and treatment group by visit interaction, with subject as a random effect 
and baseline score as a covariate. An unstructured covariance matrix will be used to estimate the 
variance-covariance structure within subjects across time points. If convergence is not obtained, 
then other covariance structures to be used will be specified in the SAP. Objective criteria for 
assessing normality assumptions and proposed alternative analyses will be specified in the SAP. 
From this analysis the least squares (LS) mean estimates for each treatment arm at each visit, 
along with the standard error and 95% confidence intervals (CIs) will be presented separately. In 
addition, estimates of the treatment difference at each visit will be presented along with standard 
errors of the difference and 95% CIs. The primary comparison for the MADRS is the estimate of 
the treatment difference at 24 hours after the start of the infusion. 
Secondary endpoints 
The change from baseline to Day 14 in MADRS, HAM-D, GAD-7 and QIDS-SR scores will be 
analyzed using similar model approaches as for MADRS. Observed and change from baseline 
values in continuous secondary endpoints will be summarized descriptively by treatment group. 
Continuous secondary efficacy endpoints assessed at more than 1 postbaseline visit will be 
analyzed using an MMRM analysis. The MMRM model will include fixed effects for treatment 
group, region, visit, study site and treatment group by visit interaction, with subject as a random 
effect and baseline score as a covariate.  
From this analysis the LS mean estimates for each treatment arm at each visit, along with the 
standard error and 95% CIs will be presented separately. In addition, estimates of the treatment 


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difference at each visit will be presented along with standard errors of the difference and 95% 
CIs.  
The numeric values of CGI-S and CGI-I assessments will be analyzed separately using similar 
model approaches as for MADRS. For CGI-S, baseline score will be included as a covariate. 
Both values for the original categorical scale and the converted numerical scale at each visit 
(including change from baseline for the CGI-S numerical scale) will be summarized using 
standard summary statistics. 
Binary exploratory endpoints will be analyzed separately and odds ratios, 95% CI and p-value 
will be presented. 
Full details of the efficacy analyses and any further supplementary analyses deemed appropriate 
will be provided in the SAP. 
9.4.3 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set. 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA; 
Version 23.0 or higher). Treatment-emergent adverse events (TEAEs) are AEs with onset or 
worsening after the start of study treatment. The AE summaries will be primarily based on 
TEAEs. The number and percentage of subjects with TEAEs will be summarized by treatment 
group, system organ class, and preferred term for all TEAEs, treatment-related TEAEs, SAEs, 
serious TEAEs, severe TEAEs, TEAEs of special interest, and all TEAEs leading to study drug 
discontinuation. All TEAEs will be further summarized by maximum severity and causality. The 
TEAEs of special interest will be identified in the SAP. 
All AEs will be presented in a by-subject listing. Serious AEs, severe AEs, and AEs leading to 
study discontinuation or death will be presented in separate listings. 
Clinical Laboratory Tests 
Laboratory data will be summarized using descriptive statistics for each parameter, including 
change from baseline at each assessment time by treatment group. Frequency tables or shift 
tables will be used to present the number and percentage of subjects with laboratory values 
within/outside reference ranges. All laboratory data will be present in the listings. A by-subject 
listing will also be provided for subjects with abnormal laboratory results. 
Electrocardiogram  
Descriptive statistics will be used to summarize the observed and change from baseline values of 
the following ECG parameters at each assessment time by treatment group: heart rate, PR 
interval, QRS interval, QT interval, and QTcF. All ECG data will be present in listings. 


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Vital Signs  
Vital sign parameters including temperature, pulse/heart rate, respiratory rate, SpO2, and blood 
pressure will be summarized descriptively for both the observed and change from baseline values 
at each assessment time by treatment group. Frequency tabulations will be provided for 
abnormalities as applicable. 
Other Safety Questionnaires and Assessments 
All physical examination results will be listed by subject. 
Prior and concomitant therapies will be summarized separately and tabulated for each treatment 
group using frequencies and percentages. Percentages will be based on the number of subjects in 
each treatment group. Prior and concomitant medications will be listed by subject. 
For the C-SSRS: suicidal ideation and behavior scores at each assessment time as well as the 
incidence rate of TEAEs will be summarized using frequency counts and percentages by 
treatment group. 
For the CADSS, BPRS+, 5D-ASC, and MOAA/S: Descriptive statistics of scores and their 
changes from baseline will be summarized at each assessment time by treatment group. 
Pregnancy test and urine drug and alcohol screen will be presented in by-subject listings. 
9.4.4 
Other Analyses  
Exploratory analyses may be done if indicated. 
9.4.5 
Missing Data 
In general, the missing data which is observed from this study will be assumed to be missing-at-
random (MAR).  
Since subjects are hospitalized at the time of the primary endpoint, it is anticipated that missing 
data will be infrequent. No imputation will be applied to primary analysis. 
Further details on the handling of missing data will be provided in the SAP. 
9.5 
Interim Analyses  
No interim analysis for efficacy is planned. 
9.6 
 Data Monitoring Committee 
Because of the short timeframe of the study, there will not be a data monitoring committee. 
 


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20 Feb 2020. doi: 10.1007/s00406-020-01110-5. 


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 Singh JB, Fedgchin M, Daly EJ, et al. Intravenous Esketamine in Adult Treatment-Resistant 
Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study Biological 
Psychiatry 2016; Sep 15;80(6):424-431. 
37. Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric 
Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric 
interview for DSM-IV and ICD-10. J Clin Psychiatry 1998;59 Suppl 20:22-33;quiz 34-57.   


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11.0 APPENDICES 


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Appendix 1 
Abbreviations 
Abbreviation 
Definition 
5D-ASC 
5-Dimensional Altered States of Consciousness Rating Scale 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
BPRS+ 
Brief Psychiatric Rating Scale - Modified 4 Components 
CADSS 
Clinician-Administered Dissociative States Scale 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical Global Impression - Severity 
CI 
Confidence interval 
COVID-19 
Coronavirus disease 2019 
CRF 
Case report form 
CRO 
Contract Research Organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP 
Cytochrome P450 
DBP 
Diastolic blood pressure 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EoI 
End-of-infusion 
EQ-5D-3L 
European Quality - 5 Dimensions - 3 Levels 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials (database) 
FAS 
Full Analysis Set 
GAD-7 
Generalized Anxiety Disorder 7-Item Scale 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HAM-D 
Hamilton Depression Rating Scale 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 


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Abbreviation 
Definition 
ICE 
Intercurrent Event 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IRB 
Independent Review Board 
IUPAC 
International Union of Pure and Applied Chemistry 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
LBBB 
Left bundle branch block 
LS 
Least squares 
LDH 
Lactate dehydrogenase 
MADRS 
Montgomery Åsberg Depression Rating Scale 
MAOI 
Monoamine oxidase inhibitor 
MAR 
Missing-at-random 
MDD 
Major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities, Version 23.0 or higher 
MGH-ATRQ 
Massachusetts General Hospital Antidepressant Response Questionnaire 
MINI 
Mini-International Neuropsychiatric Interview 
MMRM 
Mixed effects model for repeated measure 
MOAA/S 
Modified Observer’s Assessment of Alertness/Sedation 
n 
Number of subjects 
NMDA 
N-methyl-D-aspartate 
NMDAR 
N-methyl-D-aspartate receptor 
OCBP 
Of childbearing potential 
PAC 
Premature atrial contractions 
PK 
Pharmacokinetic(s) 
PVC 
Premature ventricular contractions 
QIDS-SR-14 
Quick Inventory of Depressive Symptomatology - 14 Items 
QIDS-SR-16 
Quick Inventory of Depressive Symptomatology - 16 Items 
QTc 
Corrected QT interval 
QTcF 
QT interval corrected according to Fridericia’s formula 
RBBB 
Right bundle branch block 


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Abbreviation 
Definition 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SpO2 
Oxygen saturation 
TBL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
TRD 
Treatment-resistant depression 
ULN 
Upper limit of normal 
US 
United States 
VAS 
Visual analog scale 
 


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Appendix 2 
Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines. 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IEC/IRB by the Investigator and reviewed and 
approved by the IEC/IRB before the study is initiated.  
Any amendments to the protocol will require IEC/IRB and regulatory authority approval, when 
applicable, before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to subjects.  
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IEC/IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IEC/IRB. 
• Notifying the IEC/IRB of SAEs or other significant safety findings as required by 
IEC/IRB procedures. 
• Providing oversight of the conduct of the study at the study center and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IEC/IRB, 
European regulation 536/2014 for clinical studies (if applicable), and all other applicable 
local regulations. 
After reading the protocol, each Investigator will sign the protocol signature page and send a 
copy of the signed page to the Sponsor or representative (Appendix 7). The study will not start at 
any study center at which the Investigator has not signed the protocol. 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 


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responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
Insurance 
The Sponsor will provide insurance in accordance with local guidelines and requirements as a 
minimum for the subjects in this study. The terms of the insurance will be kept in the study files. 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study to the 
subject or his/her legally authorized representative and answer all questions regarding the 
study.  
• Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorized representatives will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act requirements, where applicable, and the 
IEC/IRB or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the subject was entered in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• Subjects must be re-consented on updated ICF(s) that may impact the subject’s 
willingness to continue to participate during their participation in the study.  
• A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative. 
• Subjects who are rescreened are required to sign a new ICF. 
Data Protection 
• Subjects will be assigned a unique identifier by the Sponsor. Any subject records or 
datasets that are transferred to the Sponsor will contain the identifier only; subject names 
or any information that would make the subject identifiable will not be transferred.  
• The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the subject.  
• The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IEC/IRB members, and by inspectors from regulatory authorities. 


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Administrative Structure 
This trial will be sponsored by Perception Neuroscience, Inc.  
CROs will provide clinical operations management, data management, and medical monitoring. 
Accredited local laboratories will be used for routine monitoring; local laboratory ranges will be 
collected. 
 
Table 4 
Study Administrative Structure 
Function 
Responsible Organization 
Study Operations Management 
CRO 
Medical Monitoring 
CRO 
Trial Master File 
CRO 
Randomization Code 
CRO 
Data Management 
CRO 
Clinical Supply Management 
Rave Medidata 
Quality Assurance Auditing 
CRO 
Biostatistics 
CRO 
Medical Writing 
CRO 
Laboratory Assessments 
Site 
Electrocardiogram Collection, Review, and Analysis 
Connected Devices 
 
Sponsor Contact Details 
Sponsor: 
Perception Neuroscience, Inc. 
 
 
c/o atai Life Sciences, WeWork,  
524 Broadway,  
New York,  
NY 10012 
 
 
Safety Management and Pharmacovigilance 
Department — SAE Reporting: 
Worldwide Toll: 1-919-313-7111  
USA (Toll Free): 1-866-758-2798  
Fax: +1-919-313-1412 
Email: SafetyInbox.Biotech@IQVIA.com  
 
 


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Dissemination of Clinical Study Data 
• Disclosure of clinical study reports, periodic safety reports, and clinical study summary 
reports after review by regulatory authorities. This includes access to clinical study 
reports from studies with negative outcomes and from terminated development programs. 
• The posting of company-sponsored study information and tabular study results on the US 
National Institutes of Health’s website www.ClinicalTrials.gov and other publicly 
accessible sites.  
• Publication planning and other activities related to non-promotional, peer-reviewed 
publications, to ensure the scientific integrity and credibility of publication activities 
performed by or on behalf of the company. The granting of access to analyzable datasets 
from clinical studies through a secure system, following an independent assessment of 
the scientific merit of a rigorously defined research question from a third party.  
A summary of the results of this trial will be made available on http://www.clinicaltrials.gov and 
http://www.clinicaltrialsregister.eu/ (as applicable), as required by US and EU Law. 
Data Quality Assurance 
• All subject data relating to the study will be recorded on printed CRFs unless transmitted 
to the Sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
• The Investigator must permit study-related monitoring, audits, IEC/IRB review, and 
regulatory agency inspections and provide direct access to source data documents.  
• The Sponsor’s designee is responsible for the data management of this study including 
quality checking of the data.  
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized study center personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No 


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records may be transferred to another location or party without written notification to the 
Sponsor.  
Source Documents 
The Investigator/institution should maintain adequate and accurate source documents and study 
records that include all pertinent observations on each of the study center’s subjects. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, should not obscure the original entry, and should be explained if 
necessary (eg, via an audit trail). 
• Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s study 
center. 
• Data entered in the CRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available. 
• Definition of what constitutes source data can be found in the CRF completion 
guidelines. 
Study and Study Center Closure 
The Sponsor designee reserves the right to close the study center or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study centers will be closed upon study 
completion. A study center is considered closed when all required documents and study supplies 
have been collected and a study center closure visit has been performed. 
The Investigator may initiate study center closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study center by the Sponsor or Investigator may include but 
are not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IEC/IRB 
or local health authorities, the Sponsor’s procedures, or GCP guidelines. 
• Inadequate recruitment of subjects by the Investigator. 
• Discontinuation of further study treatment development. 
Publication Policy 
The data generated by this study are confidential information of the Sponsor. The Sponsor will 
make the results of the study publicly available. 


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• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.  
• The Sponsor will comply with the requirements for the publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
study center data. In this case, a Coordinating Investigator will be designated by mutual 
agreement. 
• Authorship will be determined by mutual agreement and in line with the International 
Committee of Medical Journal Editors authorship requirements. 


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Appendix 3 
Clinical Laboratory Tests 
Procedure Notes: 
•
Pregnancy test: Serum testing will be performed at screening and to confirm a positive
urine test. Local urine pregnancy testing will be performed at both follow-up visits.
•
Hepatitis B and hepatitis C screening: hepatitis B surface antigen and hepatitis C virus
(HCV antibody) testing will be required.
•
The tests detailed in Table 5 will be performed by a local laboratory. Urine drug screen
may be performed on site.
•
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in
Section 5.0 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary
by the Investigator or required by local regulations.
Table 5 
Protocol-required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count 
RBC indices: 
Mean corpuscular volume (MCV) 
Mean corpuscular hemoglobin (MCH) 
% Reticulocytes 
White blood cell 
count with 
differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red blood cell 
(RBC) count 
Hemoglobin 
Hematocrit 
Clinical 
chemistry 
Blood urea 
nitrogen or urea 
Lactate 
dehydrogenase 
(LDH) 
Potassium 
Aspartate aminotransferase 
(AST)/serum glutamic-
oxaloacetic transaminase (SGOT) 
Total and direct 
bilirubin 
Creatinine 
Sodium 
Chloride 
Alanine aminotransferase 
(ALT)/serum glutamic-pyruvic 
transaminase (SGPT) 
Total protein 
Glucose 
[non-fastinga] 
Calcium 
Alkaline phosphatase 
Gamma-glutamyl transferase 
(GGT) 
Albumin 


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Table 5 
Protocol-required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Routine 
urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by 
dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
Other screening 
tests 
• 
Follicle stimulating hormone and estradiol (as needed in women of non-childbearing 
potential only) 
• 
Urine alcohol and drug screen (to include at minimum: amphetamines/methamphetamines, 
ketamine, barbiturates, cocaine, and opiates) 
• 
Serum or urine human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential)b 
• 
Serology (HIV antibody, hepatitis B surface antigen, and HCV antibody) 
All study-required laboratory assessments will be performed by a local laboratory. Urine drug 
screen may be done on site. The results of each test must be entered into the CRF. 
a Non-fasting blood samples will be requested, but both fasting and non-fasting samples are acceptable. 
b Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IEC/IRB. 
 
Investigators must document their review of each laboratory safety report. 
Laboratory/analyte results that could unblind the study will not be reported to study centers or 
other blinded personnel until the study has been unblinded. 


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Appendix 4 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a patient or subject, temporally associated 
with the use of study treatment, whether or not considered related to the study treatment. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study treatment. 
 
Events Meeting the AE Definition  
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study treatment administration even though it 
may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment 
or a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it 
is an intentional overdose taken with possible suicidal/self-harming intent. Such overdoses 
should be reported regardless of sequelae. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will 
be reported as AEs or SAEs if they fulfill the definition of an AE or SAE. 
 


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Events NOT Meeting the AE Definition  
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the subject’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital, including planned hospitalization for this study). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
 
Definition of SAE 
If an event is not an AE per the definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. Complications 
that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE, nor is planned hospitalization for this study. 
d) Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 


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accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) Other situations: 
• Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the other outcomes 
listed in the above definition. These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 


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Recording and Follow-up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the CRF. Each event 
must be recorded separately. 
• It is not acceptable for the Investigator to send photocopies of the subject’s medical 
records to Safety Management in lieu of completion of the AE/SAE CRF page. 
• There may be instances when copies of medical records for certain cases are requested by 
Safety Management. In this case, all subject identifiers, with the exception of the subject 
number, will be redacted on the copies of the medical records before submission to Safety 
Management. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories:  
• Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality 
• The Investigator is obligated to assess the relationship between study treatment and each 
occurrence of each AE/SAE. The AE must be characterized as unrelated, unlikely to be 
related, possibly related, probably related, or definitely related. 
o “Definitely related” suggests that the AE has a timely relationship to administration of 
study treatment, and there is no apparent potential alternate etiology. 
o “Probably related” conveys that there are facts, evidence, and/or arguments to suggest 
a causal relationship, rather than a relationship cannot be ruled out. 
o “Possibly related” suggests that the association of the AE with the study treatment is 
unknown; however, the AE is not reasonably supported by other conditions. 
o “Unlikely to be related” suggests that only a remote connection exists between the 
study treatment and the AE. Other conditions, including chronic illness, progression or 


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expression of the disease state or reaction to concomitant therapy, appear to explain the 
reported AE. 
o “Unrelated” is used if there is not a reasonable possibility that the study treatment 
caused the AE.  
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment administration 
will be considered and investigated. 
• The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to Safety Management. However, it is very 
important that the Investigator always makes an assessment of causality for every event 
before the initial transmission of the SAE data to Safety Management. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Safety 
Management to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a subject dies during participation in the study or during a recognized follow-up period, 
the Investigator will provide Safety Management with a copy of any postmortem findings 
including histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
• The Investigator will submit any updated SAE data to the Sponsor or designee within 24 
hours of receipt of the information. 
 
Reporting of SAEs 
SAE Reporting to Safety Management via Paper CRF 
• E-mail transmission of the SAE paper CRF is the preferred method to transmit this 
information to Safety Management with facsimile transmission as the back-up 
method. 


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• In rare circumstances and in the absence of e-mail/facsimile equipment, notification 
by telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the Investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the Investigator Study Binder and in the 
contacts listed in Appendix 2. All SAEs must also be reported to Safety Management 
within 24 hours of first awareness of the event. A paper SAE Report Form should be 
completed and submitted via e-mail to SafetyInbox.Biotech@IQVIA.com or faxed to 
+1-919-313-1412. 
 
 


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Appendix 5 
Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Subject of Childbearing Potential (OCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Female Subjects in the following categories are not considered OCBP 
1. Premenarchal
2. Premenopausal female with 1 of the following > 6 months prior to screening:
a) Documented hysterectomy.
b) Documented bilateral salpingectomy.
c) Documented bilateral oophorectomy.
Note: Documentation can come from the study center personnel’s: review of the subject’s
medical records, medical examination, or medical history interview.
3. Postmenopausal female:
a) A postmenopausal state is defined as no menses for 24 months without an alternative
medical cause.
Contraception Guidance 
Male subjects 
•
Male subjects with female partners of childbearing potential are eligible to participate if
they agree to use a male condom plus partner use of a contraceptive method with a failure
rate of < 1% per year when having penile-vaginal intercourse with a partner who is of
childbearing potential who is not currently pregnant (during the protocol-defined time
frame in Section 5.1):
•
In addition, male subjects must refrain from donating sperm during the treatment period
and for at least 3 months after the last dose of study treatment.
Female subjects 
Female subjects of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in the table below. 
Hormonal contraception may be susceptible to interaction with the study treatment, which may 
reduce the efficacy of the contraceptive method. For subjects using hormonal contraception as 
the primary form of birth control, a secondary (barrier) method should be utilized during the 
treatment period and for at least 30 days after the last dose of study treatment. Doses of oral 
contraception should not contain more than 30 micrograms of ethinyl estradiol per day. 


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Protocol PCN-101-21 – Protocol Amendment 4, 19 May 2022 
PERCEPTION NEUROSCIENCE 
PROPRIETARY and CONFIDENTIAL 
 
83 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependenta  
Failure rate of < 1% per year when used consistently and correctly.  
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation in conjunction with a secondary methodb  
• Oral.  
• Intravaginal.  
• Transdermal. 
Progestogen only hormonal contraception associated with inhibition of ovulation in conjunction 
with a secondary methodb 
• Oral. 
• Injectable.  
Highly Effective Methods That Are User Independenta  
• Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
in conjunction with a secondary methodb 
• Intrauterine device (IUD). 
• Intrauterine hormone-releasing system (IUS) in conjunction with a secondary methodb 
• Bilateral tubal occlusion. 
Vasectomized Partner  
• Vasectomized male partner (sterilization performed at least 90 days prior to the Screening 
visit, with verbal confirmation of surgical success, and the sole partner for the female 
subject) 
a Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
subjects participating in clinical studies.  
b Hormonal contraception may be susceptible to interaction with the study treatment, which may 
reduce the efficacy of the contraceptive method. In this case, 2 methods (1 primary and 
1 secondary method) of birth control should be utilized during the treatment period and for at 
least 30 days after the last dose of study treatment.  


CONFIDENTIAL 
Protocol PCN-101-21 – Protocol Amendment 4, 19 May 2022 
PERCEPTION NEUROSCIENCE 
PROPRIETARY and CONFIDENTIAL 
84 
Secondary (barrier) methods of contraception 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationb  
•
male condom with spermicide
•
female condom with spermicide
•
over-the-counter sponge with spermicide
•
cervical cap with spermicide (as prescribed)
•
diaphragm with spermicide (as prescribed).
Female subjects of childbearing potential should refrain from donation of ova from Check-in 
(Day -1) until 90 days after the Follow–up visit. 
For subjects who are exclusively in same‑sex relationships, contraceptive requirements do not 
apply. If a subject who is in a same‑sex relationship at the time of signing the ICF becomes 
engaged in a heterosexual relationship, they must agree to use contraception as described 
previously. 
Pregnancy Testing: 
•
Subjects OCBP should only be included after a negative serum pregnancy test.
•
Additional pregnancy testing should be performed at the times specified in the Schedule
of Activities.
Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy is 
otherwise suspected.  
•
Pregnancy testing will be performed and assayed in the local laboratory.
Collection of Pregnancy Information 
Male subjects with partners who become pregnant 
•
The Investigator will attempt to collect pregnancy information on any male subject’s
female partner who becomes pregnant while the male subject is in this study. This applies
only to male subjects who receive PCN-101.
•
While pregnancy itself is not considered to be an AE or SAE, any pregnancy
complication or elective termination of a pregnancy will be reported as an AE or SAE. A
spontaneous abortion is always considered to be an SAE and will be reported as such.
•
Any post-study pregnancy-related- SAE considered reasonably related to the study
treatment by the Investigator will be reported to Safety Management as described in
Section 8.3.3. While the Investigator is not obligated to actively seek this information, he
or she may learn of an SAE through spontaneous reporting.


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Protocol PCN-101-21 – Protocol Amendment 4, 19 May 2022 
PERCEPTION NEUROSCIENCE 
PROPRIETARY and CONFIDENTIAL 
85 
Female subjects who become pregnant 
•
The Investigator will collect pregnancy information on any female subject who becomes
pregnant while participating in this study. Information will be recorded on the appropriate
form and submitted to Safety Management within 24 hours of learning of a subject’s
pregnancy. The subject will be followed to determine the outcome of the pregnancy. The
Investigator will collect follow-up information on the subject and the neonate, and the
information will be forwarded to the Sponsor. Generally, follow-up will not be required
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of
pregnancy will be reported, regardless of fetal status (presence or absence of anomalies)
or indication for the procedure.
•
While pregnancy itself is not considered to be an AE or SAE, any pregnancy
complication or elective termination of a pregnancy will be reported as an AE or SAE. A
spontaneous abortion is always considered to be an SAE and will be reported as such.
•
Any post-study pregnancy-related SAE considered reasonably related to the study
treatment by the Investigator will be reported to the Sponsor as described in
Section 8.3.3. While the Investigator is not obligated to actively seek this information in
former subjects, he or she may learn of an SAE through spontaneous reporting.
•
Any female subject who becomes pregnant while participating in the study will be
withdrawn from the study.


CONFIDENTIAL 
Protocol PCN-101-21 – Protocol Amendment 4, 19 May 2022 
PERCEPTION NEUROSCIENCE 
PROPRIETARY and CONFIDENTIAL 
 
86 
Appendix 6 
Permitted and Prohibited Concomitant Medications 
Table 6 provides a list of permitted and prohibited concomitant medications throughout the 
study.  
Table 6 
List of Permitted and Prohibited Concomitant Medications 
Drug 
Episodic Use 
Continuous Use 
Comments 
Amantadine 
N 
N 
 
Analgesics (except opiates) 
Y 
Y 
 
Anti-anginal drugs 
N 
N 
Angina is exclusion 
Anti-arrhythymics 
N 
N 
Arrhythmia is exclusionary 
Anticholenergics 
N 
N 
 
Anticholinesterase inhibitors 
N 
N 
 
Anticoagulants 
N 
N 
 
Anticonvulsants 
N 
N 
 
Antidepressants 
N 
Y 
MAOIs are always excluded 
Antidiarrheal 
Y 
N 
 
Anti-emetics 
Y 
N 
 
Anti-inflammatory  
Y 
Y 
 
Antipsychotics 
N 
Y 
Stable doses of quetiapine, 
aripiprazole, olanzapine, and 
brexpiprazole are permitted for 
continuous use 
Antifungals 
N 
N 
No ketoconazole, fluconazole due to 
CYP3A interaction 
Artemisinin 
 
 
 
Aspirin 
Y 
Y 
 
Benzodiazepines 
Y 
Y 
Except clobazam 
Daily doses of benzodiazepine 
receptor agonists will be limited to 
2 mg/day or less of lorazepam or 
equivalents. Benzodiazepines will 
be prohibited within 6 hours prior to 
dosing 


CONFIDENTIAL 
Protocol PCN-101-21 – Protocol Amendment 4, 19 May 2022 
PERCEPTION NEUROSCIENCE 
PROPRIETARY and CONFIDENTIAL 
 
87 
Table 6 
List of Permitted and Prohibited Concomitant Medications 
Drug 
Episodic Use 
Continuous Use 
Comments 
Clarithromycin 
N 
N 
CYP3A interaction 
Erythromycin 
N 
N 
CYP3A interaction 
Elagolix 
N 
N 
CYP3A interaction 
Fish oils 
Y 
Y 
 
HIV drugs 
N 
N 
HIV excluded 
Hormones 
N 
Y 
Glucocorticoids excluded due to 
CYP3A interaction 
Itraconazole 
N 
N 
CYP3A interaction 
Ketoconazole 
N 
N 
CYP3A interaction 
Lithium 
N 
N 
 
Methyldopa 
N 
N 
 
Modafinil 
N 
N 
 
Opiates 
N 
N 
 
Oritavancin 
N 
N 
CYP3A interaction 
Pioglitazone 
N 
N 
CYP3A interaction 
Rifabutin 
N 
N 
CYP3A interaction 
Rifampin 
N 
N 
CYP interaction 
St. john's wort 
N 
N 
CYP3A interaction 
Stimulants 
N 
N 
 
Steroids (oral) 
N 
N 
 
Steroids (inhaled, topical, 
ophthalmic) 
Y 
Y 
 
Telithromycin 
N 
N 
CYP3A interaction 
Telotristat 
N 
N 
CYP3A interaction 
Ticlopidine 
N 
N 
CYP2B6 interaction 


CONFIDENTIAL 
Protocol PCN-101-21 – Protocol Amendment 4, 19 May 2022 
PERCEPTION NEUROSCIENCE 
PROPRIETARY and CONFIDENTIAL 
 
88 
Table 6 
List of Permitted and Prohibited Concomitant Medications 
Drug 
Episodic Use 
Continuous Use 
Comments 
Troglitazone 
N 
N 
CYP3A interaction 
Troleandomycin 
N 
N 
CYP3A interaction 
Tryptophan 
N 
N 
 
Voriconazole 
N 
N 
CYP3A interaction 
Note: Permitted episodic or continuous use of a concomitant medication is indicated with a “Y” (yes). 
Prohibited episodic or continuous use of a concomitant medication is indicated with an “N” (no). 
 


CONFIDENTIAL 
Protocol PCN-101-21 – Protocol Amendment 4, 19 May 2022 
PERCEPTION NEUROSCIENCE 
PROPRIETARY and CONFIDENTIAL 
 
89 
Appendix 7 
Signature of Investigator 
PROTOCOL TITLE: A RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND 
STUDY OF INTRAVENOUS PCN-101 TO ASSESS THE SAFETY AND EFFICACY IN 
TREATMENT-RESISTANT DEPRESSION 
PROTOCOL NO: 
PCN-101-21 
VERSION:  
 
Protocol Amendment 4 
This protocol is a confidential communication of Perception Neuroscience, Inc. I confirm that I 
have read this protocol, I understand it, and I will work according to this protocol. I will also 
work consistently with the ethical principles that have their origin in the Declaration of Helsinki 
and that are consistent with Good Clinical Practice and the applicable laws and regulations. 
Acceptance of this document constitutes my agreement that no unpublished information 
contained herein will be published or disclosed without prior written approval from the Sponsor. 
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, title, and the name of the study 
center in which the study will be conducted. Return the signed copy to the CRO. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator:      __________________________            Date:  ________ 
Printed Name:                         __________________________ 
Investigator Title:                   __________________________ 
 
Name/Address of Center:               
___________________________ 
 
 
 
 
 
___________________________ 
 
 
 
 
 
___________________________ 

SAP_001.pdf: 
 
 
 
CONFIDENTIAL  
 
  
Page 1 of 33  
 
 
  
Perception Neuroscience, Inc.  
  
  
Protocol #: PCN-101-21 
 
NCT05414422  
  
  A RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND  
STUDY TO ASSESS THE SAFETY AND EFFICACY OF  
INTRAVENOUS PCN-101 IN TREATMENT RESISTANT 
DEPRESSION  
  
Version 2.0 (Final)  
  
Document last saved: 14-Nov-2022 11:05 AM  
 
  
  
 
 


Perception Neuroscience, Inc./ Protocol: PCN-101-21  
CONFIDENTIAL 
  
Page 2 of 34  
CONTENTS  
  
I.Introduction .............................................................................................................. 6  
 Background ................................................................................................ 6  
 Scope of Document .................................................................................... 6  
II.Protocol Objectives and Analysis Endpoints ........................................................... 6  
III.Study Design .......................................................................................................... 8  
 Design Overview ........................................................................................ 8  
 Study Population ........................................................................................ 9  
 Sample Size Predictions ............................................................................ 9  
 Treatment Randomization ........................................................................ 10  
 Assessment Schedule .............................................................................. 10  
IV.Interventions ........................................................................................................ 10  
 Clinical Trial Material ................................................................................ 10  
V.General Analytical Considerations ........................................................................ 10  
 Data Sources ........................................................................................... 10  
 Definition of Baseline ............................................................................... 10  
 Missing Data ............................................................................................ 11  
 Timing of Interim Analysis and Sample Size Reassessment.................... 11  
 Test Sizes ................................................................................................ 11  
 Multiple Comparisons ............................................................................... 11  
 Analysis Populations ................................................................................ 11  
 Subgroups of Analysis Populations .......................................................... 12  
Data Display Characteristics .................................................................... 13  
 
VI.Subject Accountability .......................................................................................... 13  
 Disposition ................................................................................................ 14  
 Protocol Deviations .................................................................................. 14  
 Subject Characteristics ............................................................................ 14  
 Medical History ......................................................................................... 15  
 Population Inclusions ............................................................................... 15  
VII.Efficacy Analyses ................................................................................................ 15  


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Page 3 of 34  
 Primary Estimand ..................................................................................... 15  
 Primary Efficacy Endpoints ...................................................................... 16  
 Secondary Efficacy Estimand ................................................................... 16  
 Secondary Efficacy Endpoint ................................................................... 17  
 Handling of Missing Item Efficacy Endpoint ............................................. 20  
 Primary Efficacy Outcome Analysis ......................................................... 21  
 Primary Efficacy Sensitivity Analysis ........................................................ 22  
 Secondary Efficacy Analyses ................................................................... 22  
Secondary Sensitivity Analyses ............................................................... 23  
 
Overview of Inferential Efficacy Analyses ................................................ 24  
 Exploratory Analyses ............................................................................... 25  
 Pharmacokinetics ..................................................................................... 25  
VIII.Safety Analyses ................................................................................................. 25  
 Treatment Exposure and Compliance ...................................................... 25  
 Adverse Events ........................................................................................ 25  
 C-SSRS.................................................................................................... 27  
 Clinical Laboratory Results....................................................................... 28  
 Vital Signs and Pulse Oximetry ................................................................ 28  
 Physical Examination ............................................................................... 29  
 Electrocardiograms .................................................................................. 29  
 Prior and Concomitant Therapy ............................................................... 30  
Assessments of Alertness/Sedations and other Safety Rating Scales ..... 31  
 
Others ...................................................................................................... 31 
 
IX.Interim Analysis.................................................................................................... 31  
X.References ........................................................................................................... 31  
XI.Appendices .......................................................................................................... 31  
 Missing or Partial Date Imputation ........................................................... 32  
  
  
  
 


Perception Neuroscience, Inc./ Protocol: PCN-101-21  
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Page 4 of 34  
List of Abbreviations  
  
Abbreviation  
Definition  
˚C  
Celsius  
5D-ASC  
5-Dimensional Altered States of Consciousness Rating Scale  
AE  
Adverse event  
ANCOVA  
Analysis of covariance  
BPRS+  
Brief Psychiatric Rating Scale - Modified 4 Components  
CADSS  
Clinician Administered Dissociative States Scale  
CFB  
Change from baseline  
CGI-I  
Clinical Global Impression - Improvement   
CGI-S  
Clinical Global Impression - Severity   
CI  
Confidence interval  
COVID-19  
Coronavirus disease 2019  
CSSRS  
Columbia Suicide Severity Rating Scale  
DB  
Double-blind  
ECG  
Electrocardiogram  
eCRF  
Electronic case report forms  
EQ 5D-3L  
European Quality 5 Dimensions - 3 Levels  
EU  
European Union  
FAS  
Full analysis set  
GAD-7  
Generalized Anxiety Disorder 7-Item  
HAM-D  
Hamilton Depression Rating Scale  
IV  
Intravenous  
kg  
Kilogram  
LOCF  
Last observation carried forward  
MADRS  
Montgomery Åsberg Depression Rating Scale  
MAR  
Missing-at-random  
MedDRA  
Medical Dictionary for Regulatory Activities  
mg  
Milligram  
MGH-ATRQ  
Massachusetts General Hospital Antidepressant Response 
Questionnaire  
MINI  
Mini-International Neuropsychiatric Interview  
mmHg  
Milligrams of mercury   
MMRM  
Mixed model repeated measures  
MOAA/S  
Modified Observer’s Assessment of Alertness/Sedation  
MNAR  
Missing-not-at-random  
OR  
Odds ratio  


Perception Neuroscience, Inc./ Protocol: PCN-101-21  
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Page 5 of 34  
Abbreviation  
Definition  
PPAS  
Per-protocol analysis set  
PT  
Preferred term  
Q1  
Quartile 1  
Q3  
Quartile 3  
QIDS-SR-16  
Quick Inventory of Depressive Symptomatology - 16 Items  
QTcF  
QT intervals corrected by Fridericia’s formula  
SAP  
Statistical analysis plan  
SAS  
Safety analysis set  
SD  
Standard deviation  
SOC  
System organ class  
SpO2  
Oxygen saturation  
TEAE  
Treatment-emergent AE  
TRD  
Treatment Resistant Depression  
US  
United States  
VAS  
Visual analog scale  
WHO  
World Health Organization  
  
  


 Perception Neuroscience, Inc./ Protocol: PCN-101-21  
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Page 6 of 34  
 
I.  
Introduction  
 
  
Background  
Perception Neuroscience, Inc., is developing PCN-101 (R-ketamine) for the 
treatment of treatment resistant depression (TRD). Ketamine is a parenterally 
administered anesthetic agent that was initially approved in the United States (US) in 
1970. Since then, it has seen wide use in both adult and pediatric populations.  
Intranasally administered S-ketamine was approved in 2019 in the US and European 
Union (EU) for the treatment of treatment-resistant depression. Evidence from 
nonclinical depression model studies of subanesthetic doses in rodents suggests 
that R-ketamine has equal or potentially greater efficacy compared with S-ketamine, 
and both nonclinical and preliminary clinical studies suggest that R--ketamine may 
have a more favorable safety profile with a decreased incidence of adverse events 
(AEs) (eg, dissociative, cognitive impairment, and psychotomimetic effects) 
compared with S-ketamine. Based on nonclinical studies, R-ketamine may also have 
less abuse potential than S-ketamine. Overall, the available data support the 
concept of the use of PCN-101 as a potentially better tolerated, rapidly acting 
antidepressant compared with ketamine and S-ketamine, which may support the use 
of PCN-101 outside of a supervised, in-clinic environment.  
 
  
Scope of Document  
This statistical analysis plan (SAP) is based on the amended version 4.0 of the 
protocol dated 19May2022. It will govern the analysis of data for this study. The SAP 
may be modified until the time of database lock for the final analysis. Any deviations 
from the SAP, including post- treatment unblinding, will be documented as such in 
the study report. Supportive reference materials include protocol of the study and the 
accompanying study data collection documents.  
II.  
Protocol Objectives and Analysis Endpoints  
The primary, secondary, safety, and exploratory objectives of the current study are 
shown along with their corresponding endpoints in Table 1.  
Table 1 Objectives and Endpoints  
Objectives  
Endpoints/Estimands  
Primary  
  
 To determine the efficacy of 2 doses 
(30 milligram [mg] and 60 mg) of 
intravenous (IV) PCN-101 compared 
with placebo in improving 
depressive symptoms in subjects 
with TRD as assessed by change 
• MADRS change in total score 
assessed from baseline (predose) to 
24 hours after the start of the 
infusion of PCN-101.  
• See Section VII.A Primary Estimand 
for details on estimand definition  


 Perception Neuroscience, Inc./ Protocol: PCN-101-21  
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Page 7 of 34  
 
from baseline to 24 hours after the 
start of the infusion of PCN-101 in  
 
Objectives  
Endpoints/Estimands  
the Montgomery Åsberg Depression 
Rating Scale (MADRS) total score. 
 
Secondary  
  


 Perception Neuroscience, Inc./ Protocol: PCN-101-21  
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• 
To assess the proportion of subjects 
with a response (defined as ≥ 50% 
improvement in MADRS total score 
from predose).  
  
  
  
  
  
  
  
  
  
  
  
   
• 
To assess the proportion of subjects 
with remission (defined as MADRS 
total score ≤ 10).  
   
  
• 
To define changes in Hamilton 
Depression Rating Scale (HAM-D).  
  
• 
To define changes in Generalized 
Anxiety Disorder 7-Item (GAD-7).  
  
• 
To assess Clinical Global  
Impression - Severity (CGI-S) and 
Clinical Global Impression - 
Improvement (CGI-I).  
  
• 
To define changes in Quick  
Inventory of Depressive  
Symptomatology - 16 Items 
(QIDSSR-16)*.  
  
• 
MADRS total score assessed at 2 
and 4 hours, 7 and 14 days after the 
start of the infusion (Days 8 and 15, 
respectively). Note, for the 2 hour 
and 4 hour recall periods, the sleep 
items are not assessed, and predose 
scores for these items obtained on 
the same day will be carried forward. 
  
  
• 
Proportion of subjects with ≥ 50% 
improvement in MADRS total score 
at 24 hours, 7 days and 14 days after 
start of infusion (Days 8 and 15, 
respectively).  
  
• 
Proportion of subjects with a  
MADRS total score ≤ 10 at 24 hours, 
7 days and 14 days after start of 
infusion (Days 8 and 15, 
respectively).   
  
• 
Changes in HAM-D on Day 8 and  
Day 15 after start of infusion.  
  
• 
Change from baseline in GAD-7 by 
visit.  
  
• 
Change from baseline in CGI-S by 
visit and CGI-I (calculated from 
predose CGI-S).  
  
  
• 
Change from baseline in QIDS-SR-
16-by visit*.  
  
  
  
  
Objectives  
Endpoints/Estimands  


 Perception Neuroscience, Inc./ Protocol: PCN-101-21  
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Page 9 of 34  
 
 To define changes in European 
Quality 5 Dimensions - 3 Levels 
(EQ 5D-3L).  
  
  
 Change from baseline in EQ 5D-3L 
by visit.  
Safety  
  
 To determine the safety and 
tolerability of 2 doses of PCN-101 
administered IV in subjects with 
TRD compared with placebo.  
• 
Adverse events (AEs)  
• 
Columbia Suicide Severity Rating  
Scale (C-SSRS)  
• 
Clinical laboratory parameters  
• 
Vital signs and oxygen saturation  
(SpO2)  
• 
Physical Examination  
• 
12-lead electrocardiogram (ECG)  
• 
Concomitant Therapies  
• 
Modified Observer’s Assessment of 
Alertness/Sedation (MOAA/S)  
• 
Clinician Administered Dissociative  
States Scale (CADSS)  
• 
Brief Psychiatric Rating Scale -  
Modified 4 Components (BPRS+)  
• 
5-Dimensional Altered States of  
Consciousness Rating Scale  
(5D-ASC)  
* An abbreviated version (ie, QIDS-SDR-14) is only done once at Visit 2 ‘discharge’ 
timepoint. For this timepoint, the decreased/increased weight items score from Day 
1 predose will be carried forward to Visit 2 in the calculation of the total score at Visit 
2 ‘discharge’.  
  
III.  
Study Design  
 
  
Design Overview   
This is a Phase 2a, double-blind, randomized, placebo-controlled, multicenter study 
comprised of 3 phases: screening (up to 2 weeks),  [Day -15 to Day -2]), In-Clinic 


 Perception Neuroscience, Inc./ Protocol: PCN-101-21  
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Page 10 of 34  
 
Treatment (Day -1 to Day 2; including double-blind treatment [Day 1]), and post-
treatment follow-up (7 and 14 days after infusion, on Days 8 and 15, respectively). 
The study consists of 3 arms: placebo, PCN-101 Solution for Injection 30 mg, and 
PCN-101 Solution for Injection 60 mg. A total of 93 adult subjects with TRD will be 
randomly allocated in equal cohorts of 31 subjects/arm to the 3 arms of the study in 
a blinded manner. Randomization will be stratified by region (US, EU).  
Subjects will be randomized within 14 days of screening (Visit 1). Subjects will be 
admitted to the clinic the evening prior to study treatment administration (Day -1, 
Visit 2) and undergo baseline testing to ensure continued study eligibility. Study 
treatments will be infused IV over 40 minutes the next morning (Day 1, Visit 2). 
Starting immediately prior to dosing, subjects will be monitored closely for safety. 
Additionally, the subjects’ alertness, mood, and other psychological parameters will 
be assessed by clinician- and patient completed scales and questionnaires. Subjects 
will be discharged no earlier than 24 hours postinfusion and after the final in clinic 
assessments have been completed (Day 2, Visit 2). Subjects will be asked to return 
to the clinic approximately 6 days (Day 8, Visit 3) and 13 days (Day 15, Visit 4) after 
discharge to assess the safety and tolerability of the study treatments and to 
determine the durability of the antidepressant effect.  
During the coronavirus disease 2019 (COVID-19) pandemic, the specific guidance 
from local public health and other competent authorities regarding the protection of 
individuals’ welfare must be applied. If subjects cannot attend follow  up visits in 
person because of restrictions arising as a consequence of the COVID-19 
pandemic, the Investigator must discuss with the Medical Monitor potential 
mitigation.  
 
  
Study Population  
Eligibility for participation in the study will be based on the inclusion/exclusion 
criteria. Specifically, candidates must meet all entry criteria at Screening or at the 
time point specified in the individual eligibility criteria listed in the protocol. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, 
also known as protocol waivers or exemptions, is not permitted.  
 
  
Sample Size Predictions  
The intent of the primary efficacy analysis is to demonstrate superiority of at least 1 
therapeutic dose of PCN-101 Solution for Injection (30 mg or 60 mg) versus placebo 
based on the change in the MADRS total score from predose to 24 hours postdose.  
For the primary analysis, a sample size of 93 randomized subjects (31:31:31) will 
provide 80% power to detect an 8-point difference between each PCN-101 Solution 
for Injection dose and placebo in the mean change from baseline MADRS total score 
at 24 hours postdose, using a t-test with α = 0.05 (2 tailed) and assuming a common 
standard deviation (SD) of 11.  


 Perception Neuroscience, Inc./ Protocol: PCN-101-21  
 CONFIDENTIAL 
  
Page 11 of 34  
 
Approximately 20 study centers in the EU and US are expected to participate in this 
study. The enrollment of 93 subjects is planned. Subjects who do not receive a dose 
of study treatment on Day 1 (Visit 2) will be replaced.  
 
  
Treatment Randomization  
Two doses (30 mg and 60 mg) of IV PCN-101 will be compared with placebo to 
determine the most effective dose in improving depressive symptoms in subjects 
with TRD.   
Randomization will be used to minimize the bias in the assignment of subjects to 
treatment arms and to increase the likelihood that known and unknown subject 
characteristics are evenly balanced across treatment arms. Randomization will be 
stratified by region (US, EU). This will improve the validity of the statistical 
comparisons among treatment arms across different geographical regions. Blinded 
treatment will be used to reduce any potential bias during the collection of data and 
the analysis of clinical endpoints.  
 
  
Assessment Schedule  
The various assessments that will be conducted during this study are summarized in 
the protocol.  
IV.  
Interventions  
 
  
Clinical Trial Material  
The investigational medical products are PCN-101 (30 mg and 60 mg) and Placebo.   
V.  
General Analytical Considerations  
 
  
Data Sources  
All reported study data will be recorded on the electronic case report forms (eCRF) 
using Medidata Rave EDC. During the data collection process, automated quality 
assurance programs will be used to identify missing data, out-of-range data, and 
other data inconsistencies.  
 
  
Definition of Baseline  
Unless otherwise indicated, the baseline is defined as the most recent non-missing 
and evaluable observation of the investigated parameter (including any unscheduled 
or repeat observations), prior to study drug dosing. Details are provided within the 
respective analysis sections of this SAP. 


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A change from baseline will be calculated as the post-baseline measurement minus 
the baseline measurement. If either the baseline or post-baseline value is missing, 
then the change from baseline value will be considered missing.  
 
  
Missing Data  
 
1.  
Primary and Secondary Endpoints  
In general, the missing data which is observed from this study will be assumed to be 
missing-at-random (MAR).   
Since subjects are confined to clinic at the time of the primary endpoint, it is 
anticipated that missing data will be infrequent. No imputation will be applied to 
primary analysis.   
Baseline values will not be carried forward.   
 
2.  
Imputation of Partial Dates  
Partial dates are allowed in selected eCRFs including but not limited to AE onset and 
resolution dates, concomitant therapy start and stop dates, and medical history 
dates. An entry for the year is required in the eCRF system for each of these dates. 
Only the month and day may be entered as unknown. Dates from these forms will be 
reported in listings as collected. Every effort will be made to query missing dates.  
A set of imputation rules will be implemented for the determination of whether an AE 
is treatment-emergent, or a therapy is concomitant. For the imputation methods of 
missing start or end dates in the classification of treatment-emergence or 
concomitant therapy, refer to Section XI.A Missing or Partial Date Imputation.  
 
  
Timing of Interim Analysis and Sample Size Reassessment  
Not applicable.  
 
  
Test Sizes  
Statistical hypothesis testing will be performed based on the comparison of PCN-101  
60 mg and 30 mg versus placebo, in two-sided tests with a significance level α=0.05. 
The 95% of CI of the mean treatment difference will be two-sided.  
 
  
Multiple Comparisons  
No multiple comparison adjustments will be made for analyses.   
 
  
Analysis Populations   
Analysis sets are defined as described in Table 2:  


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Table 2 Description of Analysis Sets  
Analysis set  
Description  
Screened Analysis Set  
All subjects who signed the informed consent 
form.  
Full Analysis Set (FAS)  
The FAS will consist of all randomized subjects 
who receive any amount of study treatment and 
have at least 1 postbaseline assessment 
available. This population will serve as the basis 
for efficacy analysis.   
Subjects will be analyzed according to their 
randomized treatment.  
Safety Analysis Set (SAS)  
The SAS will consist of all randomized subjects 
who receive any amount of study treatment.  
This analysis set will be used for all summaries of 
subject disposition, demographic and baseline 
data, and safety information including AE 
incidence.   
Subjects will be analyzed according to the 
treatment they actually received.  
   
 
  
Subgroups of Analysis Populations  
Data from subgroups of subjects in the defined analysis populations will be analyzed 
as specified below. These analyses will comprise descriptive summaries; the goal 
will be to identify signals of additional effects that analyses of data from the defined 
populations do not take into account.  Such analyses will be considered exploratory 
and other subgroups may be considered.  They may not be sufficient for drawing 
conclusions; hence, these analyses will not involve hypothesis testing.    
• 
Age Group (18-44, 45-65 years) )  
• 
Sex (Male, Female)  
• 
Region (United States or Europe)  
• 
Duration of depression (<5 years, 5-10 years, > 10 years)  
• 
Duration of current episode of depression (weeks)  
• 
Number of previous treatment failures in the current episode (<3, >=3)  
• 
Baseline MADRS Score (<35, ≥35)  
• 
Baseline medication  
o Selective Serotonin reuptake inhibitor (SSRI)  


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o Serotonin and norepinephrine reuptake inhibitor (SNRI)  
o Antidepressant with adjunctive medications  
  
 
  
Data Display Characteristics  
Data displays produced for this study will include three types—summary tables, data 
listings, and figures. Unless stated otherwise, data listings will be produced for all 
recorded data. Summary tables will be produced as specified in the following 
sections. Additional data listings will be produced for outcome measures that involve 
extensive procedures to derive the analyzed outcomes. Figures will be produced 
when specified in sections to follow.  
Data listings will simply list the data recorded on the CRF or derived for each 
subject. They will be ordered by treatment, site, subject number, and time of 
assessment. When expedient, additional levels of ordering hierarchy may reflect 
subsets of assessments within subject. Data listings will not display subject initials.  
Summary tables will display summary statistics calculated for each of the treatment 
groups, unless described otherwise in the following sections. Tables may have either 
of two general layouts. When the greatest interest is in direct comparison of one 
treatment group with the others at particular times, different columns of a summary 
table will display the statistics for the different treatment groups.   
The summary statistics displayed will be a function of the type of data associated 
with the summarized assessment.  Unless stated otherwise in relevant sections to 
follow, continuous data will be summarized with the number of non-missing values, 
arithmetic mean, standard deviation, minimum, quartile 1 (Q1), median, quartile 2 
(Q3), and maximum.  Categorical data will be summarized with the number of 
nonmissing values and the numbers of values equal to each of the possible values. 
Percentages of subjects with each of the possible values will be calculated from the 
number of subjects in the corresponding analysis population, unless stated 
otherwise. Some continuous variables may also be grouped into categorical levels 
and evaluated in frequency tables.  
A subset or all of the following tabular column headers will be used in presenting 
data for the study:  
• 
PCN-101 60 mg  
• 
PCN-101 30 mg  
• 
Placebo  
  
Efficacy analysis will be implemented according to the planned randomization 
treatment schedule. Safety analysis will be implemented according to the actual 
dosed treatment.   


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VI.  
Subject Accountability  
Unless otherwise indicated, the subject characteristics will be presented by 
treatment groups for the FAS. The same analysis will be repeated for the SAS if the 
composition of subjects within these analysis sets are different from the FAS.  
 
  
Disposition   
Subject disposition events (screened, randomized, completed treatment, completed 
the study, early discontinuation from the study along with the reason for 
discontinuation) will be summarized using frequency counts and percentages by 
treatment groups.  
The duration of the study will be up to 29 days per subject, which includes a 
screening period, an in-clinic visit, and 2 follow-up visits. A subject will be considered 
to have completed the study if he/she has completed all phases of the study 
including the second follow-up visit.  
All disposition data will be presented in a listing format for the FAS. Subjects who 
failed screening will be presented in a listing format for the Screening Analysis Set.  
 
  
Protocol Deviations  
Major protocol deviations will be reviewed and determined prior to the unblinding of 
this study.   
All deviation data will be presented in a listing format for the FAS.   
 
  
Subject Characteristics  
The subject characteristics defined below will be presented in summary tables using 
the most recent data collected prior to study drug dosing. No formal statistical 
comparisons will be performed.  
All subject characteristic data will be listed by subject for the FAS.  
Data collected for the following subject characteristics at Baseline will be 
summarized by treatment group. Race and ethnicity were not planned to be 
collected at the start of the study as the trial was originally held in Europe only, with 
local regulations preventing the collection of this data. With expansion of enrolment 
to US sites, it was determined by the Sponsor that it would be non-critical to include 
race and ethnicity in the analysis for this proof of concept study. As a result, no race 
or ethnicity data is collected in the study.  
• 
Age (years)  
• 
Age Category (18 to 44 years and 45 to 65 years  
• 
Sex (Male, Female)  


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• 
Region (US or EU)  
• 
Baseline MADRS total score  
• 
Baseline MADRS Score (<35, ≥35)  
• 
Baseline HAM-D total score  
• 
Body Mass Index (kg/m2)  
• 
Duration of depression (years)  
• 
Duration of depression (<5 years, 5 to 10 years, >10 years)  
• 
Total number of depressive episodes to date  
• 
Duration of current episode  
• 
Family history of psychiatric disorder (yes, no, unknown) and 
subcategories  
• 
Number of previous treatment failures in the current episode (<3, >=3)  
• 
Baseline medication*  
o Selective Serotonin reuptake inhibitor (SSRI)  
o Serotonin and norepinephrine reuptake inhibitor (SNRI)  
o Antidepressant with adjunctive medications  
*Baseline medication is defined as medication taken on Day 1.  
  
 
  
Medical History  
Medical history will be coded using Medical Dictionary for Regulatory Activities  
(MedDRA) version 23.0 or higher. System Organ Class (SOC) and Preferred Term 
(PT) will be summarized by number and percentage of subjects having at least one 
occurrence of the event for the FAS only. All Medical history information be listed by 
subject.  
 
  
Population Inclusions  
A hierarchical table of the populations in which Screened Analysis Set subjects were 
included will summarize the relationship of the analysis populations. Given 
population definitions, the Screen Analysis Set will be treated as the parent analysis 
set. The numbers and percentages of Screened Analysis Set included in the FAS, 
SAS and PPAS will be presented for each treatment group. The numbers and 
percentages of FAS subjects included in the SAS and PPAS population will be 
displayed for each treatment group. This table will be produced for subjects in both 
US and Europe regions, and as an overall.  
VII. Efficacy Analyses   
The analysis of the efficacy data obtained from the subjects in this clinical study will 
be performed on the FAS primarily.  
All efficacy analyses will be performed based on a subject’s randomized treatment 
group.  


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Primary Estimand  
The primary estimand is defined as follows  
 Population: Subjects in the FAS and analyzed according to their 
randomized treatment. The analysis population includes all 
randomized subjects who receive any amount of study treatment 
and have at least 1 postbaseline assessment available.  
 Variable: Change in total MADRS score from baseline at 24 hours 
after the start of infusion.  
 Intercurrent event: Incidents where a subject does not receive the full 
treatment infusion will be considered an intercurrent event. The 
intercurrent event will however be handled using a treatment policy 
where all observed values will be used regardless of occurrence of 
an intercurrent event. No imputation is performed in the primary 
efficacy analysis.   
 Population-level summary: Difference in mean change from baseline 
between each PCN-101 group versus placebo  
Additional methodology will be specified for sensitivity and supplementary analyses 
for assessing the robustness of results. These sensitivity or supplementary analyses 
will explore different methods for handling intercurrent events and different 
assumptions for missing data.  
  
 
  
Primary Efficacy Endpoints  
The primary efficacy endpoint will be based on the change in total MADRS score 
from baseline at 24 hours after start of infusion.   
The MADRS is a ten-item diagnostic questionnaire administered by the study staff to 
measure the overall severity of depressive symptoms.   
The total score is computed as the sum of scores across all 10 items. Higher 
MADRS score indicates more severe depression. Each item yields a score of 0 to 6, 
hence the total score ranges from 0 to 60.  
  
𝐶𝑀𝐴𝐷𝑅𝑆𝑡𝑜𝑡𝑎𝑙,24ℎ𝑟 = 𝑀𝐴𝐷𝑅𝑆𝑡𝑜𝑡𝑎𝑙,24 ℎ𝑟 − 𝑀𝐴𝐷𝑅𝑆𝑡𝑜𝑡𝑎𝑙,𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒  
where  
• 
𝐶𝑀𝐴𝐷𝑅𝑆𝑡𝑜𝑡𝑎𝑙,24ℎ𝑟: Change from baseline in total score MADRS at 24 hours 
after the start of infusion  
• 
𝑀𝐴𝐷𝑅𝑆𝑡𝑜𝑡𝑎𝑙,24ℎ𝑟: Total score MADRS at 24 hours after the start of infusion  


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• 
𝑀𝐴𝐷𝑅𝑆𝑡𝑜𝑡𝑎𝑙,𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒: Total score MADRS at Baseline   
 
  
Secondary Efficacy Estimand  
All secondary efficacy estimands are defined using the same population, intercurrent 
event strategy, and population level summary (difference in means or proportions 
between each randomized treatment and placebo, as appropriate) as described in 
Section VII.A Primary Estimand.  
  
 
  
Secondary Efficacy Endpoint  
Change from baseline in MADRS total score at 2 hours, 4 hours, 7 days, and 14 
days after the start of the infusion  
The change from baseline MADRS total score will be analyzed for all analysis 
timepoints.  
Since the sleep items will not be assessed at 2 hours and 4 hours after the start of 
infusion, and the predose scores for these items obtained on the same day will be 
carried forward.   
Proportion of subjects with at least 50% improvement (i.e. reduction) in MADRS total 
score at 24 hours, 7 days, and 14 days after start of infusion  
A subject is considered a responder at a timepoint if a ≥50% improvement in 
MADRS total score (from baseline) is achieved at that timepoint. Any subject who is 
assessed but not considered as responder at a timepoint will be assumed to be a 
non-responder at that timepoint.   
The proportion of subjects who meet this improvement criterion will be analyzed 
across different timepoints.  
Subjects with MADRS total score ≤10 at 24 hours, 7 days, and 14 days after start of 
infusion will be considered to be in remission  
The proportion of subjects who meet this criterion of MADRS total score ≤ 10 will be 
analyzed across different timepoints. Any subject who is assessed but not 
considered as remitter at a timepoint will be assumed to be a non-remitter at that 
timepoint.  
Change in QIDS-SR-16 score from baseline by analysis visit  
The QIDS-SR-16 is a 16-item self-assessed questionnaire which measures 
depression symptoms. Each item contributes a score of 0 to 3.   
Item #6 and #7 measures decreased and increased appetite respectively, hence at 
least 1 of these 2 items should be reported as 0. Similarly, item #8 and #9 measures 


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decreased and increased weights respectively, hence at least 1 of these 2 items 
should be reported as 0.   
An abbreviated version (ie, QIDS-SDR-14) is only done once at Visit 2 ‘discharge’ 
timepoint. For this timepoint, the decreased/increased weight items score from Day 
1 predose will be carried forward to Visit 2 in the calculation of the total score at Visit 
2 ‘discharge’.  
As a result, arithmetically, the maximum (most symptomatic) total score would be 42, 
while the minimum (least symptomatic) total score would be 0.  
The change from baseline QIDS-SR-16 score will be analyzed by timepoint.  
Change in GAD-7 score from baseline by analysis visit  
The GAD-7 is an initial screening tool for generalized anxiety disorder. It consists of 
7 questions pertaining to the different anxiety disorder problems over a 2 week 
period prior to the assessment. Each item contributes a score 0 to 3, where a score 
of 0 indicates ‘Not at all’ and 3 indicates ‘Nearly every day’ for each of the 7 items.  
The GAD-7 total score defined as the summation of scores across all questions. 
Arithmetically, the maximum (most anxiety) total score would be 21, while the 
minimum (no anxiety) total score would be 0.  
The change from baseline GAD-7 score will be analyzed by timepoint.  
Change in EQ-5D-3L index from baseline by analysis visit  
The EQ-5D-3L is a questionnaire that essentially consists of 2 pages - the EQ-5D 
descriptive system and a visual analog scale (VAS). The descriptive system is 
comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each dimension has 3 levels: no problems, some problems, and 
extreme problems. The subject will be asked to indicate his/her health state by 
marking the box for the most appropriate statement in each of the 5 dimensions. The 
VAS records the subject’s self-rated health on a vertical VAS where the endpoints 
are labeled “best imaginable health state” and “worst imaginable health state.” This 
information will be used as a quantitative measure of health outcome.  
The change from baseline EQ-5D-3L descriptive system and VAS will be analyzed 
by timepoint.  
Change in CGI-S (and CGI-I) score from baseline at 24 hours after start of infusion  
The CGI is the general name for two scales: the CGI-S and CGI-I. The CGI-S 
answers the question “Considering your total clinical experience with this particular 
case, how ill is the subject at this time?” on a 7-point scale:   


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 0 = Not Assessed  
 1 = Normal, not at all ill impaired  
 2 = Borderline ill  
 3 = Mildly ill  
 4 = Moderately ill  
 5 = Markedly ill  
 6 = Severely ill  
 7 = Among the most extremely ill patients  
  
CGI-I answers the question “Compared to her/his condition at admission to the 
project, how much has he/she changed?” on a 7-point scale and considers the 
response from the CGIC-S at baseline during the evaluation by the investigator:  
 0 = Not assessed  
 1 = Very much improved  
 2 = Much improved  
 3 = Minimally improved  
 4 = No change  
 5 = Minimally worse  
 6 = Much worse  
 7 = Very much worse  
The change from baseline CGI-S scores will be analyzed by timepoint. Since the 
baseline CGI-S score will be used as a basis in the evaluation of CGI-I by the 
investigator, the CGI-I is evaluated once during the study.  
Change in HAM-D score from baseline by analysis visit  
The HAM-D is a 17-item assessment tool pertaining to symptoms of depression 
experience over the 1 week period prior to assessment.   
Classification of symptoms which may be difficult to obtain can be scored as:  
• 
0 - absent;   
• 
1 - doubtful or trivial  
• 
2 - present  
Classification of symptoms where more detail can be obtained can be expanded to:  
• 
0 - absent;   


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• 
1 - mild;   
• 
2 - moderate;   
• 
3 - severe;   
• 
4 - incapacitating.  
The HAM-D total score is defined as the summation of scores across the 17 items. 
Arithmetically, the maximum (most severe) total score would be 52, while the 
minimum (least severe) total score would be 0.  
The change from baseline HAM-D total score will be analyzed by timepoint.  
 
  
Handling of Missing Item Efficacy Endpoint  
It is theoretically possible that an individual item score of a questionnaire or 
assessment scale is left missing, which would lead to an incomplete calculation of 
the total score. As a result, the following rules will be used to re-calculate total 
scores if an individual item score(s) is not reported.  
Within a single analysis timepoint per patient, if ≥25% of items used to calculate a 
total score for a given scale are missing, the total scale score for that patient and 
timepoint will be considered missing.   
If <25% of items are missing, the total score will be calculated (prorated) as the 
arithmetic mean of non-missing items multiplied by the total expected number of 
items and rounded up to the nearest integer.  
Additionally, separate sensitivity analyses will be performed with missing MADRS 
data imputed with a multiple imputation method. The multiple imputation (MI) method 
assumes a missing-at-random (MAR) data missing pattern. Imputation will be 
performed using the Fully Conditional Specifications parametric regression model. A 
total of 50 imputations will be generated using PROC MI. For each of the 50 
datasets, missing MADRS total score will be imputed using the regression model, as 
implemented in the PROC MI with the following variables considered (as given on 
the VAR statement): Treatment, Region, Baseline MADRS and each subsequent 
post-baseline MADRS score. Response status (Yes, No) and revised change from 
baseline values will be derived in each MI dataset based on the newly imputed data. 
The seed to be used in this MI model is 60773.    
  
Example SAS code for PROC MI is as follows:  
  
PROC MI DATA=MI NIMPUTE=50 SEED=&SEED. OUT=MI1 ROUND=1 MINIMUM=0;  
  
CLASS TRTP REGION1;  
  
VAR TRTP REGION1 ATPTN20 ATPTN40 ATPTN50 ATPTN70 ATPTN80  
ATPTN90;  
  
FCS REG (ATPTN20 = TRTP REGION1);  


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FCS REG (ATPTN40 = TRTP REGION1 ATPTN20);  
  
FCS REG (ATPTN50 = TRTP REGION1 ATPTN20 ATPTN40 );  
  
FCS REG (ATPTN70 = TRTP REGION1 ATPTN20 ATPTN40 ATPTN50) ;  
  
FCS REG (ATPTN80 = TRTP REGION1 ATPTN20 ATPTN40 ATPTN50  
ATPTN70 );  
  
FCS REG (ATPTN90 = TRTP REGION1 ATPTN20 ATPTN40 ATPTN50  
ATPTN70 ATPTN80);  
  
RUN;  
  
Note: TRTP = randomized treatment group, REGION1 = region (US/Europe). Note: 
Each of the ATPTNxx variables represent the MADRS score at each analysis 
timepoint (Pre-dose, 2 hours, 4 hours, 24 hours, Day 8 and Day 15).  
  
The imputation models may be modified based on the actual data if there is an issue 
in model convergence. If the missingness at the MADRS 24 hour timepoint is >5%, 
additional analyses exploring missing-not-at-random (MNAR) assumptions will be 
performed.   
  
 
  
Primary Efficacy Outcome Analysis  
The primary objective endpoint of change from baseline MADRS total score at 24 
hours post start of infusion will be tested with a 1-sided test of equivalence in means 
at 0.025 significance level, a mixed model repeated measures (MMRM) model will 
be used to analyze the change from baseline values using fixed effects of treatment 
group, analysis visit, region and treatment group-by-visit interaction. The baseline 
value will be included as a covariate. An unstructured covariance matrix will be used 
to model the within-patient variance-covariance errors. A random effect of subject will 
be included. If the unstructured covariance structure matrix results in a lack of 
convergence, the heterogenous first-order autoregressive covariance structure will 
be used as the first alternative, followed by the compound symmetry covariance 
structure. The Kenward-Roger approximation will be used to estimate the 
denominator degrees of freedom. Any missing data are assumed to be missing at 
random. . The hypothesis is defined as follows:  
𝐻0: ∆active − ∆placebo = 0          𝑣𝑠           𝐻1: ∆active − ∆placebo< 0  
  
where  
 ∆active: Mean change from baseline MADRS total score at 24 hours after start of 
infusion (Test)  
 ∆placebo: Mean change from baseline MADRS total score at 24 hours after start 
of infusion (Reference)  


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Model-based adjusted means for each treatment group, pairwise adjusted 
differences with placebo (reference), 95% CI for the differences and the associated 
p-values will be presented at each analysis visit. Each PCN-101 dose will be 
compared with placebo. An example of the SAS code is provided below:  
proc mixed data=data;   class USUBJID 
AVISITN TRTPN SITEID;  
  model CHG = BASE REGION1 AVISITN TRTPN AVISITN*TRTPN/s cl ddfm=kr;   
repeated AVISITN / TYPE=UN SUB=USUBJID;   lsmeans AVISITN * TRTPN / 
diff; run;  
Since subjects are confined to the clinic at the time of the primary endpoint, it is 
anticipated that missing data will be infrequent. No imputation will be applied for this 
primary efficacy analysis but missing data assumptions will be explored in sensitivity 
analyses.  
The described analysis will be performed on the FAS.  
 
  
Primary Efficacy Sensitivity Analysis  
Sensitivity analyses reviewing missing data assumptions will be performed using the 
same MMRM model specifications as described in Section VII.F Primary Efficacy 
Outcome Analysis. One analysis will be performed for only the data collected from 
subjects who were treatment compliant and a separate analysis will be performed 
with those who completed the study.   
  
In addition, sensitivity analysis exploring the MAR assumptions with multiple 
imputation of MADRS related endpoints will be performed as described in Section 
VII.E Handling of Missing Item Efficacy Endpoint. Analysis of each primary and 
secondary MADRS endpoints will be performed for each of the MI datasets. The 
analyzed results from the 50 imputed datasets will be combined based on Rubin’s 
rules (Rubin, 1987) using PROC MIANAYLZE in SAS to estimate the pooled 
analysis results.  
  
 
  
Secondary Efficacy Analyses  
Change from baseline in MADRS total score  
Summaries of actual values and changes from baseline score will be presented by 
treatment group for all analysis timepoints (including 24 hours after start of infusion), 
beginning with the Baseline visit for the FAS.   
  
Proportion of subjects with ≥50% improvement in MADRS total score  
For the responder analysis based on a ≥50% improvement in MADRS total score at 
each analysis visit, the proportion of responders will be calculated using frequency 
counts and percentages, presented for each treatment group.   


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The response rate between each PCN-101 dose versus Placebo at each analysis 
visit will be compared using a logistic regression using fixed effects of treatment 
group, analysis visit, region and treatment group-by-visit interaction. The baseline 
value will be included as a covariate. Odds ratios (ORs), corresponding two-sided 
95% CI and p--values will be derived.   
Proportion of subjects with a MADRS total score ≤ 10  
The same analysis will be performed as described for the endpoint of proportion of 
subjects with ≥50% improvement in MADRS total score.  
Change from baseline in QIDS-SR-16, GAD-7 and EQ-5D-3L  
The MMRM model with the same specification as detailed in Change from baseline 
in MADRS total score will be used to analyze the following secondary efficacy 
measures for the FAS. Missing data will not be imputed.  
• 
Change from baseline in QIDS-SR-16 by visit  
• 
Change from baseline in GAD-7 by visit  
• 
Change from baseline in EQ-5D-3L VAS by visit  
The adjusted means for each treatment group, pairwise adjusted differences 
between each treatment group, 95% CI for the differences will be presented at each 
visit.  
Summaries of actual values and changes from baseline scores will be presented by 
treatment group for each analysis timepoint.   
For EQ-5D-3L, frequency counts and percentages of each response to the 5 
domains descriptive system will be presented for each treatment group for all 
analysis visits.  
Clinician Global Impression-Severity (CGI-S) and Clinician Global 
ImpressionChange (CGI-I)  
Summaries of actual values and changes from baseline CGI-S scores will be 
presented by treatment group for each analysis timepoint. Only the actual values of 
CGI-I will be presented by treatment group for each analysis timepoint.  
The observed CGI-S and CGI-I will also be summarized categorically by the number 
and percentage of subjects reporting each score at each assessment.  
The CGI-S and CGI-I scores will be analyzed using the same MMRM model 
specifications as outlined in the primary efficacy analysis.   Since CGI-I cannot be 


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performed at baseline, the baseline CGI-S score will be used as a covariate in the 
CGI-I MMRM model.   
Model-based point estimates for the difference in adjusted means, 95% CIs and p-
values will be reported. Each PCN-101 dose will be compared with placebo. .    
 
  
Secondary Sensitivity Analyses  
All inferential statistical analyses as described in Section VII.H Secondary Efficacy 
Analyses will be performed with only the data collected from subjects who completed 
the study. The secondary sensitivity analyses include:  
  
• 
MMRM model for   
o Change from baseline in QIDS-SR-16  o Change from 
baseline in GAD-7  o Change from baseline in EQ-5D-
3L VAS   
• 
Logistic Regression for  o Proportion of subjects with ≥50% improvement in 
MADRS total score  
o Proportion of subjects with a MADRS total score ≤ 10  
The secondary MADRS endpoints will also be analyzed using the multiple imputation 
approach. The estimates and standard errors of the log (odds ratio) based on the 50 
imputed datasets will be combined by applying Rubin’s rules to report a pooled 
result. The combined odds ratio and associated 95% CI and the resulting p-value will 
be provided.   
  
 
  
Overview of Inferential Efficacy Analyses  
The following Table 3 shows an overview of the types of inferential analyses that will 
be performed for each efficacy endpoint.  
  
Table 3 Overview of Inferential Efficacy Analyses  
Endpoint  
Main  
Sensitivity  
Primary:   
Change from baseline MADRS total 
score   
MMRM 
(observed 
cases [OC], FAS)  
MMRM (MI, 
complete cases,  
and treatment 
compliant cases, 
FAS)  


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Secondary:   
≥50% improvement in MADRS total 
score  
Logistic Regression 
(OC, FAS)  
Logistic  
Regression (MI, 
complete cases 
and treatment 
compliant cases,  
FAS)  
MADRS total score ≤ 10  
Logistic Regression 
(OC, FAS)  
Logistic  
Regression (MI, 
complete cases 
and treatment 
compliant cases,  
FAS)  
Change from baseline in QIDS-SR-16, 
GAD-7 and EQ-5D-3L  
MMRM (OC, FAS)  
MMRM (complete 
cases and 
treatment 
compliant cases,  
FAS) 
CGI-S, CGI-I score  
MMRM (OC, FAS)  
MMRM (complete 
cases and 
treatment 
compliant case, 
FAS)  
  
  
 
  
Exploratory Analyses  
All descriptive statistics analyses which are performed on the FAS as detailed in 
Section VII Efficacy Analyses for the primary and secondary endpoints will be 
repeated based on the subgroup categories as detailed in Section V.H Subgroups of 
Analysis Populations.  
 
  
Pharmacokinetics  
Not applicable.  
VIII. Safety Analyses  
All safety related analyses will be performed on the SAS except for the listings of 
SAEs and AEs leading to death, which will be presented for the FAS.  


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Treatment Exposure and Compliance  
Study treatment non-compliance is defined as having an infusion duration with a 
deviation of more than 5 minutes from the 40 minute infusion time (ie, <35 or >45 
minutes of infusion duration).  
Exposure to PCN-101 or Placebo will be summarized with descriptive statistics for 
the following exposure measures.   
 Duration of Treatment (minutes)  
o If not interrupted, defined as the time of end of infusion – the 
time of start of infusion+1  
o If interrupted, defined as the (time of end of infusion – the time 
of start of infusion+1) - (infusion restart time –  infusion stop 
time+1)  
Details of the infusion drug administration will be listed by subject.  
 
  
Adverse Events  
Adverse events (AEs) will be documented on the AE eCRF and monitored 
continuously throughout the study. Adverse events will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA), version 23.0 or higher, associating 
lower-level terms with preferred terms and system organ classes by the primary 
hierarchy. All adverse events will be included in the listings.  
Treatment-emergent AEs (TEAEs) are defined as AEs that first occurred or 
worsened in severity after the start of infusion but no later than the second follow-up 
visit.  
The tables will display counts and percentages of subjects who reported at least one 
TEAE in each system organ class represented in the AE data. Within each system 
organ class, the tables will display the counts and percentages of subjects reporting 
at least one TEAE, as designated by the preferred terms.  
If a subject has multiple occurrences of an adverse event, the worst severity grade 
and the highest level of relationship to study drug for a given AE will be used in 
summary tables.   
Adverse events that have missing onset dates will be considered as treatment 
emergent unless the stop date is known to be prior to the first administration of the 
study medication. If the adverse event onset date is partial, the date will be 
correlated as far as possible with the date of study medication. Adverse events will 
be assumed to be treatment-emergent, unless there is clear evidence (through 
comparison of partial dates) to suggest that the adverse event started prior to the 


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first dose of study medication. Detailed imputation rules for dates can be found in 
Section V.C.2 Partial Dates.   
An overall summary of AE table will summarize the number of subjects who meet the 
following criteria for:  
 Number of subjects with any AEs  
 Number of subjects with any TEAEs  
 Number of subjects with any TEAEs by maximum severity  
 Number of subjects with any Treatment-emergent SAEs  
 Number of subjects with any Treatment-emergent SAEs by 
maximum severity   
 Number of subjects with any TEAEs related to study drug (possibly, 
probably, definitely related or unknown)  
 Number of subjects with any SAEs related to study drug (possibly, 
probably, definitely related or unknown)  
 Number of subjects with any TEAEs resulting in death  
 Number of subjects with any severe TEAEs related to study drug 
(possibly, probably, definitely related or unknown)  
 Number of subjects with any TEAEs resulting in the permanent 
discontinuation of study treatment  
 Number of subjects with any treatment-emergent SAEs resulting in 
the permanent discontinuation of study treatment  
 Number of subjects with any TEAEs resulting in the discontinuation 
from study   
 Number of subjects with any TEAEs of COVID-19   
Treatment-emergent AEs will be tabulated according to the MedDRA system organ 
class and preferred term and will include the following categories. Analysis marked 
with and asterisk (*) will also be tabulated based on the preferred term in descending 
frequency only.  
 All TEAEs *  
 TEAEs related to study drug (possibly, probably, definitely related or 
unknown)   
 Treatment-emergent SAEs  
 Treatment-emergent SAEs related to study drug (possibly, probably, 
definitely related or unknown)  
 Severe TEAEs   


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 Severe TEAEs related to study drug (possibly, probably, definitely 
related or unknown)   
 TEAEs resulting in the permanent discontinuation of study treatment  
 TEAEs by maximum severity grade  
The following AE listings (including both TEAEs and non-TEAEs) will be produced. 
AEs recorded at any time of the study (ie, not necessarily TEAEs only) will be 
included.  
 All AEs  
 All SAEs  
 Severe SAEs   
 AEs leading to discontinuation of study treatment  
 
AEs leading to death  
 
  
C-SSRS  
The C-SSRS is a questionnaire used for suicide assessment developed by multiple 
institutions, including Columbia University. The scale is evidence-supported and is 
part of a national and international public health initiative involving the assessment of 
suicidality.   
The number of subjects who reported “Yes” to each of the questions relating to 
suicidal ideation and suicidal behavior at any post-baseline timepoint will be 
summarized by treatment group.  
All C-SSRS assessments details will be listed.  
 
  
Clinical Laboratory Results  
Laboratory values will be presented in tables and data listings using System 
International (SI) units.   
For chemistry and hematology parameters, summaries of actual values and changes 
from baseline will be presented by treatment group for each scheduled assessment 
timepoint, beginning with the Baseline visit. For this analysis, any lab collection 
performed on unscheduled analysis visits will not be summarized, with the exception 
of the inclusion of unscheduled pre-dose assessments used in the classification of 
baseline, as described in Section V.B Definition of Baseline.   
For chemistry and hematology parameters, shift tables summarizing the number and 
percentages of patients who were normal at baseline, but who became abnormal 
subsequently, will also be displayed. For this analysis, any lab collection performed 
on unscheduled analysis visits will be included for analysis.  


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All laboratory data (including and not limited to chemistry, hematology, urinalysis, 
serology, pregnancy, urine alcohol, SARS-CoV-2) will be listed, including normal 
ranges and fasting status, if applicable.   
For chemistry, hematology, and urinalysis, any laboratory abnormalities will be listed 
separately. The abnormal laboratory listing will provide the entire profile for each 
subject and parameter with an abnormal post-baseline result.  
 
  
Vital Signs and Pulse Oximetry  
For vital signs (systolic and diastolic blood pressure, tympanic/temporal temperature, 
pulse, respiratory rate) and pulse oximetry, summaries of actual values and changes 
from baseline will be presented by treatment group for each scheduled assessment 
timepoint, beginning with the Baseline visit. For this analysis, any lab collection 
performed on unscheduled analysis visits will not be summarized, with the exception 
of the inclusion of unscheduled pre-dose assessments used in the classification of 
baseline, as described in Section V.B Definition of Baseline.   
Vital signs will consist of three (3) blood pressure measurements (recorded at 
intervals of at least 1 minute). The arithmetic mean of the three (3) blood pressure 
readings will be recorded in the CRF and used for this analysis.  
Temperature data collected via tympanic or temporal methods will be pooled for 
analysis.  
The incidence of clinically relevant abnormality will be summarized by treatment. For 
this analysis, any unscheduled post-baseline records will be included for 
assessment. A listing of clinically relevant abnormality vital signs will be displayed.  
  
Table 4 Potential Clinically Relevant Abnormalities in Vital Signs  
Parameter  
Unit  
Low  
High  
Systolic blood pressure  
mmHg  
≤ 90 or CFB ≤ -20  ≥ 180 or CFB ≥ 20   
Diastolic blood pressure  
mmHg  
≤ 50 or CFB ≤ -15  ≥ 105 or CFB ≥ 15   
Pulse  
beats/min  
≤ 50 or CFB ≤ -15 
≥ 120 or CFB ≥ 15  
Temperature  
˚C  
CFB ≤ -2  
≥ 38.3 or CFB ≥ 1.1 
Respiratory Rate  
breaths/min <8  
Not applicable  
Oxygen Saturation  
%  
< 90%  
Not applicable  
CFB = change from Baseline.  


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All vital signs data will be listed  
 
  
Physical Examination  
All physical examination results will be listed by subject.  
 
  
Electrocardiograms  
12-Lead ECGs will be obtained using an ECG machine that automatically calculates 
the parameters for analysis. If abnormal, the ECG needs to be repeated.   
An overall interpretation of the ECG results, PR intervals, RR intervals, QT 
uncorrected intervals, QT intervals corrected by Fridericia’s formula (QTcF) will be 
listed by subject.  
In the case where a second (repeat) measurement was taken for a particular 
timepoint, only the second (repeat) measure will be included for analysis and the first 
measure will not be analyzed.  
For the following 12-lead ECG parameters, summaries of values and its changes 
from baseline will be presented by treatment group for each scheduled assessment 
timepoint, beginning with the Baseline visit.   
• 
Heart rate   
• 
PR interval  
• 
QRS interval  
• 
QT interval (uncorrected)  
• 
QT interval corrected with Fridericia’s formula (QTcF)  
A separate summary table will provide the number and percentage of subjects 
meeting the following criteria post-baseline. For this analysis, any ECG performed 
on unscheduled analysis visits will be included for analysis. However, any initial 
measurement which was superseded by a repeat measurement within the same 
analysis timepoint would NOT be included for this analysis.  
 Absolute QTcF interval prolongation:  
o QTcF interval ≥ 450 msec  
o QTcF interval ≥ 480 msec  
o QTcF interval ≥ 500 msec  
 Change from baseline in QTcF interval:   
o QTcF interval increase from baseline ≥ 30 msec  


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o QTcF interval increase from baseline ≥ 60 msec  
In the case where a subject reports qualifying records (ie, ignoring superseded initial 
readings) of both Abnormality with Clinical Significance and Abnormality without 
Clinical Significance at different analysis timepoints in a post-baseline period, the 
most severe record (ie, abnormality with clinical significance) will be selected for 
summarization.   
A listing of all ECG measures will be presented.  
 
  
Prior and Concomitant Therapy  
Concomitant therapy is defined as any therapy with a start date after or on the date 
of the study treatment and continuing after the study treatment (ie, including up to 
the second follow-up visit or ongoing). Any therapy with a start date after the second 
follow-up visit will not be considered a concomitant therapy.   
Any therapy which started prior to the infusion of study treatment is defined as a 
prior therapy. For the imputation of missing therapy dates in the categorization of 
prior vs concomitant status, refer to Section XI.A Missing or Partial Date Imputation.  
Concomitant medications will be coded using World Health Organization (WHO) 
Drug version September 2020 or higher coding dictionary and will be summarized by 
the anatomical main class (1st level) of each coded medication and, within that, the 
preferred name of the coded medication.   
Subjects are counted only once in each therapeutic class category. Prior and 
concomitant medications will be summarized separately and tabulated for each 
treatment group using frequencies and percentages. Percentages will be based on 
the number of subjects in each treatment group. Prior and concomitant medications 
and therapies will be listed by subject.  
 
  
Assessments of Alertness/Sedations and other Safety Rating Scales  
For the following rating scales, summaries of actual values (total scores) and 
changes from baseline will be presented by treatment group for each scheduled 
assessment timepoint, beginning with the Baseline visit.   
A listing displaying the scores for these scales (individual items and total) will be 
provided by subject.  
• 
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S)  
• 
Clinician-Administered Dissociative States Scale (CADSS)  
• 
Brief Psychiatric Rating Scale - Modified 4 Components (BPRS+)  


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The 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC) is only 
assessed post-baseline and for only one (1) time during the study. A listing 
displaying the details of the 5D-ASC will be provided by subject.  
  
 
  
Others  
Any other assessments which were not described in any previous sections will be 
listed based on the FAS. This includes (and not limited to) the following:  
• 
Non-compliance in inclusion or exclusion criteria  
• 
Massachusetts General Hospital Antidepressant Response Questionnaire 
(MGH-ATRQ)  
• 
Mini-International Neuropsychiatric Interview (MINI)  
  
IX.  
Interim Analysis  
No interim analysis is planned.  
  
X.  
References  
Lee S, Lee DK. What is the proper way to apply the multiple comparison test?  
[published correction appears in Korean J Anesthesiol. 2020 Dec;73(6):572]. Korean 
J Anesthesiol. 2018;71(5):353-360. doi:10.4097/kja.d.18.00242  
  
XI.  
Appendices  
  
 
  
Missing or Partial Date Imputation  
For records with missing AE onset/resolution date, the following procedure will be 
employed for use in determining whether the AE is treatment emergent:  
• 
AE onset dates with missing day and non-missing month will be assumed to 
occur on the first day of the non-missing month, except for AEs occurring in 
the month and year of first dosing, in which case the date will be imputed 
using the date of first dosing.   
• 
AE onset dates with missing day and month will be assumed to occur on the 
first day of the non-missing year (ie, January 1), except for AEs occurring in 
the year of first dosing, in which case the date will be imputed using the date 
of the first dosing.  
• 
AEs that are not ongoing and have a resolution date with missing day and 
non-missing month, they will be assumed to occur on the last day of the 


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month, except when the end of study date or date of death is prior to the last 
day of the month. The date will be imputed as end of study date, or death 
date, whichever happens the earliest.  
• 
AEs that are not ongoing and have a resolution date with end date month 
missing, the imputed end date should be set to the last day of the year 
31DECYYYY, except when the end of study date or date of death is prior to 
the last day of the year. The date will be imputed as end of study date, or 
death date, whichever happens the earliest.  
• 
If subjects died during the study and experience AEs at the time of death, the 
AEs that lead to death will use death date as the AE end date, otherwise, AEs 
that did not lead to death will be reported as ongoing.  
For records with a missing therapy start and/or stop date, the following procedure 
will be employed for use in determining whether the therapy is prior or concomitant:  
• 
Therapy start dates with a missing day and non-missing month will be 
assumed to occur on the first day of the non-missing month.  
• 
Therapy start dates with missing day and month will be assumed to occur on 
the first day of the non-missing year (ie, January 1), except for therapies 
occurring in the year of first dosing, in which case the date will be the date of 
first dosing.  
• 
Therapies that are not ongoing and have a stop date with a missing day and 
non-missing month will be assumed to occur on the earlier of the last day of 
the non-missing month or the date of death (if applicable).  
• 
Therapies that are not ongoing and have a stop date with missing day and 
month will be assumed to occur on the earlier of the last day of the 
nonmissing year (ie, December 31) or the date of death (if applicable).  
• 
Therapies that are not ongoing but do not have a stop date will be assumed 
to occur on the earlier of the last day of the non-missing year (ie, December 
31) or the date of death (if applicable)