A Two-Part Study of CLE-100 as an Adjunct Therapy in Subjects With Major Depressive Disorder
Phase: PHASE2
Conditions: Adjunctive Treatment of Major Depressive Disorder
Sponsor: Clexio Biosciences Ltd.

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Protocol Title: 
A Two-Part Study of CLE-100 as an Adjunct Therapy in Subjects With 
Major Depressive Disorder  
 
NCT04103892 
 
03 December 2021 
 
 

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Certain portions of this protocol have been redacted in order to protect personally identifiable 
information (PII) and company confidential information (CCI). Redacted content may include, but 
is not limited to: 
• 
Names of study personnel, investigators, or institutions. 
• 
Proprietary instruments, scales, coding systems, or other methodologies designated as 
confidential. 
• 
Additional information considered necessary to protect the confidentiality of Clexio Biosciences, 
safeguard personal privacy, or maintain the scientific integrity of the clinical study. 
 
 
A Two-Part Study of CLE-100 as an Adjunct Therapy in Subjects With 
Major Depressive Disorder  
Investigational Product: Oral immediate-release esketamine tablet 
Protocol Number: CLE100-MDD-201 
 
Sponsor: 
Clexio Biosciences Limited 
 
 
 
 
 
 
Version Number: 6.0 
Original Protocol: 12 July 2019 
 
 
 
 
Amendment 5: 03 December 2021 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written consent of 
Clexio Biosciences Limited except to the extent that disclosure would be required by law and for the 
purpose of evaluating and/or conducting a clinical study for Clexio Biosciences Limited. You are allowed 
to disclose the contents of this document only to your Institutional Review Board and study personnel 
directly involved with conducting this protocol. Persons to whom the information is disclosed must be 
informed that the information is confidential and proprietary to Clexio Biosciences Limited and that it 
may not be further disclosed to third parties. 

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SIGNATURE PAGE 
STUDY TITLE: A Two-Part Study of CLE-100 as an Adjunct Therapy in Subjects With 
Major Depressive Disorder  
 
I, the undersigned, have read this protocol and agree that it contains all necessary information 
required to conduct the study. 
Signature 
 
 
 
 
 
 
 
Date 
 

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INVESTIGATOR AGREEMENT 
By signing below, I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by Clexio Biosciences Limited to study personnel under my supervision. I will discuss this material 
with them to ensure they are fully informed about the study product and study procedures. I will 
let them know that this information is confidential and proprietary to Clexio Biosciences Limited 
and that it may not be further disclosed to third parties. I understand that the study may be 
terminated or enrollment suspended at any time by Clexio Biosciences Limited, with or without 
cause, or by me if it becomes necessary to protect the best interests of the study subjects. 
I agree to conduct this study in full accordance with Food and Drug Administration Regulations, 
Institutional Review Board/Ethic Committee Regulations and International Council for 
Harmonisation Guidelines for Good Clinical Practices. 
 
 
 
 
 

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SYNOPSIS 
TITLE: A Two-Part Study of CLE-100 as an Adjunct Therapy in Subjects With Major Depressive 
Disorder  
PROTOCOL NUMBER: CLE100-MDD-201 
INVESTIGATIONAL PRODUCT: Oral immediate-release esketamine tablet 
PHASE: 2 
INDICATION(S): CLE-100 is being investigated as an adjunct therapy for patients with major depressive 
disorder (MDD) with an inadequate response to standard antidepressant therapy. 
OBJECTIVE: 
The study objective is to assess the safety, efficacy, and tolerability of 40 mg CLE-100 for the treatment 
of MDD in subjects with an inadequate response to standard antidepressant therapy. 
Part A 
The objectives for Part A of this study are to: 
• 
Evaluate the safety and tolerability of 40 mg CLE-100 administered to subjects with MDD, once 
daily for 7 days. 
• 
Evaluate the full pharmacokinetic (PK) profile of 40 mg CLE-100 in plasma. 
• 
Assess key cognitive functions important for driving. 
Part B 
The primary objective for Part B of this study is to assess the efficacy of 40 mg CLE-100 compared to 
placebo in improving depressive symptoms in subjects with MDD with an inadequate response to standard 
antidepressant therapy, as assessed by change from Baseline in the Montgomery-Asberg Depression Rating 
Scale (MADRS) to Week 4 (Day 29). 
The secondary objectives for Part B of this study are to assess the efficacy of 40 mg CLE-100 compared 
to placebo in improving depressive symptoms and associated disability in subjects with MDD with an 
inadequate response to standard antidepressant therapy, as assessed by the following: 
• 
Change in the self-rated Symptoms of Depression Questionnaire (SDQ) from Baseline to Week 4 (Day 
29). 
• 
Change in the Sheehan Disability Scale (SDS) from Baseline to Week 4 (Day 29). 
• 
Change in the MADRS score from Baseline to Week 2 (Day 15). 
• 
Change in the Clinical Global Impression – Severity (CGI-S) from Baseline to Week 4 (Day 29). 
Another secondary objective for Part B of this study is to assess the safety of 40 mg CLE-100 compared to 
placebo in subjects with MDD with an inadequate response to standard antidepressant therapy.  
POPULATIONS: 
The population for Part A is subjects suffering from MDD currently treated with an antidepressant therapy. 

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have been predominant at any time within 6 months prior to Screening based on clinical judgment, or 
that would interfere with the subject’s ability to participate in the study in the judgment of the 
Investigator. 
9. Has a history of seizure disorder or unexplained loss of consciousness (subjects who suffered childhood 
febrile seizures are allowed). 
10. Has a significant medical condition(s) or symptom(s) that, in the opinion of the Investigator, would 
prevent the subject from safely participating in the study, interfere with protocol compliance, or 
interfere with the safety or efficacy assessments. 
11. Has a positive test for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency 
virus (HIV) at Screening. 
12. Has a chronic lung disease, including asthma, that is not well controlled at Screening. 
13. Has a lifetime history of surgical procedures involving the brain or meninges, encephalitis, meningitis, 
hydrocephalus, degenerative central nervous system (CNS) disorders, epilepsy, mental retardation, or 
any other disease/procedure/accident/intervention associated with significant injury to or malfunction 
of the CNS, or a history of significant head trauma (defined as any loss of consciousness) within the 
past 2 years. 
14. Has angina pectoris, had a recent myocardial infarction (within 1 year), or congestive heart failure 
>Stage 2, based on New York Heart Association Criteria, at Screening. 
15. Has systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg that does not resolve 
on up to 3 repeated measurements. Note: At the discretion of the Investigator, subjects may be started 
on antihypertensive treatment during the screening phase to lower blood pressure into the allowed 
range with the expectation the antihypertensive medication will be stable by the time of randomization 
and remain at a stable dose during the double-blind phase of the study. 
16. Has any medical condition for which an increase in blood pressure or intracranial pressure poses a 
serious risk (eg, aneurysmal vascular disease, arteriovenous malformation, or history of intracerebral 
hemorrhage).  
17. Has a heart rate <50 or >105 beats per minute (bpm) at Screening. Note: Physically fit subjects with a 
heart rate <50 bpm may be enrolled with Sponsor approval in cases where clinically significant 
bradycardia can be ruled out. 
18. Has evidence of second or third degree atrioventricular (AV) block, or first degree AV block (PR 
interval >200 msec), left bundle branch block (LBBB), or right bundle branch block (RBBB) at 
Screening. 
19. Has a heart rate-corrected QT interval ≥450 msec for males and ≥470 for females at Screening using 
Fridericia’s formula (QTcF). 
20. Has uncontrolled hyperthyroidism or hypothyroidism at Screening, as defined by thyroid-stimulating 
hormone (TSH) levels outside the normal reference range or change in thyroid medications within 3 
months prior to Screening. 
21. Has uncontrolled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) >8.5% at Screening. 
22. Has narrow angle glaucoma. 
23. Has alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >2.5 × the upper limit of 
normal or known hepatic insufficiency or chronic liver disease at Screening. 
24. Has chronic cystitis. 

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15. Has a chronic lung disease, including asthma, that is not well controlled at Screening. 
16. Has a lifetime history of surgical procedures involving the brain or meninges, encephalitis, meningitis, 
hydrocephalus, degenerative CNS disorders, epilepsy, mental retardation, or any other 
disease/procedure/accident/intervention associated with significant injury to or malfunction of the 
CNS, or a history of significant head trauma (defined as any loss of consciousness) within the past 2 
years. 
17. Has angina pectoris, had a recent myocardial infarction (within 1 year), or congestive heart failure 
>Stage 2, based on New York Heart Association Criteria, at Screening. 
18. Has systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg that does not resolve 
on up to 3 repeated measurements. Note: At the discretion of the Investigator, subjects may be started 
on antihypertensive treatment during the screening phase to lower blood pressure into the allowed 
range with the expectation the antihypertensive medication will be stable by the time of randomization 
and remain at a stable dose during the double-blind phase of the study. 
19. Has any medical condition for which an increase in blood pressure or intracranial pressure poses a 
serious risk (eg, aneurysmal vascular disease, arteriovenous malformation, or history of intracerebral 
hemorrhage).  
20. Has a heart rate <50 or >105 bpm at Screening. Note: Physically fit subjects with a heart rate <50 bpm 
may be enrolled with Sponsor approval in cases where clinically significant bradycardia can be ruled 
out. 
21. Has evidence of second or third degree AV block, LBBB, or RBBB at Screening. 
22. Has a QTcF interval ≥450 msec for males and ≥470 msec for females at Screening. 
23. Has hypothyroidism or hyperthyroidism, unless stabilized on appropriate medication with no change 
in dosage for at least 3 months prior to Screening. Euthyroid subjects and subjects with controlled 
thyroid dysfunction may be enrolled if they meet one of the following criteria: 
o TSH levels within normal reference range; or 
o TSH ≥0.75 × the lower limit of normal and ≤1.25 × upper limit of normal AND with no clinical 
signs/symptoms of thyroid disease AND normal free triiodothyronine (T3) and thyroxine (T4). 
24. Has uncontrolled diabetes mellitus defined as HbA1c >8.5% at Screening. 
25. Has narrow angle glaucoma. 
26. Has ALT and AST >2 × the upper limit of normal or known hepatic insufficiency or chronic liver 
disease at Screening. 
27. Has chronic cystitis (subjects with acute cystitis can be enrolled after successful treatment).  
28. Has undergone a bariatric surgery for weight loss. 
29. Has known allergies or sensitivity to the excipients contained in the study drug or placebo. 
30. Has had poor tolerability or sensitivity to esketamine or ketamine. 
31. Has been randomized in Part A of this study. 
32. Has had previous non-response for treatment of depression to esketamine or ketamine with an adequate 
dose and duration per the Investigator’s judgment. 

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33. Is a female of childbearing potential (ie, ovulating, premenopausal, and not surgically sterile) who is 
not willing to use at least 1 highly effective birth control method throughout the study and for 1 month 
after study ends.  
o Female subjects will be considered to be of childbearing potential if they have begun menstruation. 
o Female subjects will not be considered to be of childbearing potential if they are: 
 
Postmenopausal, as determined by: 
a. >45 years of age with amenorrhea for at least 12 months without an alternative medical 
cause.  
b. ≤45 years of age with amenorrhea for at least 12 months and a serum FSH level >40 
mIU/mL without an alternative medical cause. 
 
Permanently sterilized (eg, have undergone a hysterectomy, bilateral oophorectomy, or tubal 
ligation ≥26 weeks prior to Screening). 
 
Otherwise incapable of pregnancy. 
34. Is a female that is pregnant or breastfeeding. 
35. Is a female with a positive pregnancy test at Screening or Visit 2. 
36. Is a male who is sexually active with a female of childbearing potential, has not had a vasectomy, and 
does not agree to use an effective method of birth control (eg, condom with spermicide), or does not 
agree to refrain from donating sperm during the study and for 3 months after receiving the last dose of 
study drug. 
37. Is currently enrolled in another investigational device or drug trial(s), or has not yet completed a period 
of at least 60 days or 5 half-lives since the last dose of the previous investigational drug, whichever is 
longer, before the administration of the first dose of the study drug in this study. 
38. Is unsuitable for participating in the study, in the opinion of the Investigator. 
39. Is taking prohibited concomitant medications or foods. 
40. Is receiving any medication(s) given to augment the efficacy of his/her antidepressant therapy (eg, 
anticonvulsants, mood stabilizers including lithium, atypical antipsychotics, psychostimulants, and 
thyroid hormones) at the time of randomization. 
41. Is known to experience, based on the Investigator’s judgment, clinically significant sedation from any 
concomitant medication planned to be taken during the 4-week treatment period. 
42. Is unwilling or unable to comply with the driving instructions of the study protocol. 
STUDY DESIGN AND DURATION: 
This is a 2-part, Phase 2 study in subjects with MDD currently treated with an oral antidepressant 
medication. In both parts, all subjects will remain on their current oral antidepressant monotherapy with no 
dose change during the study. Part A will be an inpatient study to assess the safety, tolerability, and PK of 
40 mg CLE-100. Part B will be an outpatient study to assess the safety, efficacy, and tolerability of 40 mg 
CLE-100.  
Fifteen subjects will be randomized into Part A and approximately 122 subjects will be randomized into 
Part B of this study. 

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Suicidal ideation, self-harm, and suicidal behavior will be monitored once weekly using the C-SSRS. 
Pharmacokinetic sampling will be performed at each on-site visit during the 4-week treatment period. 
The DSMB will evaluate the unblinded safety data during Part B of the study at intervals predetermined in 
the DSMB charter. The DSMB will provide their recommendation for the continuation or discontinuation 
of the study as planned or whether protocol changes are warranted. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
CLE-100 is an oral, immediate-release (IR) formulation of esketamine hydrochloride for once daily 
administration 
. For this study, 40 mg IR tablets of CLE-
100 will be used. 
Part A 
In Part A, subjects will be randomized in a 4:1 ratio to the following 2 treatment groups: 
• 
40 mg CLE-100 (12 subjects). 
• 
Placebo (3 subjects). 
Part B 
In Part B, at Visit 2 predose, subjects will be randomized in a 1:1 ratio to the following 2 treatment groups: 
• 
Placebo (61 subjects). 
• 
40 mg CLE-100 (61 subjects). 
The study drug will be administered in addition to the subject’s current oral antidepressant monotherapy 
that must be kept at a stable therapeutic dose throughout study participation. 
EFFICACY VARIABLES IN PART B:  
The primary efficacy endpoint for Part B of this study is the change from Baseline to Week 4 (Day 29) in 
the MADRS score.  
The key secondary efficacy endpoints for Part B of this study include the following: 
• 
Change in the self-rated SDQ from Baseline to Week 4 (Day 29). 
• 
Change in the SDS from Baseline to Week 4 (Day 29). 
• 
Change in the MADRS score from Baseline to Week 2 (Day 15).  
• 
Change in the clinician-administered Clinical Global Impression – Severity (CGI-S) rating from 
Baseline to Week 4 (Day 29). 
In Part B, other secondary efficacy endpoints include the following: 
• 
Responder rate 
 
 at Week 4 (Day 29). 
• 
Remission rate 
 
at Week 4 (Day 29). 
• 
Clinician-administered Clinical Global Impression – Improvement rating at Week 4 (Day 29). 
• 
Change in the General Anxiety Disorder 7-item Scale from Baseline to Week 4 (Day 29). 
SAFETY VARIABLES: 
Safety and tolerability variables measured in both Part A and Part B of this study will include the following: 

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• 
AEs. 
• 
Clinical laboratory evaluations (hematology, chemistry, and urinalysis). 
• 
Physical examination findings. 
• 
Vital signs (blood pressure, heart rate, and body temperature). 
• 
12-lead electrocardiogram findings. 
• 
Self-reported KSS. 
• 
MOAA/S. 
• 
CADSS. 
• 
C-SSRS. 
• 
4-item BPRS. 
• 
Cognitive function evaluated by Cogstate battery (Part A only) 
o Detection Test. 
o Identification Test. 
o One Back Test. 
o Groton Maze Learning Test. 
o Chase Test. 
• 
DSST. 
• 
PWC-20. 
• 
Withdrawal rates, including days and reason(s) for withdrawals. 
• 
Bladder Pain/Interstitial Cystitis Symptom Score (Part B only). 
STATISTICAL ANALYSES: 
Part A 
Fifteen subjects will be randomized into Part A using a 4:1 assignment ratio to treatment with either 40 mg 
CLE-100 (12 subjects) or placebo (3 subjects), respectively.  
The overall safety and tolerability of CLE-100 treatment will be assessed in Part A by evaluating the safety 
variables for the Safety Analysis Set for Part A. 
Part B 
Approximately 122 subjects will be randomized into Part B using a 1:1 assignment ratio to treatment with 
either placebo (61 subjects) or 40 mg CLE-100 (61 subjects). 
The significance level for Part B of this study will be 0.05 2-sided.  
For Part B, a fixed sequence gatekeeping (hierarchical) approach will be applied to adjust for multiplicity 
and to control type I error due to multiple efficacy endpoints testing of the primary and key secondary 
endpoints. The sequence order is according to the defined order of the primary and key secondary 
endpoints. If the primary analysis is statistically significant at the 2-sided 0.05 level, the key secondary 
endpoints will be analyzed sequentially according to their defined order. A key secondary endpoint will be 
considered statistically significant at the 2-sided 0.05 level only if the previous key secondary or primary