A Phase 1, Double-blind (Investigator and Participant), First-in-Human Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of CVL-354 in Healthy Participants
Phase: PHASE1
Conditions: Healthy Participants
Sponsor: Cerevel Therapeutics, LLC

 
Official Title: A Phase 1, Double-blind (Investigator and Participant), First-in-Human 
Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of 
Single and Multiple Ascending Doses of CVL-354 in Healthy 
Participants 
NCT Number: NCT05138653   
Document Dates: Protocol Version 3: 25-May-2022 
 
 
 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 1 of 96 
Version 3.0: 25 May 2022
 
CLINICAL PROTOCOL 
A PHASE 1, DOUBLE-BLIND (INVESTIGATOR AND PARTICIPANT), 
FIRST-IN-HUMAN TRIAL TO EVALUATE THE SAFETY, 
TOLERABILITY, AND PHARMACOKINETICS OF SINGLE AND 
MULTIPLE ASCENDING DOSES OF CVL-354 IN HEALTHY 
PARTICIPANTS 
Protocol: CVL-354-1001 
Compound Number: CVL-354 
Trial Phase: 1 
Short Title: A Single and Multiple Ascending Dose Trial of CVL-354 in Healthy 
Participants 
Sponsor Name: Cerevel Therapeutics, LLC 
Legal Registered Address: 222 Jacobs Street, Suite 200, Cambridge, MA 02141 United 
States 
Regulatory Agency Identifier Number 
Regulatory Agency File 
Identifying # 
IND:  
155,364 
CONFIDENTIAL – PROPRIETARY INFORMATION 
Version 3.0: 25 May 2022 
Version 2.0: 16 Sep 2021 
Version 1.0: 07 Jun 2021 
MEDICAL MONITOR NAME AND CONTACT INFORMATION IS PROVIDED IN THE 
TRIAL OPERATIONS MANUAL 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 3 of 96 
Version 3.0: 25 May 2022
 
PROTOCOL VERSION 3.0 SUMMARY OF CHANGES TABLE 
Document History 
Document:  
Date (Day-Month-Year) 
Version 3.0 
25 May 2022 
Version 2.0 
16 Sep 2021 
Original Protocol Version 1.0 
07 Jun 2021 
Amendment: Protocol Version 3.0 (25 May 2022) 
Overall Rationale for the Amendment: The overall rationale for the amendment is to provide 
information on anticipated dose levels for the multiple ascending dose (MAD) part of the trial 
based on the results from the single ascending dose (SAD) evaluation. 
 
Section # and Namea 
Description of Change 
Brief Rationale 
Sponsor Signatories 
Updated sponsor signatory 
Change in internal responsibilities 
1.1 Synopsis 
4.1 Overall Design 
Relocated text about double-blind 
design to clarify descriptions specific to 
SAD and MAD design, due to 
inclusion of food effect evaluation in 
Part A (for which IMP assignment is 
not blinded). 
Moved to descriptions specific to 
SAD and MAD design, due to 
inclusion of food effect evaluation in 
Part A (for which IMP assignment is 
not blinded)  
1.1 Synopsis 
 
4.1.1 Single Ascending Dose 
and Food Effect - Part A 
Added descriptions on Part A design 
aspects regarding SAD evaluation for 
Cohorts 1 and 2 and food effect 
evaluation for Cohort 3 
Previous protocol version noted that 
additional dose levels or food effect 
would be explored in Cohort 3. 
Based on outcome of SAD 
evaluation (Part A Cohorts 1 and 2), 
Cohort 3 will be used for evaluation 
of food effect only. 
1.1 Synopsis 
2.3 Benefit/Risk Assessment 
4.1 Overall Design 
4.1.2 Multiple Ascending 
Dose - Part B 
Revised text regarding sequential 
conduct of Parts A and B 
Dose escalation was completed in 
Part A SAD evaluation (Cohorts 1 
and 2), enabling determination of 
dosing paradigm for Part B MAD 
evaluation and rescheduling of food 
effect evaluation in Part A 
(Cohort 3) to allow overlap with Part 
B conduct 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 4 of 96 
Version 3.0: 25 May 2022
 
Section # and Namea 
Description of Change 
Brief Rationale 
1.1 Synopsis 
4.1 Overall Design 
4.1.1.2 Food Effect Evaluation 
(Cohort 3) 
4.2 Scientific Rationale for Trial 
Design 
6.1 Trial Treatments 
Administered 
6.3.1 Participant Assignment to 
Treatment 
Added dose selected for food effect 
evaluation  
Provide doses based on data from 
Part A dose escalation 
1.1 Synopsis 
1.3 Schedule of Assessments 
4.1.1.1 Single Ascending Dose 
(Cohorts 1 and 2) 
Reworded content about sentinel and 
non-sentinel participants, including 
language about check-in assessments 
To incorporate content from 
clarification memo issued by 
sponsor to site 
1.1 Synopsis 
1.3 Schedule of Assessments 
4.1.2 Multiple Ascending 
Dose - Part B 
4.4 Guidance for Dose 
Escalation/Stopping Rules 
Deleted content regarding BID dosing, 
including footnotes in both Schedule of 
Assessment tables for Part B 
To confirm that QD dosing was 
established for Part B based on 
results from Part A 
1.1 Synopsis 
4.1.2 Multiple Ascending 
Dose - Part B 
Added starting dose for Part B, details 
regarding exposure in Part A, and 
details on IMP formulations to be used 
in Part B 
To incorporate sponsor decision 
based on results from Part A dose 
escalation 
1.1 Synopsis 
4.1.3 Other Design 
Considerations 
Revised to note respective in-clinic 
periods for SAD and food effect 
cohorts 
To reflect differences between SAD 
and food effect design aspects 
1.1 Synopsis 
Revised disclosure statement  
To reflect changes to trial design 
1.1 Synopsis 
9.2 Sample Size Determination 
Specified that sample size for Part A 
includes food effect cohort 
To reflect inclusion of food effect 
evaluation, as previous text referred 
to SAD only 
1.1 Synopsis 
9.4.3 Pharmacokinetic Analyses 
9.4.4 
 
Added Q1 and Q3 to list of descriptive 
statistics 
To correct inadvertent omission in 
previous protocol version 
1.1 Synopsis 
9.4.1 General Considerations 
Noted that separate analyses will be 
performed for each part of the trial 
(Part A SAD, Part A food effect, Part B 
MAD) 
To clarify planned statistical 
analyses 
 
 
1.1 Synopsis 
 
9.4.3 Safety Analyses 
Added text regarding safety analyses in 
synopsis 
Clarified how safety endpoints will be 
summarized 
To correct inadvertent omission in 
previous protocol version 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 6 of 96 
Version 3.0: 25 May 2022
 
Section # and Namea 
Description of Change 
Brief Rationale 
4.1.1.1 Single Ascending Dose 
(Cohorts 1 and 2) 
Created new subsection specific to 
Part A SAD cohorts (Cohorts 1 and 2) 
To organize content relevant to trial 
design for SAD evaluation 
(Cohorts 1 and 2) 
4.1.1.1 Single Ascending Dose 
(Cohorts 1 and 2) 
Added statement referring to section 
where actual doses administered to 
Cohorts 1 and 2 were added 
(Section 2.2.5) 
To aid the reader in locating the 
information 
4.1.1.2 Food Effect Evaluation 
(Cohort 3) 
Created new subsection specific to 
Part A food effect cohort (Cohort 3) 
To organize content relevant to trial 
design for food effect evaluation 
(Cohort 3) 
4.1.4 Definition of Completed 
Participant 
Added text for Part A to distinguish 
definition of completed participant for 
dose escalation vs food effect  
To reflect differences between SAD 
and food effect design 
4.2 Scientific Rationale for Trial 
Design 
Revised content specific to Part A dose 
escalation and food effect cohorts  
To reflect differences and provide 
additional details on relevant trial 
design aspects  
4.2 Scientific Rationale for Trial 
Design 
Expanded on previous text regarding 
food effect evaluation 
To provide additional details 
4.2 Scientific Rationale for Trial 
Design 
Added text regarding addition of serum 
cystatin-C and urine β-2-microglobulin 
laboratory tests 
To provide rationale for additional 
tests in the trial 
4.3 Dosing Rationale 
Revised dosing rationale to provide 
content on the basis of observed PK in 
humans rather than predicted PK, 
including dose projected to provide 
90% KOR occupancy in humans, 
maximum dose in Part A, projected 
exposures at maximum dose, and 
proposed doses for Part B (with 
associated projected exposures, RO, 
and exposure margins) 
To reflect changes due to results 
obtained during Part A dose 
escalation 
4.4 Guidance for Dose 
Escalation/Stopping Rules 
Clarified that if, based on observed 
data, the next planned dose is projected 
to exceed the maximum exposures in 
Part A, that dose will not be explored. 
To reflect results from Part A of the 
trial 
5.1 Inclusion Criteria 
Specified the use of condoms as a 
contraception requirement for sexually 
active men with a pregnant or 
nonpregnant partner of childbearing 
potential 
To clarify contraception 
requirements in the trial 
5.3.1 Meals and Dietary 
Restrictions 
Added statement that actual start and 
stop times for breakfast and IMP 
administration will be recorded 
To provide details for recording of 
relevant data 
5.3.1 Meals and Dietary 
Restrictions 
Added statement that no water is 
permitted for at least 2 hours postdose 
To avoid potential abdominal 
distension 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 7 of 96 
Version 3.0: 25 May 2022
 
Section # and Namea 
Description of Change 
Brief Rationale 
6.1 Trial Treatments 
Administered 
CVL-354 Solution: 
Added unit dose strength 
 
Added actual doses for Part A 
Cohorts 1 and 2 and starting dose for 
Part B Cohort 1 
 
To align with current sponsor 
standards  
To reflect results obtained during 
Part A dose escalation 
6.1 Trial Treatments 
Administered 
CVL-354 Capsules: 
Completed corresponding rows of 
table, including anticipated dosage 
levels for Part A Cohort 3 and Part B 
Cohorts 2-5 
 
To provide information on capsule 
IMP, including anticipated doses 
based on results obtained during 
Part A dose escalation 
6.1 Trial Treatments 
Administered 
Placebo: 
Provided corresponding information 
regarding capsule dosage form 
To provide information on capsule 
IMP 
6.1 Trial Treatments 
Administered 
Overall: 
Revised presentation 
To align with current sponsor 
standards  
6.2 Preparation, Handling, 
Storage, and Accountability 
Deleted mention of “suspension” 
For consistency with revisions in 
Section 6.1 (Table 10) 
6.3.1 Participant Assignment to 
Treatment 
Added content on randomization to 
treatment sequence for food effect 
cohort 
To provide relevant details 
6.3.1 Participant Assignment to 
Treatment 
For text about mirror randomization 
number, specified that Part A applies to 
Cohorts 1 and 2 
To provide relevant details 
6.3.2 Blinding 
Added sentence that treatment 
assignment will not be blinded for food 
effect portion 
To provide relevant details 
6.3.2 Blinding 
Removed text regarding documentation 
of unblinding in eCRF 
To incorporate updated sponsor 
standard language 
8.3.3 Vital Sign Measurements 
Revised definition of orthostatic 
hypotension, including calculation 
relative to supine assessments 
To correct errors from previous 
protocol version 
10.2 Appendix 2: Clinical 
Laboratory Tests 
Added a row for “Additional Required 
Tests” and added serum cystatin-C and 
urine β-2-microglobulin as additional 
safety laboratory tests to be taken 
To permit appropriate evaluation of 
renal function following multiple 
doses 
10.6 Appendix 6: Kidney Safety 
for First-in-Human Trial 
 
11 References 
Added a new appendix with guidance 
regarding the monitoring of kidney 
function 
Added supporting references 
To provide additional safety 
monitoring in this first-in-human 
trial 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 8 of 96 
Version 3.0: 25 May 2022
 
Section # and Namea 
Description of Change 
Brief Rationale 
Overall 
Minor grammatical and wording 
corrections/clarifications made 
throughout protocol 
To correct minor errors from the 
previous version of the protocol 
Abbreviations: BID=twice daily; eCRF=electronic case report form; IMP=investigational medicinal product; 
KOR=kappa opioid receptor; MAD=multiple ascending dose; 
 
; PK=pharmacokinetic; QD=once daily; RO=receptor occupancy; SAD=single 
ascending dose. 
a Numbering (eg, section numbers and numbered lists) refers to current version of the protocol. 
 
 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 9 of 96 
Version 3.0: 25 May 2022
 
TABLE OF CONTENTS 
CLINICAL PROTOCOL .................................................................................................................1 
SPONSOR SIGNATORIES: ...........................................................................................................2 
PROTOCOL VERSION 3.0 SUMMARY OF CHANGES TABLE ..............................................3 
TABLE OF CONTENTS .................................................................................................................9 
TABLE OF TABLES ....................................................................................................................14 
TABLE OF FIGURES ...................................................................................................................15 
1. 
PROTOCOL SUMMARY ..........................................................................................16 
1.1. 
Synopsis ......................................................................................................................16 
1.2. 
Schema ........................................................................................................................22 
1.3. 
Schedule of Assessments ............................................................................................24 
2. 
INTRODUCTION ......................................................................................................35 
2.1. 
Trial Rationale ............................................................................................................35 
2.2. 
Background .................................................................................................................35 
 
 ..........................................................................................37 
 
 .........................................................37 
 
 ..............................................................................................38 
 
 .........................................................................................38 
 
 ...............................................................................................38 
 
 ............................................................................................39 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................40 
4. 
TRIAL DESIGN .........................................................................................................42 
4.1. 
Overall Design ............................................................................................................42 
4.1.1. 
Single Ascending Dose and Food Effect- Part A .......................................................43 
4.1.1.1. 
Single Ascending Dose (Cohorts 1 and 2) ..................................................................43 
4.1.1.2. 
Food Effect Evaluation (Cohort 3) .............................................................................44 
4.1.2. 
Multiple Ascending Dose - Part B ..............................................................................44 
4.1.3. 
Other Design Considerations ......................................................................................45 
4.1.4. 
Definition of Completed Participant ...........................................................................45 
4.2. 
Scientific Rationale for Trial Design ..........................................................................46 
4.3. 
Dosing Rationale ........................................................................................................46 
4.4. 
Guidance for Dose Escalation/Stopping Rules ...........................................................48 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 10 of 96 
Version 3.0: 25 May 2022
 
4.5. 
End of Trial Definition ...............................................................................................50 
5. 
TRIAL POPULATION ..............................................................................................50 
5.1. 
Inclusion Criteria ........................................................................................................50 
5.2. 
Exclusion Criteria .......................................................................................................50 
5.3. 
Lifestyle Considerations .............................................................................................53 
5.3.1. 
Meals and Dietary Restrictions ...................................................................................53 
5.3.2. 
Alcohol and Tobacco Restrictions ..............................................................................54 
5.3.3. 
Activity .......................................................................................................................54 
5.3.4. 
Effects on Ability to Drive and Use Machinery .........................................................54 
5.4. 
Screen Failures ............................................................................................................54 
6. 
TRIAL TREATMENTS .............................................................................................55 
6.1. 
Trial Treatments Administered ...................................................................................55 
6.2. 
Preparation, Handling, Storage, and Accountability ..................................................56 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................56 
6.3.1. 
Participant Assignment to Treatment .........................................................................56 
6.3.2. 
Blinding ......................................................................................................................56 
6.4. 
Trial Treatment Compliance .......................................................................................57 
6.5. 
Prior and Concomitant Therapy ..................................................................................57 
6.6. 
Dose Modification ......................................................................................................57 
6.7. 
Intervention after the End of the Trial ........................................................................58 
7. 
DISCONTINUATION OF TRIAL TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................58 
7.1. 
Discontinuation of Trial Treatment ............................................................................58 
7.2. 
Discontinuation of Trial ..............................................................................................58 
7.2.1. 
Discontinuation of Entire Trial ...................................................................................58 
7.2.2. 
Discontinuation of Individual Site ..............................................................................58 
7.2.3. 
Individual Participant Discontinuation From the Trial ...............................................59 
7.3. 
Procedures to Encourage Continued Trial Participation ............................................59 
7.4. 
Lost to Follow up ........................................................................................................60 
8. 
TRIAL ASSESSMENTS AND PROCEDURES .......................................................60 
8.1. 
Screening and Baseline Assessments .........................................................................60 
 
60 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 11 of 96 
Version 3.0: 25 May 2022
 
 
 ........................................................................60 
 
 .....................................................................................61 
8.3. 
Safety Assessments .....................................................................................................61 
8.3.1. 
Height and Weight ......................................................................................................61 
8.3.2. 
Physical/Neurological Examinations ..........................................................................62 
8.3.3. 
Vital Sign Measurements ............................................................................................62 
8.3.4. 
Electrocardiograms .....................................................................................................62 
8.3.4.1. 
Continuous Electrocardiogram Recordings ................................................................62 
8.3.4.2. 
Standard 12-Lead Electrocardiograms .......................................................................63 
8.3.5. 
Clinical Safety Laboratory Assessments ....................................................................64 
8.3.6. 
Suicidal Ideation and Behavior Risk Monitoring .......................................................64 
8.4. 
Adverse Events and Serious Adverse Events .............................................................64 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................65 
8.4.2. 
Method of Detecting AEs and SAEs ..........................................................................65 
8.4.3. 
Follow-up of AEs and SAEs .......................................................................................65 
8.4.4. 
Regulatory Reporting Requirements for SAEs/AESIs ...............................................65 
8.4.5. 
Pregnancy ...................................................................................................................66 
8.4.6. 
Adverse Events of Special Interest .............................................................................66 
8.5. 
Treatment of Overdose ...............................................................................................67 
8.6. 
Pharmacokinetics ........................................................................................................67 
8.6.1. 
Blood for Pharmacokinetic Analysis of CVL-354 .....................................................68 
8.6.2. 
Urine for Analysis of CVL-354 (MAD Portion Only) ...............................................68 
8.7. 
Pharmacodynamic Assessments .................................................................................68 
8.8. 
Pharmacogenomics .....................................................................................................68 
 
68 
8.10. 
Future Biospecimen Research ....................................................................................68 
8.11. 
Health Economics .......................................................................................................69 
9. 
STATISTICAL CONSIDERATIONS .......................................................................69 
9.1. 
Statistical Hypotheses .................................................................................................69 
9.2. 
Sample Size Determination ........................................................................................69 
9.3. 
Populations for Analyses ............................................................................................69 
9.4. 
Statistical Analyses .....................................................................................................70 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 12 of 96 
Version 3.0: 25 May 2022
 
9.4.1. 
General Considerations ...............................................................................................70 
9.4.2. 
Safety Analyses ..........................................................................................................70 
9.4.3. 
Pharmacokinetic Analyses ..........................................................................................70 
 
 ........................................................................................................70 
9.4.5. 
Interim Analyses .........................................................................................................70 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................71 
10.1. 
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations ......................71 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................71 
10.1.2. 
Financial Disclosure ...................................................................................................71 
10.1.3. 
Informed Consent Process ..........................................................................................71 
10.1.4. 
Data Protection ...........................................................................................................72 
10.1.5. 
Dissemination of Clinical Trial Data ..........................................................................72 
10.1.6. 
Data Quality Assurance ..............................................................................................73 
10.1.7. 
Source Documents ......................................................................................................73 
10.1.8. 
Trial and Site Closure .................................................................................................74 
10.1.9. 
Publication Policy .......................................................................................................74 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................74 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................76 
10.3.1. 
Definition of AE .........................................................................................................76 
10.3.2. 
Definition of SAE .......................................................................................................76 
10.3.3. 
Recording and Follow-Up of AEs and/or SAEs/AESIs .............................................78 
10.3.4. 
Reporting of SAEs and AESIs ....................................................................................80 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................81 
10.4.1. 
Definitions ..................................................................................................................81 
10.4.1.1. 
Highly Effective Form of Contraception (Failure Rate <1%) ....................................81 
10.4.1.2. 
Acceptable Birth Control Methods (Failure Rate >1% per Year) ..............................81 
10.4.1.3. 
Contraception and Pregnancy Avoidance Procedures ................................................82 
10.4.2. 
Collection of Pregnancy Information .........................................................................82 
10.4.2.1. 
Male Participants With Partners Who Become Pregnant ...........................................82 
10.5. 
Appendix 5: Future Biospecimen Research ...............................................................83 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 13 of 96 
Version 3.0: 25 May 2022
 
10.6. 
Appendix 6: Kidney Safety for First-in-Human Trial ................................................84 
10.6.1. 
Elevations in Serum Creatinine ..................................................................................84 
10.6.2. 
Potential Cases of Acute Kidney Injury .....................................................................84 
10.6.2.1. 
Marked Elevations in Serum Creatinine .....................................................................84 
10.6.2.2. 
Evaluation of Potential Cases of AKI .........................................................................85 
10.6.2.3. 
Stopping Criteria for the Cohort .................................................................................85 
10.6.2.4. 
Stopping Criteria for Dose Escalation ........................................................................85 
10.7. 
Appendix 7: Abbreviations .........................................................................................86 
10.8. 
Appendix 8: Protocol Amendment History ................................................................88 
11. 
REFERENCES ...........................................................................................................92 
CLINICAL PROTOCOL PRINCIPAL INVESTIGATOR SIGNATURE PAGE ........................96 
 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 15 of 96 
Version 3.0: 25 May 2022
 
TABLE OF FIGURES 
Figure 1: 
Trial Schematic - Part A (Single Ascending Dose, Cohorts 1 and 2) .........................23 
Figure 2: 
Trial Schematic - Part A (Food Effect, Cohort 3) ......................................................23 
Figure 3: 
Trial Schematic - Part B (Multiple Ascending Dose, Cohorts 1-5) ............................24 
 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 16 of 96 
Version 3.0: 25 May 2022
 
1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Sponsor Name: Cerevel Therapeutics, LLC 
Name of Investigational Medicinal Product: CVL-354 
Protocol Title: A Phase 1, Double-blind (Investigator and Participant), First-in-Human Trial to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses 
of CVL-354 in Healthy Participants 
Short Title: A Single and Multiple Ascending Dose Trial of CVL-354 in Healthy Participants 
IND Number: 155,364 
Trial Phase: 1 
Treatment/Indication: Major depressive disorder 
Rationale: Kappa opioid receptor (KOR) activation is implicated in reduced activity of the 
reward (mesolimbic) pathway. Recent evidence suggests that selective antagonism of KORs may 
provide therapeutic benefit in treating major depressive disorder (MDD). CVL-354 is a 
brain-penetrant, potent KOR antagonist with 
 pharmacological selectivity over mu 
opioid receptors (MORs) that is being developed for treatment of MDD. Nonclinical data 
generated to date support development of CVL-354 for treatment of MDD. 
The aim of this 2-part, first-in-human trial is to investigate the safety, tolerability, and 
pharmacokinetics (PK) of CVL-354, following single ascending dose (SAD) and multiple 
ascending dose (MAD) oral administration in healthy participants. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 17 of 96 
Version 3.0: 25 May 2022
 
Objectives and Endpoints 
Part A (Single Ascending Dose) 
Objectives 
Endpoints 
Primary 
• 
To evaluate the safety and tolerability of single 
ascending doses of CVL-354 administered orally 
to healthy participants 
• 
Treatment-emergent AEs, including AEs 
potentially related to abuse 
• 
Clinically significant changes in ECGs, vital 
signs, clinical laboratory assessments, and 
physical and neurological examination results 
• 
Changes in suicidality assessed using the C-SSRS 
Secondary 
• 
To evaluate the plasma pharmacokinetics of 
CVL-354 following single ascending doses 
administered orally to healthy participants 
• 
Pharmacokinetic parameters of CVL-354 
following single oral doses: 
o 
Cmax 
o 
Tmax 
o 
AUC24 
o 
AUClast 
o 
AUCinf 
o 
CL/F 
o 
Vz/F 
o 
t1/2 
• 
To evaluate the effect of food following single 
doses of CVL-354 administered orally to healthy 
participants 
• 
Pharmacokinetic parameters of CVL-354 
following single oral doses: 
o 
Cmax 
o 
Tmax 
o 
AUC24 
o 
AUClast 
o 
AUCinf 
o 
CL/F 
o 
Vz/F 
o 
t1/2 
Abbreviations: AE=adverse event; AUC=area under the concentration-time curve; CL/F=apparent clearance of drug 
from plasma; Cmax=maximum plasma concentration; C-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; t1/2=apparent terminal half-life; SAD=single ascending dose; Tmax=time to maximum 
plasma concentration; Vz/F=apparent volume of distribution during terminal phase. 
 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 18 of 96 
Version 3.0: 25 May 2022
 
Part B (Multiple Ascending Dose) 
Objectives 
Endpoints 
Primary 
• 
To explore the safety and tolerability of multiple 
ascending doses of CVL-354 administered orally 
to healthy participants 
• 
Treatment-emergent AEs, including AEs 
potentially related to abuse 
• 
Clinically significant changes in ECGs, vital 
signs, clinical laboratory assessments, and 
physical and neurological examination results 
• 
Changes in suicidality assessed using the C-SSRS 
Secondary 
• 
To evaluate the plasma pharmacokinetics of 
CVL-354 following multiple ascending doses 
administered orally to healthy participants 
• 
Pharmacokinetic parameters for CVL-354 on 
Days 1 and 14: 
o 
Cmax 
o 
Tmax 
o 
Ctrough 
o 
AUCτ 
o 
CL/F (Day 14 only) 
o 
VZ/F (Day 14 only) 
o 
PTR (Day 14 only) 
o 
Rac, Cmax (Day 14 only) 
o 
Rac, AUC (Day 14 only) 
o 
t1/2 (Day 14 only) 
o 
Ae (amount eliminated unchanged in urine at 
steady state on Day 14) 
o 
Renal clearance (Day 14 only) 
Abbreviations: AE=adverse event; AUC=area under the concentration-time curve; CL/F=apparent clearance of drug 
from plasma; Cmax=maximum plasma concentration; Ctrough=trough plasma concentration; 
C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; MAD=multiple ascending dose; 
PTR=peak-to-trough ratio; Rac=accumulation ratio; t1/2=apparent terminal half-life; Tmax=time to maximum plasma 
concentration; Vz/F=apparent volume of distribution during terminal phase. 
Overall Design: 
This is a Phase 1, randomized, placebo-controlled, single-center trial that will be conducted in 
2 parts to evaluate safety, tolerability, and PK of CVL-354 following single and multiple doses 
in healthy participants. 
Part B of the trial will start after completion of single dose escalation in Part A (Cohorts 1 and 2). 
The evaluation of food effect for Part A (Cohort 3) may be conducted in parallel with Part B, 
using a CVL-354 dose of 50 mg. Single doses of CVL-354 up to 200 mg are considered to be 
safe and well tolerated based on review of data from Part A Cohorts 1 and 2.  
Part A (Single Ascending Dose and Food Effect) 
Dose escalation will proceed according to a double-blind (investigator and participant), 4-period 
crossover, single ascending dose methodology. Up to 2 cohorts of participants will be evaluated. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 21 of 96 
Version 3.0: 25 May 2022
 
Dose-escalation decisions for Part A and Part B will be made by the SRT, comprising sponsor 
personnel (or designee/supporting personnel) and site investigator or physician designee. 
If a participant discontinues before completing all periods within a cohort or withdraws for 
reasons unrelated to the safety of the IMP, the participant may be replaced at the investigator’s 
and sponsor’s discretion. In Part A, if a participant discontinues from the trial, the replacement 
participant will complete the rest of original treatment sequence of discontinued participant. 
Disclosure Statement: This is a 2-part single dose (4-way crossover, Part A ascending dose;) 
and multiple ascending dose (Part B) trial that is blinded to the investigator and participants. The 
food effect evaluation in Part A is an open-label, 2-way crossover design. 
Number of Participants:  
• Part A (SAD, food effect): 8 participants per cohort for a total of approximately 
16 participants if 2 cohorts complete single ascending dose evaluation. The food 
effect cohort will comprise approximately 8 participants, for a total of approximately 
24 participants in Part A. 
• Part B (MAD): 10 participants per cohort (8 CVL-354, 2 placebo) for a total of 
approximately 50 participants if 5 cohorts complete. 
In the event of higher than anticipated early terminations due to coronavirus disease-2019 
(COVID-19) or other reasons, Cerevel may extend enrollment in order to achieve trial 
objectives. 
Key Entry Criteria:  
• Healthy women of nonchildbearing potential and men, ages 18 to 55 years, inclusive 
Intervention Groups, Trial Treatment, and Duration: 
Part A (SAD, food effect) – In Cohorts 1 and 2, all participants will receive treatment with up to 
3 single oral doses of CVL-354 and/or 1 single oral dose of placebo in a 4-period crossover 
design. The starting dose of CVL-354 will be 0.5 mg. Participants will be randomized to 1 of 4 
treatment sequences for Cohorts 1 and 2.  
Cohort 3 will be used to evaluate food effect, with participants randomized to a treatment 
sequence (fed/fasted or fasted/fed).  
Total trial duration per participant during dose escalation will be approximately up to 100 days 
and include the following: a 4-week Screening Period, a Treatment Period (in-clinic) comprising 
up to 4 periods of 3 days each, at least 5 days washout between doses, and a follow-up contact 
14 days after the final dose of IMP. 
For the food effect evaluation, total trial duration per participant will be approximately 50 days 
and include the following: a 4-week Screening Period, a Treatment Period (in-clinic) comprising 
2 periods of 3 days each, a 2-day washout between periods, and a follow-up contact 14 days after 
the final dose of IMP. 
Part B (MAD) – All participants will be randomized in a 4:1 ratio to receive treatment with 
multiple oral doses of CVL-354 (dose and regimen to be determined) or placebo. Total trial 
duration per participant will be approximately up to 58 days and include the following: a 4-week 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 22 of 96 
Version 3.0: 25 May 2022
 
Screening Period, a Treatment Period (in-clinic) of up to 14 days, follow-up (in clinic) for 3 
days, and a follow-up contact 14 days after the final dose of IMP. 
Statistical Methods:  
Sample Size Estimation:  
The sample size is not based on statistical hypothesis testing. Based on historical precedent, it is 
expected that the proposed sample sizes of 8 participants per cohort in Part A (SAD, food effect) 
and 10 participants per cohort in Part B (MAD) will address the overall aim of the trial. 
In the event of higher than anticipated early terminations due to COVID-19 or other factors, 
Cerevel may extend enrollment in order to achieve trial objectives. 
Statistical Methods:  
Descriptive statistical methods will be used to summarize the data from this trial. All available 
data for randomized participants will be listed by participant. Separate analyses will be 
performed for each part of the trial (Part A SAD, Part A food effect, Part B MAD). 
All PK exposure parameters (eg, Cmax, AUC) will be summarized by dose, where applicable, 
using descriptive statistics including the arithmetic mean, median, standard deviation, coefficient 
of variation, minimum and maximum values, Q1, Q3, and geometric mean.  
For food effect assessment, the single dose of CVL-354 administered in fasted state is the 
reference treatment and the single dose of CVL-354 administered in fed state is the test 
treatment. 
Treatment-emergent adverse events, including AEs potentially related to abuse, will be coded 
according to the Medical Dictionary for Regulatory Activities and summarized by treatment, 
system organ class, and preferred term. Further summaries will be done by seriousness, severity, 
relationship to IMP, and dose at the time of onset. Other safety endpoints will be summarized 
with descriptive statistics by treatment and timepoint, including vital sign measurements, ECG, 
clinical laboratory assessments and suicidality monitored during the trial using Columbia-Suicide 
Severity Rating Scale. 
1.2. 
Schema 
The trial schematics for the single ascending dose (Part A, Cohorts 1 and 2), food effect (Part A, 
Cohort 3), and multiple ascending dose (Part B, Cohorts 1-5) cohorts are provided in Figure 1, 
Figure 2, and Figure 3, respectively. Part B may be run in parallel with Part A Cohort 3. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 23 of 96 
Version 3.0: 25 May 2022
 
Figure 1: 
Trial Schematic - Part A (Single Ascending Dose, Cohorts 1 and 2) 
 
Abbreviations: IMP=investigational medicinal product; R=randomization; Seq=sequence. 
For each period, Check-in is on Day -1 and Check-out is on Day 3. 
Follow-up consists of a contact to check on status 14±3 days after a participant’s final dose of IMP in the trial. 
Doses/treatment may be modified based on emergent safety, tolerability, and pharmacokinetic data. 
Doses may be repeated to confirm safety/tolerability. 
Figure 2: 
Trial Schematic - Part A (Food Effect, Cohort 3) 
 
Abbreviations: IMP=investigational medicinal product; R=randomization; Seq=sequence. 
The treatment phase will comprise 2 periods with a 2-day washout between Periods 1 and 2. Participants will be 
discharged from the clinic on Period 2 Day 3 (Check-out). 
Follow-up consists of a contact to check on status 14±3 days after a participant’s final dose of IMP in the trial. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 24 of 96 
Version 3.0: 25 May 2022
 
Figure 3: 
Trial Schematic - Part B (Multiple Ascending Dose, Cohorts 1-5) 
 
Abbreviations: IMP=investigational medicinal product; R=randomization. 
Doses will be selected following completion of Part A.  
1.3. 
Schedule of Assessments 
The Schedules of Assessments are provided in Table 1 (Part A, SAD Cohorts 1 and 2), Table 2 
(Part A, Food Effect Cohort 3), and Table 3 (Part B, MAD Cohorts 1-5).  
For Part B, a detailed schedule of assessments for Days 1 and 14 is provided in Table 4 . 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 25 of 96 
Version 3.0: 25 May 2022
 
Table 1: 
Schedule of Assessments – Part A, Single Ascending Dose (Cohorts 1 and 2) 
Trial Periods/Phases 
Screening 
Treatment (In Clinic) 
Follow-upa 
Screeningb 
Initial 
Check-
inb,c 
Subsequent 
Check-insb,c 
Periods 1 to 4d 
Check-
out/ET 
Day 
-30 to -2 
-1 
-1 
1 
2 
3 
 
Trial Hour 
 
 
 
Predosee 
0 
0.5 
1 
2 
3 
4 
6 
8 
12 16 
24 
36 
48 
 
Entrance and History 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assign screening number 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and psychiatric historyg 
----------------------→ 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of drug and alcohol use 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test for alcoholh 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
Height (Screening only) and 
weight 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical/neurological 
examinationj 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Continuous ECG (telemetry) 
 
Xk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continuous ECG (Holter) 
 
 
 
----------------------------------------Xl----------------------------------→ 
 
 
 
Standard 12-lead ECGm 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 27 of 96 
Version 3.0: 25 May 2022
 
b Participants must have COVID-19 testing done with a negative test result within a maximum of 5 days prior to, but as close as possible to, each admission to the clinic. 
COVID-19 testing may be performed after admission per the investigator’s discretion. 
c Assessments can be completed at Check-in for all participants in the cohort (sentinel and non-sentinel) during each period. No additional Check-in assessments are required for 
non-sentinel participants provided that those participants remain domiciled under close observation and the Check-in assessments are performed within 48 hours prior to dosing.  
d There will be a washout period of at least 5 days between doses. 
e Predose assessments to be completed within 60 minutes of dosing unless otherwise noted. 
f Inclusion/exclusion criteria will be assessed at the start of each trial period to ensure ongoing participant eligibility with the exception of age or assessments that are only 
scheduled during Screening (eg, height). 
g Medical occurrences that begin before the start of IMP dosing but after obtaining informed consent will be recorded as medical and/or psychiatric history. This also applies to 
replacement participants. 
h An alcohol test (breathalyzer or blood/urine) is required at Screening and at Check-in for each period. The alcohol test may be conducted at any time during the trial at the 
discretion of the investigator. 
i Period 1 only. 
j Full physical and neurological examinations should be completed at Screening and Check-out of each period (or ET). A limited examination (cardiovascular, pulmonary, and 
gastrointestinal) should be completed at Check-in to clinic on Day -1 of each period. Symptom driven physical and/or neurological examinations may be done at any time point 
during the trial at the investigator’s discretion. 
k A one-time baseline report of continuous ECG telemetry will be recorded for each participant by the site for a minimum of 12 hours starting on Day -1 prior to first dose. This 
baseline report will also be required for replacement participants. 
l Continuous ECG will be recorded for a minimum of 26 hours, starting at least 2 hours predose and continuing until 24 hours postdose. Electrocardiograms will be extracted from 
the continuous recording by a central ECG service from the following time points: -45, -30, and -15 minutes predose, and 0.5, 1, 2, 3, 4, 8, 12, and 24 hours postdose. 
Participants should be resting quietly in a supine position for at least 10 minutes before and 5 minutes after each extraction time point. 
m Triplicate ECGs will be obtained to confirm eligibility at Screening. Single ECGs will be obtained at all other time points. 
n Blood pressure and heart rate measurements will be obtained from participants in a supine position after at least 3 minutes of rest. 
o Orthostatic blood pressure and heart rate measurements will be obtained from participants in the standing position. 
p The “Baseline/Screening” C-SSRS form will be completed for all participants at Screening to determine eligibility. The “Since Last Visit” C-SSRS form will be completed at 
Check-in for each period to ensure that the participant continues to qualify for the trial and will also be completed at Check-out (or ET). 
q Concomitant medications should be recorded from Screening through the participant’s last visit/contact. 
r Adverse events (serious and nonserious) will be recorded from first dose of IMP through the participant’s last visit/contact. This also applies to replacement participants. 
s Additional urine drug screening can be conducted at any time during the trial at the discretion of the investigator.  
t A confirmatory FSH is required for all post-menopausal women. 
u Predose PK samples (1 sample and 1 backup sample) will be obtained within 15 minutes prior to dosing. 
v Future biospecimen research sample is optional and is only to be collected if signed consent is obtained from the participant. Sample can be collected at any time prior to 
initiation of first dose. 
 
 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 28 of 96 
Version 3.0: 25 May 2022
 
Table 2: 
Schedule of Assessments – Part A, Food Effect (Cohort 3) 
Trial Periods/Phases 
Screening 
Treatment (In Clinic) 
Follow-upa 
Screeningb 
Check-inb 
Periods 1 and 2c 
Day 
-30 to -2 
-1 
1 
2 
3/ET 
20 
Trial Hour 
 
 
Predosed 
0 
0.5 
1 
2 
3 
4 
6 
8 
12 
16 
24 
36 
48 
 
Entrance and History 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assign screening number 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and psychiatric 
historye 
---------------------------------------→ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of drug and 
alcohol use 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test for alcoholf 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
Height (Screening only) 
and weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical/neurological 
examinationh 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Standard 12-lead ECGi 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Supine heart rate and 
blood pressurej 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Standing heart rate and 
blood pressurek 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Respiratory rate and 
temperature 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 29 of 96 
Version 3.0: 25 May 2022
 
Trial Periods/Phases 
Screening 
Treatment (In Clinic) 
Follow-upa 
Screeningb 
Check-inb 
Periods 1 and 2c 
Day 
-30 to -2 
-1 
1 
2 
3/ET 
20 
Trial Hour 
 
 
Predosed 
0 
0.5 
1 
2 
3 
4 
6 
8 
12 
16 
24 
36 
48 
 
C-SSRSl 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Prior/concomitant 
treatmentsm 
---------------------------------------------------------------------------------------------------------------------------------------------------------------------→ 
Adverse event 
monitoringn 
 
 
-----------------------------------------------------------------------------------------------------------------------------------→ 
Laboratory 
Blood for safety 
laboratory  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Urine for safety laboratory 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Urine drug screeningo 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSHp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood sample 
 
 
Xq 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood sample for future 
biospecimen researchr 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
Dosing 
 
 
 
Xs 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telephone contact 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xa 
Abbreviations: COVID-19=coronavirus disease-2019; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ET=early termination; FSH=follicle 
stimulating-hormone; IMP=investigational medicinal product; PK=pharmacokinetic. 
a Contact with participant via phone call, internet/web, or other acceptable means of communication to check on their status 14±3 days after their final dose of IMP in the trial. 
b Participants must have COVID-19 testing done with a negative test result within a maximum of 5 days prior to, but as close as possible to, admission to the clinic. COVID-19 
testing may be performed after admission per the investigator’s discretion. 
c The treatment phase will comprise 2 periods with a 2-day washout between Periods 1 and 2. Participants will be discharged from the clinic on Period 2 Day 3 (Check-out). 
d Predose assessments to be completed within 60 minutes of dosing unless otherwise noted. 
e Medical occurrences that begin before the start of IMP dosing but after obtaining informed consent will be recorded as medical and/or psychiatric history.  

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 30 of 96 
Version 3.0: 25 May 2022
 
f An alcohol test (breathalyzer or blood/urine) is required at Screening and at Check-in. The alcohol test may be conducted at any time during the trial at the discretion of the 
investigator. 
g Period 1 only. 
h Full physical and neurological examinations should be completed at Screening and Check-out (or ET). A limited examination (cardiovascular, pulmonary, and gastrointestinal) 
should be completed at Check-in. Symptom driven physical and/or neurological examinations may be done at any time point during the trial at the investigator’s discretion. 
i Triplicate ECGs will be obtained to confirm eligibility at Screening. Single ECGs will be obtained at all other time points. 
j Blood pressure and heart rate measurements will be obtained from participants in a supine position after at least 3 minutes of rest. 
k Orthostatic blood pressure and heart rate measurements will be obtained from participants in the standing position. 
l The “Baseline/Screening” C-SSRS form will be completed for all participants at Screening to determine eligibility. The “Since Last Visit” C-SSRS form will be completed at 
Check-in to ensure that the participant continues to qualify for the trial and will also be completed at Check-out (or ET). 
m Concomitant medications should be recorded from Screening through the participant’s last visit/contact. 
n Adverse events (serious and nonserious) will be recorded from first dose of IMP through the participant’s last visit/contact. 
o Additional urine drug screening can be conducted at any time during the trial at the discretion of the investigator.  
p A confirmatory FSH is required for all post-menopausal women. 
q Predose PK samples (1 sample and 1 backup sample) will be obtained within 15 minutes prior to dosing. 
r Future biospecimen research sample is optional and is only to be collected if signed consent is obtained from the participant. Sample can be collected at any time prior to 
initiation of first dose. 
s Dose to be administered after a high-fat breakfast during fed period and under fasted conditions during fasted period. Further details on fed and fasting conditions are provided in 
Section 5.3.1. 
 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 31 of 96 
Version 3.0: 25 May 2022
 
Table 3: 
Schedule of Assessments – Part B, Multiple Ascending Dose (Cohorts 1 to 5) 
Trial Periods/Phases 
Screening 
Treatment (In Clinic) 
Follow-up 
Screeninga Check-ina 
In Clinic 
Contactb 
Day 
-30 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8-9 
10 
11-13 
14 
15/16 17/ET 
29 
Entrance and History 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assign screening number 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and psychiatric historyc  
-------------------------------→ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of drug and alcohol use 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test for alcohold 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
Height (Screening only) and weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Physical/neurological examinationf 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Continuous ECG (Holter) 
 
 
Xg 
 
 
 
 
 
 
 
 
 
Xg 
 
 
 
Standard 12-lead ECGh  
X 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Supine heart rate and blood pressurei 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Standing heart rate and blood pressurej 
X 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
Respiratory rate and temperature 
X 
X 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
X 
X 
 
C-SSRSl 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
Prior/concomitant treatmentsm 
-----------------------------------------------------------------------------------------------------------------------------------------------------------→ 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 33 of 96 
Version 3.0: 25 May 2022
 
d An alcohol test (breathalyzer or blood/urine) is required at Screening and at Check-in. The alcohol test may be conducted at any time during the trial at the discretion of the 
investigator. 
e 
 
f Full physical and neurological examinations should be completed at Screening, Day 7, and Day 17/ET. A limited examination (cardiovascular, pulmonary, and gastrointestinal) 
should be completed at Check-in. Symptom driven physical and/or neurological examinations may be done at any time during the trial at the investigator’s discretion. 
g Continuous ECG will be recorded for a minimum of 26 hours, starting at least 2 hours predose and continuing until 24 hours postdose. Electrocardiograms will be extracted from 
the continuous recording by a central ECG service from the following time points on Days 1 and 14: -45, -30, and -15 minutes predose and 0.5, 1, 2, 3, 4, 8, 12, and 24 hours 
after the morning dose. Participants should be resting quietly in a supine position for at least 10 minutes before and 5 minutes after each extraction time point. 
h Triplicate ECGs will be obtained to confirm eligibility at Screening. See Table 4 for details on Day 1 and Day 14 assessments. Single ECGs will be obtained at predose for all 
other time points.  
i Blood pressure and heart rate measurements will be obtained from participants in a supine position after at least 3 minutes of rest. On Day 1 and on Day 14, blood pressure and 
heart rate measurements will be obtained at -30 minutes predose and at 0.5, 1, 2, 4, 8, 12, and 24 hours after the morning dose. On Days 4 and 7, blood pressure and heart rate 
measurements will be obtained at predose and at 2 hours after the morning dose. On all other days, blood pressure and pulse rate measurements will be obtained at predose. 
j On dosing days, orthostatic blood pressure and heart rate measurements will be obtained at 2 hours after the morning dose with the participants in the standing position. 
k Respiratory rate and body temperature will be taken at predose on Days 1 through 14. 
l The “Baseline/Screening” C-SSRS form will be completed for all participants at Screening to determine eligibility. The “Since Last Visit” C-SSRS form will be completed at 
Check-in to ensure that the participant continues to qualify for the trial and will also be completed on Days 2, 7, 14, and 17/ET. 
m Concomitant medications should be recorded from Screening through the participant’s last visit/contact. 
n Adverse events (serious and nonserious) should be recorded from first dose of IMP through the participant’s last visit/contact. 
o Additional urine drug screening can be conducted at any time during the trial at the discretion of the investigator. 
p A confirmatory FSH is required for all post-menopausal women. 
q Laboratory test not part of eligibility. 
r The participant should empty their bladder and then drink ~250 mL water. The participant's urine should be collected ~1 hour later. 
s PK samples (1 sample and 1 backup sample) will be obtained predose (within 15 minutes prior to dosing) and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, and 24 hours following administration 
of the first dose of IMP on Day 1 and on Day 14 at predose (within 15 minutes prior to dosing) and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours after the morning dose. A 
single predose PK sample will be taken on Days 3, 5, 7, 9, and 11. 
t 
 
u Spot urine samples will be collected on Day -1. Cumulative urine samples will be collected on Day 14 (0-24 hour collection). 
v Future biospecimen research sample is optional and is only to be collected if signed consent is obtained from the participant. Sample can be collected at any time prior to 
initiation of first dose. 
w Meals consist of a light breakfast (~0700 hours, 1 hour prior to dosing), lunch (~1200 hours, 4 hours after dosing), and dinner (~1800 hours), and an evening snack (~2130 
hours). On days with intensive ECGs (extractions by central ECG service), participants will fast for at least 10 hours prior to dosing and will remain fasting for the first 4 hours 
following dosing with a small snack given right after the 4-hour time point and lunch right after the 6-hour time point. Participants must abstain from all food and drink (except 
water) for at least 4 hours prior to any safety laboratory evaluations and 10 hours prior to collection of PK samples on days when intensive sampling will be done (Days 1 and 
14). 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 34 of 96 
Version 3.0: 25 May 2022
 
Table 4: 
Schedule of Assessments – Part B, Multiple Ascending Dose (Detailed Assessments on Days 1 and 14) 
Assessment 
Predose (minutes) 
Post Morning Dose (hours) 
 
 
0.5 
1 
2 
3 
4 
6 
8 
12 
16 
24 
36/48/72 
Continuous ECG (Holter)a 
X (-45, -30, and -15 minutes) 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
Standard 12-lead ECG 
X (-15 minutes) 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
Supine HR and BPb 
X (-30 minutes) 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
RR and temperature 
X 
 
 
 
 
 
 
 
 
 
 
 
Standing HR and BPc 
 
 
 
X 
 
 
 
 
 
 
 
 
PKd 
X (-15 minutes) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
Abbreviations: BP=blood pressure; 
; ECG=electrocardiogram; HR=heart rate; PK=pharmacokinetic; QD=once daily; RR=respiratory rate; 
 
Note: When multiple assessments are planned for the same time points, the preferred order assessment is as reflected in the table (ie, ECG, followed by HR and BP, etc). 
a ECGs for exposure-response modeling analysis will be recorded for a minimum of 26 hours from 2 hours predose until 24 hours postdose. Participants should be resting quietly 
in a supine position for at least 10 minutes before the nominal ECG extraction time points and 5 minutes after each extraction time point, without any significant environmental 
distractions (noise, loud music, TV, computer or phone use, etc). Holter leads will be checked for proper connectivity prior to each time point. For time points with multiple 
assessments, ECGs will be obtained, then vital signs, followed by PK samples. 
b BP and HR measurements will be obtained from participants after at least 3 minutes of rest. 
c Orthostatic BP and HR measurements will be obtained from participants in the standing position. 
d One sample and 1 backup sample at time points indicated. 
e These samples will be obtained after the morning dose on Day 14 only. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 35 of 96 
Version 3.0: 25 May 2022
 
2. 
INTRODUCTION 
2.1. 
Trial Rationale 
Major depressive disorder (MDD) is a debilitating and chronic illness characterized by a broad 
spectrum of emotional and physical symptoms. Despite the availability of numerous treatments 
(eg, pharmacotherapy, cognitive behavioral psychotherapy, electroconvulsive therapy), 
approximately 30% of patients remain untreated, only 40% to 70% of patients respond to their 
treatment, and 10% to 30% of patients are treatment-resistant (Jaffe et al, 2019; Hasin et al, 
2018; Khan and Brown, 2015; Al-Harbi, 2012). In treatment-responsive patients, high rates of 
relapse and recurrence have been reported (Bai et al, 2020; Rush et al, 2006). Moreover, 
remission rates are low (approximately ≤50%) across clinical trials evaluating antidepressants 
(Oluboka et al, 2018; Machado et al, 2006; Thase et al, 2005) and partial response is common 
(Trivedi et al, 2006). Incomplete (inadequate) response to treatment for MDD is associated with 
an increased risk of relapse (Mulder et al, 2009; Möller, 2008), impaired social and occupational 
functioning (Jaffe et al, 2019; Judd et al, 2002) and consequently, an increased economic burden 
(Gauthier et al, 2019; Jaffe et al, 2019; Sobocki et al, 2006; McIntyre and O'Donovan, 2004). 
Thus, novel antidepressant therapies that can achieve consistent and more favorable short- and 
long-term outcomes represent an unmet medical need in patients with MDD. 
Kappa opioid receptor (KOR) activation is implicated in reduced activity of the reward 
(mesolimbic) pathway, negative mood states, and dysphoria. Recent evidence suggests that 
selective antagonism of KORs may provide therapeutic benefit in treating MDD (Jacobson et al, 
2020a). CVL-354 is a brain-penetrant potent KOR antagonist with >10-fold pharmacological 
selectivity over mu opioid receptors (MORs), which is being developed for treatment of MDD. 
Nonclinical pharmacology and safety data generated to date support CVL-354 for treatment of 
MDD. 
The aim of this 2-part, first-in-human trial is to investigate the safety, tolerability, and 
pharmacokinetics (PK) of CVL-354, following single ascending dose (SAD) and multiple 
ascending dose (MAD) oral administration in healthy participants. 
2.2. 
Background 
A growing body of data suggests that antagonism of KORs is a promising approach to 
addressing mood disorders (Carlezon and Krystal, 2016). KORs are highly expressed in brain 
regions associated with anhedonia, depression (nucleus accumbens) and anxiety (amygdala) 
(Cahill et al, 2014; Naganawa et al, 2016). As regulators of key circuits involved in reward and 
mood, KORs present a unique therapeutic target to intervene in MDD (Jacobson et al, 2020a). 
Nonclinical studies have demonstrated that activation of KORs results in 1) reduced 
dopaminergic tone in the nucleus accumbens and 2) induction of negative mood states (Carlezon 
et al, 2006). In humans, KOR agonism led to dose-dependent dysphoric and psychotomimetic 
effects (Pfeiffer et al, 1986).  
KOR antagonism is a well-known target for treatment of MDD and there have been efforts at 
development of therapeutic agents for this mechanism of action. In an example of polypharmacy 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 41 of 96 
Version 3.0: 25 May 2022
 
Table 6: 
Objectives and Endpoints - Part A (SAD) 
Objectives 
Endpoints 
Primary 
• 
To evaluate the safety and tolerability of single 
ascending doses of CVL-354 administered orally 
to healthy participants 
• 
Treatment-emergent AEs, including AEs 
potentially related to abuse 
• 
Clinically significant changes in ECGs, vital 
signs, clinical laboratory assessments, and 
physical and neurological examination results 
• 
Changes in suicidality assessed using the C-SSRS 
Secondary 
• 
To evaluate the plasma pharmacokinetics of 
CVL-354 following single ascending doses 
administered orally to healthy participants 
• 
Pharmacokinetic parameters of CVL-354 
following single oral doses: 
o 
Cmax 
o 
Tmax 
o 
AUC24 
o 
AUClast 
o 
AUCinf 
o 
CL/F 
o 
Vz/F 
o 
t½  
• 
To evaluate the effect of food following single 
doses of CVL-354 administered orally to healthy 
participants 
• 
Pharmacokinetic parameters of CVL-354 
following single oral doses: 
o 
Cmax 
o 
Tmax 
o 
AUC24 
o 
AUClast 
o 
AUCinf 
o 
CL/F 
o 
Vz/F 
o 
t1/2 
Abbreviations: AE=adverse event; AUC=area under the concentration-time curve; CL/F=apparent clearance of drug 
from plasma; Cmax=maximum plasma concentration; C-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; t1/2=apparent terminal half-life; SAD=single ascending dose; Tmax=time to maximum 
plasma concentration; Vz/F=apparent volume of distribution during terminal phase. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 42 of 96 
Version 3.0: 25 May 2022
 
Table 7: 
Objectives and Endpoints - Part B (MAD) 
Objectives 
Endpoints 
Primary 
• 
To explore the safety and tolerability of multiple 
ascending doses of CVL-354 administered orally 
to healthy participants 
• 
Treatment-emergent AEs, including AEs 
potentially related to abuse 
• 
Clinically significant changes in ECGs, vital 
signs, clinical laboratory assessments, and 
physical and neurological examination results 
• 
Changes in suicidality assessed using the C-SSRS 
Secondary 
• 
To evaluate the plasma pharmacokinetics of 
CVL-354 following multiple ascending doses 
administered orally to healthy participants 
• 
Pharmacokinetic parameters for CVL-354 on 
Days 1 and 14: 
o 
Cmax 
o 
Tmax 
o 
Ctrough 
o 
AUCτ 
o 
CL/F (Day 14 only) 
o 
VZ/F (Day 14 only)  
o 
PTR (Day 14 only) 
o 
Rac, Cmax (Day 14 only) 
o 
Rac, AUC (Day 14 only) 
o 
t1/2 (Day 14 only) 
o 
Ae (amount eliminated unchanged in urine at 
steady state on Day 14) 
o 
Renal clearance 
Abbreviations: AE=adverse event; AUC=area under the concentration-time curve; CL/F=apparent clearance of drug 
from plasma; Cmax=maximum plasma concentration; Ctrough=trough plasma concentration; C-SSRS=Columbia-
Suicide Severity Rating Scale; ECG=electrocardiogram; MAD=multiple ascending dose; PTR=peak-to-trough ratio; 
Rac=accumulation ratio; t1/2=apparent terminal half-life; Tmax=time to maximum plasma concentration; 
Vz/F=apparent volume of distribution during terminal phase. 
4. 
TRIAL DESIGN 
4.1. 
Overall Design 
This is a Phase 1, randomized, placebo-controlled, single-center trial that will be conducted in 
2 parts to evaluate safety, tolerability, and PK of CVL-354 following single and multiple doses 
in healthy participants. The single ascending dose and food effect portion (Part A) are described 
in Section 4.1.1 and the multiple ascending dose portion (Part B) is described in Section 4.1.2.  
Part B of the trial will start after completion of single dose escalation in Part A (Cohorts 1 and 2). 
The evaluation of food effect for Part A (Cohort 3) may be conducted in parallel with Part B, 
using a CVL-354 dose of 50 mg. Single doses of CVL-354 up to 200 mg are considered to be 
safe and well tolerated based on review of data from Part A Cohorts 1 and 2. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 43 of 96 
Version 3.0: 25 May 2022
 
4.1.1. 
Single Ascending Dose and Food Effect- Part A 
4.1.1.1. 
Single Ascending Dose (Cohorts 1 and 2) 
Dose escalation will proceed according to a double-blind (investigator and participant), 4-period 
crossover, single ascending dose methodology. Up to 2 cohorts of participants will be evaluated. 
Cohorts 1 and 2 will be dosed in a sequential manner for up to 4 periods each (see schema in 
Section 1.2). Progression to each dose level will occur following evaluation of all available 
cumulative safety, tolerability, PK, and other emergent data from the previous cohorts and 
periods.  
The current trial may evaluate up to 8 different dose levels in Cohorts 1 and 2; however, some 
doses may be repeated, if required. The starting dose for Part A will be 0.5 mg. Doses, in 
general, will be escalated in Cohort 1 and Cohort 2 until the maximum tolerated dose is achieved 
or the CVL-354 exposures (Cmax and AUC24) reach, or are projected to reach, the predefined 
human exposure limits 
 
 Dose escalation may also be stopped if it is determined that sufficient 
exposures are achieved, based on estimated target occupancy. The proposed doses in Part A for 
Cohorts 1 and 2 are presented in Table 8. Based on emergent data, the actual doses may change 
(from those presented in Table 8); however, new doses will not exceed half-log increments 
(3.3-fold) from previous dose. Smaller increments (eg, ≤2-fold) will be evaluated as exposures 
approach the proposed stopping criteria. All dosing decisions will be made jointly by the sponsor 
and the investigator after review of all available safety, tolerability (through 72 hours postdose), 
and PK data (through 24 hours postdose) at an SRT meeting. 
Actual doses administered to Cohorts 1 and 2 at the time of the protocol amendment 
(Version 3.0) are provided in Section 2.2.5. 
Table 8: 
Example Dosing Paradigms for CVL-354 Single Ascending Dose in Cohorts 1 
and 2 
Cohort 
N 
Period 1 
Period 2 
Period 3 
Period 4 
Cohort 1 
2 
Placebo 
1.5 mg 
5 mg 
10 mg 
2 
0.5 mg 
Placebo 
5 mg 
10 mg 
2 
0.5 mg 
1.5 mg 
Placebo 
10 mg 
2 
0.5 mg 
1.5 mg 
5 mg 
Placebo 
Cohort 2 
2 
Placebo 
40 mg 
80 mg 
100 mg 
2 
20 mg 
Placebo 
80 mg 
100 mg 
2 
20 mg 
40 mg 
Placebo 
100 mg 
2 
20 mg 
40 mg 
80 mg 
Placebo 
Doses/treatment may be modified based on emergent safety, tolerability, and pharmacokinetic data. 
Doses may be repeated to confirm safety/tolerability. 
During dose escalation, Cohorts 1 and 2 will employ sentinel dosing (n=2; 1 CVL-354 and 
1 placebo) during each period to ensure safety and tolerability before proceeding to dosing of 
non-sentinel participants for that period. The investigator will review AEs (serious and 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 44 of 96 
Version 3.0: 25 May 2022
 
nonserious) and all available safety data from the first 24 hours after dosing for the 2 sentinel 
participants. If clinically significant safety concerns are observed in sentinel participants, dosing 
of the rest of the cohort will be paused in order for the SRT to discuss the findings and determine 
subsequent actions. If no safety concerns are observed in the sentinel participants, the 
investigator will provide written documentation for sponsor confirmation before proceeding to 
dosing of non-sentinel participants.  
Check-in assessments conducted on Day -1 of each period will include both sentinel and 
non-sentinel participants. No additional check-in assessments will be required for non-sentinel 
participants prior to dosing if the Check-in assessments are performed within 48 hours prior to 
dosing. 
Each dosing period for the dose escalation portion of Part A will be separated by a washout 
period of at least 5 days (ie, administration of subsequent doses of investigational medicinal 
product [IMP] will not occur until at least 5 days after the previous dose of IMP). 
Cohorts 1 and 2 will comprise approximately 8 participants each (3:1 ratio of CVL-354 to 
placebo within each treatment period). All participants will receive single oral doses of CVL-354 
or placebo during each period. All doses during dose escalation will be administered under fasted 
conditions following a 10-hour overnight fast. Participants will continue to fast for 4 hours 
following dosing on Day 1.  
4.1.1.2. 
Food Effect Evaluation (Cohort 3) 
Cohort 3 will be scheduled after completion of single dose escalation to evaluate the effect of 
food on CVL-354 exposures after a single 50 mg dose. The selected dose is 4-fold lower than the 
top single CVL-354 200 mg dose that is considered to be safe and tolerated. For evaluation of 
food effect, a 2-period crossover design will be utilized, with approximately 8 participants 
randomized to 1 of 2 sequences (fed/fasted or fasted/fed). Details of fasted and fed conditions are 
provided in Section 5.3.1. Sentinel dosing will not be employed for evaluation of food effect. 
Participants will remain domiciled after Check-in for both periods of the food effect evaluation. 
The duration of each period will be 3 days, with a 2-day washout between Period 1 and Period 2.  
4.1.2. 
Multiple Ascending Dose - Part B 
The safety and PK of double-blind (investigator and participant), multiple-dose administration of 
CVL-354 will be evaluated in Part B of the trial after completion of dose escalation in Part A. 
Part B may overlap with Part A Cohort 3 (evaluation of food effect on CVL-354 exposures). 
A schematic of the trial design is provided in Section 1.2.  
Up to 5 sequential cohorts of 10 participants each will be evaluated in Part B. Participants will 
receive oral doses of either CVL-354 or placebo for up to 14 days. Eligible participants will be 
admitted to the clinic on Day -1 and will be randomized in a 4:1 ratio (8 participants active 
treatment: 2 participants placebo). Cohorts will be initiated in a sequential manner after review 
of all available safety, tolerability, and PK data (at least up to Day 15) from previous cohorts.  
Each dose of CVL-354 will be administered once daily (QD) throughout Part B of the trial based 
on data obtained during Part A of the trial. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 50 of 96 
Version 3.0: 25 May 2022
 
4.5. 
End of Trial Definition 
The end of the trial is defined as the date of the last visit (including phone contact) of the last 
participant in the trial globally. 
5. 
TRIAL POPULATION 
Healthy women of nonchildbearing potential and men 18 to 55 years of age, inclusive, will be 
enrolled into this trial.  
5.1. 
Inclusion Criteria 
Individuals are eligible for participation in this trial only if all of the following criteria apply: 
1. 
 
Women of nonchildbearing potential and men 18 to 55 years, inclusive, at the time of signing the 
ICF. The criteria for determination of childbearing potential are provided in Section 10.4.1.3.  
2. 
 
Overtly healthy as determined by medical evaluation, including medical and psychiatric history, 
physical and neurological examinations, ECG, vital sign measurements, and laboratory test results, 
as evaluated by the investigator. 
3. 
 
Body mass index of 18.5 to 30.0 kg/m2, inclusive, and total body weight >50 kg (110 lb) at 
Screening. 
4. 
 
Sexually active men with a pregnant or nonpregnant partner of childbearing potential must agree to 
comply with the following contraception requirements during the trial and for 14 days after the last 
dose of IMP: 
• 
Use acceptable (at minimum) or highly effective contraception as defined in 
Section 10.4.1.2 and Section 10.4.1.1, respectively, or remain abstinent. 
• 
Use condoms. 
In addition, male participants should not donate sperm for a minimum of 14 days following the last 
dose of IMP. 
5. 
 
Capable of giving signed informed consent as described in Section 10.1.3 (Appendix 1), which 
includes compliance with the requirements and restrictions listed in the ICF and in this protocol. 
6. 
 
Ability, in the opinion of the investigator, to understand the nature of the trial and comply with 
protocol requirements, including the prescribed dosage regimens, scheduled visits, laboratory tests, 
and other trial procedures. 
Abbreviations: ECG=electrocardiogram; ICF=informed consent form; IMP=investigational medicinal product. 
5.2. 
Exclusion Criteria  
Individuals are not eligible for participation in this trial if any of the following criteria apply: 
Medical History and Concurrent Conditions 
1. 
 
Current or past history of significant cardiovascular, pulmonary, gastrointestinal, renal, hepatic, 
metabolic, genitourinary, endocrine (including diabetes mellitus), malignancy (except for basal 
cell carcinoma of the skin and cervical carcinoma in situ, at the discretion of the investigator), 
hematological, immunological, neurological, or psychiatric disease that, in the opinion of the 
investigator or medical monitor, could compromise either participant safety or the results of the 
trial. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 51 of 96 
Version 3.0: 25 May 2022
 
2. 
 
“Yes” responses for any of the following items on the C-SSRS (within the individual’s 
lifetime):  
• 
Suicidal Ideation Item 3 (Active Suicidal Ideation with Any Methods [Not Plan] 
without Intent to Act) 
• 
Suicidal Ideation Item 4 (Active Suicidal Ideation with Some Intent to Act, without 
Specific Plan) 
• 
Suicidal Ideation Item 5 (Active Suicidal Ideation with Specific Plan and Intent) 
• 
Any of the Suicidal Behavior items (Actual Attempt, Interrupted Attempt, Aborted 
Attempt, Preparatory Acts or Behavior) 
“Yes” responses for any of the following items on the C-SSRS (within past 12 months):  
• 
Suicidal Ideation Item 1 (Wish to be Dead) 
• 
Suicidal Ideation Item 2 (Non-Specific Active Suicidal Thoughts) 
Serious risk of suicide in the opinion of the investigator is also exclusionary. 
3. 
 
History of substance or alcohol-use disorder (excluding nicotine or caffeine) as per DSM-5 
criteria within 12 months prior to signing the ICF. 
4. 
 
Any condition that could possibly affect drug absorption, including, but not limited to, 
complicated appendectomy or cholecystectomy, bowel resections, bariatric weight loss surgery, 
gastric banding, or gastrectomy. 
5. 
 
Receipt of SARS-CoV2 vaccination or booster as follows: 
• 
mRNA: within 14 days prior to dosing 
• 
Non-mRNA: within 28 days prior to dosing 
In addition, participants who plan to receive SARS-CoV2 vaccination or booster while 
participating in the trial or for at least 14 days after the last dose of IMP will be excluded. 
6. 
 
Have recently been diagnosed with symptomatic COVID-19 or test positive for COVID-19 
within 30 days prior to signing the ICF. 
Prior or Concomitant Therapies 
7. 
 
Use of prohibited medication prior to randomization or likely to require prohibited concomitant 
therapy (eg, prescription and over-the-counter medications, herbal medications, vitamins, and 
supplements) during the trial (see Section 6.5). 
Laboratory Test Results 
8. 
 
Either of the following: 
• 
History of HIV, hepatitis B, or hepatitis C infection 
• 
Positive result for HIV, hepatitis B surface antigen, hepatitis B core antibody, or 
hepatitis C antibody 
9. 
 
Positive drug screen (including nicotine) or a positive test for alcohol (note: individuals who 
test positive for nicotine or alcohol may be rescreened). 
10. 
 
Any of the following clinical laboratory test results (and confirmed by a single repeat 
measurement, if deemed necessary): 
• 
AST or ALT ≥1.5 × ULN 
• 
Total bilirubin ≥1.5 × ULN. Individuals with a history or suspicion of Gilbert’s 
syndrome may be eligible provided the direct bilirubin is <ULN. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 52 of 96 
Version 3.0: 25 May 2022
 
11. 
 
Estimated glomerular filtration rate at Screening <90 mL/min/1.73 m2, as calculated using the 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (Levey et al, 2009). 
Other Exclusionary Assessments 
12. 
 
12-lead ECG demonstrating any of the following at Screening or initial Check-in (Day -1): 
• 
QTcF interval >450 ms 
• 
QRS interval >120 ms 
• 
PR interval >220 ms 
Note: at Screening, eligibility will be determined based on the average of a centrally read 
triplicate set of ECGs. At initial Check-in (Day -1), a single ECG will be obtained. If any of the 
above criteria are not met at subsequent Check-ins, consult the medical monitor to determine 
whether the participant remains eligible to continue in the trial. 
13. 
 
Blood pressure measurements demonstrating any of the following at Screening or Check-in 
(Day -1 of each period): 
• 
Systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg 
o 
Blood pressure will be measured after at least 3 minutes in supine position. 
At Screening, the average of 2 measurements will be used to determine 
eligibility and a single measurement at each Check-in. 
• 
Orthostatic hypotension, defined as a decrease of ≥20 mmHg in systolic blood 
pressure upon standing compared with the supine blood pressure measurement (at 
Screening, relative to the average measurement) 
• 
Symptomatic orthostatic dizziness 
14. 
 
Heart rate <45 bpm or >100 bpm based on vital signs assessment (rather than ECG). 
Heart rate will be measured in a supine position after at least 3 minutes of rest. The average of 
2 measurements taken 1-2 minutes apart will be used to determine eligibility at Screening and a 
single measurement at each Check-in. 
15. 
 
Any other abnormal safety findings unless, based on the investigator’s judgment, the findings 
are not medically significant and would not impact the safety of the participant or the 
interpretation of the trial results. The medical monitor should be contacted to discuss individual 
cases, as needed.  
Tests with abnormal results may be repeated to ensure the reproducibility of the result before 
excluding a potential participant based on criteria provided in the protocol.  
Lifestyle or Other Miscellaneous Exclusions 
16. 
 
Refusal to abstain from grapefruit-containing foods or beverages or Seville orange-containing 
foods or beverages from 7 days prior to Day -1 through Check-out from the clinic for each 
treatment period. 
17. 
 
Current use of tobacco or nicotine-containing products (cigarettes, cigars, chewing tobacco, 
snuff, e-cigarettes, etc). 
18. 
 
History of chronic consumption of >400 mg/day of caffeine-containing drinks or food (eg, 
>4 cups [8 ounces] of brewed coffee, 9 cans [12 oz] of diet cola, 12 cans [12 oz] of cola, 8.5 
cups of brewed black tea, 2 energy shot drinks). 
19. 
 
Refusal to adhere to lifestyle considerations as defined in Section 5.3. 
20. 
 
Considering or scheduled to undergo any surgical procedure during the trial. 
21. 
 
Any other condition that would preclude IMP administration or trial participation (eg, difficulty 
swallowing, poor venous access).  

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 53 of 96 
Version 3.0: 25 May 2022
 
22. 
 
Known allergy or hypersensitivity to the IMP, closely related compounds, or any of their 
specified ingredients. 
23. 
 
Donated more than 500 mL of blood in the 2 months prior to signing the ICF. 
24. 
 
Current enrollment or past participation within 30 days or 5 half-lives (whichever is longer) 
prior to signing the ICF in any other clinical trial involving an IMP.  
25. 
 
Employee of the investigator, clinic, or sponsor with direct involvement in the proposed trial or 
other trials under the direction of the investigator or clinic, as well as family members of the 
employee or investigator. 
26. 
 
Anyone who should not participate in the trial in the opinion of the sponsor, investigator, or 
medical monitor. 
27. 
 
Part B only: anyone who participated in Part A of the trial. 
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; COVID-19=coronavirus 
disease-2019; C-SSRS=Columbia-Suicide Severity Rating Scale; DSM-5=Diagnostic and Statistical Manual of 
Mental Disorders, 5th edition; ECG=electrocardiogram; ICF=informed consent form; IMP=investigational medicinal 
product; mRNA=messenger ribonucleic acid; QTcF=QT interval corrected for heart rate using Fridericia’s formula; 
SARS-CoV2=severe acute respiratory syndrome coronavirus 2; ULN=upper limit of normal. 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
Participants are required to abstain from consumption of caffeine-containing foods or caffeinated 
beverages (eg, coffee, tea, cola, energy drinks), grapefruit-containing foods or beverages, and 
Seville orange-containing foods or beverages from 7 days prior to Day -1 through Check-out 
from the clinic for each treatment period.  
On days with intensive ECGs (extractions by central ECG service) and PK collection (Day 1 in 
Part A, Days 1 and 14 in Part B), participants will fast for at least 10 hours prior to dosing and 
remain fasting for the first 4 hours following dosing with a small snack given right after the 
4-hour time point and lunch right after the 6-hour time point. Participants must abstain from all 
food and drink (except water) for at least 4 hours prior to any safety laboratory evaluations. 
Water is permitted until 1 hour prior to IMP administration and can be consumed ad libitum after 
dosing.  
Meals consist of a light breakfast (~0700 hours, 1 hour prior to dosing), lunch (~1200 hours, 
4 hours after dosing), and dinner (~1800 hours), and an evening snack (~2130 hours).  
The following guidelines apply for dosing under “fed” conditions during food effect evaluation: 
• Following an overnight fast of at least 10 hours, participants should start breakfast 
approximately 25 minutes prior to administration of IMP.  
• The entire breakfast will be consumed approximately over a 20-minute period with 
the IMP administered within approximately 5 minutes of completion of the meal. 
Actual start and stop times for breakfast and IMP administration time will be 
recorded. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 54 of 96 
Version 3.0: 25 May 2022
 
• There are no water restrictions prior to dosing for participants dosed under fed 
conditions. The IMP should be administered with 240 mL of ambient temperature 
water.  
• No water is permitted for at least 2 hours postdose. No food will be allowed for at 
least 4 hours postdose.  
• The breakfast will be a high calorie/high fat meal (approximately 150, 250, and 
500-600 calories from protein, carbohydrate, and fat, respectively) consisting of 
2 eggs fried in butter, 2 strips of bacon or 50 g of meat or sausage, 2 slices of toast 
with butter, 4 ounces of hash brown potatoes, and 8 ounces of whole milk.  
5.3.2. 
Alcohol and Tobacco Restrictions 
Participants will abstain from alcohol for at least 24 hours prior to each admission to the clinic 
until each Check-out. Participants may undergo an alcohol breath test or blood/urine alcohol test 
at the discretion of the investigator.  
Use of tobacco or nicotine-containing products (cigarettes [including e-cigarettes], cigars, 
chewing tobacco, snuff, etc) is prohibited within 28 days prior to signing the informed consent 
form (ICF) and during the trial. Vaping is not permitted during the trial. 
5.3.3. 
Activity 
Participants will abstain from strenuous exercise for 48 hours before each blood collection for 
clinical laboratory tests. Participants may participate in light recreational activities during the 
trial (eg, walking, watching television, reading). 
5.3.4. 
Effects on Ability to Drive and Use Machinery 
The effect of CVL-354 on the ability to drive and use machines has not been systematically 
evaluated.  
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomized to trial treatment. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, and eligibility 
criteria. 
Individuals who do not meet the criteria for participation in this trial (screen failure) at screening 
may be rescreened once at the discretion of the investigator and after consultation with the 
sponsor unless screen failure is due to a positive urine drug screen for illicit substances. 
Rescreened participants will be assigned a new participant number. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 55 of 96 
Version 3.0: 25 May 2022
 
6. 
TRIAL TREATMENTS 
Trial treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a trial participant according to the trial protocol. 
Investigational medicinal product refers to a pharmaceutical form of any active substance or 
placebo being tested in this clinical trial and will be used to refer to the trial treatment in this 
protocol. 
6.1. 
Trial Treatments Administered 
A summary of the IMP to be administered during this trial is presented in Table 10. 
Table 10: 
Investigational Medicinal Product Administered 
IMP 
CVL-354 Solution 
(Extemporaneous) 
CVL-354 Capsules 
Placebo 
Type  
Drug 
Drug 
Drug 
Dose 
Formulation 
Oral solution 
Capsule 
Matching oral solution 
vehicle (without active 
pharmaceutical ingredient)  
Matching capsule filled with 
silicified microcrystalline 
cellulose 
Unit Dose 
Strength(s) 
0.5 mg/10 mL – 500 mg/10 mL 
5 mg, 25 mg, 100 mg 
Not applicable 
Dosage 
Level(s) 
Part A Cohort 1 
0.5, 1.5 mg, 5 mg, or 15 mg 
 
Part A Cohort 2 
45 mg, 90 mg, 150 mg, or 
200 mg 
 
Part B Cohort 1 
10 mg QD 
Part A Cohort 3 
50 mg 
 
Part B Cohorts 2-5 
25 mg QD, 50 mg QD, 
100 mg QD, or 150 mg QD 
Not applicable 
Route of 
Administration 
Oral 
Oral 
Oral 
Sourcing 
CVL-354 capsules will be provided by Cerevel.  
The CVL-354 oral solution preparation will be supplied by Cerevel and the solution will be 
prepared by the pharmacy of the trial site. 
Packaging and 
Labeling 
Capsule IMP provided by Cerevel will be in 60 cc HDPE bottles and should be stored in 
accordance with the drug label.  
The CVL-354 API for oral solution provided by Cerevel and oral solution will be supplied in 
amber-glass bottles. The bottles will be labeled according to local regulatory requirements and 
language. Oral solution will be prepared before dosing by the pharmacy of the trial site. 
Abbreviations: API=active pharmaceutical ingredient; HDPE=high-density polyethylene; IMP=investigational 
medicinal product; QD=once daily. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 56 of 96 
Version 3.0: 25 May 2022
 
6.2. 
Preparation, Handling, Storage, and Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit (original shipment and/or moving of IMP supply from 1 office or 
facility to another within the site’s network) for all IMP received and any discrepancies are 
reported and resolved before use of the IMP. 
CVL-354 and placebo oral dosing solution will be prepared by site staff and details of the dose 
preparation requirements will be provided by Cerevel in a separate extemporaneous dispensing 
record. Prepared doses will be provided in unit dose containers and labeled in accordance with 
appropriate regulations and the investigator’s site labeling requirements. 
Only participants enrolled in the trial may receive IMP and only authorized site staff may supply 
or administer IMP. All IMP 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 site staff. 
The investigator is responsible for IMP accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
Further guidance and information for the preparation, handling, storage, accountability, and 
disposition of IMP are provided in the pharmacy manual.  
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1. 
Participant Assignment to Treatment 
Treatment assignments will be based on a computer-generated randomization code provided by 
the sponsor or designee.  
For the food effect evaluation (Part A, Cohort 3), participants will receive the same 50 mg dose 
and will be randomized to a treatment sequence (fed/fasted or fasted/fed).  
Participants who discontinue may be replaced at the discretion of the sponsor and investigator. If 
a participant is replaced, he or she will receive a mirror randomization number (such that the 
same sequence [Part A, Cohorts 1 and 2] or treatment [Part B] assigned to the original 
discontinued participant would be assigned to the replacement participant). Participants who 
discontinue during Part A (SAD portion) of the trial may be replaced; however, the replacement 
participant will only need to complete the trial periods that were not completed by the original 
participant.  
Further instructions on replacement participants are available in the Operations Manual.  
6.3.2. 
Blinding 
During the entire trial, treatment will be blinded such that participants and the investigator and 
other site personnel (with the exception of pharmacy staff) will not have knowledge of the 
treatment assignment at any visit.  
Treatment assignment will not be blinded for the food effect portion of the trial.  

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 57 of 96 
Version 3.0: 25 May 2022
 
At the initiation of the trial, investigators and site personnel will be instructed on the method for 
breaking the blind. In case of an emergency, the investigator has the sole responsibility for 
determining if unblinding of the treatment assignment for an individual participant is warranted. 
Participant 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 before unblinding a participant’s treatment assignment unless this could 
delay emergency treatment of the participant. The sponsor must be notified within 24 hours after 
breaking the blind for a trial participant.  
Documentation of unblinding should be recorded in the participant’s medical record, including 
the reason for breaking the blind, the date and time the blind was broken, and the names of the 
personnel involved. Once the blind is broken for a participant, treatment with the IMP may not 
be reinitiated for that participant. 
A list of sponsor personnel who will be unblinded to treatment allocation for the purposes of 
dose escalation and safety monitoring (SRT) will be provided in a separate document. 
6.4. 
Trial Treatment Compliance 
The time and dose of each IMP administration, along with information on any missed or 
inappropriately administered dose, will be recorded in source documents and the eCRF. 
Compliance will be ensured by a hand and mouth check during the oral dosing administration.  
6.5. 
Prior and Concomitant Therapy 
All prescription and over-the-counter medications are prohibited from 28 days prior to first dose 
of IMP through the end of the trial (as defined Section 4.5) with the exception of acetaminophen 
(maximum total daily dose of 1 g) and topical steroid use as needed for treatment of an AE. Use 
of herbal medications, vitamins, and supplements is also prohibited during the trial. 
The investigator will record all medications and therapies taken by the participant for treatment 
of an AE until the end of the trial. The following information will be recorded in the eCRF: 
medication, indication, dose, frequency, route, start date, and end date.  
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.6. 
Dose Modification 
Guidance for dose escalation/stopping rules is provided in Section 4.4. 
The decision to proceed to the next dose level of CVL-354 in successive cohorts/periods will be 
made by the SRT based on a full review of the safety, tolerability, and preliminary PK data 
obtained from the completed prior doses. 
If ongoing data surveillance during the treatment interval reveals consistent notable AEs or 
safety concerns at a dose, which are determined to be attributable to the drug treatment, 
continued dosing within the cohort will be temporarily halted and no participants will be dosed 
until full safety review can take place to determine if dose modification or termination of the 
cohort are appropriate. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 58 of 96 
Version 3.0: 25 May 2022
 
6.7. 
Intervention after the End of the Trial 
There will be no provision of CVL-354 for participants after they complete or discontinue 
treatment in this trial.  
7. 
DISCONTINUATION OF TRIAL TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Trial Treatment 
After treatment assignment, a participant may stop treatment permanently for a variety of 
reasons. Treatment discontinuations may be initiated by a participant or may become medically 
necessary due to AEs, required treatment with a disallowed medication or therapy, or other 
issues, as determined by the investigator. If IMP is permanently discontinued, the participant will 
be encouraged to remain in the trial for the evaluations at safety follow-up. See the Schedule of 
Assessments (Section 1.3) for data to be collected at the time of discontinuation of IMP and 
follow-up and for any further evaluations that need to be completed. 
The IMP may be discontinued for any of the following reasons listed below: 
• Adverse event 
• Protocol deviation 
• Noncompliance with study schedule 
• Withdrawal by participant 
• Physician decision 
If a participant discontinues the IMP due to an AE, the investigator or other trial personnel will 
make every effort to follow the event until it has resolved or stabilized.  
7.2. 
Discontinuation of Trial 
7.2.1. 
Discontinuation of Entire Trial 
If the sponsor terminates or suspends the trial for any reason, prompt notification will be given to 
investigators, Institutional Review Boards (IRBs), and regulatory authorities in accordance with 
regulatory requirements. 
7.2.2. 
Discontinuation of Individual Site 
Trial site participation may be discontinued by the sponsor, the investigator, or the IRB if judged 
to be necessary for medical, safety, regulatory, ethical, or other reasons consistent with 
applicable laws, regulations, and Good Clinical Practice (GCP). The investigator will notify the 
sponsor promptly if the trial is terminated by the investigator or the IRB at the site. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 59 of 96 
Version 3.0: 25 May 2022
 
7.2.3. 
Individual Participant Discontinuation From the Trial  
All participants have the right to withdraw their consent from further participation in the trial at 
any time without prejudice. Participants cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation. The investigator can also 
discontinue a participant’s participation in the trial at any time if medically necessary.  
At the time of discontinuing from the trial, if possible, an early termination visit should be 
conducted. See the Schedule of Assessments (Section 1.3) for data to be collected at the time of 
trial discontinuation and follow-up and for any further evaluations that need to be completed. 
The participant will be permanently discontinued both from the IMP and from the trial at that 
time. 
Complete withdrawal of consent requires a participant’s refusal of ALL of the following 
methods of follow-up: 
• Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by an in-home visit). 
• Participation in a subset of protocol-specified follow-up procedures (by a frequency 
schedule and method, as agreed by participant and staff). 
• Contact of the participant by trial personnel, even if only by telephone, to assess 
current medical condition, and obtain necessary medical or laboratory reports relevant 
to the trial’s objectives. 
• Contact of alternative person(s) who have been designated in source records as being 
available to discuss the participant’s medical condition, even if only by telephone, 
mail, or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician). 
• Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources). 
Withdrawal of consent is a critical trial event and, therefore, should be approached with the same 
degree of importance and care as is used in initially obtaining informed consent. The reasons for 
a participant’s intended withdrawal need to be completely understood, documented, and 
managed to protect the rights of the participant and the integrity of the trial. A participant may, 
however, indicate that further trial participation is creating a burden on their work, school, or 
social schedule. Therefore, the investigator should determine if the participant can continue 
participation in the trial if modifications to his/her treatment and/or schedule of assessments can 
be accommodated. Only participants who withdraw their permission for all of the above methods 
of follow-up are considered to have completely withdrawn their consent to participate in the trial. 
7.3. 
Procedures to Encourage Continued Trial Participation 
In all cases of impending consent withdrawal, investigators will be instructed to meet and discuss 
(without undue coercion) with the participant their options of continuing in the trial. The 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 62 of 96 
Version 3.0: 25 May 2022
 
8.3.2. 
Physical/Neurological Examinations 
The full physical examination will include a review of the following body systems: head, ears, 
eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, and 
musculoskeletal systems. 
The limited physical examinations will include evaluation of cardiovascular, pulmonary, and 
gastrointestinal systems. 
A full neurological examination will include an assessment of the participant’s mental status 
(level of consciousness, orientation, speech, memory, etc), cranial nerves, motor (muscle 
appearance, tone, strength and reflexes), sensation (including Romberg sign), coordination, and 
gait. 
The investigator (or designee) is responsible for performing the physical and neurological 
examinations. If the appointed designee is to perform these examinations, he or she must be 
permitted by local regulations and his or her name must be included on the delegation of 
authority log. Whenever possible, the same individual should perform all physical and 
neurological examinations.  
Any condition present at the post-treatment physical and neurological examinations that was not 
present at the baseline examination should be documented as an AE and followed to a 
satisfactory conclusion. 
8.3.3. 
Vital Sign Measurements 
Vital signs include systolic and diastolic blood pressures, heart rate, respiratory rate, and body 
temperature. Supine blood pressure and heart rate measurements will be obtained after at least 
3 minutes of rest.  
At specified time points (see Schedule of Assessments [Section 1.3]), the supine measurements 
will be followed by measurements in the standing position (after standing for at least 3 minutes) 
to allow for orthostatic assessments. Orthostatic hypotension is defined as a decrease of 
≥20 mmHg in systolic blood pressure upon standing compared with the supine blood pressure 
measurement (at Screening, relative to the average measurement). 
Any clinically relevant changes occurring during the trial will be recorded in the AE section of 
the eCRF. 
Further details on taking vital sign measurements are provided in the appropriate trial specific 
manuals. 
8.3.4. 
Electrocardiograms 
This section describes the procedures for continuous ECG recordings and standard 12-lead 
ECGs.  
8.3.4.1. 
Continuous Electrocardiogram Recordings 
During the SAD portion of the trial (Part A), a one-time baseline report of continuous ECG 
telemetry will be recorded for each participant by the site for a minimum of 12 hours starting on 
Day -1 prior to first dose. This baseline report will also be required for any replacement 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 63 of 96 
Version 3.0: 25 May 2022
 
participants during Part A. The investigator is required to review the baseline telemetry report 
prior to randomizing each participant. 
During the SAD and MAD portions of the trial, continuous ECGs will be recorded for a 
minimum of 26 hours, starting at least 2 hours predose and continuing until 24 hours postdose on 
the days indicated in the Schedule of Assessments (Section 1.3). Electrocardiograms will be 
extracted from the continuous recording by a central ECG service (note: these data are not 
required for dose escalation decision-making). Participants should be resting quietly in a supine 
position for at least 10 minutes before the nominal ECG extraction time points and 5 minutes 
after each extraction time point without any significant environmental distractions (noise, loud 
music, TV, computer or phone use, etc). Holter leads will be checked for proper connectivity 
prior to each time point. 
Procedures to limit the sources of electrocardiographic variability will be used throughout the 
trial and will include the following: staff training to ensure proper recording technique, 
standardized lead placement including ink marks on the skin to allow for exact duplication of 
lead position, shaving lead placement sites prior to lead placement and controlling the timing of 
ECG assessments relative to phlebotomy, sleep, activity, and meals.  
Instructions regarding the collection and transfer of continuous ECG data are detailed in a 
separate manual. 
8.3.4.2. 
Standard 12-Lead Electrocardiograms 
Electrocardiogram recordings will be obtained after the participant has been supine and at rest 
for approximately 3 minutes. Additional 12-lead ECGs may be obtained at the investigator’s 
discretion and should always be obtained in the event of an early termination. The ECG results 
will be evaluated at the investigational site to determine the participant’s eligibility, to monitor 
safety during the trial and dose escalation decisions. The principal investigator (or qualified 
designee) will review, sign, and date each ECG reading, noting whether or not any abnormal 
results are of clinical significance. The ECG will be repeated if any results are considered to be 
clinically significant. Any clinically relevant changes occurring during the trial will be recorded 
in the AE section of the eCRF. Additional guidance on collection of ECGs will be provided in 
the Operations Manual. 
At Screening, triplicate 12-lead ECGs are required to assess participant eligibility. A triplicate 
set of ECGs is 3 consecutive ECGs collected 1 to 2 minutes apart over a 5-minute period. If, 
during screening, according to the investigator’s judgment, any abnormal ECG finding is deemed 
medically significant (impacting the safety of the participant or the interpretation of the trial 
results) or meets an exclusion criterion (see Section 5.2), the participant should be excluded from 
the trial. The central ECG service will provide the QTcF corrections and average of the 3 ECGs 
performed. 
At all other specified time points in the Schedule of Assessments (Section 1.3) where an ECG 
recording must be performed, only a single ECG is required. 
Exclusion criteria for screening do not apply as mandatory discontinuation criteria for 
participants who are already randomized. A repeat ECG should be performed in case of any 
clinically significant abnormality that is identified in a randomized participant during the 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 64 of 96 
Version 3.0: 25 May 2022
 
treatment period and, in these cases, the medical monitor should be consulted on the 
appropriateness of the participant continuing in the trial. 
8.3.5. 
Clinical Safety Laboratory Assessments 
See Section 10.2 (Appendix 2) for the list of clinical laboratory tests to be performed and the 
Schedule of Assessments (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 trial in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents.  
All laboratory tests with values considered clinically significantly abnormal during participation 
in the trial 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 medical monitor notified. 
All protocol-required laboratory assessments, as defined in Section 10.2 (Appendix 2), must be 
conducted in accordance with the laboratory manual and the Schedule of Assessments. 
8.3.6. 
Suicidal Ideation and Behavior Risk Monitoring 
Suicidality will be monitored during the trial using the C-SSRS. This semi-structured interview 
was originally developed to evaluate the link between antidepressants and suicidal behavior and 
ideation in youth and adverse events from pediatric clinical trials (Posner et al, 2011). It was 
designed to quantify the severity of suicidal ideation and behavior. Trial personnel administering 
the C-SSRS must have completed the appropriate training and have valid certification. Access to 
training on the scale will be provided by the sponsor or designee. 
This trial will use the “Baseline/Screening” and “Since Last Visit” versions of the scale. The 
“Baseline/Screening” version, which assesses the lifetime experience of the participant with 
suicide events and suicidal ideation and the occurrence of suicide events or ideation within a 
specified time period prior to entry into the trial, will be completed for all participants at 
screening to determine eligibility. The exclusion criteria based on the C-SSRS are provided in 
Section 5.2. 
The “Since Last Visit” C-SSRS form will be completed at all specified time points after 
screening. The investigator will review the results of the “Since Last Visit” C-SSRS during the 
trial to determine whether it is safe for the participant to continue in the trial. If a participant has 
any “YES” answers on the C-SSRS for the suicidal ideation or suicidal behavior items, the 
investigator will evaluate whether a risk assessment by a qualified mental health professional (or 
the investigator alone if the investigator is a qualified mental health professional) is needed and 
discuss with the medical monitor whether the participant should continue in or be discontinued 
from the trial. 
8.4. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Section 10.3 (Appendix 3). 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 65 of 96 
Version 3.0: 25 May 2022
 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative). 
The investigator and any qualified 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 IMP or trial procedures, or that caused the 
participant to discontinue IMP (see Section 7) 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be recorded from the first dose of IMP until follow-up contact at the time 
points specified in the Schedules of Assessments (Section 1.3). 
Medical occurrences that begin before the start of IMP dosing but after obtaining informed 
consent will be recorded as medical and/or psychiatric history. 
All SAEs will be recorded and reported to the medical monitor immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3 (Appendix 3). The 
investigator will submit any updated SAE data to the medical monitor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the trial 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the trial, and he/she considers the event to be related to 
the IMP or trial participation, the investigator must promptly notify the sponsor. 
8.4.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3 (Appendix 3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.4). Further 
information on follow-up procedures is given in Section 10.3 (Appendix 3). 
8.4.4. 
Regulatory Reporting Requirements for SAEs/AESIs 
Prompt notification by the investigator to the sponsor regarding an SAE/AESI is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the safety of 
an IMP 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 an IMP under clinical investigation. The sponsor will 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 66 of 96 
Version 3.0: 25 May 2022
 
comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB, and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and sponsor 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, acknowledge, 
and then file it along with the Investigator’s Brochure and will notify the IRB, if appropriate 
according to local requirements. 
8.4.5. 
Pregnancy 
Details of all pregnancies in female partners of male participants will be collected after the start 
of IMP and until the final contact.  
If a pregnancy in a female partner is reported, the investigator should inform the medical monitor 
within 24 hours of learning of the pregnancy and should follow the procedures outlined in 
Section 10.4 (Appendix 4). 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.4.6. 
Adverse Events of Special Interest 
All AESIs should be reported according to the procedures and timelines for SAEs (see 
Section 10.3.4). Detailed narratives will be written for any participant who develops an AESI. 
The following events will be reported as AESIs: 
• AEs that result in the discontinuation of IMP  
• Events that satisfy the criteria for suspected Hy’s Law (alanine aminotransferase 
[ALT] or aspartate aminotransferase [AST] >3 × upper limit of normal [ULN], AND 
serum bilirubin ≥2 × ULN 
− Repeat for confirmation and notify the medical monitor immediately 
• QTcF >500 ms or increase >60 ms from baseline  
− Repeat for confirmation and notify the medical monitor immediately 
• Grade 2 moderate AEs that are related to the gastrointestinal system (eg, nausea, 
vomiting, diarrhea, constipation, dyspepsia, etc) 
• Grade 2 moderate AEs that are related to the central nervous system (eg, headache, 
dizziness, syncope, irritability, anxiety, etc) 
• AEs potentially related to abuse (refer to the APMP document for details) 
The primary objective of the APMP is to monitor events that may suggest that CVL-354 
produces drug effects that could be sought out for abuse purposes. In addition to monitoring for 
irregularities in medication handling, AEs that may be suggestive of a developing abuse issue 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 67 of 96 
Version 3.0: 25 May 2022
 
will also receive special attention. As part of the APMP, AEs potentially related to abuse and 
medication handling irregularities related to suspected or known abuse of IMP must be reported 
as AESIs. Investigators and site staff at each trial site will be trained on reporting potentially 
abuse-related AEs. While the investigators will be provided with examples of AE terms as a 
guide during trial conduct, the analysis of potentially abuse-related AEs will be based on a search 
by the sponsor of all relevant Medical Dictionary for Regulatory Activities (MedDRA) terms, all 
verbatim terms, and any open text fields within the AE data to identify text strings suggestive of 
abuse potential, consistent with US FDA guidance (FDA Guidance for Industry, 2017). 
8.5. 
Treatment of Overdose 
An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a trial participant, at a dose above that which is assigned to that individual 
participant according to the protocol. 
There is no specific antidote for overdose with CVL-354. In the event of an overdose, treatment 
should consist of general supportive measures. The investigator should complete the following: 
1. Contact the medical monitor immediately 
2. Closely monitor the participant for any AE/SAE and clinically significant vital signs, 
ECG, or laboratory abnormalities. Additional safety procedures may need to be 
performed at the investigator’s discretion.  
3. Document the quantity of the excess dose as well as the duration of the overdose (if 
multiple time points) in the eCRF 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant. 
8.6. 
Pharmacokinetics 
This section includes descriptions of the blood and urine samples obtained for PK assessments, 
including metabolite scouting.  
All PK samples should be obtained at the exact nominal time relative to dosing. Samples 
obtained within 10% of the nominal time point (eg, within 6 minutes of a 60-minute sample) will 
not be considered a protocol deviation, as long as the exact time of sampling is captured in the 
source documents.  
Plasma and urine samples will be processed, stored, and shipped to the bioanalytical facility 
according to the instructions provided to the investigator in advance of the trial. A fully validated 
bioanalytical method will be used to quantitate the concentrations of CVL-354 in plasma and in 
urine. Plasma and urine PK samples from this trial may be used for further evaluation of 
bioanalytical methods and identification of additional metabolites. Plasma samples from this trial 
may be stored up to 1 year after completion of the clinical study report (CSR).  
The results from metabolite scouting work (plasma and urine) will be captured in an exploratory 
metabolite scouting report, which will not be included in the CSR. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 69 of 96 
Version 3.0: 25 May 2022
 
variation patterns of participants who respond well and those who respond poorly to treatment 
may help to better define the most appropriate group of participants in which to target a given 
treatment. Collecting biospecimens for exploratory pharmacogenomic/biomarker analyses and 
retaining them at Cerevel makes it possible to better understand the drug’s mechanism of action 
and to seek explanations for differences in, for example, exposure, pharmacodynamics, 
tolerability, or safety not anticipated prior to the beginning of this trial. 
Future biospecimen research samples will be collected from participants who provide additional 
consent specifically for this sample collection. Research performed on these samples may 
include genetic analyses (DNA), gene expression profiling (RNA), proteomics, metabolomics 
and/or the measurement of other analytes. Such research is for biomarker testing to address 
emergent questions not described elsewhere in the protocol (as part of the main trial). The 
objective of collecting these specimens is to explore and identify biomarkers that inform the 
scientific understanding of diseases or their therapeutic treatments. 
8.11. 
Health Economics 
Not applicable.  
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
No formal hypothesis testing is planned for this trial. 
9.2. 
Sample Size Determination 
The sample size is not based on statistical hypothesis testing. Based on historical precedent, it is 
expected that the proposed sample sizes of 8 participants per cohort in Part A (SAD, food effect) 
and 10 participants per cohort in Part B (MAD) will address the overall aim of the trial. 
In the event of higher than anticipated early terminations due to COVID-19 or other factors, 
Cerevel may extend enrollment in order to achieve trial objectives. 
9.3. 
Populations for Analyses 
The analysis sets that are defined for this trial are described in Table 11. 
Table 11: 
Analysis Set Descriptions 
Term 
Description 
All Screened 
All participants who consent to participate in the clinical trial 
Randomized 
All participants who are randomized to IMP 
Safety Analysis Set 
All randomized participants who receive at least 1 dose of IMP 
PK Analysis Set 
All participants in the Safety Analysis Set who have at least 1 quantifiable 
CVL-354 concentration 
Abbreviations: IMP=investigational medicinal product; PK=pharmacokinetic. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 71 of 96 
Version 3.0: 25 May 2022
 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This trial 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) 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 IRB by the investigator and reviewed and approved 
by the IRB before the trial is initiated. 
Any substantial amendments to the protocol will require IRB approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate hazard 
to trial participants. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the trial to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB 
• Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures 
• Providing oversight of the conduct of the trial at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB, European regulation 536/2014 for 
clinical trials (if applicable), and all other applicable local regulations 
10.1.2. 
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 
responsible for providing information on financial interests during the course of the trial and for 
1 year after completion of the trial. 
10.1.3. 
Informed Consent Process 
The investigator or his/her representative will explain the nature of the trial to the participant and 
answer all questions regarding the trial. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 72 of 96 
Version 3.0: 25 May 2022
 
Participants must be informed that their participation is voluntary. Participants 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 of 1996 
requirements, where applicable, and the IRB or trial center.  
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the trial and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the trial. 
A copy of the ICF(s) must be provided to the participant. 
10.1.4. 
Data Protection 
Participants will be assigned a unique identifier by the sponsor or designee. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal trial-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 participant and outlined in the ICF. 
The participant 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 IRB members, and by inspectors from regulatory authorities. 
10.1.5. 
Dissemination of Clinical Trial Data 
Cerevel fulfills its commitment to publicly disclose clinical trial results through posting trial 
results on ClinicalTrials.gov, the European Clinical Trials Database (EudraCT), and other public 
registries in accordance with applicable local laws/regulations. 
In all cases, trial results are reported by Cerevel in an objective, accurate, balanced, and complete 
manner and are reported regardless of trial outcome or the country in which the trial was 
conducted. 
Clinical trial US Basic Results are posted on Clinicaltrials.gov for all Cerevel-sponsored 
interventional trials conducted in participants that evaluate the safety and/or efficacy of a Cerevel 
product, regardless of the geographical location in which the trial is conducted. US Basic Results 
are submitted for posting within 1 year of the primary completion date as defined in Section 4.5 
for trials in adult populations or within 6 months of the primary completion date for trials in 
pediatric populations. 
Cerevel posts European Union (EU) Basic Results on EudraCT for all Cerevel-sponsored 
interventional trials that are in scope of EU requirements. EU Basic Results are submitted for 
posting within 1 year of the primary completion date as defined in Section 4.5 for trials in adult 
populations or within 6 months of the primary completion date for trials in pediatric populations. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 73 of 96 
Version 3.0: 25 May 2022
 
10.1.6. 
Data Quality Assurance 
All participant data relating to the trial will be recorded on printed or eCRFs 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 
eCRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The investigator must permit trial-related monitoring, audits, IRB review, and regulatory agency 
inspections and provide direct access to source data documents. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the Clinical Monitoring Plan. 
The sponsor or designee is responsible for the data management of this trial including quality 
checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations). 
Trial monitors will perform ongoing source data verification to confirm that data entered into the 
eCRF by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the trial is being conducted 
in accordance with the currently approved protocol and any other trial agreements, ICH GCP, 
and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this trial must be 
retained by the investigator for the longest of the following periods: 
• At least 2 years after the date on which approval to market the drug is obtained (or if 
IMP developments is discontinued, the date regulatory authorities were notified of 
discontinuation) 
• At least 3 years after the sponsor notified the investigator that the final report has 
been filed with regulatory authorities  
• A longer period if required by local regulations or institutional policies 
No records may be destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without written notification 
to the sponsor. 
10.1.7. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data entered in the eCRF 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 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 74 of 96 
Version 3.0: 25 May 2022
 
previous medical records or transfer records, depending on the trial. Also, current medical 
records must be available. 
10.1.8. 
Trial and Site Closure 
The sponsor or designee reserves the right to close the trial site or terminate the trial at any time 
for any reason at the sole discretion of the sponsor. Trial sites will be closed upon trial 
completion. A trial site is considered closed when all required documents and trial supplies have 
been collected and a trial-site closure visit has been performed. 
The investigator may initiate trial-site 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 trial site 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 IRB or 
local health authorities, the sponsor’s procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator 
• Discontinuation of further trial treatment development 
10.1.9. 
Publication Policy 
The results of this trial may be published or presented at scientific meetings at the sponsor’s 
discretion.  
The sponsor will comply with the requirements for publication of trial results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter trials only in their entirety and not as individual site data. In this case, a coordinating 
investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 12 will be performed by the local laboratory. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5. 
Additional tests may be performed at any time during the trial as determined necessary by the 
investigator or required by local regulations. 
Participants must have COVID-19 testing done with a negative test result within a maximum of 
5 days prior to, but as close as possible to each admission to the clinic. COVID-19 testing may 
be performed after admission per the investigator’s discretion.  

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 77 of 96 
Version 3.0: 25 May 2022
 
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. 
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 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 participant or may require medical or surgical intervention to prevent one 
of the other outcomes listed in the above definition. These events should usually be considered serious. 
Examples of such events include invasive malignant cancers, intensive treatment in an emergency room or at 
home for allergic bronchospasm, or blood dyscrasias. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 81 of 96 
Version 3.0: 25 May 2022
 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
10.4.1. 
Definitions 
10.4.1.1. Highly Effective Form of Contraception (Failure Rate <1%) 
A highly effective form of contraception (failure rate of <1%) is defined as follows: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
− Oral 
− Intravaginal 
− Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
− Oral 
− Injectable 
− Implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner 
• Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the trial treatments. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred and usual lifestyle of the 
participant. 
10.4.1.2. Acceptable Birth Control Methods (Failure Rate >1% per Year) 
Acceptable birth control methods that result in a failure rate of more than 1% per year include 
the following: 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action 
• Male or female condom with or without spermicide* 
• Cap, diaphragm or sponge with spermicide* 
*A combination of male condom with a cap, diaphragm, or sponge with spermicide (double-
barrier methods) is also considered acceptable but is not a highly effective birth control method. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 82 of 96 
Version 3.0: 25 May 2022
 
10.4.1.3. Contraception and Pregnancy Avoidance Procedures 
The following definitions apply for contraception and pregnancy avoidance procedures: 
A woman is considered a woman of childbearing potential following menarche and until 
becoming postmenopausal unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral oophorectomy, and complete salpingectomy.  
In this trial, postmenopausal state is defined as no menses for at least 12 consecutive months 
without an alternative medical cause in addition to an FSH level >40 IU/mL.  
Sterilized male participants should be at least 1 year postbilateral vasectomy and have confirmed 
that they have obtained documentation of the absence of sperm in the ejaculate or have had 
bilateral orchidectomy. 
10.4.2. 
Collection of Pregnancy Information 
10.4.2.1. Male Participants With Partners Who Become Pregnant 
• The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this trial. This applies only to male participants who receive IMP. 
• After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
sponsor. Generally, the follow-up will be no longer than 12 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.  
 
 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 83 of 96 
Version 3.0: 25 May 2022
 
10.5. 
Appendix 5: Future Biospecimen Research 
Use/Analysis of Deoxyribonucleic Acid 
• Genetic variation may impact a participant’s response to trial treatment, susceptibility 
to, and severity and progression of disease. Variable response to trial treatment may 
be due to genetic determinants that impact drug absorption, distribution, metabolism, 
and excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated.  
• DNA samples will be used for research related to CVL-354 or major depressive 
disorder and related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to CVL-354 and/or interventions of this drug class and major 
depressive disorder. Genetic research may consist of the analysis of one or more 
candidate genes or the analysis of genetic markers throughout the genome or analysis 
of the entire genome (as appropriate). 
• There are no planned analyses of DNA samples. Analyses may be conducted if it is 
hypothesized that this may help further understand the clinical data. 
• The samples may be analyzed as part of a multi-trial assessment of genetic factors 
involved in the response to CVL-354 or IMPs of this class to understand trial disease 
or related conditions. 
• The results of genetic analyses may be reported in the CSR or in a separate trial 
summary. 
• The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• The samples will be retained while research on CVL-354 or trial treatments of this 
class or major depressive disorder continues but no longer than 15 years or other 
period as per local requirements. 
 
 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 84 of 96 
Version 3.0: 25 May 2022
 
10.6. 
Appendix 6: Kidney Safety for First-in-Human Trial 
10.6.1. 
Elevations in Serum Creatinine 
Serum creatinine (SCr) level may be affected by age, muscle mass, diet, activity, and tubular 
transporter activity, and SCr elevations can occur without impacting overall kidney function. 
Nonetheless, kidney function is closely monitored using blood urea nitrogen (BUN), serum 
creatinine, and urinalysis. 
Table 20: 
Monitoring of Abnormal Kidney Function Tests 
Lab Result 
Action 
Serum creatinine > ULN 
Repeat for confirmation approximately 1 hour 
after drinking a large glass (~250 mL) of water 
Urinalysis (UA) 
• 
≥ +1 protein 
• 
+ glucose 
• 
Active urine sediments 
(eg, hematuria, pyuria, casts [WBC, 
RBC, tubular epithelial, or granular]) 
Repeat for confirmation approximately 1 hour 
after drinking a large glass (~250 mL) of water 
Abbreviations: RBC=red blood cell; ULN=upper limit of normal; WBC=white blood cell. 
Contact the medical monitor if the repeat confirmation SCr >1.2× ULN or urine continues to 
have proteinuria, glucosuria, or active urine sediments. 
10.6.2. 
Potential Cases of Acute Kidney Injury 
Abnormal values in SCr that meet the KDIGO 2012 (KDIGO, 2012) criteria below, in the 
absence of other causes of kidney injury, are considered potential cases of acute kidney injury 
(AKI) and should be regarded as important medical events. 
• Increase in SCr ≥0.3 mg/dL (26.5 mmol/L) within 48 hours  
• Increase in SCr ≥50% from baseline  
• Urine volume output <0.5 mL/kg/h for 6 hours 
The baseline is defined as the most recent SCr prior to randomization/dosing. 
10.6.2.1. Marked Elevations in Serum Creatinine 
For increases of SCr ≥50% relative to the participant baseline: 
• Temporarily withhold IMP until a repeat SCr as soon as practically feasible, 
preferably within 24 hours of awareness.  
• If the second measurement of SCr is still ≥50% from the participant baseline, IMP 
should be permanently discontinued.  
• Adequate, immediate, supportive measures should be taken if AKI is suspected. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 85 of 96 
Version 3.0: 25 May 2022
 
10.6.2.2. Evaluation of Potential Cases of AKI 
Participants suspected of having potential AKI should promptly (as soon as practically feasible, 
preferably within 24 hours of awareness) have an evaluation, which includes a detailed medical 
history, physical examination, and laboratory tests.  
Laboratory tests include, at a minimum: 
• Serum: 
− BUN, creatinine, sodium, potassium, chloride, bicarbonate, phosphorus, and 
calcium 
− Creatine kinase and cystatin-C 
• Urine: Dipstick, microscopic examination, indices, and β-2-microglobulin. 
Consider consultation with a nephrologist. 
Close daily observation of the participant and assessment of kidney function should be continued 
until the SCr elevations and the associated abnormal UA results return to baseline or normalize. 
10.6.2.3. Stopping Criteria for the Cohort 
Further dosing with IMP will be stopped for the cohort if ≥2 healthy participants within a given 
dose level meet the criteria established in Section 10.6.2.1 and permanently discontinued IMP. 
10.6.2.4. Stopping Criteria for Dose Escalation 
Serum creatinine may be potentially impacted by OCT2, MATE1, and MATE2K transporter 
inhibition by test drugs. Serum cystatin-C, which is not affected by the above transporters, may 
be used to monitor renal function. If ≥2 healthy participants within the same dosing level/cohort 
have a decline in eGFR cystatin-C ≥25% from baseline using the CKD-EPI 2012 formula for 
cystatin-C (Inker et al, 2012), then dose escalation stops. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 86 of 96 
Version 3.0: 25 May 2022
 
10.7. 
Appendix 7: Abbreviations 
Abbreviation 
Definition 
ACLS 
Advanced Cardiovascular Life Support 
AE 
adverse event 
AESI 
adverse event of special interest 
AKI 
acute kidney injury 
ALT 
alanine aminotransferase 
APMP 
Abuse Potential Monitoring Plan 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BID 
twice daily 
BUN 
blood urea nitrogen 
Cavg 
average plasma concentration 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
maximum plasma concentration 
COVID-19 
coronavirus disease-2019 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450 
DAMGO 
[D-Ala2, N-MePhe4, Gly-ol] enkephalin 
 
 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EU 
European Union 
F 
bioavailability 
fa 
fraction absorbed 
fh 
fraction escaping hepatic metabolism 
fm 
fraction metabolized 
FSH 
follicle stimulating-hormone 
fu 
fraction unbound 
GCP 
Good Clinical Practice 
HED 
human equivalent dose 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
ID50 
dose required for 50% inhibition 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 87 of 96 
Version 3.0: 25 May 2022
 
Abbreviation 
Definition 
IMP 
investigational medicinal product 
KDIGO 
Kidney Disease: Improving Global Outcomes 
IRB 
Institutional Review Board 
Ki 
inhibition constant 
KOR 
kappa opioid receptor 
MAD 
multiple ascending dose 
MATE 
multidrug and toxin extrusion protein 
MDD 
major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOR 
mu opioid receptor 
MTD 
maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NOAEL 
no observed adverse effect level 
OCT 
organic cation transporter 
PK 
pharmacokinetic(s) 
QD 
once daily 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCr 
serum creatinine 
SRT 
Safety Review Team 
t1/2 
apparent terminal half-life 
Tmax 
time of maximum observed concentration 
UA 
urinalysis 
UGT 
UDP-glucuronosyltransferase 
ULN 
upper limit of normal 
 
 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 88 of 96 
Version 3.0: 25 May 2022
 
10.8. 
Appendix 8: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents. 
Amendment: Protocol Version 2.0 (16 Sep 2021) 
 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
3 Objectives and Endpoints 
Added AEs potentially related to abuse 
to TEAE endpoint (SAD and MAD 
tables) 
To align with addition of such events 
to Section 8.4.6 (Adverse Events of 
Special Interest) 
 
Added clarification that the following 
PK endpoints are for Day 14: CL/F; 
VZ/F; PTR; Rac, Cmax; Rac, AUC; t1/2; 
and renal clearance (MAD table) 
Data required for calculation of 
these endpoints are only collected at 
steady state 
1.1 Synopsis 
4.2 Scientific Rationale for Trial 
Design 
Deletion of parallel-group language 
(MAD) 
Internal consistency about sequential 
dosing of cohorts 
1.2 Schema 
4.1.1 Single Ascending Dose - 
Part A 
Figure 1 and Table 6: 
Revised CVL-354 dosing paradigms 
for Cohort 2 
 
To align with proposed doses as 
presented in Table 7 
1.2 Schema 
Figure 1: 
Randomization symbol (R) moved 
from beginning of Treatment Phase to 
text boxes for each cohort 
 
To reflect randomization to sequence 
rather than to cohort 
 
Figure 1, Figure 2: 
Changed text boxes for cohorts in 
Treatment Phase from parallel to 
staggered 
 
To more accurately depict sequential 
dosing of cohorts 
1.3 Schedule of Assessments 
Table 1 (SAD), Table 2 (MAD): 
Revised tables to indicate that medical 
occurrences before the start of IMP 
dosing but after obtaining informed 
consent will be recorded as medical 
and/or psychiatric history and that AEs 
will be recorded from the first dose of 
IMP 
 
To clarify recording timeframes 
relative to informed consent and first 
dose of IMP, including for 
replacement participants 
 
SAD: Changed limited physical and 
neurological examinations to full 
examinations at each Check-out (or 
ET) 
MAD: Changed limited physical and 
neurological examinations to full 
examinations on Day 7 and Day 17/ET 
To provide additional opportunities 
to potentially identify AEs related to 
the gastrointestinal or central 
nervous systems, reflecting the 
addition of such events to 
Section 8.4.6 (Adverse Events of 
Special Interest) 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 90 of 96 
Version 3.0: 25 May 2022
 
Section # and Name 
Description of Change 
Brief Rationale 
5.2 Exclusion Criteria 
Exclusion Criterion #11: 
Added “at Screening” to criterion for 
estimated glomerular filtration rate 
 
To clarify timeframe for 
determination of eligibility 
 
Exclusion Criterion #13: 
Moved symptomatic orthostatic 
dizziness text to a separate bullet 
within the criterion 
 
To separate the text from the bullet 
that defines orthostatic hypotension 
5.2 Exclusion Criteria 
 
Exclusion Criterion #16: 
Increased duration of abstention from 
48 hours prior to Day -1 to 7 days prior 
to Day -1 
 
To ensure minimal to no interaction 
with IMP 
5.3.1 Meals and Dietary 
Restrictions 
Increased duration of abstention from 
48 hours prior to Day -1 to 7 days prior 
to Day -1 
 
5.4 Screen Failures 
Deleted language about SAEs 
To align with changes to language 
about AE recording starting from 
first dose of IMP 
6.3.1 Participant Assignment to 
Treatment 
Revised language to specify that 
replacement participants in Part A 
(SAD) will be randomized to the same 
sequence and replacement participants 
in Part B (MAD) will be randomized to 
the same treatment 
To reflect differences in trial design 
between SAD (randomization to 
sequence) and MAD (randomization 
to treatment) 
6.3.2 Blinding 
Added instructions in the event of 
emergency unblinding 
To clarify unblinding procedures in 
case of emergency 
8.4.1 Time Period and 
Frequency for Collecting AE 
and SAE/AESI Information 
Clarified that AEs will be recorded 
from the first dose of IMP and medical 
occurrences that begin before the start 
of IMP dosing but after obtaining 
informed consent will be recorded as 
medical and/or psychiatric history 
To confirm timeframes for medical 
history and AE recording relative to 
informed consent and first dose of 
IMP 
8.4.6 Adverse Events of Special 
Interest 
Detailed narratives, rather than brief 
narratives, will be written for any 
participant who develops an AESI 
Revised AESI definitions as follows: 
Added Grade 2 moderate AEs related 
to the gastrointestinal system 
Added Grade 2 moderate AEs related 
to the central nervous system 
Added AEs potentially related to abuse 
(followed by summary of key aspects 
of the APMP) 
To enhance understanding of the 
safety profile of CVL-354 and to 
provide guidance to site personnel 
for identification and reporting of 
AEs potentially related to abuse 
8.6 Pharmacokinetics 
Added a sentence regarding possible 
retention of samples for evaluation of 
bioanalytical methods and metabolites 
for up to 1 year after CSR completion 
Updated as per sponsor’s policy on 
PK sample management 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 91 of 96 
Version 3.0: 25 May 2022
 
Section # and Name 
Description of Change 
Brief Rationale 
9.4.2 Safety Analyses 
Added AEs potentially related to abuse 
To align with addition of such events 
to Section 8.4.6 (Adverse Events of 
Special Interest) 
10.3.3 Recording and Follow-
Up of AEs and/or SAEs/AESIs 
Deleted the following language: 
...that are identified at any time during 
the trial... 
...having been identified throughout the 
trial... 
To align with changes to language 
about AE recording starting from 
first dose of IMP 
10.3.3 Recording and Follow-
Up of AEs and/or SAEs/AESIs 
10.3.4 Reporting of SAEs and 
AESIs 
Addition of “AESI” or “AESIs” to 
section headings and throughout tables 
within the respective sections 
To correct inadvertent omission in 
the previous version of the protocol 
11 REFERENCES 
Added new reference: 
FDA Guidance for Industry, 2017 
To reflect inclusion of citation in 
content regarding abuse potential 
monitoring added to Section 8.4.6 
(Adverse Events of Special Interest) 
Overall 
General grammatical and wording 
corrections/clarifications made 
throughout protocol 
To correct minor errors from the 
previous version of the protocol 
Abbreviations: AE=adverse event; AESI=adverse event of special interest; APMP=Abuse Potential Monitoring 
Plan; AUC=area under the concentration-time curve; CL/F=apparent clearance of drug from plasma; 
Cmax=maximum plasma concentration; CSR=clinical study report; C-SSRS=Columbia-Suicide Severity Rating 
Scale; 
; ET=Early Termination; IMP=investigational medicinal product; 
MAD=multiple ascending dose; MTD=maximum tolerated dose; PK=pharmacokinetic; PTR=peak-to-trough ratio; 
R=randomization; Rac=accumulation ratio; SAD=single ascending dose; SAE=serious adverse event; SRT=Safety 
Review Team; t1/2= apparent terminal half-life; TEAE=treatment-emergent adverse event; VZ/F= apparent volume of 
distribution during terminal phase. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 95 of 96 
Version 3.0: 25 May 2022
 
Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for 
depression using measurement-based care in STAR*D: implications for clinical practice. Am J 
Psychiatry. 2006;163(1):28-40. 
Zajecka JM, Stanford AD, Memisoglu A, Martin WF, Pathak S. Buprenorphine/samidorphan 
combination for the adjunctive treatment of major depressive disorder: results of a phase III 
clinical trial (FORWARD-3). Neuropsychiatr Dis Treat. 2019;15:795-808. 

Protocol CVL-354-1001
CVL-354
 
 
Confidential 
Page 96 of 96 
Version 3.0: 25 May 2022
 
CLINICAL PROTOCOL PRINCIPAL INVESTIGATOR 
SIGNATURE PAGE 
A PHASE 1, DOUBLE-BLIND (INVESTIGATOR AND PARTICIPANT), 
FIRST-IN-HUMAN TRIAL TO EVALUATE THE SAFETY, 
TOLERABILITY, AND PHARMACOKINETICS OF SINGLE AND 
MULTIPLE ASCENDING DOSES OF CVL-354 IN HEALTHY 
PARTICIPANTS 
 
Protocol: CVL-354-1001 
Compound Number: CVL-354 
Trial Phase: 1 
Sponsor Name: Cerevel Therapeutics, LLC 
Legal Registered Address: 222 Jacobs Street, Suite 200, Cambridge, MA 02141 United 
States 
Version 3.0: 25 May 2022 
 
I, the undersigned principal investigator, have read and understand the protocol and agree 
that it contains the ethical, legal, and scientific information necessary to conduct this trial 
in accordance with the principles of Good Clinical Practices and as described herein and in 
the sponsor’s (or designee’s) Clinical Research Agreement. 
 
 
 
Principal Investigator Printed Name 
 
 
 
 
 
Principal Investigator Signature 
 
 
Date (DD MMM YYYY)