Conditions: Healthy Participants
Keywords: Healthy Volunteer CVL-354
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 73
Healthy volunteers: yes

Brief summary:
This is a 2-part, double-blind, randomized, placebo-controlled, first-in-human trial evaluating a single ascending dose (4-way crossover, Part A) and multiple ascending doses (Part B) of CVL-354.

Detailed description:

Arms:
arm 1: Participants were randomized to sequence 1 to receive placebo on Day 1 of Period 1 followed by CVL-354 1.5 milligrams (mg) on Day 1 of Period 2, followed by CVL-354 5 mg on Day 1 of Period 3 \& followed by CVL-354 15 mg on Day 1 of Period 4. Each dosing period was separated by a washout period of at least 5 days. arm 2: Participants were randomized to sequence 2 to receive CVL-354 0.5 mg on Day 1 of Period 1 followed by placebo on Day 1 of Period 2, followed by CVL-354 5 mg on Day 1 of Period 3 \& followed by CVL-354 15 mg on Day 1 of Period 4. Each dosing period was separated by a washout period of at least 5 days. arm 3: Participants were randomized to sequence 3 to receive CVL-354 0.5 mg on Day 1 of Period 1 followed by CVL-354 1.5 mg on Day 1 of Period 2, followed by placebo on Day 1 of Period 3 \& followed by CVL-354 15 mg on Day 1 of Period 4. Each dosing period was separated by a washout period of at least 5 days. arm 4: Participants were randomized to sequence 4 to receive CVL-354 0.5 mg on Day 1 of Period 1 followed by CVL-354 1.5 mg on Day 1 of Period 2, followed by CVL-354 5 mg on Day 1 of Period 3 \& followed by placebo on Day 1 of Period 4. Each dosing period was separated by a washout period of at least 5 days. arm 5: Participants were randomized to sequence 1 to receive placebo on Day 1 of Period 1 followed by CVL-354 90 mg on Day 1 of Period 2, followed by CVL-354 150 mg on Day 1 of Period 3 \& followed by CVL-354 200 mg on Day 1 of Period 4. Each dosing period was separated by a washout period of at least 5 days. arm 6: Participants were randomized to sequence 2 to receive CVL-354 45 mg on Day 1 of Period 1 followed by placebo on Day 1 of Period 2, followed by CVL-354 150 mg on Day 1 of Period 3 \& followed by CVL-354 200 mg on Day 1 of Period 4. Each dosing period was separated by a washout period of at least 5 days. arm 7: Participants were randomized to sequence 3 to receive CVL-354 45 mg on Day 1 of Period 1 followed by CVL-354 on 90 mg Day 1 of Period 2, followed by placebo on Day 1 of Period 3 \& followed by CVL-354 200 mg on Day 1 of Period 4. Each dosing period was separated by a washout period of at least 5 days. arm 8: Participants were randomized to sequence 4 to receive CVL-354 45 mg on Day 1 of Period 1 followed by CVL-354 90 mg on Day 1 of Period 2, followed by CVL-354 150 mg on Day 1 of Period 3 \& placebo on Day 1 of Period 4. Each dosing period was separated by a washout period of at least 5 days. arm 9: Participants first received a single oral dose of CVL-354 50 mg, under fed state on Day 1 of Period 1 followed by a single oral dose of CVL-354 50 mg under fasted state on Day 1 of Period 2, with a washout period of 2 days between both periods. arm 10: Participants first received a single oral dose of CVL-354 50 mg, under fasted state on Day 1 of Period 1 followed by a single oral dose of CVL-354 50 mg under fed state on Day 1 of Period 2, with a washout period of 2 days between both periods arm 11: Participants received oral dose of CVL-354 10 mg or Placebo, once daily (QD) from Day 1 up to Day 14 in Cohort 1. arm 12: Participants received oral dose of CVL-354 25 mg or Placebo, QD from Day 1 up to Day 14 in Cohort 2. arm 13: Participants received oral dose of CVL-354 50 mg or Placebo, QD from Day 1 up to Day 14 in Cohort 3. arm 14: Participants received oral dose of CVL-354 80 mg or Placebo, QD from Day 1 up to Day 14 in Cohort 4. arm 15: Participants received oral dose of CVL-354 85 mg or Placebo, QD from Day 1 up to Day 14 in Cohort 5.

Interventions: intervention 1: CVL-354 intervention 2: Placebo intervention 3: CVL-354
Intervention descriptions: intervention 1: Oral solution/suspension intervention 2: Placebo matched to CVL-354 intervention 3: Capsule

Protocol document:
Prot_000.pdf: 
 
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) 
 

SAP_001.pdf: 
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: Statistical Analysis Plan Version 1: 17-Mar-2023 


 
Clinical Study Report 
 
 
16.1.9 Documentation of Statistical Methods 
 
CVL-354-1001 
 
 
Cerevel Confidential 
Page 1 of 1
 
16.1.9 
DOCUMENTATION OF STATISTICAL METHODS 
 
 
cvl-354-1001-statistical-method.pdf   Page 1 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 1 of 53 
Version 1.0: 17 March 2023
 
STATISTICAL ANALYSIS PLAN 
 
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 Number: CVL-354-1001 
Compound: 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 
Protocol Version: 
Version 3.0: 25 May 2022 
 
Version 2.0: 16 Sep 2021 
 
Version 1.0: 07 Jun 2021 
 
Analysis Plan Version: 
Final 1.0: 17 Mar 2023 
 
Page 1 of 78
cvl-354-1001-statistical-method.pdf   Page 2 of 79






 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 4 of 53 
Version 1.0: 17 March 2023
 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................1 
STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL ................................................2 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................7 
1. 
INTRODUCTION ........................................................................................................8 
1.1. 
Study Overview ............................................................................................................8 
1.1.1. 
Part A (Single Ascending Dose: Cohorts 1 and 2) .......................................................8 
1.1.2. 
Part A (Food Effects: Cohort 3) ....................................................................................9 
1.1.3. 
Part B (Multiple Ascending Dose) .............................................................................10 
1.2. 
Sample Size Considerations .......................................................................................11 
1.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................12 
1.3.1. 
Subject Assignment to Treatment ...............................................................................12 
1.3.2. 
Blinding ......................................................................................................................12 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................13 
3. 
KEY ASSESSMENTS AND DERIVATIONS ..........................................................15 
3.1. 
Efficacy Assessments .................................................................................................15 
3.2. 
Screening and Baseline Assessments .........................................................................15 
 
.15 
 
.15 
 
.15 
3.4. 
Safety Assessments .....................................................................................................15 
3.4.1. 
Vital Signs ..................................................................................................................15 
3.4.2. 
Electrocardiograms .....................................................................................................15 
3.4.2.1. 
Continuous Electrocardiogram Recordings ................................................................15 
3.4.2.2. 
Standard 12-Lead Electrocardiograms .......................................................................16 
3.4.3. 
Clinical Safety Laboratory Assessments ....................................................................16 
3.4.4. 
Suicidal Ideation and Behavior Risk Monitoring .......................................................16 
3.4.5. 
Physical/Neurological Examinations ..........................................................................16 
3.4.6. 
Adverse Events (AEs) .................................................................................................17 
3.4.6.1. 
Adverse Events of Special Interest .............................................................................17 
3.5. 
Pharmacokinetics ........................................................................................................18 
 
Page 4 of 78
cvl-354-1001-statistical-method.pdf   Page 5 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 5 of 53 
Version 1.0: 17 March 2023
 
4. 
DATA CONVENTIONS AND VISIT WINDOWS ..................................................19 
4.1. 
Data Conventions ........................................................................................................19 
4.1.1. 
Missing Data and Outliers ..........................................................................................19 
4.1.1.1. 
Missing Severity or Relationship for Adverse Events ................................................19 
4.1.1.2. 
Incomplete or Missing Dates ......................................................................................19 
4.1.1.3. 
Missing Time ..............................................................................................................20 
4.1.1.4. 
Imputation for Alphanumeric Data .............................................................................20 
4.1.1.5. 
Derived and Transformed Data ..................................................................................21 
4.1.2. 
Definitions and Terminology ......................................................................................21 
4.1.2.1. 
Screen Failure .............................................................................................................21 
4.1.2.2. 
Analysis Period ...........................................................................................................21 
4.1.2.3. 
Age ..............................................................................................................................21 
4.1.2.4. 
Baseline Value ............................................................................................................21 
4.2. 
Visit Windows ............................................................................................................25 
4.2.1. 
Method of Aligning Measurements to Treatment for Part A (SAD) ..........................25 
4.2.2. 
By-Study Visit Displays .............................................................................................26 
5. 
STATISTICAL ANALYSIS METHODS ..................................................................27 
5.1. 
General Considerations ...............................................................................................27 
5.2. 
Populations for Analyses ............................................................................................27 
5.3. 
Statistical Hypotheses .................................................................................................27 
5.4. 
Multiplicity Adjustment..............................................................................................28 
5.5. 
Strata and Covariates ..................................................................................................28 
5.6. 
Subject Disposition, Demographic and Baseline Characteristics ...............................28 
5.7. 
Exposure to Treatment ................................................................................................28 
 
28 
 
 ....................................................................................................28 
 
 .........................................................................................................................28 
5.9. 
Safety Analysis ...........................................................................................................29 
5.9.1. 
Adverse Events ...........................................................................................................29 
5.9.2. 
COVID-19 Coronavirus Infection Testing .................................................................29 
5.9.3. 
Concomitant Medications and Non-Drug Therapy/Procedures .................................29 
5.9.4. 
Clinical Laboratory Assessments ...............................................................................30 
 
Page 5 of 78
cvl-354-1001-statistical-method.pdf   Page 6 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 6 of 53 
Version 1.0: 17 March 2023
 
5.9.5. 
Vital Signs ..................................................................................................................31 
5.9.6. 
Electrocardiograms (ECGs) ........................................................................................32 
5.9.6.1. 
Continuous Electrocardiogram Recordings (Holter) ..................................................32 
5.9.6.2. 
Standard 12-lead Electrocardiograms .........................................................................32 
5.9.7. 
Suicidal Ideation and Behavior Risk Monitoring .......................................................32 
5.10. 
Pharmacokinetics ........................................................................................................32 
5.11. 
Protocol Deviations ....................................................................................................32 
5.12. 
Timing of Analyses .....................................................................................................32 
6. 
CHANGES IN THE PLANNED ANALYSES ..........................................................34 
7. 
REVISION HISTORY ...............................................................................................35 
8. 
REFERENCES ...........................................................................................................36 
9. 
APPENDICES ............................................................................................................37 
9.1. 
Schedule of Assessments ............................................................................................37 
9.2. 
Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation and 
Suicidal Behavior Scores ............................................................................................47 
9.3. 
Programming Conventions .........................................................................................49 
9.4. 
Abbreviations ..............................................................................................................51 
9.5. 
Pharmacokinetic Analysis Plan ..................................................................................53 
 
 
 
Page 6 of 78
cvl-354-1001-statistical-method.pdf   Page 7 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 7 of 53 
Version 1.0: 17 March 2023
 
LIST OF TABLES 
Table 1: 
Part A (Single Ascending Dose) .................................................................................13 
Table 2: 
Part B (Multiple Ascending Dose) .............................................................................14 
Table 3: 
Analysis Set Descriptions ...........................................................................................27 
Table 4: 
Schedule of Assessments – Part A, Single Ascending Dose (Cohorts 1 and 2) .........38 
Table 5: 
Schedule of Assessments – Part A, Food Effect (Cohort 3) .......................................41 
Table 6: 
Schedule of Assessments – Part B, Multiple Ascending Dose 
(Cohorts 1 to 5) ...........................................................................................................44 
 
 
LIST OF FIGURES 
Figure 1: 
Trial Schematic - Part A (Single Ascending Dose, Cohorts 1 and 2) ...........................9 
Figure 2: 
Trial Schematic - Part A (Food Effect, Cohort 3) ......................................................10 
Figure 3: 
Trial Schematic - Part B (Multiple Ascending Dose, Cohorts 1-5) ............................11 
 
 
Page 7 of 78
cvl-354-1001-statistical-method.pdf   Page 8 of 79




 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 9 of 53 
Version 1.0: 17 March 2023
 
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. 
The planned trial design for Part A: Cohorts 1 and 2, is depicted in Figure 1. 
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. 
1.1.2. 
Part A (Food Effects: 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). Sentinel dosing will not be employed 
for evaluation of food effect. 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 9 of 78
cvl-354-1001-statistical-method.pdf   Page 10 of 79




 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 11 of 53 
Version 1.0: 17 March 2023
 
administered as capsule. During Part B, all preceding doses should be deemed safe and tolerated 
before progressing to higher doses. Similar to Part A, dose increments in Part B will not exceed 
half-log increments (3.3-fold) early in escalation and smaller escalation steps (≤2‑fold) will be 
implemented at doses closer to stopping criteria. Standard safety laboratory assessments, vital 
sign measurements, safety electrocardiograms (ECGs), and AE data will provide the relevant 
safety data up to Day 17 to make the dose‑escalation decision. Furthermore, dose-escalation 
decisions will be made by the SRT. 
On days with intensive PK sampling (Days 1 and 14), IMP will be administered under fasted 
conditions following a 10-hour overnight fast. Participants will continue to fast for 4 hours 
following dosing on these intensive PK sampling days. On other days, each dose of IMP will be 
administered at approximately the same time each morning at least 1 hour following the morning 
meal. Each dose of IMP will be administered orally with approximately 240 mL of water. 
The Trial Design for Part B is in Figure 3. 
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.  
1.2. 
Sample Size Considerations 
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, Cerevel may extend enrollment in 
order to achieve trial objectives. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Page 11 of 78
cvl-354-1001-statistical-method.pdf   Page 12 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 12 of 53 
Version 1.0: 17 March 2023
 
1.3. 
Measures to Minimize Bias: Randomization and Blinding 
1.3.1. 
Subject 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. 
1.3.2. 
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.  
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. 
 
Page 12 of 78
cvl-354-1001-statistical-method.pdf   Page 13 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 13 of 53 
Version 1.0: 17 March 2023
 
2. 
OBJECTIVES AND ENDPOINTS 
The trial objectives and endpoints are summarized in Table 1 and Table 2. 
Table 1: 
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 
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 
t½ 
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; 
t½=apparent terminal half-life; SAD=single ascending dose; Tmax=time to maximum plasma concentration; Vz/F=apparent 
volume of distribution during terminal phase. 
 
 
Page 13 of 78
cvl-354-1001-statistical-method.pdf   Page 14 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 14 of 53 
Version 1.0: 17 March 2023
 
 
Table 2: 
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 
t½ (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; PTR=peak to trough ratio; Rac=accumulation ratio; t½=apparent terminal half-life; 
Tmax=time to maximum plasma concentration; Vz/F=apparent volume of distribution during terminal phase. 
 
Page 14 of 78
cvl-354-1001-statistical-method.pdf   Page 15 of 79




Protocol CVL-354-1001 
Final Statistical Analysis Plan 
Confidential 
Page 16 of 53 
Version 1.0: 17 March 2023
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 (Appendix 9.1). Electrocardiograms will be 
extracted from the continuous recording by a central ECG service. 
3.4.2.2. 
Standard 12-Lead Electrocardiograms 
Electrocardiogram recordings will be obtained after the participant has been supine and at rest 
for approximately 3 minutes. During the SAD and MAD portions of the trial, 12-leads ECG will 
be performed according to the Schedule of Assessments (Appendix 9.1). The central ECG 
service will provide the QTcF corrections and average of the 3 ECGs performed. 
3.4.3. 
Clinical Safety Laboratory Assessments 
Clinical laboratory tests will be performed according to the Schedule of Assessments 
(Appendix 9.1). 
3.4.4. 
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 “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. 
3.4.5. 
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. 
 
Page 16 of 78
cvl-354-1001-statistical-method.pdf   Page 17 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 17 of 53 
Version 1.0: 17 March 2023
 
The abbreviated 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. 
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. 
3.4.6. 
Adverse Events (AEs) 
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject, 
temporally associated with the use of trial intervention, whether considered related to the trial 
intervention.  
All adverse events will be recorded on the ADVERSE EVENTS CRF. Adverse events with 
missing severity will have the severity imputed as ‘Grade 3’ for the AE tabulations. Adverse 
events with missing relationship to IMP will have the relationship imputed as ‘Related’ for the 
AE tabulations if the AE started on or after the first dose of IMP. However, in the data listings 
these missing intensity and/or relationship will be presented as missing. 
3.4.6.1. 
Adverse Events of Special Interest 
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 
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 
 
Page 17 of 78
cvl-354-1001-statistical-method.pdf   Page 18 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 18 of 53 
Version 1.0: 17 March 2023
 
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, 2017). 
3.5. 
Pharmacokinetics 
Plasma and urine samples for pharmacokinetics assessments 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.  
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. 
 
Page 18 of 78
cvl-354-1001-statistical-method.pdf   Page 19 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 19 of 53 
Version 1.0: 17 March 2023
 
4. 
DATA CONVENTIONS AND VISIT WINDOWS 
4.1. 
Data Conventions 
4.1.1. 
Missing Data and Outliers 
Every effort will be made to obtain required data at each scheduled evaluation from all subjects 
who have been randomized. In situations where it is not possible to obtain all data, it may be 
necessary to impute missing data. These situations are described below. Unless otherwise 
specified, all other missing data will not be imputed. 
4.1.1.1. 
Missing Severity or Relationship for Adverse Events 
Adverse events (AEs) with missing severity (Common Terminology Criteria for Adverse Events 
[CTCAE] toxicity grade) will have the severity imputed as ‘Grade 3’ or ‘Severe’. Adverse events 
with missing relationship to IMP will have the relationship imputed as ‘Related’ if the AE started 
after the first dose of IMP. Actual values will be presented in the data listings. 
4.1.1.2. 
Incomplete or Missing Dates 
An incomplete date occurs when the exact date an event occurred or ended cannot be obtained 
from a subject. The database contains data fields for month, day, and year. A date is incomplete 
if at least one of these three fields is not known.  
For many of the planned analyses, a complete date is necessary to determine if the event should 
be included in the analysis (ie, if the event is treatment-emergent) or to establish the duration of 
an event. In such cases, incomplete dates will be imputed. 
For the purposes of handling partially reported start and stop dates for an event the following 
algorithm will be applied: 
• Missing start day, but month and year present: 
o If the event occurs same month and year as the dosing of IMP, then the start day of 
the IMP will be assigned to the day of first dose of IMP. 
o Otherwise, the start day will be set to the first day of the month. 
• Missing start day and month, but year present: 
o If event occurs in the same year as IMP dosing, then the start date of the event will be 
assigned to Day 1. 
o Otherwise, the start day and month will be set to 01 January. 
• Missing all components of a start date:  
o Assign the date of Day 1. 
• Missing end day, but month and year present: 
o The day will be set to the last day of the month. 
• Missing end day and month, but year present: 
 
Page 19 of 78
cvl-354-1001-statistical-method.pdf   Page 20 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 20 of 53 
Version 1.0: 17 March 2023
 
o The end day and month will be set to the date of study completion/discontinuation. 
o However, if study completion/discontinuation year is greater than the year of the 
event, then the day and month will be set to 31 December. 
• In the event of a completely missing end date (year not present and ongoing not checked), the 
end date will be considered as ‘ongoing’ and will not be imputed. 
If any imputed date causes the end date to occur prior to the start date of the event, the start date 
of the event will be used for the imputation of the end date. If any imputed date causes the start 
date of the event to occur after the end date of the event, the end date of the event will be used 
for the imputation of the start date. If the imputed date is later than the date of study withdrawal, 
then the date of study withdrawal will be imputed for the date. In subject data listings, start and 
stop date of events will be displayed as reported on the eCRF (ie, imputed values will not be 
listed). 
4.1.1.3. 
Missing Time 
If time is missing for a laboratory assessment taken on the first day of IMP administration, ie 
Day 1, but the time of IMP administration is available, then time for the laboratory assessment 
will be assumed to have occurred prior to IMP administration and will serve as the baseline 
value, assuming that the timepoint for the assessment was designated as predose. If the timepoint 
for the assessment was designated as postdose, then the assessment will be assumed to have been 
taken postdose.  
4.1.1.4. 
Imputation for Alphanumeric Data  
Should there be instances where a clinical laboratory parameter is reported with imbedded non-
numeric characters, as for example, “<0.1” or “>10”, the data will be imputed for quantitative 
summaries. The actual values as reported in the database will be presented in data listings.  
For incorporation in quantitative summaries, the following imputation rules will be employed: 
the lower limit of quantification will be replaced with ½ the value of the lower limit. For 
example, < 0.1 will be replaced with 0.05.  
The upper limit of quantitation will be increased by one level of precision that precedes the 
value. For example, “>0.1” will be imputed to “0.11”, and “>10” will be imputed to “10.1”.  
Additionally, the upper limit of normal (ULN)/lower limit of normal (LLN) values may be 
reported as alphanumeric (eg, ‘<5’, ‘≤5’, ‘>5’, ‘≥5’).  In these cases, if the ULN or LLN is 
necessary for determination of the laboratory severity grade, the following conventions will be 
employed: 
If the value is in the form of ≤5, the ULN will be populated with the value after removing the 
symbol (ie, the ULN is set to 5). If the value is in the form of <5, the ULN will be decreased 
by two levels of precision in the direction of the symbol (ie, the ULN is set to 4.99).  
If the value is in the form of ≥5, the LLN will be populated with the value after removing the 
symbol (ie, the LLN is set to 5). If the value is in the form of >5, the LLN will be increased 
by two levels of precision in the direction of the symbol (ie, the LLN is set to 5.01). 
 
Page 20 of 78
cvl-354-1001-statistical-method.pdf   Page 21 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 21 of 53 
Version 1.0: 17 March 2023
 
4.1.1.5. 
Derived and Transformed Data  
There are no planned derivations or transformations. 
4.1.2. 
Definitions and Terminology   
4.1.2.1. 
Screen Failure 
Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
subsequently randomized in the trial. 
4.1.2.2. 
Analysis Period 
Given the crossover design of Part A, in which each unique subject receives four treatments in a 
randomly ordered sequence, Period 1 is the subset of study days between the start of dosing for 
the initial treatment in the sequence until the dosing for Period 2, the second treatment in the 
sequence. This includes the washout period between dose 1 and dose 2. Period 2 is the subset of 
study days between the start of dosing for the second treatment until the dosing for Period 3, 
including the washout period between dose 2 and dose 3. Period 3 is the subset of study days 
between the start of dosing for the third treatment until the dosing for Period 4, including the 
washout period between dose 3 and dose 4. Period 4 is the subset of study days between the start 
of dosing for the fourth period until the end of study. 
4.1.2.3. 
Age 
Age is defined as age at the time of signing the ICF. 
4.1.2.4. 
Baseline Value 
For purposes of analysis, the baseline value is defined as the last value obtained prior to initiation 
of IMP. For ECG via Holter monitoring, the baseline value will be the average of the -15, -30, 
and -45 timepoints.  
Period Baseline Value (Part A) 
For purposes of analysis of data within each Study Period, the period baseline value will be 
defined as the last valid evaluation done before the IMP administration within each of the 
treatment periods.  
Day 1 (Baseline) (Part B) 
Baseline for Part B (Day 1) is defined as the day IMP is first initiated.  
Period Day (Part A) 
For Part A, within each period, Period Day is defined relative to the first day of the sentinel 
dosing within each phase. Thus, the period day of an event is calculated as: 
Period Day = event date – first date of period dosing (+1, if event date ≥ date of Period Day 1) 
 
Page 21 of 78
cvl-354-1001-statistical-method.pdf   Page 22 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 22 of 53 
Version 1.0: 17 March 2023
 
This calculation will result in negative period days being assigned to visits occurring prior to 
treatment with IMP within each period, and positive study days being assigned on or after the 
start of IMP. 
Study Day (Part B) 
Study Day is defined relative to Baseline (Day 1). Thus, the study day of an event is calculated 
as:  
Study Day = event date – date of Day 1 (+ 1, if event date > date of Day 1). 
This calculation will result in negative study days being assigned to visit occurring prior to the 
start of IMP and positive study days being assigned on or after the start of IMP. There will be no 
Day 0 value to match the schedule of events. 
Change from Baseline  
Change from baseline for a given endpoint is defined as the Study Day X value minus the 
Baseline Value. 
Days on Study 
Days on study is the number of days from Study Day 1 to the date of study completion or early 
termination as recorded on the End of Study eCRF page. 
Days on IMP (Part B) 
Days on IMP is the number of days from Study Day 1 to the date of last dose of IMP as recorded 
on the End of Treatment eCRF page. 
Cumulative Dose of IMP (Part B) 
The cumulative dose of IMP is calculated in milligrams and is calculated as the sum of each 
daily dose on IMP as recorded on the Exposure eCRF page. 
Treatment-emergent Adverse Event (TEAE) 
Any event reported on the eCRF that occurs on or after the initiation of IMP and up to the final 
follow-up contact is considered treatment-emergent. Additionally, it is assumed that an Adverse 
Event which was reported to have started on Day 1 without an associated onset time may have 
occurred after the initiation of IMP. Hence, Adverse Events occurring on Day 1 with no 
associated onset time are assumed to be treatment-emergent.  
For Part A, treatment-emergent adverse events will be attributed to a period based on the start 
date. An adverse event starting on or after the initiation of IMP in Period 1 and before dosing 
with IMP for Period 2, or through follow-up contact if subject discontinues prior to Period 2, is 
considered a Period 1 TEAE. For Cohort 1 and 2, an adverse event starting on or after the 
initiation of IMP in Period 2 and before dosing with IMP for Period 3, or through follow-up 
contact if subject discontinues prior to Period 3 is considered a Period 2 TEAE. An adverse event 
starting on or after the initiation of IMP in Period 3 and before dosing with IMP for Period 4, or 
through follow-up contact if subject discontinues prior to Period 4, is considered a Period 3 
 
Page 22 of 78
cvl-354-1001-statistical-method.pdf   Page 23 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 23 of 53 
Version 1.0: 17 March 2023
 
TEAE. An adverse event occurring after dosing for Period 4, through follow-up contact, is 
considered a Period 4 TEAE. 
Treatment-emergent Laboratory Abnormality 
A treatment-emergent laboratory abnormality is defined as value outside the normal range which 
occurs on or after the start of IMP and up to the follow-up contact following discontinuation of 
IMP of a given analysis period. 
In Part A, treatment-emergent laboratory abnormalities will be attributed to a period based on the 
start date. A laboratory abnormality occurring on or after the initiation of IMP in Period 1 and 
before dosing with IMP for Period 2, or through the follow-up contact if subject discontinues 
prior to Period 2, is considered a Period 1 laboratory abnormality. For Cohort 1 and 2, a 
laboratory abnormality occurring on or after the initiation of IMP in Period 2 and before dosing 
with IMP for Period 3, or through the follow-up contact if subject discontinues prior to Period 3, 
is considered a Period 2 laboratory abnormality. A laboratory abnormality occurring on or after 
the initiation of IMP in Period 3 and before dosing with IMP for Period 4, or through the follow-
up contact if subject discontinues prior to Period 4, is considered a Period 3 laboratory 
abnormality. A laboratory abnormality occurring after dosing for Period 4 through the follow-up 
contact is considered a Period 4 treatment-emergent laboratory abnormality. 
Treatment-emergent Laboratory Toxicity 
A treatment-emergent laboratory toxicity is defined as an increase of at least one toxicity grade 
from the baseline assessment at any post baseline visit. The post baseline visit must occur after 
the administration of IMP and through the follow-up contact. For defining treatment-emergent 
laboratory events, it is assumed that a laboratory assessment obtained on Day 1 with missing 
collection times occurred prior to the initiation of IMP unless a protocol deviation is identified. If 
the relevant baseline assessments are missing, then any graded toxicity (ie, at least Grade 1) is 
considered treatment-emergent.   
For Part A, treatment-emergent laboratory toxicities will be attributed to a period based on the 
start date. A laboratory toxicity occurring on or after the initiation of IMP in Period 1 and before 
dosing with IMP for Period 2, or through the follow-up contact if subject discontinues prior to 
Period 2, is considered a Period 1 treatment-emergent toxicity. For Cohort 1 and 2, a laboratory 
toxicity occurring after dosing for Period 2 and before dosing with IMP for Period 3, or through 
the follow-up contact if subject discontinues prior to Period 3, is considered a Period 2 treatment-
emergent toxicity. A laboratory toxicity occurring on or after the initiation of IMP in Period 3 
and before dosing with IMP for Period 4, or through the follow-up contact if subject discontinues 
prior to Period 4, is considered a Period 3 laboratory toxicity. A laboratory toxicity occurring 
after dosing for Period 4 through the follow-up contact post Period 4 is considered a Period 4 
treatment-emergent toxicity. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is comprised of 10 categories with binary responses. Details of the assessments and 
definitions are provided in Appendix 9.2. 
 
Page 23 of 78
cvl-354-1001-statistical-method.pdf   Page 24 of 79








 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 27 of 53 
Version 1.0: 17 March 2023
 
5. 
STATISTICAL ANALYSIS METHODS 
5.1. 
General Considerations 
Descriptive statistical methods will be used to summarize the data from this study. No formal 
hypothesis testing is planned for this trial. Unless stated otherwise, the term “descriptive 
statistics” refers to number of subjects (N), number of observations (n), mean, median, standard 
deviation (SD), Q1, Q3, minimum, and maximum for continuous data and frequencies and 
percentages for categorical data. Figure presentations will include appropriate variability 
indicator such as SD or standard error (SE). 
All data collected during the study will be included in data listings. Unless otherwise noted, the 
data presentations will be sorted first by trial part (A or B), cohort, and subject number. Unless 
otherwise noted, summary tables will be separated into Part A Cohorts 1 and 2, Part A Food 
Effects, and Part B. 
In Part A, the term “treatment sequence” refers to the sequence of treatment for each individual. 
“Treatment group” refers to treatment with CVL-354, at different doses, or placebo. Since Part A 
is a crossover study, subjects will appear in multiple groups. For Part A Cohorts 1 and 2, 
“Treatment period” refers to Periods 1 through 4 described in Figure 1. For Part A Food Effects, 
“Treatment period” refers to Period 1 and 2 described in Figure 2. 
In Part B, “treatment group” refers to treatment with CVL-354, at different doses, or placebo QD 
or BID. Doses will be determined based on data from Part A.  
For summary presentations, placebo subjects will be combined across cohorts within a given 
Part. 
The statistical analyses will be conducted with the SAS® software package Version 9.4 or higher. 
5.2. 
Populations for Analyses 
The analysis sets that are defined for this trial are described in Table 3. 
Table 3: 
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. 
5.3. 
Statistical Hypotheses 
No formal hypothesis testing is planned for this trial. 
 
Page 27 of 78
cvl-354-1001-statistical-method.pdf   Page 28 of 79




 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 29 of 53 
Version 1.0: 17 March 2023
 
 
5.9. 
Safety Analysis 
All safety analyses will be performed on the Safety Analysis Set. Should any subjects receive a 
treatment other than their randomized treatment, the treatment received will be used in the safety 
presentation. All analyses will be presented separately by Part. Analyses will be presented by 
treatment group.  For Part A, treatments will be assigned as described in Section 4.2.1. 
5.9.1. 
Adverse Events 
Adverse events will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA) 
version 25.1 or later by system organ class, preferred term, and severity. If a subject experiences 
multiple events that map to a single preferred term, the greatest Common Terminology Criteria 
for Adverse Events (CTCAE) toxicity grade and strongest investigator assessment of relation to 
IMP will be assigned to the preferred term for the appropriate summaries. Events with missing 
severity or relationship, will be classified as outlined in Section 4.1.1.1.  
For Part A, all TEAEs will be attributed to a treatment period based on start date as specified in 
Section 4.2.1. Any TEAE occurring during the washout period will be attributed to the treatment 
most recently administered.  
The occurrence of TEAEs will be summarized by treatment group for Part A and Part B, using 
preferred terms, system organ class, and severity. Separate summaries of TEAEs, treatment-
emergent serious adverse events (TESAEs), TEAEs by severity, TEAEs related to IMP, AESIs, 
and events leading to the discontinuation of study will be generated by system organ class and 
preferred terms. For Part B, a separate analysis of AEs leading to the discontinuation of IMP will 
be provided. 
All AEs reported will be listed for individual subjects showing both verbatim and preferred terms 
and treatment group at onset of the AE. All AEs that occurred prior to the initiation of IMP will 
be excluded from the tables but will be included in the listings.  
Missing onset dates will be imputed as previously outlined in Section 4.1.1.2 as required to 
determine treatment-emergent events. 
5.9.2. 
COVID-19 Coronavirus Infection Testing 
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. An AE will be recorded if the 
result is positive or indeterminate. Indeterminate tests will be repeated. COVID-19 testing results 
will be listed. 
5.9.3. 
Concomitant Medications and Non-Drug Therapy/Procedures 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug dictionary (Version: Global B3, March 2021 or later). Concomitant medications will be 
summarized by frequency of classification and preferred term and presented by treatment group.  
 
Page 29 of 78
cvl-354-1001-statistical-method.pdf   Page 30 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 30 of 53 
Version 1.0: 17 March 2023
 
Prior and concomitant non-drug therapy/procedures will be coded using MedDRA Version 24.0 
or higher. Concomitant non-drug therapy/procedures will be summarized by frequency of system 
organ class and preferred term and presented by treatment group. 
5.9.4. 
Clinical Laboratory Assessments 
Descriptive summaries of selected (quantitative) clinical laboratory results will be presented by 
study day and treatment group. Laboratory values outside the normal range for each parameter 
will be identified using shift tables. Each subject’s hematology, blood chemistry, and 
quantitative urinalysis values will be flagged as “low” (below the lower limit of normal/LLN), 
“normal” (within the normal range), or “high” (above the upper limit of normal/ULN) relative to 
the normal ranges of the central laboratory. Each subject’s qualitative urinalysis values will be 
flagged as “normal” or “abnormal”. Shifts from baseline, or period baseline if Part A, to 
high/normal/low status for hematology and blood chemistry parameters that are not CTCAE 
graded will be presented to the maximum post-baseline/post-period baseline value and the 
minimum post-baseline/post-period baseline value for each laboratory test. Shifts from baseline, 
or period baseline if Part A, to normal/abnormal status for urinalysis parameters that are not 
CTCAE graded will be presented to the maximum post-baseline/post-period baseline value and 
the minimum post-baseline/post-period baseline value for each laboratory test. Otherwise, for 
hematology, blood chemistry, and urinalysis parameters that are CTCAE graded, laboratory 
toxicities will be programmatically graded by severity using Cerevel’s modified CTCAE Version 
5.0. Shifts from baseline, or period baseline if Part A, to greatest (worst) treatment-emergent 
laboratory toxicity will be presented. 
The number and percentage of subjects who have post-baseline/post-period baseline elevations 
in liver transaminase (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) or 
bilirubin abnormalities in relation to fold above the ULN will be summarized according to the 
Food and Drug Administration's Premarketing Clinical Evaluation on Drug-Induced Liver Injury 
Guidance for Industry (FDA, 2009). Abnormal hepatic laboratory values will be categorized and 
evaluated for any occurrence among all post-baseline/post-period baseline assessments (where 
“and” in the bulleted list below indicates elevations occurring at the same visit). Within each 
laboratory parameter grouping, a subject may be counted once per elevation criteria using the 
worst-case result. That is, a subject with a worst case ALT elevation >3 × ULN would be 
counted once in the ALT >1.5 × ULN category and once in the ALT >3 × ULN category, 
regardless of how many ALT elevations the subject had that met the >3 × ULN and >1.5 × ULN 
elevation criteria. 
• ALT and/or AST >3 × ULN and total bilirubin >1.5 or 2 × ULN 
• AST >1.5, 3, 5, 10, 20 × ULN 
• ALT >1.5, 3, 5, 10, 20 × ULN  
• Total bilirubin >1, 1.5, 2 × ULN  
• Alkaline phosphatase (ALP) >1.5 × ULN 
In addition, a Hy’s law plot, a shift plot showing liver safety panel tests over time 
(baseline/period baseline vs. post-baseline/post-period baseline), and distribution plots of ALT, 
AST, ALP, and bilirubin over time will be produced. The plots to be included are the scatter plot 
 
Page 30 of 78
cvl-354-1001-statistical-method.pdf   Page 31 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 31 of 53 
Version 1.0: 17 March 2023
 
of maximum transaminase versus maximum bilirubin, the liver test safety panel over time and 
the distribution of ALT by time and treatment. The distribution plots for AST, ALP, and 
bilirubin will use the same format as is used for ALT. 
5.9.5. 
Vital Signs 
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), 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 symptomatic orthostatic 
dizziness or a decrease of ≥20 mmHg in systolic blood pressure upon standing compared with 
the average of the resting blood pressure measurement.  
Descriptive summaries of vital signs (body temperature, respiratory rate, systolic blood pressure, 
diastolic blood pressure, and heart rate; including orthostatic change) and their change from 
baseline/period-baseline will be presented by visit/study day, time point, position (as applicable), 
and treatment.  
The following out-of-range vital signs will be summarized for analysis records occurring post-
baseline: 
• Heart Rate – Supine 
o <45 bpm 
o <60 bpm 
o >100 bpm 
• Systolic Blood Pressure- Supine 
o ≤90 mmHg 
o ≥140 mmHg 
• Diastolic Blood Pressure- Supine 
o ≤60 mmHg 
o ≥90 mmHg 
• Respiratory Rate 
o <10 bpm 
o <12 bpm 
o >20 bpm 
• Temperature  
o <35.3°C 
o >37.7°C 
 
Page 31 of 78
cvl-354-1001-statistical-method.pdf   Page 32 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 32 of 53 
Version 1.0: 17 March 2023
 
Vital sign results, including orthostatic changes, will be listed. An additional listing of out-of-
range vital signs will also be listed. 
5.9.6. 
Electrocardiograms (ECGs) 
5.9.6.1. 
Continuous Electrocardiogram Recordings (Holter) 
Continuous ECGs readings and corresponding changes from period baseline, if Part A, or study 
baseline, if Part B, will be summarized by time point using descriptive statistics. The results of 
individual subjects at each timepoint will also be listed. 
5.9.6.2. 
Standard 12-lead Electrocardiograms 
ECG parameters and corresponding changes from period baseline, if Part A, or study baseline, if 
Part B, will be summarized by time point using descriptive statistics. The results of individual 
subjects at each timepoint will also be listed. 
The number and proportion of subjects having a worst post-baseline QTcF values from 
>450 msec to 480 msec, >480 msec to 500 msec, and >500 msec will be summarized. In 
addition, subjects with an increase from baseline of >30 msec to 60 msec and >60 msec will be 
summarized. 
5.9.7. 
Suicidal Ideation and Behavior Risk Monitoring 
The maximum post-baseline/post-period baseline results from the C-SSRS will be summarized 
by treatment. The maximum of each subscale (suicidal ideation [Categories 1-5], suicidal 
behavior [Categories 6-10], suicidal ideation or behavior [Categories 1-10], and self-injurious 
behavior without suicidal intent) will be presented. The number of patients with suicide-related 
treatment-emergent events, treatment-emergent suicidal ideation, and suicidal behavior, based on 
a comparison of the C-SSRS at baseline and/or previous lifetime experience to maximum 
C-SSRS scores across all post-baseline assessments will be provided for each treatment period.  
All C-SSRS elements will be reflected in a listing. 
5.10. 
Pharmacokinetics 
The pharmacokinetic analysis is detailed in a separate PK Analysis Plan (Appendix 9.5). 
5.11. 
Protocol Deviations 
All protocol deviations will be reviewed by the project team prior to unblinding to identify 
subjects with important protocol deviations. Summaries of important deviations for the Safety 
Analysis Set will be presented by category and subcategory of deviation. All deviations from the 
protocol of the Safety Analysis Set will be listed by category along with a description and any 
additional comments. 
5.12. 
Timing of Analyses 
An interim database lock and analysis once Part A is complete may be conducted. Should the 
circumstance arise that the safety, tolerability, and pharmacokinetic data summary of completed 
cohorts are required for regulatory purpose, other interim analyses may also be conducted. 
 
Page 32 of 78
cvl-354-1001-statistical-method.pdf   Page 33 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 33 of 53 
Version 1.0: 17 March 2023
 
A final analysis will be conducted once the last subject completes or discontinues the study, the 
resulting clinical database has been cleaned and quality checked, the pre-analysis meeting has 
occurred, and the database has been locked. 
 
Page 33 of 78
cvl-354-1001-statistical-method.pdf   Page 34 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 34 of 53 
Version 1.0: 17 March 2023
 
6. 
CHANGES IN THE PLANNED ANALYSES 
Should any deviations from the analyses specified in the authorized statistical analysis plan arise, 
such deviations will be documented in the final clinical study report. 
 
 
Page 34 of 78
cvl-354-1001-statistical-method.pdf   Page 35 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 35 of 53 
Version 1.0: 17 March 2023
 
7. 
REVISION HISTORY 
 
Date 
Revision 
Rationale 
 
 
 
 
 
 
 
 
Page 35 of 78
cvl-354-1001-statistical-method.pdf   Page 36 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 36 of 53 
Version 1.0: 17 March 2023
 
8. 
REFERENCES 
Posner K, Brown GK, Stanley B, et al. The Columbia–Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-77. 
US Food and Drug Administration (FDA). Guidance for industry: Drug-induced liver injury: 
premarketing clinical evaluation; Jul 2009. Accessed 17 Mar 2023. 
https://www.fda.gov/media/116737/download 
US FDA. Guidance for industry: Assessment of abuse potential of drugs; Jan 2017. Accessed 
13 Sep 2021. https://www.fda.gov/media/116739/download 
 
Page 36 of 78
cvl-354-1001-statistical-method.pdf   Page 37 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 37 of 53 
Version 1.0: 17 March 2023
 
9. 
APPENDICES 
9.1. 
Schedule of Assessments 
The Schedules of Assessments, as taken from the protocol, are provided in Table 4 (Part A, SAD 
Cohorts 1 and 2), Table 5 (Part A, Food Effect Cohort 3), and Table 6 (Part B, MAD 
Cohorts 1-5). 
 
Page 37 of 78
cvl-354-1001-statistical-method.pdf   Page 38 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 38 of 53 
Version 1.0: 17 March 2023
 
 
Table 4: 
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----------------------------------→ 
 
 
 
 
Page 38 of 78
cvl-354-1001-statistical-method.pdf   Page 39 of 79




 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 40 of 53 
Version 1.0: 17 March 2023
 
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, 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. 
 
 
 
Page 40 of 78
cvl-354-1001-statistical-method.pdf   Page 41 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 41 of 53 
Version 1.0: 17 March 2023
 
Table 5: 
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 
 
 
Page 41 of 78
cvl-354-1001-statistical-method.pdf   Page 42 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 42 of 53 
Version 1.0: 17 March 2023
 
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.  
 
Page 42 of 78
cvl-354-1001-statistical-method.pdf   Page 43 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 43 of 53 
Version 1.0: 17 March 2023
 
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.  
 
 
 
Page 43 of 78
cvl-354-1001-statistical-method.pdf   Page 44 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 44 of 53 
Version 1.0: 17 March 2023
 
Table 6: 
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 
-----------------------------------------------------------------------------------------------------------------------------------------------------------→ 
 
Page 44 of 78
cvl-354-1001-statistical-method.pdf   Page 45 of 79




 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 46 of 53 
Version 1.0: 17 March 2023
 
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. 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). 
 
 
Page 46 of 78
cvl-354-1001-statistical-method.pdf   Page 47 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 47 of 53 
Version 1.0: 17 March 2023
 
9.2. 
Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation 
and Suicidal Behavior Scores 
The C-SSRS is comprised of 10 categories with binary responses. The 10 categories include: 
• Category 1 – Wish to be Dead  
• Category 2 – Non-specific Active Suicidal Thoughts  
• Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to 
Act  
• Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan  
• Category 5 – Active Suicidal Ideation with Specific Plan and Intent  
• Category 6 – Preparatory Acts or Behavior  
• Category 7 – Aborted Attempt  
• Category 8 – Interrupted Attempt  
• Category 9 – Actual Attempt (non-fatal)  
• Category 10 – Completed Suicide 
Categories 1-5 represent Suicidal Ideation and categories 6-10 represent Suicidal Behavior. Each 
category is scored as 1 if there is a positive response in the category and a 0 if there are no 
positive responses in the category.    
Self-Injurious Behavior Without Suicidal Intent During Treatment 
A subject will be categorized as having self-injurious behavior without suicidal intent if there is 
an occurrence of non-suicidal self-injurious behavior on the C-SSRS – Since Last Visit CRF at 
any post-baseline visit. 
Baseline C-SSRS Score  
Baseline represents the pre-treatment assessment of recent history, with elements of suicidal 
ideation assessed over the prior 6 months and elements of suicidal behavior assessed over the 
prior 2 years. It is scaled from 0 (no suicidal ideation or behavior) to 10 (completed suicide) 
Treatment-Emergent Suicide-Related Event  
A subject will be categorized as having a treatment-emergent suicide-related event if at least one 
post-baseline suicidal ideation or suicidal behavior score is greater than 0.  
Treatment-Emergent Suicidal Ideation Compared to Recent History 
A subject will be categorized as having treatment-emergent suicidal ideation compared to recent 
history when there is at least one post-baseline suicidal ideation score >0 and is an increase from 
baseline. Lifetime scores are not considered for baseline suicidal ideation responses. 
 
 
 
Page 47 of 78
cvl-354-1001-statistical-method.pdf   Page 48 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 48 of 53 
Version 1.0: 17 March 2023
 
Treatment-Emergent Serious Suicidal Ideation Compared to Recent History 
A subject will be categorized as having treatment-emergent serious suicidal ideation compared to 
recent history if the baseline score was <4 and the post-baseline suicidal ideation score increases 
to 4 or 5. Lifetime scores are not considered for baseline suicidal ideation responses. 
Emergence of Serious Suicidal Ideation Compared to Recent History 
A subject will be categorized as having emergence of serious suicidal ideation compared to 
recent history if baseline score was 0 (no suicidal ideation) and post-baseline C-SSRS suicidal 
ideation score is either 4 or 5. Lifetime scores are not considered for baseline suicidal ideation 
responses.  
Emergence of Suicidal Behavior Compared to all Prior History 
A subject will be categorized as having emergence of suicidal behavior compared to all prior 
history if there had been no suicidal behavior in Categories 6-10 reported at any pre-treatment 
assessment, including responses to lifetime history questions, and there is at least one positive 
post-baseline C-SSRS assessment in Categories 6-10. ‘All Prior History’ represents lifetime 
history. 
 
 
Page 48 of 78
cvl-354-1001-statistical-method.pdf   Page 49 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 49 of 53 
Version 1.0: 17 March 2023
 
9.3. 
Programming Conventions 
• Page orientation, margins, and fonts: Summary tables, listings, and figures will appear in 
landscape orientation. There should be a minimum of a 1” boundary on the upper (bound) 
edge, and a minimum of a 1.0” boundary on the remaining three edges.  Output should be 
printed in Courier New with a point size of 8. 
• Identification of analysis population: Every summary table and figure should clearly specify 
the analysis population being summarized. Listings will be prepared for all subjects. 
• Group headers: In the summary tables, the group headers will identify the summary group 
and the sample size for the indicated analysis population. Of note, the header’s sample size 
does not necessarily equal the number of subjects actually summarized within any given 
summary module; some subjects in the analysis population may have missing values and thus 
may not be summarized. 
• Suppression of percentages corresponding to null categories: When count data are presented 
as category frequencies and corresponding percentages, the percent should be suppressed 
when the count is zero in order to draw attention to the non-zero counts. 
• Presentation of sample sizes: Summary modules should indicate, in one way or another, the 
number of subjects actually contributing to the summary statistics presented in any given 
summary module. As mentioned above, this may be less than the number of subjects in the 
analysis population due to missing data. 
o In the quantitative modules describing continuous variables (and thus presenting sample 
size, means, and standard deviations), the sample size should be the number of non-
missing observations. The number of missing observations, if any, will be noted. 
o For categorical variables that are presented in frequency tables, the module should 
present the total count in addition to the count in each category. Percentages should be 
calculated using this total as the denominator, and the percentage corresponding to the 
sum itself (that is, 100%) should be presented so as to indicate clearly to a reviewer the 
method of calculation. The number of missing observations, if any, will be noted. 
• Sorting: Listings will be sorted by part, subject number, and date, if applicable. If a listing is 
sorted in a different manner, the listing shells will indicate as such.  
• General formatting rules: Rounding for all variables will occur only as the last step, 
immediately prior to presentation in listings, tables, and figures. No intermediate rounding 
will be performed on derived variables. The standard rounding practice of rounding numbers 
ending in 0-4 down and numbers ending in 5-9 up will be employed.   
• Numerical Values: The presentation of numerical values will adhere to the following 
guidelines:  
o Raw measurements will be reported to the number of significant digits as captured 
electronically or on the CRFs.   
o Standard deviations will be reported to two decimal places beyond the number of decimal 
places the original parameter is presented. 
 
Page 49 of 78
cvl-354-1001-statistical-method.pdf   Page 50 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 50 of 53 
Version 1.0: 17 March 2023
 
o Means, Medians, Q1 and Q3 values will be reported to one decimal place beyond the 
number of decimal places as the original parameter is presented.  
o Calculated percentages will be reported with no decimals. 
o Dates will be formatted as DDMMMYYYY. Partial dates will be presented on data 
listings as recorded on CRFs. 
o Time will be presented according to the 24-hour clock (HH:MM). 
 
 
 
Page 50 of 78
cvl-354-1001-statistical-method.pdf   Page 51 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 51 of 53 
Version 1.0: 17 March 2023
 
9.4. 
Abbreviations 
Abbreviation 
Definition 
AE  
adverse event  
Ae 
amount of the dose administered recovered 
AESI  
adverse event of special interest  
ALT  
alanine aminotransferase  
ALP 
alkaline phosphatase 
APMP  
Abuse Potential Monitoring Plan  
AST  
aspartate aminotransferase  
AUC  
area under the concentration-time curve  
AUC24 
area under the concentration-time curve over the time interval 0 to 24 hours 
postdose 
AUCinf 
area under the concentration-time curve from time zero extrapolated to infinity 
AUClast 
area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration 
AUCτ 
area under the concentration-time curve over a dosing interval (τ) 
BID  
twice daily  
BMI 
body mass index 
Cmax  
maximum plasma concentration  
CL/F 
apparent clearance of drug from plasma 
COVID-19  
coronavirus disease-2019  
CSR  
clinical study report  
C-SSRS  
Columbia-Suicide Severity Rating Scale  
  
  
ECG  
electrocardiogram  
eCRF  
electronic case report form  
ET 
early termination 
F  
bioavailability  
FSH  
follicle stimulating-hormone  
HIV 
human immunodeficiency virus 
ICF  
informed consent form  
ICH  
International Council for Harmonisation  
IMP  
investigational medicinal product  
 
Page 51 of 78
cvl-354-1001-statistical-method.pdf   Page 52 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 52 of 53 
Version 1.0: 17 March 2023
 
Abbreviation 
Definition 
KOR  
kappa opioid receptor  
LLN 
lower limit of normal 
MAD  
multiple ascending dose  
MedDRA  
Medical Dictionary for Regulatory Activities  
NOAEL  
no-observed-adverse-effect-level  
PK  
pharmacokinetic(s)  
PTR 
peak to trough ratio 
QD  
once daily  
QTcF  
QT interval corrected for heart rate using Fridericia’s formula  
Rac 
accumulation ratio 
SAD  
single ascending dose  
SAE  
serious adverse event  
SAP  
statistical analysis plan  
SD 
standard deviation 
SE 
standard error 
SRT  
Safety Review Team  
t½ 
apparent terminal half-life  
TEAE 
treatment-emergent adverse event 
Tmax 
time to last quantifiable concentration 
ULN  
upper limit of normal  
  
  
Vz/F 
apparent volume of distribution during the terminal phase 
WHO 
World Health Organization 
 
 
 
 
Page 52 of 78
cvl-354-1001-statistical-method.pdf   Page 53 of 79


 
Protocol CVL-354-1001 
 
 
Final Statistical Analysis Plan 
 
 
Confidential 
Page 53 of 53 
Version 1.0: 17 March 2023
 
9.5. 
Pharmacokinetic Analysis Plan 
 
 
Page 53 of 78
cvl-354-1001-statistical-method.pdf   Page 54 of 79






Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
 
Final, Version 1, 10Feb2023  
Page 3 of 25 
 
2 
TABLE OF CONTENTS 
1 
PHARMACOKINETIC ANALYSIS PLAN APPROVAL SIGNATURES ...........................2 
2 
TABLE OF CONTENTS .........................................................................................................3 
3 
ABBREVIATIONS ..................................................................................................................5 
4 
INTRODUCTION ....................................................................................................................8 
4.1 Background ........................................................................................................................8 
5 
STUDY OBJECTIVES ............................................................................................................8 
6 
STUDY DESIGN ...................................................................................................................10 
6.1 SAD and Food Effect– Part A .........................................................................................11 
6.1.1 SAD (Cohorts 1 and 2) ........................................................................................11 
6.1.2 Food Effect Evaluation (Cohort 3) ......................................................................12 
6.2 MAD – Part B ..................................................................................................................12 
6.3 PK Stopping Criteria – Part A and Part B .......................................................................13 
6.4 Dose Administration ........................................................................................................13 
6.5 PK Sample Collections ....................................................................................................14 
6.6 PK Sample Bioanalysis ....................................................................................................14 
7 
ANALYSIS SETS ..................................................................................................................14 
7.1 Safety Analysis Set ..........................................................................................................14 
7.2 Pharmacokinetics Analysis Set ........................................................................................14 
8 
PHARMACOKINETIC ANALYSIS .....................................................................................14 
8.1 Pharmacokinetic Analysis ...............................................................................................14 
8.1.1 Criteria for the Calculation of Apparent Terminal Elimination Rate Constant and 
Half-life ...............................................................................................................17 
8.1.2 Criteria for Calculation and Reporting of Area Under the Concentration-time 
Curve ...................................................................................................................18 
8.1.3 Calculation of Urinary Parameters ......................................................................18 
8.1.4 Criteria for Handling Concentrations Below the Limit of Quantification or 
Missing Concentrations for Pharmacokinetic Analysis ......................................19 
8.1.5 Treatment of Outliers in Pharmacokinetic Analysis ...........................................19 
8.2 Presentation of Pharmacokinetic Data .............................................................................19 
8.2.1 Presentation of Urine Drug Concentration Data .................................................20 
8.2.2 Presentation of Pharmacokinetic Parameters ......................................................20 
Page 56 of 78
cvl-354-1001-statistical-method.pdf   Page 57 of 79


Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
 
Final, Version 1, 10Feb2023  
Page 4 of 25 
 
9 
STATISTICAL METHODOLOGY .......................................................................................20 
9.1 General .............................................................................................................................20 
9.2 Statistical Evaluation of Dose Proportionality and Food Effect ......................................21 
10 PHARMACOKINETIC REPORT .........................................................................................22 
10.1 
Interim PK Analyses ................................................................................................22 
10.2 
Final Report ..............................................................................................................22 
11 REGULATORY REQUIREMENTS .....................................................................................22 
12 REFERENCES .......................................................................................................................23 
13 TABLES, FIGURES, AND LISTINGS .................................................................................24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 57 of 78
cvl-354-1001-statistical-method.pdf   Page 58 of 79


Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
 
Final, Version 1, 10Feb2023  
Page 5 of 25 
 
3 
ABBREVIATIONS  
%AUCextrap 
percentage of area under the concentration-time curve due to extrapolation 
from the last quantifiable concentration to infinity 
%Fluctuation 
percentage fluctuation at steady state 
Ae 
amount of the dose administered recovered 
Aet1-t2 
amount of the dose administered recovered in urine over the time interval t1 to 
t2 at steady state 
ANOVA 
analysis of variance 
AUC 
area under the concentration-time curve 
AUC24 
area under the concentration-time curve over the time interval 0 to 24 hours 
postdose 
AUCinf 
area under the concentration-time curve from time zero extrapolated to infinity 
AUClast 
area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration 
AUCτ 
area under the concentration-time curve over a dosing interval (τ) 
BID 
twice daily 
BLQ 
below the limit of quantification 
Cavg 
average plasma concentration  
CI 
confidence interval 
CL/F 
apparent clearance of drug from plasma 
CLR 
renal clearance 
Cmax 
maximum plasma concentration 
CSR 
clinical study report 
Ctrough 
trough plasma concentration 
CV 
coefficient of variation 
DAUC24 
area under the concentration-time curve over a dosing interval (τ) normalized 
by dose administered 
DAUCinf 
area under the concentration-time curve from time zero extrapolated to infinity 
normalized by dose administered 
DAUClast 
area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration normalized by dose administered 
DAUCτ 
area under the concentration-time curve over a dosing interval (τ) normalized 
by dose administered 
DCmax 
maximum plasma concentration normalized by dose administered 
fe 
percentage of the dose administered recovered 
fet1-t2 
percentage of the dose administered recovered in urine over the time interval 
t1 to t2 at steady state 
GLSM 
geometric least squares mean 
IMP 
investigational medicinal product 
Page 58 of 78
cvl-354-1001-statistical-method.pdf   Page 59 of 79


Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
 
Final, Version 1, 10Feb2023  
Page 6 of 25 
 
KOR 
Kappa opioid receptor 
λz 
apparent terminal elimination rate constant 
λz Lower 
start of exponential fit 
λz N 
number of data points included in the log-linear regression 
λz Span Ratio time period over which apparent terminal elimination rate constant was 
determined as a ratio of apparent terminal half-life 
λz Upper 
end of exponential fit 
LC/MS/MS 
liquid chromatography with tandem mass spectrometry 
ln 
natural log 
LR 
linearity ratio 
LSM 
least squares mean 
MAD 
multiple ascending dose 
max 
maximum 
MDD 
major depressive disorder 
min 
minimum 
MOR 
mu opioid receptors 
N 
number of participants 
n 
number of observations 
NA 
not applicable 
NC 
not calculated 
NOAEL 
no observed adverse effect level 
PK 
pharmacokinetic(s) 
PKAP 
pharmacokinetic analysis plan 
PTR 
peak to trough ratio 
QD 
once daily 
R 
randomization 
Rac 
accumulation ratio 
Rac, AUCτ 
accumulation ratio based on area under the concentration-time curve over a 
dosing interval (τ) 
Rac, Cmax 
accumulation ratio based on maximum plasma concentration during the dosing 
interval  
SAD 
single ascending dose 
Seq 
sequence 
SD 
standard deviation 
SOP 
Standard Operating Procedures 
SRT 
Safety Review Team 
TBD 
to be determined 
tlast 
time of the last quantifiable concentration 
Page 59 of 78
cvl-354-1001-statistical-method.pdf   Page 60 of 79


Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
 
Final, Version 1, 10Feb2023  
Page 7 of 25 
 
Tmax 
time to maximum plasma concentration 
t1/2 
apparent terminal elimination half-life 
Vz/F 
apparent volume of distribution during the terminal phase 
 
 
 
Page 60 of 78
cvl-354-1001-statistical-method.pdf   Page 61 of 79


Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
 
Final, Version 1, 10Feb2023  
Page 8 of 25 
 
4 
INTRODUCTION 
This PKAP has been developed after review of the Clinical Study Protocol CVL-354-1001 
version 3.0, dated 25 May Sep2022 (1). This PKAP describes the planned analysis of the PK 
data from this study.  
The intent of this document is to provide guidance for the PK and statistical analyses of PK data. 
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement between the Sponsor and Labcorp Drug Development (hereafter, referred 
to as Labcorp) Clinical Pharmacology Services. A limited amount of information concerning this 
study (eg, objectives, study design) is given to help the reader’s interpretation. When the PKAP 
is agreed upon and finalized, it will serve as guidance for this study’s PK report. 
This PKAP supersedes the PK considerations identified in the protocol. If additional analyses are 
required to supplement the planned analyses described in this PKAP, they may be performed and 
identified in the PK report. Any substantial deviations from this PKAP will be agreed upon 
between the Sponsor and Labcorp Clinical Pharmacology Services and identified in the PK 
report.  
4.1 
Background 
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 >10-fold 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.  
5 
STUDY OBJECTIVES 
The scope of this PKAP and the PK report will address a component of the following secondary 
objectives from the study protocol: 
Part A (Single Ascending Dose [SAD]) 
x To evaluate the plasma pharmacokinetics of CVL-354 following single ascending doses 
administered orally to healthy participants 
o Pharmacokinetics parameters of CVL-354 following single oral doses: 
 Cmax 
 Tmax 
 AUC24 
 AUClast 
 AUCinf 
 CL/F 
 VZ/F 
Page 61 of 78
cvl-354-1001-statistical-method.pdf   Page 62 of 79


Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
 
Final, Version 1, 10Feb2023  
Page 9 of 25 
 
 t1/2 
x To evaluate the effect of food following single doses of CVL-354 administered orally to 
healthy participants 
o Pharmacokinetics parameters of CVL-354 following single oral doses: 
 Cmax 
 Tmax 
 AUC24 
 AUClast 
 AUCinf 
 CL/F 
 VZ/F 
 t1/2 
Part B (Multiple Ascending Dose [MAD]) 
x To evaluate the plasma pharmacokinetics of CVL-354 following multiple ascending 
doses administered orally to healthy participants 
o Pharmacokinetics parameters of CVL-354 on Days 1 and 14: 
 Cmax 
 Tmax 
 Ctrough 
 AUCτ 
 CL/F (Day 14 only) 
 VZ/F (Day 14 only) 
 PTR (Peak-to-trough ratio) (Day 14 only) 
 Rac, Cmax (Day 14 only) 
 Rac, AUC (Day 14 only) 
 t1/2 (Day 14 only) 
 Ae (Day 14 only) 
 CLR (renal clearance; Day 14 only) 
 
 
Page 62 of 78
cvl-354-1001-statistical-method.pdf   Page 63 of 79


Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
 
Final, Version 1, 10Feb2023  
Page 10 of 25 
 
6 
STUDY DESIGN 
This is a Phase 1, double-blind (investigator and participant), 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.  
Information regarding the study design is detailed in the CVL-354-1001 Protocol version 3.0 (1). 
Figure 1: Study Design Schematics 
Part A (SAD, Cohorts 1 and 2) 
 
 
Abbreviations: n=number of observations; R=randomization; Seq=sequence 
 
 
 
Part A (Food Effect, Cohort 3) 
 
 
Abbreviations: IMP=investigational medicinal product; n=number of observations; R=randomization; Seq=sequence 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
Page 63 of 78
cvl-354-1001-statistical-method.pdf   Page 64 of 79


Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
 
Final, Version 1, 10Feb2023  
Page 11 of 25 
 
Part B (MAD, Cohorts 1-5) 
Abbreviations: IMP=investigational medicinal product; N=number of participants; R=randomization. 
 
6.1 
SAD and Food Effect– Part A 
6.1.1 SAD (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 may be evaluated. 
 
Cohorts 1 and 2 will be dosed in a sequential manner for up to 4 periods each. 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. Each dosing period will be separated by 
a washout period of at least 5 days.  
 
Cohorts 1 and 2 will comprise of approximately 8 participants (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.  
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 established based on the no observed adverse effect level 
(NOAEL) exposures 
. 
Dose escalation may also be stopped if it is determined that sufficient exposures are achieved, 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Page 64 of 78
cvl-354-1001-statistical-method.pdf   Page 65 of 79




Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
 
Final, Version 1, 10Feb2023  
Page 13 of 25 
 
doses. Similar to Part A, dose increments in Part B will not exceed half-log increments (3.3-fold) 
early in escalation and smaller escalation steps (≤2-fold) will be implemented at doses closer to 
stopping criteria.  
 
6.3 
PK Stopping Criteria – Part A and Part B 
x SAD: If, based on the observed data, the group mean Cmax or AUC24 (based on total 
plasma concentrations) of the next planned dose is projected to exceed the exposure 
limits 
 that dose will not be 
explored. Modified doses may be explored if they are not expected to exceed PK 
stopping criteria. 
 
x MAD: If, based on the observed data, the group mean steady state (Day 14) Cmax or 
AUC24 (based on total plasma concentrations) of the next planned dose is projected to 
exceed the maximum exposure in SAD 
 
, that dose will not be explored. Modified doses may be explored if they are not 
expected to exceed PK stopping criteria. 
Progression to the next dose will occur if the last dose was tolerated and after satisfactory review 
of the available safety, tolerability, and PK data from a minimum of 6 participants (including at 
least 1 placebo participant) within a treatment period. 
The dose increments will be based on observed exposures and forward predictions. The size of 
the exposure increments may be changed (not exceeding 3.3-fold [half-log] increments) as the 
trial progresses, dependent upon emerging PK, safety, and tolerability data. Any decision to 
change the size of the exposure increment will be made jointly by the investigator and the trial 
team and after careful evaluation of all available data. 
 
6.4 
Dose Administration 
x All doses in Parts A, except for dosing under “fed” conditions, will be administered under 
fasted conditions following an overnight fast of at least 10 hours. Participants will 
continue to fast for 4 hours following dosing on Day 1. 
x For dosing under “fed” conditions during food evaluation, following an overnight fast of 
at least 10 hours, participants will start breakfast approximately 25 minutes prior to 
administration of IMP. The IMP will then be administered within approximately 5 minutes 
of completion of the meal.  
x For Part B, on days with intensive PK sampling (Day 1 and Day 14), the IMP will be 
administered under fasted conditions following an overnight fast of at least 10 hours. 
Participants will continue to fast for 4 hours following dosing on these intensive PK 
sampling days. On other days, each dose of IMP will be administered at approximately 
the same time each morning at least 1 hour following the morning meal.  
x Each dose will be administered with 240 mL of water. 
Page 66 of 78
cvl-354-1001-statistical-method.pdf   Page 67 of 79


Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
 
Final, Version 1, 10Feb2023  
Page 14 of 25 
 
6.5 
PK Sample Collections 
Blood and urine (MAD part only) samples will be obtained during the study for measurement of 
CVL-354 concentrations in plasma and urine. For PK assessments, there will be an acceptable 
blood collection window of ±10% of the nominal time point (eg, within 6 minutes of a 60-minute 
sample). 
SAD and Food effect 
Serial PK blood samples (1 sample and 1 backup sample) will be collected during the SAD 
portion for each participant receiving drug and placebo at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 
36, and 48 hours postdose. Predose PK samples (1 sample and 1 backup sample) will be obtained 
within 15 minutes prior to dosing.  
 
MAD 
PK blood 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.  
 
Cumulative pharmacokinetic urine samples will be collected during the MAD study for each 
participant receiving drug and placebo on Day 14 (0-24 hour) postdose.  
6.6 
PK Sample Bioanalysis 
Plasma and urine samples will be stored and shipped to Q2 Solutions who will perform 
bioanalysis of CVL-354 using a validated LC/MS/MS method to determine plasma and urine 
concentrations. The details of the bioanalysis method will be described in the bioanalysis plan 
prior to the analysis. Further instructions and details on the processing, collection, and handling 
of samples will be provided in separately defined Laboratory Manual. 
7 
ANALYSIS SETS 
7.1 
Safety Analysis Set 
All randomized participants who receive at least 1 dose of IMP.  
 
7.2 
Pharmacokinetics Analysis Set 
All participants in the Safety Analysis Set who have at least 1 quantifiable CVL-354 
concentration.  
8 
PHARMACOKINETIC ANALYSIS 
8.1 
Pharmacokinetic Analysis 
The following PK parameters will be determined where possible from the plasma and urine 
concentrations of CVL-354 using noncompartmental methods in validated software program 
Phoenix WinNonlin (Certara, Version 8.3.5 or higher): 
 
Page 67 of 78
cvl-354-1001-statistical-method.pdf   Page 68 of 79


Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
 
Final, Version 1, 10Feb2023  
Page 15 of 25 
 
Part A* (SAD and Food Effect) 
Parameter 
Unitsa 
Definition 
AUClast 
h*ng/mL 
area under the concentration-time curve from time zero to the time 
of the last quantifiable concentrationb 
AUC24 
h*ng/mL 
area under the concentration-time curve over the time interval 0 to 
24 hours postdoseb 
AUCinf 
h*ng/mL 
area under the concentration-time curve from time zero 
extrapolated to infinityb, c 
%AUCextrap 
% 
percentage of area under the concentration-time curve due to 
extrapolation from the last quantifiable concentration to infinity 
Cmax 
ng/mL 
maximum plasma concentration 
Tmax 
h 
time to maximum plasma concentration 
tlast 
h 
time of the last quantifiable concentration 
t1/2 
h 
apparent terminal elimination half-life 
CL/F 
L/h 
apparent clearance of drug from plasma 
Vz/F 
L 
apparent volume of distribution during the terminal phase 
DAUClast 
h*ng/mL/mg 
AUClast normalized by dose administeredd 
DAUC24 
h*ng/mL/mg 
AUCτ normalized by dose administeredd 
DAUCinf 
h*ng/mL/mg 
AUCinf normalized by dose administeredd 
DCmax 
ng/mL/mg 
Cmax normalized by dose administeredd 
a Units are based on concentration units (provided by the bioanalytical lab or preferred units for presentation of PK parameters) 
and dose units used in the study. 
b The area under the concentration-time curve will be calculated using the linear trapezoidal rule for increasing concentrations 
and the logarithmic rule for decreasing concentrations (linear up/log down rule). 
c Based on the last observed quantifiable concentration. 
d Calculated by dividing the parameter by the dose (mg). 
* Concentration-time profile following each discrete single dose in Part A Profile Day 1, including all periods of the food effect 
evaluation. 
 
 
Part B*  
Parameter 
Unitsa 
Definition 
AUClast 
h*ng/mL 
area under the concentration-time curve from time zero to the 
time of the last quantifiable concentrationb 
AUC24  
h*ng/mL 
area under the concentration-time curve over the time interval 0 
to 24 hours postdose  
(Day 1 only)b 
AUCinf  
h*ng/mL 
area under the concentration-time curve from time zero 
extrapolated to infinity (Day 1 only)b, e 
Page 68 of 78
cvl-354-1001-statistical-method.pdf   Page 69 of 79


Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
 
Final, Version 1, 10Feb2023  
Page 16 of 25 
 
%AUCextrap 
% 
percentage of area under the concentration-time curve due to 
extrapolation from the last quantifiable concentration to infinity 
(Day 1 only) 
AUCτ  
h*ng/mL 
area under the concentration‑time curve over a dosing interval 
(τ) (Day 14 only)b,d 
Cmax 
ng/mL 
maximum plasma concentration 
Ctrough 
ng/mL 
trough plasma concentration; observed at the end of the dosing 
interval  
%Fluctuation 
% 
percentage fluctuation at steady state, equivalent to peak-to-
trough ratio (PTR) in the protocol  
Tmax 
h 
time to maximum plasma concentration 
tlast 
h 
time of the last quantifiable concentration 
t1/2  
h 
apparent terminal elimination half-life (Day 14 only) 
CL/F  
L/h 
apparent clearance of drug from plasma (Day 14 only) 
Vz/F  
L 
apparent volume of distribution during the terminal phase  
(Day 14 only) 
Rac, AUCτ  
NA 
accumulation ratio based on AUCτ (Day 14 only) 
Rac, Cmax  
NA 
accumulation ratio based on Cmax during the dosing interval 
(Day 14 only) 
LR 
NA 
linearity ratio (Day 14 only) 
Aet1-t2  
mg 
amount of the dose administered recovered in urine over a 
dosing interval (t1 to t2) at steady state (Day 14 only) 
Cum Ae t1-t2 
mg 
cumulative amount of the dose administered recovered in urine 
over a dosing interval (t1 to t2) at steady state (Day 14 only) 
fet1-t2  
% 
percentage of the dose administered recovered in urine over a 
dosing interval (t1 to t2) at steady state (Day 14 only) 
Cum fe t1-t2 
% 
cumulative percentage of the dose administered recovered in 
urine over a dosing interval (t1 to t2) at steady state (Day 14 
only) 
CLR  
L/h 
renal clearance of drug from plasma (Day 14 only) 
DAUCτ 
h*ng/mL/mg AUCτ normalized by dose administeredc  
DAUClast 
h*ng/mL/mg AUClast normalized by dose administeredc 
DCmax 
ng/mL/mg 
Cmax normalized by dose administeredc 
a Units are based on concentration units (provided by the bioanalytical lab or preferred units for presentation of PK parameters) 
and dose units used in the study. 
b Area under the concentration-time curve will be calculated using the linear trapezoidal rule for increasing concentrations and 
the logarithmic rule for decreasing concentrations (linear up/log down rule).  
c Calculated by dividing the parameter by the dose administered (mg). 
d The dosing interval τ throughout part B will be 24 hours . 
e Based on the last observed quantifiable concentration. 
* Concentration-time profile following multiple dosing on Profile Day 1 and Day 14. 
NA = not applicable 
Additional PK parameters may be determined where appropriate. 
Page 69 of 78
cvl-354-1001-statistical-method.pdf   Page 70 of 79


Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
 
Final, Version 1, 10Feb2023  
Page 17 of 25 
 
Pharmacokinetic analysis will be carried out where possible using actual dose administered (mg) 
and actual postdose blood sampling times. If an actual time is missing, the sample concentration 
result will be treated as missing unless there is scientific justification to include the result using 
the nominal time. 
The parameters Cmax, Ctrough, tlast, and Tmax will be obtained directly from the concentration-time 
profiles. If Cmax occurs at more than 1 timepoint, Tmax will be assigned to the first occurrence of 
Cmax. 
Predose (trough) plasma concentrations on dosing days 3, 5, 7, 9 and 11 will be listed. 
The accumulation ratio(s) (Rac, AUC and Rac, Cmax) will be calculated as follows: 
Rac, AUC = AUCτ Profile Day 14 / AUC24 Profile Day 1 
Rac, Cmax = Cmax Profile Day 14 / Cmax Profile Day 1 
The linearity ratio (LR) will be calculated as ratio of AUCτ following multiple dosing (Day 14) 
to AUCinf following a single dose (Day 1): 
LR = AUCτ Profile Day 14 / AUCinf Profile Day 1 
8.1.1 Criteria for the Calculation of Apparent Terminal Elimination Rate Constant and 
Half-life 
The start of the terminal elimination phase for each participant will be defined by visual 
inspection and generally will be the first point at which there is no systematic deviation from the 
log-linear decline in concentrations. 
The apparent terminal elimination rate constant (λz) will only be calculated when a reliable 
estimate can be obtained using at least 3 data points, preferably not including Cmax, and the 
adjusted coefficient for determination of exponential fit (R2-adj) of the regression line is ≥0.7. 
Parameters requiring λz for their calculation (eg, AUCinf, t1/2, CL/F (Profile Day 1 only), and 
Vz/F) will only be calculated if the R2-adj value of the regression line is ≥0.7. 
The following regression-related diagnostic PK parameters will be determined where possible: 
Parameter 
Units 
Definition 
λz 
1/h 
apparent terminal elimination rate constant 
λz Upper 
h 
end of exponential fit 
λz Lower 
h 
start of exponential fit 
λz N 
NA 
number of data points included in the log-linear regression 
λz Span Ratio 
NA 
time period over which λz was determined as a ratio of t1/2 
R2-adj 
NA 
adjusted coefficient for determination of exponential fit 
NA = not applicable 
Page 70 of 78
cvl-354-1001-statistical-method.pdf   Page 71 of 79


Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
 
Final, Version 1, 10Feb2023  
Page 18 of 25 
 
Where possible, the span of time used in the determination of λz (ie, the difference between λz 
Upper and λz Lower) should be ≥2 half-lives. If the λz Span Ratio is <2, the robustness of the t1/2 
values will be discussed in the clinical study report (CSR). 
8.1.2 Criteria for Calculation and Reporting of Area Under the Concentration-time 
Curve 
The minimum requirement for the calculation of AUC will be the inclusion of at least 
3 consecutive concentrations above the lower limit of quantification. If there are only 
3 consecutive concentrations, at least 1 should follow Cmax.  
If the extrapolated area is >20%, AUCinf (and derived parameters) may be excluded from the 
summary statistics and statistical analysis at the discretion of the sponsor or pharmacokineticist. 
For evaluation of food effect, if AUCinf cannot be determined reliably for all participants, an 
alternative AUC measure, such as AUC to a fixed timepoint, may be used in the statistical 
analysis of food effect. 
If the τ PK blood sample is collected slightly early (ie, the 24-hour), the actual sampling time of 
the τ sample may be used for the calculation of AUCτ. However, the AUCτ parameter will be 
calculated if the τ sample is within 60 minutes of the nominal sampling time. 
8.1.3 Calculation of Urinary Parameters  
The amount of the dose administered recovered (Ae) in urine as CVL-354 for each urine 
collection interval (t1-t2) will be calculated as the product of urine analyte concentration and 
urine volume. Where only urine sample weight is supplied, a specific gravity of 1 g/mL will be 
assumed, and it will be considered equivalent to urine volume.  
A total cumulative Ae0-x h will be calculated by summing the Aet1-t2 values over the 0-x h 
interval, where x = the end of the dosing interval. 
The percentage of the dose administered recovered over the time interval t1 to t2 (fet1-t2) as CVL-
354 will be calculated for each urine collection interval (equivalent to a dosing interval) as 
follows: 
fet1-t2 = (Aet1-t2 / dose) × 100% 
Cumulative fe0-x h will be calculated by summing the fet1-t2 values over the 0-x h period in the 
same manner as cumulative Ae0-x h. 
Renal clearance (CLR) will be calculated over 0-t2 according to the following formula, where 
cumulative Ae is calculable over the dosing interval (0-t2 equivalent to τ): 
CLR = Ae0-t2 / AUCτ  
Page 71 of 78
cvl-354-1001-statistical-method.pdf   Page 72 of 79


Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
 
Final, Version 1, 10Feb2023  
Page 19 of 25 
 
8.1.4 Criteria for Handling Concentrations Below the Limit of Quantification or Missing 
Concentrations for Pharmacokinetic Analysis 
Plasma concentrations below the limit of quantification (BLQ) will be assigned a value of 0 
before the first measurable concentration and thereafter BLQ concentrations will be treated as 
missing. The following rules apply to the specific situations defined below: 
● If an entire concentration-time profile is BLQ, it will be excluded from PK analysis. 
● Where 2 or more consecutive concentrations are BLQ at the end of a profile, the profile 
will be deemed to have terminated and any further quantifiable concentrations will be set 
to missing for the calculation of the PK parameters, unless they are considered to be a 
true characteristic of the profile of the drug. 
● If a predose plasma concentration is missing, it will be set to 0 by default within Phoenix 
WinNonlin for the first dosing day of all parts of the study (Study Profile Day 1). 
● For multiple dose part of the study (Study Profile Day 14), if the analyte concentration at 
τ (24 hours postdose) is missing, this may be substituted with the predose concentration. 
Similarly, if the predose concentration is missing then this may be substituted with the 
concentration at τ. 
Urine concentrations that are BLQ will be set to 0 for the calculation of Aet1-t2. 
8.1.5 Treatment of Outliers in Pharmacokinetic Analysis 
If a value is considered to be anomalous due to being inconsistent with the expected PK profile, 
it may be appropriate to exclude the value from the PK analysis. However, the exclusion of any 
data must have strong justification and will be documented in the CSR. 
Any quantifiable predose concentration value on the first dosing day of all parts of the study 
(Study Profile Day 1) will be considered anomalous and set to missing for the PK analysis. This 
will be set to 0 by default in Phoenix WinNonlin. 
For Cohort 3 of Part A, if the predose concentration is >5% of Cmax in the second treatment 
period, all PK concentration and parameter data will be excluded from the summary statistics 
and statistical analysis for that period. 
8.2 
Presentation of Pharmacokinetic Data 
If the actual time of sample collection deviates from the nominal time by more than ±10%, the 
plasma concentration will be flagged and excluded from the concentration summary statistics. 
Individual concentrations deemed to be anomalous will be flagged in the listings and excluded 
from the summary statistics. 
For plasma concentration data, the following rules will apply: 
● Values that are BLQ will be set to 0 for the calculation of summary statistics. 
Page 72 of 78
cvl-354-1001-statistical-method.pdf   Page 73 of 79


Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
 
Final, Version 1, 10Feb2023  
Page 20 of 25 
 
● Arithmetic mean or median values that are BLQ will be presented as 0. 
● Concentrations will be reported to the level of precision in which they were received from 
the analytical laboratory. 
For PK parameters, the following rule will apply: 
● Geometric mean and coefficient of variation will not be calculated for tlast or Tmax. 
8.2.1 Presentation of Urine Drug Concentration Data 
Urine drug concentrations will be listed only to the level of precision in which they were 
received from the analytical laboratory.  
8.2.2 Presentation of Pharmacokinetic Parameters 
For the calculation of summary statistics of PK parameters, all not calculated (NC) values in a 
data series will be set to missing. 
Individual PK parameters will be presented to three significant figures. For the calculation of 
summary statistics, data will be handled and presented as described in section 9.1. 
9 
STATISTICAL METHODOLOGY 
9.1 
General 
All PK concentrations and parameters will be listed. 
Summary tables by treatment will be provided for all concentrations and PK parameters. 
Summary statistics will only be presented for data where detailed in this PKAP. Summary 
statistics will include the arithmetic mean, standard deviation (SD), geometric mean, coefficient 
of variation (CV) of geometric mean, median, minimum (min), maximum (max), and number of 
observations (n) for concentrations and all PK parameters (except tlast or Tmax, where geometric 
mean and CV of geometric mean will not be calculated). Summary statistics will be calculated 
for concentration and PK parameter data for participants included in the PK analysis set and will 
be stratified by treatment.  
Summary tables, mean (±SD) figures, and overlaying individual figures will be provided for 
plasma PK concentrations. All figures will be produced on both linear and semi-logarithmic 
scales. 
For the calculation of summary statistics for plasma concentrations, data will be used as received 
from the bioanalytical laboratory. For calculation of summary statistics for PK parameters, 
unrounded data will be used. Statistics will be reported to three significant figures with the 
exception of N and n which will be presented to the nearest integer. Individual PK parameters 
will be presented to three significant figures. 
The full battery of summary statistics will only be calculated if there are at least three values in 
the data series. Zeros are considered to be values. If there are fewer than three values in the data 
Page 73 of 78
cvl-354-1001-statistical-method.pdf   Page 74 of 79


Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
 
Final, Version 1, 10Feb2023  
Page 21 of 25 
 
series, only min, max, and n will be presented. The other summary statistics will be denoted as 
NC. If the value of the arithmetic mean and/or median is BLQ, these will be presented as zero.  
All statistical summaries and figures for concentration and PK parameter data will be performed 
using SAS software Version 9.4 or higher.  
9.2 
Statistical Evaluation of Dose Proportionality and Food Effect  
A dose-normalized plot will be produced to investigate the dose proportionality of AUClast, 
AUC24, AUCinf and Cmax for Part A and Part B (Day 1 and Day 14). A statistical analysis will be 
conducted to investigate the food effect on the treatment by comparing Test treatment (fed) to 
Reference treatment (fasted). 
For Food effect:  
The ln-transformed2 AUCinf, AUClast, AUC24 and Cmax for CVL-354 will be analyzed using a 
linear mixed model.3 The model will include planned treatment sequence, period, and actual 
treatment (i.e., fast/fed status) as fixed effects, and participant within planned treatment sequence 
as a random effect.  
For each PK parameter separately, the least squares mean (LSM) for each treatment, difference 
in LSMs between the fed and fasted treatments, and corresponding 90% CI will be calculated; 
these values will then be back-transformed to give the GLSM, ratio of GLSMs, and 
corresponding 90%.  
Additionally, the pooled estimate (across treatments) of the within-subject CV will be calculated, 
and residual plots will be produced to assess the adequacy of the model(s) fitted.  
Examples of the SAS code that will be used are as follows: 
Mixed Model Analysis  
proc mixed data = <data in>; 
 by parcat1n parcat1 pkday paramn param; 
 class trtan aperiod trtseqp usubjid; 
 model lpk = trtan aperiod trtseqp / cl residual ddfm = kr2; 
 lsmeans trtan / cl pdiff = control('1') alpha = 0.1; 
 random intercept / subject = usubjid(trtseqp);  
 ods output lsmeans = <data out>;  
 ods output diffs = <data out>; 
 ods output covparms = <data out>; 
run; 
Page 74 of 78
cvl-354-1001-statistical-method.pdf   Page 75 of 79


Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
 
Final, Version 1, 10Feb2023  
Page 22 of 25 
 
10 PHARMACOKINETIC REPORT 
10.1 Interim PK Analyses  
An interim PK analysis is planned for Part A after each period (1-4) for cohorts 1 and 2 to assess 
drug exposures. Cohort 3 of Part A will be used to study food effect. Part B will evaluate oral 
doses of either CVL-354 or placebo for up to 14 days that will be administered QD throughout 
Part B of the trial based on data obtained during Part A. The interim analysis consists of only 
group summary using descriptive statistics. Individual level data will be kept strictly confidential 
and will not be accessible to any study personnel except Bioanalytical laboratory personnel, 
Labcorp PK analysts, and Cerevel Clinical Pharmacology personnel pre-specified in the Cerevel 
Study Blind Protection Plan. It is critical to maintain the integrity of blind for the study. 
Additional interim PK analyses may be performed based on the results of the interim analyses. 
Interim PK reports will be completed after each interim analysis in support of dose escalation.  
10.2 Final Report 
The PK report for the analysis of CVL-354 in plasma and urine will contain a summary of the 
methodology, results, and conclusions. Prior to issuing a final report, Labcorp Clinical 
Pharmacology Services will provide the draft report to the Sponsor for review and comment. The 
report will include, but will not necessarily be limited to the following: 
x Any changes from the planned analyses indicated in the PKAP 
x The dates on which the study protocol are approved and the final report is issued 
The report will be finalized after incorporation of Sponsor comments, as applicable. Unless 
otherwise specified, one electronic copy of the report will be sent to the Sponsor. The report will 
be finalized after approval from Sponsor or 6 months after issuing of draft report. 
11 REGULATORY REQUIREMENTS 
This pharmacokinetic analysis and report will be conducted in accordance with the protocol, this 
PKAP, Labcorp Standard Operating Procedures (SOPs), and other applicable regulatory 
requirements.  
 
 
Page 75 of 78
cvl-354-1001-statistical-method.pdf   Page 76 of 79


Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
Final, Version 1, 10Feb2023 
Page 23 of 25 
12 REFERENCES 
1. 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, Study Protocol version 3.0 (25 May 2022), Cerevel 
Therapeutics, LLC, Sponsor Reference No. CVL-354-1001
2. Keene ON. The log transformation is special. Stat Med. 1995;14(8):811819.
3. Brown H, Prescott R. Applied Mixed Models in Medicine. Chichester: John Wiley & 
Sons, 1999.
Page 76 of 78
cvl-354-1001-statistical-method.pdf   Page 77 of 79


Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
 
Final, Version 1, 10Feb2023  
Page 24 of 25 
 
13 TABLES, FIGURES, AND LISTINGS 
Shells are provided in a separate document to present examples of data presentation.  
List of Tables, Figures, and Listings 
Table 14.2.1.1a Summary of Pharmacokinetic Concentrations (Pharmacokinetic Analysis Set) 
Part A 
Table 14.2.1.1b Summary of Pharmacokinetic Concentrations (Pharmacokinetic Analysis Set) 
Part B 
Table 14.2.1.2a Summary of Pharmacokinetic Parameters (Pharmacokinetic Analysis Set) Part A 
Table 14.2.1.2b Summary of Pharmacokinetic Parameters (Pharmacokinetic Analysis Set) Part B 
Table 14.2.1.3 Summary of Pharmacokinetic Excretion Parameters by Time Interval 
(Pharmacokinetic Analysis Set) Part B 
Table 14.2.1.4 Summary of Pharmacokinetic Cumulative Excretion Parameters by Time Interval 
(Pharmacokinetic Analysis Set) Part B 
Table 14.2.1.5 Statistical Analysis of Pharmacokinetic Parameters (Food Effect Assessment) 
(Pharmacokinetic Analysis Set) 
 
Figure 14.2.1.1a Arithmetic Mean (±SD) Pharmacokinetic Concentration-time Profiles  
(Pharmacokinetic Analysis Set) Part A 
Figure 14.2.1.1b Arithmetic Mean (±SD) Pharmacokinetic Concentration-time Profiles  
(Pharmacokinetic Analysis Set) Part B 
Figure 14.2.1.2a Overlaying Individual Pharmacokinetic Concentration-time Profiles 
(Pharmacokinetic Analysis Set) Part A 
Figure 14.2.1.2b Overlaying Individual Pharmacokinetic Concentration-time Profiles 
(Pharmacokinetic Analysis Set) Part B 
Figure 14.2.1.3 Overlaying Individual Pharmacokinetic Concentration-time Profiles Across All 
Days (Pharmacokinetic Analysis Set) Part B 
Figure 14.2.1.4a Boxplots of Dose-Normalized Pharmacokinetic Parameters (Pharmacokinetic 
Analysis Set) Part A 
Figure 14.2.1.4b Boxplots of Dose-Normalized Pharmacokinetic Parameters (Pharmacokinetic 
Analysis Set) Part B (Day 1 and Day 14) 
 
Listing 16.2.6.1.1 Pharmacokinetic Blood Collections (Safety Analysis Set) 
Listing 16.2.6.1.2 Pharmacokinetic Urine Collections (Safety Analysis Set)  
Listing 16.2.6.1.3 Pharmacokinetic Concentrations (Safety Analysis Set) 
Listing 16.2.6.1.4 Pharmacokinetic Parameters (Safety Analysis Set) 
Listing 16.2.6.1.5 Regression Analysis Data for the Apparent Terminal Elimination Phase  
(Safety Analysis Set) 
Listing 16.2.6.1.6 Pharmacokinetic Excretion Parameters by Time Interval  
(Safety Analysis Set) 
Listing 16.2.6.1.7 Pharmacokinetic Cumulative Excretion Parameters by Time Interval  
(Safety Analysis Set) 
 
Figure 16.2.6.1a Individual Pharmacokinetic Concentration-time Profiles (Safety Analysis Set) 
Part A 
Page 77 of 78
cvl-354-1001-statistical-method.pdf   Page 78 of 79


Pharmacokinetic Analysis Plan 
CONFIDENTIAL 
Labcorp Study No. 8473318 
Sponsor Reference No. CVL-354-1001 
 
Final, Version 1, 10Feb2023  
Page 25 of 25 
 
Figure 16.2.6.1b Individual Pharmacokinetic Concentration-time Profiles (Safety Analysis Set) 
Part B 
 
Page 78 of 78
cvl-354-1001-statistical-method.pdf   Page 79 of 79