A Randomized, Double-Blind, Placebo-Controlled Trial To Evaluate the Safety, Tolerability, and Pharmacodynamics of CVL-871 in Subjects With Dementia-Related Apathy
Phase: PHASE2
Conditions: Apathy in Dementia
Sponsor: AbbVie

Protocol CVL-871-2001
CVL-871
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CLINICAL PROTOCOL 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
TRIAL TO EVALUATE THE SAFETY, TOLERABILITY, AND 
PHARMACODYNAMICS OF CVL-871 IN SUBJECTS WITH 
DEMENTIA-RELATED APATHY 
Protocol: CVL-871-2001 
Compound Number: CVL-871 
Trial Phase: 2a 
Short Title: A Trial of the Safety, Tolerability, and Pharmacodynamics of CVL-871 
in Subjects With Dementia-Related Apathy 
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: 
150,086 
CONFIDENTIAL – PROPRIETARY INFORMATION 
Version 4.0: 14 Feb 2023 
Version 3.0: 08 Apr 2022 
Version 2.0: 19 Feb 2021 
Version 1.0: 17 Nov 2020 
MEDICAL MONITOR NAME AND CONTACT INFORMATION IS PROVIDED IN 
THE TRIAL OPERATIONS MANUAL 
NCT04958031

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PROTOCOL VERSION 4.0 SUMMARY OF CHANGES TABLE 
Document History 
Document: 
Date (Day-Month-Year) 
Version 4.0 
14 Feb 2023 
Version 3.0 
08 Apr 2022 
Version 2.0 
19 Feb 2021 
Original Protocol Version 1.0 
17 Nov 2020 
A summary of the protocol amendment issued prior to the present amendment is provided 
in Section 10.8. 
Amendment: Protocol Version 4.0 (14 Feb 2023) 
Overall Rationale for the Amendment: 
The overall rationale for the amendment is to modify the number of assessments 
performed to reduce the burden in an elderly patient population.  
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis 
Schedule of Assessments 
3 Objectives and Endpoints 
4.2 Scientific Rationale for 
Trial Design 
8.7 Pharmacodynamic 
Assessments 
Minimize cognitive assessment by 
removal of Digit Span (WAIS-IV), 
Trail Making Test (Part A), and 
COWAT 
Reduce burden for elderly 
patient population 
Synopsis 
Schedule of Assessments 
3 Objectives and Endpoints 
4.2 Scientific Rationale for 
Trial Design 
8.7 Pharmacodynamic 
Assessments 
Minimize assessments by removal 
of DAD 
Reduce burden for elderly 
patient population 
Synopsis 
Schedule of Assessments 
3 Objectives and Endpoints 
4.2 Scientific Rationale for 
Trial Design 
8.7 Pharmacodynamic 
Assessments 
9.4.1 General Considerations 
Remove assessment of caregiver 
burden (assessed using Zarit Burden 
Interview) 
Reduce burden for elderly 
patient population 

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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis 
Trial Schematic 
4.1.1 Screening/Baseline 
Period 
9.2 Sample Size 
Determination 
Added flexibility for total number 
of subjects required for trial 
This is an exploratory trial. 
With the target trial population 
of patients with dementia-
related apathy, a sample size 
between 60 and 75 should 
provide sufficient data to assess 
effect of CVL-871 without 
undue delay 
Synopsis 
9.2 Sample Size 
Determination 
In sentence referring to extending 
enrollment due to higher anticipated 
early terminations, removed 
language “due to COVID-19 or 
other reasons”  
Modification due to impacts 
from COVID pandemic no 
longer necessary 
Trial Schematic 
Schedule of Assessments 
4.1.2 Treatment Period 
6.2 Preparation/Handling/ 
Storage/Accountability/ 
Disposition 
Modified such that Visits 3, 4, and 7 
will only be conducted on site 
Option for remote visits to 
accommodate potential issues 
due to COVID-19 pandemic no 
longer necessary  
Schedule of Assessments 
4.1.1 Screening/Baseline 
Period 
Added information that extension of 
screening period beyond 30 days is 
permitted in rare cases with medical 
monitor approval 
Additional flexibility needed 
due to length of 
screening/baseline visit and 
need for caregiver to also be 
present at visits 
Schedule of Assessments 
4.1.2 Treatment Period 
Removed psychosocial intervention 
Reduce burden in elderly 
patient population 
Schedule of Assessments 
4.1.2 Treatment Period 
Removed 4-hour post-dose 
observation period at Visit 3 and 
Visit 4 
Reduce burden for elderly 
patient population. Visits 3 and 
4 will be conducted in clinic; 
subjects will be monitored 
following dosing while 
concurrently undergoing 
scheduled assessments 
Schedule of Assessments 
Added clarification that prolactin 
results will be “partially” blinded 
Procedural clarification 
5.1 Inclusion Criteria 
Modified such that total body 
weight has to be greater than or 
equal to 50 kg (110 lbs) 
Mathematical inconsistency as 
50 kg is 110.2 lbs 
5.2 Exclusion Criteria 
Removed sentence regarding 
exclusion of subjects with 
symptoms of agitation of aggression 
that are being controlled using 
SSRIs/SNRIs from Exclusion #1 
Maintain consistency with 
changes made to 
prior/concomitant medications 
permitted 

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Section # and Name 
Description of Change 
Brief Rationale 
5.2 Exclusion Criteria 
Added to Exclusion #1 that anxiety 
or depressive symptoms secondary 
to dementia or other medical 
condition are not exclusionary 
provided they are not the primary 
diagnosis and are stable 
Updated to be more reflective 
of proposed target patient 
population 
5.2 Exclusion Criteria 
Modified exclusionary scores on 
NPI for other NPI subdomains of 
disinhibition, agitation/aggression, 
delusions, and hallucinations in 
Exclusion #4 
Update to be more reflective of 
proposed target patient 
population 
5.4 Screen Failures 
Modified to allow for more than 1 
rescreening to be conducted with 
medical monitor approval 
Increase flexibility needed for 
elderly patient population 
6.5.2 Prohibited Medications 
Reduced period required for stable 
doses of cholinesterase inhibitors, 
memantine, and SSRI/SNRIs to 60 
days 
Update to be more reflective of 
medication use in proposed 
target patient population 
6.5.2 Prohibited Medications 
Removed requirements for dosage 
and indication (agitation/aggression) 
for SSRI/SNRI use 
Update to be more reflective of 
medication use in proposed 
target patient population 
6.5.2 Prohibited Medications 
Added that pregabalin and 
gabapentin are prohibited unless 
being used to treat pain, dose has 
been stable for at least 60 days prior 
to randomization, and dosage does 
not exceed recommended limits per 
US Package Insert 
Update to be more reflective of 
medication use in proposed 
target patient population 
6.5.2 Prohibited Medications 
Added armodafinil to list of 
prohibited prior and concomitant 
medications 
Update to be more reflective of 
medication use in proposed 
target patient population 
6.5.2 Prohibited Medications 
Added in dose limits for age/sex for 
nonbenzodiazepine sleep agents 
Update to be more reflective of 
medication use in proposed 
target patient population 
6.5.2 Prohibited Medications 
Moved footnote regarding 
additional information on use of 
nonbenzodiazepine sleep aids into 
body of table. 
Increase prominence of 
important information so not 
inadvertently overlooked 
6.5.2 Prohibited Medications 
Revised wording regarding 
prohibited nutritional supplements 
and herbal preparations to indicate 
these are restricted due to potential 
CYP3A4 drug-drug interactions 
rather than central nervous system 
effect; remove omega 3 fatty acids 
Based on literature that these 
supplements do not have 
known central nervous system 
effect and removal of omega 3 
fatty acids as it does not 
interact with CYP3A4 

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Section # and Name 
Description of Change 
Brief Rationale 
8.5 Treatment of Overdose 
Modified language to clarify when a 
potential overdose should be 
considered 
Removed redundant language 
and clarified potential overdose 
Section 10.6 Appendix 6: 
Moderate to Strong Inducers 
and Inhibitors of Cytochrome 
P450 3A (not exhaustive) 
Updated table 
Reflect current medication use 
and updates made per Cerevel 
standards 
Overall 
Minor grammatical and wording 
corrections/clarifications made 
throughout protocol 
Correct errors in original 
protocol 
Abbreviations: COVID-19 = coronavirus disease-2019; COWAT = Controlled Oral Word Association 
Test; DAD = Disability Assessment for Dementia; NPI = Neuropsychiatric Inventory; SNRI = serotonin-
norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; WAIS-IV = Wechsler 
Adult Intelligence Scale-IV. 
  
 

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TABLE OF CONTENTS 
 
CLINICAL PROTOCOL ..................................................................................................1 
PROTOCOL VERSION 4.0 SUMMARY OF CHANGES TABLE .............................3 
TABLE OF CONTENTS ..................................................................................................7 
TABLE OF TABLES .......................................................................................................10 
TABLE OF FIGURES .....................................................................................................10 
1 
PROTOCOL SUMMARY .......................................................................................11 
1.1 
Synopsis .................................................................................................................11 
1.2 
Schema ..................................................................................................................15 
1.3 
Schedule of Assessments ......................................................................................15 
2 
INTRODUCTION ....................................................................................................21 
2.1 
Trial Rationale .....................................................................................................21 
2.2 
Background ..........................................................................................................21 
2.2.1 
Disease Background .......................................................................................21 
2.2.2 
Dopaminergic Signaling in Apathy ..............................................................22 
2.2.3 
Pharmacological Treatment of Apathy ........................................................24 
2.2.4 
CVL-871 ..........................................................................................................25 
2.3 
Benefit/Risk Assessment ......................................................................................26 
3 
OBJECTIVES AND ENDPOINTS .........................................................................27 
4 
TRIAL DESIGN .......................................................................................................28 
4.1 
Overall Design ......................................................................................................28 
4.1.1 
Screening/Baseline Period .............................................................................28 
4.1.2 
Treatment Period ...........................................................................................28 
4.1.3 
Safety Follow-up Period ................................................................................30 
4.1.4 
Definition of Completed Subject...................................................................30 
4.2 
Scientific Rationale for Trial Design ..................................................................31 
4.3 
Dosing Rationale ..................................................................................................31 
4.4 
End of Trial Definition ........................................................................................32 
5 
TRIAL POPULATION ............................................................................................32 
5.1 
Inclusion Criteria .................................................................................................32 
5.2 
Exclusion Criteria ................................................................................................34 
5.3 
Lifestyle Considerations ......................................................................................38 
5.4 
Screen Failures .....................................................................................................38 
6 
TRIAL TREATMENTS ...........................................................................................38 
6.1 
Trial Treatments Administered ..........................................................................39 
6.2 
Preparation/Handling/Storage/Accountability/Disposition .............................39 
6.3 
Measures to Minimize Bias: Randomization and Blinding..............................40 
6.3.1 
Subject Assignment to Treatment ................................................................40 
6.3.2 
Blinding ...........................................................................................................40 
6.4 
Trial Treatment Compliance ..............................................................................41 
6.5 
Prior and Concomitant Therapy ........................................................................41 
6.5.1 
Prior and Concomitant Medications ............................................................41 
6.5.2 
Prohibited Medications .................................................................................41 
6.6 
Dose Modification ................................................................................................45 

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6.7 
Intervention after the End of the Trial ..............................................................45 
7 
DISCONTINUATION OF TRIAL TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ...............................................................45 
7.1 
Discontinuation of Trial Treatment ...................................................................45 
7.2 
Discontinuation of Trial ......................................................................................46 
7.2.1 
Discontinuation of Entire Trial.....................................................................46 
7.2.2 
Discontinuation of Individual Site ................................................................46 
7.2.3 
Individual Subject Discontinuation From the Trial ...................................46 
7.3 
Procedures to Encourage Continued Trial Participation ................................47 
7.4 
Lost to Follow up ..................................................................................................47 
8 
TRIAL ASSESSMENTS AND PROCEDURES ....................................................48 
8.1 
Screening and Baseline Assessments ..................................................................48 
8.1.1 
Diagnostic Criteria for Apathy .....................................................................49 
8.1.2 
Mini Mental State Examination ...................................................................49 
8.1.3 
Neuropsychiatric Inventory Rating Scale ....................................................49 
8.2 
Efficacy Assessments ...........................................................................................49 
8.3 
Safety Assessments ...............................................................................................49 
8.3.1 
Physical Examinations ...................................................................................50 
8.3.2 
Vital Sign Measurements ..............................................................................50 
8.3.3 
Electrocardiograms........................................................................................51 
8.3.4 
Clinical Safety Laboratory Assessments ......................................................51 
8.3.5 
Suicidal Ideation and Behavior Risk Monitoring .......................................52 
8.4 
Adverse Events and Serious Adverse Events ....................................................52 
8.4.1 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................53 
8.4.2 
Method of Detecting AEs and SAEs .............................................................53 
8.4.3 
Follow-up of AEs and SAEs ..........................................................................53 
8.4.4 
Regulatory Reporting Requirements for SAEs/AESIs ...............................54 
8.4.5 
Pregnancy .......................................................................................................54 
8.4.6 
Adverse Events of Special Interest ...............................................................54 
8.5 
Treatment of Overdose ........................................................................................56 
8.6 
Pharmacokinetics .................................................................................................57 
8.7 
Pharmacodynamic Assessments .........................................................................57 
8.7.1 
Neuropsychiatric Inventory-Clinician and Neuropsychiatric 
Inventory Rating Scales .................................................................................57 
8.7.2 
Dementia Apathy Interview and Rating ......................................................58 
8.7.3 
Apathy Evaluation Scale-Clinician ..............................................................58 
8.7.4 
Alzheimer’s Disease Assessment Scale – Cognition Subscale ....................58 
8.7.5 
Modified Alzheimer’s Disease Cooperative Study–Clinical Global 
Impression of Change ....................................................................................58 
8.7.6 
Modified Clinical Global Impression-Severity Scale ..................................59 
8.7.7 
Caregiver Global Impression-Severity Scale...............................................59 
8.7.8 
Caregiver Global Impression-Change Scale ...............................................59 
8.8 
Pharmacogenomics ..............................................................................................60 
8.9 
Biomarkers ...........................................................................................................60 
8.10 
Future Biospecimen Research ............................................................................60 

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8.11 
Health Economics.................................................................................................60 
9 
STATISTICAL CONSIDERATIONS ....................................................................60 
9.1 
Statistical Hypotheses ..........................................................................................60 
9.2 
Sample Size Determination .................................................................................61 
9.3 
Populations for Analyses .....................................................................................61 
9.4 
Statistical Analyses...............................................................................................61 
9.4.1 
General Considerations .................................................................................61 
9.4.2 
Pharmacodynamic Analyses .........................................................................62 
9.4.3 
Pharmacokinetic Analyses ............................................................................62 
9.4.4 
Safety Analyses ...............................................................................................62 
9.4.5 
Interim Analyses ............................................................................................63 
9.4.6 
Safety Review Team .......................................................................................63 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ................................................................................................63 
10.1 
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations .........63 
10.1.1 
Regulatory and Ethical Considerations .......................................................63 
10.1.2 
Financial Disclosure .......................................................................................64 
10.1.3 
Informed Consent Process ............................................................................64 
10.1.4 
Data Protection...............................................................................................65 
10.1.5 
Dissemination of Clinical Trial Data ............................................................65 
10.1.6 
Data Quality Assurance .................................................................................65 
10.1.7 
Source Documents ..........................................................................................66 
10.1.8 
Trial and Site Closure ....................................................................................67 
10.1.9 
Publication Policy...........................................................................................67 
10.2 
Appendix 2: Clinical Laboratory Tests..............................................................67 
10.3 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ...........................................69 
10.3.1 
Definition of AE..............................................................................................69 
10.3.2 
Definition of SAE ...........................................................................................70 
10.3.3 
Recording and Follow-Up of AE and/or SAE .............................................71 
10.3.4 
Reporting of SAEs and AESIs ......................................................................73 
10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information ...........................................................................................................74 
10.4.1 
Definitions .......................................................................................................74 
10.4.2 
Collection of Pregnancy Information ...........................................................75 
10.5 
Appendix 5: Future Biospecimen Research ......................................................76 
10.6 
Appendix 6: Moderate to Strong Inducers and Inhibitors of 
Cytochrome P450 3A (not exhaustive) ...............................................................77 
10.7 
Appendix 7: Abbreviations .................................................................................78 
10.8 
Appendix 8: Protocol Amendment History .......................................................80 
11 REFERENCES .........................................................................................................86 
CLINICAL PROTOCOL PRINCIPAL INVESTIGATOR 
SIGNATURE PAGE ................................................................................................94 
 

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TABLE OF TABLES 
Table 1 
Schedule of Assessments ..........................................................................16 
Table 2 
Objectives and Endpoints........................................................................27 
Table 3 
CVL-871 and Placebo Dosing Schedule .................................................29 
Table 4 
Investigational Medicinal Product Administered .................................39 
Table 5 
Prohibited Prior Medications .................................................................42 
Table 6 
Prohibited Concomitant Medications ....................................................44 
Table 7 
Populations for Analysis ..........................................................................61 
Table 8 
Protocol-Required Safety Laboratory Assessments .............................68 
Table 9 
Definition of AE........................................................................................69 
Table 10 
Events Meeting the AE Definition ..........................................................69 
Table 11 
Definition of SAE .....................................................................................70 
Table 12 
Recording and Follow-Up of AE and/or SAE .......................................71 
Table 13 
Follow-Up of AEs and SAEs ...................................................................73 
Table 14 
SAE Reporting to the Sponsor of Designee via an Electronic Data 
Collection Tool .........................................................................................73 
Table 15 
SAE Reporting to the Sponsor or Designee via Paper Form (if needed)
....................................................................................................................74 
 
TABLE OF FIGURES 
Figure 1 
Trial Schematic ........................................................................................15 
Figure 2 
Dosing Schematic .....................................................................................30 
 

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1 PROTOCOL SUMMARY 
1.1 
Synopsis 
Sponsor Name: Cerevel Therapeutics, LLC 
Name of Investigational Medicinal Product: CVL-871 
Protocol Title: A Randomized, Double-blind, Placebo-controlled Trial to Evaluate the 
Safety, Tolerability, and Pharmacodynamics of CVL-871 in Subjects With 
Dementia-Related Apathy  
Short Title: A Trial of the Safety, Tolerability, and Pharmacodynamics of CVL-871 in 
Subjects With Dementia-Related Apathy  
IND Number: 150,086 
Trial Phase: 2a 
Treatment/Indication: Treatment of dementia-related apathy 
Rationale: CVL-871 is a dopamine D1/D5 receptor partial agonist that is being evaluated 
for the treatment of dementia-related apathy. The aim of this trial is to evaluate the safety, 
tolerability, and pharmacodynamics of CVL-871 in subjects with dementia-related 
apathy. 

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Objectives and Endpoints 
Objective 
Endpoint 
Primary 
 
• 
To assess the safety and tolerability of 2 
fixed doses of CVL-871 in subjects with 
dementia-related apathy 
• 
Incidence and severity of TEAEs 
• 
Clinically significant changes in ECG results, 
clinical laboratory evaluations, vital sign 
measurements, and physical and neurological 
examination results 
• 
Clinically significant findings in suicidality 
assessed using the C-SSRS 
Secondary 
 
• 
To assess the pharmacodynamic effects of 
2 fixed doses of CVL-871 on apathy in 
subjects with dementia-related apathy 
• 
Change from baseline to Visit 5 (Week 6) and 
Visit 6 (Week 12) in the following: 
○ 
NPI-C apathy domain score 
○ 
NPI apathy domain score 
○ 
DAIR score 
○ 
AES-C score 
Exploratory 
 
• 
To evaluate the plasma concentrations of 
CVL-871 in subjects with dementia-related 
apathy 
• 
Plasma concentrations of CVL-871 at Visits 2 
(Week 1), 4 (Week 3), 5 (Week 6), and 6 (Week 
12) 
• 
To evaluate the effect of CVL-871 
neuropsychiatric symptoms other than 
apathy 
• 
NPI-C dysphoria domain score 
• 
NPI domain scores (other than apathy) 
• 
To assess the effects of 2 fixed doses of 
CVL-871 on cognition in subjects with 
dementia-related apathy 
• 
Change from baseline to Visit 6 (Week 12) in the 
ADAS-Cog13 score 
• 
To assess the effects of 2 fixed doses of 
CVL-871 on functional assessments (eg, 
activities of basic living, and cognitive, 
functional, and behavioral performance) in 
subjects with dementia-related apathy 
• 
Change from baseline to Visit 5 (Week 6) and 
Visit 6 (Week 12) in the following: 
○ 
mADCS-CGIC scores 
○ 
mCGI-S scores 
○ 
CaGI-S scores 
○ 
CaGI-C scores 
• 
Investigate the impact of COMT (Val-
Met) status on safety and 
pharmacodynamics 
• 
Evaluation of safety and pharmacodynamic 
endpoints in subgroups of subjects based on their 
COMT (Val-Met) status  
Abbreviations: ADAS-Cog13 = Alzheimer’s Disease Assessment Scale – Cognition 13-item scale; AES-C 
= Apathy Evaluation Scale-Clinician; COMT = catechol-O-methyltransferase; C-SSRS = Columbia-
Suicide Severity Rating Scale; DAIR = Dementia Apathy Interview and Rating; ECG = electrocardiogram; 
mADCS-CGIC = modified Alzheimer’s Disease Cooperative Study–Clinical Global Impression of Change; 
CaGI-C = Caregiver Global Impression–Change Scale; CaGI-S = Caregiver Global Impression–Severity 
Scale; mCGI-S = modified Clinical Global Impression–Severity Scale; NPI = Neuropsychiatric Inventory; 
NPI-C = Neuropsychiatric Inventory-Clinician; TEAE = treatment-emergent adverse event. 
Overall Design: 
This is a Phase 2a, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, 12-week trial to evaluate the safety, tolerability, and pharmacodynamics 
of 2 fixed doses of CVL-871 (1.0 mg daily [QD] and 3.0 mg QD) in male and female 
subjects aged 50 to 85 years who have dementia-related apathy.  

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The trial will include a 30-day Screening Period, a 12-week Treatment Period, and a 
4-week Safety Follow-up Period. Each subject will participate in the trial for up to 
approximately 20 weeks.  
Disclosure Statement: This is a parallel-group treatment trial with 3 arms that are 
blinded to the subjects and the investigator. 
Number of Subjects:  
Approximately 150 subjects will be screened to achieve the target of approximately 
75 subjects randomly assigned to treatment (25 per group).  
The trial may be considered as complete and be closed out following the randomization 
of 60 subjects in the event of significantly slower recruitment rate than anticipated to 
avoid unduly long delay of the final analysis.  
Key Entry Criteria:  
• Male subjects and female subjects of nonchildbearing potential, ages 50 to 85 years, 
inclusive 
• Meet the International Society for Central Nervous System Clinical Trials and 
Methodology Apathy Working Group diagnostic criteria for apathy in neurocognitive 
disorders and have clinically significant apathy defined as Neuropsychiatric Inventory 
(NPI) apathy domain frequency score of ≥2 and NPI apathy domain severity score of 
≥2 
• Clinical diagnosis of 1 or more of the following: 
a) Possible or probable Alzheimer’s disease dementia according to the 2011 
National Institute of Aging – Alzheimer’s Association score clinical criteria at the 
Screening Visit; diagnosis must be stable for at least 6 months  
b) Frontotemporal dementia (FTD; behavioral variant FTD, semantic variant 
primary progressive aphasia, or nonfluent/agrammatic variant primary progressive 
aphasia)  
c) Vascular dementia (ie, not vascular cognitive impairment) due to either of the 
following: 
a. Large vessel or atherothromboembolic disease 
b. Small vessel disease according to the diagnostic criteria for vascular 
cognitive disorders  
d) Possible or probable dementia with Lewy bodies according to the revised criteria 
for the clinical diagnosis of probable and possible dementia with Lewy bodies  
Intervention Groups, Trial Treatment, and Duration: 
Subjects will be randomized in a 1:1:1 ratio to receive CVL-871 1.0 mg QD, CVL-871 
3.0 mg QD, or placebo QD. The dose of CVL-871 will be titrated to the target dose using 

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a fixed titration scheme. Randomization will be stratified by use of allowed 
serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor at the 
time of randomization (as applicable). The planned duration of treatment is 12 weeks. 
The investigational medicinal products (IMPs) will be taken orally. 
Statistical Methods:  
Sample Size Estimation: While formal hypothesis testing is not the key objective of this 
trial, a target sample size of approximately 75 subjects randomized in a 1:1:1 manner 
between the placebo and 2 CVL-871 arms should allow the trial to have approximately 
80% probability to detect an effect size (treatment difference/population standard 
deviation [SD]) of 0.678 in change from Baseline on the NPI apathy domain score at 
Week 12 between an active dose group and placebo, at a 2-sided alpha = 0.2 level (ie, an 
80% confidence interval excluding zero). A minimum sample size of 60 subjects 
randomized 1:1:1 to the 3 treatment groups would allow this exploratory trial to detect an 
effect size of 0.761 with 80% power at a 2-sided alpha level of 0.2, and thus would be 
considered adequate. A discontinuation rate of 20% was taken into consideration in the 
sample size calculations. As a reference, in the ADMET 1 trial (6 weeks of treatment 
with methylphenidate for apathy in Alzheimer’s disease), an effect size 0.5625 (mean 
difference of 1.8 and SD of 3.2) on the change from baseline in the NPI apathy domain 
score was observed. 
Statistical Methods: Descriptive statistical methods will be used to summarize the data 
from this trial. Pharmacodynamic endpoints with repeated post-baseline assessments will 
be analyzed for the modified intent-to-treat (mITT) population using a mixed-model 
repeated measures (MMRM) analysis, including baseline score (if applicable), treatment, 
concomitant selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake 
inhibitor use, visit, and the interaction between treatment group and visit as fixed factors 
in the model. Subject will be included as a random effect in the model.  
The trial is designed as a learning trial instead of a confirmatory trial. The key research 
question for the pharmacodynamic endpoints will be primarily addressed with an 
estimand based on the following attributes: 1) treatments as randomized regardless of the 
final dose level achieved following the titration steps, 2) subjects in the mITT population 
who reach dose increases to at least Step 4 on Day 21 during titration as the target trial 
population, 3) change from Baseline to Week 12 as the key time point for assessing 
change from baseline in measured endpoints of interest, 4) the treatment differences 
estimated based on the least square mean and the corresponding 80% confidence interval 
from the MMRM model as the population level summary, and 5) a hypothetical strategy 
to address intercurrent events (ICEs) of potential death, treatment discontinuations, 
missed visits, and start of prohibited concomitant medications, unless a treatment-related 
reason can be identified for a given ICE. As the trial is of exploratory nature, a 
hypothetical strategy will be used to address the ICEs unless a treatment-related reason 
can be identified for an ICE. If such reasons are identified, a composite strategy may be 
taken, eg, assigning highest severity to the case, to ensure appropriate interpretation of 
the data. Further details, including additional estimands for the research questions on the 

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effect of combined CVL-871 treatment group versus placebo and on the effect of final 
dose levels of CVL-871 following the completion of titration versus placebo, will be 
described in the statistical analysis plan. 
Safety Review Team: 
A Safety Review Team will review the blinded safety data from this trial. 
1.2 
Schema 
Figure 1 
Trial Schematic 
 
Abbreviations: AD = Alzheimer’s disease; DLB = dementia with Lewy bodies; ET = Early Termination; 
FTD = frontotemporal dementia; QD = once daily; VAD = vascular dementia.  
1.3 
Schedule of Assessments 
 

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Table 1 
Schedule of Assessments 
Trial Period 
Screening 
Perioda,b 
Treatment Period (12 weeks) 
Post-treatment 
Follow-up 
(4 weeks) 
Visit/Contactc 
Visit 1 
Visit 2/ 
Baseline 
Visit 3d 
Contact 
Visit 4e 
Contact 
Visit 5 
Contact 
Contact 
Visit 6/ 
ETf 
Visit 7 
Con-
tact 
Trial Day 
-31 to -1 
1 
8 
14g/18 
22 
29 
43 
57 
71 
85 
99 
113 
Trial Week 
 
 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16 
Window 
 
 
±3 days 
±5 days 
Entrance and History 
Informed consenth 
X 
 
 
 
 
 
 
 
 
 
 
 
Assign subject number 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical and psychiatric history  
X 
 
 
 
 
 
 
 
 
 
 
 
Demography  
X 
 
 
 
 
 
 
 
 
 
 
 
History of drug and alcohol use 
X 
 
 
 
 
 
 
 
 
 
 
 
DCA (electronic form)i 
X 
 
 
 
 
 
 
 
 
 
 
 
MMSE (electronic form)i 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic and Other Endpoint Assessments 
Electronic Formsi 
NPI 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
NPI-C (apathy only) 
 
X 
 
 
 
 
X 
 
 
X 
 
 
NPI-C (dysphoria) 
 
X 
 
 
 
 
X 
 
 
X 
 
 
DAIR 
 
X 
 
 
 
 
X 
 
 
X 
 
 

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Trial Period 
Screening 
Perioda,b 
Treatment Period (12 weeks) 
Post-treatment 
Follow-up 
(4 weeks) 
Visit/Contactc 
Visit 1 
Visit 2/ 
Baseline 
Visit 3d 
Contact 
Visit 4e 
Contact 
Visit 5 
Contact 
Contact 
Visit 6/ 
ETf 
Visit 7 
Con-
tact 
Trial Day 
-31 to -1 
1 
8 
14g/18 
22 
29 
43 
57 
71 
85 
99 
113 
Trial Week 
 
 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16 
Window 
 
 
±3 days 
±5 days 
AES-C 
 
X 
 
 
 
 
X 
 
 
X 
 
 
ADAS-Cog13 
 
X 
 
 
 
 
 
 
 
X 
 
 
mADCS-CGIC worksheet 
 
X 
 
 
 
 
 
 
 
 
 
 
mADCS-CGICj 
 
 
 
 
 
 
X 
 
 
X 
 
 
mCGI-S 
 
X 
 
 
 
 
X 
 
 
X 
 
 
CaGI-S 
 
X 
 
 
 
 
X 
 
 
X 
 
 
CaGI-Cj 
 
 
 
 
 
 
X 
 
 
X 
 
 
Safety Assessments 
Physical/ neurological 
examinationk 
X 
 
 
 
 
 
 
 
 
X 
 
 
ECGl 
X 
X 
X 
 
X 
 
X 
 
 
X 
X 
 
Vital sign measurementsm 
X 
X 
X 
 
X 
 
X 
 
 
X 
X 
 
C-SSRSn(electronic form)i 
X 
X 
X 
 
X 
 
X 
 
 
X 
X 
 
Prior/concomitant treatmentso 
--------------------------------------------------------------------------------------------------------------------------------------------------→ 
Adverse event monitoringo 
--------------------------------------------------------------------------------------------------------------------------------------------------→ 
Laboratory 
Blood for safety laboratory sample 
X 
X 
X 
 
X 
 
X 
 
 
X 
X 
 
Urine for safety laboratoryp 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 

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Trial Period 
Screening 
Perioda,b 
Treatment Period (12 weeks) 
Post-treatment 
Follow-up 
(4 weeks) 
Visit/Contactc 
Visit 1 
Visit 2/ 
Baseline 
Visit 3d 
Contact 
Visit 4e 
Contact 
Visit 5 
Contact 
Contact 
Visit 6/ 
ETf 
Visit 7 
Con-
tact 
Trial Day 
-31 to -1 
1 
8 
14g/18 
22 
29 
43 
57 
71 
85 
99 
113 
Trial Week 
 
 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16 
Window 
 
 
±3 days 
±5 days 
Prolactin levelq 
 
X 
 
 
 
 
 
 
 
X 
 
 
Urine drug screeningr 
X 
 
 
 
 
 
 
 
 
 
 
 
Test for alcohol 
X 
X 
 
 
 
 
 
 
 
 
 
 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
PK blood samples 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Blood collection for COMT 
genotypingt 
 
X 
 
 
 
 
 
 
 
 
 
 
Blood samples for future 
biospecimen researchu 
 
X 
 
 
 
 
 
 
 
 
 
 
Other 
IMP dispensingv 
 
X 
X 
 
X 
 
X 
 
 
 
 
 
IMP compliance assessmentv 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Abbreviations: AD = Alzheimer’s disease; ADAS-Cog13 = Alzheimer’s Disease Assessment Scale – Cognition 13-item scale; AES-C = Apathy Evaluation 
Scale-Clinician; COMT = catechol-O-methyltransferase; COVID-19 = coronavirus disease-2019; C-SSRS = Columbia-Suicide Severity Rating Scale; DAIR = 
Dementia Apathy Interview and Rating; DCA = diagnostic criteria for apathy; DLB = dementia with Lewy bodies; ECG = electrocardiogram; eCRF = electronic 
case report form; ET = early termination; FTD = frontotemporal dementia; HIV = human immunodeficiency virus; IMP = investigational medicinal product; IRT 
= interactive response technology; mADCS-CGIC = modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change; CaGI-C = 
Caregiver Global Impression–Change Scale; CaGI-S = Caregiver Global Impression–Severity Scale; mCGI-S = modified Clinical Global Impression–Severity 
Scale; MMSE = Mini-Mental State Examination; NPI = Neuropsychiatric Inventory; NPI-C = Neuropsychiatric Inventory-Clinician; PK = pharmacokinetic(s); 
SARS-CoV2 = severe acute respiratory syndrome coronavirus 2; VAD = vascular dementia. 
a. 
Extension of screening may be allowed following discussion and documented approval by the medical monitor prior to the expiration of the Screening 
Period. Extension will only be granted in rare circumstances and the 30-day duration should be adhered to whenever possible. 

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b. Individual sites may require subjects to have SARS-CoV2 testing done prior to randomization. SARS-CoV2 testing may be performed any time after 
randomization per the investigator’s discretion. 
c. 
Contact with subject via phone call, internet/web, or other acceptable means of communication to check on their status. 
d. Subjects will be monitored during scheduled assessments following dosing and those who do not tolerate the increase to Step 3 dose may decrease back 
down to Step 2 dose. See Section 4.1.2. 
e. 
Subjects will be monitored during scheduled assessments following dosing and those who do not tolerate the increase to Step 5 dose may decrease back 
down to Step 4 dose. See Section 4.1.2. 
f. 
The assessments scheduled for Visit 6 are to be performed for any subject who early terminates from the trial. 
g. Subjects who receive the Step 3 dose increase (rechallenge) on Day 13 will be instructed to call the site on Day 14 (day after they again receive the Step 3 
dose) to ensure that they can tolerate the rechallenge.  
h. Informed consent must be obtained before any trial-related procedures are performed. 
i. 
Assessments will be completed using electronic forms. However, if it is not possible to complete electronic form, then paper forms are permitted.  
j. 
All responses will be relative to the subject’s condition at Visit 2/Baseline, prior to the first dose of IMP.  
k. Full physical and neurological examinations should be completed at Screening and Visit 6/ET. The physical examination should include weight at all time 
points and height at the Screening Visit only. Physical and/or neurological examinations can be done at any time point during the trial at the investigator’s 
discretion. 
l. 
At Screening, a triplicate set of 12-lead ECGs is required to assess subject eligibility. A triplicate set of ECGs is 3 consecutive ECGs collected 1 to 2 minutes 
apart over a 5-minute period. At all other noted time points, a single ECG is required. All ECGs should be performed after the subject has been at rest in a 
supine/semi-recumbent position for approximately 3 minutes. See Section 8.3.3 for more details.  
m. Vital sign measurements include blood pressure, heart rate, and body temperature. Duplicate blood pressure and heart rate measurements will be obtained 
sitting/supine (after 5 minutes of rest) followed by a single standing measurement (after 2 minutes of rising from sitting/supine position). At each visit, body 
temperature will be obtained once, at the time of the first blood pressure measurement. 
n. The “Baseline/Screening” C-SSRS form will be completed for all subjects at Screening to determine eligibility and the “Since Last Visit” C-SSRS form will 
be completed at the Baseline Visit to ensure that the subject continues to qualify for the trial. The “Since Last Visit” C-SSRS form will also be completed at 
all visits after Baseline. 
o. Adverse events (serious and non-serious) and concomitant medications should be recorded from screening through the subject’s last visit. 
p. Dipstick urinalysis results are not to be recorded on the eCRFs; any clinically significant abnormality should be captured as an adverse event. 
q. Prolactin results will be partially blinded. 
r. 
A urine drug screen is required at screening; see the exclusion criteria for exclusions based on the urine drug screen. The urine drug screen can be conducted 
at any time during the trial at the discretion of the investigator.  
s. 
PK samples will be collected at all clinic visits except Day 1. The date and time of the most recent dose, the dose step, and the time of the blood draw will be 
recorded. For Visit 3 and 4, PK samples to be collected approximately 2 hours post dose. PK samples should be drawn just after the ECGs at all visits. 

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t. 
Blood samples for genotyping are to be collected prior to initiation of dosing. 
u. Future biospecimen research sample is optional and is to only be collected if signed consent is obtained from the subject. Sample can be collected any time 
prior to initiation of dosing. 
v. The first dose of IMP (at the Baseline Visit) will be taken in the clinic; subjects will be dispensed IMP to take at home between visits. Subjects will be 
instructed to bring their IMP to each clinic visit and take their daily dose at the clinic on visit days. Compliance will be assessed through self-reporting by the 
subject and by tablet count. 

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2 INTRODUCTION 
2.1 
Trial Rationale 
CVL-871 is a dopamine D1/D5 receptor partial agonist that is being evaluated for the 
treatment of dementia-related apathy that is thought to arise from insufficient 
dopaminergic signaling. The aim of this trial is to evaluate the safety, tolerability, and 
pharmacodynamics of CVL-871 in subjects with dementia-related apathy. 
2.2 
Background 
2.2.1 
Disease Background 
Dementia is a progressive disorder, characterized by a decline in cognition involving 
multiple domains, that can significantly affect social or occupational function. It is 
currently estimated that approximately 50 million people worldwide are affected by 
dementia with numbers increasing by approximately 10 million per year (World Health 
Organization, 2019). Dementia has a strong negative emotional impact on patients and 
caregivers, and the economic burden is estimated to be 818 billion dollars per year 
worldwide (Prince et al, 2015). Several conditions cause dementia; the most common are 
Alzheimer’s disease (AD; ~50% to 70% of cases), frontotemporal dementia (FTD; ~20% 
of cases), vascular dementia (VAD; ~5% of cases), and dementia with Lewy body (DLB; 
~5% of cases; Cunningham et al, 2015).  
Although dementia is primarily defined based on cognitive and functional impairment, 
neuropsychiatric symptoms, such as agitation, delusions, hallucinations, depression, sleep 
disturbance, and apathy, are common features in most patients.  
Apathy in neurocognitive disorders was defined in 2009 by a task force (Robert et al, 
2009), and updated by the 2018 International Consensus Group (Robert et al, 2018) as a 
quantitative reduction of goal-directed activity in comparison with the patient’s previous 
level of functioning. The proposed diagnostic criteria in the 2018 revision required that 
symptoms be persistent for at least 4 weeks and affect at least 2 of 3 apathy dimensions: 
1) behavior/cognition, 2) emotion, and 3) social interaction. More recently, the 
International Society for CNS Clinical Trials and Methodology (ISCTM) Working Group 
on Apathy, which included members from the Food and Drug Administration (FDA), has 
updated the diagnostic criteria for apathy (DCA) of neurocognitive disorders, which is 
now in prepublication. The updated consensus DCA has refined the 3 core clinical 
domains to the following: 1) diminished initiative (less spontaneous and/or active than 
usual self), 2) diminished interest (less enthusiastic about usual activities), and 3) 
diminished emotional expression/responsiveness. An apathy diagnosis, based on the 
ISCTM updated DCA, retains the requirement from the 2018 International Consensus 
Group (Robert et al, 2018) for symptoms to be persistent or frequently recurrent for at 
least 4 weeks in at least 2 of the 3 core clinical domains (Miller et al, 2021).   

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Clinically significant apathy is one of the most prevalent and important neuropsychiatric 
symptoms in patients with dementia (Benoit et al, 2012; Bjoerke-Bertheussen et al, 2012; 
Cipriani et al, 2014; van der Linde et al, 2012; Breitve et al, 2018). Apathy represents a 
constellation of symptoms, such as social disengagement, cognitive impairment, and loss 
of emotion that result in impaired decision-making, loss of interest in personal wellbeing 
or external issues, inability to initiate and maintain activities, and interference with 
complex and basic daily function, including motivation to eat, dress, maintain personal 
hygiene, and take medications (Ishii et al, 2009; Lanctôt et al, 2017; Landes et al, 2001; 
Nobis and Husain, 2018).  
Apathy has been demonstrated to predict functional status in patients with dementia 
independent of age, global cognition, memory and executive function, and comorbid 
depression (You et al, 2015; Boyle et al, 2003; Freels et al, 1992). The presence of apathy 
has been shown to be related to decreased quality of life, increased morbidity and 
mortality, and early institutionalization and greater resource utilization resulting from 
increased caregiver distress and burden (Nobis and Husain, 2018; van Dijk et al, 1994; 
Spalletta et al, 2015; Nijsten et al, 2017; Onyike et al, 2007; Hongisto et al, 2017; Bakker 
et al, 2013; Landes et al, 2001; George, 2013; Kaufer et al, 1998; Dauphinot et al, 2015). 
In addition, apathy is a key predictor of progression from mild cognitive impairment to 
AD dementia (Palmer et al, 2010; Richard et al, 2012; Starkstein et al, 2006). Therefore, 
the management of apathy is an important component in caring for patients with 
dementia. 
Currently, there are no approved treatments for apathy. Consequently, pharmacologic 
treatment of patients is comprised of off-label use of drugs such as acetylcholinesterase 
inhibitors, selective serotonin reuptake inhibitors (SSRIs), and psychostimulants (eg, 
methylphenidate). Acetylcholinesterase inhibitors, such as donepezil and rivastigmine, 
have shown only limited effects in clinical trials (Rea et al, 2014; Theleritis et al, 2019; 
Berman et al, 2012). Use of antidepressants, such as SSRIs, for apathy treatment in 
dementia is not supported by clinical evidence, and may actually contribute to worsening 
effect (Barnhart et al, 2004; Wongpakaran et al, 2007; Theleritis et al, 2019; Berman et 
al, 2012).  
2.2.2 
Dopaminergic Signaling in Apathy 
A pronounced loss of dopamine function in prefrontal cortex occurs along with the 
natural aging process. Deficient D1 receptor signaling has been directly implicated in 
age-related declines of cognitive functions including memory capacity and flexibility 
(Volkow et al, 1998; Bäckman and Farde, 2001). For example, with advancing age, there 
is a prominent loss of dopamine and dopamine metabolism in the dorsolateral prefrontal 
cortex and anterior cingulate cortex of monkeys and humans (Ota et al, 2006). Both 
cognitive deficits and prefrontal cortex dopamine depletion emerge early in the aging 
process and progressively worsen with advancing age (Bachevalier et al, 1991). Changes 
in the prefrontal cortex, one of the most sensitive regions to aging influences, usually 
precede age-related changes in the majority of other cortical regions in individuals 
without dementia (Raz et al, 2000), and may increase vulnerability to the development of 

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several neurophysiological disturbances and neuropsychiatric disorders. Positron 
emission tomography trials demonstrate a loss of striatal D1 but not D2 receptors in 
patients with AD vs matched controls (Kemppainen et al, 2000). 
There is a clear scientific basis for considering the mesolimbic dopamine system as a key 
part of the neurocircuitry that modulates motivation and reward processing, and thus a 
potential target for treatment of apathy (Le Heron et al, 2019). Motivated behaviors have 
been demonstrated to involve the dopaminergic mesolimbic brain reward system 
(Salamone and Correa, 2012; Ruthirakuhan et al 2018). In addition, apathy has been 
shown to be associated with neuroimaging changes in specific medial frontal cortex and 
subcortical structures and these changes are consistent across a disparate range of 
underlying pathologies (Berridge and Arnsten, 2013; Kos et al, 2016; Le Heron et al, 
2018). Agents that can correct imbalances or deficits in the dopaminergic tone within 
those regions may promote normalization of impaired motivation, reward processing, and 
goal-directed behaviors (Mitchell et al, 2011).  
Evidence supporting the hypothesis that modulation of dopamine signal may improve 
apathy in patients with dementia has been obtained from clinical trials with 
methylphenidate (Rosenberg et al, 2013; Padala et al, 2018). Significant improvements in 
apathy symptoms were reported following treatment with 20 mg/day. Although the exact 
mechanism involved in methylphenidate’s effect on apathy is poorly understood, there is 
sufficient evidence pointing towards increase of extracellular dopamine levels in striatum 
and prefrontal cortex by blockade of dopamine transporters (Volkow et al, 2001; Volkow 
et al, 1998; van Dyck et al, 2020), which are critical regions of the mesolimbic reward 
system that modulates goal-directed behavior (Le Heron et al, 2018). Following a single 
oral dose of 60 mg of methylphenidate, dopamine levels in striatum increased, which was 
evidenced by reduction of raclopride (selective D2 antagonist) by approximately 20% 
(Volkow et al, 2001).  
Dopamine acts on 5 receptor subtypes, which have distinct localization and primary 
signaling cascades and are commonly divided into 2 groups based on their function. The 
D1-like family includes the D1 and D5 subtypes, which stimulate cellular activity by 
increasing intracellular cyclic adenosine monophosphate (cAMP) levels, and the D2-like 
family includes the D2, D3, and D4 subtypes, which decrease intracellular cAMP when 
activated. Both D1-like and D2-like family receptors are involved in the dopaminergic 
pathways of the mesolimbic system that control reward-based decision-making and 
motivation, with apparent divergent distribution and mechanistic roles, similar to the 
delineations observed in the nigrostriatal motor circuits (Lopez et al, 2017; Keeler et al, 
2014; West and Grace, 2002; Hikida et al, 2010). 
Given their distribution, D1 receptors are thought to play important roles in regulating 
affective, reward-related, and motivational processes, including promotion of goal-
directed behavior and learning from positive outcomes (de la Mora et al, 2010; Katz et al, 
2006; D’Aquila and Galistu, 2012; Short et al, 2006; Baik, 2013; Wall et al, 2011; 
Flanigan and LeClair, 2017; Bromberg-Martin et al, 2010; Beninger and Miller, 1998). 
For example, Yohn and coworkers (Yohn et al, 2015) demonstrated specific impact of D1 

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agonism as a driver of goal related behavioral activation and increased effort in rodents 
using an effort-based decision-making task to compare the efficacy of selective D1 
agonists reversing the effects of a selective D1/D5 receptor antagonist. In addition, 
Schweimer (Schweimer and Hauber, 2006) demonstrated that D1, but not D2 receptors, 
regulate effort-based decision-making in the rodent anterior cingulate cortex, while 
Soutscheck (Soutschek et al, 2020) showed that a D1 agonist increased the willingness of 
healthy volunteer subjects to exert effort for reward.   
2.2.3 
Pharmacological Treatment of Apathy 
As described above, there are no currently approved treatments for apathy; however, 
significant improvements in apathy symptoms in patients with AD were reported 
following treatment with methylphenidate (Rosenberg et al, 2013; Padala et al, 2018). 
Despite the observed positive treatment response, adverse effects of methylphenidate-
containing medications (eg, anxiety, weight loss, delusions, irritability, hypertension), 
which would be significant for older persons with a dementing illness, may limit their 
overall clinical utility for the treatment of dementia-related apathy (Theleritus et al, 
2017). A retrospective case-control study of adult methylphenidate users with attention 
deficit hyperactivity disorder (including more than 4,000 adults ≥65 years of age), 
showed that initiation of methylphenidate treatment was associated with nearly a 
doubling of the rate of sudden death or ventricular arrhythmia (propensity score adjusted 
overall hazard ratio 1.84; in users ≥65 years of age 1.73; Schelleman et al, 2012). These 
findings are consistent with the current approved labeling for methylphenidate-containing 
medications in the United States (US), which contain a Warning for Serious 
Cardiovascular Events in adults, noting “Sudden death, stroke, and myocardial infarction 
have been reported in adults taking stimulant drugs at usual doses for ADHD” (Ritalin 
package insert, 2019; Concerta package insert, 2017).  
In addition, psychostimulants like methylphenidate-containing medications have 
significant abuse potential and are Schedule II controlled substances in the US. 
Furthermore, broad clinical experience has also established that, in contrast to reuptake 
inhibition, direct activation of dopamine receptors by selective and nonselective 
dopamine agonists does not produce immediate euphoria leading to abuse of these agents. 
Accordingly, none of the currently approved dopamine agonists have been classified as a 
scheduled drug under the Controlled Substances Act. Furthermore, they have safety 
profiles that do not show frequent incidences of pleasurable adverse events (eg, euphoria, 
drunk, high). A search of PubMed revealed no publications that describe the abuse of 
dopamine agonists, while a search of the Drug Abuse Warning Network database showed 
that dopamine agonists have not been associated with a significant number of visits to 
emergency departments for misuse/abuse in the period of 2004 to 2011. From these 
evidential sources, it can be concluded that the risk for human abuse posed by dopamine 
agonists is negligible in the generally population. 
Therefore, due to the potential risks for abuse, serious cardiovascular side effects, and 
other systemic and psychological side effects that can be associated with use of 
psychostimulants, which may be more concerning in an elderly adult population, there 
remains a need for the evaluation of new dopaminergic therapies for the treatment of 

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dementia-related apathy that can provide meaningful therapeutic benefit while limiting 
the risk of significant side effects.  
Given the proposed role of D1 receptor activation in regulation of the motivation 
neurocircuitry, the use of a D1-specific partial agonist for the treatment of dementia-
related apathy in elderly patients may be beneficial. While currently available D2/D3 full 
agonists can be associated with dose-limiting hypotension/acute orthostasis, 
hallucinations, impulse control disorders, and sudden daytime sleepiness (Stowe et al, 
2008; Antonini et al, 2009), these are believed to be mechanistically and specifically 
linked to D2/D3 receptor activation (Monti and Monti, 2007; Howes and Kapur, 2009; 
Seeman, 2015; Lopez et al, 2017; Vriend, 2018). Thus, D1 activation with a specific 
partial agonist is not expected to convey these same risks. 
2.2.4 
CVL-871 
CVL-871 is a dopamine D1 receptor partial agonist being evaluated for the treatment of 
dementia-related apathy.  
In vitro functional testing against recombinant human D1 (hD1) and D5 (hD5) receptors 
established that the compound is an agonist, which stimulates cAMP formation with the 
concentration required for half maximal effect (EC50) values of 46 nM and 34 nM, 
respectively. Comparison of the cAMP response to the full agonist dopamine indicated 
that CVL-871 is a partial agonist at D1 receptors with intrinsic activity (maximum effect) 
of 44% and 58% for the hD1 and hD5 receptors, respectively. 
CVL-871 has been evaluated for safety and tolerability in 2 clinical trials. In Trial 
B7821001, the safety, tolerability, and pharmacokinetics (PK) of CVL-871 were 
evaluated in single ascending dose (SAD) and multiple ascending dose (MAD) cohorts of 
healthy subjects. Overall, CVL-871 was safe and well tolerated in 48 healthy subjects 
following single oral doses of up to 1 mg (n=16) and multiple doses of up to 3 mg once 
daily (QD; n=32). A Phase 1b trial (B7821002) in Parkinson’s disease patients (n=19; 
age range for subjects who received CVL-871 was 54 to 74 years) with motor 
fluctuations showed that a 3 mg QD dose of CVL-871 (1 mg for Day 1-3 and 3 mg for 
Days 4-7) resulted in improvement of motor scores, suggesting dopaminergic activity in 
brain regions involved in motor function (Gurrell et al, 2018). Safety data available from 
patients treated with CVL-871 (n=10) indicated that CVL-871 was generally safe and 
well tolerated in this trial. There were no deaths, serious adverse event (SAEs), or severe 
adverse events (AEs) reported in either trial. The most frequently reported AE in both the 
SAD and MAD phases of Trial B7821001 and in Trial B7821002 was nausea. 
Please refer to the CVL-871 Investigator’s Brochure for more detailed information on 
nonclinical studies and clinical trials. 
The aim of this exploratory trial is to evaluate the safety, tolerability, and 
pharmacodynamics of 2 doses of CVL-871 for treatment of apathy in subjects with 
dementia-related apathy. In addition, data from this trial will be used to evaluate the 
appropriateness of currently available apathy clinical assessments in an interventional 

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setting. Current evidence suggests that CVL-871 has the potential to promote 
normalization of impaired dopamine signaling at D1 receptors in brain regions that 
control reward and motivation, while limiting the risk of significant side effects that are 
associated with psychostimulants and nonselective or D2/3 preferring dopamine agonists. 
2.3 
Benefit/Risk Assessment 
This trial is designed primarily to generate safety, tolerability, and pharmacodynamic 
data for further clinical development of CVL-871 in a subject population with 
dementia-related apathy.  
As described in Section 2.2.1, dementia-related apathy is a major health problem with no 
currently approved treatments. Given the proposed role of D1 receptor activation in 
regulation of the motivation neurocircuitry, the use of a D1-selective partial agonist, such 
as CVL-871, for the treatment of dementia-related apathy in elderly patients may be 
beneficial.  
Based on the safety and toxicology data available to date, the doses chosen are not 
expected to pose any significant safety risk to the subjects.  
Reproductive and developmental toxicity studies with CVL-871 have not been 
conducted. In the absence of reproductive or developmental toxicology data, women of 
childbearing potential are excluded from participation in this trial. 
More detailed information about the known and expected benefits and potential risks and 
expected adverse events of CVL-871 are found in the Investigator’s Brochure. 

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3 OBJECTIVES AND ENDPOINTS 
Table 2 
Objectives and Endpoints 
Objectives and Endpoints 
Objective 
Endpoint 
Primary 
 
• 
To assess the safety and tolerability of 2 
fixed doses of CVL-871 in subjects with 
dementia-related apathy 
• 
Incidence and severity of TEAEs 
• 
Clinically significant changes in ECG results, 
clinical laboratory evaluations, vital sign 
measurements, and physical and neurological 
examination results 
• 
Clinically significant findings in suicidality 
assessed using the C-SSRS 
Secondary 
 
• 
To assess the pharmacodynamic effects of 
2 fixed doses of CVL-871 on apathy in 
subjects with dementia-related apathy 
• 
Change from baseline to Visit 5 (Week 6) and 
Visit 6 (Week 12) in the following: 
○ 
NPI-C apathy domain score 
○ 
NPI apathy domain score 
○ 
DAIR score 
○ 
AES-C score 
Exploratory 
 
• 
To evaluate the plasma concentrations of 
CVL-871 in subjects with dementia-related 
apathy 
• 
Plasma concentrations of CVL-871 at Visits 2 
(Week 1), 4 (Week 3), 5 (Week 6), and 6 (Week 
12) 
• 
To evaluate the effect of CVL-871 
neuropsychiatric symptoms other than 
apathy 
• 
NPI-C dysphoria domain score 
• 
NPI domain scores (other than apathy) 
• 
To assess the effects of 2 fixed doses of 
CVL-871 on cognition in subjects with 
dementia-related apathy 
• 
Change from baseline to Visit 6 (Week 12) in the 
ADAS-Cog13 score 
• 
To assess the effects of 2 fixed doses of 
CVL-871 on functional assessments (eg, 
activities of basic living, and cognitive, 
functional, and behavioral performance) in 
subjects with dementia-related apathy 
• 
Change from baseline to Visit 5 (Week 6) and 
Visit 6 (Week 12) in the following: 
○ 
mADCS-CGIC scores 
○ 
mCGI-S scores 
○ 
CaGI-S scores 
○ 
CaGI-C scores 
• 
Investigate the impact of COMT (Val-
Met) status on safety and 
pharmacodynamics 
• 
Evaluation of safety and pharmacodynamic 
endpoints in subgroups of subjects based on their 
COMT (Val-Met) status  
Abbreviations: ADAS-Cog13 = Alzheimer’s Disease Assessment Scale – Cognition 13-item scale; AES-C 
= Apathy Evaluation Scale-Clinician; COMT = catechol-O-methyltransferase; C-SSRS = Columbia-
Suicide Severity Rating Scale; DAIR = Dementia Apathy Interview and Rating; ECG = electrocardiogram; 
mADCS-CGIC = modified Alzheimer’s Disease Cooperative Study–Clinical Global Impression of Change; 
CaGI-C = Caregiver Global Impression–Change Scale; CaGI-S = Caregiver Global Impression–Severity 
Scale; mCGI-S = modified Clinical Global Impression–Severity Scale; NPI = Neuropsychiatric Inventory; 
NPI-C = Neuropsychiatric Inventory-Clinician; TEAE = treatment-emergent adverse event. 

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4 TRIAL DESIGN 
4.1 
Overall Design 
This is a Phase 2a, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, 12-week trial to evaluate the safety, tolerability, and pharmacodynamics 
of 2 fixed doses of CVL-871 (1.0 mg QD and 3.0 mg QD) in male and female subjects 
aged 50 to 85 years who have dementia-related apathy. The trial will include a 30-day 
Screening Period, a 12-week Treatment Period, and a 4-week Safety Follow-up Period 
(Table 1). Each subject will participate in the trial for up to approximately 20 weeks.  
4.1.1 
Screening/Baseline Period 
Subjects who provide written informed consent will be screened for eligibility during the 
Screening Period. Subjects who are confirmed to be eligible for the trial will be 
scheduled for a Baseline Visit within 30 days after the Screening Visit Extension of 
screening may be allowed following discussion and documented approval by the medical 
monitor prior to the expiration of the Screening Period. Extension will only be granted in 
rare circumstances and the 30-day duration should be adhered to whenever possible. 
Eligible subjects will be randomized in a 1:1:1 ratio to 3 treatment groups at the Baseline 
Visit: 
• 
CVL-871 1.0 mg QD 
• 
CVL-871 3.0 mg QD 
• 
Placebo QD 
Approximately 150 subjects will be screened to achieve the target of approximately 
75 subjects randomly assigned to treatment (25 per group). The trial may be considered 
as complete and be closed out following the randomization of 60 subjects in the event of 
significantly slower recruitment rate than anticipated to avoid unduly long delay of the 
final analysis. 
Randomization will be stratified by 2 distinct strata: 1) subjects currently using SSRIs or 
serotonin-norepinephrine reuptake inhibitors (SNRIs) during the trial, 2) subjects not 
using SSRIs or SNRIs during the trial (see Section 6.5). 
4.1.2 
Treatment Period 
The dose of CVL-871 will be titrated in a blinded fashion to either 1.0 mg QD or 3.0 mg 
QD and then maintained for the duration of the 12-week Treatment Period, as shown in 
Table 3. Subjects will be administered a combination of CVL-871/placebo tablets across 
all doses throughout the trial to maintain the trial blind. 

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Table 3 
CVL-871 and Placebo Dosing Schedule 
Trial Day 
Titration 
Step 
Target Dose 
Placebo QD 
CVL-871 1.0 mg QD 
CVL-871 3.0 mg QD 
 
Days 1-3: 
Step 1 
0.25 mg CVL-871 QD 
0.25 mg CVL-871 QD 
Placebo QD 
Days 4-7: 
Step 2 
0.5 mg CVL-871 QD 
0.5 mg CVL-871 QD 
Placebo QD 
Days 8-16: 
Step 3 
1.0 mg CVL-871 QD 
1.0 mg CVL-871 QD 
Placebo QD 
Days 17-21: 
Step 4 
1.0 mg CVL-871 QD 
2.0 mg CVL-871 QD 
Placebo QD 
Days 22-84: 
Step 5 
1.0 mg CVL-871 QD 
3.0 mg CVL-871 QD 
Placebo QD 
Abbreviation: QD = once daily. 
This titration scheme will be implemented for all treatment groups, including placebo, in 
a blinded fashion for all subjects who are randomized. Exceptions for subjects who 
experience tolerability issue at specific time points are described below.  
The first dose of investigational medicinal product (IMP; Step 1) will be taken at the trial 
site at the Baseline Visit (Day 1). No deviations in the titration schedule up through 
Step 2 are allowed. Subjects who cannot achieve or tolerate the dose at Step 2 must be 
discontinued from the trial.  
On Day 8 (Visit 3), subjects will take the Step 3 dose of IMP at the clinic. Subjects will 
be monitored for tolerability while undergoing concurrent assessments; after completion 
of all visit procedures, the investigator will assess whether the participant will continue 
with the new dose. Subjects who are unable to tolerate the dose at Step 3 may go back to 
the dose at Step 2. These subjects will remain at the Step 2 dose until Day 13, at which 
time they will again receive the Step 3 dose (rechallenge). Subjects will be instructed to 
call the site on Day 14 (day after they again receive the Step 3 dose) to ensure that they 
can tolerate the rechallenge. Subjects who are unable to tolerate the Step 3 dose upon 
rechallenge will be discontinued from the trial.  
On Day 17, all subjects will take the Step 4 dose; subjects will be contacted by phone on 
Day 18 and evaluated for tolerability after the dose increase. Subjects who are unable to 
tolerate the Step 4 dose will be discontinued from the trial.  
On Day 22 (Visit 4), all subjects will take the Step 5 dose of IMP at the clinic. Subjects 
will be monitored for tolerability while undergoing concurrent assessments; after 
completion of all visit procedures, the investigator will assess whether the participant will 
continue with the new dose. Subjects who are unable to tolerate the dose at Step 5 may go 
back to the dose at Step 4 and continue on that dose for the remainder of the trial. 
Subjects who are able to tolerate the Step 5 dose will continue on this dose for the 
remainder of the trial and no further dosing adjustments are allowed.  
Lack of tolerability should be of sufficient severity that it results in significant 
dysfunction or distress to the subject (eg, Common Terminology Criteria for Adverse 
Events [CTCAE] Grade 2/3). The medical monitor should be contacted in any instance 

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where the investigator is uncertain whether the subject is able to tolerate the stepwise 
dose increase.  
No deviations in the dosing schedule, other than those noted above, are allowed. 
The titration scheme, including the dosing decision time points, is presented in Figure 2. 
Figure 2 
Dosing Schematic 
 
 
Abbreviations: PBO = placebo. 
Note: If “Yes” then continue with new dose; if “No” then stay at previous dose.  
Assessments will be conducted at the Week 1, 3, 6, and 12 visits. Subjects will be 
instructed to take their dose of IMP at the clinic on days when visits occur. Blood 
samples for PK analysis will be collected at the Week 1, 3, 6, and 12 visits.  
4.1.3 
Safety Follow-up Period 
Subjects will have a Safety Follow-up visit at 14 days after discontinuation of IMP (either 
after completing the full 12-week Treatment Period or upon premature discontinuation 
from the trial). Subjects will also be contacted at 4 weeks after the last dose of IMP. 
4.1.4 
Definition of Completed Subject 
A subject is considered to have completed the trial if he/she has completed all phases of 
the trial including the last Treatment Period visit (Visit 6/Week 12), as shown in the 
Schedule of Assessments in Section 1.3.  
A subject who completed all procedures except the Follow-up visit (Visit 7) and 
Follow-up phone contact would not be considered an early termination subject.   

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4.2 
Scientific Rationale for Trial Design 
The randomized, double-blind, placebo-controlled, parallel-group trial design is widely 
accepted as one that minimizes the risk of bias and that is appropriate for evaluating the 
effects of a trial treatment in indications in which use of a placebo is ethical (US FDA, 
2001). Randomization reduces bias in the assignment of subjects to a treatment group, the 
double-blind design prevents differential treatment and assessments, and the 
placebo-controlled design controls for all potential influences on the actual or apparent 
course of the disease other than those arising from the pharmacologic action of the drug. 
The 12-week duration of the current trial should be of sufficient length to show a 
treatment effect on apathy symptoms. Previous trials examining the effect of 
methylphenidate on apathy symptoms should a significant effect of methylphenidate 
compared with placebo at 4 weeks (using Apathy Evaluation Scale-Clinician [AES-C] 
scale; Padala et al, 2018) and 6 weeks (using Neuropsychiatric Inventory-Clinician 
[NPI-C] scale; Rosenburg et al, 2013).  
To date, there is no accepted standard for evaluation of symptoms of dementia-related 
apathy in elderly subjects. Therefore, in this trial, apathy and other neuropsychiatric 
symptoms will be evaluated using several assessments including the apathy domain of the 
NPI-C, the Neuropsychiatric Inventory (NPI; all 12 domains, including apathy), the 
Dementia Apathy Interview and Rating (DAIR), and the AES-C. The cognition 
assessment used is  the Alzheimer’s Disease Assessment Scale–Cognition (ADAS-Cog) 
13-item scale (ADAS-Cog13). Other assessments include the modified Alzheimer’s 
Disease Cooperative Study–Clinical Global Impression of Change (mADCS-CGIC), 
modified Clinical Global Impression-Severity Scale (CGI-S), Caregiver Global 
Impression–Severity Scale (CaGI-S), and the Caregiver Global Impression–Change Scale 
(CaGI-C).  
One of the aims of this trial will be to collect data that will be used to evaluate the 
appropriateness of valid apathy assessments in an interventional setting, which may serve 
as a primary outcome measure for subsequent trials. The appropriateness would be 
determined by a scale’s ability to correlate with the new diagnostic criteria, reflecting 
changes in the domains that define the underlying neurobiology, as well as reflecting 
changes that are meaningful to clinicians, patients, and caregivers.   
The safety endpoints, including physical and neurological examinations, vital sign 
measurements, electrocardiograms (ECGs), laboratory evaluations, and AEs, are those 
commonly used to assess the safety and tolerability of trial treatments. The 
Columbia-Suicide Severity Rating Scale (C-SSRS) is commonly used for stringent 
monitoring of suicidality in clinical trials of neurological compounds (Posner et al, 2011).  
4.3 
Dosing Rationale 
Significant improvements in apathy symptoms have been reported following treatment 
with methylphenidate in patients with AD (Rosenberg et al, 2013; Padala et al, 2018). As 
mentioned previously, CVL-871 is a D1/D5 receptor partial agonist and can provide 

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increased dopaminergic stimulation without the abuse liability and potential for 
cardiovascular and other systemic side effects associated with psychostimulants. The top 
dose of 3 mg QD CVL-871 has been demonstrated to provide improvement of motor 
symptoms in patients with Parkinson’s disease (Gurrell et al, 2018). This dose was well 
tolerated and was achieved using a quick titration scheme in both healthy subjects and 
patients with Parkinson’s disease. Based on in vitro estimates, this dose is expected to 
result in approximately 80% occupancy at target receptors in humans. The terminal 
elimination half-life of 24 hours is expected to provide stable plasma concentrations, 
approximately 2-fold peak-to-trough ratio, following QD dosing. Based on exposures 
from B7821001, 3 mg QD is the maximum dose that can be administered without 
exceeding the exposure limiting criteria based on nonclinical toxicological data.  
The lower dose of 1.0 mg QD will provide the pharmacodynamic data at approximately 
60% target occupancy. Data from these 2 doses will support evaluation of the dose 
relatedness of the response. It is important to acknowledge the potential that optimizing 
cortical D1 circuitry may show significant sensitivity to several factors beyond dose, 
including individual baseline dopaminergic state, genetics, central nervous system (CNS) 
disease and neurodegeneration, and concomitant medication that impact dopamine 
neurotransmission. Evaluation of 2 fixed doses with distinctly different levels of target 
occupancy in this exploratory trial will facilitate the determination of a dose range for D1 
partial agonist therapy for dementia-related apathy in subsequent trials.  
In order to mitigate the effects of nausea and vomiting, the target doses of CVL-871 will 
be achieved using a slow titration paradigm. The starting dose for titration, 0.25 mg/day, 
is anticipated to be well tolerated with minimal nausea. Also, dose increments every 3 to 
4 days was successful in achieving the target dose of 3 mg in healthy subjects 
(B7821001) with minimal tolerability issues. Moreover, for subjects who do experience 
tolerability issues associated with dose increases at prespecified time points during the 
trial (see Section 4.1.2), down titration options are available to improve tolerability.   
4.4 
End of Trial Definition 
The end of the trial is defined as the date of the last visit (including phone contact) of the 
last subject in the trial globally. 
5 TRIAL POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the trial only if all of the following criteria apply: 

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General and Administrative 
1.  
Male subjects and female subjects of nonchildbearing potential, ages 50 to 85 years, inclusive, at 
the time of signing the ICF. 
Women of nonchildbearing potential are defined as follows: 
• 
Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 
12 consecutive months with no alternative pathological or physiological cause. 
• 
Premenopausal women with 1 of the following categories are considered to be of 
nonchildbearing potential: 
○ 
Documented hysterectomy 
○ 
Documented bilateral salpingectomy 
○ 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determine trial entry. 
Note: Documentation can come from the site personnel’s review of the subject’s medical records 
or medical history interview. 
2.  
Sexually active men with female partners of childbearing potential must agree to practice 
acceptable birth control (at minimum), as defined in Section 10.4 (Appendix 4), during the trial 
and for 4 weeks after the last dose of IMP.  
3.  
Body mass index of 18.5 to 35.0 kg/m2 and a total body weight ≥50 kg (110 lbs). 
4.  
Have a reliable caregiver, defined as an identified adult who is willing to participate in the trial 
and who spends greater than 10 hours a week with the potential subject, supervises his/her care, 
and will accompany the subject to trial visits. The caregiver must, in the opinion of the 
investigator, be able to knowledgeably report on the subject’s daily cognition, function, behavior, 
safety, compliance, and adherence to protocol requirements. The same caregiver must assist the 
subject throughout the duration of the trial. 
5.  
Subjects/legally authorized representative and caregiver are capable of giving signed informed 
consent as described in Section 10.1.3, which includes compliance with the requirements and 
restrictions listed in the ICF. 
6.  
Ability, in the opinion of the investigator, of the caregiver and subject to understand the nature of 
the trial, participate in trial visits, and comply with protocol requirements, including the 
prescribed dosage regimens, scheduled visits, laboratory tests, outcomes measures, and other trial 
procedures. 
Target Disease Characteristics 
7.  
Meet the ISCTM Apathy Working Group diagnostic criteria for apathy in neurocognitive 
disorders (Miller et al, 2021) at the Screening Visit. 
8.  
Have clinically significant apathy, defined as NPI apathy domain frequency score of ≥2 and NPI 
apathy domain severity score of ≥2 at Screening and Baseline Visits. 

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9.  
Have a clinical diagnosis of 1 or more of the following:  
a) Possible or probable AD dementia according to the 2011 NIA-AA score clinical criteria 
(McKhann et al, 2011) at the Screening Visit; diagnosis must be stable for at least 6 months 
prior to signing the ICFa 
b) Frontotemporal dementia of any of the following subtypes:  
a. 
Behavioral variant FTD (Rascovsky et al, 2011)  
b. Semantic variant primary progressive aphasia (Gorno-Tempini et al, 2011) 
c. 
Nonfluent/agrammatic variant primary progressive aphasia (Gorno-Tempini et 
al, 2011) 
c) VAD (ie, not vascular cognitive impairment) due to either of the following: 
a. 
Large vessel or atherothromboembolic disease 
b. Small vessel disease according to the diagnostic criteria for vascular cognitive 
disorders (Sachdev et al, 2014) 
d) Possible or probable DLB according to the revised criteria for the clinical diagnosis of 
probable and possible dementia with Lewy bodies (McKeith et al, 2017) 
 
Note: Subjects who meet the criteria above for more than 1 form of the allowed dementias (eg, 
mixed dementia) are eligible for the trial.  
10.  
Have an MMSE score of 12 through 26, inclusive, at the Screening Visit. 
11.  
Have prior neuroimaging evidence (CT or MRI) collected after the onset of dementia symptoms 
that is consistent with the diagnosis of AD, FTD, VAD, or DLB and not reflecting any other 
underlying structural abnormality potentially causing dementia; eg, hydrocephalus, tumor.  
Note: in the event a subject does not have available neuroimaging evidence but is otherwise 
eligible for the trial, the medical monitor should be contacted for discussion on eligibility.  
Abbreviations: AD = Alzheimer’s disease; CT =computed tomography; DLB = dementia with Lewy 
bodies; FTD = frontotemporal dementia; ICF = informed consent form; IMP = investigational medicinal 
product; ISCTM = International Society for CNS Clinical Trials and Methodology; MMSE = Mini-Mental 
State Examination; MRI = magnetic resonance imaging; NIA-AA = National Institute of Aging – 
Alzheimer’s Association; NPI = Neuropsychiatric Inventory; VAD = vascular dementia. 
a Subjects with a definitive diagnosis of Alzheimer’s disease based on the 2018 NIA-AA criteria (Jack et 
al, 2018) are eligible for enrollment. 
5.2 
Exclusion Criteria  
Subjects are excluded from participation in the trial if any of the following criteria apply: 
Medical History 
1.  
Subjects with a diagnosis of another significant psychiatric disorder per DSM-5 including, but 
not limited to, anxiety disorders or major depressive disorder (current diagnosis) or schizophrenia 
or bipolar disorder (current diagnosis or history) at the time of signing the ICF. Subjects with 
anxiety OR depressive symptoms that are secondary to dementia or another medical condition are 
not exclusionary provided they do not meet criteria for a primary diagnosis, are relatively stable, 
and are not expected to change during the trial.  

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2.  
Subjects with a current diagnosis of a neurological disorder other than AD, FTD, VAD, or DLB 
including, but not limited to, the following: 
• 
History of hemorrhagic strokes ascertained by history and/or brain imaging findings  
• 
History ischemic stroke or transient ischemic attacks within 12 months prior to signing the 
ICF 
• 
History of multiple ischemic strokes or ischemic stroke with persistent physical disability 
• 
History of clinically serious brain infection 
• 
History of or current space occupying cerebral lesion or extra-axial lesion producing a mass 
effect 
• 
History of clinically significant concussion or repeated head trauma associated with 
sustained cognitive impairment in the 5 years prior to signing the ICF 
• 
Huntington’s disease 
• 
Parkinson’s disease 
• 
Dementia related to substance use disorder 
• 
Normal pressure hydrocephalus 
• 
Tourette’s syndrome 
• 
History of seizures (except for childhood febrile) or epilepsy 
3.  
Subjects with an acute or chronic, clinically significant medical or psychiatric condition or 
laboratory abnormality that is not otherwise specified in these exclusion criteria that might 
increase the risk associated with trial participation or administration of trial treatment or interfere 
with the interpretation of the trial results or that, in the judgment of the investigator, would make 
the subject inappropriate for entry into this trial. 
Medical conditions that are minor or well controlled may be considered acceptable if the 
condition is stable and does not expose the subject to an undue risk of a significant AE or 
interfere with the assessments of safety or efficacy during the course of the trial. The medical 
monitor should be contacted in any instance where the investigator is uncertain regarding the 
stability of a subject’s medical conditions(s) and the potential impact of the condition(s) on trial 
participation. 
4.  
Subjects with either of the following at the time of the Screening Visit based on any single NPI 
domain score in agitation/aggression, hallucinations, delusions, or disinhibition: 
• 
Frequency score is a 4 (very frequently) OR 
• 
Frequency score is a 3 (frequently) AND the severity score is either 2 (moderate) or 3 
(severe) 
5.   Subjects with a history of impulse control disorder or clinically significant impulsive, socially 
inappropriate, or compulsive behavior secondary to dementia.  
6.  
Delirium or history of delirium with the 30 days prior to signing the ICF per investigator 
judgment or medical history (eg, caretaker reports or medical records). 
7.  
Subjects with a history of myocardial infarction with residual atrial, nodal, or ventricular 
arrhythmias that are not controlled with medical and/or surgical intervention; second- or 
third-degree atrioventricular block; sustained ventricular tachycardia/ventricular fibrillation; sick 
sinus syndrome; or severe or unstable angina. A recent (≤12 months) history of myocardial 
infarction with secondary arrhythmias is exclusionary regardless of the therapeutic control. 

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8.  
Subjects with symptomatic heart failure, as defined by the following New York Heart 
Association functional classes:  
• 
Class III – Patients with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary activity causes fatigue, 
palpitation, or dyspnea.  
• 
Class IV – Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms are present even at rest or minimal exertion. If 
any physical activity is undertaken, discomfort is increased. 
9.  
Subjects with a history of atrial fibrillation or chronic thrombosis requiring treatment with 
anticoagulants, eg, warfarin, rivaroxaban (see Table 6). 
10.  
Subject with a recent history (<6 months) of clinically significant orthostatic hypotension or falls. 
11.  
Subjects who answer “yes” on the C-SSRS Suicidal Ideation Item 4 or Item 5 (Active Suicidal 
Ideation with Some Intent to Act, Without Specific Plan, or Active Suicidal Ideation with 
Specific Plan and Intent) and whose most recent episode meeting the criteria for C-SSRS Item 4 
or Item 5 occurred within the last 6 months, OR 
Subjects who answer “yes” on any of the 5 C-SSRS Suicidal Behavior Items (actual attempt, 
interrupted attempt, aborted attempt, preparatory acts, or behavior) and whose most recent 
episode meeting the criteria for any of these 5 C-SSRS Suicidal Behavior Items occurred within 
the last 2 years, OR 
Subjects who, in the opinion of the investigator, present a serious risk of suicide. 
12.  
Subjects with substance abuse or dependence disorder, including alcohol, benzodiazepines, and 
opioids, but excluding nicotine, within 6 months prior to signing the ICF. 
13.  
Subjects with any condition or surgery 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. 
14.  
Subjects with a history of malignancy other than the following: 
• 
Non-metastatic basal or squamous cell carcinoma of the skin or carcinoma in situ that 
was surgically removed in total >1 year before signing the ICF and had not recurred 
• 
Another type of malignancy that had been in remission for ≥5 years before signing the 
ICF and had not recurred 
• 
Subjects with history of localized malignancy that was surgically removed and has been 
in remission for <5 years may be eligible for the trial only with explicit approval by the 
medical monitor 
Prior or Concomitant Medications 
15.  
Subjects with a positive urine drug screen or a positive test for alcohol are excluded (note: 
individuals who test positive for alcohol may be rescreened). Subjects with a positive urine drug 
screen resulting from use of marijuana (any THC-containing product), prescription, or 
over-the-counter medications or products that, in the investigator’s documented opinion, do not 
signal a clinical condition that would impact the safety of the subject or interpretation of the trial 
results may continue evaluation for the trial following consultation and approval by the medical 
monitor. 
16.  
Subjects who are using prohibited medications prior to randomization (as listed in Table 5) or 
who would be likely to require prohibited concomitant therapy (as listed in Table 6) during the 
trial. 

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Physical Examination and Clinical Laboratory Results 
17.  
Subject with clinically significant orthostatic hypotension at screening associated with either of 
the following: 
• 
Loss of consciousness (eg, syncope) 
• 
Presyncope (eg, severe dizziness/lightheadedness) requiring stabilization to avoid fall 
18.  
• 
Subjects with a supine/sitting blood pressure ≥160 mmHg (systolic) or ≥100 mmHg 
(diastolic). The average of 2 supine/sitting measurements will be used to assess 
eligibility.  
• 
For subjects with a supine/sitting blood pressure ≥140 mmHg (systolic) or ≥90 mmHg 
(diastolic), approval is required by medical monitor on a case-by-case basis.  
• 
Subjects receiving >2 antihypertensive medications for blood pressure control. 
19.  
Subjects with a 12-lead ECG demonstrating a QTcF interval ≥450 msec. 
At Screening (Visit 1): 
• 
Subjects with an ECG QTcF interval ≥450 msec based on the average of a centrally read 
triplicate set of ECGs.  
At Baseline (Visit 2): 
• 
If the QTcF interval is ≥450 msec on the machine reading, consult the medical monitor to 
determine whether the subject remains eligible to be randomized while awaiting the reading 
from the central service. 
20.  
Subjects with moderate to severe renal impairment (defined as Stage 3b estimated glomerular 
filtration rate <45 mL/min/1.73 m2, as calculated using the 4 parameters Modification of Diet in 
Renal Disease formula [Levey et al, 1999]). 
21.  
Subjects with any of the following abnormalities in clinical laboratory tests at the Screening 
Visit, as assessed by the central laboratory and confirmed by a single repeat measurement, if 
deemed: 
• 
AST or ALT ≥2 × ULN 
• 
Total bilirubin ≥1.5 mg/dL. Subjects with a history of Gilbert’s syndrome may be 
eligible provided they have a value <ULN for direct bilirubin 
• 
Positive result for HIV antibodies, HbsAg, or HCV antibodies 
o 
If a subject has completed treatment for hepatitis and is in remission with a 
viral load of 0, they may be eligible for the trial only with explicit approval by 
the medical monitor 
22.  
Subjects with uncontrolled thyroid disease or clinical laboratory results indicating hypo- or 
hyperthyroidism at the time of signing the ICF.  
23.  
Subjects with other abnormal laboratory test results, vital sign results, or ECG findings unless, in 
the judgment of the investigator, the findings are not medically significant and would not impact 
the safety of the subjects or the interpretation of the trial results. The medical monitor should be 
contacted to discuss individual cases, as needed. Tests with exclusionary results should be 
repeated to ensure reproducibility of the abnormality before excluding a subject based on the 
criteria provided in the protocol.  
Other 
24.  
Subjects who previously participated in any CVL-871 trial, including this trial, and received IMP. 

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25.  
Subjects who received treatment with any other investigational drug within 60 days before 
signing the ICF or who have participated in more than 2 drug intervention clinical trials within 
the year prior to signing the ICF. 
26.  
Subjects who have a known or suspected intolerance or hypersensitivity to the IMP, closely 
related compounds, or any of their stated ingredients. 
27.  
Subjects with significant communicative, auditory or visual impairment that would affect their 
ability to do neuropsychological testing or take part in a clinical trial, based on investigator 
judgment.  
28.  
Subject who resides in a long-term continuous care facility. 
29.  
Subject who is non-ambulatory or wheelchair bound. 
30.  
Any subject who, in the opinion of the sponsor, investigator, or medical monitor, should not 
participate in the trial. 
Abbreviations: AD = Alzheimer’s disease; AE = adverse event; ALT = alanine aminotransferase; 
AST = aspartate aminotransferase; C-SSRS = Columbia-Suicide Severity Rating Scale; 
DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, 5th Edition; DLB = dementia with Lewy 
bodies; ECG = electrocardiogram; FTD = frontotemporal dementia; HbsAg = hepatitis B surface antigen; 
HCV = hepatitis C virus; HIV = human immunodeficiency virus; ICF = informed consent form; IMP = 
investigational medicinal product; NPI = Neuropsychiatric Inventory; QTcF = QT interval corrected for 
heart rate using Fridericia’s formula; THC = tetrahydrocannabinol; ULN = upper limit of normal range; 
VAD = vascular dementia. 
5.3 
Lifestyle Considerations 
Subjects should take the IMP at approximately the same time each day (preferably in the 
morning at ~24-hour intervals), with or without food. No lifestyle restrictions are 
imposed. 
5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are not subsequently randomly assigned to trial treatment. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet 
the Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this trial (screen failure) at 
screening may be rescreened at the discretion of the investigator and after consultation 
with the medical monitor, unless screen failure is due to a positive urine drug screen. 
Rescreened subjects will be assigned a new subject number. 
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 subject according to 
the trial protocol. Investigational medicinal product refers to a pharmaceutical form of 

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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 administered during this trial is presented in Table 4. 
Table 4 
Investigational Medicinal Product Administered 
Treatment Group 
CVL-871 
Placebo 
Type  
Drug 
Drug 
Dose Formulation 
Tablet 
Matching tablet 
Unit Dose Strengths 
0.25, 0.5, 1, 2, and 3 mg 
0 mg 
Dosage Levels 
1 and 3 mg QD 
0 mg 
Route of 
Administration 
Oral 
Oral 
Sourcing 
Provided centrally by Cerevel 
Provided centrally by Cerevel 
Packaging and 
Labeling 
Trial treatment will be provided in 
bottles. Each dispensable unit will be 
labeled as per country requirement. 
Trial treatment will be provided in 
bottles. Each dispensable unit will be 
labeled as per country requirement. 
Abbreviations: QD = once daily. 
6.2 
Preparation/Handling/Storage/Accountability/Disposition 
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 sites network) for all IMP received and any discrepancies 
are reported and resolved before use of the IMP. In cases where caregivers/subjects are 
taking IMP from the site to their home following a site visit, it is not required for 
caregivers/subjects to document IMP temperature conditions during transit.  
Only subjects enrolled in the trial or their caregivers may be dispensed IMP and only 
authorized site staff or designee 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.  

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6.3 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1 
Subject Assignment to Treatment 
During the entire trial, treatment will be double-blind, ie, neither the investigator nor the 
subject will have knowledge of the treatment assignment at any visit.  
Treatment assignments will be based on a computer-generated randomization code 
provided by Cerevel or designee. Sponsor personnel, including those involved in 
monitoring, data management, and data analysis, will not have access to the treatment 
codes during the trial. Access to the treatment codes will be restricted to personnel 
charged with generating and maintaining randomization files, packaging IMP, operating 
the interactive response technology (IRT), and reporting SAEs to regulatory agencies.  
Once a randomization number has been assigned, it must not be reassigned.  
6.3.2 
Blinding 
The CVL-871 and placebo tablets will be identical in appearance and will be packaged in 
identically appearing bottles. All subjects will take a single tablet, either CVL-871 or 
placebo, once daily throughout the Treatment Period. Tablets will be packaged to allow 
dosage adjustments (as shown in Table 3) to be made without breaking the trial blind. 
Treatment assignments will be blinded to the investigators and other trial site personnel, 
the subjects, and all sponsor personnel who are involved in the conduct of the trial 
(including trial monitoring, data management, and data analysis). Access to the treatment 
codes will be restricted to personnel who are responsible for generating and maintaining 
the randomization code, packaging the IMPs, operating the IRT, analyzing the PK blood 
samples, or reporting SAEs or adverse events of special interest (AESI) to regulatory 
agencies. 
Although the integrity of blinding is critical to the validity of the trial assessments, 
subject safety must always be the first consideration. The IRT will be programmed with 
blind-breaking instructions. At the initiation of the trial, investigators and site personnel 
will be instructed on the method for breaking the blind in the event of subject safety 
emergency. In case of an emergency, the investigator has the sole responsibility for 
determining if unblinding of a subjects’ treatment assignment is warranted. However, the 
investigator should make every effort to contact the medical monitor prior to unblinding a 
subject’s treatment assignment unless this could delay emergency treatment of the 
subject. If a subject’s treatment assignment is unblinded, the medical monitor must be 
notified within 24 hours after breaking the blind. 
Documentation of breaking the blind should be recorded on the subject’s medical record 
with 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 subject, reinitiation of treatment 
with IMP cannot occur for that subject.  

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6.4 
Trial Treatment Compliance 
Responsible trial personnel will dispense the IMP. 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 electronic case report form (eCRF). 
The guidance and intent of this trial is for caregivers to administer IMP. Therefore, 
subjects and caregivers must be counseled on the importance of taking the IMP as 
directed. If poor compliance is encountered (eg, multiple missed doses resulting in less 
than 80% overall compliance at any point in the trial), discontinuation of the subject from 
the trial should be considered. Subjects who habitually miss visits or habitually attend 
visits outside of the protocol-defined visit window are also defined as noncompliant and 
should be considered for discontinuation. The medical monitor should be contacted if the 
investigator is uncertain whether a subject’s lack of compliance merits discontinuation 
from the trial. 
6.5 
Prior and Concomitant Therapy 
6.5.1 
Prior and Concomitant Medications 
The investigator will record all medications and therapies (including vaccines, over-the-
counter or prescription medicines, vitamins, and/or herbal supplements) taken by the 
subject from 30 days prior to signing of informed consent through the end of the 
evaluation period (defined as the time period during which subjects are evaluated for 
primary and/or secondary objectives) on the eCRF. The investigator will also record all 
medications and therapies taken by the subject for treatment of an AE or which caused an 
AE until the end of the trial (defined as the last date of contact or date of final contact 
attempt) on the eCRF. 
For concomitant medications, the following will be recorded in the eCRF: medication, 
indication, dose, frequency, route, start date and end date. For concomitant therapy, the 
following will be recorded in the eCRF: therapy, indication, start date, and end date. 
The medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
6.5.2 
Prohibited Medications 
All subjects must agree to discontinue all prohibited medications per times defined in 
Table 5. Other medications to treat medical conditions that are not specifically defined 
below are allowed. 

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Table 5 
Prohibited Prior Medications 
 
Prohibited Prior Medications 
Prohibited Duration 
of Use Prior to 
Randomization 
1. 
Cholinesterase inhibitors and memantine are prohibited with the 
following exception: 
• 
Dose has been stable for 60 days prior to randomization  
30 days (unless dose 
stable for 60 days prior 
to randomization) 
2. 
Antipsychotics 
3 months 
3. 
Tricyclic antidepressants and bupropion 
30 days 
4. 
SSRI/SNRIs (other than trazodone) are prohibited with the following 
exceptions: 
• 
Dose has been stable for 60 days prior to randomization 
 
30 days (unless dose 
stable for 60 days prior 
to randomization) 
5. 
Trazodone >50 mg/day for the treatment of depression.  
30 days 
6. 
Mood stabilizers and anticonvulsants (eg, lithium, valproate, 
carbamazepine) 
30 days 
7. 
Pregabalin and gabapentin are prohibited with the following 
exceptions: 
• 
Dose has been stable for 60 days prior to randomization 
• 
Medication is being used for pain indication. Usage for other 
indications (eg, behavioral management) is not allowed 
during the trial.  
• 
Dose should not exceed the recommended doses as listed in 
the respective US Package Inserts Dosage and Administration 
sections, including the maximum recommended dose in 
subgroup populations (as applicable) 
30 days (unless dose 
stable for 60 days prior 
to randomization) 
8. 
Benzodiazepines 
30 days 
9. 
Opioid analgesics 
30 days 
10. 
• 
High CNS penetrant anticholinergics used to treat tremor, other 
movement disorders, and overactive bladder (eg, benzatropine, 
oxybutynin, solifenacin, tolterodine).  
• 
Low CNS penetrant anticholinergics used to treat overactive 
bladder (eg, trospium) are allowed provided the dose does not 
exceed the maximum recommended doses as listed in the 
respective US Package Inserts Dosage and Administration 
sections, including the maximum recommended dose in subgroup 
populations (as applicable; eg, patients greater than 60 years of 
age). 
30 days 
11. 
Atomoxetine, modafinil, armodafinil, and varenicline 
30 days 
12. 
Psychostimulants (eg, methylphenidate, amphetamine, 
lisdexamfetamine) 
30 days 
13. 
Levodopa and/or other dopamine agonists (including levodopa 
inhalation powder or apomorphine) 
7 daysa 

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Prohibited Prior Medications 
Prohibited Duration 
of Use Prior to 
Randomization 
14. 
Nutritional supplements and nonprescription herbal preparations (eg, 
St. John’s wort, kava extracts, GABA supplements) that are provided 
in a medicinal form (eg, pill, capsule) due to the potential for CYP3A4 
drug-drug interactions  
30 days 
15. 
Strong or moderate inducers or inhibitors of CYP3A4 metabolism (see 
Section 10.6 [Appendix 6]).  
Inhibitors: 5 half-lives 
or 30 days (shorter of 
the 2)  
Inducers: 5 half-lives or 
21 days (longer of the 
2)  
16. 
Any investigational agent 
60 days or 5 half-lives 
(longer of the 2) 
Abbreviations: CNS = central nervous system; CYP = cytochrome P450, GABA = gamma-aminobutyric 
acid; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; 
US = United States. 
a. Contact the medical monitor for additional instruction if needed. 
Table 6 lists all medications prohibited during the trial, including exceptions where 
appropriate. Initiation of a new medication for treatment of a medical condition may be 
permitted if it is medically indicated due to a change in the subject’s underlying medical 
condition and is not otherwise prohibited (eg, cytochrome P450 [CYP] interaction). 
Consultation with the medical monitor is encouraged.  

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Table 6 
Prohibited Concomitant Medications 
 
Prohibited Concomitant Medications 
1. 
Cholinesterase inhibitors and memantine are prohibited with the following exception: 
o 
Dose was stable for 60 days prior to randomization and subject remains on the same 
dose throughout the duration of treatment 
2. 
All antipsychotics 
3. 
• 
Tricyclic antidepressants and bupropion are prohibited 
o 
SSRI and SNRI antidepressants are allowed provided the following: 
▪ 
The dose has been stable for 60 days prior to randomization and expected 
to remain unchanged for the duration of the trial.  
▪ 
 
4. 
Trazodone >50 mg/day for the treatment of depression 
5. 
Mood stabilizers and anticonvulsants (eg, lithium, valproate, carbamazepine) 
6. 
Pregabalin and gabapentin are prohibited with the following exceptions: 
• 
Dose has been stable for 60 days prior to randomization 
• 
Medication is being used for pain indication. Usage for other indications (eg, behavioral 
management) is not allowed during the trial.  
• 
Dose should not exceed the recommended doses as listed in the respective US Package 
Inserts Dosage and Administration sections, including the maximum recommdned dose 
in subgroup populations (as applicable) 
7. 
• 
Benzodiazepines and buspirone are prohibited 
o 
Nonbenzodiazepine sleep agents (ie, zolpidem, zaleplon, zopiclone, and 
eszopiclone) and low-dose trazodone (up to 50 mg) are allowed for treatment of 
insomnia 
▪ 
For the nonbenzodiazepine sleep aids, only one of the listed medications 
may be used. Country-specific prescribing information must be followed to 
determine the maximum allowable daily dose for the treatment of insomnia 
in elderly or debilitated patients (typically half of the normal adult 
maximum dose). 
8. 
Opioid analgesics 
9. 
• 
High CNS penetrant anticholinergics used to treat tremor, other movement disorders, and 
overactive bladder (eg, benzatropine, oxybutynin, solifenacin, tolterodine). 
o 
Low CNS penetrant anticholinergics used to treat overactive bladder (eg, trospium) 
are allowed provided the dose does not exceed the maximum recommended doses 
as listed in the respective US Package Inserts Dosage and Administration sections, 
including the maximum recommended dose in subgroup populations (as applicable; 
eg, patients greater than 60 years of age). 
10. 
Atomoxetine, modafinil, armodafinil, and varenicline 

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Prohibited Concomitant Medications 
11. 
Psychostimulants (eg, methylphenidate, amphetamine, lisdexamfetamine) 
12. 
• 
Antihistamines with sedating effects (eg, diphenhydramine) 
o 
Nonsedating antihistamines (eg, fexofenadine, loratadine) are allowed 
13. 
• 
Anticoagulants such as warfarin, heparin, direct thrombin inhibitors (eg, dabigatran), and 
direct factor Xa inhibitors (eg, rivaroxaban, apixaban).  
o 
Anti-platelet medications (eg, aspirin, clopidogrel) are permitted. 
14. 
• 
Levodopa and/or other dopamine agonists (including levodopa inhalation powder or 
apomorphine) 
15. 
Nutritional supplements and nonprescription herbal preparations (eg, St. John’s wort, kava 
extracts, GABA supplements) that are provided in a medicinal form (eg, pill, capsule) due to the 
potential for CYP3A4 drug-drug interactions 
16. 
Strong or moderate inducers or inhibitors of CYP3A4 metabolism (see Section 10.6 [Appendix 
6]).   
17. 
Any investigational agent 
Abbreviations: CNS = central nervous system; CYP = cytochrome P450, GABA = gamma-aminobutyric 
acid; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; 
US = United States. 
6.6 
Dose Modification 
This is a fixed-dose trial of CVL-871 1.0 mg QD and CVL-871 3.0 mg QD. The dose of 
CVL-871 will be titrated to the randomized dose, as shown in Table 3, and then 
maintained for the remainder of the trial. Procedures for dose modification are provided 
in Section 4.1.2.  
Dose modifications will be achieved by issuing the subject new bottles with the adjusted 
dose such that the subject continues to take 1 tablet each day. The IMP will be packaged 
in a manner that will allow dose modifications to be made without unblinding the trial. 
6.7 
Intervention after the End of the Trial 
There will be no provision of CVL-871 for subjects after they complete or discontinue 
treatment in this trial. Subjects/caregivers should consult with the investigator to 
determine appropriate treatment regimens following completion or discontinuation of 
trial treatment. 
7 DISCONTINUATION OF TRIAL TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Trial Treatment 
After treatment assignment, a subject may stop treatment permanently for a variety of 
reasons. Treatment discontinuations may be initiated by a subject who is not satisfied 
with treatment or may become medically necessary due to AEs, required treatment with a 

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disallowed medication or therapy, or other issues, as determined by the investigator. If 
IMP is permanently discontinued, the subject will be encouraged to remain in the trial for 
the evaluations at safety follow-up. See the Schedule of Assessments (Table 1) 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 subject 
• 
Physician decision 
If a subject 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)/Independent Ethics 
Committees (IECs), and regulatory authorities in accordance with regulatory 
requirements. 
7.2.2 
Discontinuation of Individual Site 
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB/IEC 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/IEC at the site. 
7.2.3 
Individual Subject Discontinuation From the Trial  
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects 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 subject’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, as shown in the Schedule of Assessments (Table 1). See the Schedule of 
Assessments (Table 1) for data to be collected at the time of trial discontinuation and 
follow-up and for any further evaluations that need to be completed. 

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The subject will be permanently discontinued both from the IMP and from the trial at that 
time. 
Complete withdrawal of consent requires a subject’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 subject and staff). 
○ Contact of the subject 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 subject’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 subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject 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 
subject can continue participation in the trial if modifications to his/her treatment and/or 
schedule of assessments can be accommodated. Only subjects 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 subject their options of continuing in the trial. 
The investigator should ensure understanding and documentation of the reasons for the 
subject’s desire to withdraw consent. 
7.4 
Lost to Follow up 
A subject will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the trial site personnel. 

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The following actions must be taken if a subject fails to return to the site for a required 
trial visit: 
• The site personnel must attempt to contact the subject and reschedule the missed visit 
as soon as possible and counsel the subject on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the subject wishes to and/or 
should continue in the trial. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls, and 
a certified letter to the subject’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject’s medical 
record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the trial. 
8 TRIAL ASSESSMENTS AND PROCEDURES 
Trial procedures and their timing are summarized in the Schedule of Assessments  
(Table 1). Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue trial 
intervention.  
Adherence to the trial design requirements, including those specified in the Schedule of 
Assessments, is essential and required for trial conduct. 
8.1 
Screening and Baseline Assessments 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. Protocol waivers or exemptions are not allowed. The 
investigator will maintain a screening log to record details of all subjects who are 
screened and to confirm eligibility or record reasons for screening failure, as applicable.  
The sponsor reserves the right to utilize oversight methods to ensure the validity of 
diagnosis, severity of illness, and other factors determining appropriateness of subject 
selection. 
Procedures that are conducted as part of the subject’s routine clinical management (eg, 
blood count) and obtained before the informed consent form (ICF) is signed may be used 
for screening or baseline purposes provided the procedures meet the protocol-specified 
criteria and were performed within the time frame that is defined in the Schedule of 
Assessments (Table 1). 

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The following screening tests will be completed to ensure the subject is suitable for 
inclusion in the trial.  
8.1.1 
Diagnostic Criteria for Apathy 
The subject will be evaluated for apathy at screening using the recently published ISCTM 
diagnostic criteria for apathy in neurocognitive disorders (see Section 5.1; Miller et al, 
2021). These criteria require that a subject’s must meet all 4 of the following: 1) meet 
criteria for a syndrome of cognitive impairment or dementia, 2) exhibit at least 1 
symptom in 2 of 3 domains (diminished initiative, diminished interest, diminished 
emotional expression/responsiveness), which are persistent or frequently recurrent for a 
minimum of 4 weeks and represent a change from patient’s normal behavior, 3) 
symptoms are not exclusively explained by other factors, and 4) symptoms cause 
clinically significant impairment in personal, social, occupational, and/or other important 
areas of functioning.  
8.1.2 
Mini Mental State Examination 
The Mini Mental State Examination (Folstein et al, 1975) will be conducted at screening 
to evaluate the subject’s mental status and confirm it meets the inclusion criteria score of 
12 to 26 (see Section 5.1).  
8.1.3 
Neuropsychiatric Inventory Rating Scale 
The NPI (see Section 8.7.1) will be utilized at screening for confirmation of subject’s 
clinically significant apathy (see Section 5.1) and to rule out exclusionary comorbid 
psychiatric diagnoses (see Section 5.2). 
8.2 
Efficacy Assessments 
Not applicable; pharmacodynamic assessments are discussed in Section 8.7. 
8.3 
Safety Assessments 
Planned time points for all safety assessments are provided in the Schedule of 
Assessments (Table 1). 
Safety assessments should be performed after all pharmacodynamic assessments have 
been completed. Assessments should be performed in the following order: 
• C-SSRS 
• Physical and neurological examinations 
• Vital sign measurements  
• ECGs 

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• Blood specimen collection 
• Other procedures (eg, concomitant medications, AEs): all other procedures may be 
obtained before or after blood specimen collection 
8.3.1 
Physical Examinations 
A full physical examination will consist of measurement of height (screening only) and 
weight and a review of the following body systems: head, ears, eyes, nose, mouth, skin, 
heart and lung examinations, lymph nodes, gastrointestinal, and musculoskeletal systems. 
A full neurological examination will include an assessment of the subject’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 following guidelines will aid in the standardization of body weight measurements: 
• Scales should be calibrated and reliable; scales should be at zero just prior to each 
subject’s weigh-in session 
• A subject should void prior to being weighed and be minimally clothed (ie, no shoes 
or heavy overgarments) 
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. 
8.3.2 
Vital Sign Measurements 
Vital signs include systolic and diastolic blood pressures, heart rate, and body 
temperature. Duplicate blood pressure and heart rate measurements will be obtained 
sitting/supine (after 5 minutes of rest) followed by a single standing measurement (after 
2 minutes of rising from sitting/supine position). The duplicate values will be 
individually recorded, and the values will be averaged by the sponsor for the time point 
assessment. At each visit, body temperature will be obtained once, at the time of the first 
blood pressure measurement. 
Any clinically relevant changes occurring during the trial will be recorded in the AE 
section of the eCRF. 

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Further details on taking vital sign measurements are provided in the appropriate trial 
specific manuals. 
8.3.3 
Electrocardiograms 
Electrocardiogram recordings will be obtained after the subject has been 
supine/semi-recumbent and at rest for approximately 3 minutes. Additional ECGs may be 
obtained at the investigator’s discretion and should always be obtained in the event of 
early termination. The ECG results will be evaluated at the investigational site to 
determine the subject’s eligibility and to monitor safety during the trial. The investigator 
(or qualified designee) will review, sign, and date each ECG reading, noting whether or 
not any abnormal results are of clinical significance. Any clinically relevant changes 
occurring during the trial will be recorded in the AE section of the eCRF. The ECG will 
be repeated if any results are considered to be clinically significant. A central ECG 
service will be used for reading all ECGs in order to standardize interpretations for the 
safety analysis. 
At Screening, a triplicate set of 12-lead ECGs is required to assess subject 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 
subject or the interpretation of the trial results) or meets an exclusion criterion (see 
Section 5.2), the subject should be excluded from the trial. Based on the QT interval as 
corrected for heart rate by Fridericia’s formula (QTcF), a subject will be excluded if the 
average QTcF interval of the triplicate set of screening ECGs is ≥450 msec, as read by 
the central ECG service.  
At all other specified time points in the Schedule of Assessments (Table 1) where an 
ECG recording must be performed, only a single ECG is required. If, at the Baseline 
Visit, the QTcF interval is ≥450 msec on the machine reading, consult the medical 
monitor to determine whether the subject remains eligible to be randomized while 
awaiting the reading from the central service. 
Exclusion criteria for screening do not apply as mandatory discontinuation criteria for 
subjects who are already randomized. A repeat ECG should be performed to confirm any 
clinically significant abnormality that is identified in a randomized subject during the 
treatment period (which will be confirmed by central service read) and, in these cases, the 
medical monitor should be consulted on the appropriateness of the subject continuing in 
the trial. 
8.3.4 
Clinical Safety Laboratory Assessments 
See Section 10.1 (Appendix 2) for the list of clinical laboratory tests to be performed and 
the Schedule of Assessments (Table 1) for the timing and frequency. 

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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 10.1 (Appendix 2), 
must be conducted in accordance with the laboratory manual and the Schedule of 
Assessments (Table 1). 
8.3.5 
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 subject 
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 
subjects at screening to determine eligibility. Any subject with active suicidal ideation 
within the last 6 months, suicidal behaviors within the last 2 years, or who in the clinical 
judgment of the investigator presents a serious risk of suicide should be excluded from 
the trial (Section 5.2). 
The “Since Last Visit” C-SSRS form will be completed at all visits 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 subject to continue in the trial. If a subject 
demonstrates potential suicidal ideation associated with actual intent or method or plan as 
indicated by “YES” answers on item 4 or 5 of the C-SSRS, 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 whether 
the subject 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). 

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Adverse events will be reported by the subject (or, when appropriate, by a caregiver, 
surrogate, or the subject’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 subject 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 collected from the signing of the ICF until follow-up contact 
on Day 113 at the time points specified in the Schedule of Assessments (Table 1). 
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 subject has been discharged from the trial, and he/she considers the event to 
be reasonably 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 subject 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 
subject at subsequent visits/contacts. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the subject is lost to follow-up (as 
defined in Section 7.4). Further information on follow-up procedures is given in Section 
10.3 (Appendix 3). 

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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 
subjects 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 comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC, 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 a 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/IEC, if appropriate according to local requirements. 
8.4.5 
Pregnancy 
Details of all pregnancies in female partners of male subjects will be collected after the 
start of IMP and until the final contact on Day 113.  
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). 
Brief narratives will be written for any subject who reports an AESI. 
8.4.6.1 
Symptoms Suggestive of Symptomatic Orthostatic Hypotension 
• Syncope 
• Presyncope requiring stabilization to avoid fall 
• Generalized weakness, sensations described as dizziness or lightheadedness, visual 
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8.4.6.2 
Nausea Grade 3 
• Grade 3 nausea, defined as inadequate oral caloric or fluid intake; tube feeding, total 
parenteral nutrition, or hospitalization indicated 
8.4.6.3 
Vomiting Grade 2 or Higher 
• Grade 2 vomiting, defined as vomiting requiring outpatient intravenous hydration or 
other medical intervention (eg, anti-emetic) 
8.4.6.4 
Abnormal Liver Function Tests 
The finding of an elevated value for alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) of >3 × the upper limit of normal (ULN) in combination with 
either an elevated value for total bilirubin >2 × ULN or clinical jaundice in the absence of 
cholestasis or other causes of hyperbilirubinemia is considered to be an indicator of 
severe liver injury. Investigators must report the occurrence of either of the following as 
AESI to the sponsor with 24 hours: 
• 
Treatment-emergent value of >3 × ULN for ALT or AST and >2 × ULN for total 
bilirubin 
• 
Treatment-emergent value of >3 × ULN for ALT or AST and clinical jaundice 
8.4.6.5 
Abnormal Dreams/Nightmares 
Either of the following AEs: 
• Abnormal dreams 
• Nightmares 
8.4.6.6 
Adverse Events Potentially Related to Abuse 
A key objective of the Abuse Potential Monitoring Plan (APMP) is to monitor for 
instances of abuse or diversion of the trial medication and other psychoactive substances. 
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, medication handling irregularities (MHIs) must be reported, and AEs related to 
abuse potential and AEs involving MHIs must be reported as events subject to additional 
monitoring (ESAMs), with detailed narratives. 
Investigators and site staff at each trial site will be trained on reporting potentially 
abuse-related AEs (eg, recording a description of the event in the subject’s own words in 
the source documents as well as the eCRF, in addition to the clinical term, and to be 
aware that a subject’s report may encompass more than one event and that these should 

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be recorded separately). The investigators will be provided with examples of potentially 
abuse-related AEs and trained on how to handle such events (eg, additional monitoring). 
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 (Guidance for 
Industry: Assessment of Abuse Potential of Drugs, January 2017). 
Complete details, including documenting and reporting procedures, examples of 
potentially abuse-related terms and guidance for the training of investigators and trial site 
staff are provided in the APMP. 
8.4.6.7 
Adverse Events Leading to Discontinuation 
Any AE that leads to discontinuation of IMP or from the trial will be classified as an 
AESI.  
8.5 
Treatment of Overdose 
For this trial, any dose of CVL-871 greater than 3 mg/day could potentially be considered 
an overdose. Refer to Table 3 for the number of tablets that could result in the maximum 
dose at each titration step. Consult with the medical monitor if there are any questions. 
There is no specific antidote for overdose with CVL-871. Treatment of overdose should 
consist of general supportive measures.  
In the event of an overdose, the investigator should complete the following: 
1. 
Contact the medical monitor immediately. 
2. 
Closely monitor the subject for any AE/SAE and laboratory abnormalities until 
CVL-871 can no longer be detected systemically (at least 5 days). 
3. Obtain a plasma sample for PK analysis within 1 day from the date of the last dose 
of CVL-871, if requested by the medical monitor (determined on a case-by-case 
basis). 
4. 
Document the quantity of the excess dose as well as the duration of the 
overdose in the eCRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator 
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8.6 
Pharmacokinetics 
Single blood samples will be collected in appropriately labeled tubes for determination of 
the concentration of CVL-871 in plasma at times specified in the Schedule of 
Assessments (Table 1).  
As part of understanding the PK of CVL-871, samples may be used for metabolite 
identification and/or evaluation of the bioanalytical method. These data will be used for 
internal exploratory purposes and will not be included in the Clinical Study Report. 
Additional details regarding the collection, processing, storage, and shipping of all PK 
plasma samples will be provided in a laboratory manual. All plasma samples will be 
analyzed for analyte using a validated bioanalytical method.  
8.7 
Pharmacodynamic Assessments 
The planned time points for pharmacodynamic assessments are shown in the Schedule of 
Assessments (Table 1). At each clinic visit, pharmacodynamic assessments should be 
completed first, followed by the safety assessments. 
A caregiver must be identified during the Screening Period for participation in and/or 
completion of appropriate assessments. 
The same caregiver must assist the subject and complete all assessments throughout the 
duration of the trial. 
8.7.1 
Neuropsychiatric Inventory-Clinician and Neuropsychiatric 
Inventory Rating Scales 
The NPI assesses 12 behavioral and psychiatric symptoms in dementia including domains 
for delusions, hallucinations, agitation/aggression, apathy, depression, euphoria, aberrant 
motor behavior, irritability, disinhibition, anxiety, sleeping, and eating (Cummings et al, 
1994). The NPI domain score for each domain is the product of frequency score × 
severity score reported by the caregiver in response to clinician administered questions 
specific to each domain. Higher scores are indicative of more frequent and/or severe 
symptoms. The NPI-C is a revised version of the original NPI and includes expanded 
domains and domain subitems, and a clinician rated severity score as the principle 
scoring methodology (de Medeiros et al, 2010). Unlike the NPI, the NPI-C allows the 
rater to obtain additional caregiver and patient information to inform the rating for each 
item within a domain. The frequency and the severity of each behavior item are 
determined on 5-point (0 to 4) and 4-point (0 to 3) scales, respectively, based on 
caregiver interview responses. An additional rating of caregiver distress is included 
(6-point scale from 0 to 5). The clinician also observes and interviews the patient, when 
possible, to inform on the frequency of symptoms and overall clinical presentation. The 
clinician provides a clinical impression severity score for each item within the domain 
using a 4-point (0 to 3) scale, which is based on all available clinical (eg, medical 
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information. An NPI-C total domain score based on the clinician impression can be 
calculated by summing the individual rating score for each domain item. Higher scores 
are indicative of more frequent and/or severe symptoms. The instrument can be used as a 
stand-alone measure for specific neuropsychiatric domains (eg, dysphoria, apathy) or a 
combination of both (combination of domains with focus on one or more specific 
domains). Only the NPI-C apathy and dysphoria domains will be utilized as assessment 
measures in this trial; other NPI-C domains will not be utilized. The NPI will be utilized 
to assess all 12 neuropsychiatric domains, including apathy and dysphoria, for 
confirmation of inclusion/exclusion criteria and for ongoing evaluation during the 
treatment phase. 
8.7.2 
Dementia Apathy Interview and Rating 
The DAIR is a 16-item structured interview with the primary caregiver designed to assess 
illness-related changes in motivation, emotional responsiveness, and engagement (Strauss 
and Sperry, 2002). Each interview question consists of 2 parts: 1) how often a specific 
behavior was observed over the past month and 2) whether the behavior in first item had 
changed from the time prior to the memory loss. Apathy item scores range from 0 
(patient shows apathetic behavior almost never or less than once a week) to 3 (patient 
shows apathetic behavior almost always or almost every day). Items are counted only if 
the behavior represents a changed toward apathy from pre-illness behavior. The total 
apathy score is a sum of all items reflecting change, divided by the number of items 
completed, with higher scores representing greater average apathy.  
8.7.3 
Apathy Evaluation Scale-Clinician 
The AES-C is an 18-item rating scale which is completed by a clinician that measures 
apathy severity as defined by deficits in behavioral, cognitive, and emotional constructs 
of goal-directed behavior. Higher scores reflect greater apathy severity (Marin et al, 
1991).  
8.7.4 
Alzheimer’s Disease Assessment Scale – Cognition Subscale 
The ADAS-Cog is the most widely used general cognitive measure in clinical trials of 
AD. The original ADAS-Cog (Rosen et al, 1984) includes 11 items assessing cognitive 
function. The domains include memory, language, praxis, and orientation. The modified 
ADAS-Cog13 (Mohs et al, 1997), which will be used in this trial, includes all original 
ADAS-Cog items with the addition of a number cancellation task and a delayed free 
recall task, for a total of 85 points. As in the parent instrument, higher scores indicated 
greater severity. 
8.7.5 
Modified Alzheimer’s Disease Cooperative Study–Clinical Global 
Impression of Change 
The original ADCS-CGIC focuses on clinicians’ observations of change in the subject’s 
cognitive, functional, and behavioral performance (Schneider et al, 2009). The original 
ADCS-CGIC has been modified specially for apathy in dementia. 

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Scoring is based on an interview with the caregiver by an independent, skilled, and 
experienced clinician with questions related to the severity of the subject’s overall 
clinical condition and apathy symptoms specifically. Scores are on a 7-point scale where 
1 is “marked improvement” and 7 is “marked worsening” with a rating of 4 representing 
“no change”. It is important to note that the assessment will reflect the subject’s current 
condition compared with their condition at baseline (Visit 2). A baseline worksheet will 
be completed by the rater to assist in making all post-baseline comparisons and ratings.  
8.7.6 
Modified Clinical Global Impression-Severity Scale 
The mCGI-S is an observer-rated scale that will be used to measure both the severity of 
the subject’s overall clinical condition and their apathy symptoms specifically.  
To perform this assessment, the investigator (or designee) will answer questions related 
to the severity of the subject’s overall dementing illness (cognition, behavior, and 
function) and apathy symptoms specifically, providing a severity rating score based upon 
their total clinical experience with the patient population and upon observed and reported 
symptoms, behavior, and function in the past 4 weeks. Scores are on a 7-point scale 
where 1 is “normal, not at all ill/no symptoms” and 7 is “among the most extremely ill 
patients/very severe symptoms”.  
8.7.7 
Caregiver Global Impression-Severity Scale 
The CaGI-S is a caregiver-rated scale that will be used to measure both the severity of the 
subject’s overall clinical condition and their apathy symptoms specifically.  
To perform this assessment, the caregiver will answer the questions related to the severity 
of the subject’s overall dementing illness (cognition, behavior, and function) and apathy 
symptoms specifically based upon their observations over the past 4 weeks. Scores are on 
a 7-point scale where 1 is “normal, no symptoms of apathy/normal, not at all impaired” 
and 7 is “extremely severe apathy/extremely severely ill”.  
8.7.8 
Caregiver Global Impression-Change Scale 
The CaGI-C is a caregiver-rated scale that will be used to measure change in both the 
subject’s overall dementing illness (cognition, behavior, and function) and their apathy 
symptoms specifically compared with before initiation of treatment with IMP. It is 
important to note that the caregiver will provide their assessment of the subject’s current 
condition compared with their condition at baseline (Visit 2).   
To perform this assessment, the caregiver will rate the subject’s change from baseline in 
their overall dementing illness (cognition, behavior, and function) and in their apathy 
symptoms specifically. Scores are on a 7-point scale where 1 is “marked improvement in 
apathy/overall dementia” and 7 is “marked worsening in apathy/overall dementia”.  

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8.8 
Pharmacogenomics 
Blood samples will be collected for analysis of catechol-O-methyltransferase (COMT) 
genotype. 
8.9 
Biomarkers 
Biomarkers are not evaluated in this trial. 
8.10 Future Biospecimen Research 
Studying the variation in genetic markers and other biomarkers may help to explain some 
of the variability in response seen with some drugs among different individuals. This is 
referred to as pharmacogenomic/biomarker research. Comparing the deoxyribonucleic 
acid (DNA), ribonucleic acid (RNA), protein, and metabolite variation patterns of 
subjects who respond well and those who respond poorly to treatment may help to better 
define the most appropriate group of subjects 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 subjects 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) and will only be conducted on specimens from appropriately 
consented subjects.  
8.11 Health Economics 
Not applicable.  
9 STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
The trial is designed primarily to assess the safety and tolerability of CVL-871 in subjects 
with dementia-related apathy and to estimate the treatment response in pharmacodynamic 
endpoints. Formal hypothesis testing is not the key objective of this trial of exploratory 
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9.2 
Sample Size Determination 
While formal hypothesis testing is not the key objective of this trial, a sample size of 
approximately 75 subjects randomized in a 1:1:1 manner between the placebo and 2 
CVL-871 arms should allow the trial to have approximately 80% probability to detect an 
effect size (treatment difference/population standard deviation [SD]) of 0.678 in change 
from Baseline on the NPI apathy domain score at Week 12 between an active dose group 
and placebo, at a 2-sided alpha = 0.2 level (ie, an 80% confidence interval excluding 
zero). A sample size of 60 subjects randomized 1:1:1 to the 3 treatment groups would 
allow this exploratory trial to detect an effect size of 0.761 with 80% power at a 2-sided 
alpha level of 0.2. A discontinuation rate of 20% was taken into considerationin the 
sample size calculation. As a reference, in the ADMET 1 trial (6 weeks of treatment with 
methylphenidate for apathy in Alzheimer’s disease), an effect size 0.5625 (mean 
difference of 1.8 and SD of 3.2) on the change from baseline in the NPI apathy domain 
score was observed (Rosenberg et al, 2013) . 
In the event of higher than anticipated early terminations, Cerevel may extend enrollment 
in order to maintain the planned statistical power of the trial. 
9.3 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Table 7 
Populations for Analysis 
Population 
Description 
Enrolled 
Comprises all subjects who consent to participate in the clinical trial. 
Intent-to-Treat 
Comprises all randomized subjects. 
Full Analysis Set 
Comprises all randomized subjects who receive at least 1 dose of IMP. 
Modified ITT Set 
Comprises all randomized subjects who receive at least 1 dose of IMP and 
have at least 1 post-baseline assessment of the NPI apathy subscale score. 
Abbreviations: IMP = investigational medicinal product; ITT = intent-to-treat; NPI = Neuropsychiatric 
Inventory. 
9.4 
Statistical Analyses 
The statistical analysis plan (SAP) will be developed and finalized before database lock 
and will describe the details on subject populations to be included in the analyses, and 
procedures for accounting for missing, unused, and spurious data. This section is a 
summary of the key statistical analyses planned for the primary and secondary endpoints. 
9.4.1 
General Considerations 
Descriptive statistical methods will be used to summarize the safety/tolerability, 
pharmacodynamic, and PK  data from this trial. Statistical modelling will also be 
performed for the pharmacodynamic endpoints.  

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All statistical analyses will be conducted with the SAS® System, version 9.4 or higher. 
Full details of all planned analyses will be provided in the SAP.  
9.4.2 
Pharmacodynamic Analyses 
Pharmacodynamic endpoints with repeated post-baseline assessments will be analyzed 
using a mixed-model repeated measures (MMRM) analysis, including baseline score (if 
applicable), treatment, concomitant SSRI/SNRI use, visit, and the interaction between 
treatment group and visit as fixed factors in the model. Subject will be included as a 
random effect in the model.  
The trial is designed as a learning trial instead of a confirmatory trial. The key research 
question for the pharmacodynamic endpoints will be primarily addressed with an 
estimand based on the following attributes: 1) treatments as randomized regardless of the 
final dose level achieved following the titration steps, 2) subjects in the modified intent-
to-treat (mITT) population who tolerate dose increases to at least Step 4 on Day 21 
during titration as the target trial population, 3) change from Baseline to Week 12 as the 
key endpoint of interest, 4) the treatment differences estimated based on the least square 
mean and the corresponding 80% confidence interval from the MMRM model as the 
population level summary, and 5) a hypothetical strategy to address intercurrent events 
(ICEs) of potential death, treatment discontinuations, missed visits, and start of prohibited 
concomitant medications unless a treatment-related reason can be identified for a given 
ICE. If such reasons are identified, a composite strategy may be taken, eg, assigning 
highest severity to the case, to ensure appropriate interpretation of the data. Further 
details, including additional estimands for the research questions on the effect of 
combined CVL-871 treatment group versus placebo and on the effect of final dose levels 
of CVL-871 following the completion of titration versus placebo, will be described in the 
SAP. 
9.4.3 
Pharmacokinetic Analyses 
Plasma concentration data of CVL-871 will be summarized for each dose at each time 
point using descriptive statistics and graphs.  
9.4.4 
Safety Analyses 
The safety analysis will be conducted on the full analysis set. Analyses will be performed 
based on the actual treatment received. Treatment-emergent adverse events will be coded 
according to the MedDRA and summarized by treatment group, 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 group, 
including suicidality monitored during the trial using C-SSRS.  
All data collected for subjects in the screen failures data set will be listed separately. 

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9.4.5 
Interim Analyses  
No interim analyses are planned. 
9.4.6 
Safety Review Team 
In addition to routine safety monitoring during trial conduct, a Safety Review Team 
(SRT) will review blinded safety data at specified time points and provide a 
recommendation on trial conduct, which will be described in a separate SRT charter. 
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 Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the trial is initiated. 
Any substantial amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the trial design, except for changes necessary to 
eliminate an immediate hazard to trial subjects. 
The investigator will be responsible for the following: 
○ Providing written summaries of the status of the trial to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
○ Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
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○ Providing oversight of the conduct of the trial at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, 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 subject 
and caregiver and answer all questions regarding the trial. 
Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorized representative (as applicable by local law) 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/IEC or trial center. Caregivers will also 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/IEC or trial center. 
The medical record must include a statement that written informed consent was obtained 
before the subject 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. 
Subjects/legally authorized representatives and caregivers 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 subject/legally authorized representative 
and caregiver. 
A separate and similar consent process will be followed for the optional future 
biospecimen research samples. The investigator or authorized designee will explain to 
each subject the objectives of the exploratory research. Subjects will be told that they are 
free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. A separate signature will be required to document a 
subject's agreement to allow specimens to be used for exploratory research. Subjects who 
decline to participate in this optional research will not provide this separate signature. 

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10.1.4 
Data Protection 
Subjects will be assigned a unique identifier by the sponsor or designee. Any subject 
records or datasets that are transferred to the sponsor will contain the identifier only; 
subject names or any information which would make the subject identifiable will not be 
transferred. 
The subject 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 subject and outlined in the ICF. 
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC 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, 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 subjects 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 4.4 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 4.4 for 
trials in adult populations or within 6 months of the primary completion date for trials in 
pediatric populations. 
10.1.6 
Data Quality Assurance 
All subject 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. 

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The investigator must permit trial-related monitoring, audits, IRB/IEC 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 subjects 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 reports 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 subject 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 previous medical records or transfer records, depending on the trial. Also, 
current medical records must be available. 

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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 subjects 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 8 will be performed by the central laboratory. 
Protocol-specific requirements for inclusion or exclusion of subjects 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. 
Serology (screening for human immunodeficiency virus, hepatitis B virus, hepatitis C 
virus) will be done at screening and SARS-CoV2 tests may be done at investigator 
discretion.  

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• 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 
subject. 
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. 
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 and bilateral oophorectomy.  
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
Sterilized male subjects 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 Subjects With Partners Who Become Pregnant 
• The investigator will attempt to collect pregnancy information on any male subject’s 
female partner who becomes pregnant while the male subject is in this trial. This 
applies only to male subjects 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 

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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 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure.  
10.5 Appendix 5: Future Biospecimen Research 
Use/Analysis of DNA 
• 
Genetic variation may impact a subject’s response to IMP, susceptibility to, and 
severity and progression of disease. Variable response to IMP 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. Therefore, where local regulations and 
IRB/IEC allow, a blood sample will be collected for DNA analysis from 
consenting subjects. 
• 
DNA samples will be used for research related to CVL-871, Alzheimer’s disease 
and other dementia disorders, or apathy or other cognition disorders. They may 
also be used to develop tests/assays including diagnostic tests related to CVL-871 
or interventions of this drug class and dementia disorders. 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-871 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-871 or interventions of this 
drug class or dementia disorders continues but no longer than 15 years or other 
period as per local requirements. 

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10.6 Appendix 6: Moderate to Strong Inducers and Inhibitors of 
Cytochrome P450 3A (not exhaustive) 
Note that this is not a complete list and that the investigator is responsible for ensuring that 
subjects are not receiving any strong or moderate inducers or inhibitors of CYP3A during the 
trial.  
CYP 3A Inhibitors 
CYP 3A Inducers 
Antivirals 
Antivirals 
Nirmatrelvir/ritonavira 
Efavirenz 
Indinavir 
Nevirapine 
Nelfinavir 
Etravirine 
Ritonavir 
Tipranavir 
Saquinavir 
Miscellaneous 
Boceprevir 
Barbiturates 
Lopinavir/ritonavir 
Carbamazepine 
Amprenavir 
Cenobamate 
Atazanavir 
Eslicarbazepine 
Telaprevir 
Glucocorticoids (systemic) 
Darunavir/ritonavir 
Modafinil 
Fosamprenavir 
Oxcarbazepined 
Antibiotics 
Phenobarbital 
Clarithromycin 
Phenytoin 
Erythromycin 
 Rifabutin 
Telithromycin 
Rifampin 
Ciprofloxacin 
St. John’s wort 
Anti-infectives 
Bosentan 
Itraconazole 
 
Ketoconazole 
 
Fluconazole 
 
Posaconazole 
 
Voriconazole 
 
Anti-anginal therapy 
 
Diltiazem 
 
Verapamil 
 
Anti-cancer therapy 
Crizotinib 
Imatinib 
Miscellaneous 
Nefazodone 
Aprepitant 
Grapefruit juiceb 
Conivaptan 
a Paxlovid (nirmatrelvir co-packed with ritonavir) is prohibited. 
b A 2-week washout prior to dosing is required if grapefruit juice was being consumed continually. 

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10.7 Appendix 7: Abbreviations 
Abbreviation 
Definition 
AD 
Alzheimer’s disease 
ADAS-Cog 
Alzheimer’s Disease Assessment Scale – Cognition 
ADAS-Cog13 
Alzheimer’s Disease Assessment Scale – Cognition 13-item scale 
AE 
adverse event 
AES-C 
Apathy Evaluation Scale-Clinician 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
APMP 
Abuse Potential Monitoring Plan  
AST 
aspartate aminotransferase 
cAMP 
cyclic adenosine monophosphate  
CNS 
central nervous system 
COMT 
catechol-O-methyltransferase  
COVID-19 
coronavirus disease-2019 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DAIR 
Dementia Apathy Interview and Rating  
DCA 
diagnostic criteria for apathy  
DLB 
dementia with Lewy bodies 
DNA 
deoxyribonucleic acid 
DX 
dopamine X receptor (1 through 5) 
EC50 
concentration required for half maximal effect 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ESAM 
event subject to additional monitoring 
EU 
European Union 
FDA 
Food and Drug Administration 
FTD 
frontotemporal dementia 
GCP 
Good Clinical Practice 
hDX 
human DX receptor (D1-D5) 
ICE 
intercurrent event 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 

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Abbreviation 
Definition 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ISCTM 
International Society for CNS Clinical Trials and Methodology 
MAD 
multiple ascending dose 
mADCS-CGIC 
modified Alzheimer’s Disease Cooperative Study–Clinical Global Impression of 
Change 
CaGI-C 
Caregiver Global Impression–Change Scale 
CaGI-S 
Caregiver Global Impression–Severity Scale 
mCGI-S 
modified Clinical Global Impression–Severity Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHI 
medication handling irregularity 
mITT 
modified intent-to-treat 
MMRM 
mixed-model repeated measures 
NPI 
Neuropsychiatric Inventory 
NPI-C 
Neuropsychiatric Inventory-Clinician 
PK 
pharmacokinetic 
QD 
once daily 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RNA 
ribonucleic acid 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SNRI 
serotonin-norepinephrine reuptake inhibitor 
SRT 
Safety Review Team 
SSRI 
selective serotonin reuptake inhibitor 
ULN 
upper limit of normal 
US 
United States 
VAD 
vascular dementia 

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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.  
Document History 
Document:  
Date (Day-Month-Year) 
Version 4.0 
14 Feb 2023 
Version 3.0 
08 Apr 2022 
Version 2.0 
19 Feb 2021 
Original Protocol Version 1.0 
17 Nov 2020 
Amendment: Protocol Version 3.0 (08 Apr 2022) 
Overall Rationale for the Amendment: 
The overall rationale for the amendment is to update the inclusion and exclusion criteria 
to more accurately represent the proposed patient population.  
Section # and Name 
Description of Change 
Brief Rationale 
Signature Page 
Updated sponsor signatory 
Change in internal 
responsibilities 
Synopsis 
4.1.1 Screening/Baseline 
Period 
Increased number of screened 
subjects from approximately 100 to 
approximately 150 
Adjusted for higher than 
anticipated rate of screen 
failures 
Synopsis 
1.3 Schedule of Assessments 
5.1 Inclusion Criteria 
8.1.3 Clinical Dementia 
Rating 
Removed the requirement for 
Global Clinical Dementia Rating 
score 0.5 to 2.0 for subject to be 
eligible for trial 
Updated to be more reflective 
of proposed target population 
and streamline evaluation of 
dementia 
1.3 Schedule of Assessments 
Adjusted table such that the 
“±3 days” window starts at Remote 
Visit 3 rather than at Visit 
2/Baseline 
Correction to prior version of 
protocol 
1.3 Schedule of Assessments 
4.1.2 Treatment Period 
Deleted “up to” text in footnote “v” 
and other sections referring to 
observation time following dosing 
Correction to prior version of 
protocol 
2.2.1 Disease Background 
5.1 Inclusion Criteria 
8.1.1 Diagnostic Criteria for 
Apathy 
11 References 
Added reference for updated criteria 
for diagnosing apathy 
Reference was not published at 
time of prior protocol 

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Section # and Name 
Description of Change 
Brief Rationale 
2.3 Benefit/Risk Assessment 
Removed information about risk 
assessment completed for 
COVID-19 pandemic effects on trial 
Text should not be included in 
this section of protocol, 
mitigation efforts will be 
described elsewhere 
5.1 Inclusion Criteria 
8.1.2 Mini Mental State 
Examination 
Modified the lower range of MMSE 
score for inclusion in trial to 12 
Updated to be more reflective 
of proposed target population 
5.2 Exclusion Criteria 
Removed the caveat allowing 
subjects with symptoms of anxiety 
or depression that are stable and 
adequately controlled to be enrolled 
Consistency with change in 
Exclusion Criterion #4 
5.2 Exclusion Criteria 
Removed the exclusion of subjects 
with score >3 on NPI domains for 
anxiety, irritability, or dysphoria in 
Exclusion Criterion #4 
Updated to be more reflective 
of proposed target population 
5.2 Exclusion Criteria 
Modified wording regarding 
exclusion subjects with conditions 
that could affect drug absorption  
Updated for consistency with 
Cerevel standards 
5.2 Exclusion Criteria  
1.3 Schedule of Assessments 
5.4 Screen Failures 
10.2 Appendix 2: Clinical 
Laboratory Tests 
Modified wording regarding 
exclusion subjects based on urine 
drug screen or positive alcohol test 
Updated for consistency with 
Cerevel standards 
6.3.2 Blinding 
Removed text indicating 
information regarding 
documentation of unblinding is in 
eCRF 
Inaccurate as only limited 
information on unblinding in 
eCRF (time blind is broken and 
name of personnel involved 
only in medical record) 
6.5.2 Prohibited Medications 
Added levodopa and/or other 
dopamine agonists to list of 
prohibited prior and concomitant 
medications 
To rectify oversight of not 
including these prohibited 
medications in the previous 
version of protocol 
Overall 
Minor grammatical and wording 
corrections/clarifications made 
throughout protocol 
Correct errors in original 
protocol 
Abbreviations: COVID-19 = coronavirus disease-2019; eCRF = electronic case report form; MMSE = 
Mini-Mental State Examination; NPI = Neuropsychiatric Inventory. 
  
Amendment: Protocol Version 2.0 (19 Feb 2021) 
This version of the protocol (Version 2.0) represents the first version to be submitted to 
any health authority; therefore, no subjects were enrolled under Version 1.0.  
Overall Rationale for the Amendment: 

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The overall rationale for the amendment is correct errors in original protocol and ensure 
the protocol is accurate prior to enrollment of any subjects in the trial.  
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis 
3 Objectives and Endpoints 
Condense safety endpoints and 
specify defined as “clinically 
significant changes/findings” 
Ensure consistency with 
Cerevel standard practice 
Synopsis 
5.1 Inclusion Criteria 
Explicitly state in Inclusion 
Criterion 9 that subjects with more 
than 1 form of allowed dementias 
(eg, mixed dementia) may be 
included in the trial 
Modify wording to clarify that 
subjects with dementia due to 
more than 1 neurodegenerative 
cause (eg, mixed dementia) are 
allowed to participate in the 
trial 
Synopsis 
5.1 Inclusion Criteria 
11 References 
Text and references describing 
frontotemporal dementia were 
clarified; reworded to clearly reflect 
the dementia and subtypes that are 
allowed 
Clarify that subjects with a 
diagnosis of frontotemporal 
dementia that is any 1 of the 3 
variants are eligible to 
participate in the trial 
Synopsis 
5.1 Inclusion Criteria 
Expand the accepted inclusion range 
for Global CDR score and include 
caveats regarding scores for 
functional CDR domains 
Allow for enrollment of more 
eligible subjects with mild 
dementia. The caveat requiring 
scores >0 in 1 of 3 functional 
domains ensures the 0.5 Global 
CDR score indicates early/mild 
dementia vs mild cognitive 
impairment/questionable 
dementia, which is consistent 
with the 2011 NIA-AA criteria 
for all-cause dementia. 
1.3 Schedule of Assessments 
Add information describing which 
forms are provided in electronic 
format and which are in paper 
format and provide clarification that 
if it is not possible to complete the 
form in electronic format then it is 
permissible to do on a paper format 
Additional clarification for site 
personnel 
1.3 Schedule of Assessments 
5.2 Exclusion Criteria 
8.1.3 Clinical Dementia 
Rating 
Remove language requiring a score 
of ≥2 on the NACC-FTLD Behavior 
Domain (Item 9) of the CDR Plus 
NACC FTLD Staging Instrument 
and replace with language specific 
to impulse control-related behaviors 
due to frontotemporal dementia 
Original criteria could have 
resulted in excluding subjects 
with frontotemporal dementia 
with significant apathy, loss of 
empathy or social interest, 
without other significant 
impulsive, inappropriate, or 
compulsive behavior issues.  
1.3 Schedule of Assessments 
8.7.9 Modified Alzheimer’s 
Disease Cooperative Study-
Clinical Global Impression of 
Change 
Add completion of the 
mADCS-CGIC worksheet at 
baseline 
Inadvertent omission of the 
baseline version for the 
mADCS-CGIC to be completed 
prior to dosing for the rater to 
use as a reference when 
completing the post-baseline 
form 

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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Assessments 
Removed the urine drug screen at 
Visits 2 and 6/ET 
The urine drug screen is only 
needed at the Screening Visit, 
unless the investigator feels it is 
needed during the trial (as 
described in footnote p) 
1.3 Schedule of Assessments 
Add line and footnote to indicate 
site personnel need to request IMP 
assignment and IMP shipping prior 
to remote visits 
Additional clarification for site 
personnel 
2.2.4 CVL-871 
Added age range of subjects to 
description of Trail B781002  
Demonstrate CVL-871 has 
been tested in an older 
population 
4.1 Overall Design 
Move information that was 
previously included in Section 4.4 
Definition of Completed Subject 
into Section 4.1 as a new subsection 
(Section 4.1.4) 
Ensure consistency with 
Cerevel standard practice 
4.1.1 Screening/Baseline 
Period 
Modify wording regarding 
randomization stratification by use 
of SSRIs or SNRIs during the trial 
Additional clarification 
regarding definition of 2 strata  
4.1.2 Treatment Period 
Add sentence indicating medical 
monitor should be contacted if 
investigator needs further 
clarification on whether subject is 
able to tolerate the stepwise dose 
increase 
Include process in cases where 
investigator is unclear as to 
what defines a lack of 
tolerability to stepwise dose 
increase 
5.1 Inclusion Criteria 
Change timing requirement for 
subject to need neuroimaging 
evidence consistent with dementia 
diagnosis from “within 12 months 
prior to randomization” to “anytime 
after onset of dementia symptoms” 
Requirement for neuroimaging 
evidence within 12 months of 
randomization was deemed too 
restrictive and not necessary to 
rule out other causes of 
dementia. This change is 
consistent with criteria used in 
other clinical trials using a 
clinical diagnosis of dementia.  
5.2 Exclusion Criteria 
Add text clarifying that space 
occupying cerebral lesions is 
inclusive of extra-axial lesions 
producing a mass effect 
Inadvertent omission from 
protocol; extra-axial lesions 
producing a mass effect are 
considered equivocal to space 
occupying cerebral lesions 
5.2 Exclusion Criteria 
Separate out anxiety, irritability, and 
dysphoria scores and increase the 
exclusionary criteria to scores 
greater than 3 at Screening or 
Baseline visits 
Prior criteria were too rigid as 
these symptoms do not 
represent a confounder to 
outcomes if present at a level 
that is not clinically significant 
(generally defined as NPI 
domain score of 4 or greater) 

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Section # and Name 
Description of Change 
Brief Rationale 
6.5.2 Prohibited Medications 
Modify footnote a regarding 
nonbenzodiazepine sleep aids with 
respect to the maximum allowable 
daily dose permitted for treatment 
of insomnia 
The dose cap will be enforced 
to mitigate increase in potential 
fall risk from higher doses of 
nonbenzodiazepine sleep aids 
8.1 Screening and Baseline 
Assessments 
Add sentence indicating sponsor can 
employ additional methods to 
ensure appropriateness of subject 
selection 
Provide flexibility to use 
additional methods to ensure 
subjects adequately fulfill entry 
criteria 
8.7.1 Neuropsychiatric 
Inventory-Clinician and 
Neuropsychiatric Inventory 
Rating Scales 
Remove text stating the NPI-C 
screening strategy examines and 
scores only behavioral domains with 
positive responses to screening 
questions 
Text removed as it was 
applicable to situation when 
NPI-C was administered in its 
entirety. When only a few 
domains are administered, the 
guidance recommends that all 
items should be administered 
regardless of the response to 
the screening questions.  
8.7.5 Digit Span: Wechsler 
Adult Intelligence Scale IV 
Modify the digit span length range 
for forward and backward span 
Error in original protocol 
8.7.10 Modified Clinical 
Global Impression-Severity 
Scale 
Update to reflect final text in actual 
scale 
Text for newly created scale 
was not final in original 
protocol  
8.7.11 Caregiver Global 
Impression-Severity Scale 
Update to reflect final text in actual 
scale 
Text for newly created scale 
was not final in original 
protocol  
8.7.12 Caregiver Global 
Impression-Change Scale 
Update to reflect final text in actual 
scale 
Text for newly created scale 
was not final in original 
protocol  
10.5 Appendix 5: Future 
Biospecimen Research 
Add that samples may also be used 
for research related to apathy or 
other cognitive disorders 
Provide flexibility in case want 
to investigate findings in data 
and as they would apply to 
cognition and apathy more 
broadly than in just dementia 
disorders 
10.6 Appendix 6: Moderate to 
Strong Inducers and Inhibitors 
of Cytochrome P450 3A (not 
exhaustive)a 
Revise section title and add 
sentence stating list provided in 
appendix may not be exhaustive and 
that the investigator is ultimately 
responsible for ensuring subjects do 
not receive any prohibited 
concomitant medication 
List in appendix was not 
exhaustive and subject to 
change as new drugs may come 
to market during the trial period 
Overall 
Minor grammatical and wording 
corrections/clarifications made 
throughout protocol 
Correct errors in original 
protocol 
Abbreviations: CDR = Clinical Dementia Rating; ET = early termination; IMP = investigational medicinal 
product; mADCS-CGIC = modified Alzheimer’s Disease Cooperative Study–Clinical Global Impression of 
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NIA-AA = National Institute of Aging – Alzheimer’s Association; NPI-C = Neuropsychiatric Inventory-
Clinician; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake 
inhibitor. 
a Section number refers to current version of the protocol. 
 

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CLINICAL PROTOCOL PRINCIPAL INVESTIGATOR 
SIGNATURE PAGE 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
TRIAL TO EVALUATE THE SAFETY, TOLERABILITY, AND 
PHARMACODYNAMICS OF CVL-871 IN SUBJECTS WITH 
DEMENTIA-RELATED APATHY 
 
Protocol Number: CVL-871-2001 
Compound: CVL-871 
Trial Phase: 2a 
Sponsor Name: Cerevel Therapeutics, LLC 
Legal Registered Address: 222 Jacobs Street, Suite 200, Cambridge, MA 02141 
United States 
Version 4.0: 14 Feb 2023 
 
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)