Solriamfetol's Effect on Cognitive Health in Apnea Participants During a Randomized Placebo-controlled Study (SHARP): a 5-Week Double-blind, Placebo-controlled, Randomized, Crossover, Multicenter Study of Solriamfetol in Improving Cognitive Function in Participants With Excessive Daytime Sleepiness Associated With Obstructive Sleep Apnea Plus Impaired Cognitive Function
Phase: PHASE4
Conditions: Excessive Daytime Sleepiness, Obstructive Sleep Apnea, Impaired Cognitive Function
Sponsor: Axsome Therapeutics, Inc.

Document Type: Protocol
Protocol Title: Solriamfetol’s Effect on Cognitive Health in Apnea Participants During a 
Randomized Placebo-controlled Study (SHARP): a 5-Week Double-blind, Placebo-controlled, 
Randomized, Crossover, Multicenter Study of Solriamfetol in Improving Cognitive Function in 
Participants With Excessive Daytime Sleepiness Associated With Obstructive Sleep Apnea Plus 
Impaired Cognitive Function 
ClinicalTrials.gov Identifier:  NCT04789174
Document Date: August 12, 2022
Certain information within this protocol has been redacted to protect either personally identifiable 
information (PII) or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
•
Named persons or organizations associated with the study.
•
Proprietary information, such as scales or coding systems, which are considered confidential
information.
•
Other information as needed to protect the confidentiality of Axsome Therapeutics, personal
information, or to otherwise protect the integrity of the clinical study.

Axsome Therapeutics
Protocol JZP110-405
Amendment 1 (12Aug2022)
CONFIDENTIAL 
Page 1
TITLE PAGE 
Protocol Title: Solriamfetol’s Effect on Cognitive Health in Apnea Participants During a 
Randomized Placebo-controlled Study (SHARP): a 5-Week Double-blind, Placebo-controlled, 
Randomized, Crossover, Multicenter Study of Solriamfetol in Improving Cognitive Function in 
Participants With Excessive Daytime Sleepiness Associated With Obstructive Sleep Apnea Plus 
Impaired Cognitive Function 
Protocol Number: JZP110-405
Amendment 1: Aug 12, 2022 
 
 
Compound: Sunosi® (solriamfetol) 
Brief Title: Solriamfetol’s Effect on Cognitive Health in Apnea Participants During a 
Randomized Placebo-controlled Study (SHARP)
Study Phase: 4 
 
 
 
 
This study will be performed in compliance with Good Clinical Practices and applicable 
regulatory requirements, including the archiving of essential documents. Information contained 
in this protocol is confidential in nature, and may not be used, divulged, published, or otherwise 
disclosed to others except to the extent necessary to obtain approval of the institutional review 
board or independent ethics committee, or as required by law. Persons to whom this information 
is disclosed should be informed that this information is confidential and may not be further 
disclosed without the express permission of Axsome Therapeutics, Inc.

Axsome Therapeutics
Protocol JZP110-405
Amendment 1 (12Aug2022)
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APPROVAL SIGNATURES 
PROTOCOL NUMBER: 
JZP110-405 
 
PROTOCOL TITLE: 
 
Solriamfetol’s Effect on Cognitive Health in Apnea Participants 
During a Randomized Placebo controlled Study (SHARP): a 5 Week 
Double blind, Placebo controlled, Randomized, Crossover, 
Multicenter Study of Solriamfetol in Improving Cognitive Function 
in Participants With Excessive Daytime Sleepiness Associated With 
Obstructive Sleep Apnea Plus Impaired Cognitive Function 
 
PROTOCOL VERSION: 
Amendment 1 (V2.0)  
 
 
 
PROTOCOL DATE:  
August 12, 2022
 
I, the undersigned, have read this protocol and confirm that to the best of my knowledge it 
accurately describes the planned conduct of the study.

Axsome Therapeutics
Protocol JZP110-405
Amendment 1 (12Aug2022)
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STUDY CONTACT AND DETAILS 
SPONSORED BY: 
Axsome Therapeutics, Inc.
 
 
  
 
 
 
 
 
 
 
 
 
 
INVESTIGATOR: 
 
Multi-center. A list of sites will be housed in the Trial Master File.

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TABLE OF CONTENTS 
TITLE PAGE..............................................................................................................................1
APPROVAL SIGNATURES ......................................................................................................2
STUDY CONTACT AND DETAILS .........................................................................................3
TABLE OF CONTENTS ............................................................................................................ 4
LIST OF TABLES......................................................................................................................9
LIST OF FIGURES ..................................................................................................................10
1. 
PROTOCOL SUMMARY...................................................................................... 11
1.1.
Synopsis ................................................................................................................. 11
1.2.
Schema ...................................................................................................................19
1.3.
Schedule of Assessments ........................................................................................ 20
2. 
INTRODUCTION .................................................................................................. 24
2.1.
Study Rationale ...................................................................................................... 24
2.2.
Background ............................................................................................................ 24
2.3.
Benefit/Risk Assessment ........................................................................................ 25
2.3.1. 
Risk Assessment..................................................................................................... 25
2.3.2. 
Benefit Assessment.................................................................................................25
2.3.3. 
Overall Benefit:Risk Conclusion.............................................................................26
3. 
OBJECTIVES AND ESTIMANDS AND ENDPOINTS ........................................27
4. 
STUDY DESIGN................................................................................................... 31
4.1.
Overall Design ........................................................................................................31
4.1.1.
Screening Period.....................................................................................................31
4.1.2.
Baseline and Randomization...................................................................................31
4.1.3. 
Double-blind Treatment Period (Treatment Period 1) .............................................32
4.1.4. 
Washout Period ...................................................................................................... 32
4.1.5. 
Double-blind Crossover Treatment Period (Treatment Period 2).............................32
4.1.6. 
Safety Follow-up or Early Discontinuation ............................................................. 32
4.2.
Scientific Rationale for Study Design ..................................................................... 32
4.3.
Justification for Dose ..............................................................................................33
4.4.
End of Study Definition..........................................................................................33
5. 
STUDY POPULATION.........................................................................................34
5.1.
Inclusion Criteria .................................................................................................... 34

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5.2.
Exclusion Criteria................................................................................................... 35
5.3.
Lifestyle Considerations .........................................................................................38
5.3.1. 
Caffeine, Alcohol, and Tobacco..............................................................................38
5.4.
Screen Failures .......................................................................................................38
5.5.
Criteria for Temporarily Delaying Enrollment ........................................................38
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ....................... 39
6.1.
Study Intervention(s)/Treatment(s) Administered ...................................................39
6.2.
Preparation/Handling/Storage/Accountability .........................................................41
6.3.
Measures to Minimize Bias: Randomization and Blinding ......................................41
6.4.
Study Intervention/Treatment Compliance..............................................................42
6.5.
Dose Modification .................................................................................................. 42
6.6.
Continued Access to Study Intervention After the End of the Study ........................ 42
6.7.
Treatment of Overdose, Medication Errors, or Misuse ............................................ 42
6.8.
Prohibited Concomitant Therapy ............................................................................42
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL...................................... 44
7.1.
Discontinuation of Study Intervention..................................................................... 44
7.1.1. 
Temporary Discontinuation/Study Intervention Interruption ...................................44
7.2.
Participant Discontinuation/Withdrawal From the Study.........................................44
7.3.
Lost to Follow-up ................................................................................................... 45
8. 
STUDY ASSESSMENTS AND PROCEDURES ...................................................46
8.1.
General Administrative Procedures.........................................................................46
8.1.1. 
Informed Consent................................................................................................... 46
8.1.2. 
Assignment of Participant Number ......................................................................... 46
8.1.3. 
Medical History ...................................................................................................... 46
8.1.4. 
Medication Review (Prior and Concomitant Medications) ...................................... 46
8.1.5. 
Inclusion and Exclusion Criteria Review ................................................................47
8.1.6. 
Timing of Study Intervention Dosing...................................................................... 47
8.1.7. 
Reminder Phone Calls ............................................................................................47
8.2.
Efficacy Assessments .............................................................................................48
8.2.1. 
Digit Symbol Substitution Test ............................................................................... 48
8.2.1.1. 
Digit Symbol Substitution Test Wechsler Adult Intelligence Scale Fourth 
Edition....................................................................................................................48

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8.2.1.2. 
Digit Symbol Substitution Test Repeatable Battery for the Assessment of 
Neuropsychological Status Version......................................................................... 48
8.2.2. 
British Columbia-Cognitive Complaints Inventory .................................................49
8.2.3.
Patient Global Impression of Severity.....................................................................49
8.2.4.
Epworth Sleepiness Scale .......................................................................................50
8.3.
Other Assessments .................................................................................................. 50
8.3.1. 
Sleep Habits Assessment ........................................................................................ 50
8.3.2. 
Sleep Diary.............................................................................................................50
8.3.3.
Obstructive Sleep Apnea Therapy Adherence.........................................................51
8.3.4.
Caffeine and/or Nicotine Intake Check ...................................................................51
8.4.
Safety Assessments.................................................................................................51
8.4.1. 
Physical Examinations............................................................................................51
8.4.2. 
Vital Signs ..............................................................................................................51
8.4.3. 
Electrocardiograms................................................................................................. 52
8.4.4. 
Clinical Safety Laboratory Assessments .................................................................52
8.4.5. 
Pregnancy Testing .................................................................................................. 53
8.4.6. 
Alcohol and Drug Screen........................................................................................ 53
8.4.7. 
Suicidal Ideation and Behavior Risk Monitoring.....................................................53
8.5.
Adverse Events, Serious Adverse Events, and Other Safety Reporting....................54
8.5.1. 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Events Information ...................................................................................54
8.5.2. 
Method of Detecting Adverse Events and Serious Adverse Events..........................54
8.5.3. 
Follow-up of Adverse Events and Serious Adverse Events .....................................54
8.5.4. 
Regulatory Reporting Requirements for Serious Adverse Events ............................ 55
8.5.5. 
Pregnancy............................................................................................................... 55
8.5.6. 
Overdose, Medication Errors, and Misuse ...............................................................56
8.6.
Pharmacokinetics.................................................................................................... 56
8.7.
Genetics.................................................................................................................. 56
8.8.
Biomarkers............................................................................................................. 56
8.9.
Immunogenicity Assessments ................................................................................. 56
8.10.
Health Economics................................................................................................... 56
9. 
STATISTICAL CONSIDERATIONS ....................................................................57
9.1.
Statistical Hypotheses ............................................................................................. 57

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9.1.1. 
Primary Hypothesis ................................................................................................57
9.2.
Sample Size Determination.....................................................................................57
9.3.
Analysis Populations ..............................................................................................57
9.4.
Statistical Analyses.................................................................................................58
9.4.1.
General Considerations...........................................................................................58
 
9.4.1.2. 
Definition of Study Periods for Analysis.................................................................58
9.4.1.3. 
Intercurrent Event Strategies...................................................................................58
9.4.1.4.
Pooling of Investigational Centers ..........................................................................59
9.4.1.5.
Dropouts and Missing Data.....................................................................................59
9.4.2. 
Primary Endpoints .................................................................................................. 59
9.4.3. 
Secondary Endpoints ..............................................................................................59
9.4.4. 
Exploratory Endpoint(s)..........................................................................................59
9.4.5. 
Safety Analyses ...................................................................................................... 59
9.4.6. 
Other Analyses .......................................................................................................59
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..............................................................................................60
10.1.
Regulatory, Ethical, and Study Oversight Considerations........................................60
10.1.1. 
Regulatory and Ethical Considerations.................................................................... 60
10.1.2. 
Financial Disclosure ...............................................................................................60
10.1.3. 
Informed Consent Process ......................................................................................61
10.1.4. 
Data Protection.......................................................................................................61
10.1.5. 
Safety Committee Structure....................................................................................61
10.1.6. 
Dissemination of Clinical Study Data ..................................................................... 61
10.1.7. 
Data Quality Assurance ..........................................................................................62
10.1.8. 
Source Documents .................................................................................................. 62
10.1.9. 
Study and Site Start and Closure .............................................................................63
10.1.9.1. 
First Act of Recruitment .........................................................................................63
10.1.9.2. 
Study/Site Termination ...........................................................................................63
10.1.10. 
Publication Policy................................................................................................... 63
APPENDIX 1.
ABBREVIATIONS AND DEFINTIONS .......................................................64
APPENDIX 2.
REFERENCES...............................................................................................66

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APPENDIX 3.
CLINICAL LABORATORY TESTS..............................................................68
APPENDIX 4.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING .............................................69
APPENDIX 5.
CONTRACEPTIVE AND BARRIER GUIDANCE .......................................74
APPENDIX 9.
SIGNATURE OF INVESTIGATOR’S AGREEMENT..................................79
 

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LIST OF TABLES 
Table 1: 
Objectives and Endpoints ....................................................................................... 12
Table 2: 
Overall Study Design..............................................................................................17
Table 3:
Schedule of Assessments ........................................................................................20
Table 4: 
Study Treatment/Intervention ................................................................................. 40
 
 
Table 6: 
Protocol-required Safety Laboratory Tests..............................................................68
 

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LIST OF FIGURES 
Figure 1: 
Study Schema.........................................................................................................19

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: Solriamfetol’s Effect on Cognitive Health in Apnea Participants During a 
Randomized Placebo-controlled Study (SHARP): a 5-Week Double-blind, Placebo-controlled, 
Randomized, Crossover, Multicenter Study of Solriamfetol in Improving Cognitive Function in 
Participants With Excessive Daytime Sleepiness Associated With Obstructive Sleep Apnea Plus 
Impaired Cognitive Function 
Brief Title: Solriamfetol’s Effect on Cognitive Health in Apnea Participants During a Randomized 
Placebo-controlled Study (SHARP) 
Rationale: The purpose of study JZP110-405 is to determine whether solriamfetol is effective at 
improving cognitive function in participants with excessive daytime sleepiness (EDS) associated 
with obstructive sleep apnea (OSA). The need for this proposed phase 4 study was identified 
following patient and physician input. An important element that patients consider when 
evaluating whether to start a treatment is how the treatment will affect their ability to work. The 
primary statistical hypothesis for this study is to show whether solriamfetol has a significantly 
improved effect versus placebo on the primary endpoint of changes in Digit Symbol Substitution 
Test (DSST) scores after 2 weeks of treatment. Demonstrating that solriamfetol improves both 
objective and subjective cognitive function would address a major unmet need for patients. In 
addition, characterizing the duration of effect across the 8-hour postdose period is also of interest.

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Objectives and Endpoints:  
Table 1: 
Objectives and Endpoints
Objectives
Estimands and Endpoints
Primary Objective
To evaluate the efficacy of 
solriamfetol on cognitive function 
in adult participants with EDS 
associated with OSA plus impaired 
cognitive functioning 
The primary estimand is defined by the following:
Population: Participants aged 18 to 65, with EDS associated 
with OSA and impaired cognitive function in the mITT set, 
defined as: all randomized participants with at least 1 dose of 
study drug and 1 postdose assessment of DSST RBANS  
 
Variable: Change from the average of the DSST RBANS 
scores at Baseline (Visit 3) to the average of the postdose 
DSST RBANS scores (hours 2, 4, 6, and 8) at the end of each 
double-blind treatment period 
 
Intercurrent events:  
- The participant’s DSST RBANS data are not collected if 
the participant discontinued the treatment (while on 
treatment policy strategy) 
- Missing assessments after discontinuation of treatment 
due to AE, lack of efficacy, or any other reasons will not 
be imputed for primary analysis. 
 Population level summary: Difference in mean DSST 
RBANS from the average of the scores at Baseline (Visit 3) 
to the average of the postdose scores (at Visit 5 and Visit 8) 
between solriamfetol and placebo 

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Objectives 
Estimands and Endpoints 
Secondary Objectives  
Secondary Estimands 
To further evaluate the efficacy
of solriamfetol on cognitive 
function in adult participants with 
EDS associated with OSA plus 
impaired cognitive functioning 
The first estimand for secondary objective evaluating efficacy is 
defined by the following:  
 
Population: Participants aged 18 to 65, with EDS associated 
with OSA and impaired cognitive function in the mITT 
analysis set, defined as: all randomized participants with at 
least 1 dose of study drug and 1 postdose assessment of 
DSST RBANS  
 
Variable: Change from Baseline (Visit 3) to the end of each 
double-blind treatment period (Visit 5 and Visit 8) in overall 
score in BC-CCI 
 
Intercurrent events: 
- The participant’s British Columbia-Cognitive Complaints 
Inventory (BC-CCI) data are not collected if the 
participant discontinued the treatment (while on 
treatment policy strategy) 
- Missing assessments after discontinuation of treatment 
due to AE, lack of efficacy, or any other reasons will not 
be imputed 
 
Population level summary: Difference in mean overall 
BC-CCI score from Baseline (Visit 3) to the end of 
double-blind treatment period (Visit 5 and Visit 8) between 
solriamfetol and placebo 
The second estimand for secondary objective evaluating efficacy 
is defined by the following:  
 
Population: Participants aged 18 to 65, with EDS associated 
with OSA and impaired cognitive function in the mITT 
analysis set, defined as: all randomized participants with at 
least 1 dose of study drug and 1 postdose assessment of 
DSST RBANS  
 
Variable: Categorical change from Baseline (Visit 3) to the 
end of each double-blind treatment period (Visit 5 and 
Visit 8) in each category of the BC-CCI  
 
Intercurrent events: 
- The participant’s BC-CCI data are not collected if the 
participant discontinued the treatment (while on 
treatment policy strategy) 
- Missing assessments after discontinuation of treatment 
due to AE, lack of efficacy, or any other reasons will not 
be imputed 
 
Population level summary: Percentage of patients with an at 
least 1 category improvement in the BC-CCI score from 
Baseline (Visit 3) to the end of double-blind treatment period 
(Visit 5 and Visit 8) in each treatment group 

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Objectives 
Estimands and Endpoints 
To evaluate the effect of 
solriamfetol on cognitive function 
at individual post-dose timepoints 
in adult participants with EDS 
associated with OSA plus impaired 
cognitive functioning 
The estimand for this secondary objective to evaluate the effect 
on cognitive function at individual post-dose timepoints is 
defined by the following: 
• 
Population: Participants aged 18 to 65, with EDS associated 
with OSA and impaired cognitive function in the mITT 
analysis set, defined as: all randomized participants with at 
least 1 dose of study drug and 1 postdose assessment of 
DSST RBANS  
• 
Variable(s): Change from each of the 2-, 4-, 6-, and 8-hour 
DSST RBANS sores at Baseline (Visit 3) to each of the 
corresponding 2-, 4-, 6-, and 8-hour postdose DSST RBANS 
scores at the end of each double-blind treatment period 
(Visit 5 and Visit 8)  
• 
Intercurrent events:  
- The participant’s DSST RBANS data are not collected if 
the participant discontinued the treatment (while on 
treatment policy strategy) 
- Missing assessments after discontinuation of treatment 
due to AE, lack of efficacy, or any other reasons will not 
be imputed  
• 
Population level summary: Difference in mean DSST 
RBANS from each of the 2-, 4-, 6-, and 8-hour DSST 
RBANS scores at Baseline (Visit 3) to each of the 
corresponding 2-, 4-, 6-, and 8-hour postdose (at Visit 5 and 
Visit 8) DSST RBANS scores between solriamfetol and 
placebo 

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Objectives 
Estimands and Endpoints 
To evaluate the efficacy of 
solriamfetol on patient-reported 
global impression of 
concentration, memory, and 
thinking skills in adult participants 
with EDS associated with OSA 
plus impaired cognitive 
functioning 
The first estimand for this secondary objective evaluating 
efficacy is defined by the following:  
• 
Population: Participants aged 18 to 65, with EDS associated 
with OSA and impaired cognitive function in the mITT 
analysis set, defined as: all randomized participants with at 
least 1 dose of study drug and 1 postdose assessment of 
DSST RBANS  
• 
Variable: Change from Baseline (Visit 3) to the end of each 
double-blind treatment period (Visit 5 and Visit 8) in Patient 
Global Impression of Severity (PGI-S) score 
• 
Intercurrent events: 
- The participant’s PGI-S data are not collected if the 
participant discontinued the treatment (while on 
treatment policy strategy) 
- Missing assessments after discontinuation of treatment 
due to AE, lack of efficacy, or any other reasons will not 
be imputed 
• 
Population level summary: Difference in mean PGI-S score 
from Baseline (Visit 3) to the end of double-blind treatment 
period (Visit 5 and Visit 8) between solriamfetol and placebo 
The second estimand for this secondary objective evaluating 
efficacy is defined by the following:  
• 
Population: Participants aged 18 to 65, with EDS associated 
with OSA and impaired cognitive function in the mITT 
analysis set, defined as: all randomized participants with at 
least 1 dose of study drug and 1 postdose assessment of 
DSST RBANS  
• 
Variable: Categorical improvement from baseline on the 
PGI-S to the end of each double-blind treatment period 
(Visit 5 and Visit 8)  
• 
Intercurrent events: 
- The participant’s PGI-S data are not collected if the 
participant discontinued the treatment (while on 
treatment policy strategy) 
- Missing assessments after discontinuation of treatment 
due to AE, lack of efficacy, or any other reasons will not 
be imputed 
• 
Population level summary: Percentage of participants 
reporting an at least 1 category improvement from baseline 
on the PGI-S to the end of each double-blind treatment 
period (Visit 5 and Visit 8) in each treatment group 

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Objectives 
Estimands and Endpoints 
To evaluate the efficacy of 
solriamfetol on improving EDS in 
adult participants with EDS 
associated with OSA plus impaired 
cognitive functioning  
The estimand for this secondary objective evaluating efficacy is 
defined by the following:  
• 
Population: Participants aged 18 to 65, with EDS associated 
with OSA and impaired cognitive function in the mITT 
analysis set, defined as: all randomized participants with at 
least 1 dose of study drug and 1 postdose assessment of 
DSST RBANS  
• 
Variable: Change from Baseline (Visit 3) to the end of each 
double-blind treatment period (Visit 5 and Visit 8) in ESS 
score  
• 
Intercurrent events:  
- The participant’s ESS data are not collected if the 
participant discontinued the treatment (while on 
treatment policy strategy)  
- Missing assessments after discontinuation of treatment 
due to AE, lack of efficacy, or any other reasons will not 
be imputed  
• 
Population level summary: Difference in mean ESS score 
from Baseline (Visit 3) to the end of double-blind treatment 
period (Visit 5 and Visit 8) between solriamfetol and placebo  
To evaluate the safety and 
tolerability of solriamfetol 
administered once daily in adult 
participants with EDS associated 
with OSA plus impaired cognitive 
functioning 
Safety and tolerability evaluations will be determined by the 
occurrence of and/or changes in: 
• 
Incidence and severity treatment emergent adverse events 
(TEAEs) 
• 
Vital signs 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Exploratory Objectives 
Exploratory Endpoints 
To evaluate the association 
between the improvement in EDS 
and improvement in cognitive 
function following solriamfetol 
treatment in adult participants with 
EDS associated with OSA plus 
impaired cognitive functioning 
The exploratory endpoints for the exploratory objective of 
evaluating the association between the improvement in EDS and 
improvement in cognitive function are: 
• 
The correlation between the change from Baseline (Visit 3) at 
the end of each double-blind treatment period (Visit 5 and 
Visit 8) in ESS and DSST RBANS score 
• 
The correlation between the change from Baseline (Visit 3) at 
the end of each double-blind treatment period (Visit 5 and 
Visit 8) in ESS and BC-CCI score 
• 
The correlation between the change from Baseline (Visit 3) at 
the end of each double-blind treatment period (Visit 5 and 
Visit 8) in ESS and PGI-S 
Abbreviations: AE = adverse event; BC-CCI = British Columbia-Cognitive Complaints Inventory; DSST 
RBANS = Digit Symbol Substitution Test Repeatable Battery for the Assessment of Neuropsychological Status; 
EDS = excessive daytime sleepiness; ESS = Epworth Sleepiness Scale; mITT = modified Intent-to-Treat; 
OSA = obstructive sleep apnea; PGI-S = Patients Global Impression of Severity; TEAE = treatment-emergent adverse 
event. 

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Brief Summary: 
This is a prospective, multicenter, two-arm, randomized, double-blind, placebo-controlled 
interventional crossover study comparing solriamfetol 150 mg to placebo on tests of cognitive 
function in participants with EDS due to OSA. Participants will be in the study for approximately 
8 weeks, including 2 weeks of solriamfetol treatment and 2 weeks of placebo treatment. Each 
participant will receive both double-blind treatment conditions, but will be randomized to undergo 
the conditions in a different sequence. 
Cognitive function in this study will be assessed by the DSST (an objective test) and the British 
Columbia-Cognitive Complaints Inventory (BC-CCI) (a subjective test). The DSST has been used 
for decades to measure cognitive function. The BC-CCI was developed to measure cognitive 
complaints in individuals with major depressive disorder (MDD), but has also been used to 
measure cognitive deficits in individuals with poor sleep quality. Therefore, each test should be 
able to detect changes in cognitive function. 
The primary endpoint is the change from the average of the DSST RBANS scores at Baseline to 
the average of the postdose DSST RBANS scores at the end of each double-blind treatment period. 
The secondary endpoints include: the change in overall score and categorical change from Baseline 
at the end of each double-blind treatment period in BC-CCI; the change from each of the 2-, 4-, 6-
, and 8-hour DSST RBANS scores at Baseline to each of the corresponding 2-, 4-, 6-, and 8-hour 
postdose DSST RBANS scores at the end of each double-blind treatment period; change in overall 
score and categorical change from Baseline at the end of each double-blind treatment period in the 
PGI-S; and change in overall score from Baseline to the end of each double-blind treatment period 
in ESS. 
Overall Design: 
This is a phase 4, multicenter, randomized, double-blind, placebo-controlled, crossover study to 
evaluate the efficacy of solriamfetol in improving cognitive function in adult participants with 
EDS associated with OSA plus impaired cognitive function. 
Table 2: 
Overall Study Design 
Overall Design 
Study Phase 
4 
Clinical Indication 
EDS associated with OSA 
Study Type 
Interventional 
Type of Design 
Randomized, crossover, multicenter study 
Type of Control 
Placebo 
Study Blinding 
Double-blind 
Population 
Participants with a diagnosis of OSA according to the ICSD-3, with 
sleepiness as demonstrated by subjective criteria (ESS), and cognitive 
impairment based on a combination of subjective (BC-CCI) and objective 
(DSST WAIS) measures.  

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Overall Design 
Participants must also meet 1 of the following criteria: 1) have stable, current 
use of a PAP machine with downloadable history as primary OSA therapy on 
at least 5 nights/week for 1 month prior to Baseline (with or without prior 
OSA surgery); 2) no current OSA therapy use for at least 1 month but with a 
history of prior PAP for at least 1 month with at least 1 documented 
adjustment attempting to optimize therapy (with or without prior OSA 
surgery); or 3) have undergone OSA surgery but continue to experience 
residual sleepiness (with or without current PAP use). 
Number of 
Participants  
Approximately 116 participants are planned for enrollment. 
Duration of 
Participation 
Each participant will participate in the study from the time they sign the ICF 
through the end of the study procedures. Each participant will be enrolled for 
approximately 8 weeks. 
Number of 
Treatment Arms 
2 
Treatment Groups  
1) Solriamfetol 
2) Placebo  
Treatment Sequences 1) Solriamfetol followed by placebo  
2) Placebo followed by solriamfetol 
Abbreviations: BC-CCI = British Columbia-Cognitive Complaints Inventory; DSST = Digit Symbol Substitution 
Test; EDS = excessive daytime sleepiness; ESS = Epworth Sleepiness Scale; ICF = informed consent form; 
ICSD-3 = International Classification of Sleep Disorders, Third Edition; OSA = obstructive sleep apnea; 
PAP = positive airway pressure; WAIS = Wechsler Adult Intelligence Scale. 

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1.2.
Schema
Figure 1:
Study Schema
Abbreviations: BC-CCI = British Columbia-Cognitive Complaints Inventory; d = day; DSST = Digit Symbol Substitution Test; ESS = Epworth Sleepiness Scale; 
PGI-S = Patients Global Impression of Severity; RBANS = Repeatable Battery for the Assessment of Neuropsychological Status; DSST WAIS-IV = Digit Symbol 
Substitution Test Wechsler Adult Intelligence Scale, Fourth Edition. 

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2.
INTRODUCTION
2.1. 
Study Rationale 
The rationale for this phase 4 study was identified following patient and physician input. The study 
was designed to evaluate the impact of solriamfetol on cognitive outcome measures in participants 
with EDS associated with OSA plus impaired cognitive function.
An important element that patients consider when evaluating whether to start a treatment is how 
the treatment will affect their ability to work. Therefore demonstrating that solriamfetol not only 
improves cognitive function, but cognitive improvement is sustained throughout the day would 
address a major unmet need for patients. Further, this would differentiate solriamfetol from other 
treatment options that have not consistently demonstrated such an impact.
2.2.
Background
Sunosi (henceforth referred to as solriamfetol; previously known as JZP-110, ADX-N05, 
R228060, and YKP10A) is a selective dopamine and norepinephrine reuptake inhibitor that has 
received marketing approval in the United States (US) for improving wakefulness in adult patients 
with EDS associated with narcolepsy or OSA. Solriamfetol also has received marketing approval 
in the European Union (EU) and the United Kingdom for improving wakefulness and reducing 
EDS in adults with narcolepsy (with or without cataplexy) and in adults with OSA whose EDS has 
not been satisfactorily treated by primary OSA therapy, such as continuous positive airway 
pressure. The recommended dose range for solriamfetol is 37.5 mg (OSA only) to 150 mg once 
daily. 
Obstructive sleep apnea is a common disorder of breathing during sleep characterized by repeated 
obstruction of the upper airway (Bassiri and Guilleminault 2000). These obstructive events often 
lead to reduced blood oxygen saturation (hypoxia), resulting in increased respiratory effort and 
arousals from sleep to resume breathing (Ferguson 1995). A consequence of these repetitive 
obstructions and arousals is that normal sleep architecture is disturbed and sleep fragmented, 
particularly the time spent in rapid eye movement sleep and slow-wave sleep (stages N3/4), which 
are often decreased (Borak 1996). 
Intermittent hypoxia is thought to contribute to cognitive dysfunction in OSA patients by 
impacting sleepiness, memory, and executive dysfunction (Naismith 2004; Beebe and 
Gozal 2002). Likewise, sleep fragmentation seen in OSA patients could result in cognitive 
impairment via its impact on attention (Verstraeten 2004). The basis of this argument is the strong 
similarity between cognitive deficits seen in OSA and those seen in healthy individuals who have 
been experimentally deprived of sleep (Verstraeten 2004). Additionally, sleep-deprived healthy 
individuals show reduced activity in the prefrontal and posterior parietal cortices and in the 
thalamus. These functional, central, neural changes have been associated with reductions in 
attention and vigilance (Verstraeten 2007). 
The decrease in cognitive function seen in patients with OSA has implications for work 
performance and social functioning and increases the risk for occupational and motor vehicle 
accidents (Garbarino 2015; Garbarino 2016). In aggregate, about 40% of OSA patients (with or 
without positive airway pressure [PAP] use) complain of cognitive difficulties, and cognitive 

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difficulties are 1 of the top 5 symptoms that have a severe or moderate impact on patients’ daily 
activities (American Sleep Apnea Association 2018). None of the treatments for EDS associated 
with OSA have consistently shown improvement in cognitive function despite how common 
complaints around cognitive function are in the disease (Wang 2020; Avellar 2016). Thus, there 
remains a large unmet need for therapies that can not only assist OSA patients with EDS but also 
improve their cognitive outcomes. 
2.3.
Benefit/Risk Assessment
2.3.1. 
Risk Assessment 
Solriamfetol has a robust clinical safety database comprised of healthy adult participants and 
participants with OSA, narcolepsy, Parkinson’s disease, and MDD with a consistent safety profile 
across conditions. Solriamfetol is approved in the US for the indication of improving wakefulness 
in adult patients with EDS associated with OSA or narcolepsy. Solriamfetol is approved in the EU
for the indication of improving wakefulness and for reducing EDS in adults with narcolepsy (with 
or without cataplexy) or OSA, whose EDS has not been satisfactorily treated by primary OSA 
therapy. The risks to participants in this study are expected to be similar to those seen in prior 
clinical studies that evaluated the effects of 75 mg and 150 mg solriamfetol in OSA and narcolepsy 
participants, including those on concomitant antidepressants. Current information on the efficacy, 
pharmacokinetics (PK), and safety of solriamfetol is provided in the solriamfetol Investigator’s 
Brochure (IB), the United States Package Insert (USPI) and the Summary of Product 
Characteristics (SmPC). 
Underlying psychiatric comorbidities (ie, affective disorders and suicidal ideation), commonly 
seen in OSA and narcolepsy patients, could be exacerbated by the use of a stimulant or 
wake-promoting agent. In the solriamfetol clinical development program, serious psychiatric 
events occurred more commonly in the narcolepsy population than the OSA population. Further, 
although solriamfetol blocks dopamine and norepinephrine reuptake, nonclinical and clinical data 
show that the potential for abuse for solriamfetol is low.
Transient and dose-dependent increases in blood pressure (BP) and heart rate (HR) have been seen 
in clinical studies with OSA and narcolepsy participants. This population may be at risk for 
cardiovascular events due to certain intrinsic factors, such as increasing age, obesity, concurrent 
diabetes mellitus or cardiovascular disease, hyperlipidemia, and hypertension. In addition, the 
underlying disease pathophysiology may also predispose patients to cardiovascular disease. Based 
on the cardiovascular comorbidities in this population and depending on the cardiovascular risk 
profile, these events are anticipated to occur in this population.
In addition to the risks associated with the use of solriamfetol, participants with who enroll in this 
study may encounter study procedure-related risks, including risks and/or discomfort associated 
with blood collection, electrocardiogram (ECG), physical examination (PE), and completion of 
questionnaires and other assessments.
2.3.2.
Benefit Assessment
Solriamfetol has demonstrated robust, clinically meaningful wake-promoting effects and reduced 
EDS in adult subjects with narcolepsy or OSA. The primary potential benefits of solriamfetol to 

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participants in this study is anticipated to be a significant improvement in cognitive function. 
However, not every participant on solriamfetol is anticipated to benefit.
Additional benefits to the participants include: 
 Medical evaluations/assessments associated with this study’s procedures (eg, 
comprehensive PE, clinical safety assessments, and laboratory testing). 
 Close monitoring, advice, care, and support by a research team of doctors and other 
health care professionals who understand the disease or condition.
The chance for the participant to play an active role in their own health care and gain 
a greater understanding of their disease or condition.
The chance for the participant to help society by contributing to medical research. 
Even if the participant does not experience a direct benefit, the results of the clinical 
trial may help others and add to scientific knowledge. 
2.3.3.
Overall Benefit:Risk Conclusion
Previous clinical studies provide compelling evidence that solriamfetol has robust wake-promoting 
efficacy and a predictable safety profile that can be characterized, monitored and managed through 
routine clinical practice measures. Solriamfetol has a comprehensive clinical efficacy and safety 
database (including postmarketing experience) comprising healthy participants and those with 
EDS associated with OSA and narcolepsy, with a consistent safety profile across conditions. The 
benefit/risk profile is favorable in participants with OSA and narcolepsy, which supported the 
approval of doses up to 150 mg in each of these conditions. In the proposed trial, we will be 
targeting a final dose of 150 mg. This dose showed the highest level of improvement in 
wakefulness and reduction in sleepiness during the pivotal trials. The overall safety finding in 
participants taking the 150 mg dose was not significantly different from the 75 mg dose, and based 
on the titration schedule in clinical studies, the data from pivotal trials with solriamfetol 
(Studies 14-004 and 14-005) support the initiation of solriamfetol at 75 mg once daily.
Potential safety risks with the use of solriamfetol are serious psychiatric events, increases in BP 
and HR, and a potential for abuse. The risks to participants are expected to be similar to those seen 
in prior clinical studies, which are summarized in Section 2.3. Adverse events (AEs) following a 
single dose have generally been transient and mild to moderate. 
More detailed information about the known and expected benefits and risks and reasonably 
anticipated AEs of solriamfetol may be found in the IB, USPI and SmPC. 

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Objectives 
Estimands and Endpoints 
The second estimand for secondary objective evaluating efficacy is 
defined by the following:  
• 
Population: Participants aged 18 to 65, with EDS associated 
with OSA and impaired cognitive function in the mITT analysis 
set, defined as: all randomized participants with at least 1 dose 
of study drug and 1 postdose assessment of DSST RBANS  
• 
Variable: Categorical change from Baseline (Visit 3) to the end 
of each double-blind treatment period (Visit 5 and Visit 8) in 
each category of the BC-CCI 
• 
Intercurrent events: 
- The participant’s BC-CCI data are not collected if the 
participant discontinued the treatment (while on treatment 
policy strategy) 
- Missing assessments after discontinuation of treatment due 
to AE, lack of efficacy, or any other reasons will not be 
imputed 
• 
Population level summary: Percentage of patients with an at 
least 1 category improvement in the BC-CCI score from 
Baseline (Visit 3) to the end of double-blind treatment period 
(Visit 5 and Visit 8) in each treatment group 
To evaluate the effect of 
solriamfetol on cognitive 
function at individual post-dose 
timepoints in adult participants 
with EDS associated with OSA 
plus impaired cognitive 
functioning 
The estimand for this secondary objective to evaluate the effect on 
cognitive function at individual post-dose timepoints is defined by 
the following: 
• 
Population: Participants aged 18 to 65, with EDS associated 
with OSA and impaired cognitive function in the mITT analysis 
set, defined as: all randomized participants with at least 1 dose 
of study drug and 1 postdose assessment of DSST RBANS  
• 
Variable(s): Change from each of the 2-, 4-, 6-, and 8-hour 
DSST RBANS sores at Baseline (Visit 3) to each of the 
corresponding 2-, 4-, 6-, and 8-hour postdose DSST RBANS 
scores at the end of each double-blind treatment period (Visit 5 
and Visit 8) 
• 
Intercurrent events:  
- The participant’s DSST RBANS data are not collected if the 
participant discontinued the treatment (while on treatment 
policy strategy) 
- Missing assessments after discontinuation of treatment due 
to AE, lack of efficacy, or any other reasons will not be 
imputed  
• 
Population level summary: Difference in mean DSST RBANS 
from each of the 2-, 4-, 6-, and 8-hour DSST RBANS sores at 
Baseline (Visit 3) to each of the corresponding 2-, 4-, 6-, and 
8-hour postdose (at Visit 5 and Visit 8) DSST RBANS scores 
between solriamfetol and placebo 

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Objectives 
Estimands and Endpoints 
To evaluate the efficacy of 
solriamfetol on patient-reported 
global impression of 
concentration, memory, and 
thinking skills in adult 
participants with EDS 
associated with OSA plus 
impaired cognitive functioning 
The first estimand for this secondary objective evaluating efficacy is 
defined by the following:  
• 
Population: Participants aged 18 to 65, with EDS associated 
with OSA and impaired cognitive function in the mITT analysis 
set, defined as: all randomized participants with at least 1 dose 
of study drug and 1 postdose assessment of DSST RBANS  
• 
Variable: Change from Baseline (Visit 3) to the end of each 
double-blind treatment period (Visit 5 and Visit 8) in PGI-S 
score 
• 
Intercurrent events: 
- The participant’s PGI-S data are not collected if the 
participant discontinued the treatment (while on treatment 
policy strategy) 
- Missing assessments after discontinuation of treatment due 
to AE, lack of efficacy, or any other reasons will not be 
imputed 
Population level summary: Difference in mean PGI-S score from 
Baseline (Visit 3) to the end of double-blind treatment period 
(Visit 5 and Visit 8) between solriamfetol and placebo 
The second estimand for this secondary objective evaluating 
efficacy is defined by the following:  
• 
Population: Participants aged 18 to 65, with EDS associated 
with OSA and impaired cognitive function in the mITT analysis 
set, defined as: all randomized participants with at least 1 dose 
of study drug and 1 postdose assessment of DSST RBANS  
• 
Variable: Categorical improvement from baseline on the PGI-S 
to the end of each double-blind treatment period (Visit 5 and 
Visit 8)  
• 
Intercurrent events: 
- The participant’s PGI-S data are not collected if the 
participant discontinued the treatment (while on treatment 
policy strategy) 
- Missing assessments after discontinuation of treatment due 
to AE, lack of efficacy, or any other reasons will not be 
imputed 
Population level summary: Percentage of participants reporting an at 
least 1 category improvement from baseline on the PGI-S to the end 
of each double-blind treatment period (Visit 5 and Visit 8) in each 
treatment group 

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Objectives 
Estimands and Endpoints 
To evaluate the efficacy of 
solriamfetol on improving EDS 
in adult participants with EDS 
associated with OSA plus 
impaired cognitive functioning 
The estimand for this secondary objective evaluating efficacy is 
defined by the following:  
• Population: Participants aged 18 to 65, with EDS associated with 
OSA and impaired cognitive function in the mITT analysis set, 
defined as: all randomized participants with at least 1 dose of study 
drug and 1 postdose assessment of DSST RBANS  
• Variable: Change from Baseline (Visit 3) to the end of each 
double-blind treatment period (Visit 5 and Visit 8) in ESS score  
• Intercurrent events:  
- The participant’s ESS data are not collected if the participant 
discontinued the treatment (while on treatment policy strategy)  
- Missing assessments after discontinuation of treatment due to 
AE, lack of efficacy, or any other reasons will not be imputed  
 
Population level summary: Difference in mean ESS score from 
Baseline (Visit 3) to the end of double-blind treatment period (Visit 
5 and Visit 8) between solriamfetol and placebo  
To evaluate the safety and 
tolerability of solriamfetol 
administered once daily in adult 
participants with EDS 
associated with OSA plus 
impaired cognitive functioning  
Safety and tolerability evaluations will be determined by the 
occurrence of and/or changes in: 
• 
Incidence and severity of TEAEs 
• 
Vital signs 
• 
C-SSRS 
Exploratory  
To evaluate the association 
between the improvement in 
EDS and improvement in 
cognitive function following 
solriamfetol treatment in adult 
participants with EDS 
associated with OSA plus 
impaired cognitive functioning 
The exploratory endpoints for the exploratory objective of 
evaluating the association between the improvement in EDS and 
improvement in cognitive function are: 
• 
The correlation between the change from Baseline (Visit 3) at 
the end of each double-blind treatment period (Visit 5 and 
Visit 8) in ESS and DSST RBANS score 
• 
The correlation between the change from Baseline (Visit 3) at 
the end of each double-blind treatment period (Visit 5 and 
Visit 8) in ESS and BC-CCI score 
• 
The correlation between the change from Baseline (Visit 3) at 
the end of each double-blind treatment period (Visit 5 and 
Visit 8) in ESS and PGI-S 
Abbreviations: 
AE = adverse 
event; 
BC-CCI = British 
Columbia-Cognitive 
Complaints 
Inventory; 
C-SSRS = Columbia-Suicide Severity Rating Scale; DSST RBANS = Digit Symbol Substitution Test Repeatable 
Battery for the Assessment of Neuropsychological Status; EDS = excessive daytime sleepiness; ESS = Epworth 
Sleepiness Scale; mITT = modified Intent-to-Treat; OSA = obstructive sleep apnea; PGI-S = Patients Global 
Impression of Severity; RBANS = ; TEAE = treatment-emergent adverse event. 

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4.
STUDY DESIGN
4.1. 
Overall Design 
The study is designed as a prospective, multicenter, 2-arm, randomized, double-blind, placebo-
controlled interventional crossover trial of solriamfetol (75 mg titrated to 150 mg after 3 days) or 
matched placebo, then continued for a 2 week period total before completing a 1-week washout 
followed by the crossover period. Study intervention will be administered in a balanced 2 × 2 Latin 
square design, where half of the participants will receive placebo first and half of the participants
will receive solriamfetol first. 
Cognitive function is assessed by an objective measure, the DSST (collected at 2, 4, 6 and 8 hours
postdose), and a subjective measures, the BC-CCI and the Patients Global Impression of Severity 
(PGI-S) (both are collected at Baseline and at the end of each treatment period). The DSST has 
been frequently used in neuropsychological testing and dates back to the 1940s (Boake 2002). The 
DSST is a measure that requires attention, vigilance, processing speed and psychomotor speed, 
and it is sensitive to the effects of sleep deprivation and pharmacologic agents (Jaeger 2018). The 
DSST has previously been shown to be sensitive to pharmacologic alleviation of cognitive 
dysfunction in clinical studies of vortioxetine. Those findings are now included in the Trintellix™
(vortioxetine) product label (Trintellix 2013), and therefore warrant inclusion of the DSST in the 
current investigation of solriamfetol’s ability to alleviate cognitive impairment linked to EDS 
associated with OSA. Similarly, the BC-CCI, originally developed to measure cognitive 
complaints in individuals with MDD (Iverson and Lam 2013), has been used successfully to 
measure the relationship between cognitive complaints and impaired sleep quality among 
individuals with chronic kidney disease (Zubair 2017) and chronic insomnia (Kyle 2020). The 
PGI-S is a 5-point Likert-type rating scale to evaluate the severity of illness and is a widely used 
measure to assess efficacy in clinical psychopharmacology trials (FDA 2018). 
4.1.1.
Screening Period 
The Screening period will be 14 days (up to a maximum of 28 days) prior to Day 1 to minimize 
carry over learning effect of the DSST, and will serve to determine eligibility. During Screening, 
participants will provide informed consent and undergo a series of assessments to verify if they 
are eligible to participate in the study, as outlined in the Schedule of Assessments (SoA, 
Section 1.3). 
4.1.2. 
Baseline and Randomization  
The Baseline and Randomization visit will be used to confirm participant eligibility, and to assign 
participants to 1 of 2 treatment sequences: 1) solriamfetol in first double-blind treatment period 
(Treatment Period 1) followed by placebo in the second double-blind crossover treatment period
(Treatment Period 2); or 2) placebo in first double-blind treatment period followed by solriamfetol 
in the second double-blind crossover treatment period. Participants will be randomly assigned to 
1 of 2 treatment sequences in a 1:1 ratio, and each participant and will complete the assessments 
outlined in the SoA (Section 1.3). At the end of the Baseline and Randomization visit, participants 
will receive the double-blind study intervention for Treatment Period 1. 

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4.1.3. 
Double-blind Treatment Period (Treatment Period 1) 
Throughout this protocol, the Double-blind Treatment Period will be referred to as Treatment 
Period 1. Treatment Period 1 begins the day after the Baseline and Randomization visit. 
Participants will take the first dose of study intervention at home upon waking the first day of the 
period. Participants will take study intervention at home until the next visit, but will be instructed 
by site staff to not take the final dose until after arrival at the study site, and to bring pill 
bottle/blister pack of study intervention to the site.  
The last day of Treatment Period 1 is a site visit. Participants will turn in pill bottle/blister pack, 
take the final dose of study intervention for that treatment period in the presence of site staff, and 
undergo the assessments outlined in Section 1.3. At the end of the study site visit, participants will 
be provided with a supply of double-blind crossover study intervention for Treatment Period 2, 
but will be instructed to not to take any doses until after the 1-week washout. Site staff will then 
schedule the next visit to occur after the 1-week washout and 2-week double-blind crossover 
treatment periods are completed. 
4.1.4. 
Washout Period 
Participants will not take any study treatment during the 1-week washout period. At the end of the 
washout period, sites will call the participant to remind them to start taking the study intervention
(see SoA, Section 1.3). 
4.1.5. 
Double-blind Crossover Treatment Period (Treatment Period 2) 
Throughout this protocol, the Double-blind Crossover Treatment Period will be referred to as 
Treatment Period 2. Treatment Period 2 begins after completion of the 7-day washout period. 
During Treatment Period 2, participants will take the study intervention once daily at home in the 
morning upon wakening. The last day of the Treatment Period 2 is a site visit. Participants will 
turn in pill bottle/blister pack, take the final dose of Treatment Period 2 intervention in the presence 
of site staff, and undergo the assessments outlined in Section 1.3. 
4.1.6. 
Safety Follow-up or Early Discontinuation 
Participants will complete either the Safety Follow-up (SFU) or the Early Discontinuation (ED) 
visit as outlined in the SoA (Section 1.3). 
The same procedures will be administered during the SFU or ED visits. The SFU/ED visit can be 
virtual or onsite based on local regulations and/or site preference. The SFU visit will occur 4 to 
10 days after the final dose of study intervention. The ED 
 4 days after the last 
dose taken for participants who do not take all planned doses of either Treatment Period 1or 
Treatment Period 2.  
4.2. 
Scientific Rationale for Study Design 
A randomized, double-blind, placebo-controlled crossover study design has been selected for this 
study as it allows for an intra-participant comparison between solriamfetol and placebo in 
evaluating cognitive function. The crossover study design is appropriate in this study as the 
cognitive impairment and EDS associated with OSA are chronic and stable conditions, and the 

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treatment would not result in total cure but only alleviate the condition. This design also reduces 
the overall number of participants exposed to the test hypothesis required for evaluation. 
Two-week treatment for each period is selected for the following reasons: 
 Solriamfetol has a half-life of approximately 7 hours. 
Once daily solriamfetol dose of 150 mg reaches steady state within 3 days.
Pivotal studies evaluating solriamfetol demonstrated that the effect of solriamfetol 
was seen as early as after 1-week treatment. 
A 1-week washout period between the 2 double-blind treatment periods will minimize any 
potential carryover effect. 
4.3. 
Justification for Dose 
Results from the dose-dependent efficacy observed in the previous Studies 14-002 and 14-003 and 
in the open-label dosing periods in Studies 14-004 and 14-005, and supportive clinical 
pharmacology information (including population PK and exposure-response modeling data) 
suggest that the efficacious dose range for most participants is 75 mg to 300 mg once daily. 
As the study is aimed to evaluate the efficacy of solriamfetol on cognitive function improvement 
and not to identify the optimal dose, solriamfetol dose of 150 mg per the prescribing label will be 
administered to participants. Based on the titration schedule in clinical studies in OSA 
(Studies 14-003, 14-004, 14-005), the data support the initiation of solriamfetol at 75 mg once 
daily. These data also show that solriamfetol may be increased by doubling the dose at intervals 
of 3 or more days. Starting the dose at 75 mg will shorten the duration of the titration period and 
maximize the duration of participant exposure to the prescribed dose of 150 mg. Hence, after 
starting solriamfetol at 75 mg for the first 3 days of the treatment period, the dose will then be 
titrated up to 150 mg for the remainder of the treatment period.  
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of the 
study, including the SFU visit. 
The end of study is defined as when all participants have completed the study, or have withdrawn 
or have been lost to follow-up. 

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5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex 
1. Male or female between 18 (or the legal age of consent in the jurisdiction in which the 
study takes place) and 65 years of age, inclusive.
Type of Participant and Disease Characteristics 
2. Diagnosis of OSA according to International Classification of Sleep Disorders, Third 
Edition criteria.
3. Participant report (with clinician concurrence) of at least 1 of the following primary OSA 
therapy criteria: 
 Consistent number of hours of primary PAP therapy use (with downloadable history) 
for OSA on at least 5 nights/week for at least 1 month prior to Baseline (with or 
without prior OSA surgical intervention), OR
 No current use of PAP therapy for at least 1 month prior to Baseline but a history of at 
least 1 month of attempting to use PAP as the primary OSA therapy with at least 
1 documented adjustment that was made in an attempt to optimize the therapy (with or 
without prior OSA surgical intervention), OR
History of a surgical intervention intended to treat OSA symptoms (with or without 
current PAP use as primary OSA therapy). 
4. The participant has an age-
8 on the DSST Wechsler Adult 
Intelligence Scale, Fourth Edition (WAIS-IV) at the Screening visit. 
5. British Columbia-Cognitive Complaints Inventory
9 at Screening and Baseline. 
6. Epworth Sleepiness Scale (ESS) score > 10 at Screening and Baseline.
7.
6 hours.
Weight
8. Body mass index from 18.5 to < 40 kg/m2.
Sex and Contraceptive/Barrier Requirements
9. Male and female Participants
a. Male participants:
Male participants are eligible to participate if they agree to the following during the study 
intervention period and for at least 14 days after the last dose of study intervention:
Refrain from donating sperm

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PLUS, either:
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent
OR 
Must agree to use contraception/barrier as detailed below
Agree to use a male condom with female partner use of an additional highly effective 
contraceptive method with a failure rate of < 1% per year as described in Appendix 5
Contraceptive and Barrier Requirements when having sexual intercourse with a women 
of childbearing potential (WOCBP) who is not currently pregnant. 
b. Female participants: 
 A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and 1 of the following conditions applies: 
 Is a woman of nonchildbearing potential (WONCBP) as defined in Appendix 5 
Contraceptive and Barrier Guidance 
OR 
 Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of < 1% per year), as described in 0 Contraceptive and Barrier Guidance 
during the study intervention period and for at least 14 days after the last dose of 
study intervention. The investigator should evaluate the potential for contraceptive 
method failure (eg, noncompliance, recently initiated) in relationship to the first 
dose of study intervention. 
 A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within the Screening/Baseline period (once at the time of 
Screening for participation in the study and again at the time of the study Baseline 
assessment) before the first dose of study intervention, see Section 8.4.5 Pregnancy 
Testing.  
 Additional requirements for pregnancy testing during and after study intervention are 
located in Section 8.4.5. 
 The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.  
Informed Consent 
10. Capable of giving signed informed consent as described in Section 10.1.3, which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
5.2. 
Exclusion Criteria  
Participants who demonstrate any of the following will be excluded from the study: 

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Medical and Sleep Conditions
1. Female participants who are pregnant, nursing, or lactating. 
2. Usual bedtime later than 1 AM (0100 hours). 
3. Occupation requiring nighttime or variable shift work. 
4. Unable to understand or perform DSST test per investigator’s judgement. 
5. Use a PAP machine with no adherence data downloadable ability. 
6. Diagnosis of another sleep disorder (other than OSA) including: circadian rhythm sleep 
disorders, narcolepsy, restless legs syndrome determined by participant sleep history. 
7. Presence of acutely unstable major depression or current major depressive episode as based 
on the judgement of the investigator. 
8. Participants with active clinically significant illness, including endocrine, neoplastic, 
gastrointestinal, 
hematological, 
hepatic, 
immunologic, 
metabolic, 
neurological, 
pulmonary, and/or renal disease, and/or surgical history which could interfere with the 
study efficacy, safety, conduct or the ability of the participant to complete the study based 
on the judgement of the investigator, or place the participant at risk during the trial or 
compromise the study objectives.
9. History or presence of any other clinically relevant medical, behavioral, or psychiatric 
disorder other than OSA that is associated with an impact on cognitive function; including 
history or presence of neurodegenerative condition (eg, mild cognitive impairment due to 
Alzheimer’s), autism, vascular dementia, active suicidal ideation, that could affect the 
safety of the participant or interfere with study efficacy, safety, conduct or the ability of 
the participant to complete the trial based on the judgment of the investigator.  
10. History or presence of bipolar disorder, bipolar related disorders, schizophrenia, 
schizophrenia spectrum disorders, or other psychotic disorders according to Diagnostic and
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. 
11. History of bariatric surgery within the past year or a history of any gastric bypass 
procedure.
12. Participants with movement or motor disorders such as Parkinson’s disease, as they will 
not be able to complete the DSST.
Diagnostic Assessments 
13. Presence of renal impairment or calculated creatinine clearance < 60 mL/minute.
14. Clinically significant ECG abnormality in the opinion of the investigator.
15. Presence of significant cardiovascular disease including but not limited to: myocardial 
infarction within the past year, unstable angina pectoris, symptomatic congestive heart 
failure (ACC/American Heart Association stage C or D), revascularization procedures 
within the past year, uncontrolled atrial fibrillation, ventricular cardiac arrhythmias 
requiring automatic implantable cardioverter defibrillator or medication therapy, 
uncontrolled hypertension (as defined by Centers for Disease Control and Prevention), 
systolic blood press
155
 95 mmHg (at Screening 

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or Baseline), or any history of cardiovascular disease or any significant cardiovascular 
condition that in the investigator’s opinion may jeopardize participant safety in the study.
16. Laboratory value(s) outside the laboratory reference range that is considered to be 
clinically significant by the investigator (clinical chemistry, hematology, and urinalysis). 
NOTE: Screening labs may be repeated once.
17. Hypothyroidism or hyperthyroidism, unless stabilized by appropriate medication for at 
least 3 months prior to Screening (a normal thyroid-stimulating hormone is required prior 
to Randomization at Baseline).
Prior/Concomitant Therapy
18. Use of any over-the-counter (OTC) or prescription medications that could affect the 
evaluation of EDS within a time period prior to the Baseline visit corresponding to at least 
5 half-lives of the drug(s) or planned use of such drug(s) at some point throughout the 
duration of the 5-week double-blind treatment period. Examples of excluded medications 
include OTC sleep aids, stimulants (eg methylphenidate, amphetamines, modafinil, and 
armodafinil), sodium oxybate, pemoline, pitolisant, bupropion, trazodone, vortioxetine, 
duloxetine, tricyclic antidepressants, hypnotics, benzodiazepines, pseudoephedrine, 
barbiturates, and opioids. Medications should be discontinued such that, in the opinion of 
the investigator, the participant has returned to his/her Baseline level of daytime sleepiness 
at least 7 days prior to the Baseline visit. 
19. Current or recent (within the past 2 years) diagnosis of a moderate or severe substance use 
disorder (excluding caffeine) according to DSM-5 criteria, or seeking treatment for a 
substance-related disorder. Nicotine use disorder is excluded only if it has an effect on 
sleep (ie, a participant who routinely awakens at night to smoke).
20. Excessive caffeine use, defined as > 600 mg/day of caffeine (eg, more than 6 cups of 
brewed coffee, 15 cans of cola or 3 “energy shot” drinks), 1 week prior to Screening or 
anticipated excessive use during the study.
21. Urine drug screen positive for amphetamine, methamphetamine, tricyclic antidepressants, 
propoxyphene, benzodiazepines, barbiturates, cocaine, marijuana, morphine, ecstasy, 
oxycodone, buprenorphine, methadone, or phencyclidine at Screening or at any point 
throughout the duration of the study. 
22. History of regular heavy use of tetrahydrocannabinol (THC) is excluded. Sporadic 
recreational users of THC can complete a repeat urine drug screen during the Screening 
period. If this is negative, the participant may be allowed to enter the study pending 
agreement to completely refrain from the use of THC during the course of the study. 
23. Positive alcohol test at Screening.  
24. Participants who binge drink, defined as 5 or more drinks in a day for men or 4 or more 
drinks in a day for women at least once in past month. 
25. History of phenylketonuria or history of hypersensitivity to phenylalanine-derived 
products. 
26. Currently receiving MAO inhibitors or having had received MAO inhibitors for 14 days 
prior to the Baseline visit. 

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Prior/Concurrent Clinical Study Experience 
27. Previous exposure to solriamfetol (JZP-110, ADX-N05, R228060, or YKP-10A) in a 
clinical study or prescribed by a physician. 
28. Received an investigational drug in the past 30 days or 5 half-lives (whichever is longer) 
prior to the Baseline visit, or plans to use an investigational drug (other than the study drug) 
during the study. 
29. Is currently participating in another clinical study. 
5.3.
Lifestyle Considerations
Participants in this study will be asked to commit a good-faith effort to adhere to the study protocol.
5.3.1.
Caffeine, Alcohol, and Tobacco
1. Participants will be allowed to drink a maximum of 200 mg of caffeine (eg, 2 cups of 8 oz 
coffee) the morning of the Baseline visit assessment session. During each subsequent visit, 
participants will be instructed to consume the same amount of caffeine as they did prior to 
the Baseline visit. No additional caffeine is allowed during the visit. 
2. Participants who use tobacco products will be instructed to use the same amount of tobacco 
during each visit. Tobacco/nicotine products should not be consumed within 1 hour of 
performing the DSST assessment. 
3. Participants will be asked to abstain from alcohol 24 hours prior to the start of each 
assessment visit. Participants will be screened (breath alcohol test) prior to each Test 
Session. Participant with positive breath alcohol tests will be permanently discontinued 
from the study and asked to complete an ED visit. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE).
Participants may be allowed to repeat lab tests following resolution of transient exclusionary 
conditions or stabilization of conditions that were exclusionary and reversible (eg, unstable 
hypothyroidism, electrolyte abnormalities) and with the approval of the Medical Monitor. 
Participants who are approved for repeat labs must complete them within the 28-day Screening 
window. Rescreening for any purpose other than repeat laboratory testing will not be permitted.
5.5. 
Criteria for Temporarily Delaying Enrollment 
Not applicable. 

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6.
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study intervention/treatment is defined as any investigational intervention(s), marketed product(s), 
or placebo intended to be administered to a study participant according to the study protocol.
6.1. 
Study Intervention(s)/Treatment(s) Administered 
The Sponsor will provide the clinical study unit with a supply of solriamfetol and placebo tablets 
as described in Table 4.

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Table 4: 
Study Treatment/Intervention 
Treatment 
Arm 
Intervention/ 
Treatment 
Name 
Formulation 
Unit Dose 
Strength(s) 
Dosage 
Level(s) 
Route of 
Administration 
Use 
Sourcing 
Pkg 
Labeling 
Storage 
Conditions 
1
Matching 
Placebo 
Overencapsulated 
tablets 
To match 
study 
intervention 
N/A 
Oral 
Placebo 
Sponsor  
1 PBO Bottle & 
1 Blister 
Card/PBO: 
33 capsules in 
PBO/Bottle & 
3 capsules in 
PBO/BC  
 
Blinded 
Do not store 
above 
30°C/86°F. 
Do not 
refrigerate or 
freeze.  
2 
Solriamfetol 
Overencapsulated 
tablets 
75 mg,  
150 mg 
75 mg, 
150 mg 
Oral 
Active 
Sponsor 
150 mg/1 Bottle 
& 75 mg 
1 Blister Card  
33 capsules in 
150 mg/Bottle & 
3 Capsules in 
75 mg BC 
Blinded 
Do not store 
above 
30°C/86°F. 
Do not 
refrigerate or 
freeze. 
Solriamfetol 
should be 
stored 
according to 
regulations 
for a DEA 
Schedule IV 
controlled 
substance in 
the US and 
according to 
any other 
regional 
regulations 
that apply. 
Abbreviations: BC = blister card; DEA = Drug Enforcement Administration; PBO = placebo; Pkg = package; US = United States

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6.2.
Preparation/Handling/Storage/Accountability 
1. Further guidance and information for the final disposition of unused study interventions 
are provided in the Investigator Trial Site Binder and the IMP Pharmacy Manual for sites 
to follow.  
2. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
3. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study intervention 
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. 
4. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
All participants who sign the ICF will receive a participant number. The participant number 
identifies the participant for all study procedures that occur throughout the study. This number is 
unique and once assigned, cannot be reassigned to another study participant.  
Treatment Randomization for this study will occur centrally through the use of an interactive 
response technology (IRT) system. Randomization numbers also cannot be reused. Participants 
cannot be rescreened, but may have repeat laboratory testing. The IRT will be programmed with 
blind-breaking instructions. 
Emergency Unblinding 
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a participant’s intervention assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the sponsor prior to unblinding a 
participant’s intervention assignment unless this could delay emergency treatment of the 
participant. If a participant’s intervention assignment is unblinded, the sponsor must be notified 
within 24 hours after breaking the blind. The date and reason that the blind was broken must be 
recorded in the source documentation and the IRT, as applicable. 
Regulatory Reporting
The participant’s treatment assignment may be unblinded for regulatory reporting purposes. 
Notification of the treatment assignment is only made known to those who require it for safety 
reporting and submission processes. All other individuals involved in the study, including the 
investigator, will remain blinded to treatment assignment. Participants for whom the blind is 
broken for this reason will not be withdrawn from the study.  

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6.4.
Study Intervention/Treatment Compliance
Participants that are dosed at the site will receive study intervention directly from the investigator 
or designee, under medical supervision. The date and time of each dose administered in the clinic 
will be recorded. The dose of study intervention and study participant identification should be 
confirmed at the time of dosing by a member of the study site staff other than the person 
administering the study intervention.
Sites will verify the participant’s compliance with self-administered study intervention at each site 
visit. Compliance of the participant’s self-administered study intervention at home will be assessed 
at each visit. Deviation(s) from the prescribed dosage regimen will be recorded.
A record of the quantity of placebo and solriamfetol dispensed to and administered to each 
participant must be maintained and reconciled with study intervention and compliance records. 
Intervention start and stop dates, including dates for intervention delays, will be collected. For 
in-clinic dosing on test days, study site staff will verify the study intervention has been taken and 
ingested properly.
6.5. 
Dose Modification 
For the solriamfetol treatment arm, participants will take 75 mg for the first 3 days and 150 mg for 
the remainder of the treatment period. For the placebo treatment arm, participants will take the 
placebo treatment for the entire period. There will be a washout period between the 2 treatment 
periods, during which no study intervention will be taken.  
No dose adjustments or modifications (other than titration from 75 mg to 150 mg as described 
above) are allowed in this study. Participants who do not tolerate their assigned fixed dose of 
solriamfetol will be discontinued from the study intervention (see Section 7.1).
6.6. 
Continued Access to Study Intervention After the End of the Study 
No extension study is planned. Upon completing the SFU/ED visit, participants should follow-up 
with their health care provider regarding the resumption of any medications that were discontinued 
prior to study participation.
6.7. 
Treatment of Overdose, Medication Errors, or Misuse 
For this study, any dose of solriamfetol greater than 300 mg within a 24-hour period will be 
considered an overdose. 
A specific reversal agent for solriamfetol is not available. 
In the event of an overdose, the investigator should:
 Contact the Medical Monitor immediately. 
 Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
solriamfetol can no longer be detected systemically (at least 2 days). 
 Document the quantity of the excess dose as well as the duration of the overdose.
6.8. 
Prohibited Concomitant Therapy 
The following concomitant medications are prohibited during the study: 

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 Use of any OTC or prescription medications that could affect the evaluation of EDS 
within a time period prior to the Baseline visit corresponding to at least 5 half-lives of 
the drug(s) or planned use of such drug(s) at some point throughout the duration of 
the 5-week double-blind treatment period. Refer to Section 5.2 exclusion criteria #18 
for the list of prohibited OTC or prescription medications. Medications should be 
discontinued such that, in the opinion of the investigator, the participant has returned 
to his/her Baseline level of daytime sleepiness at least 7 days prior to the Baseline 
visit.  
 Phenylketonuria or phenylalanine-derived products. 
 Monoamine oxidase inhibitor (MAOI) in the past 14 days or 5 half-lives (whichever 
is longer) prior to the Baseline visit, or MAOI use during the study is also not 
allowed.
In addition to the prescription medications listed above, use of the following substances are 
prohibited: 
 Nicotine use disorder which has an effect on sleep (ie, a participant who routinely 
awakens at night to smoke).
 Excessive caffeine use, defined as > 600 mg/day of caffeine (eg, more than 6 cups of 
brewed coffee, 15 cans of cola or 3 “energy shot” drinks), 1 week prior to Screening 
or anticipated excessive use during the study.
 Regular heavy use of THC.
 Binge drinking, defined as 5 or more drink in a day for men or 4 or more drinks in a 
day for women at least once a year.
 Participants must also refrain from any alcohol use during the 24 hours prior to each 
assessment visit. 
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements or other specific categories of interest) that the 
participant is receiving within 30 days of Screening or receives during the study must be 
recorded along with: 
 Reason for use 
 Dates of administration including start and end dates 
 Dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 

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7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
Participants may discontinue from study intervention at any time for any reason, or at the discretion 
of the investigator. In addition, a participant may be withdrawn from study intervention by the 
investigator or sponsor for safety, behavioral, compliance, and/or administrative reasons. For 
participants that discontinue study intervention, all effort should be made to complete the 
procedures listed in the SFU/ED visit (Section 1.3 and Section 4.1.1). 
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will remain in the 
study to be evaluated for SFU/ED visit. See the SoA for data to be collected at the time of 
discontinuation of study intervention and follow-up and for any further evaluations that need to be 
completed. 
A participant must be discontinued from study intervention for any of the following reasons: 
 The participant or participant’s legal representative requests to discontinue study 
intervention 
 The participant has an AE that may compromise the participant’s continued 
participation 
 The participant has a positive serum pregnancy test (Section 1.3 and Section 8.4.5) 
 The participant is noncompliant with study intervention or procedures 
 The sponsor decides to terminate the study prior to completion.  
 The investigator determines the participant should not continue on study intervention.  
7.1.1. 
Temporary Discontinuation/Study Intervention Interruption
Temporary discontinuation or study intervention interruption are not allowed in this study, and 
participants who do not tolerate their assigned fixed dose of solriamfetol will be discontinued from 
the study intervention (see Section 6.5). 
7.2. 
Participant Discontinuation/Withdrawal From the Study 
 A participant may withdraw from the study at any time at his/her own request or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, or 
compliance reasons. The participant will be permanently discontinued both from the 
study intervention and from the study at that time. This is expected to be uncommon.
 At the time of discontinuing from the study, if possible, an ED visit should be 
conducted, as shown in the SoA (Section 1.3).  
 If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent.  

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 If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records.  
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
 Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
 Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study and lost to follow-up.  
Discontinuation of specific sites or of the study as a whole are handled as part of Study and Site 
Start and Closure Section 10.1.9. 

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8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA (Section 1.3). 
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential and 
required for study conduct. 
All Screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator should maintain a Screening log to record details of 
all participants screened and to confirm eligibility or record reasons for Screening failure, as 
applicable. The site is responsible for ensuring that reason for screen failure is entered into the IRT 
system. 
Safety or laboratory results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded. The maximum amount of blood 
collected from each participant over the duration of the study, including any extra assessments that 
may be required, will not exceed 21 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
8.1. 
General Administrative Procedures 
Planned time points for general administrative procedures are provided in the SoA (Section 1.3). 
8.1.1. 
Informed Consent 
The investigator or medically qualified designee (consistent with local requirements) must obtain 
documented consent from each potential participant/legal representative prior to participation in 
this study. A signed copy of the ICF should be given to the participant and the original should be 
placed in the participant’s medical records. 
8.1.2.
Assignment of Participant Number
Each participant who signs the ICF will be assigned a unique number that will identify the 
participant throughout the study. Once a number has been assigned, it cannot be reassigned to 
another study participant.
8.1.3.
Medical History
A medical history will be obtained by the investigator or a medically qualified designee (consistent 
with local regulations). All active conditions should be recorded and any condition that the 
investigator deems clinically significant and relevant to the study.
8.1.4.
Medication Review (Prior and Concomitant Medications)
The investigator or medically qualified designee should review the participant’s prior medication 
use within 30 days. Medication that is required to be washed out prior to the study should also be 
recorded. All medication currently taken by the participant should be recorded. 

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8.1.5. 
Inclusion and Exclusion Criteria Review
All inclusion and exclusion criteria should be reviewed by the investigator to ensure the participant 
qualifies for the study.
8.1.6. 
Timing of Study Intervention Dosing
Participants should take the study intervention dose once daily upon awakening (except for site 
visit days) and avoid administration within 9 hours of planned bedtime because of the potential to 
interfere with sleep. If the subject cannot take the study drug at least 9 hours before his/her 
anticipated bedtime, the subject should not take the study drug for that day. 
For site visits, participants should not take their daily dose upon awakening. Instead, they should 
arrive at the study site 30 minutes prior to the time of drug administration (eg, 8:30 AM) for 
assessments so that they can take study intervention under site supervision promptly as scheduled 
(eg, 9:00 AM). 
After the first Treatment Period 1 visit, participants will undergo a 1-week washout, where 
participants will not take any study intervention during this time.  
8.1.7. 
Reminder Phone Calls 
There will be several reminder phone calls made to participants throughout the study. If phone 
calls are not feasible, at their discretion sites can given participants the opportunity to “opt in” to 
an alternate, Health Insurance Portability and Accountability Act (HIPAA)-compliant method of 
contact; however, sites must record in source documents confirmation that notification was 
received. 
The 
first 
phone 
contact 
is 
Visit 2, 
and 
should 
occur 
3 days 
prior 
to 
Visit 3 
(Baseline/Randomization). Participants will be reminded to:  
complete their sleep diary for 3 nights and bring the diary with them to site visit  
 bring their PAP device 
 not drink more than 200 mg of caffeine (eg, 2 cups of 8 oz coffee) the morning of the 
visit (see Section 5.3.1 for details) 
 get the usual night’s sleep the night before the site visit 
 abstain from alcohol 24 hours before the site visit 
The site will also confirm that the participant does not have plans to travel over the next 3 days 
and request the participant restrict any significant travel (eg, crossing time zone) before next visit.  
The second phone contact is Visit 4, and should occur 3 days before Visit 5 (Treatment Period 1). 
Participants will be reminded to:  
 complete their sleep diary for 3 nights and bring diary with them to site visit  
 bring their PAP device 
 bring all medications and medication bottles/blister packs 
 not drink more than 200 mg of caffeine (eg, 2 cups of 8 oz coffee) the morning of the 
visit (see Section 5.3.1 for details) 

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 get the usual night’s sleep the night before the site visit 
abstain from alcohol 24 hours before the site visit
not to take study drug on day of the visit
The site will also confirm that the participant does not have plans to travel over the next 3 days 
and request the participant restrict any significant travel (eg, crossing time zone) before next visit.
The third phone contact is Visit 6, and should occur during the Washout Period 1 day before the 
first dose of Treatment Period 2 intervention. Participants will be reminded to begin taking 
crossover treatment next morning, and to continue taking it until the next site visit.
The fourth phone contact is Visit 7, and should occur 3 days before Visit 8 (Treatment Period 2). 
This reminder call is identical to the reminder phone call Visit 4. 
8.2. 
Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Digit Symbol Substitution Test 
The DSST is a measure that requires attention, vigilance, processing speed and psychomotor 
speed, and it is sensitive to the effects of sleep deprivation and pharmacologic agents 
(Jaeger 2018). The DSST generally requires matching of a list of symbols and digits to each other 
using a given digit symbol pairing key, as fast as possible within a given timeframe while 
remaining as accurate as possible. Two versions of the DSST will be administered in this study: 
1) the DSST WAIS-IV at Screening, and 2) the DSST RBANS version for all other visits during 
the study. 
8.2.1.1.
Digit Symbol Substitution Test Wechsler Adult Intelligence Scale Fourth Edition
The DSST WAIS-IV will be used to determine eligibility. Participants will need an age-corrected 
score of  8 to be eligible for the study. To complete the WAIS-IV form, participants will receive 
a number and must match the symbol, as quickly and accurately as possible, within 120 seconds. 
8.2.1.2.
Digit Symbol Substitution Test Repeatable Battery for the Assessment of 
Neuropsychological Status Version
The DSST RBANS will serve as the primary efficacy endpoint. Although different staff can 
administer the DSST to a given participant, the participants should complete each of their DSSTs 
throughout the study in the same physical location at the study site. 
To complete the RBANS form, participants will receive a symbol and must match the number, as 
quickly and accurately as possible, within 90 seconds. The number of correct symbol/number 
pairings determines the participants score.  
 
 
 
 

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8.2.2. 
British Columbia-Cognitive Complaints Inventory 
The BC-CCI was developed to measure cognitive complaints in individuals with MDD (Iverson 
and Lam 2013). It is a 6-item self-report measure that asks respondents to rate problems with 
specific cognitive symptoms over the past 7 days. It takes less than 5 minutes to complete. A 
4-point scale (0 “Not at all” to 3 “Very much”) is used to rate each item. The total score (ranges 
from 0 to 18) that is generated assesses domains of memory, concentration, trouble expressing 
thoughts, word-finding, and problem solving. Higher scores indicate greater severity of cognitive 
impairment, with 4 established classification ranges for the BC-CCI total score: 0 to 4 = “broadly 
normal”; 5 to 8 = “mild” cognitive complaints; 9 to 14 = “moderate” cognitive complaints; and 15 
to 18 = “severe” cognitive complaints. Three additional items that ask about how these symptoms 
impact work, relationships and social/recreational activities are also included to provide further 
information on the nature of functional impairment (however, those items are not included in the 
total score calculation). 
Site personnel should ensure that the participant has completed the entire BC-CCI according to the 
instructions in the BC-CCI training manual.
8.2.3.
Patient Global Impression of Severity
The PGI-S is a 5-point Likert-type rating scale and a widely used assessment in clinical 
psychopharmacology trials to assess severity of illness (FDA 2018). Participants will be asked to 
rate the level of severity of their problems with concentration, memory, and thinking skills during 
the past 7 days. The responses of this participant-completed scale range from “none” (0) to “very 

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Each participant’s diary will be collected (if available) and stored with other source documents. If 
a diary is missing or incomplete, site staff should ask the participant about their sleep during the 
last 3 nights and recent travel to evaluate whether the visit should be rescheduled due to insufficient 
sleep or travel.
For any study site visits that are rescheduled due to insufficient sleep (ie, < 4 hours on any of the 
3 prior nights) prior to the visit or significant travel (ie, crossing a time zone), the visit window 
will be extended without being considered a protocol violation. 
8.3.3. 
Obstructive Sleep Apnea Therapy Adherence 
Study site personnel should collect and record participants’ OSA therapy adherence information; 
data will be recorded but will not be used to discontinue/early discontinue any participants. 
Typically, this will consist of downloading data from the PAP machine. Participants who have 
undergone surgery and are not currently using PAP therapy will not require documented 
adherence. During the Screening and Baseline visits, adherence will be reviewed to assess 
inclusion/exclusion criteria. Adherence will be recorded according to the SoA (Section 1.3). 
8.3.4. 
Caffeine and/or Nicotine Intake Check
Sites should ask about caffeine and/or nicotine intake as described in the SoA (Section 1.3). 
Specifically, sites should verify that participants are complying with the caffeine/nicotine 
restrictions outlined Section 6.8 before, and during site visits. Sites should record in the source 
documents any noncompliance, and determine if participants should be rescheduled or terminated 
as deemed appropriate by the investigator.  
8.4. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.4.1. 
Physical Examinations 
 A complete PE will include, at a minimum, assessment of the cardiovascular, 
respiratory, gastrointestinal and neurological systems. Height and weight will also be 
measured and recorded. At Screening and Baseline/Randomization visits, sites must 
calculate body mass index in order to verify eligibility.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Any abnormalities identified at the Screening PE should be recorded as medical 
history.  
Any clinically significant abnormalities identified after initiating study 
intervention should be recorded as AEs.
8.4.2.
Vital Signs
Vital signs will be collected prior to study intervention administration for Visit 5 and Visit 8.  
 Oral temperature, pulse rate, respiratory rate, and BP will be assessed. 

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 Blood pressure and pulse measurements will be assessed in the sitting position with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available.
 Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (eg, television, cell 
phones). 
 Vital signs (to be taken before blood collection for laboratory tests) will consist of 
1 pulse and 3 BP measurements (3 consecutive BP readings will be recorded at 
intervals of at least 1 minute). The average of the 3 BP readings will be recorded.
 For clinically significant abnormal vital signs results, sites should document them in 
the medical history (Screening and Randomization) or as AEs (after initiating study 
intervention).
8.4.3. 
Electrocardiograms
 Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically calculates the HR and measures PR, QRS, QT, and 
corrected QT interval (QTc) intervals. Any abnormal safety assessments including 
ECG readings considered clinically significant in the medical and scientific judgment 
of the investigator should be reported as an AE (Appendix 4). The investigator should 
review the ECG and document that review in the source documents.
 For clinically significant abnormal ECG results, sites should document them in the 
medical history (Screening results) or as AEs (after initiating study intervention).
8.4.4. 
Clinical Safety Laboratory Assessments
 See Appendix 3 for the list of clinical laboratory tests to be performed and to the SoA 
(Section 1.3) for the timing and frequency.
 The investigator must review the laboratory report, document this review, and record 
any clinically significant changes occurring during the study as an AE (after initiation 
study intervention). The laboratory reports must be filed with the source documents.  
 Abnormal laboratory findings associated with the underlying disease are not 
considered clinically significant unless judged by the investigator to be more severe 
than expected for the participant’s condition. 
 All laboratory tests with abnormal values considered clinically significant during 
participation in the study or within 14 days after the last dose of study intervention
(and considered by the investigator to be related to study drug) 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 clinically significant values do not return to normal/Baseline within a period of 
time judged reasonable by the investigator, the etiology should be identified, and 
the sponsor notified. 

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for lifetime and over the past 5 years with the Baseline/Screening Version of the C-SSRS. The 
C-SSRS (since last visit version) will be administered to participants at subsequent times as 
indicated in the Schedule of Events (Section 1.3).
8.5.
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting 
The definitions of AEs and SAEs can be found in Appendix 4.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs (see Appendix 4).
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 4.  
8.5.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Events Information 
All AEs and SAEs will be collected from the start of intervention until the follow-up visit at the 
time points specified in the SoA (Section 1.3). 
Note: All SAEs that occur after the consent form is signed but before study intervention/treatment 
must be reported by the investigator if they cause the participant to be excluded from the trial, or 
are the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment, or a procedure. 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded as Medical History/Current Medical Conditions, not as AEs. 
All SAEs will be recorded and reported to the sponsor or designee immediately and within 
24 hours of first knowledge of the event by study personnel, as indicated in Appendix 4. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being available.
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator should promptly 
notify the sponsor.
8.5.2.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.5.3.
Follow-up of Adverse Events and Serious Adverse Events
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 

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otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is provided in Appendix 4.  
8.5.4. 
Regulatory Reporting Requirements for Serious Adverse Events
Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.
 An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.
 Investigator safety reports will be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy 
and forwarded to investigators as necessary. The Reference Safety Information for the 
determination of expectedness of solriamfetol can be found in the IB.
8.5.5. 
Pregnancy
 Details of all pregnancies in female participants and female partners of male 
participants will be collected after the start of study intervention and until 14 days 
after the last dose of the study intervention.
 If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the 
female participant or female partner of male participant (after obtaining the necessary 
signed informed consent from the female partner) pregnancy.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such.
The participant (or the participant’s pregnant female partner) will be followed to 
determine the outcome of the pregnancy. The investigator will collect follow-up 
information on the participant (or the participant’s pregnant female partner) and the 
neonate, and the information will be forwarded to the sponsor.
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.5.4. While the investigator is not obligated to actively seek this information 

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in former study participants (or the participant’s pregnant female partner), he or she 
may learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
8.5.6. 
Overdose, Medication Errors, and Misuse 
Overdose (defined as any dose administered or received that was higher than the intended dose), 
medication errors (defined as any unintentional error in the dispensing or administration of the 
study drug), and misuse of the study drug are considered reportable experiences. The method for 
completing and transmitting reports of these experiences are provided in Appendix 4. 
If any overdose, medication error, or misuse of the study drug results in an AE, this must be 
recorded. If the AE is serious, it must also be reported as described in Appendix 4.  
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.6. 
Pharmacokinetics 
Pharmacokinetics will not be evaluated in this study.
8.7. 
Genetics 
Genetics will not be evaluated in this study.
8.8. 
Biomarkers 
Biomarkers will not be evaluated in this study. 
8.9. 
Immunogenicity Assessments 
Immunogenicity assessments are not applicable to this study. 
8.10. 
Health Economics 
Health economics will not be evaluated in this study.

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9.
STATISTICAL CONSIDERATIONS
9.1. 
Statistical Hypotheses 
9.1.1.
Primary Hypothesis
The primary statistical hypothesis for this study is to show whether solriamfetol has a significantly 
improved effect versus placebo on the primary endpoint of the changes in average DSST scores 
(average of the postdose DSST scores [hour 2, 4, 6, and 8] versus average of the Baseline DSST 
scores) after 2 weeks of treatment (H1: µsol – µpl > 0) using a 1-sided significance level of 0.025.
The statistical null hypothesis is that solriamfetol does not improve versus placebo on the change 
in DSST scores after 2 weeks of treatment (H0: µsol – µpl  0). 
9.2. 
Sample Size Determination 
A sample size of 49 participants per treatment sequence for a total sample size of 98 will provide 
90% power to detect a difference of 3 points in means for the change from Baseline to Week 2 on 
DSST RBANS scores between solriamfetol and placebo, assuming a standard deviation of 9 points 
in the change in DSST (the cross over analysis of variance [ANOVA] root mean squared error
(RMSE) is 6.36). The sample size estimates are based on the results from Trintellix randomized 
parallel placebo-controlled trials (McIntyre 2014; Mahableshwarkar 2015). The change from 
Baseline to Week 8 resulted in an estimated delta on DSST performance score of 1.8 ~ 4.3 (average 
3.4) and SD of 6.6 ~ 8.6. Another reference is a crossover study with 5 dosages of MK-0249, 
modafinil 200 mg, and placebo and each period is 2 weeks, the RMSEs are estimated from 
4.4 ~ 5.7 (Herring 2013). It is increased to 6.36 to account for uncertainty in sample size 
assumptions. A 1-sided significance level of 0.025 using a 2 group t-test (crossover ANOVA) is 
used in the sample size calculation. Assuming a correlation of 0.5 between periods on DSST, a 
delta of 3, a standard deviation of 9, and a 15% dropout rate, a total of 116 (58 participants per 
treatment sequence) will be randomized.  
Note: “Randomized” means a participant who consented to the study and was assigned to a 
randomized treatment group and received at least 1 dose of study intervention. 
9.3.
Analysis Populations
Population 
Description
Safety 
All randomized participants who receive at least 1 dose of study intervention. This 
analysis set will be used for safety analyses and participants should be summarized 
according to actual treatment. This population will be analyzed for safety evaluations 
and will be presented in the tables and listings of safety data. 
ITT  
All randomized participants. 
mITT  
All participants who were randomized, received at least 1 dose of study medication, 
have Baseline and at least 1 postdose evaluation of DSST. If a participant in the 
mITT population does not have an assessment for a particular endpoint, it will be 
excluded in the analysis of that endpoint. The primary efficacy analyses will be 
based on the mITT population. 
Abbreviations: DSST = Digit Symbol Substitution Test; ITT = Intent-to-Treat; mITT = modified ITT  

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9.4.
Statistical Analyses
The statistical analysis plan (SAP) will be finalized prior to the database lock and it will include a 
more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints, including 
primary and secondary endpoints. 
9.4.1. 
General Considerations 
All study data will be summarized using descriptive statistics. Categorical variables (eg, race, 
ethnicity) will be reported as frequency and percent. Continuous variables will be reported as 
number of participants, mean, SD, median, minimum, and maximum (eg, age, weight). All 
summaries, statistical analyses, and individual participant data listings described below will be 
completed using the SAS Statistical Analysis System (SAS Institute, Inc.; Cary, NC)
 
 
9.4.1.2. 
Definition of Study Periods for Analysis 
There are 2 periods, treatment period and crossover treatment period. Efficacy will be analyzed 
and summarized based on the modified Intent-to-Treat analysis set. Safety will be summarized 
based on the Safety Population.  
9.4.1.3. 
Intercurrent Event Strategies 
The following are intercurrent events that may occur during the study: 
 Study treatment discontinuation due to AEs, lack of efficacy or use of other 
(prohibited) concomitant medications, etc.
 Withdrawal from the study 

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 Lost to follow-up 
Participant’s DSST data will not be collected if the participant discontinues the treatment (while 
on treatment policy strategy). Missing assessments after discontinuation of treatment due to AE, 
lack of efficacy, or any other reasons will not be imputed for primary analysis. 
9.4.1.4. 
Pooling of Investigational Centers 
Data from all investigational centers will be pooled for primary and secondary endpoints analyses. 
Data may also be pooled by region as appropriate for exploratory analyses. 
9.4.1.5. 
Dropouts and Missing Data 
Missing data will not be imputed. For the primary endpoint, if any of the 2-, 4-, 6-, or 8-hour DSST 
RBANS are missing, the average of the nonmissing assessments be used. If all assessments are 
missing then it will be considered missing. 
9.4.2. 
Primary Endpoints
The primary estimand is described in Section 3. The primary outcome measure is the change from 
the average of the DSST RBANS scores at Baseline to the average of the postdose DSST RBANS 
scores at the end of each double-blind treatment period. This will be analyzed using a Mixed Model 
with Repeated Measures (MMRM). The model will include sequence, participant within sequence, 
treatment (solriamfetol and placebo), period as fixed effects, and the baseline average of the DSST 
RBANS scores as the covariate. The unstructured covariance for the repeated measurements will 
be assumed. The treatment effects, the 2 sided 95% confidence interval (CI) of treatment difference 
(solriamfetol - placebo) will be presented. 
9.4.3. 
Secondary Endpoints
The secondary estimands are described in Section 3. The same methods used for primary efficacy 
analysis will be used for the secondary endpoints. .
9.4.4. 
Exploratory Endpoint(s)
The exploratory endpoints are the correlations between the change from Baseline at the end of 
each double-blind study treatment period in ESS and DSST RBANS score, BC-CCI, and PGI-S. 
Nominal p-values will be provided with appropriate 95% CIs for the exploratory endpoints. 
9.4.5. 
Safety Analyses 
Safety analyses will be performed for the Safety Population. No formal statistical testing will be 
performed. 
9.4.6. 
Other Analyses 
There are no other analysis (eg, subgroups of interest) planned for this study. 

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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations 
10.1.1.
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
Applicable International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) 
Guidelines 
 Applicable laws and regulations 
 The protocol, protocol amendments, ICF, IB, 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 study is initiated.
 Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants.  
 Protocols and any substantial amendments to the protocol will require regulatory 
authority approval as applicable according to local regulations prior to initiation, 
except for changes necessary to eliminate an immediate hazard to study participants. 
 The investigator will be responsible for the following: 
 Providing written summaries of the status of the study 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 
IRB/IEC procedures
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), 
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations. 
10.1.2. 
Financial Disclosure 
Investigators and subinvestigators 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 study and for 
1 year after completion of the study. 

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10.1.3. 
Informed Consent Process 
 The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study.
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, HIPAA requirements, where 
applicable, and the IRB/IEC or study center.
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.
 Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study.
A copy of the ICF(s) must be provided to the participant.
10.1.4.
Data Protection
 Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred. 
 The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant who will be required to give consent for 
their data to be used as described in the informed consent. 
 The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.5. 
Safety Committee Structure 
The Sponsor recognizes the importance of ongoing review of the accumulating safety and efficacy 
data. The Sponsor will perform periodic safety data monitoring regularly by data listing review. In 
addition, safety data from the study will be reviewed on an ongoing basis as part of routine 
pharmacovigilance and safety surveillance activities. Reports of safety findings (from either single 
events or based on aggregate review) that suggest a significant risk to humans will be distributed 
to all participating Investigators and to the relevant regulatory authorities and IRBs/IECs.
10.1.6. 
Dissemination of Clinical Study Data 
The sponsor of the study is solely responsible for disclosing results on ClinicalTrials.gov, 
EudraCT, and other public registries in accordance with applicable global laws and regulations. 
By signing this protocol, the investigator acknowledges that all posting requirements are solely the 

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responsibility of the sponsor, and agrees not to submit any information about the study or its 
results. 
10.1.7. 
Data Quality Assurance
Investigators and site staff will be trained on protocol procedures and electronic case 
report form (eCRF) completion prior to enrolling participants in the study.
 All participant data relating to the study, will be recorded on printed or eCRF 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 case report form (CRF).
 Guidance on completion of CRFs will be provided in the CRF completion guidelines.
 The investigator must permit study-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 onsite 
monitoring) are provided in the Monitoring Plan. 
 The sponsor or designee is responsible for the data management of this study, 
including quality checking of the data.
 The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organization [CRO]). 
 Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator or institution/site as applicable, for the 
period of time established in the clinical study agreement entered into by the 
investigator’s study site unless local regulations or institutional policies require a 
longer retention period. No records may be destroyed during the retention period 
without the written approval of the sponsor. No records may be transferred to another 
location or party without written notification to the sponsor.
10.1.8. 
Source Documents
 Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.
 Data reported on the CRF or 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 study. Also, current medical records must be available.
 Definition of what constitutes source data can be found in the eCRF Completion 
Guidelines. 

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 The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 
 Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
10.1.9. 
Study and Site Start and Closure 
10.1.9.1. First Act of Recruitment
The study start date is the date on which the first participant has the first visit.
10.1.9.2. Study/Site Termination
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The investigator may initiate study 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 study site by the sponsor or investigator may include but are 
not limited to:
For study termination: 
 Discontinuation of further study intervention development
For site termination: 
 Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
 Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
 Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and should assure appropriate participant therapy 
and/or follow-up. 
10.1.10. 
Publication Policy  
Details on the Publication Policy for this study are provided in the Clinical Trial Agreement.  
 
 

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APPENDIX 1.
ABBREVIATIONS AND DEFINTIONS
Abbreviation 
Description 
AE 
adverse event 
BC-CCI 
British Columbia-Cognitive Complaints Inventory 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
CI
confidence interval
CRF
case report form
C-SSRS
Columbia-Suicide Severity Rating Scale 
CRO
Contract Research Organization
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
DSST 
Digit Symbol Substitution Test 
ECG
electrocardiogram 
ED 
early discontinuation 
EDS 
excessive daytime sleepiness 
eCRF 
electronic case report form 
ESS 
Epworth Sleepiness Scale 
EU 
European Union 
FDA
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
HIPAA
Health Insurance Portability and Accountability Act
HR
heart rate
HRT
hormonal replacement therapy 
IB
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
MAOI 
monoamine oxidase inhibitor 
MDD 
major depressive disorder 
MMRM 
Mixed Model of Repeat Measures 

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Abbreviation 
Description 
OREs 
other reportable events 
OSA 
obstructive sleep apnea 
OTC
over-the-counter 
PAP 
positive airway pressure 
PE 
physical examination 
PGI-S
Patients Global Impression of Severity 
PK 
pharmacokinetic(s) 
RBANS 
Repeatable Battery for the Assessment of Neuropsychological Status 
SAE 
serious adverse event 
SFU 
Safety Follow-up 
SmPC 
Summary of Product Characteristics 
SoA 
Schedule of Assessments 
solriamfetol 
Also known as Sunosi, JZP-110, ADX-N05, R228060, and YKP10A 
THC
tetrahydrocannabinol 
US 
United States 
USPI 
United States Package Insert 
WAIS 
Wechsler Adult Intelligence Scale 
WONCBP 
woman of nonchildbearing potential 

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APPENDIX 2.
REFERENCES
American Sleep Apnea Association (ASAA). Raising voices for progress in treatment and care: 
report of the patient-focused medical product development meeting on obstructive sleep apnea. 
AWAKE Sleep Apnea, 2018; 1-88. 
Avellar A, Carvalho L, Prado G, et al. Pharmacotherapy for residual excessive sleepiness and 
cognition in CPAP-treated patients with obstructive sleep apnea syndrome: A systematic review 
and meta-analysis.  Sleep medicine reviews. 2016 Dec 1;30:97-107. 
Bassiri A, Guilleminault C. Clinical features and evaluation of obstructive sleep apnea-hypopnea 
syndrome. In, Kryger M, Roth T, Dement W,(eds). Principles and practice of sleep medicine 
Third edition.
Beebe DW, Gozal DJ. Obstructive sleep apnea and the prefrontal cortex: towards a 
comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and 
behavioral deficits. Journal of sleep research. 2002 Mar;11(1):1-6.
Boake C. From the Binet-Simon to the Wechsler-Bellevue: Tracing the history of intelligence 
testing. Journal of clinical and experimental neuropsychology. 2002 May 1;24(3):383-405.
Effects of CPAP treatment on psychological status in 
patients with severe obstructive sleep apnoea. Journal of Sleep Research. 1996 Jun;5(2):123-7.
Ferguson KA, Fleetham JA. Sleep-related breathing disorders. 4. Consequences 
of sleep disordered breathing. Thorax. 1995 Sep;50(9):998. 
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development guidance public workshop 2018 Oct. 
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Are Independently Associated with Road Accidents. A Cross-Sectional Study on Truck Drivers.
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Garbarino S, Guglielmi O, Sanna A, et al. OSA and Work-Related Injuries: Searching for 
Evidence.  
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studySleep medicine. 2013 Oct 1;14(10):955-63. 
Iverson GL, Lam RW. Rapid screening for perceived cognitive impairment in major depressive 
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Jaeger J. Digit Symbol Substitution Test: The Case for Sensitivity Over Specificity in 
Neuropsychological Testing. Journal of clinical psychopharmacology. 2018 Oct;38(5):513. 
Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. 
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McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study 
of vortioxetine on cognitive function in depressed adults. International Journal of 
Neuropsychopharmacology. 2014 Oct 1;17(10):1557-67.
Mahableshwarkar AR, Zajecka J, Jacobson W, et al. A randomized, placebo-controlled, active-
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Verstraeten E. Neurocognitive effects of obstructive sleep apnea syndrome. Current neurology 
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APPENDIX 4.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING 
Definition of Adverse Events
AE Definition 
 
An AE is any untoward medical occurrence in a clinical study participant, temporally associated 
with the use of study intervention, whether or not considered related to the study intervention. 
 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of study intervention. 
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting
Definition of Unsolicited and Solicited AE
 
An unsolicited AE is an AE that was not solicited using a Participant Diary and that is 
communicated by a participant who has signed the informed consent. Unsolicited AEs include 
serious and nonserious AEs. 
 
Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring a 
hospitalization, or emergency room visit, or visit to/by a health care provider). The participant will 
be instructed to contact the site as soon as possible to report medically attended event(s), as well as 
any events that, though not medically attended, are of participant concern. Detailed information 
about reported unsolicited AEs will be collected by qualified site personnel and documented in the 
participant’s records 
 
Unsolicited AEs that are not medically attended nor perceived as a concern by the participant will 
be collected during interview with the participant and by review of available medical records at the 
next visit 
 
Solicited AEs are predefined local and systemic events for which the participant is specifically 
questioned, and which are noted by the participant in their diary. 

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SAE Reporting to the Sponsor or its designee  
SAEs must be reported to the sponsor (or designee) using an SAE Reporting Form within 24 hours 
of first knowledge of the event by study personnel. 
 
The site will also enter the SAE data into the case report form (CRF) as soon as it becomes 
available. 
The form, instructions on completion, and contact information can be found in the Investigator trial 
binder. 
 
The SAE Reporting Form should be completed as much as possible before transmittal. 
 
Contacts for SAE reporting can be found in the Investigator trial binder. 
Reporting of Other Reportable Experiences 
 
Other reportable experiences (OREs) must be reported to the sponsor or its designee using an ORE 
Reporting Form within 24 hours of first knowledge of the event by study personnel.  
 
The form, instructions on completion, and contact information can be found in the Investigator trial 
binder. 
 
The ORE Reporting Form should be completed as much as possible before transmittal.  
 
Contacts for ORE reporting can be found in the Investigator trial binder. 
 

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APPENDIX 9. SIGNATURE OF INVESTIGATOR’S AGREEMENT 
PROTOCOL NUMBER: 
JZP110-405 
PROTOCOL TITLE: 
PROTOCOL 
Solriamfetol’s Effect on Cognitive Health in Apnea Participants 
During a Randomized Placebo controlled Study (SHARP): a 5 
Week Double blind, Placebo controlled, Randomized, Crossover, 
Multicenter Study of Solriamfetol in Improving Cognitive 
Function in Participants With Excessive Daytime Sleepiness 
Associated With Obstructive Sleep Apnea Plus Impaired 
Cognitive Function 
Amendment 1: 12Aug2022 
I have read this protocol and the Investigator’s Brochure and agree to conduct this clinical study 
as outlined herein. I will ensure that all sub-investigators and other study staff members have read 
and understand all aspects of this protocol. I agree to cooperate fully with Axsome and its 
designated vendors during the study. I carry out the study in accordance with the revised 
Declaration of Helsinki 1996. I will adhere to all applicable regulations and guidelines regarding 
clinical studies on a study drug during and after study completion. 
Having considered fully all the available information, I consider it is ethically justifiable to give 
the study drug to selected participants in my care according to the study protocol. I: 
•
Agree to use the study material, including the study drug, only as specified in the protocol and
understand that changes cannot be made to the protocol without prior written approval from
Axsome Therapeutics.
•
Understand that any violation of the protocol may lead to early termination of the study.
•
Agree to report any serious AE, whether or not considered related to administration of the
study drug, to Axsome Therapeutics within the required timeframe.
•
Agree to comply with Axsome Therapeutics and regulatory requirements for the monitoring
and auditing of this study.
I, the undersigned, have carefully read this protocol and agree that it contains all the necessary 
information required to conduct the study. 
Principal Investigator: 
Printed Name: 
Signature: 
Date: 
Investigator’s site name and address: