Conditions: Obstructive Sleep Apnea
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 140
Healthy volunteers: no

Brief summary:
This is a randomized, double blind, placebo-controlled, repeat-dose, parallel arm, outpatient and inpatient phase 2 clinical study to examine the efficacy and safety of three dose levels of AD036 versus placebo in patients with obstructive sleep apnea.

Detailed description:
This was a randomized, double-blind, placebo-controlled, repeat-dose, parallel arm, outpatient and inpatient, multicenter, dose-finding study of the combination of atomoxetine and oxybutynin in adults with OSA documented by polysomnography (PSG).

Approximately 140 subjects were to be randomized 1:1:1:1 to receive 1 of 3 different fixed-dose combinations of oxybutynin and atomoxetine or matching placebo.

For all subjects, the study consisted of:

* A screening and baseline period in which subjects' eligibility was determined
* An initial 2-night, at-home blinded baseline period in which all subjects received placebo
* A 3-night, run-in period in which subjects received:

  * Low-dose combination for subjects randomized to one of the 3 study treatment arms
  * Placebo for subjects randomized to the placebo treatment arm
* A 7-night treatment period in which subjects received the treatment to which they were randomized, i.e., 1 of the 3 different fixed-dose combinations of drugs, or placebo
* An end of study visit

Arms:
arm 1: An initial 2-night, at-home blinded baseline period in which all subjects received placebo arm 2: AD036 Dose 1 (Low Dose: 25/5) or Placebo arm 3: A 7-night treatment period in which subjects received the treatment to which they were randomized, i.e., 1 of the 3 different fixed-dose combinations of drugs, or placebo arm 4: End of Study Visit

Interventions: intervention 1: AD036 Dose 1 intervention 2: AD036 Dose 2 intervention 3: AD036 Dose 3 intervention 4: Placebo
Intervention descriptions: intervention 1: AD036 Dose 1 oral capsule administered before sleep intervention 2: AD036 Dose 2 oral capsule administered before sleep intervention 3: AD036 Dose 3 oral capsule administered before sleep intervention 4: Placebo oral capsule administered before sleep

Protocol document:
Prot_000.pdf: 
 
Apnimed, Inc.
20 Holyoke Street
Cambridge, MA 02138
info@apnimed.com
 
Page 1 of 1 
CONFIDENTIAL. DO NOT DISTRIBUTE WITHOUT PERMISSION. 
 
 
 
-
 
-
 
-
 
 
 IND number 
-
Sincerely, 
 
 
 
 
 
Jeanne Brittain 
 
 
 
Quality Approval:    
Name 
 
Signature 
 
 
Senior Director, GXP 
Quality Assurance 
-
 
-
 
 
 
 
  
 
11/7/2022


Apnimed, Inc. 
Clinical Study Report Appendices 
Protocol APN-002 
Final 
04 May 2020 
16.1 Study Information  
16.1.1 
Protocol and Protocol Amendments  
Clinical Study Protocol, Final Version 1.4, Dated 04 Dec 2018 
Clinical Study Protocol Amendment 1, Final Version 1.4, Dated 12 Apr 2019 
 


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Title Page 
Protocol Title: Phase 2, Placebo-Controlled, Parallel Group Dose-Finding Study to Evaluate the 
Efficacy and Safety of Three Fixed-Dose Combinations of AD036 in Adults With Obstructive 
Sleep Apnea 
Protocol Number: APN-002 
Amendment Number: Not applicable 
Compound Number: AD036 
Short Title: Dose Finding Study of AD036 in Obstructive Sleep Apnea 
Sponsor Name and Legal Registered Address:  
Apnimed, Inc. 
19 Ware Street, #3 
Cambridge, MA 02138 
Regulatory Agency Identifying Number: IND 136752 
Approval Date: 04-Dec-2018 
Date and Version of Previous Protocol: Not applicable 
 
 
 


Apnimed, Inc. 
Proto co I APN-002/IND 136752 
Sponsor Signatory: 
Lawrence Miller, MD 
Chief Executive Officer 
Clinical Study Protocol 
CONFIDENTlAL 
Medical Monitor Name and Contact Information: provided in the Study Reference Manual. 
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Table of Contents 
 
Table of Contents..................................................................................................................... 3 
1 
Protocol Summary ............................................................................................................. 6 
1.1 
Synopsis ........................................................................................................................ 6 
1.2 
Schema.........................................................................................................................10 
1.3 
Schedule of Activities (SoA) ......................................................................................... 11 
2 
Introduction ......................................................................................................................16 
2.1 
Study Rationale ............................................................................................................16 
2.2 
Background ..................................................................................................................16 
2.2.1 
Obstructive Sleep Apnea ...........................................................................................16 
2.2.2 
Unmet Medical Need ................................................................................................16 
2.2.3 
Biological Rationale..................................................................................................17 
3 
Objectives and Endpoints ..................................................................................................19 
4 
Study Design ....................................................................................................................20 
4.1 
Overall Design..............................................................................................................20 
4.2 
Scientific Rationale for Study Design ............................................................................21 
4.3 
Justification for Dose ....................................................................................................22 
4.4 
End of Study Definition ................................................................................................22 
5 
Study Population ..............................................................................................................22 
5.1 
Inclusion Criteria ..........................................................................................................22 
5.2 
Exclusion Criteria .........................................................................................................24 
5.3 
Meals and Dietary Restrictions ......................................................................................26 
5.4 
Caffeine, Alcohol, and Tobacco .....................................................................................27 
5.5 
Activity ........................................................................................................................27 
5.6 
Screen Failures .............................................................................................................27 
6 
Study Treatment ...............................................................................................................27 
6.1 
Study Treatment(s) Administered ..................................................................................27 
6.2 
Preparation/Handling/Storage/Accountability ................................................................28 
6.3 
Measures to Minimize Bias: Randomization and Blinding..............................................28 
6.4 
Study Treatment Compliance ........................................................................................29 


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6.5 
Concomitant Therapy....................................................................................................29 
6.6 
Dose Modification ........................................................................................................31 
6.7 
Treatment After the End of the Study.............................................................................31 
7 
Discontinuation of Study Treatment and Participant Discontinuation ..................................32 
7.1 
Discontinuation of Study Treatment...............................................................................32 
7.2 
Stopping Criteria ..........................................................................................................32 
7.2.1 
Individual Participant Stopping Criteria .....................................................................32 
7.3 
Participant Discontinuation/Withdrawal from the Study .................................................32 
7.4 
Loss of Participants to Follow-Up .................................................................................33 
8 
Study Assessments and Procedures ....................................................................................33 
8.1 
Efficacy Assessments ....................................................................................................34 
8.1.1 
Efficacy Endpoint Scales ...........................................................................................34 
8.1.2 
Safety and Abuse Liability Scale ...............................................................................35 
8.1.3 
Functional Endpoints ................................................................................................35 
8.1.4 
Screening/Eligibility Scales .......................................................................................36 
8.1.5 
Polysomnography .....................................................................................................36 
8.1.6 
Home Oximetry ........................................................................................................37 
8.2 
Safety Assessments .......................................................................................................37 
8.2.1 
Physical Examinations ..............................................................................................38 
8.2.2 
Vital Signs ................................................................................................................38 
8.2.3 
Electrocardiograms ...................................................................................................39 
8.2.4 
Clinical Safety Laboratory Assessments.....................................................................39 
8.2.5 
Suicide Risk Monitoring............................................................................................39 
8.3 
Adverse Events and Serious Adverse Events ..................................................................40 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ..........................40 
8.3.2 
Method of Detecting AEs and SAEs ..........................................................................41 
8.3.3 
Follow-up of AEs and SAEs ......................................................................................41 
8.3.4 
Regulatory Reporting Requirements for SAEs ...........................................................41 
8.3.5 
Pregnancy .................................................................................................................42 
8.4 
Treatment of Overdose..................................................................................................42 
8.5 
Pharmacokinetics..........................................................................................................42 
8.6 
Genetics .......................................................................................................................43 
9 
Statistical Considerations ..................................................................................................43 
9.1 
Statistical Hypotheses ...................................................................................................43 


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9.2 
Sample Size Determination ...........................................................................................43 
9.3 
Populations for Analyses ...............................................................................................43 
9.4 
Primary and Secondary Analyses...................................................................................44 
9.5 
Interim Analyses ...........................................................................................................45 
10 Supporting Documentation and Operational Considerations ...............................................45 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations............................45 
10.1.1 
Regulatory and Ethical Considerations.......................................................................45 
10.1.2 
Financial Disclosure..................................................................................................46 
10.1.3 
Informed Consent Process .........................................................................................46 
10.1.4 
Data Protection .........................................................................................................47 
10.1.5 
Dissemination of Clinical Study Data ........................................................................47 
10.1.6 
Data Quality Assurance .............................................................................................48 
10.1.7 
Source Documents ....................................................................................................49 
10.1.8 
Study and Site Closure ..............................................................................................49 
10.1.9 
Publication Policy .....................................................................................................50 
10.1.10 Protocol Approval and Amendment ...........................................................................50 
10.1.11 Liability and Insurance ..............................................................................................50 
10.2 Appendix 2: Clinical Laboratory Tests ...........................................................................51 
10.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting..............................................................................................53 
10.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ..............60 
10.5 Appendix 5: List of Abbreviations .................................................................................65 
11 References........................................................................................................................67 
 


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1 Protocol Summary 
1.1 Synopsis 
Protocol Title: Phase 2, Placebo-Controlled, Parallel Group Dose-Finding Study to Evaluate the 
Efficacy and Safety of Three Fixed-Dose Combinations of AD036 in Adults With Obstructive 
Sleep Apnea 
Sponsor Study No.: APN-002 
Phase 2 
Sponsor: Apnimed, Inc. 
Rationale: 
At the doses used in the initial human studies of the AD036 combination (atomoxetine 
80 mg/oxybutynin 5 mg), there was support for efficacy and safety in participants with 
obstructive sleep apnea (OSA). This Phase 2 clinical study will further examine the efficacy and 
safety of both similar and lower dose AD036 combinations versus placebo. Overall, the study is 
expected to provide dose selection guidance and a deeper understanding of repeat-dose safety 
and tolerability for the ongoing clinical development of this combination. 


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Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To assess the efficacy of 3 
different fixed doses of 
AD036 (the combination of 
atomoxetine and oxybutynin) 
vs. placebo 
 
To evaluate safety and 
tolerability of the 
combination AD036 
 
 
 
 
 
 
AHI, proportion of participants with ≥50% reduction, PSG nights, high-
dose (atomoxetine 75 mg/oxybutynin 5 mg) arm vs. placebo 
 
 
Spontaneous adverse events, including the post-dosing period 
 
Physical exam and laboratory testing 
 
DSST 
 
Delayed Word Recall Test 
 
CSSA, Modified for study treatment 
 
Prospective Suicidality Assessment (item 17 “suicidality” of CSSA) 
 
PSG parameters: heart rate, ECG, EEG, oximetry  
 
Physical exam, vital signs, clinical laboratory assessment, ECG 
Secondary 
To assess the efficacy of 3 
different fixed doses of the 
combination of AD036 vs. 
placebo 
High dose vs placebo, in order: 
 
Percent change AHI, high-dose arm vs. placebo 
 
AHI in supine position, proportion of participants with ≥50% reduction, 
PSG nights 
 
Oxygen desaturation index (number of desaturations/hour ≥4% below 
baseline), proportion of participants with ≥50% reduction, at-home nights 
 
ESS 
 
PGI-S, OSA, PSG nights 
 
AHI, proportion of participants with ≥50% reduction, PSG nights, 
high-dose (atomoxetine 75 mg/oxybutynin 5 mg) arm vs. each low dose 
arm (atomoxetine 75 mg /oxybutynin 1.5 mg, and atomoxetine 25 mg/ 
oxybutynin 5 mg)  
Tertiary/Exploratory 
 
Unranked 
 
Proportion of participants with ≥50% AHI decrease and final 
AHI<15/hour, PSG nights 
 
Total time with SaO2 <90%, PSG nights 
 
Total time with SaO2 <80%, PSG nights 
 
Snoring index, PSG nights  
 
Sleep stages distribution and % of time in the various sleep stages, PSG 
nights 
 
Arousal index, PSG nights 
 
Oxygen desaturation index, low-dose run-in vs baseline, at home nights 
 
Proportion of apneas to hypopneas 
Abbreviations: AHI = apnea-hypopnea index; CSSA = Cocaine Selective Severity Assessment; DSST = Digit 
Symbol Substitution Test; ECG = electrocardiogram; EEG = electroencephalogram; ESS = Epworth Sleepiness 
Scale; OSA = obstructive sleep apnea; PGI-S = Participant Global Impression of Severity; PSG = 
polysomnography; SaO2 = oxygen saturation. 
Overall Design: 


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This is a randomized, double blind, placebo-controlled, repeat-dose, parallel arm, outpatient and 
inpatient, multi-center dose finding study of the combination of atomoxetine and oxybutynin in 
adults with OSA documented by polysomnography (PSG). Participants will be randomized 
equally to receive 1 of 3 different fixed-dose combinations of oxybutynin and atomoxetine, or 
matching placebo. For all participants, there is an initial 2-night at-home blinded baseline period 
in which placebo is dosed. Following this baseline placebo period, participants randomized to 
any of the 3 study treatment arms receive 3 nights of a low-dose run-in of the combination, 
consisting of atomoxetine 25 mg/oxybutynin 1.5mg. In contrast, during this 3-night run-in 
period, participants randomized to placebo receive placebo. Following this 3-night run-in period, 
participants will receive the treatment to which they were randomized, i.e., 1 of the 3 different 
fixed-dose combinations of study treatment, or placebo. Dosing of the study treatment will occur 
approximately 30 minutes prior to bedtime. Participants who withdraw from the study will not be 
replaced.  
Study participants will undergo eligibility screening that will include an initial exam to 
determine whether non- PSG enrollment criteria are met, followed by a 1-night inpatient PSG 
test for participants who qualify based on non-PSG criteria. For participants who are eligible and 
enroll in the study, the screening PSG night will serve as the baseline measure for 
apnea-hypopnea index (AHI) and other PSG efficacy and safety endpoints. Baseline measures 
for additional secondary and tertiary endpoints based on home oximetry will be recorded at home 
during the placebo period, and these endpoint measures will continue to be collected over the 
subsequent at-home study treatment dosing period. On the final night of dosing, participants will 
return for inpatient PSG. The primary efficacy endpoint is the proportion of participants with 
≥50% reduction in AHI from screening/baseline to final day of treatment with study treatment 
(study Day 11±2). 
Participants will return 2 weeks after the last dose for an end of study (EOS) Visit. No 
subsequent open-label extension is planned following the study. 
Number of Participants: 
Approximately 140 participants will be randomized to study treatment in equal ratio (1:1:1:1), 
35 participants per arm, to 1 of 4 parallel treatment groups. 
Treatment Groups and Duration: 
There will be 4 parallel treatment groups, as follows: 


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Group 
Atomoxetine/oxybutynin (mg) 
Subjects 
(n) 
1 
75/5 
35 
2 
75/1.5 
35 
3 
25/5 
35 
4 
Placebo 
35 
 
All participants will receive placebo for 2 days to establish baseline measures. Participants 
assigned to active treatment will subsequently receive low dose (25 mg atomoxetine/1.5 mg 
oxybutynin) for a 3-day dose-escalation period. Following the dose-escalation period, 
participants will receive the dose level to which they were randomized (75/5; 75/1.5; 25/5; 
placebo). Participants randomized to placebo will have a placebo run-in period. 
The overall study duration will be up to 8 weeks, as follows:  
 Up to 28 days for screening and baseline PSG; 
 2 nights of baseline placebo treatment, at home; 
 3 nights of low dose atomoxetine/oxybutynin, at home, for participants randomized to study 
treatment (participants randomized to placebo will receive placebo during this period); 
 7 (±2) nights of randomized study treatment; 6 nights at home, seventh night inpatient PSG; 
 Follow-up safety visit, 2 weeks post study treatment dosing (±2 days), or upon early 
withdrawal. 


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1.2 Schema 
Figure 1 
Study Design Schema 
 
 
Abbreviations: ATO = atomoxetine; EoS = end of study; OXY = oxybutynin; PSG = polysomnography.


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1.3 Schedule of Activities (SoA) 
Table 1 
Schedule of Activities 
Procedures 
Screening and Baseline 
PSG1 
 
Treatment Period 
Visit 5 
EOS2 
Notes 
Non-PSG 
Daytime 
Visit 1 
PSG night 
and next 
morning, 
Visit 2  
Blinded 
baseline 
placebo, 
at-home 
dosing 
Double-
blind study 
treatment, 
at-home 
Dosing 
Daytime 
Visit 3 
Visit 4 
PSG Visit 
Trial Day (Visit Window) 
-28 to -3 
-7 to -13 
1 to 24 
3 – 11 ± 25 
66 
12 ± 27 
26 ± 4 
 
Pre-screening 
X8 
 
 
 
 
 
 
Determination of basic 
eligibility for the study 
Informed consent9 
X 
 
 
 
 
 
 
 
Consent for genetic testing 
for CYP2D6  
X 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
STOP-Bang Questionnaire 
X 
 
 
 
 
 
 
Only used for participants 
without a history of 
diagnosis of OSA or CPAP 
use 
Physical exam  
X 
 
 
 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
 
 
Includes drug and substance 
usage and psychiatric 
history 
Blood sample for CYP2D6 
genotype 
X 
 
 
 
 
 
 
 
Serum pregnancy test 
(WOCBP only) 
X 
 
 
 
 
 
X 
 


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Procedures 
Screening and Baseline 
PSG1 
 
Treatment Period 
Visit 5 
EOS2 
Notes 
Non-PSG 
Daytime 
Visit 1 
PSG night 
and next 
morning, 
Visit 2  
Blinded 
baseline 
placebo, 
at-home 
dosing 
Double-
blind study 
treatment, 
at-home 
Dosing 
Daytime 
Visit 3 
Visit 4 
PSG Visit 
Urine drugs of abuse10 
testing, ethanol testing  
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Randomization takes place 
the morning after PSG 
testing for participants that 
qualify 
Medication distribution to 
participant, and study 
instructions and device 
 
X 
 
 
 
 
 
Prior to discharge morning 
after PSG 
QHS self-administration of 
baseline placebo  
 
 
X 
 
 
 
 
2 nights of QHS placebo, at 
home, all participants; 
administer ~30 minutes 
prior to bedtime 
International Prostate 
Symptom Scale 
X 
 
 
 
 
 
 
Male participants only 
QHS administration of 
randomized study treatment 
(combination drug or 
placebo) 
 
 
 
X 
 
X 
 
Total of 10 nights: 3 nights 
low dose (25 mg 
atomoxetine/ 1.5 mg 
oxybutynin) followed by 
7 nights randomized study 
treatment for participants 
randomized to active drug; 
10 nights placebo for 
participants randomized to 
placebo. 
“Reminder” telephone 
call/message 
 
 
 
X 
 
 
 
Day 10, participants 
reminded about study 
procedures and upcoming 
PSG visit11  


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Procedures 
Screening and Baseline 
PSG1 
 
Treatment Period 
Visit 5 
EOS2 
Notes 
Non-PSG 
Daytime 
Visit 1 
PSG night 
and next 
morning, 
Visit 2  
Blinded 
baseline 
placebo, 
at-home 
dosing 
Double-
blind study 
treatment, 
at-home 
Dosing 
Daytime 
Visit 3 
Visit 4 
PSG Visit 
Clinical laboratory 
assessments (hematology, 
clinical chemistry and 
urinalysis) 
X 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
X 
 
Vital signs12 
X 
 
 
 
X 
X 
X 
Visit 4 measure both pre-
dose and post-awakening 
from PSG 
AE/SAE monitoring 
 
X 
X 
X 
X 
X 
X 
 
Study Instruction Reminder 
 
 
 
 
X 
 
 
 
Oximeter Battery Change 
 
 
 
 
X 
 
 
 
Prior/concomitant 
medication monitoring 
 
 
 
 
 
X 
X 
 
Inpatient Polysomnography 
 
X 
 
 
 
X 
 
 
ESS 
X 
X 
 
 
 
X 
 
Measured to determine  
eligibility and as efficacy 
outcome on PSG nights 
CSSA 
X 
 
 
 
 
X 
X13 
Item 17 of the CSSA is 
used to assess suicidality 
Patient Global Impression-
Severity 
 
X 
 
 
 
X 
 
Measured evening of 
baseline PSG and Visit 4 
PSG 
Patient Global Satisfaction 
with Treatment 
 
 
 
 
 
 
X 
 


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Procedures 
Screening and Baseline 
PSG1 
 
Treatment Period 
Visit 5 
EOS2 
Notes 
Non-PSG 
Daytime 
Visit 1 
PSG night 
and next 
morning, 
Visit 2  
Blinded 
baseline 
placebo, 
at-home 
dosing 
Double-
blind study 
treatment, 
at-home 
Dosing 
Daytime 
Visit 3 
Visit 4 
PSG Visit 
Home Oximetry  
 
 
X 
X 
 
 
 
Oximeter used all at-home 
dosing nights 
Delayed Word Recall Test  
 
X 
 
 
 
X 
 
Administer at similar time 
after awakening after each 
PSG  
DSST 
 
X 
 
 
 
X 
 
Administer at similar time 
after awakening after each 
PSG  
Abbreviations: AE = adverse event; CPAP = continuous positive airway pressure; CSSA = Cocaine Selective Severity Assessment; CYP2D6 = cytochrome 
P450 2D6; DSST = Digit Symbol Substitution Test; ECG = electrocardiogram; EOS = end of study; ESS = Epworth Sleepiness Scale; HIV = human 
immunodeficiency virus; ICF = informed consent form; IRB = Institutional Review Board; IRT = Interactive Response Technology; OSA = obstructive sleep 
apnea; PSG = polysomnography; QHS = 1 dose taken at bedtime; SAE = serious adverse event; STOP-Bang = Snoring, Tiredness, Observed apnea, Blood 
Pressure-Body mass index, Age, Neck circumference and Gender criteria; WOCBP = women of childbearing potential. 
1 
Following pre-screening, participants who meet basic eligibility requirements will be screened during a visit that includes non- PSG evaluations. Participants 
who otherwise are eligible will be scheduled for an overnight PSG study. 
2 
If a participant discontinues from the study, all EOS procedures should be performed at the discontinuation visit, within 48 hours of the last study dose. 
3 
Final study eligibility is determined the morning after the PSG exam, based on PSG and non-PSG findings, and enrolled participants are randomized and 
dispensed the study drug. The first dose of study drug should generally be taken that night; however, at the discretion of th e investigator, the first night of 
study treatment dosing can occur up to 1 week later to accommodate scheduling of the on-drug PSG exam. 
4 
Trial day includes overnight through morning completion of endpoints.  
5 
Daily bedtime dosing (qhs in the protocol synopsis) continues through Visit 4 PSG night, i.e., through PSG visit window; final night of study treatment 
dosing is PSG night. 
6 
Can occur as late as day as Day 7, if necessary for scheduling. 
 


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7 
Preference is for PSG Visit 4 to be on Day 12, but, if necessary to fit individual participant scheduling, may be ± 2 days..  
8 
Conducted prior to screening/PSG admission; per IRB-approved pre-screening procedures. 
9 
No trial-related assessment is to be carried out before the participant has signed the ICF. Any participant who provides informed consent will have a 
screening number assigned by the IRT system. 
10 Includes amphetamine; barbiturates; benzodiazepines; buprenorphine/metabolite; cannabinoids, cocaine/metabolites; Methylenedioxymethamphetamine; 
methadone/metabolite; opiates; oxycodone/oxymorphone; phencyclidine; by enzyme-linked immunosorbent assay method; test sample is urine. 
11 Participants must return to PSG lab with study medication,pulse oximeter and study diary. 
12 Vital signs include the following: seated blood pressure, pulse, respiratory rate; AE collection refers to spontaneous AEs. Participants who experience 
systolic blood pressure ≥ 160, or diastolic blood pressure ≥ 100, or heart rate ≥ 120 beats per minute will be further evaluated. 
13 If there are any responses to individual items at EOS Visit that are more than 4 points worse than baseline exam, CSSA is repeated by telephone at 1 week 
post EOS Visit. 
 


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2 Introduction 
2.1 Study Rationale 
At the doses used in the initial human studies of the AD036 combination (atomoxetine 
80 mg/oxybutynin 5 mg) there was support for efficacy and safety in patients with OSA. This 
Phase 2 clinical study will further examine the efficacy and safety both similar and lower dose 
AD036 combinations versus placebo. Overall, the study is expected to provide dose selection 
guidance and a deeper understanding of repeat-dose safety and tolerability for the ongoing 
clinical development of this combination. 
2.2 Background 
2.2.1 Obstructive Sleep Apnea 
The National Commission on Sleep Disorders Research identified sleep disorders as a major 
public health burden. OSA is the most common and serious of these sleep disorders and affects 
approximately 20 million people in the United States (US), with approximately 13% of men and 
6% of women affected (Peppard et al, 2013). OSA is characterized by repetitive collapse or 
‘obstruction’ of the pharyngeal airway during sleep, manifesting as repetitive episodes of 
hypopnea (i.e., shallow breathing) or apnea (i.e., paused breathing). These episodes of hypopnea 
or apnea may lead to arousal from sleep, sleep fragmentation, excessive daytime sleepiness, 
and/or neuropsychological impairment. 
Research has shown that a number of pathogenic factors, or traits, contribute to the development 
of OSA (Eckert et al, 2013; Wellman et al, 2011; Wellman et al, 2013;Younes, 2003). The most 
important factors are the presence of an anatomically small, collapsible upper airway and a loss 
of pharyngeal muscle tone or responsiveness during sleep. 
Long-term, OSA is associated with increased mortality and a number of adverse cardiovascular, 
neurocognitive, metabolic, and daytime functioning consequences (Somers et al, 1995; Nieto et al, 
2000; Brooks et al, 1997; Peppard et al, 2000; Hung et al, 1990; Wessendorf et al, 2000; Hoffstein, 1994; 
Shahar et al, 2001; Redline et al, 1997; Findley et al, 1988). 
2.2.2 Unmet Medical Need 
Treatment for OSA changed little over the past 40 years, with the overwhelming majority of 
patients treated with positive airway pressure, the most common of which is continuous positive 
airway pressure (CPAP), provided by a machine that mechanically maintains an open airway. 
Other treatments, such as pharyngeal surgery, mandibular advancement devices, and implantable 


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nerve stimulators, were developed to address the anatomical predisposition to collapse; however, 
they have shown limited efficacy for niche populations. 
While CPAP and related therapies are effective in improving sleep characteristics and 
oxygenation, many, perhaps most, patients find these devices uncomfortable or intolerable, and 
most estimates indicate that fewer than 50% of patients prescribed CPAP use it more than 4 hours 
per night, if at all (Weaver and Sawyer, 2010). Efforts to develop pharmacologic therapies, such 
as antidepressants, stimulants, and hormonal agents, for the treatment of OSA have been ongoing 
for at least 20 years, with no success thus far. 
As many patients cannot use CPAP because they find it intolerable, this represents a significant 
health concern, as OSA is associated with numerous co-morbidities and increased mortality. 
Alternative options, such as drugs that activate the pharyngeal muscles are needed. 
2.2.3 Biological Rationale 
AD036 is a new fixed dose drug combination of atomoxetine and oxybutynin being developed 
for OSA. Atomoxetine is a pre-synaptic norepinephrine reuptake inhibitor indicated for the 
treatment of attention deficit hyperactivity disorder in children and adults. Oxybutynin is an 
antispasmodic drug that inhibits the muscarinic action of acetylcholine on smooth muscle and is 
indicated for the treatment of symptoms of bladder instability associated with voiding in patients 
with uninhibited neurogenic or reflex neurogenic bladder such as urgency, frequency, urinary 
leakage, urge incontinence and dysuria.  
Efficacy of the combination of these 2 small molecules for the signs and symptoms of OSA has 
been previously evaluated in a small number of patients in National Institutes of Health-
supported studies in the academic setting. The pharmacokinetics (PK) of the atomoxetine and 
oxybutynin combination have recently been studied in a Phase 1 clinical program sponsored by 
Apnimed. New research in animals improved understanding of the state-dependent 
neurotransmitters involved in pharyngeal muscle activation during sleep, namely that both 
noradrenergic and antimuscarinic processes are involved. Specifically, the loss of noradrenergic 
activity is now thought to play a key role in the sleep-related hypotonia of pharyngeal muscles 
during non-rapid eye movement (NREM) sleep and muscarinic activity is involved in rapid eye 
movement (REM) atonia. 
Chan and colleagues (Chan et al, 2006) showed in rats that the noradrenergic antagonist terazosin 
substantially reduced genioglossus (a major muscle of the upper airway) activity (i.e., 
genioglossal electromyographic [EMGgg] activity) during wakefulness and produced REM-like 
atonia during NREM sleep, illustrating the importance of noradrenergic mechanisms. Other 


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studies (Lai et al, 2001; Fenik et al, 2005) also support the notion that progressive withdrawal of 
noradrenergic tone, from wakefulness to NREM and REM sleep, is the major mechanism causing 
sleep-related pharyngeal hypotonia. While noradrenergic withdrawal is thought to be the main 
cause of pharyngeal hypotonia in NREM sleep, there are additional mechanisms that cause 
further reduction during REM sleep. Chan and colleagues (Chan et al, 2006) failed to reverse 
REM atonia with alpha-1 receptor agonists applied to the hypoglossal nucleus, suggesting that 
another, possibly inhibitory, mechanism is at work. Horner and colleagues identified this 
inhibitory process as muscarinic by demonstrating restoration of EMGgg activity during REM 
sleep with the muscarinic antagonist scopolamine applied directly to the hypoglossal nucleus in 
rats (Grace et al, 2013; Grace et al, 2013). 
However, due to the only recent identification of these processes, until now there has not yet 
been an attempt to stimulate the pharyngeal muscles with both noradrenergic and antimuscarinic 
drugs in sleeping humans. Atomoxetine (a noradrenergic) and oxybutynin (an antimuscarinic) are 
2 drugs within these pharmacologic classes that have been Food and Drug Administration-
approved for over 16 years and 40 years, respectively, thereby having a long history of clinical 
use. Atomoxetine and oxybutynin as individual drugs have well-established PK, tolerability and 
safety profiles, but have not previously been studied in combination. 


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3 Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To assess the efficacy of 3 
different fixed doses of AD036 
(the combination of 
atomoxetine and oxybutynin) 
vs. placebo 
 
 
 
To evaluate safety and 
tolerability of the combination 
AD036 
 
 
 
 
 
 
 
 
AHI, proportion of participants with ≥50% reduction, PSG 
nights, high-dose (atomoxetine 75 mg/oxybutynin 5 mg) arm 
vs. placebo 
 
 
Spontaneous adverse events, including the post-dosing period 
 
Physical exam and laboratory testing 
 
DSST 
 
Delayed Word Recall Test 
 
CSSA, Modified for study treatment 
 
Prospective Suicidality Assessment (item 17 “suicidality” of 
CSSA) 
 
PSG parameters: heart rate, ECG, EEG, oximetry 
 
Physical exam, vital signs, clinical laboratory assessment, 
ECG 
Secondary 
To assess the efficacy of 3 
different fixed doses of AD036 
vs. placebo 
High dose vs placebo, in order: 
 
Percent change AHI, high-dose arm vs. placebo 
 
AHI in supine position, proportion of participants with ≥50% 
reduction, PSG nights 
 
Oxygen desaturation index (number of desaturations/hour ≥4% 
below baseline), proportion of participants with ≥50% 
reduction, at-home nights 
 
ESS 
 
PGI-S, OSA, PSG nights 
 
AHI, proportion of participants with ≥50% reduction, PSG 
nights, high-dose (atomoxetine 75 mg/oxybutynin 5 mg) arm 
vs. each low dose arm (atomoxetine 75 mg /oxybutynin 
1.5 mg, and atomoxetine 25 mg/ oxybutynin 5 mg).  


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Objectives 
Endpoints 
Tertiary/Exploratory 
 
Unranked 
 
Proportion of participants with ≥50% AHI decrease and final 
AHI<15/hour, PSG nights 
 
Total time with SaO2 <90%, PSG nights 
 
Total time with SaO2 <80%, PSG nights 
 
Snoring index, PSG nights  
 
Sleep stages distribution and % of time in the various sleep 
stages, PSG nights 
 
Arousal index, PSG nights 
 
Oxygen desaturation index, low-dose run-in vs baseline, at 
home nights 
 
Proportion of apneas to hypopneas 
Abbreviations: AHI = apnea-hypopnea index; CSSA = Cocaine Selective Severity Assessment; DSST = Digit 
Symbol Substitution Test; ECG = electrocardiogram; EEG = electroencephalogram; ESS = Epworth Sleepiness 
Scale; OSA = obstructive sleep apnea; PGI-S = Participant Global Impression of Severity; PSG = 
polysomnography; SaO2 = oxygen saturation. 
4 Study Design 
4.1 Overall Design 
This is a randomized, double blind, placebo-controlled, repeat-dose, parallel arm, outpatient and 
inpatient, multi-center, dose finding study of the combination of atomoxetine and oxybutynin in 
adults with OSA documented by PSG. Approximately 140 participants will be randomized 
equally to receive 1 of 3 different fixed-dose combinations of oxybutynin and atomoxetine, or 
matching placebo. For all participants, there is an initial 2-night at-home blinded baseline period 
in which placebo is dosed. Following this baseline placebo period, participants randomized to the 
3 study treatment arms receive 3 nights of a low-dose run-in of the combination, consisting of 
atomoxetine 25 mg/oxybutynin 1.5 mg. In contrast, during this 3-night run-in period, participants 
randomized to placebo receive placebo. Following this 3-night run-in period, participants will 
receive the treatment to which they were randomized, i.e., 1 of the 3 different fixed-dose 
combinations of drug, or placebo. Overall study duration will be up to 8-9 weeks. Dosing of the 
study treatment will occur approximately 30 minutes prior to bedtime. Participants who 
withdraw from the study will not be replaced.  
Study participants will undergo eligibility screening that will include an initial exam to 
determine whether non-PSG enrollment criteria are met, followed by a 1-night inpatient PSG test 
for participants who qualify based on non-PSG criteria. For participants who are eligible and 
enroll in the study, the screening PSG night will serve as the baseline measure for AHI and other 


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PSG efficacy and safety endpoints. Baseline measures for additional secondary and tertiary 
endpoints based on home oximetry will be recorded at home during the placebo period, and these 
endpoint measures will continue to be collected over the subsequent at-home study treatment 
dosing period. On the final night of dosing, participants will return for inpatient PSG. The 
primary efficacy endpoint is the proportion of participants with ≥50% reduction in AHI from 
screening/baseline to final day of treatment with study treatment (study Day 11± 2). 
Participants will return 2 weeks after the last dose for an EOS Visit (Figure 2). No subsequent 
open-label extension is planned following the study. 
Figure 2: 
Overview of Study Design 
 
Abbreviations: ATO = atomoxetine; EoS = end of study; OXY = oxybutynin; PSG = polysomnography. 
4.2 Scientific Rationale for Study Design 
At the doses used in the initial human studies of AD036 there was support for efficacy and safety 
in patients with OSA. This Phase 2 clinical study will further examine the efficacy and safety of 
lower dose AD036 versus placebo. Overall, the study is expected to provide dose selection 
guidance and a deeper understanding of repeat-dose safety and tolerability for the ongoing 
clinical development of this combination. 


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4.3 Justification for Dose 
The high-dose AD036 in this study is atomoxetine 75 mg/ oxybutynin 5 mg, similar to the dose 
used in initial human studies (atomoxetine 80 mg/oxybutynin 5 mg). To explore the potential 
efficacy and safety of lower atomoxetine and oxybutynin doses, the following 2 additional dose 
arms will be studied: atomoxetine 75 mg/oxybutynin 1.5 mg and atomoxetine 25 mg/oxybutynin 
5 mg. 
Prescribing information for atomoxetine specifies at least 3 days of dose escalation prior to 
dosing >40 mg. This study incorporates a 3-day dose escalation period using atomoxetine 
25 mg/oxybutynin 1.5 mg for participants assigned to active drug in the randomized dosing 
period. Participants assigned to placebo in the randomized dosing period will correspondingly be 
dosed with placebo in the 3-day dose escalation period. 
Prior to the dose escalation period all participants will be assigned to 2 days of placebo to 
establish baseline measures. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of AD036 is 
provided in the Investigator’s Brochure. 
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 final Follow-up visit or the last scheduled procedure shown in the Schedule 
of Activities (SoA). 
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the SoA for the last participant in the study globally. 
5 Study Population 
The study population will consist of male and female participants between 25 and 65 years of 
age, inclusive, with OSA documented by PSG. Participants must be able to provide written 
consent and meet all the inclusion criteria and none of the exclusion criteria. 
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: 


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Age and Sex 
1. Male or female participants between 25 to 65 years of age, inclusive, at the Screening 
Visit. 
Type of Participant and Disease Characteristics 
2. Participants are eligible for screening PSG if any of the following: 
 Prior history of diagnosis of OSA of a severity for which CPAP is typically 
recommended (according to International Classification of Sleep Disorders, Version 3 
criteria) at any time in the past (participant self-report acceptable if medical records 
unavailable); or, for participants without a prior diagnosis of OSA, participants are 
eligible for screening if the Snoring, Tiredness, Observed apnea, and Blood pressure 
(STOP), and Body mass index, Age, Neck circumference, and Gender (Bang) score is ≥5, 
or STOP ≥ 2 + body mass index (BMI) >35 kg/m2. 
 CPAP intolerance or poor compliance (compliance is defined as use of CPAP 4 hours per 
night for 70% of nights; per participant self-report); or CPAP-naïve. 
 Participants who had been using CPAP at least 4 hours nightly for at least 70% of the 
nights are eligible for further screening and baseline PSG for this study only if CPAP will 
not have been used for 1 month prior to the screening/baseline PSG for this study. 
3. AHI ≥ 20 on screening PSG, based on initial reading the night of Screening PSG1. 
4. Epworth Sleepiness Scale (ESS) score ≥ 8 for participants not using CPAP. 
5. Previous surgical treatment for OSA is allowed if ≥ 1 year prior to enrollment. 
6. If male, International Prostate Symptom Score (IPSS) must be less than 15. 
Weight 
7. BMI between 18.5 and 40.0 kg/m2, inclusive, at the pre-PSG visit. 
                                              
1 The assessment of the PSG technician at the time of PSG recording is used to determine PSG eligibility criteria 
including AHI, central apnea index, and periodic limb movement arousal index; for the purposes of study endpoint 
analysis, the results of the PSG centralized reading will be used. 


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Male participants: 
8. If male and sexually active with female partner(s) of childbearing potential, participant 
must agree, from Study Day 1 through 1 week after the last dose of study drug, to practice 
the protocol specified contraception (see Appendix 4: Contraceptive Guidance and 
Collection of Pregnancy Information). 
Female participants: 
9. If a woman of childbearing potential (WOCBP), the participant must agree, from Study 
Day 1 through 1 week after the last dose of study drug, to practice the protocol specified 
contraception (See Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information). All WOCBP must have negative result of a serum pregnancy test performed 
at screening.  
10. If female and of non-childbearing potential, the participant must be either postmenopausal 
(defined as age ≥ 55 years with no menses for 12 or more months without an alternative 
medical cause) or permanently surgically sterile (bilateral oophorectomy, bilateral 
salpingectomy or hysterectomy).  
Informed Consent 
11. Participant voluntarily agrees to participate in this study and signs an Institutional Review 
Board (IRB)-approved informed consent prior to performing any of the Screening Visit 
procedures. 
12. Participant must be able to understand the nature of the study and must have the 
opportunity to have any questions answered. 
5.2 Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. History of narcolepsy. 
2. Clinically significant craniofacial malformation.  
3. Clinically significant cardiac disease (e.g., rhythm disturbances, coronary artery disease 
or cardiac failure) or hypertension requiring more than 2 medications for control.  
4. Clinically significant neurological disorder, including epilepsy/convulsions. 


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5. History of schizophrenia, schizoaffective disorder or bipolar disorder according to 
Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) or International 
Classification of Disease tenth edition criteria. 
6. History of attempted suicide or suicidal ideation within 1 year prior to screening, or 
current suicidal ideation. 
7. History of clinically significant constipation, gastric retention, or urinary retention. 
8. Positive screen for drugs of abuse or substance use disorder as defined in DSM-V within 
24 months prior to Screening Visit. 
9. A significant illness or infection requiring medical treatment in the past 30 days. 
10. Clinically significant cognitive dysfunction. 
11. Untreated narrow angle glaucoma.  
12. Women who are pregnant or nursing. 
Prior/Concomitant Therapy 
13. History of using oral or nasal devices for the treatment of OSA may enroll as long as the 
devices are not used during participation in the study. 
14. History of using devices to affect participant sleeping position for the treatment of OSA, 
e.g. to discourage supine sleeping position, may enroll as long as the devices are not used 
during participation in the study. 
15. History of oxygen therapy. 
16. Use of medications from the list of disallowed concomitant medications. 
17. Treatment 
with 
strong 
cytochrome 
P450 
3A4 
(CYP3A4) 
inhibitors, 
strong 
cytochrome P450 2D6 (CYP2D6) inhibitors, or monoamine oxidase inhibitors (MAOI) 
within 14 days of the start of treatment, or concomitant with treatment. 
Prior/Concurrent Clinical Study Experience 
18. Use of another investigational agent within 90 days or 5 half-lives, whichever is longer, 
prior to dosing.  
Diagnostic Assessments 
19. ESS total score > 18. 


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20. Central apnea index > 5/hour on baseline PSG. 
21. Periodic limb movement arousal index >15/hour on baseline PSG. 
22. Hepatic transaminases >3X the upper limit of normal (ULN), total bilirubin >2X ULN 
(unless confirmed Gilbert syndrome), serum creatinine >2X ULN.  
Other Exclusions 
23. <6 hours typical sleep duration.  
24. Night- or shift-work sleep schedule.  
25. Employment as a commercial driver or operator of heavy or hazardous equipment. 
26. Smoking more than 10 cigarettes or 2 cigars per day. 
27. Unwilling to use specified contraception.  
28. Unwilling to limit alcohol consumption to no greater than 2 units/day or less, not to be 
consumed within 3 hours of bedtime. 
29. Unwilling to limit caffeinated beverage intake (e.g., coffee, cola, tea) to 400 mg/day or 
less of caffeine, not to be used within 3 hours of bedtime. 
30. Any condition that in the investigator’s opinion would present an unreasonable risk to the 
participant, or which would interfere with their participation in the study or confound 
study interpretation. 
31. Participant considered by the investigator, for any reason, an unsuitable candidate to 
receive AD036 or unable or unlikely to understand or comply with the dosing schedule or 
study evaluations. 
5.3 Meals and Dietary Restrictions 
1. Participants should refrain from consumption of any nutrients known to modulate CYP 
enzyme activity (e.g., grapefruit or grapefruit juice, pomelo juice, star fruit, pomegranate, 
and Seville or Moro [blood] orange products) within 72 hours before the first 
administration of study drug, during the study, and until final discharge.  
2. Diet should be generally stable during the study, e.g., new diet programs should not be 
initiated. 


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5.4 Caffeine, Alcohol, and Tobacco 
1. Participants should refrain from more than 2 units per day of alcohol, consumed no less 
than 3 hours prior to bedtime.  
2. Moderate consumption of caffeinated beverages, containing up to a total of 400 mg 
caffeine per day, is permitted, consumed no less than 3 hours prior to bedtime. 
5.5 Activity 
There are no restrictions on physical activity during the study other than that physical activity 
should be generally stable during the study (e.g., new exercise programs should not be initiated). 
5.6 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized to study treatment/entered into the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants that 
meets 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 events (SAEs). 
Individuals who do not meet the criteria for participation in this study (screen failure) will not be 
rescreened. 
6 Study Treatment 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 Study Treatment(s) Administered 
Two different blinded capsules are taken each night of drug treatment, as arranged in blister 
packaging. On placebo nights, 2 placebo tablets will be taken. On nights of randomized study 
treatment, 1 capsule of atomoxetine and 1 capsule of oxybutynin, or of corresponding placebo, 
are taken approximately 30 minutes before the participant’s planned bedtime. 


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Study Treatment Name: 
Atomoxetine 
hydrochloride  
Oxybutynin chloride 
Dosage Formulation: 
Capsule 
Capsule 
Dosage Level: 
75 mg or 25 mg 
5 mg or 1.5 mg 
Route of Administration: 
Oral 
Oral 
Dosing Instructions: 
1 capsule will be 
administered daily with at 
least 20 mL water  
1 capsule will be 
administered daily with at 
least 20 mL water  
Storage/Packaging/Labeling: 
 
Store per package insert. 
Study treatment will be 
provided in blister 
packaging. Each blister 
package will be labeled as 
required per country 
requirement.  
Store per package insert. 
Study treatment will be 
provided in blister 
packaging. Each blister 
package will be labeled as 
required per country 
requirement. 
6.2 Preparation/Handling/Storage/Accountability 
1. The Investigator or designee must maintain a log to confirm appropriate temperature 
conditions have been maintained during transit for all study treatments received and any 
discrepancies are reported and resolved before use of the study treatment. 
2. Only participants enrolled in the study may receive study treatments and only authorized 
site staff may supply or administer study treatments. All study treatments 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. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). 
4. After receiving Sponsor approval in writing, PAREXEL is responsible for returning all 
unused or partially used study treatment to the Sponsor or designated third party or for 
preparing the study treatment for destruction via incineration. 
6.3 Measures to Minimize Bias: Randomization and Blinding 
All participants will be centrally randomized using an Interactive Response Technology (IRT). 
Each participant will be assigned a unique number (randomization number) that encodes the 
participant’s assignment to 1 of the 4 arms of the study, according to the randomization schedule 


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generated by the Sponsor (or designee) using a validated computer program. Details of the 
procedure are described in the IRT Manual provided to all sites. 
Study treatment will be dispensed the morning after PSG screening, as summarized in 
Section 1.3. 
Returned study treatment should not be redispensed to the participants. 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
Investigator has the sole responsibility for determining if unblinding of a participant’s study 
treatment 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 
study treatment assignment unless this could delay emergency treatment of the participant. If a 
participant’s study treatment 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 electronic case report form (eCRF), as applicable. 
Participants will be randomly assigned in a 1:1:1:1 equal allocation ratio to receive 1 of 3 
different study treatment doses or placebo, using permuted blocked randomization. Investigators 
will remain blinded to each participant’s assigned study treatment throughout the study. 
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study treatment records at the site(s) to verify that randomization/dispensing has been done 
accurately. 
6.4 Study Treatment Compliance 
Participants will be required to return any unused study treatment capsules at Visit 4. Unused 
capsules will be counted and recorded by study personnel to assess study treatment compliance.  
6.5 Concomitant Therapy 
Concomitant therapy with the following medications is disallowed: 
 MAOIs or other drugs that affect monoamine concentrations (e.g., rasagiline) [MAOIs are 
contraindicated for use with atomoxetine] 
 Selective Serotonin Reuptake Inhibitors (e.g., paroxetine) 
 Selective Norephinephrine Reuptake Inhibitors (e.g., duloxetine) 


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 Norephinephrine Reuptake Inhibitors (e.g., reboxetine) 
 Alpha-1 antagonists (e.g., tamsulosin) 
 Tricyclic antidepressants (e.g., desipramine) 
 CYP2D6 inhibitors  
 Strong CYP3A4 inhibitors (e.g., ketoconazole) 
 Benzodiazepines and other anxiolytics 
 Opioids 
 Sedatives other than nonbenzodiazepine “Z-drugs” (zolpidem, zaleplon, eszopiclone) 
 Muscle relaxants  
 Pressor agents 
 Drugs with clinically significant cardiac QT-interval prolonging effects 
 Drugs known to lower seizure threshold (e.g., chloroquine) 
 Amphetamines 
 Antiepileptics  
 Antiemetics 
 Modafinil or armodafinil 
 Beta2 agonists, (e.g., albuterol) 
 Antipsychotics 
 Anticholinergics and anticholinesterase inhibitors, including drugs with substantial 
anticholinergic side effects, (e.g., first generation antihistamines) 
 Sedating antihistamines 
 Pseudoephedrine, phenylephrine, oxymetazoline 
 Nicotine replacement products 
 Most drugs for Parkinson’s, Alzheimer’s, Huntington’s, Amyotrophic Lateral Sclerosis, or 
drugs for other neurodegenerative diseases 
Medications that do not have substantial effects on the central nervous system (CNS), 
respiration, or muscle activity are generally allowed if dose and frequency is stable for 3 months 


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prior to enrollment and during the course of the study, including, but not necessarily limited to, 
the following drugs and drug classes: 
 Antihypertensives (angiotensin-converting-enzyme/angiotensin II receptor blocker inhibitors, 
calcium channel blockers, spironolactone, hydrochlorothiazide, etc.) 
 Statins 
 Proton pump inhibitors and histamine h2 receptor blockers 
 Over-the-counter (OTC) antacids 
 Non-sedating antihistamines (e.g., cetirizine, loratadine) 
 Eszopiclone, zolpidem, or zaleplon 
 Melatonin 
 Non-steroidal anti-inflammatory drugs and acetaminophen 
 Laxatives 
 Erectile dysfunction drugs 
 Inhaled corticosteroids (e.g., fluticasone) 
 Antidiabetics 
 Ocular hypotensives and other ophthalmics (e.g., timolol) 
 Hormonal therapy (e.g., estrogen replacement or anti-estrogens) and hormonal contraceptives 
 Thyroid medications 
 Anticoagulants 
 OTC topicals (e.g., topical pain relievers) 
 Osteoporosis drugs 
6.6 Dose Modification 
Through protocol amendment, planned doses may be decreased on an individual or group basis 
according to emerging safety and tolerability data. 
6.7 Treatment After the End of the Study 
Not applicable. No subsequent open-label extension is planned following the study. 
Study treatment will not be available after the end of study participation. 


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7 Discontinuation of Study Treatment and Participant Discontinuation 
Refer to the SoA for data that are to be collected at the time of study discontinuation, during 
follow-up, and for any further evaluations that need to be completed. 
7.1 Discontinuation of Study Treatment 
If a clinically significant finding is identified, the Investigator or qualified designee will 
determine if the participant can continue in the study and if any change in participant 
management is needed. Any new clinically relevant finding should be reported as an adverse 
event (AE). 
7.2 Stopping Criteria 
7.2.1 Individual Participant Stopping Criteria 
 Incidents of abuse, diversion, or misuse of the study treatment. 
 Incidents of clinical significance: hallucinations, amnesia, delusional thinking, delirium, 
manic symptoms, aggressive behavior, suicidality, homicidality, agitation, confusion, or 
convulsions/seizures. 
 Participants reporting any SAE. 
 Acute urinary obstruction. 
 Any other AE that in the judgment of the Investigator necessitates the participant stopping to 
protect participant safety. 
Participants discontinued from dosing will undergo end of study procedures with follow-up 
monitoring of the AE(s) as clinically indicated. 
7.3 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 
administrative reasons. 
 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. 
 All participants who withdraw from the study with an ongoing AE must be followed until the 
event is resolved or deemed stable. 
 Participation may be terminated before completing the study and the reason recorded as 
follows: 
o Withdrawal due to AE 
o Withdrawal due to incident abuse, diversion, or misuse of the study treatment 
o Loss to follow-up 
o Participant withdrew consent at own request 
o Other 
7.4 Loss of Participants 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 within the visit window, where one is defined) 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. 
 In cases in which the 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/eCRF. 
 Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8 Study Assessments and Procedures 
 Study procedures and their timing are summarized in the SoA. 


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 As protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns, these should be discussed with the Sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study treatment. 
 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 will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
 The maximum amount of blood collected from each participant over the duration of the 
study, excluding any extra assessments that may be required for safety or technical issues, 
will not exceed around 50 mL. 
 Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples, as per the Investigator or designee’s discretion. 
8.1 Efficacy Assessments 
The Study Reference Manual provides detailed information for the various scales discussed in 
Section 8.1.1 through Section 8.1.6. 
8.1.1 Efficacy Endpoint Scales 
 The ESS is a self-administered questionnaire with 8 questions. Respondents are asked to rate, 
on a 4-point scale (0-3), their usual chances of dozing off or falling asleep while engaged in 8 
different activities in recent times. The ESS score (the sum of 8 item scores, 0-3) can range 
from 0 to 24. The higher the ESS score, the higher that person’s average sleep propensity in 
daily life, or their ‘daytime sleepiness’. The questionnaire takes approximately 2 or 3 minutes 
to answer. The ESS is asked during screening as an enrollment criterion. The ESS is also 
used as a study efficacy outcome. The ESS is administered the day of the non-PSG screening 
and approximately the same time of day prior to PSG recordings. 


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 The Participant Global Impression of Severity (PGI-S) is a global index that may be used to 
rate the severity of a specific condition, (i.e., it is a single-state scale). The scale consists of a 
1-item questionnaire designed to assess the participant’s impression of disease severity. The 
scale is considered to have clinical relevance for the participant because it allows participants 
to respond based on factors that they judge to be the most important in their health status. 
The PGI-S is administered at the baseline/screening PSG Visit 2 and at PSG Visit 4. The 
PGI-S is administered at approximately the same time prior to each PSG recording. 
 The Participant Global Satisfaction with Treatment scale consists of a 1-item questionnaire 
designed to assess the participant’s satisfaction with the experimental treatment, considering 
both safety and efficacy. The scale is administered at the end of the study, at the EOS Visit. 
8.1.2 Safety and Abuse Liability Scale 
 The Cocaine Selective Severity Assessment (CSSA) was designed to measure cocaine 
withdrawal signs and symptoms during detoxification, and includes psychiatric symptoms of 
general safety interest such as changes in sleep, anxiety, energy level, activity level, tension, 
attention, paranoid ideation, anhedonia, depression, suicidality, and irritability. The CSSA 
will be used in this study to identify psychiatric issues and to characterize the potential of the 
atomoxetine/oxybutynin combination to elicit withdrawal symptoms similar to those elicited 
by cocaine withdrawal. A modified version of the assessment will be used in this study to 
measure potential withdrawal signs and symptoms from the study treatment; “cocaine” will 
be replaced with “study drug”. The scale is administered by clinical staff. A score of ≥3 on 
Item 17, or Investigator judgment that the patient is suicidal, will initiate further clinical 
evaluation and appropriate measures to protect participant safety. (Note: Questions 4 and 5 of 
the CSSA will not be asked at baseline). 
8.1.3 Functional Endpoints 
 The Digit Symbol Substitution Test (DSST) is a paper-and-pencil cognitive and psychomotor 
test that requires patients to identify and copy symbols that are matched to numbers 
according to an instruction key located at the top of the page. The DSST is commonly used to 
screen for impairment related to pharmaceuticals and is also sensitive to sleep restriction. The 
DSST is administered the morning after the inpatient PSG nights,  at approximately the same 
time after awaking from each PSG. 


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 The Delayed Word Recall Test (DWRT) is a brief and efficient test of verbal learning and 
recent memory. The DWRT is administered the morning after the screening/baseline PSG 
(Visit 2) and in the morning after PSG Visit 4. The DWRT is administered at approximately 
the same time after awaking from each PSG. 
8.1.4 Screening/Eligibility Scales 
 The IPSS is typically used to diagnose benign prostatic hyperplasia and to monitor disease 
progression and response to therapy. The participant is asked to choose the rating that best 
represents their condition. The scale ranges from 1 to 5, with 5 representing the most 
symptomatic disease and giving an overall maximum possible score of 35. The IPSS is 
administered to males as an enrollment criterion. 
 The STOP-Bang questionnaire has been developed and validated as a screening tool for 
OSA. The STOP-Bang questionnaire is used in the study only for participants who do not 
have a previous diagnosis of OSA or use of CPAP, to determine whether there is a high 
enough pre-test probability of moderate to severe OSA to conduct enrollment screening. The 
standard STOP-Bang scoring used in the sleep clinic has only moderate specificity. For the 
purposes of this study, scoring with higher specificity is used (STOP-Bang score ≥5, or STOP 
≥ 2 + BMI >35 kg/m2) to decrease screening participants who are unlikely to meet 
enrollment criteria. 
8.1.5 Polysomnography 
 Methods: Standard overnight PSG recording and data interpretation will be performed in 
accordance with the American Academy of Sleep Medicine (AASM) scoring manual. 
Participants will be instrumented with standard PSG electrodes. Time of lights out will be 
established according to the participants’ habitual schedule and kept constant across the PSG 
study nights. The participants will be given 8 hours of time-in bed. 
 Technically Adequate Test: The screening/baseline PSG study must meet the following 
criteria for participants to enroll: 
o At least 4 hours of sleep. 
o At least 2 electroencephalograms (EEGs) and 2 electrooculography traces for 
the full night. 
o P nasal for at least 60% of the night and thermistor or both respiratory belts 
signals for the full night for scoring respiratory events. 


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o At least 30% of sleep in supine position.  
Participants who do not have a technically adequate test at baseline can be retested at the 
discretion of the investigator. 
 Scoring: For uses other than study enrollment, all studies will be scored by centralized PSG 
technologists, blinded to treatment assignment. Baseline and on-treatment PSGs for each 
individual participant will be scored by the same technologist. Scoring will be conducted 
according to the American Academy of Sleep Medicine manual scoring criteria. 
8.1.6 Home Oximetry 
 Participants will be instructed on the at-home use of oximetry at Visit 2 and will be provided 
with an oximeter that is capable of nightly recording and storage of data for the entire at-
home period (study Days 1-11). Participant use of oximeter will be reinforced during the 
study visit on Day 6 (Visit 3), and through a reminder telephone contact on Day 10. The 
study personnel will replace the batteries in the oximeter during the Day 6 study visit. The 
number per hour of oxygen desaturations ≥ 4% will be compared between the average of the 
baseline nights and the average of the randomized study treatment nights. 
8.2 Safety Assessments 
 Planned time points for all safety assessments are provided in the SoA. 
 Safety monitoring will be guided by the established safety profiles of atomoxetine and 
oxybutynin, and by Phase 1 safety data for the combination. Safety assessments will include 
physical examinations, measurement of vital signs, monitoring and recording of AEs, SAEs, 
and pregnancies, suicidality assessment, recording of study or treatment discontinuations, 
measurement of ECGs, clinical laboratory evaluations, and memory testing. Effects on OSA 
and sleep parameters (e.g., sleep time and sleep stages) will also be monitored by PSG. 
 Adverse events of special interest include effects on urine outflow, as both atomoxetine and 
oxybutynin are associated with urinary retention. Effects of atomoxetine on heart rate and 
blood pressure are expected to be modest, as indicated by the initial data described above, 
and will also be monitored. Participants with serious cardiac abnormalities will be excluded 
from the study. Suicidal ideation in children and adolescents is a boxed warning for 
atomoxetine; however, analysis in adult patients, the target population for the proposed OSA 
study, did not reveal an increased risk of suicidal ideation or behavior in association with 
atomoxetine. Safety monitoring in the dose-finding study will use an appropriate 
questionnaire to monitor for the potential emergence of suicidal ideation or behavior. 


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 Daytime sleepiness is both a potential safety outcome and efficacy outcome in OSA. Both 
atomoxetine and oxybutynin are associated with somnolence, and oxybutynin is additionally 
associated with anticholinergic CNS effects such as memory difficulty. Safety monitoring 
will therefore include psychomotor vigilance testing and memory testing.  
8.2.1 Physical Examinations 
 Physical examinations at screening/baseline include anthropomorphic data relevant to OSA: 
neck circumference at superior border of cricothyroid cartilage; waist circumference at 
highest point of iliac crest; evaluation of the oropharynx, hypopharynx, and facial skeletal 
structure; Mallampati score; tonsils evaluation (0-3+); presence of micrognathia; nasal 
patency.  
 The general physical examination at screening/baseline includes an assessment of general 
appearance and a review of physical systems (dermatologic, head, eyes, ears, nose, 
mouth/throat/neck, thyroid, lymph nodes, respiratory, cardiovascular, gastrointestinal, 
extremities, musculoskeletal, neurologic, and psychiatric systems). Height and weight will 
also be measured and recorded (with shoes removed and wearing light indoor clothing). 
 Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2 Vital Signs 
 Assessment of vital signs (seated blood pressure, pulse rate, body temperature, respiratory 
rate) will be performed at the time points indicated in the SoA (Section 1.3).  
 Vital signs will be measured at all visits in a seated position after 5 minutes rest and will 
include temperature, respiratory rate, systolic and diastolic blood pressure, and pulse. 
Measurements should be made in the same arm of the participant at each visit. 
 Systolic and diastolic blood pressure will be repeated for a total of 3 measurements, each at 
least 2 minutes apart. 
 The method used to measure body temperature at screening should be maintained throughout 
the study for each participant, and should be indicated (e.g., ear, mouth, armpit). 


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8.2.3 Electrocardiograms 
 A 12-lead ECG will be obtained using an ECG machine that automatically calculates the 
heart rate and measures the PR, QRS, and QT intervals, and the corrected QT-interval (QTc). 
The ECG will be recorded in the semi-supine position after the participant has rested in this 
position for at least 10 minutes. 
8.2.4 Clinical Safety Laboratory Assessments 
 Refer to Appendix 10.2 (Section 10.2) for the list of clinical laboratory tests to be performed 
and to the SoA for the timing and frequency. 
 The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically relevant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the Investigator to be more severe than expected for the participant's condition. 
 All laboratory tests with values considered clinically significant during participation in the 
study should be repeated until the values return to normal or baseline. If such values do not 
return to normal/baseline within a period of time judged reasonable by the Investigator, the 
etiology should be identified, where possible, and the Sponsor notified. 
 All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must 
be conducted in accordance with the laboratory manual and the SoA. 
 If laboratory values from laboratory assessments not specified in the protocol and performed 
at the institution’s local laboratory result in the need for a change in participant management 
or are considered clinically relevant by the Investigator (e.g., are considered to be an SAE or 
an AE or require dose modification), then the results must be recorded in the eCRF. 
8.2.5 Suicide Risk Monitoring 
Atomoxetine and oxybutynin are CNS-active drugs. There has been concern that some 
CNS-active drugs may be associated with an increased risk of suicidal ideation or behavior when 
given to participants with certain conditions or baseline characteristics. Although this study 
treatment or other similar drugs in this class have not been shown to be associated with an 
increased risk of suicidal thinking or behavior when given to adults, it is important to monitor for 
such events during this clinical study. 


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Suicidal ideation in children and adolescents is a boxed warning for atomoxetine; however, 
analysis in adult participants, the target population for the proposed OSA study, did not reveal an 
increased risk of suicidal ideation or behavior in association with atomoxetine. 
The CSSA item 17, “suicidality”, will be used to monitor participants for suicidality during the 
study (whether or not abuse-related). A score of ≥3 will be considered an AE and will initiate 
further clinical evaluation and appropriate measures to protect participant safety. Participants 
should be monitored appropriately and observed closely for suicidal ideation and behavior or any 
other unusual changes in behavior. Consideration should be given to discontinuing participants 
who experience signs of suicidal ideation or behavior. Families and caregivers of participants 
should be instructed to monitor participants for the emergence of unusual changes in behavior, as 
well as the emergence of suicidal ideation and behavior, and to report such symptoms 
immediately to the study Investigator. 
8.3 Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Appendix 3. 
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 
reporting events that meet the definition of an AE or SAE and remain responsible for following 
up on AEs that are serious, considered related to the study treatment or the study, or that caused 
the participant to discontinue the study and/or study treatment (see Section 7). 
8.3.1 Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of informed consent form (ICF) until 
Visit 5/EOS at the timepoints specified in the SoA (Section 1.3). 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 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 AEs or SAEs after the conclusion of 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 


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related to the study treatment or study participation, the Investigator must promptly notify the 
Sponsor. 
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 3. 
8.3.2 Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrence. 
8.3.3 Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, until the 
event is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.4). 
Further information on follow-up procedures is given in Appendix 3. 
8.3.4 Regulatory Reporting Requirements for SAEs 
 Prompt notification (within 24 hours, see Appendix 3) 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 treatment 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 treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/Independent Ethics Committees (IEC), and 
Investigators. 
 Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
 An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAE) from the Sponsor will file it 
along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according 
to local requirements. 


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8.3.5 Pregnancy 
 Details of all pregnancies in female participants and female partners of male participants 
after the start of study treatment and until at least 5 terminal half-lives after the last dose will 
be collected.  
 If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4. 
 Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered to be SAEs. 
If a female partner of a male study participant who has been exposed to the study treatment 
becomes pregnant, the pregnancy and outcome of pregnancy should be monitored. 
8.4 Treatment of Overdose 
For this study, any dose of atomoxetine greater than 75 mg and of oxybutynin greater than 5 mg 
more frequently than QHS will be considered an overdose. 
In the event of an overdose, the Investigator should refer to the approved product label for advice 
on overdose and: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until 
atomoxetine hydrochloride and/or oxybutynin chloride can no longer be detected 
systemically. 
3. Obtain a plasma sample for PK analysis within 1 day from the date of the last dose of 
study treatment if requested by the Medical Monitor (determined on a case by case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5 Pharmacokinetics 
PK parameters are not evaluated in this study. 


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8.6 Genetics 
A genetic sample will be taken during Treatment Period 1 only, on the screening/baseline visit 
(prior to randomization) to test for CYP2D6 poor metabolizers. 
9 Statistical Considerations 
9.1 Statistical Hypotheses 
The null hypothesis is no change in the proportion of participants with ≥50% improvement in 
AHI from baseline to the second PSG visit (Visit 4) in the 75 mg/5 mg dose group compared 
with placebo. 
9.2 Sample Size Determination 
The effect of the drug combination in OSA has been investigated in preliminary academic studies 
that provide an estimate of effect size in a population similar to the planned Phase 2 study 
population. Data from a single-night cross-over study showed that a high proportion of 
participants, 8/9 (88.9%), with demographic characteristics matched to the planned enrollment 
criterion of the planned Phase 2 study (baseline AHI ≥20, BMI between 18.5 and 40 kg/m2, and 
age from 25 to 65 years) when treated with a combination of 80 mg atomoxetine and 5 mg 
oxybutynin achieved a clinically relevant threshold of at least a 50% improvement in AHI score. 
Using a proposed sample size of n=35 for each of the 4 treatment groups, given 90% power and 
2-sided alpha of 0.05, the sample size is powered to detect a difference in proportion of 
responders between the high-dose group and placebo, assuming a response rate as low as 37% in 
the high-dose group (compared with the preliminary data that suggests response rate may be as 
high as 90%) and 5% in the placebo group, estimated based on typical test-retest variability of 
PSG. Alternatively, if test-retest variability of PSG is higher, resulting in a higher placebo 
response rate of 10%, the study retains 90% power assuming a response rate in the high-dose 
group of 46%. Participants that discontinue prior to the second PSG visit will not be replaced, 
and will be considered non-responders. 
9.3 Populations for Analyses 
For the purposes of analysis, the following analysis sets are defined: 


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Population 
Description 
Enrolled 
All participants who signed the ICF (including screening failures). 
Modified Intent to Treat 
(mITT) Population 
The mITT Population comprises all participants who are 
randomized, take at least 1 dose of any of the study treatments, and 
have at least 1 measurement on the primary endpoint. Participants 
will be analyzed for efficacy according to the treatment group into 
which they are randomized. 
Safety Population 
The Safety Population consists of all participants who are 
randomized and receive at least 1 dose of any of the study 
treatments. Participants will be analyzed for safety based on the 
treatment received. A precise definition of “as actually received” 
will be added in the Statistical Analysis Plan (SAP). 
Per Protocol (PP) 
Population 
The PP Population consists of all participants without any major 
protocol violations that could influence efficacy assessment, and 
who are at least 80% compliant with the study medication. 
Participants in this population will be analyzed according to the 
treatment they actually received. 
The primary endpoint comparison between the high dose (75/5) and placebo will consider all 
mITT participants randomized to those 2 groups; participants not returning for their second PSG 
night will be considered treatment non-responders. 
9.4 Primary and Secondary Analyses 
The SAP will be developed and finalized prior to database lock. Below is a summary of planned 
statistical analyses of the primary and secondary endpoints. Further details are presented in the 
SAP. 
Hypothesis tests will be performed in a sequential manner to avoid the need to adjust type I error 
rates for multiplicity, at a 2-sided 0.05 significance level. The sequential order of hypothesis tests 
will occur as follows: 
 Comparison of the proportion of participants with ≥50% improvement in AHI from baseline 
to the second PSG visit in the 75/5 dose group compared with placebo. 
 Percent change AHI, high-dose arm vs. placebo. 


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 Proportion of participants with ≥50% improvement in AHI, measured in the supine sleeping 
position, from baseline to the second PSG visit in the 75/5 dose group compared with 
placebo. OSA is often more severe in the supine sleeping position, and variability in time 
spent in the supine position between baseline and during on-drug PSG tests can otherwise 
introduce variability. 
 Proportion of participants with ≥50% improvement in Oxygen desaturation index from 
baseline (average of 2 baseline nights) to study treatment nights (average of 6 nights) for the 
75/5 dose group compared with placebo.  
 Change from baseline in the ESS from baseline to the second PSG visit in the 75/5 dose 
group compared with placebo.  
 Change from baseline in the PGI-S from baseline to the second PSG visit in the 75/5 dose 
group compared with placebo.  
 Proportion of participants with ≥50% improvement in AHI from baseline to the second PSG 
visit in the 75/5 dose group compared with the lower treatment dose of 25/5. 
 In the case that a statistically significant result for the AHI comparison of dose 75/5 to 25/5 is 
observed, then the proportion of participants with ≥50% improvement in AHI from baseline 
to the second PSG visit in the 75/5 dose group compared with the lower treatment dose of 
75/1.5.  
9.5 Interim Analyses 
No formal interim analysis is planned. 
10 Supporting Documentation and Operational Considerations 
10.1 Appendix 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: 
 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 Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 


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 Applicable laws and regulations. 
 The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (e.g., 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 IEC/IRB approval before implementation of 
changes made to the study design, 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 SAE or other significant safety findings as required by 
IRB/IEC procedures. 
 Overall conduct of the study at the site and adherence to requirements of 21 Code of 
Federal Regulations (CFR), ICH GCP guidelines, the IRB/IEC guidelines, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations. 
10.1.2 Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations 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. 
10.1.3 Informed Consent Process 
 The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative 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, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center. 


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 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 re-consented to the most current version of the ICF(s) during their 
participation in the study. 
 A copy of the signed ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the 
protocol. If the ICF is revised, it must be reviewed and approved by the appropriate IEC/IRB, 
and signed by all participants subsequently enrolled in the study as well as those currently 
enrolled in the study. 
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. 
 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 Dissemination of Clinical Study Data 
When the clinical study report is completed, the Sponsor will provide the major findings of the 
study to the Investigator. A summary of the study results will also be posted in a publicly 
accessible database (e.g., www.ClinTrials.gov). The results may also be submitted for 
publication.  


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10.1.6 Data Quality Assurance 
 All participant data relating to the study will be recorded on printed or eCRFs unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The Investigator 
is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF. 
 The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
 The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
 The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
 Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
 Records and documents, including signed ICF, pertaining to the conduct of this study must be 
retained by the Investigator for 5 years after study completion 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. 
 All data generated by the site personnel will be captured electronically at each study center 
using eCRFs. Data from external sources (such as laboratory data) will be imported into the 
database. Once the eCRF clinical data have been submitted to the central server at the 
independent data center, corrections to the data fields will be captured in an audit trail. The 
reason for change, the name of the person who performed the change, together with the time 
and date will be logged to provide an audit trail. 
 If additional corrections are needed, the responsible monitor or data manager will raise a 
query in the electronic data capture (EDC) application. The appropriate staff at the study site 
will answer queries sent to the Investigator. The name of the staff member responding to the 
query, and time and date stamp will be captured to provide an audit trail. Once all source data 
verification is complete and all queries are closed, the monitor will lock the database. 


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 The specific procedures to be used for data entry and query resolution using the EDC 
system/eCRF will be provided to study sites in a training manual. In addition, site personnel 
will receive training on the EDC system/eCRF. 
10.1.7 Source Documents 
 Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
 Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request 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 Section 10.1.11.1. 
10.1.8 Study and Site Closure 
The Sponsor 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: 
 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 recruitment of participants by the Investigator. 
 Discontinuation of further study treatment development. 


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10.1.9 Publication Policy 
 The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows the Sponsor to protect proprietary information and to provide 
comments. 
 The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In this 
case, a coordinating Investigator will be designated by mutual agreement. 
 Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
10.1.10 Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IEC/IRB/Competent Authorities, in accordance with local legal requirements. The 
Sponsor must ensure that all ethical and legal requirements have been met before the first 
participant is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/IEC/Competent Authority 
approval prior to implementation (if appropriate). Following approval, the protocol 
amendment(s) will be submitted to the US Investigational New Drug (IND) under which the 
study is being conducted. 
Administrative changes (not affecting the participant benefit/risk ratio) may be made without the 
need for a formal amendment. All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
10.1.11 Liability and Insurance 
The Sponsor will take out reasonable third-party liability insurance cover in accordance with all 
local legal requirements. The civil liability of the Investigator, the persons instructed by him or 
her and the hospital, practice, or institute in which they are employed and the liability of the 
Sponsor with respect to financial loss due to personal injury and other damage that may arise as a 
result of the carrying out of this study are governed by the applicable law. 


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The Sponsor will arrange for participants participating in this study to be insured against 
financial loss due to personal injury caused by the pharmaceutical products being tested or by 
medical steps taken in the course of the study. 
10.1.11.1 Access to Source Data 
During the study, a monitor will make site visits to review protocol compliance, compare 
EDC/eCRF entries and individual participant’s medical records, assess drug accountability, and 
ensure that the study is being conducted according to pertinent regulatory requirements. The 
EDC/eCRF entries will be verified with source documentation. The review of medical records 
will be performed in a manner to ensure that participant confidentiality is maintained. 
Checking of the EDC/eCRF entries for completeness and clarity, and cross-checking with source 
documents, will be required to monitor the progress of the study. Moreover, regulatory 
authorities of certain countries, IRBs, IECs, and/or the Sponsor’s Clinical Quality Assurance 
Group may wish to carry out such source data checks and/or on-site audit inspections. Direct 
access to source data will be required for these inspections and audits; they will be carried out 
giving due consideration to data protection and medical confidentiality. The Investigator assures 
PAREXEL and the Sponsor of the necessary support at all times. 
10.2 Appendix 2: Clinical Laboratory Tests 
 The tests detailed in Table 2 will be performed by the central laboratory. 
 Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
 Laboratory testing is performed non-fasting. 
 Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations. 


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Table 2: Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Hematocrit 
Hemoglobin 
Platelet Count 
RBC Count 
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with Differential: 
Basophils 
Eosinophils 
Lymphocytes 
Neutrophils 
Monocytes 
Serum Chemistry 
Albumin 
BUN 
Creatinine 
Potassium 
Sodium  
Total and direct 
bilirubin 
Total Protein  
Uric acid 
ALT 
AST 
Alkaline phosphatase 
Calcium 
γGTP 
Glucose  
Total cholesterol 
Chloride 
Bicarbonate 
Routine 
Urinalysis 
Specific gravity 
pH, protein (albumin), glucose, ketones, blood (RBC), WBC by dipstick 
Microscopic examination (if blood or protein is abnormal) 
Other Tests 
 HbA1c (Screening Visit only) 
 CYP2D6 genotype 
 Serum hCG pregnancy test at screening and urine hCG tests at baseline. 
Additional testing may be performed if needed in WOCBP. 
 Alcohol and drugs of abuse screening 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
CYP2D6 = cytochrome P450 2D6; γ-GTP = gamma guanosine-5’-triphosphate; HbA1c = hemoglobin A1c 
(glycated hemoglobin); hCG = human chorionic gonadotropin; MCH = mean corpuscular hemoglobin; MCV = 
mean corpuscular volume; RBC = red blood cell count; WBC= white blood cell; WOCBP = women of 
childbearing potential. 
Investigators must document their review of each laboratory safety report. 


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10.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
 An AE is any untoward medical occurrence in a participant or clinical study 
participant, temporally associated with the use of a study treatment, whether or not 
considered related to the medicinal product. 
 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 a study treatment. 
 
Events Meeting the AE Definition  
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the Investigator (i.e., not related to progression of 
underlying disease). 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
 "Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as an AE or SAE if they fulfill the definition of an 
AE or SAE. 
 


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Events NOT Meeting the AE Definition  
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
Results in death 
Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 


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Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
Results in persistent disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Other situations 
 Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical treatment to prevent one 
of the other outcomes listed in the above definition. These events should usually be 
considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 


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Recording and Follow-up of AE and SAE 
AE and SAE Recording 
 When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
 The Investigator will then record all relevant AE/SAE information in the eCRF. 
 It is not acceptable for the Investigator to send photocopies of the participant’s 
medical records in lieu of completion of the AE/SAE eCRF page. 
 There may be instances when copies of medical records for certain cases are 
requested by the PAREXEL Clinical Studies Safety Center. In this case, all 
participant identifiers, with the exception of the participant number, will be blinded 
on the copies of the medical records before submission to the PAREXEL Clinical 
Studies Safety Center. 
 The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to one of the following categories: 
 Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities. 
 Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
 Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
 The Investigator is obligated to assess the relationship between study treatment and 


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each occurrence of each AE/SAE. 
 A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
 The Investigator will use clinical judgment to determine the relationship. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
 The Investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
 For each AE/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report to the Clinical Studies Safety 
Center. However, it is very important that the Investigator always make an 
assessment of causality for every event before the initial transmission of the SAE 
data to the PAREXEL Clinical Studies Safety Center. 
 The Investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AE and SAE 
 The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 
PAREXEL Clinical Studies Safety Center to elucidate the nature and/or causality of 
the AE or SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals. 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide PAREXEL with a copy of any post-mortem 


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findings including histopathology. 
 New or updated information will be recorded in the originally completed eCRF. 
 
The Investigator will submit any updated SAE data to PAREXEL Clinical Studies 
Safety Center within 24 hours of receipt of the information. 
 
Reporting of SAE to PAREXEL Clinical Studies Safety Center 
SAE Reporting to PAREXEL Clinical Studies Safety Center 
Via EDC Tool 
 The Investigator must report any SAEs to the PAREXEL Clinical Studies Safety 
Center within 24 hours of becoming aware of the event. 
 When calling to report an SAE, state that you are reporting an SAE and give the 
Investigator’s name, your name, the telephone number where you can be reached, and 
the protocol number and title. 
 The Investigator and the Sponsor (or Sponsor’s designated agent) will review each 
SAE report and the Sponsor/PAREXEL will evaluate the seriousness and the causal 
relationship of the event to study treatment. In addition, the Sponsor (or Sponsor’s 
designated agent) will evaluate the expectedness according to the reference 
documents (Investigator’s Brochure or US product labeling for atomoxetine or 
oxybutynin). Based on the Investigator and Sponsor’s assessment of the event, a 
decision will be made concerning the need for further action. 
 After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or by telephone. 
 
Contacts for SAE reporting can be found in the Study Reference Manual. 
 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Any AE that is serious, associated with the use of the study treatment, and unexpected 
(SUSAR) has additional reporting requirements, as described below. 


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 If the SUSAR is fatal or life-threatening, associated with study treatment, and 
unexpected, regulatory authorities and IECs will be notified within 7 calendar days 
after the Sponsor learns of the event. Additional follow-up (cause of death, autopsy 
report, and hospital report) information should be reported within an additional 8 days 
(15 days total). 
 If the SUSAR is not fatal or life-threatening but is otherwise serious, associated with 
study treatment, and unexpected, regulatory authorities and IECs will be notified 
within 15 calendar days after the Sponsor learns of the event. 
The Sponsor will notify the Investigators in a timely fashion of relevant information 
about SUSARs that could adversely affect the safety of participants. Follow-up 
information may be submitted if necessary. 
The Sponsor will also provide annual safety updates to the regulatory authorities and 
IECs responsible for the study. These updates will include information on SUSARs and 
other relevant safety findings. 
Reporting Serious Adverse Events 
The Investigator must report any SAEs to the PAREXEL Clinical Studies Safety Center within 
24 hours of becoming aware of the event. 
When calling to report an SAE, state that you are reporting an SAE and give the Investigator’s 
name, your name, the telephone number where you can be reached, and the protocol number and 
title. 
The Investigator and the Sponsor (or Sponsor’s designated agent) will review each SAE report 
and the Sponsor/PAREXEL will evaluate the seriousness and the causal relationship of the event 
to study treatment. In addition, the Sponsor (or Sponsor’s designated agent) will evaluate the 
expectedness according to the reference documents (Investigator’s Brochure or US product 
labeling for atomoxetine or oxybutynin). Based on the Investigator and Sponsor’s assessment of 
the event, a decision will be made concerning the need for further action. 
All SAEs will be recorded from signing of informed consent until the end of the study. Serious 
adverse events occurring after the end of the study and coming to the attention of the Investigator 
must be reported only if they are considered (in the opinion of the Investigator) causally-related 
to study treatment. 
 


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SERIOUS ADVERSE EVENT REPORTING INSTRUCTIONS 
PAREXEL International Corporation 
Clinical Studies Safety Center 
 
The names and contact information for SAE reporting 
will be provided in the Study Reference Manual. 
1. 
Telephone the Medical Monitor/Drug Safety Specialist to inform him/her that you are 
faxing an SAE form. If the Medical Monitor is not available or you are calling after business 
hours (8:30 am to 5:30 pm Eastern time, Monday to Friday), leave a message in his/her voice 
mailbox. 
2. 
Provide the Medical Monitor with the Principal Investigator’s name, your name, the 
telephone number where you can be reached, and the protocol number and title. 
3. 
Fax the completed SAE form and any supporting documentation within 24 hours of 
becoming aware of the event to the email address or fax number listed on the SAE reporting 
form (investigator site file). 
10.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions 
WOCBP 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with one of the following: 
 Documented hysterectomy 
 Documented bilateral salpingectomy 
 Documented bilateral oophorectomy 


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NOTE: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Post-menopausal female 
 A post-menopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the post-
menopausal range may be used to confirm a post-menopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 
 Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status before study enrollment. 
Contraception Guidance: 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if the 
agree to ONE of the following during the protocol-defined time frame in Section 5.1: 
 Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent. 
 Agree to use a contraceptive method with a failure rate of <1% per year as described 
in the table below when having penile-vaginal intercourse with a WOCBP who is not 
currently pregnant. 
In addition, male participants must refrain from donating sperm for the duration of the study and 
for 3 months after the last dose of study treatment. 
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or to use a male condom during each episode of penile penetration 
during the protocol-defined time frame. 
Female Participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in the table 
below. 


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Highly Effective Contraceptive Methods That Are User Dependent1 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestin-containing) hormonal contraception associated with 
inhibition of ovulation2 
 Oral 
 Intravaginal 
 Transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
 Oral 
 Injectable 
Highly Effective Contraceptive Methods That Are User Independent1 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
 IUD 
 Intrauterine hormone-releasing system (IUS) 
 Bilateral tubal occlusion 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant. 
NOTES: 
1 Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
 
 
Pregnancy Testing 
 WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test. 
 An additional serum pregnancy testing should be performed at Visit 5 (EOS). 


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 Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
Collection of Pregnancy Information: 
Male participants with partners who become pregnant 
 The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This applies 
only to male participants who receive study treatment. 
 After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the Sponsor. Generally, the follow up will 
be no longer than 6 to 8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
Female participants who become pregnant 
 The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of a participant’s pregnancy. 
The participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect any follow up information on the participant and the neonate and the information 
will be forwarded to the Sponsor. Generally, follow up will not be required for longer than 6 
to 8 weeks beyond the estimated delivery date. Any termination of the pregnancy will be 
reported, regardless of fetal state (presence or absence of anomalies) or indication for the 
procedure. 
 While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous 
abortion is always considered to be an SAE and will be reported as such. Any post-study 
pregnancy-related SAE considered reasonably related to the study treatment by the 
Investigator will be reported to the Sponsor as described in Section 8.3.4. While the 
Investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting. 


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 Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study. 


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10.5 Appendix 5: List of Abbreviations 
AHI 
apnea-hypopnea index 
AE 
adverse event 
Bang 
Body mass index, Age, Neck circumference, and Gender criteria 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CPAP 
continuous positive air pressure 
CSSA 
Cocaine Selective Severity Assessment 
CYP2D6 
cytochrome P450 2D6 
CYP3A4 
cytochrome P450 3A4 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
ECG 
electrocardiogram 
EEG 
electroencephalogram 
eCRF 
electronic case report form(s) 
EDC 
electronic data capture 
EMGgg 
genioglossal electromyographic 
EOS 
end of study 
ESS 
Epworth Sleepiness Scale 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
 
 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IPSS 
International Prostate Symptom Score 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
OSA 
obstructive sleep apnea 
OTC 
over-the-counter 
MAOI 
monoamine oxidase inhibitor 
NREM 
non-rapid eye movement 
PGI-S 
Participant Global Impression of Severity 


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PK 
pharmacokinetic(s) 
PSG 
polysomnography 
DWRT 
Delayed Word Recall Test 
QHS 
1 dose every night at bedtime 
REM 
rapid eye movement 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SoA 
Schedule of Activities 
STOP 
Snoring, Tiredness, Observed apnea, and Blood pressure criteria 
SUSAR 
suspected unexpected serious adverse reaction 
ULN 
upper limit of normal 
US 
United States 
WOCBP 
woman of childbearing potential 
 
 
 


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11 References 
Brooks D, Horner RL, Kozar LF, Render-Teixeira CL, Phillipson EA. Obstructive  sleep apnea as 
a cause of systemic hypertension. Evidence from a canine model. J Clin Invest 1997;99:106-109. 
Chan E, Steenland HW, Liu H, Horner RL. Endogenous excitatory drive modulating respiratory 
muscle activity across sleep-wake states. Am J Respir Crit Care Med 2006;174:1264-1273. 
Eckert DJ, White DP, Jordan AS, Malhotra A, Wellman A. Defining phenotypic causes of 
obstructive sleep apnea. Identification of novel therapeutic targets. Am J Respir Crit Care Med 
2013;188:996-1004. 
Fenik VB, Davies RO, Kubin L. REM sleep-like atonia of hypoglossal (XII) motoneurons is 
caused by loss of noradrenergic and serotonergic inputs. Am J Respir Crit Care Med 
2005;172:1322-1330. 
Findley LJ, Unverzagt ME, Suratt PM. Automobile accidents involving patients with obstructive 
sleep apnea. Am Rev Respir Dis 1988;138:337-340. 
Grace KP, Hughes SW, Horner RL. Identification of the mechanism mediating genioglossus 
muscle suppression in REM sleep. Am J Respir Crit Care Med 2013;187:311-319. 
Grace KP, Hughes SW, Shahabi S, Horner RL. K+ channel modulation causes genioglossus 
inhibition in REM sleep and is a strategy for reactivation. Respir Physiol Neurobiol 
2013;188:277-288. 
Hoffstein V. Blood pressure, snoring, obesity, and nocturnal hypoxaemia. Lancet 
1994;344:643-645. 
Hung J, Whitford EG, Parsons RW, Hillman DR. Association of sleep apnoea with myocardial 
infarction in men. Lancet 1990;336:261-264. 
Lai YY, Kodama T, Siegel JM. Changes in monoamine release in the ventral horn and 
hypoglossal nucleus linked to pontine inhibition of muscle tone: An in vivo microdialysis study. J 
Neurosci 2001;21:7384-7391. 


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Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, et al. Association of sleep-
disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep 
Heart Health Study. JAMA 2000; 283:1829-1836. 
Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-
disordered breathing in adults. Am J Epidemiol 2013;177(9):1006–1014. 
Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-
disordered breathing and hypertension. N Engl J Med 2000; 342:1378-1384. 
Redline S, Strauss ME, Adams N, Winters M, Roebuck T, Spry K, et al. Neuropsychological 
function in mild sleep-disordered breathing. Sleep 1997; 20:160-167. 
Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Nieto FJ, et al. Sleep-disordered 
breathing and cardiovascular disease: Cross-sectional results of the Sleep Heart Health Study. 
Am J Respir Crit Care Med 2001;163:19-25. 
Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive 
sleep apnea. J Clin Invest 1995;96:1897-1904. 
Weaver TE, Sawyer AM. Adherence to continuous positive airway pressure treatment for 
obstructive sleep apnea: implications for future interventions. Indian J Med Res 
2010;131:245-258. 
Wellman A, Eckert DJ, Jordan AS, Edwards BA, Passaglia CL, Jackson AC, et al. A method for 
measuring and modeling the physiological traits causing obstructive sleep apnea. J Appl Physiol 
(1985) 2011; 110:1627-1637. 
Wellman A, Edwards BA, Sands SA, Owens RL, Nemati S, Butler J, et al. A simplified method 
for determining phenotypic traits in patients with obstructive sleep apnea. J Appl Physiol (1985) 
2013;114:911-922. 
Wessendorf TE, Teschler H, Wang YM, Konietzko N, Thilmann AF. Sleep-disordered breathing 
among patients with first-ever stroke. J Neurol 2000;247:41-47. 
Younes M. Contributions of upper airway mechanics and control mechanisms to severity of 
obstructive apnea. Am J Respir Crit Care Med 2003;168:645-658. 
 
 


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Declaration of the Investigator 
Title: Phase 2 Placebo-Controlled, Parallel Group Dose-Finding Study to Evaluate the Efficacy 
and Safety of Three Fixed-Dose Combinations of AD036 in Adults With Obstructive Sleep 
Apnea 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence. This documentation includes this study 
protocol, Investigator's Brochure, EDC system/eCRF, and other scientific data. 
The study will not be commenced without the prior written approval of a properly constituted 
IRB or IEC. No changes will be made to the study protocol without the prior written approval of 
the Sponsor and the IRB or IEC, except where necessary to eliminate an immediate hazard to the 
participants. 
I have read and understood and agree to abide by all the conditions and instructions contained in 
this protocol. 
Responsible Investigator of the local study center 
 
_____________________________________ 
_____________________ 
Signature 
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number 


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Title Page 
Protocol Title: Phase 2, Placebo-Controlled, Parallel Group Dose-Finding Study to Evaluate the 
Efficacy and Safety of Three Fixed-Dose Combinations of AD036 in Adults With Obstructive 
Sleep Apnea 
Protocol Number: APN-002 
Amendment Number: 1 
Compound Number: AD036 
Short Title: Dose Finding Study of AD036 in Obstructive Sleep Apnea 
Sponsor Name and Legal Registered Address:  
Apnimed, Inc. 
19 Ware Street, #3 
Cambridge, MA 02138 
Regulatory Agency Identifying Number: IND 136752 
Approval Date: 12 April 2019 
Date and Version of Previous Protocol:  04 December 2018 
 
 
 


Apnimed, Inc. 
Protocol APN-002/IND 136752 
Sponsor Signatory: 
Lawrence Miller, MD 
ChiefExecutive Officer 
Clinical Study Protocol 
CONFIDENTIAL 
Medical Monitor Name and Contact Information: provided in the Study Reference Manual. 
12 April2019 
2of69 
Final V 1.4 - Amendment I 


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Summary of Changes for IND 136752 
Protocol APN-002 
Version 1.4 (December 2018) to Version 1.4, Amendment 1 (April 2019)  
 
Section 
Description of Change 
Rationale 
Title Page 
Protocol approval date  
Protocol amendment 
Table of Contents 
Revised per contents 
Reflects revised contents 
1.1 Synopsis 
Minor editorial changes 
Increase clarity 
1.3 Schedule of Activities 
a) Visit 1 window changed from day 
-28 to -3 to day -28 to -1 
a) Visit 1 activities can occur 
through day -1 
b) Drug of Abuse: 
Oxycodone/oxymorphone test 
removed  
b) Test is for opiates 
c) AE/SAE monitoring added at 
Visit 1 
c) AE/SAE collected after signing 
informed consent 
d) Reminder phone call changed 
from day 10 to day 10 ± 2 
d) To align with Visit 4 PSG window 
e) Prior/concomitant medication 
monitoring added to Visit 3 
e) Prior/concomitant medication 
monitoring takes place at Visit 3 
f) 
ESS measured evening of baseline 
PSG and Visit 4 PSG 
f) 
Clarify time of administration 
3 Objectives and Endpoints 
Minor editorial changes 
Increase clarity 
4.1 Overall Design 
final day of treatment corrected to day 
12± 2 
Typographical error 
Inclusion criterion 1 
Age range 
Increase maximum enrollment age of 
women from 65 to 70 years 
Upper age limit had been based on risk 
of urinary retention related to benign 
prostatic hypertrophy,  which is not a 
factor in women 
Inclusion criterion 4 
Epworth Sleepiness Scale 
Minimum score required for 
enrollment reduced from 8 to 4 
Score of 8 was unnecessarily 
restrictive of enrollment 
5.6 Screen Failures 
Allow rescreening if enabled by a 
protocol amendment 
Patient for screening becomes fully 
compliant with the amended protocol 
6.5 Concomitant therapy 
Minor spelling errors corrected 
Typographical error 
 
 


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Table of Contents 
 
Table of Contents ............................................................................................................................ 4 
1 
Protocol Summary .................................................................................................................... 7 
1.1 
Synopsis ................................................................................................................................ 7 
1.2 
Schema ................................................................................................................................11 
1.3 
Schedule of Activities (SoA) .............................................................................................. 12 
2 
Introduction............................................................................................................................. 16 
2.1 
Study Rationale .................................................................................................................. 16 
2.2 
Background......................................................................................................................... 16 
2.2.1 
Obstructive Sleep Apnea ................................................................................................ 16 
2.2.2 
Unmet Medical Need ...................................................................................................... 16 
2.2.3 
Biological Rationale ....................................................................................................... 17 
3 
Objectives and Endpoints ....................................................................................................... 19 
4 
Study Design ........................................................................................................................... 20 
4.1 
Overall Design .................................................................................................................... 20 
4.2 
Scientific Rationale for Study Design ................................................................................ 21 
4.3 
Justification for Dose .......................................................................................................... 21 
4.4 
End of Study Definition...................................................................................................... 22 
5 
Study Population ..................................................................................................................... 23 
5.1 
Inclusion Criteria ................................................................................................................ 23 
5.2 
Exclusion Criteria ............................................................................................................... 24 
5.3 
Meals and Dietary Restrictions .......................................................................................... 27 
5.4 
Caffeine, Alcohol, and Tobacco.......................................................................................... 27 
5.5 
Activity ............................................................................................................................... 27 
5.6 
Screen Failures ................................................................................................................... 27 
6 
Study Treatment ...................................................................................................................... 27 
6.1 
Study Treatment(s) Administered ....................................................................................... 28 
6.2 
Preparation/Handling/Storage/Accountability ................................................................... 28 
6.3 
Measures to Minimize Bias: Randomization and Blinding ................................................ 29 
6.4 
Study Treatment Compliance ............................................................................................. 29 


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6.5 
Concomitant Therapy ......................................................................................................... 29 
6.6 
Dose Modification .............................................................................................................. 31 
6.7 
Treatment After the End of the Study ................................................................................. 32 
7 
Discontinuation of Study Treatment and Participant Discontinuation ................................... 32 
7.1 
Discontinuation of Study Treatment ................................................................................... 32 
7.2 
Stopping Criteria ................................................................................................................ 32 
7.2.1 
Individual Participant Stopping Criteria ......................................................................... 32 
7.3 
Participant Discontinuation/Withdrawal from the Study ................................................... 32 
7.4 
Loss of Participants to Follow-Up ...................................................................................... 33 
8 
Study Assessments and Procedures ........................................................................................ 33 
8.1 
Efficacy Assessments ......................................................................................................... 34 
8.1.1 
Efficacy Endpoint Scales ................................................................................................ 34 
8.1.2 
Safety and Abuse Liability Scale .................................................................................... 35 
8.1.3 
Functional Endpoints ...................................................................................................... 35 
8.1.4 
Screening/Eligibility Scales ............................................................................................ 36 
8.1.5 
Polysomnography ........................................................................................................... 36 
8.1.6 
Home Oximetry .............................................................................................................. 37 
8.2 
Safety Assessments ............................................................................................................. 37 
8.2.1 
Physical Examinations .................................................................................................... 38 
8.2.2 
Vital Signs ...................................................................................................................... 38 
8.2.3 
Electrocardiograms ......................................................................................................... 39 
8.2.4 
Clinical Safety Laboratory Assessments ........................................................................ 39 
8.2.5 
Suicide Risk Monitoring ................................................................................................. 39 
8.3 
Adverse Events and Serious Adverse Events ..................................................................... 40 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ........................... 40 
8.3.2 
Method of Detecting AEs and SAEs .............................................................................. 41 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................... 41 
8.3.4 
Regulatory Reporting Requirements for SAEs .............................................................. 41 
8.3.5 
Pregnancy ....................................................................................................................... 42 
8.4 
Treatment of Overdose ....................................................................................................... 42 
8.5 
Pharmacokinetics ................................................................................................................ 42 
8.6 
Genetics .............................................................................................................................. 43 
9 
Statistical Considerations........................................................................................................ 43 
9.1 
Statistical Hypotheses ......................................................................................................... 43 


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9.2 
Sample Size Determination ................................................................................................ 43 
9.3 
Populations for Analyses .................................................................................................... 43 
9.4 
Primary and Secondary Analyses ....................................................................................... 44 
9.5 
Interim Analyses ................................................................................................................. 45 
10 Supporting Documentation and Operational Considerations ................................................. 45 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............................ 45 
10.1.1 
Regulatory and Ethical Considerations .......................................................................... 45 
10.1.2 
Financial Disclosure ....................................................................................................... 46 
10.1.3 
Informed Consent Process .............................................................................................. 46 
10.1.4 
Data Protection ............................................................................................................... 47 
10.1.5 
Dissemination of Clinical Study Data ............................................................................ 47 
10.1.6 
Data Quality Assurance .................................................................................................. 48 
10.1.7 
Source Documents .......................................................................................................... 49 
10.1.8 
Study and Site Closure ................................................................................................... 49 
10.1.9 
Publication Policy ........................................................................................................... 50 
10.1.10 Protocol Approval and Amendment ............................................................................... 50 
10.1.11 Liability and Insurance ................................................................................................... 50 
10.2 Appendix 2: Clinical Laboratory Tests ............................................................................... 51 
10.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ................................................................................................... 53 
10.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information .............. 60 
10.5 Appendix 5: List of Abbreviations ..................................................................................... 65 
11 References............................................................................................................................... 67 
 


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1 Protocol Summary 
1.1 Synopsis 
Protocol Title: Phase 2, Placebo-Controlled, Parallel Group Dose-Finding Study to Evaluate the 
Efficacy and Safety of Three Fixed-Dose Combinations of AD036 in Adults With Obstructive 
Sleep Apnea 
Sponsor Study No.: APN-002 
Phase 2 
Sponsor: Apnimed, Inc. 
Rationale: 
At the doses used in the initial human studies of the AD036 combination (atomoxetine 
80 mg/oxybutynin 5 mg), there was support for efficacy and safety in participants with 
obstructive sleep apnea (OSA). This Phase 2 clinical study will further examine the efficacy and 
safety of both similar and lower dose AD036 combinations versus placebo. Overall, the study is 
expected to provide dose selection guidance and a deeper understanding of repeat-dose safety 
and tolerability for the ongoing clinical development of this combination. 


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Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To assess the efficacy of 3 
different fixed doses of 
AD036 (the combination of 
atomoxetine and 
oxybutynin) vs. placebo 
 
To evaluate safety and 
tolerability of the 
combination AD036 
 
 
 
 
Primary Efficacy Endpoint 
 
AHI, proportion of participants with ≥50% reduction, PSG nights, high-
dose (atomoxetine 75 mg/oxybutynin 5 mg) arm vs. placebo 
 
Safety Endpoints  
 
Spontaneous adverse events, including the post-dosing period 
 
Physical exam and laboratory testing 
 
DSST 
 
Delayed Word Recall Test 
 
CSSA, Modified for study treatment 
 
Prospective Suicidality Assessment (item 17 “suicidality” of CSSA) 
 
PSG parameters: heart rate, ECG, EEG, oximetry  
 
Physical exam, vital signs, clinical laboratory assessment, ECG 
Secondary 
To assess the efficacy of 3 
different fixed doses of the 
combination of AD036 vs. 
placebo 
Secondary Efficacy Endpoints 
High dose vs placebo, in order: 
 
Percent change AHI, high-dose arm vs. placebo 
 
AHI in supine position, proportion of participants with ≥50% reduction, 
PSG nights 
 
Oxygen desaturation index (number of desaturations/hour ≥4% below 
baseline), proportion of participants with ≥50% reduction, at-home nights 
 
ESS 
 
PGI-S, OSA, PSG nights 
 
AHI, proportion of participants with ≥50% reduction, PSG nights, 
high-dose (atomoxetine 75 mg/oxybutynin 5 mg) arm vs. each low dose arm 
(atomoxetine 75 mg /oxybutynin 1.5 mg, and atomoxetine 25 mg/ 
oxybutynin 5 mg)  
Tertiary/Exploratory 
 
Unranked Efficacy Endpoints 
 
Proportion of participants with ≥50% AHI decrease and final AHI<15/hour, 
PSG nights 
 
Total time with SaO2 <90%, PSG nights 
 
Total time with SaO2 <80%, PSG nights 
 
Snoring index, PSG nights  
 
Sleep stages distribution and % of time in the various sleep stages, PSG 
nights 
 
Arousal index, PSG nights 
 
Oxygen desaturation index, low-dose run-in vs baseline, at home nights 
 
Proportion of apneas to hypopneas 
Abbreviations: AHI = apnea-hypopnea index; CSSA = Cocaine Selective Severity Assessment; DSST = Digit 
Symbol Substitution Test; ECG = electrocardiogram; EEG = electroencephalogram; ESS = Epworth Sleepiness 
Scale; OSA = obstructive sleep apnea; PGI-S = Participant Global Impression of Severity; PSG = 
polysomnography; SaO2 = oxygen saturation. 
Overall Design: 


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This is a randomized, double blind, placebo-controlled, repeat-dose, parallel arm, outpatient and 
inpatient, multi-center dose finding study of the combination of atomoxetine and oxybutynin in 
adults with OSA documented by polysomnography (PSG). Participants will be randomized 
equally to receive 1 of 3 different fixed-dose combinations of oxybutynin and atomoxetine, or 
matching placebo. For all participants, there is an initial 2-night at-home blinded baseline period 
in which placebo is dosed. Following this baseline placebo period, participants randomized to 
any of the 3 study treatment arms receive 3 nights of a low-dose run-in of the combination, 
consisting of atomoxetine 25 mg/oxybutynin 1.5mg. In contrast, during this 3-night run-in 
period, participants randomized to placebo receive placebo. Following this 3-night run-in period, 
participants will receive the treatment to which they were randomized, i.e., 1 of the 3 different 
fixed-dose combinations of study treatment, or placebo. Dosing of the study treatment will occur 
approximately 30 minutes prior to bedtime. Participants who withdraw from the study will not be 
replaced.  
Study participants will undergo eligibility screening that will include an initial exam to 
determine whether non- PSG enrollment criteria are met, followed by a 1-night inpatient PSG 
test for participants who qualify based on non-PSG criteria. For participants who are eligible and 
enroll in the study, the screening PSG night will serve as the baseline measure for 
apnea-hypopnea index (AHI) and other PSG efficacy and safety endpoints. Baseline measures 
for additional secondary and tertiary endpoints based on home oximetry will be recorded at home 
during the placebo period, and these endpoint measures will continue to be collected over the 
subsequent at-home study treatment dosing period. On the final night of dosing, participants will 
return for inpatient PSG. The primary efficacy endpoint is the proportion of participants with 
≥50% reduction in AHI from screening/baseline to final day of treatment with study treatment 
(study Day 11±2). 
Participants will return 2 weeks after the last dose for an end of study (EOS) Visit. No 
subsequent open-label extension is planned following the study. 
Number of Participants: 
Approximately 140 participants will be randomized to study treatment in equal ratio (1:1:1:1), 
35 participants per arm, to 1 of 4 parallel treatment groups. 
Treatment Groups and Duration: 
There will be 4 parallel treatment groups, as follows: 


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Group
Atomoxetine/oxybutynin (mg) 
Subjects 
(n) 
1 
75/5 
35 
2 
75/1.5 
35 
3 
25/5 
35 
4 
Placebo 
35 
 
All participants will receive placebo for 2 days to establish baseline measures. Participants 
assigned to active treatment will subsequently receive low dose (25 mg atomoxetine/1.5 mg 
oxybutynin) for a 3-day dose-escalation period. Following the dose-escalation period, 
participants will receive the dose level to which they were randomized (75/5; 75/1.5; 25/5; 
placebo). Participants randomized to placebo will have a placebo run-in period. 
The overall study duration will be up to 8 weeks, as follows:  
 Up to 28 days for screening and baseline PSG; 
 2 nights of baseline placebo treatment, at home; 
 3 nights of low dose atomoxetine/oxybutynin, at home, for participants randomized to study 
treatment (participants randomized to placebo will receive placebo during this period); 
 7 (±2) nights of randomized study treatment; 6 nights at home, seventh night inpatient PSG; 
 Follow-up safety visit, 2 weeks post study treatment dosing (±2 days), or upon early 
withdrawal. 


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1.2 Schema 
Figure 1 
Study Design Schema 
 
 
Abbreviations: ATO = atomoxetine; EoS = end of study; OXY = oxybutynin; PSG = polysomnography.


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1.3 Schedule of Activities (SoA) 
Table 1 
Schedule of Activities 
Procedures 
Screening and Baseline 
PSG1 
 
Treatment Period 
Visit 5 
EOS2 
Notes 
Non-PSG 
Daytime 
Visit 1 
PSG night 
and next 
morning, 
Visit 2  
Blinded 
baseline 
placebo, 
at-home 
dosing 
Double-
blind study 
treatment, 
at-home 
Dosing 
Daytime 
Visit 3 
Visit 4 
PSG Visit 
Trial Day (Visit Window) 
-28 to -1 
-7 to -13 
1 to 24 
3 – 11 ± 25 
66 
12 ± 27 
26 ± 4 
 
Pre-screening 
X8 
 
 
 
 
 
 
Determination of basic 
eligibility for the study 
Informed consent9 
X 
 
 
 
 
 
 
 
Consent for genetic testing 
for CYP2D6  
X 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
STOP-Bang Questionnaire 
X 
 
 
 
 
 
 
Only used for participants 
without a history of 
diagnosis of OSA or CPAP 
use 
Physical exam  
X 
 
 
 
 
 
 
 
Medical and surgical 
history 
X 
 
 
 
 
 
 
Includes drug and substance 
usage and psychiatric 
history 
Blood sample for CYP2D6 
genotype 
X 
 
 
 
 
 
 
 
Serum pregnancy test 
(WOCBP only) 
X 
 
 
 
 
 
X 
 


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Urine drugs of abuse10 
testing, ethanol testing  
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Randomization takes place 
the morning after PSG 
testing for participants that 
qualify 
Medication distribution to 
participant, and study 
instructions and device 
 
X 
 
 
 
 
 
Prior to discharge morning 
after PSG 
QHS self-administration of 
baseline placebo  
 
 
X 
 
 
 
 
2 nights of QHS placebo, at 
home, all participants; 
administer ~30 minutes 
prior to bedtime 
International Prostate 
Symptom Scale 
X 
 
 
 
 
 
 
Male participants only 
QHS administration of 
randomized study treatment 
(combination drug or 
placebo) 
 
 
 
X 
 
X 
 
Total of 10 nights: 3 nights 
low dose (25 mg 
atomoxetine/ 1.5 mg 
oxybutynin) followed by 
7 nights randomized study 
treatment for participants 
randomized to active drug; 
10 nights placebo for 
participants randomized to 
placebo. 
“Reminder” telephone 
call/message 
 
 
 
X 
 
 
 
Day 10±2, participants 
reminded about study 
procedures and upcoming 
PSG visit11  
Clinical laboratory 
assessments (hematology, 
clinical chemistry and 
urinalysis) 
X 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
X 
 


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Vital signs12 
X 
 
 
 
X 
X 
X 
Visit 4 measure both pre-
dose and post-awakening 
from PSG 
AE/SAE monitoring 
X 
X 
X 
X 
X 
X 
X 
 
Study Instruction Reminder 
 
 
 
 
X 
 
 
 
Oximeter Battery Change 
 
 
 
 
X 
 
 
 
Prior/concomitant 
medication monitoring 
 
 
 
 
X 
X 
X 
 
Inpatient Polysomnography 
 
X 
 
 
 
X 
 
 
ESS 
X 
X 
 
 
 
X 
 
Measured at Visit 1 to 
determine eligibility and as 
efficacy outcome on PSG 
nights; measured evening 
of baseline PSG and Visit 4 
PSG
CSSA 
X 
 
 
 
 
X 
X13 
Item 17 of the CSSA is 
used to assess suicidality
Patient Global Impression-
Severity 
 
X 
 
 
 
X 
 
Measured evening of 
baseline PSG and Visit 4 
PSG 
Patient Global Satisfaction 
with Treatment 
 
 
 
 
 
 
X 
 
Home Oximetry  
 
 
X 
X 
 
 
 
Oximeter used all at-home 
dosing nights 
Delayed Word Recall Test  
 
X 
 
 
 
X 
 
Administer at similar time 
after awakening after each 
PSG  
DSST 
 
X 
 
 
 
X 
 
Administer at similar time 
after awakening after each 
PSG 


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Abbreviations: AE = adverse event; CPAP = continuous positive airway pressure; CSSA = Cocaine Selective Severity Assessment; CYP2D6 = cytochrome 
P450 2D6; DSST = Digit Symbol Substitution Test; ECG = electrocardiogram; EOS = end of study; ESS = Epworth Sleepiness Scale; HIV = human 
immunodeficiency virus; ICF = informed consent form; IRB = Institutional Review Board; IRT = Interactive Response Technology; OSA = obstructive sleep 
apnea; PSG = polysomnography; QHS = 1 dose taken at bedtime; SAE = serious adverse event; STOP-Bang = Snoring, Tiredness, Observed apnea, Blood 
Pressure-Body mass index, Age, Neck circumference and Gender criteria; WOCBP = women of childbearing potential. 
1 
Following pre-screening, participants who meet basic eligibility requirements will be screened during a visit that includes non- PSG evaluations. Participants 
who otherwise are eligible will be scheduled for an overnight PSG study. 
2 
If a participant discontinues from the study, all EOS procedures should be performed at the discontinuation visit, within 48 hours of the last study dose. 
3 
Final study eligibility is determined the morning after the PSG exam, based on PSG and non-PSG findings, and enrolled participants are randomized and 
dispensed the study drug. The first dose of study drug should generally be taken that night; however, at the discretion of the investigator, the first night of 
study treatment dosing can occur up to 1 week later to accommodate scheduling of the on-drug PSG exam. 
4 
Trial day includes overnight through morning completion of endpoints.  
5 
Daily bedtime dosing (qhs in the protocol synopsis) continues through Visit 4 PSG night, i.e., through PSG visit window; final night of study treatment 
dosing is PSG night. 
6 
Can occur as late as day as Day 7, if necessary for scheduling. 
7 
Preference is for PSG Visit 4 to be on Day 12, but, if necessary to fit individual participant scheduling, may be ± 2 days..  
8 
Conducted prior to screening/PSG admission; per IRB-approved pre-screening procedures. 
9 
No trial-related assessment is to be carried out before the participant has signed the ICF. Any participant who provides informed consent will have a 
screening number assigned by the IRT system. 
10 Includes amphetamine; barbiturates; benzodiazepines; buprenorphine/metabolite; cannabinoids, cocaine/metabolites; Methylenedioxymethamphetamine; 
methadone/metabolite; opiates;; phencyclidine; by enzyme-linked immunosorbent assay method; test sample is urine. 
11 Participants must return to PSG lab with study medication, pulse oximeter and study diary. 
12 Vital signs include the following: seated blood pressure, pulse, respiratory rate; AE collection refers to spontaneous AEs. Participants who experience 
systolic blood pressure ≥ 160, or diastolic blood pressure ≥ 100, or heart rate ≥ 120 beats per minute will be further evaluated. 
13 If there are any responses to individual items at EOS Visit that are more than 4 points worse than baseline exam, CSSA is repeated by telephone at 1 week 
post EOS Visit. 


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2 Introduction 
2.1 Study Rationale 
At the doses used in the initial human studies of the AD036 combination (atomoxetine 
80 mg/oxybutynin 5 mg) there was support for efficacy and safety in patients with OSA. This 
Phase 2 clinical study will further examine the efficacy and safety both similar and lower dose 
AD036 combinations versus placebo. Overall, the study is expected to provide dose selection 
guidance and a deeper understanding of repeat-dose safety and tolerability for the ongoing 
clinical development of this combination. 
2.2 Background 
2.2.1 
Obstructive Sleep Apnea 
The National Commission on Sleep Disorders Research identified sleep disorders as a major 
public health burden. OSA is the most common and serious of these sleep disorders and affects 
approximately 20 million people in the United States (US), with approximately 13% of men and 
6% of women affected (Peppard et al, 2013). OSA is characterized by repetitive collapse or 
‘obstruction’ of the pharyngeal airway during sleep, manifesting as repetitive episodes of 
hypopnea (i.e., shallow breathing) or apnea (i.e., paused breathing). These episodes of hypopnea 
or apnea may lead to arousal from sleep, sleep fragmentation, excessive daytime sleepiness, 
and/or neuropsychological impairment. 
Research has shown that a number of pathogenic factors, or traits, contribute to the development 
of OSA (Eckert et al, 2013; Wellman et al, 2011; Wellman et al, 2013;Younes, 2003). The most 
important factors are the presence of an anatomically small, collapsible upper airway and a loss 
of pharyngeal muscle tone or responsiveness during sleep. 
Long-term, OSA is associated with increased mortality and a number of adverse cardiovascular, 
neurocognitive, metabolic, and daytime functioning consequences (Somers et al, 1995; Nieto et al, 
2000; Brooks et al, 1997; Peppard et al, 2000; Hung et al, 1990; Wessendorf et al, 2000; Hoffstein, 1994; 
Shahar et al, 2001; Redline et al, 1997; Findley et al, 1988). 
2.2.2 
Unmet Medical Need 
Treatment for OSA changed little over the past 40 years, with the overwhelming majority of 
patients treated with positive airway pressure, the most common of which is continuous positive 
airway pressure (CPAP), provided by a machine that mechanically maintains an open airway. 
Other treatments, such as pharyngeal surgery, mandibular advancement devices, and implantable 


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nerve stimulators, were developed to address the anatomical predisposition to collapse; however, 
they have shown limited efficacy for niche populations. 
While CPAP and related therapies are effective in improving sleep characteristics and 
oxygenation, many, perhaps most, patients find these devices uncomfortable or intolerable, and 
most estimates indicate that fewer than 50% of patients prescribed CPAP use it more than 4 hours 
per night, if at all (Weaver and Sawyer, 2010). Efforts to develop pharmacologic therapies, such 
as antidepressants, stimulants, and hormonal agents, for the treatment of OSA have been ongoing 
for at least 20 years, with no success thus far. 
As many patients cannot use CPAP because they find it intolerable, this represents a significant 
health concern, as OSA is associated with numerous co-morbidities and increased mortality. 
Alternative options, such as drugs that activate the pharyngeal muscles are needed. 
2.2.3 
Biological Rationale 
AD036 is a new fixed dose drug combination of atomoxetine and oxybutynin being developed for 
OSA. Atomoxetine is a pre-synaptic norepinephrine reuptake inhibitor indicated for the treatment 
of attention deficit hyperactivity disorder in children and adults. Oxybutynin is an antispasmodic 
drug that inhibits the muscarinic action of acetylcholine on smooth muscle and is indicated for the 
treatment of symptoms of bladder instability associated with voiding in patients with uninhibited 
neurogenic or reflex neurogenic bladder such as urgency, frequency, urinary leakage, urge 
incontinence and dysuria.  
Efficacy of the combination of these 2 small molecules for the signs and symptoms of OSA has 
been previously evaluated in a small number of patients in National Institutes of Health-
supported studies in the academic setting. The pharmacokinetics (PK) of the atomoxetine and 
oxybutynin combination have recently been studied in a Phase 1 clinical program sponsored by 
Apnimed. New research in animals improved understanding of the state-dependent 
neurotransmitters involved in pharyngeal muscle activation during sleep, namely that both 
noradrenergic and antimuscarinic processes are involved. Specifically, the loss of noradrenergic 
activity is now thought to play a key role in the sleep-related hypotonia of pharyngeal muscles 
during non-rapid eye movement (NREM) sleep and muscarinic activity is involved in rapid eye 
movement (REM) atonia. 
Chan and colleagues (Chan et al, 2006) showed in rats that the noradrenergic antagonist terazosin 
substantially reduced genioglossus (a major muscle of the upper airway) activity (i.e., 
genioglossal electromyographic [EMGgg] activity) during wakefulness and produced REM-like 
atonia during NREM sleep, illustrating the importance of noradrenergic mechanisms. Other 


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studies (Lai et al, 2001; Fenik et al, 2005) also support the notion that progressive withdrawal of 
noradrenergic tone, from wakefulness to NREM and REM sleep, is the major mechanism causing 
sleep-related pharyngeal hypotonia. While noradrenergic withdrawal is thought to be the main 
cause of pharyngeal hypotonia in NREM sleep, there are additional mechanisms that cause 
further reduction during REM sleep. Chan and colleagues (Chan et al, 2006) failed to reverse 
REM atonia with alpha-1 receptor agonists applied to the hypoglossal nucleus, suggesting that 
another, possibly inhibitory, mechanism is at work. Horner and colleagues identified this 
inhibitory process as muscarinic by demonstrating restoration of EMGgg activity during REM 
sleep with the muscarinic antagonist scopolamine applied directly to the hypoglossal nucleus in 
rats (Grace et al, 2013; Grace et al, 2013). 
However, due to the only recent identification of these processes, until now there has not yet 
been an attempt to stimulate the pharyngeal muscles with both noradrenergic and antimuscarinic 
drugs in sleeping humans. Atomoxetine (a noradrenergic) and oxybutynin (an antimuscarinic) are 
2 drugs within these pharmacologic classes that have been Food and Drug Administration-
approved for over 16 years and 40 years, respectively, thereby having a long history of clinical 
use. Atomoxetine and oxybutynin as individual drugs have well-established PK, tolerability and 
safety profiles, but have not previously been studied in combination. 
 
 


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3 Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To assess the efficacy 
of 3 different fixed 
doses of AD036 (the 
combination of 
atomoxetine and 
oxybutynin) vs. 
placebo 
 
To evaluate safety and 
tolerability of the 
combination AD036 
 
Primary Efficacy Endpoint 
 
AHI, proportion of participants with ≥50% reduction, PSG nights, high-dose 
(atomoxetine 75 mg/oxybutynin 5 mg) arm vs. placebo 
Safety Endpoints  
 
Spontaneous adverse events, including the post-dosing period 
 
Physical exam and laboratory testing 
 
DSST 
 
Delayed Word Recall Test 
 
CSSA, Modified for study treatment 
 
Prospective Suicidality Assessment (item 17 “suicidality” of CSSA) 
 
PSG parameters: heart rate, ECG, EEG, oximetry 
 
Physical exam, vital signs, clinical laboratory assessment, ECG 
Secondary 
To assess the efficacy 
of 3 different fixed 
doses of AD036 vs. 
placebo 
Secondary Efficacy Endpoints 
High dose vs placebo, in order: 
 
Percent change AHI, high-dose arm vs. placebo 
 
AHI in supine position, proportion of participants with ≥50% reduction, PSG 
nights 
 
Oxygen desaturation index (number of desaturations/hour ≥4% below 
baseline), proportion of participants with ≥50% reduction, at-home nights 
 
ESS 
 
PGI-S, OSA, PSG nights 
 
AHI, proportion of participants with ≥50% reduction, PSG nights, high-dose 
(atomoxetine 75 mg/oxybutynin 5 mg) arm vs. each low dose arm 
(atomoxetine 75 mg /oxybutynin 1.5 mg, and atomoxetine 25 mg/ 
oxybutynin 5 mg).  
Tertiary/Exploratory
 
Unranked Efficacy Endpoints 
 
Proportion of participants with ≥50% AHI decrease and final AHI<15/hour, 
PSG nights 
 
Total time with SaO2 <90%, PSG nights 
 
Total time with SaO2 <80%, PSG nights 
 
Snoring index, PSG nights  
 
Sleep stages distribution and % of time in the various sleep stages, PSG 
nights 
 
Arousal index, PSG nights 
 
Oxygen desaturation index, low-dose run-in vs baseline, at home nights 
 
Proportion of apneas to hypopneas 
Abbreviations: AHI = apnea-hypopnea index; CSSA = Cocaine Selective Severity Assessment; DSST = Digit 
Symbol Substitution Test; ECG = electrocardiogram; EEG = electroencephalogram; ESS = Epworth Sleepiness 
Scale; OSA = obstructive sleep apnea; PGI-S = Participant Global Impression of Severity; PSG = 
polysomnography; SaO2 = oxygen saturation. 


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4 Study Design 
4.1 Overall Design 
This is a randomized, double blind, placebo-controlled, repeat-dose, parallel arm, outpatient and 
inpatient, multi-center, dose finding study of the combination of atomoxetine and oxybutynin in 
adults with OSA documented by PSG. Approximately 140 participants will be randomized 
equally to receive 1 of 3 different fixed-dose combinations of oxybutynin and atomoxetine, or 
matching placebo. For all participants, there is an initial 2-night at-home blinded baseline period 
in which placebo is dosed. Following this baseline placebo period, participants randomized to the 
3 study treatment arms receive 3 nights of a low-dose run-in of the combination, consisting of 
atomoxetine 25 mg/oxybutynin 1.5 mg. In contrast, during this 3-night run-in period, participants 
randomized to placebo receive placebo. Following this 3-night run-in period, participants will 
receive the treatment to which they were randomized, i.e., 1 of the 3 different fixed-dose 
combinations of drug, or placebo. Overall study duration will be up to 8-9 weeks. Dosing of the 
study treatment will occur approximately 30 minutes prior to bedtime. Participants who 
withdraw from the study will not be replaced.  
Study participants will undergo eligibility screening that will include an initial exam to 
determine whether non-PSG enrollment criteria are met, followed by a 1-night inpatient PSG test 
for participants who qualify based on non-PSG criteria. For participants who are eligible and 
enroll in the study, the screening PSG night will serve as the baseline measure for AHI and other 
PSG efficacy and safety endpoints. Baseline measures for additional secondary and tertiary 
endpoints based on home oximetry will be recorded at home during the placebo period, and these 
endpoint measures will continue to be collected over the subsequent at-home study treatment 
dosing period. On the final night of dosing, participants will return for inpatient PSG. The 
primary efficacy endpoint is the proportion of participants with ≥50% reduction in AHI from 
screening/baseline to final day of treatment with study treatment (study Day 12± 2). 
Participants will return 2 weeks after the last dose for an EOS Visit (Figure 2). No subsequent 
open-label extension is planned following the study. 


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Figure 2: 
Overview of Study Design 
 
Abbreviations: ATO = atomoxetine; EoS = end of study; OXY = oxybutynin; PSG = polysomnography. 
4.2 Scientific Rationale for Study Design 
At the doses used in the initial human studies of AD036 there was support for efficacy and safety 
in patients with OSA. This Phase 2 clinical study will further examine the efficacy and safety of 
lower dose AD036 versus placebo. Overall, the study is expected to provide dose selection 
guidance and a deeper understanding of repeat-dose safety and tolerability for the ongoing 
clinical development of this combination. 
4.3 Justification for Dose 
The high-dose AD036 in this study is atomoxetine 75 mg/ oxybutynin 5 mg, similar to the dose 
used in initial human studies (atomoxetine 80 mg/oxybutynin 5 mg). To explore the potential 
efficacy and safety of lower atomoxetine and oxybutynin doses, the following 2 additional dose 
arms will be studied: atomoxetine 75 mg/oxybutynin 1.5 mg and atomoxetine 25 mg/oxybutynin 
5 mg. 
Prescribing information for atomoxetine specifies at least 3 days of dose escalation prior to 
dosing >40 mg. This study incorporates a 3-day dose escalation period using atomoxetine 
25 mg/oxybutynin 1.5 mg for participants assigned to active drug in the randomized dosing 


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period. Participants assigned to placebo in the randomized dosing period will correspondingly be 
dosed with placebo in the 3-day dose escalation period. 
Prior to the dose escalation period all participants will be assigned to 2 days of placebo to 
establish baseline measures. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of AD036 is 
provided in the Investigator’s Brochure. 
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 final Follow-up visit or the last scheduled procedure shown in the Schedule of 
Activities (SoA). 
The end of the study is defined as the date of the last visit of the last participant in the study or last 
scheduled procedure shown in the SoA for the last participant in the study globally. 
 
 


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5 Study Population 
The study population will consist of male and female participants between 25 and 65 years of 
age, inclusive, with OSA documented by PSG. Participants must be able to provide written 
consent and meet all the inclusion criteria and none of the exclusion criteria. 
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 participants between 25 to 65 years of age or female participants between 25 to 70 
years of age, inclusive, at the Screening Visit. 
Type of Participant and Disease Characteristics 
2. Participants are eligible for screening PSG if any of the following: 
 Prior history of diagnosis of OSA of a severity for which CPAP is typically recommended 
(according to International Classification of Sleep Disorders, Version 3 criteria) at any time 
in the past (participant self-report acceptable if medical records unavailable); or, for 
participants without a prior diagnosis of OSA, participants are eligible for screening if the 
Snoring, Tiredness, Observed apnea, and Blood pressure (STOP), and Body mass index, 
Age, Neck circumference, and Gender (Bang) score is ≥5, or STOP ≥ 2 + body mass index 
(BMI) >35 kg/m2. 
 CPAP intolerance or poor compliance (compliance is defined as use of CPAP 4 hours per 
night for 70% of nights; per participant self-report); or CPAP-naïve. 
 Participants who had been using CPAP at least 4 hours nightly for at least 70% of the nights 
are eligible for further screening and baseline PSG for this study only if CPAP will not 
have been used for 1 month prior to the screening/baseline PSG for this study. 
3. AHI ≥ 20 on screening PSG, based on initial reading the night of Screening PSG1. 
                                                 
1 The assessment of the PSG technician at the time of PSG recording is used to determine PSG eligibility criteria 
including AHI, central apnea index, and periodic limb movement arousal index; for the purposes of study endpoint 
analysis, the results of the PSG centralized reading will be used. 


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4. Epworth Sleepiness Scale (ESS) score ≥ 4 for participants not using CPAP. 
5. Previous surgical treatment for OSA is allowed if ≥ 1 year prior to enrollment. 
6. If male, International Prostate Symptom Score (IPSS) must be less than 15. 
Weight 
7. BMI between 18.5 and 40.0 kg/m2, inclusive, at the pre-PSG visit. 
Male participants: 
8. If male and sexually active with female partner(s) of childbearing potential, participant 
must agree, from Study Day 1 through 1 week after the last dose of study drug, to practice 
the protocol specified contraception (see Appendix 4: Contraceptive Guidance and 
Collection of Pregnancy Information). 
Female participants: 
9. If a woman of childbearing potential (WOCBP), the participant must agree, from Study 
Day 1 through 1 week after the last dose of study drug, to practice the protocol specified 
contraception (See Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information). All WOCBP must have negative result of a serum pregnancy test performed 
at screening.  
10. If female and of non-childbearing potential, the participant must be either postmenopausal 
(defined as age ≥ 55 years with no menses for 12 or more months without an alternative 
medical cause) or permanently surgically sterile (bilateral oophorectomy, bilateral 
salpingectomy or hysterectomy).  
Informed Consent 
11. Participant voluntarily agrees to participate in this study and signs an Institutional Review 
Board (IRB)-approved informed consent prior to performing any of the Screening Visit 
procedures. 
12. Participant must be able to understand the nature of the study and must have the 
opportunity to have any questions answered. 
5.2 Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 


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1. History of narcolepsy. 
2. Clinically significant craniofacial malformation.  
3. Clinically significant cardiac disease (e.g., rhythm disturbances, coronary artery disease or 
cardiac failure) or hypertension requiring more than 2 medications for control.  
4. Clinically significant neurological disorder, including epilepsy/convulsions. 
5. History of schizophrenia, schizoaffective disorder or bipolar disorder according to 
Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) or International 
Classification of Disease tenth edition criteria. 
6. History of attempted suicide or suicidal ideation within 1 year prior to screening, or current 
suicidal ideation. 
7. History of clinically significant constipation, gastric retention, or urinary retention. 
8. Positive screen for drugs of abuse or substance use disorder as defined in DSM-V within 
24 months prior to Screening Visit. 
9. A significant illness or infection requiring medical treatment in the past 30 days. 
10. Clinically significant cognitive dysfunction. 
11. Untreated narrow angle glaucoma.  
12. Women who are pregnant or nursing. 
Prior/Concomitant Therapy 
13. History of using oral or nasal devices for the treatment of OSA may enroll as long as the 
devices are not used during participation in the study. 
14. History of using devices to affect participant sleeping position for the treatment of OSA, 
e.g. to discourage supine sleeping position, may enroll as long as the devices are not used 
during participation in the study. 
15. History of oxygen therapy. 
16. Use of medications from the list of disallowed concomitant medications. 
17. Treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors, strong 
cytochrome P450 2D6 (CYP2D6) inhibitors, or monoamine oxidase inhibitors (MAOI) 
within 14 days of the start of treatment, or concomitant with treatment. 


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Prior/Concurrent Clinical Study Experience 
18. Use of another investigational agent within 90 days or 5 half-lives, whichever is longer, 
prior to dosing.  
Diagnostic Assessments 
19. ESS total score > 18. 
20. Central apnea index > 5/hour on baseline PSG. 
21. Periodic limb movement arousal index >15/hour on baseline PSG. 
22. Hepatic transaminases >3X the upper limit of normal (ULN), total bilirubin >2X ULN 
(unless confirmed Gilbert syndrome), serum creatinine >2X ULN.  
Other Exclusions 
23. <6 hours typical sleep duration.  
24. Night- or shift-work sleep schedule.  
25. Employment as a commercial driver or operator of heavy or hazardous equipment. 
26. Smoking more than 10 cigarettes or 2 cigars per day. 
27. Unwilling to use specified contraception.  
28. Unwilling to limit alcohol consumption to no greater than 2 units/day or less, not to be 
consumed within 3 hours of bedtime. 
29. Unwilling to limit caffeinated beverage intake (e.g., coffee, cola, tea) to 400 mg/day or less 
of caffeine, not to be used within 3 hours of bedtime. 
30. Any condition that in the investigator’s opinion would present an unreasonable risk to the 
participant, or which would interfere with their participation in the study or confound study 
interpretation. 
31. Participant considered by the investigator, for any reason, an unsuitable candidate to 
receive AD036 or unable or unlikely to understand or comply with the dosing schedule or 
study evaluations. 


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5.3 Meals and Dietary Restrictions 
1. Participants should refrain from consumption of any nutrients known to modulate CYP 
enzyme activity (e.g., grapefruit or grapefruit juice, pomelo juice, star fruit, pomegranate, 
and Seville or Moro [blood] orange products) within 72 hours before the first 
administration of study drug, during the study, and until final discharge.  
2. Diet should be generally stable during the study, e.g., new diet programs should not be 
initiated. 
5.4 Caffeine, Alcohol, and Tobacco 
1. Participants should refrain from more than 2 units per day of alcohol, consumed no less 
than 3 hours prior to bedtime.  
2. Moderate consumption of caffeinated beverages, containing up to a total of 400 mg 
caffeine per day, is permitted, consumed no less than 3 hours prior to bedtime. 
5.5 Activity 
There are no restrictions on physical activity during the study other than that physical activity 
should be generally stable during the study (e.g., new exercise programs should not be initiated). 
5.6 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized to study treatment/entered into the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants that 
meets 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 events (SAEs). 
Individuals who do not meet the criteria for participation in this study (screen failure) will not be 
rescreened, except if the opportunity for rescreening has been enabled by protocol amendment. 
6 Study Treatment 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study 
protocol. 


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6.1 Study Treatment(s) Administered 
Two different blinded capsules are taken each night of drug treatment, as arranged in blister 
packaging. On placebo nights, 2 placebo tablets will be taken. On nights of randomized study 
treatment, 1 capsule of atomoxetine and 1 capsule of oxybutynin, or of corresponding placebo, 
are taken approximately 30 minutes before the participant’s planned bedtime. 
Study Treatment Name: 
Atomoxetine 
hydrochloride  
Oxybutynin chloride 
Dosage Formulation: 
Capsule 
Capsule 
Dosage Level: 
75 mg or 25 mg 
5 mg or 1.5 mg 
Route of Administration: 
Oral 
Oral 
Dosing Instructions: 
1 capsule will be 
administered daily with at 
least 20 mL water  
1 capsule will be 
administered daily with at 
least 20 mL water  
Storage/Packaging/Labeling: 
 
Store per package insert. 
Study treatment will be 
provided in blister 
packaging. Each blister 
package will be labeled as 
required per country 
requirement.  
Store per package insert. 
Study treatment will be 
provided in blister 
packaging. Each blister 
package will be labeled as 
required per country 
requirement. 
6.2 Preparation/Handling/Storage/Accountability 
1. The Investigator or designee must maintain a log to confirm appropriate temperature 
conditions have been maintained during transit for all study treatments received and any 
discrepancies are reported and resolved before use of the study treatment. 
2. Only participants enrolled in the study may receive study treatments and only authorized 
site staff may supply or administer study treatments. All study treatments 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. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). 
4. After receiving Sponsor approval in writing, PAREXEL is responsible for returning all 
unused or partially used study treatment to the Sponsor or designated third party or for 
preparing the study treatment for destruction via incineration. 


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6.3 Measures to Minimize Bias: Randomization and Blinding 
All participants will be centrally randomized using an Interactive Response Technology (IRT). 
Each participant will be assigned a unique number (randomization number) that encodes the 
participant’s assignment to 1 of the 4 arms of the study, according to the randomization schedule 
generated by the Sponsor (or designee) using a validated computer program. Details of the 
procedure are described in the IRT Manual provided to all sites. 
Study treatment will be dispensed the morning after PSG screening, as summarized in 
Section 1.3. 
Returned study treatment should not be redispensed to the participants. 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
Investigator has the sole responsibility for determining if unblinding of a participant’s study 
treatment 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 
study treatment assignment unless this could delay emergency treatment of the participant. If a 
participant’s study treatment 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 electronic case report form (eCRF), as applicable. 
Participants will be randomly assigned in a 1:1:1:1 equal allocation ratio to receive 1 of 3 
different study treatment doses or placebo, using permuted blocked randomization. Investigators 
will remain blinded to each participant’s assigned study treatment throughout the study. 
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study treatment records at the site(s) to verify that randomization/dispensing has been done 
accurately. 
6.4 Study Treatment Compliance 
Participants will be required to return any unused study treatment capsules at Visit 4. Unused 
capsules will be counted and recorded by study personnel to assess study treatment compliance.  
6.5 Concomitant Therapy 
Concomitant therapy with the following medications is disallowed: 


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 MAOIs or other drugs that affect monoamine concentrations (e.g., rasagiline) [MAOIs are 
contraindicated for use with atomoxetine] 
 Selective Serotonin Reuptake Inhibitors (e.g., paroxetine) 
 Selective Norepinephrine Reuptake Inhibitors (e.g., duloxetine) 
 Norepinephrine Reuptake Inhibitors (e.g., reboxetine) 
 Alpha-1 antagonists (e.g., tamsulosin) 
 Tricyclic antidepressants (e.g., desipramine) 
 CYP2D6 inhibitors  
 Strong CYP3A4 inhibitors (e.g., ketoconazole) 
 Benzodiazepines and other anxiolytics 
 Opioids 
 Sedatives other than nonbenzodiazepine “Z-drugs” (zolpidem, zaleplon, eszopiclone) 
 Muscle relaxants  
 Pressor agents 
 Drugs with clinically significant cardiac QT-interval prolonging effects 
 Drugs known to lower seizure threshold (e.g., chloroquine) 
 Amphetamines 
 Antiepileptics  
 Antiemetics 
 Modafinil or armodafinil 
 Beta2 agonists, (e.g., albuterol) 
 Antipsychotics 
 Anticholinergics and anticholinesterase inhibitors, including drugs with substantial 
anticholinergic side effects, (e.g., first generation antihistamines) 
 Sedating antihistamines 
 Pseudoephedrine, phenylephrine, oxymetazoline 
 Nicotine replacement products 


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 Most drugs for Parkinson’s, Alzheimer’s, Huntington’s, Amyotrophic Lateral Sclerosis, or 
drugs for other neurodegenerative diseases 
Medications that do not have substantial effects on the central nervous system (CNS), 
respiration, or muscle activity are generally allowed if dose and frequency is stable for 3 months 
prior to enrollment and during the course of the study, including, but not necessarily limited to, 
the following drugs and drug classes: 
 Antihypertensives (angiotensin-converting-enzyme/angiotensin II receptor blocker inhibitors, 
calcium channel blockers, spironolactone, hydrochlorothiazide, etc.) 
 Statins 
 Proton pump inhibitors and histamine h2 receptor blockers 
 Over-the-counter (OTC) antacids 
 Non-sedating antihistamines (e.g., cetirizine, loratadine) 
 Eszopiclone, zolpidem, or zaleplon 
 Melatonin 
 Non-steroidal anti-inflammatory drugs and acetaminophen 
 Laxatives 
 Erectile dysfunction drugs 
 Inhaled corticosteroids (e.g., fluticasone) 
 Antidiabetics 
 Ocular hypotensives and other ophthalmics (e.g., timolol) 
 Hormonal therapy (e.g., estrogen replacement or anti-estrogens) and hormonal contraceptives 
 Thyroid medications 
 Anticoagulants 
 OTC topicals (e.g., topical pain relievers) 
 Osteoporosis drugs 
6.6 Dose Modification 
Through protocol amendment, planned doses may be decreased on an individual or group basis 
according to emerging safety and tolerability data. 


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6.7 Treatment After the End of the Study 
Not applicable. No subsequent open-label extension is planned following the study. 
Study treatment will not be available after the end of study participation. 
7 Discontinuation of Study Treatment and Participant Discontinuation 
Refer to the SoA for data that are to be collected at the time of study discontinuation, during 
follow-up, and for any further evaluations that need to be completed. 
7.1 Discontinuation of Study Treatment 
If a clinically significant finding is identified, the Investigator or qualified designee will 
determine if the participant can continue in the study and if any change in participant 
management is needed. Any new clinically relevant finding should be reported as an adverse 
event (AE). 
7.2 Stopping Criteria 
7.2.1 
Individual Participant Stopping Criteria 
 Incidents of abuse, diversion, or misuse of the study treatment. 
 Incidents of clinical significance: hallucinations, amnesia, delusional thinking, delirium, 
manic symptoms, aggressive behavior, suicidality, homicidality, agitation, confusion, or 
convulsions/seizures. 
 Participants reporting any SAE. 
 Acute urinary obstruction. 
 Any other AE that in the judgment of the Investigator necessitates the participant stopping to 
protect participant safety. 
Participants discontinued from dosing will undergo end of study procedures with follow-up 
monitoring of the AE(s) as clinically indicated. 
7.3 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 
administrative reasons. 


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 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. 
 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. 
 All participants who withdraw from the study with an ongoing AE must be followed until the 
event is resolved or deemed stable. 
 Participation may be terminated before completing the study and the reason recorded as 
follows: 
o Withdrawal due to AE 
o Withdrawal due to incident abuse, diversion, or misuse of the study treatment 
o Loss to follow-up 
o Participant withdrew consent at own request 
o Other 
7.4 Loss of Participants 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 within the visit window, where one is defined) 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. 
 In cases in which the 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/eCRF. 
 Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8 Study Assessments and Procedures 
 Study procedures and their timing are summarized in the SoA. 


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 As protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns, these should be discussed with the Sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study treatment. 
 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 will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
 The maximum amount of blood collected from each participant over the duration of the 
study, excluding any extra assessments that may be required for safety or technical issues, 
will not exceed around 50 mL. 
 Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples, as per the Investigator or designee’s discretion. 
8.1 Efficacy Assessments 
The Study Reference Manual provides detailed information for the various scales discussed in 
Section 8.1.1 through Section 8.1.6. 
8.1.1 
Efficacy Endpoint Scales 
 The ESS is a self-administered questionnaire with 8 questions. Respondents are asked to rate, 
on a 4-point scale (0-3), their usual chances of dozing off or falling asleep while engaged in 8 
different activities in recent times. The ESS score (the sum of 8 item scores, 0-3) can range 
from 0 to 24. The higher the ESS score, the higher that person’s average sleep propensity in 
daily life, or their ‘daytime sleepiness’. The questionnaire takes approximately 2 or 3 minutes 
to answer. The ESS is asked during screening as an enrollment criterion. The ESS is also 
used as a study efficacy outcome. The ESS is administered the day of the non-PSG screening 
and approximately the same time of day prior to PSG recordings. 


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 The Participant Global Impression of Severity (PGI-S) is a global index that may be used to 
rate the severity of a specific condition, (i.e., it is a single-state scale). The scale consists of a 
1-item questionnaire designed to assess the participant’s impression of disease severity. The 
scale is considered to have clinical relevance for the participant because it allows participants 
to respond based on factors that they judge to be the most important in their health status. 
The PGI-S is administered at the baseline/screening PSG Visit 2 and at PSG Visit 4. The 
PGI-S is administered at approximately the same time prior to each PSG recording. 
 The Participant Global Satisfaction with Treatment scale consists of a 1-item questionnaire 
designed to assess the participant’s satisfaction with the experimental treatment, considering 
both safety and efficacy. The scale is administered at the end of the study, at the EOS Visit. 
8.1.2 
Safety and Abuse Liability Scale 
 The Cocaine Selective Severity Assessment (CSSA) was designed to measure cocaine 
withdrawal signs and symptoms during detoxification, and includes psychiatric symptoms of 
general safety interest such as changes in sleep, anxiety, energy level, activity level, tension, 
attention, paranoid ideation, anhedonia, depression, suicidality, and irritability. The CSSA 
will be used in this study to identify psychiatric issues and to characterize the potential of the 
atomoxetine/oxybutynin combination to elicit withdrawal symptoms similar to those elicited 
by cocaine withdrawal. A modified version of the assessment will be used in this study to 
measure potential withdrawal signs and symptoms from the study treatment; “cocaine” will 
be replaced with “study drug”. The scale is administered by clinical staff. A score of ≥3 on 
Item 17, or Investigator judgment that the patient is suicidal, will initiate further clinical 
evaluation and appropriate measures to protect participant safety. (Note: Questions 4 and 5 of 
the CSSA will not be asked at baseline). 
8.1.3 
Functional Endpoints 
 The Digit Symbol Substitution Test (DSST) is a paper-and-pencil cognitive and psychomotor 
test that requires patients to identify and copy symbols that are matched to numbers 
according to an instruction key located at the top of the page. The DSST is commonly used to 
screen for impairment related to pharmaceuticals and is also sensitive to sleep restriction. The 
DSST is administered the morning after the inpatient PSG nights,  at approximately the same 
time after awaking from each PSG. 


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 The Delayed Word Recall Test (DWRT) is a brief and efficient test of verbal learning and 
recent memory. The DWRT is administered the morning after the screening/baseline PSG 
(Visit 2) and in the morning after PSG Visit 4. The DWRT is administered at approximately 
the same time after awaking from each PSG. 
8.1.4 
Screening/Eligibility Scales 
 The IPSS is typically used to diagnose benign prostatic hyperplasia and to monitor disease 
progression and response to therapy. The participant is asked to choose the rating that best 
represents their condition. The scale ranges from 1 to 5, with 5 representing the most 
symptomatic disease and giving an overall maximum possible score of 35. The IPSS is 
administered to males as an enrollment criterion. 
 The STOP-Bang questionnaire has been developed and validated as a screening tool for 
OSA. The STOP-Bang questionnaire is used in the study only for participants who do not 
have a previous diagnosis of OSA or use of CPAP, to determine whether there is a high 
enough pre-test probability of moderate to severe OSA to conduct enrollment screening. The 
standard STOP-Bang scoring used in the sleep clinic has only moderate specificity. For the 
purposes of this study, scoring with higher specificity is used (STOP-Bang score ≥5, or STOP 
≥ 2 + BMI >35 kg/m2) to decrease screening participants who are unlikely to meet 
enrollment criteria. 
8.1.5 
Polysomnography 
 Methods: Standard overnight PSG recording and data interpretation will be performed in 
accordance with the American Academy of Sleep Medicine (AASM) scoring manual. 
Participants will be instrumented with standard PSG electrodes. Time of lights out will be 
established according to the participants’ habitual schedule and kept constant across the PSG 
study nights. The participants will be given 8 hours of time-in bed. 
 Technically Adequate Test: The screening/baseline PSG study must meet the following 
criteria for participants to enroll: 
o At least 4 hours of sleep. 
o At least 2 electroencephalograms (EEGs) and 2 electrooculography traces for 
the full night. 
o P nasal for at least 60% of the night and thermistor or both respiratory belts 
signals for the full night for scoring respiratory events. 


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o At least 30% of sleep in supine position.  
Participants who do not have a technically adequate test at baseline can be retested at the 
discretion of the investigator. 
 Scoring: For uses other than study enrollment, all studies will be scored by centralized PSG 
technologists, blinded to treatment assignment. Baseline and on-treatment PSGs for each 
individual participant will be scored by the same technologist. Scoring will be conducted 
according to the American Academy of Sleep Medicine manual scoring criteria. 
8.1.6 
Home Oximetry 
 Participants will be instructed on the at-home use of oximetry at Visit 2 and will be provided 
with an oximeter that is capable of nightly recording and storage of data for the entire at-
home period (study Days 1-11). Participant use of oximeter will be reinforced during the 
study visit on Day 6 (Visit 3), and through a reminder telephone contact on Day 10. The 
study personnel will replace the batteries in the oximeter during the Day 6 study visit. The 
number per hour of oxygen desaturations ≥ 4% will be compared between the average of the 
baseline nights and the average of the randomized study treatment nights. 
8.2 Safety Assessments 
 Planned time points for all safety assessments are provided in the SoA. 
 Safety monitoring will be guided by the established safety profiles of atomoxetine and 
oxybutynin, and by Phase 1 safety data for the combination. Safety assessments will include 
physical examinations, measurement of vital signs, monitoring and recording of AEs, SAEs, 
and pregnancies, suicidality assessment, recording of study or treatment discontinuations, 
measurement of ECGs, clinical laboratory evaluations, and memory testing. Effects on OSA 
and sleep parameters (e.g., sleep time and sleep stages) will also be monitored by PSG. 
 Adverse events of special interest include effects on urine outflow, as both atomoxetine and 
oxybutynin are associated with urinary retention. Effects of atomoxetine on heart rate and 
blood pressure are expected to be modest, as indicated by the initial data described above, 
and will also be monitored. Participants with serious cardiac abnormalities will be excluded 
from the study. Suicidal ideation in children and adolescents is a boxed warning for 
atomoxetine; however, analysis in adult patients, the target population for the proposed OSA 
study, did not reveal an increased risk of suicidal ideation or behavior in association with 
atomoxetine. Safety monitoring in the dose-finding study will use an appropriate 
questionnaire to monitor for the potential emergence of suicidal ideation or behavior. 


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 Daytime sleepiness is both a potential safety outcome and efficacy outcome in OSA. Both 
atomoxetine and oxybutynin are associated with somnolence, and oxybutynin is additionally 
associated with anticholinergic CNS effects such as memory difficulty. Safety monitoring 
will therefore include psychomotor vigilance testing and memory testing.  
8.2.1 
Physical Examinations 
 Physical examinations at screening/baseline include anthropomorphic data relevant to OSA: 
neck circumference at superior border of cricothyroid cartilage; waist circumference at 
highest point of iliac crest; evaluation of the oropharynx, hypopharynx, and facial skeletal 
structure; Mallampati score; tonsils evaluation (0-3+); presence of micrognathia; nasal 
patency.  
 The general physical examination at screening/baseline includes an assessment of general 
appearance and a review of physical systems (dermatologic, head, eyes, ears, nose, 
mouth/throat/neck, thyroid, lymph nodes, respiratory, cardiovascular, gastrointestinal, 
extremities, musculoskeletal, neurologic, and psychiatric systems). Height and weight will 
also be measured and recorded (with shoes removed and wearing light indoor clothing). 
 Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2 
Vital Signs 
 Assessment of vital signs (seated blood pressure, pulse rate, body temperature, respiratory 
rate) will be performed at the time points indicated in the SoA (Section 1.3).  
 Vital signs will be measured at all visits in a seated position after 5 minutes rest and will 
include temperature, respiratory rate, systolic and diastolic blood pressure, and pulse. 
Measurements should be made in the same arm of the participant at each visit. 
 Systolic and diastolic blood pressure will be repeated for a total of 3 measurements, each at 
least 2 minutes apart. 
 The method used to measure body temperature at screening should be maintained throughout 
the study for each participant, and should be indicated (e.g., ear, mouth, armpit). 


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8.2.3 
Electrocardiograms 
 A 12-lead ECG will be obtained using an ECG machine that automatically calculates the 
heart rate and measures the PR, QRS, and QT intervals, and the corrected QT-interval (QTc). 
The ECG will be recorded in the semi-supine position after the participant has rested in this 
position for at least 10 minutes. 
8.2.4 
Clinical Safety Laboratory Assessments 
 Refer to Appendix 10.2 (Section 10.2) for the list of clinical laboratory tests to be performed 
and to the SoA for the timing and frequency. 
 The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically relevant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the Investigator to be more severe than expected for the participant's condition. 
 All laboratory tests with values considered clinically significant during participation in the 
study should be repeated until the values return to normal or baseline. If such values do not 
return to normal/baseline within a period of time judged reasonable by the Investigator, the 
etiology should be identified, where possible, and the Sponsor notified. 
 All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must 
be conducted in accordance with the laboratory manual and the SoA. 
 If laboratory values from laboratory assessments not specified in the protocol and performed 
at the institution’s local laboratory result in the need for a change in participant management 
or are considered clinically relevant by the Investigator (e.g., are considered to be an SAE or 
an AE or require dose modification), then the results must be recorded in the eCRF. 
8.2.5 
Suicide Risk Monitoring 
Atomoxetine and oxybutynin are CNS-active drugs. There has been concern that some 
CNS-active drugs may be associated with an increased risk of suicidal ideation or behavior when 
given to participants with certain conditions or baseline characteristics. Although this study 
treatment or other similar drugs in this class have not been shown to be associated with an 
increased risk of suicidal thinking or behavior when given to adults, it is important to monitor for 
such events during this clinical study. 


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Suicidal ideation in children and adolescents is a boxed warning for atomoxetine; however, 
analysis in adult participants, the target population for the proposed OSA study, did not reveal an 
increased risk of suicidal ideation or behavior in association with atomoxetine. 
The CSSA item 17, “suicidality”, will be used to monitor participants for suicidality during the 
study (whether or not abuse-related). A score of ≥3 will be considered an AE and will initiate 
further clinical evaluation and appropriate measures to protect participant safety. Participants 
should be monitored appropriately and observed closely for suicidal ideation and behavior or any 
other unusual changes in behavior. Consideration should be given to discontinuing participants 
who experience signs of suicidal ideation or behavior. Families and caregivers of participants 
should be instructed to monitor participants for the emergence of unusual changes in behavior, as 
well as the emergence of suicidal ideation and behavior, and to report such symptoms 
immediately to the study Investigator. 
8.3 Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Appendix 3. 
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 
reporting events that meet the definition of an AE or SAE and remain responsible for following 
up on AEs that are serious, considered related to the study treatment or the study, or that caused 
the participant to discontinue the study and/or study treatment (see Section 7). 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of informed consent form (ICF) until 
Visit 5/EOS at the timepoints specified in the SoA (Section 1.3). 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 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 AEs or SAEs after the conclusion of 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 


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related to the study treatment or study participation, the Investigator must promptly notify the 
Sponsor. 
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 3. 
8.3.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrence. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, until the 
event is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.4). 
Further information on follow-up procedures is given in Appendix 3. 
8.3.4 
Regulatory Reporting Requirements for SAEs 
 Prompt notification (within 24 hours, see Appendix 3) 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 treatment 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 treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/Independent Ethics Committees (IEC), and 
Investigators. 
 Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
 An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAE) from the Sponsor will file it 
along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according 
to local requirements. 


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8.3.5 
Pregnancy 
 Details of all pregnancies in female participants and female partners of male participants 
after the start of study treatment and until at least 5 terminal half-lives after the last dose will 
be collected.  
 If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4. 
 Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered to be SAEs. 
If a female partner of a male study participant who has been exposed to the study treatment 
becomes pregnant, the pregnancy and outcome of pregnancy should be monitored. 
8.4 Treatment of Overdose 
For this study, any dose of atomoxetine greater than 75 mg and of oxybutynin greater than 5 mg 
more frequently than QHS will be considered an overdose. 
In the event of an overdose, the Investigator should refer to the approved product label for advice 
on overdose and: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until atomoxetine 
hydrochloride and/or oxybutynin chloride can no longer be detected systemically. 
3. Obtain a plasma sample for PK analysis within 1 day from the date of the last dose of study 
treatment if requested by the Medical Monitor (determined on a case by case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5 Pharmacokinetics 
PK parameters are not evaluated in this study. 


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8.6 Genetics 
A genetic sample will be taken during Treatment Period 1 only, on the screening/baseline visit 
(prior to randomization) to test for CYP2D6 poor metabolizers. 
9 Statistical Considerations 
9.1 Statistical Hypotheses 
The null hypothesis is no change in the proportion of participants with ≥50% improvement in 
AHI from baseline to the second PSG visit (Visit 4) in the 75 mg/5 mg dose group compared 
with placebo. 
9.2 Sample Size Determination 
The effect of the drug combination in OSA has been investigated in preliminary academic studies 
that provide an estimate of effect size in a population similar to the planned Phase 2 study 
population. Data from a single-night cross-over study showed that a high proportion of 
participants, 8/9 (88.9%), with demographic characteristics matched to the planned enrollment 
criterion of the planned Phase 2 study (baseline AHI ≥20, BMI between 18.5 and 40 kg/m2, and 
age from 25 to 65 years) when treated with a combination of 80 mg atomoxetine and 5 mg 
oxybutynin achieved a clinically relevant threshold of at least a 50% improvement in AHI score. 
Using a proposed sample size of n=35 for each of the 4 treatment groups, given 90% power and 
2-sided alpha of 0.05, the sample size is powered to detect a difference in proportion of 
responders between the high-dose group and placebo, assuming a response rate as low as 37% in 
the high-dose group (compared with the preliminary data that suggests response rate may be as 
high as 90%) and 5% in the placebo group, estimated based on typical test-retest variability of 
PSG. Alternatively, if test-retest variability of PSG is higher, resulting in a higher placebo 
response rate of 10%, the study retains 90% power assuming a response rate in the high-dose 
group of 46%. Participants that discontinue prior to the second PSG visit will not be replaced, 
and will be considered non-responders. 
9.3 Populations for Analyses 
For the purposes of analysis, the following analysis sets are defined: 


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Population 
Description 
Enrolled 
All participants who signed the ICF (including screening 
failures). 
Modified Intent to Treat 
(mITT) Population 
The mITT Population comprises all participants who are 
randomized, take at least 1 dose of any of the study treatments, 
and have at least 1 measurement on the primary endpoint. 
Participants will be analyzed for efficacy according to the 
treatment group into which they are randomized. 
Safety Population 
The Safety Population consists of all participants who are 
randomized and receive at least 1 dose of any of the study 
treatments. Participants will be analyzed for safety based on the 
treatment received. A precise definition of “as actually received” 
will be added in the Statistical Analysis Plan (SAP). 
Per Protocol (PP) 
Population 
The PP Population consists of all participants without any major 
protocol violations that could influence efficacy assessment, and 
who are at least 80% compliant with the study medication. 
Participants in this population will be analyzed according to the 
treatment they actually received. 
The primary endpoint comparison between the high dose (75/5) and placebo will consider all 
mITT participants randomized to those 2 groups; participants not returning for their second PSG 
night will be considered treatment non-responders. 
9.4 Primary and Secondary Analyses 
The SAP will be developed and finalized prior to database lock. Below is a summary of planned 
statistical analyses of the primary and secondary endpoints. Further details are presented in the 
SAP. 
Hypothesis tests will be performed in a sequential manner to avoid the need to adjust type I error 
rates for multiplicity, at a 2-sided 0.05 significance level. The sequential order of hypothesis tests 
will occur as follows: 
 Comparison of the proportion of participants with ≥50% improvement in AHI from baseline 
to the second PSG visit in the 75/5 dose group compared with placebo. 
 Percent change AHI, high-dose arm vs. placebo. 


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 Proportion of participants with ≥50% improvement in AHI, measured in the supine sleeping 
position, from baseline to the second PSG visit in the 75/5 dose group compared with 
placebo. OSA is often more severe in the supine sleeping position, and variability in time 
spent in the supine position between baseline and during on-drug PSG tests can otherwise 
introduce variability. 
 Proportion of participants with ≥50% improvement in Oxygen desaturation index from 
baseline (average of 2 baseline nights) to study treatment nights (average of 6 nights) for the 
75/5 dose group compared with placebo.  
 Change from baseline in the ESS from baseline to the second PSG visit in the 75/5 dose 
group compared with placebo.  
 Change from baseline in the PGI-S from baseline to the second PSG visit in the 75/5 dose 
group compared with placebo.  
 Proportion of participants with ≥50% improvement in AHI from baseline to the second PSG 
visit in the 75/5 dose group compared with the lower treatment dose of 25/5. 
 In the case that a statistically significant result for the AHI comparison of dose 75/5 to 25/5 is 
observed, then the proportion of participants with ≥50% improvement in AHI from baseline 
to the second PSG visit in the 75/5 dose group compared with the lower treatment dose of 
75/1.5.  
9.5 Interim Analyses 
No formal interim analysis is planned. 
10 Supporting Documentation and Operational Considerations 
10.1 Appendix 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: 
 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 Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 


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 Applicable laws and regulations. 
 The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (e.g., 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 IEC/IRB approval before implementation of 
changes made to the study design, 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 SAE or other significant safety findings as required by 
IRB/IEC procedures. 
 Overall conduct of the study at the site and adherence to requirements of 21 Code of 
Federal Regulations (CFR), ICH GCP guidelines, the IRB/IEC guidelines, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations. 
10.1.2 Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations 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. 
10.1.3 Informed Consent Process 
 The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative 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, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center. 


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 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 re-consented to the most current version of the ICF(s) during their 
participation in the study. 
 A copy of the signed ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the 
protocol. If the ICF is revised, it must be reviewed and approved by the appropriate IEC/IRB, 
and signed by all participants subsequently enrolled in the study as well as those currently 
enrolled in the study. 
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. 
 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 Dissemination of Clinical Study Data 
When the clinical study report is completed, the Sponsor will provide the major findings of the 
study to the Investigator. A summary of the study results will also be posted in a publicly 
accessible database (e.g., www.ClinTrials.gov). The results may also be submitted for 
publication.  


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10.1.6 Data Quality Assurance 
 All participant data relating to the study will be recorded on printed or eCRFs unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The Investigator 
is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF. 
 The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
 The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
 The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
 Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
 Records and documents, including signed ICF, pertaining to the conduct of this study must be 
retained by the Investigator for 5 years after study completion 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. 
 All data generated by the site personnel will be captured electronically at each study center 
using eCRFs. Data from external sources (such as laboratory data) will be imported into the 
database. Once the eCRF clinical data have been submitted to the central server at the 
independent data center, corrections to the data fields will be captured in an audit trail. The 
reason for change, the name of the person who performed the change, together with the time 
and date will be logged to provide an audit trail. 
 If additional corrections are needed, the responsible monitor or data manager will raise a 
query in the electronic data capture (EDC) application. The appropriate staff at the study site 
will answer queries sent to the Investigator. The name of the staff member responding to the 
query, and time and date stamp will be captured to provide an audit trail. Once all source data 
verification is complete and all queries are closed, the monitor will lock the database. 


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 The specific procedures to be used for data entry and query resolution using the EDC 
system/eCRF will be provided to study sites in a training manual. In addition, site personnel 
will receive training on the EDC system/eCRF. 
10.1.7 Source Documents 
 Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
 Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request 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 Section 10.1.11.1. 
10.1.8 Study and Site Closure 
The Sponsor 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: 
 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 recruitment of participants by the Investigator. 
 Discontinuation of further study treatment development. 


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10.1.9 Publication Policy 
 The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows the Sponsor to protect proprietary information and to provide 
comments. 
 The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In this 
case, a coordinating Investigator will be designated by mutual agreement. 
 Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
10.1.10 Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IEC/IRB/Competent Authorities, in accordance with local legal requirements. The 
Sponsor must ensure that all ethical and legal requirements have been met before the first 
participant is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/IEC/Competent Authority 
approval prior to implementation (if appropriate). Following approval, the protocol 
amendment(s) will be submitted to the US Investigational New Drug (IND) under which the 
study is being conducted. 
Administrative changes (not affecting the participant benefit/risk ratio) may be made without the 
need for a formal amendment. All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
10.1.11 Liability and Insurance 
The Sponsor will take out reasonable third-party liability insurance cover in accordance with all 
local legal requirements. The civil liability of the Investigator, the persons instructed by him or 
her and the hospital, practice, or institute in which they are employed and the liability of the 
Sponsor with respect to financial loss due to personal injury and other damage that may arise as a 
result of the carrying out of this study are governed by the applicable law. 


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The Sponsor will arrange for participants participating in this study to be insured against 
financial loss due to personal injury caused by the pharmaceutical products being tested or by 
medical steps taken in the course of the study. 
10.1.11.1 Access to Source Data 
During the study, a monitor will make site visits to review protocol compliance, compare 
EDC/eCRF entries and individual participant’s medical records, assess drug accountability, and 
ensure that the study is being conducted according to pertinent regulatory requirements. The 
EDC/eCRF entries will be verified with source documentation. The review of medical records 
will be performed in a manner to ensure that participant confidentiality is maintained. 
Checking of the EDC/eCRF entries for completeness and clarity, and cross-checking with source 
documents, will be required to monitor the progress of the study. Moreover, regulatory 
authorities of certain countries, IRBs, IECs, and/or the Sponsor’s Clinical Quality Assurance 
Group may wish to carry out such source data checks and/or on-site audit inspections. Direct 
access to source data will be required for these inspections and audits; they will be carried out 
giving due consideration to data protection and medical confidentiality. The Investigator assures 
PAREXEL and the Sponsor of the necessary support at all times. 
10.2 Appendix 2: Clinical Laboratory Tests 
 The tests detailed in Table 2 will be performed by the central laboratory. 
 Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
 Laboratory testing is performed non-fasting. 
 Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations. 


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Table 2: Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Hematocrit 
Hemoglobin 
Platelet Count 
RBC Count 
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with Differential: 
Basophils 
Eosinophils 
Lymphocytes 
Neutrophils 
Monocytes 
Serum Chemistry Albumin 
BUN 
Creatinine 
Potassium 
Sodium  
Total and direct 
bilirubin 
Total Protein  
Uric acid 
ALT 
AST 
Alkaline phosphatase 
Calcium 
γGTP 
Glucose  
Total cholesterol 
Chloride 
Bicarbonate 
Routine 
Urinalysis 
Specific gravity 
pH, protein (albumin), glucose, ketones, blood (RBC), WBC by dipstick 
Microscopic examination (if blood or protein is abnormal) 
Other Tests 
 HbA1c (Screening Visit only) 
 CYP2D6 genotype 
 Serum hCG pregnancy test at screening and urine hCG tests at baseline. 
Additional testing may be performed if needed in WOCBP. 
 Alcohol and drugs of abuse screening 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
CYP2D6 = cytochrome P450 2D6; γ-GTP = gamma guanosine-5’-triphosphate; HbA1c = hemoglobin A1c 
(glycated hemoglobin); hCG = human chorionic gonadotropin; MCH = mean corpuscular hemoglobin; MCV = 
mean corpuscular volume; RBC = red blood cell count; WBC= white blood cell; WOCBP = women of 
childbearing potential. 
Investigators must document their review of each laboratory safety report. 


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10.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
 An AE is any untoward medical occurrence in a participant or clinical study 
participant, temporally associated with the use of a study treatment, whether or not 
considered related to the medicinal product. 
 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 a study treatment. 
 
Events Meeting the AE Definition  
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the Investigator (i.e., not related to progression of 
underlying disease). 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
 "Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as an AE or SAE if they fulfill the definition of an 
AE or SAE. 
 


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Events NOT Meeting the AE Definition  
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
Results in death 
Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 


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Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
Results in persistent disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Other situations 
 Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical treatment to prevent one 
of the other outcomes listed in the above definition. These events should usually be 
considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 


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Recording and Follow-up of AE and SAE 
AE and SAE Recording 
 When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
 The Investigator will then record all relevant AE/SAE information in the eCRF. 
 It is not acceptable for the Investigator to send photocopies of the participant’s 
medical records in lieu of completion of the AE/SAE eCRF page. 
 There may be instances when copies of medical records for certain cases are 
requested by the PAREXEL Clinical Studies Safety Center. In this case, all 
participant identifiers, with the exception of the participant number, will be blinded 
on the copies of the medical records before submission to the PAREXEL Clinical 
Studies Safety Center. 
 The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to one of the following categories: 
 Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities. 
 Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
 Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
 


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Assessment of Causality 
 The Investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE. 
 A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
 The Investigator will use clinical judgment to determine the relationship. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
 The Investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
 For each AE/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report to the Clinical Studies Safety 
Center. However, it is very important that the Investigator always make an 
assessment of causality for every event before the initial transmission of the SAE 
data to the PAREXEL Clinical Studies Safety Center. 
 The Investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AE and SAE 
 The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 
PAREXEL Clinical Studies Safety Center to elucidate the nature and/or causality of 
the AE or SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals. 


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 If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide PAREXEL with a copy of any post-mortem 
findings including histopathology. 
 New or updated information will be recorded in the originally completed eCRF. 
 
The Investigator will submit any updated SAE data to PAREXEL Clinical Studies 
Safety Center within 24 hours of receipt of the information. 
 
Reporting of SAE to PAREXEL Clinical Studies Safety Center 
SAE Reporting to PAREXEL Clinical Studies Safety Center 
Via EDC Tool 
 The Investigator must report any SAEs to the PAREXEL Clinical Studies Safety 
Center within 24 hours of becoming aware of the event. 
 When calling to report an SAE, state that you are reporting an SAE and give the 
Investigator’s name, your name, the telephone number where you can be reached, and 
the protocol number and title. 
 The Investigator and the Sponsor (or Sponsor’s designated agent) will review each 
SAE report and the Sponsor/PAREXEL will evaluate the seriousness and the causal 
relationship of the event to study treatment. In addition, the Sponsor (or Sponsor’s 
designated agent) will evaluate the expectedness according to the reference 
documents (Investigator’s Brochure or US product labeling for atomoxetine or 
oxybutynin). Based on the Investigator and Sponsor’s assessment of the event, a 
decision will be made concerning the need for further action. 
 After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or by telephone. 
 
Contacts for SAE reporting can be found in the Study Reference Manual. 
 


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Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Any AE that is serious, associated with the use of the study treatment, and unexpected 
(SUSAR) has additional reporting requirements, as described below. 
 If the SUSAR is fatal or life-threatening, associated with study treatment, and 
unexpected, regulatory authorities and IECs will be notified within 7 calendar days 
after the Sponsor learns of the event. Additional follow-up (cause of death, autopsy 
report, and hospital report) information should be reported within an additional 8 days 
(15 days total). 
 If the SUSAR is not fatal or life-threatening but is otherwise serious, associated with 
study treatment, and unexpected, regulatory authorities and IECs will be notified 
within 15 calendar days after the Sponsor learns of the event. 
The Sponsor will notify the Investigators in a timely fashion of relevant information 
about SUSARs that could adversely affect the safety of participants. Follow-up 
information may be submitted if necessary. 
The Sponsor will also provide annual safety updates to the regulatory authorities and 
IECs responsible for the study. These updates will include information on SUSARs and 
other relevant safety findings. 
Reporting Serious Adverse Events 
The Investigator must report any SAEs to the PAREXEL Clinical Studies Safety Center within 
24 hours of becoming aware of the event. 
When calling to report an SAE, state that you are reporting an SAE and give the Investigator’s 
name, your name, the telephone number where you can be reached, and the protocol number and 
title. 
The Investigator and the Sponsor (or Sponsor’s designated agent) will review each SAE report 
and the Sponsor/PAREXEL will evaluate the seriousness and the causal relationship of the event 
to study treatment. In addition, the Sponsor (or Sponsor’s designated agent) will evaluate the 
expectedness according to the reference documents (Investigator’s Brochure or US product 
labeling for atomoxetine or oxybutynin). Based on the Investigator and Sponsor’s assessment of 
the event, a decision will be made concerning the need for further action. 
All SAEs will be recorded from signing of informed consent until the end of the study. Serious 
adverse events occurring after the end of the study and coming to the attention of the Investigator 


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must be reported only if they are considered (in the opinion of the Investigator) causally-related 
to study treatment. 
 
SERIOUS ADVERSE EVENT REPORTING INSTRUCTIONS 
PAREXEL International Corporation 
Clinical Studies Safety Center 
 
The names and contact information for SAE reporting 
will be provided in the Study Reference Manual. 
1. 
Telephone the Medical Monitor/Drug Safety Specialist to inform him/her that you are 
faxing an SAE form. If the Medical Monitor is not available or you are calling after business 
hours (8:30 am to 5:30 pm Eastern time, Monday to Friday), leave a message in his/her voice 
mailbox. 
2. 
Provide the Medical Monitor with the Principal Investigator’s name, your name, the 
telephone number where you can be reached, and the protocol number and title. 
3. 
Fax the completed SAE form and any supporting documentation within 24 hours of 
becoming aware of the event to the email address or fax number listed on the SAE reporting 
form (investigator site file). 
10.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions 
WOCBP 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with one of the following: 
 Documented hysterectomy 


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 Documented bilateral salpingectomy 
 Documented bilateral oophorectomy 
NOTE: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Post-menopausal female 
 A post-menopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the post-
menopausal range may be used to confirm a post-menopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 
 Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status before study enrollment. 
Contraception Guidance: 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if the 
agree to ONE of the following during the protocol-defined time frame in Section 5.1: 
 Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent. 
 Agree to use a contraceptive method with a failure rate of <1% per year as described 
in the table below when having penile-vaginal intercourse with a WOCBP who is not 
currently pregnant. 
In addition, male participants must refrain from donating sperm for the duration of the study and 
for 3 months after the last dose of study treatment. 
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or to use a male condom during each episode of penile penetration 
during the protocol-defined time frame. 
Female Participants 


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Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in the table 
below. 
Highly Effective Contraceptive Methods That Are User Dependent1 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestin-containing) hormonal contraception associated with 
inhibition of ovulation2 
 Oral 
 Intravaginal 
 Transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
 Oral 
 Injectable 
Highly Effective Contraceptive Methods That Are User Independent1 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
 IUD 
 Intrauterine hormone-releasing system (IUS) 
 Bilateral tubal occlusion 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant. 
NOTES: 
1 Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
 
 


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Pregnancy Testing 
 WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test. 
 An additional serum pregnancy testing should be performed at Visit 5 (EOS). 
 Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
Collection of Pregnancy Information: 
Male participants with partners who become pregnant 
 The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This applies 
only to male participants who receive study treatment. 
 After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the Sponsor. Generally, the follow up will 
be no longer than 6 to 8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
Female participants who become pregnant 
 The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of a participant’s pregnancy. 
The participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect any follow up information on the participant and the neonate and the information 
will be forwarded to the Sponsor. Generally, follow up will not be required for longer than 6 
to 8 weeks beyond the estimated delivery date. Any termination of the pregnancy will be 
reported, regardless of fetal state (presence or absence of anomalies) or indication for the 
procedure. 


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 While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous 
abortion is always considered to be an SAE and will be reported as such. Any post-study 
pregnancy-related SAE considered reasonably related to the study treatment by the 
Investigator will be reported to the Sponsor as described in Section 8.3.4. While the 
Investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting. 
 Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study. 
 
 


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10.5 Appendix 5: List of Abbreviations 
AHI 
apnea-hypopnea index 
AE 
adverse event 
Bang 
Body mass index, Age, Neck circumference, and Gender criteria 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CPAP 
continuous positive air pressure 
CSSA 
Cocaine Selective Severity Assessment 
CYP2D6 
cytochrome P450 2D6 
CYP3A4 
cytochrome P450 3A4 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
ECG 
electrocardiogram 
EEG 
electroencephalogram 
eCRF 
electronic case report form(s) 
EDC 
electronic data capture 
EMGgg 
genioglossal electromyographic 
EOS 
end of study 
ESS 
Epworth Sleepiness Scale 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
 
 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IPSS 
International Prostate Symptom Score 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
OSA 
obstructive sleep apnea 
OTC 
over-the-counter 
MAOI 
monoamine oxidase inhibitor 
NREM 
non-rapid eye movement 
PGI-S 
Participant Global Impression of Severity 


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PK 
pharmacokinetic(s) 
PSG 
polysomnography 
DWRT 
Delayed Word Recall Test 
QHS 
1 dose every night at bedtime 
REM 
rapid eye movement 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SoA 
Schedule of Activities 
STOP 
Snoring, Tiredness, Observed apnea, and Blood pressure criteria 
SUSAR 
suspected unexpected serious adverse reaction 
ULN 
upper limit of normal 
US 
United States 
WOCBP 
woman of childbearing potential 


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11 References 
Brooks D, Horner RL, Kozar LF, Render-Teixeira CL, Phillipson EA. Obstructive  sleep apnea as 
a cause of systemic hypertension. Evidence from a canine model. J Clin Invest 1997;99:106-109. 
Chan E, Steenland HW, Liu H, Horner RL. Endogenous excitatory drive modulating respiratory 
muscle activity across sleep-wake states. Am J Respir Crit Care Med 2006;174:1264-1273. 
Eckert DJ, White DP, Jordan AS, Malhotra A, Wellman A. Defining phenotypic causes of 
obstructive sleep apnea. Identification of novel therapeutic targets. Am J Respir Crit Care Med 
2013;188:996-1004. 
Fenik VB, Davies RO, Kubin L. REM sleep-like atonia of hypoglossal (XII) motoneurons is 
caused by loss of noradrenergic and serotonergic inputs. Am J Respir Crit Care Med 
2005;172:1322-1330. 
Findley LJ, Unverzagt ME, Suratt PM. Automobile accidents involving patients with obstructive 
sleep apnea. Am Rev Respir Dis 1988;138:337-340. 
Grace KP, Hughes SW, Horner RL. Identification of the mechanism mediating genioglossus 
muscle suppression in REM sleep. Am J Respir Crit Care Med 2013;187:311-319. 
Grace KP, Hughes SW, Shahabi S, Horner RL. K+ channel modulation causes genioglossus 
inhibition in REM sleep and is a strategy for reactivation. Respir Physiol Neurobiol 
2013;188:277-288. 
Hoffstein V. Blood pressure, snoring, obesity, and nocturnal hypoxaemia. Lancet 
1994;344:643-645. 
Hung J, Whitford EG, Parsons RW, Hillman DR. Association of sleep apnoea with myocardial 
infarction in men. Lancet 1990;336:261-264. 
Lai YY, Kodama T, Siegel JM. Changes in monoamine release in the ventral horn and 
hypoglossal nucleus linked to pontine inhibition of muscle tone: An in vivo microdialysis study. J 
Neurosci 2001;21:7384-7391. 
Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, et al. Association of sleep-
disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep 
Heart Health Study. JAMA 2000; 283:1829-1836. 


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Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-
disordered breathing in adults. Am J Epidemiol 2013;177(9):1006–1014. 
Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-
disordered breathing and hypertension. N Engl J Med 2000; 342:1378-1384. 
Redline S, Strauss ME, Adams N, Winters M, Roebuck T, Spry K, et al. Neuropsychological 
function in mild sleep-disordered breathing. Sleep 1997; 20:160-167. 
Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Nieto FJ, et al. Sleep-disordered 
breathing and cardiovascular disease: Cross-sectional results of the Sleep Heart Health Study. 
Am J Respir Crit Care Med 2001;163:19-25. 
Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive 
sleep apnea. J Clin Invest 1995;96:1897-1904. 
Weaver TE, Sawyer AM. Adherence to continuous positive airway pressure treatment for 
obstructive sleep apnea: implications for future interventions. Indian J Med Res 
2010;131:245-258. 
Wellman A, Eckert DJ, Jordan AS, Edwards BA, Passaglia CL, Jackson AC, et al. A method for 
measuring and modeling the physiological traits causing obstructive sleep apnea. J Appl Physiol 
(1985) 2011; 110:1627-1637. 
Wellman A, Edwards BA, Sands SA, Owens RL, Nemati S, Butler J, et al. A simplified method 
for determining phenotypic traits in patients with obstructive sleep apnea. J Appl Physiol (1985) 
2013;114:911-922. 
Wessendorf TE, Teschler H, Wang YM, Konietzko N, Thilmann AF. Sleep-disordered breathing 
among patients with first-ever stroke. J Neurol 2000;247:41-47. 
Younes M. Contributions of upper airway mechanics and control mechanisms to severity of 
obstructive apnea. Am J Respir Crit Care Med 2003;168:645-658. 
 
 


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Declaration of the Investigator 
Title: Phase 2 Placebo-Controlled, Parallel Group Dose-Finding Study to Evaluate the Efficacy 
and Safety of Three Fixed-Dose Combinations of AD036 in Adults With Obstructive Sleep 
Apnea 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence. This documentation includes this study 
protocol, Investigator's Brochure, EDC system/eCRF, and other scientific data. 
The study will not be commenced without the prior written approval of a properly constituted 
IRB or IEC. No changes will be made to the study protocol without the prior written approval of 
the Sponsor and the IRB or IEC, except where necessary to eliminate an immediate hazard to the 
participants. 
I have read and understood and agree to abide by all the conditions and instructions contained in 
this protocol. 
Responsible Investigator of the local study center 
 
_____________________________________ 
_____________________ 
Signature 
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number 

SAP_001.pdf: 
 
Apnimed, Inc.
20 Holyoke Street
Cambridge, MA 02138
info@apnimed.com
 
Page 1 of 1 
CONFIDENTIAL. DO NOT DISTRIBUTE WITHOUT PERMISSION. 
 
November 3, 2022 
 
To: ClinicalTrials.gov 
 
This is a cover page to the redacted SAP for APN-002 titled Phase 2, Placebo-Controlled, 
Parallel Group Dose-Finding Study to Evaluate the Efficacy and Safety of Three Fixed-Dose 
Combinations of AD036 in Adults With Obstructive Sleep Apnea 
 
The APN-002 SAP is associated with NCT 03845023.   
 
The following proprietary information was redacted from the SAP for APN-002:  
 IND number 
 Reference to the CRO (Contract Research Organization).   
 
Sincerely, 
 
 
 
 
 
Jeanne Brittain 
Director, Program Management 
 
 
Quality Approval:   
Name 
Title 
Signature 
Date 
Francesca 
Kelvy 
Senior Director, GXP 
Quality Assurance 
 
 
 
 
 
 
 
 
 
11/7/2022


Apnimed, Inc. 
Clinical Study Report Appendices 
Protocol APN-002 
Final 
04 May 2020 
16.1.9 
Documentation of Statistical Methods  
Statistical Analysis Plan, Final Version 1.0, Dated 03 Oct 2019 


PAREXEL International 
Apnimed  
  Apnimed IND 136752 
APN-002 (240495)                                                                                   
Statistical Analysis Plan 
TP-GDO-WW-133-01.a 
CONFIDENTIAL 
Project Document Version No. 1.0
Effective Date:  30 Jan 19 
Project Document Effective Date: 03Oct2019 
Related to:  SOP-GDO-WW-019 
Page 1 of 39 
PAREXEL International 
Apnimed  
APN-002 (240495) 
Phase 2, Placebo-Controlled, Parallel Group Dose-Finding Study to Evaluate the Efficacy and 
Safety of Three Fixed-Dose Combinations of AD036 in Adults With Obstructive Sleep Apnea
Statistical Analysis Plan 
Version: Final 1.0 
PAREXEL Project Number: 240495


P AREXEL International 
Apnimed 
APN-002 (240495) 
SPONSOR SIGNATURE PAGE 
Approved by: 
Ronald F k 
Chief Medical Officer 
Apnimed 
TP-GDO-WW-133-0l.a 
Effective Date: 30 Jan 19 
Related to: SOP-GDO-WW-019 
CONFIDENTIAL 
Apnimed IND 136752 
Statistical Analysis Plan 
3 pJLc:t'j 
Date 
Project Document Version No. 1.0 
Project Document Effective Date: 030ct2019 
Page2 of39 


PAREXEL International 
Apnimed  
  Apnimed IND 136752 
APN-002 (240495)                                                                                   
Statistical Analysis Plan 
TP-GDO-WW-133-01.a 
CONFIDENTIAL 
Project Document Version No. 1.0
Effective Date:  30 Jan 19 
Project Document Effective Date: 03Oct2019 
Related to:  SOP-GDO-WW-019 
Page 3 of 39 
PAREXEL SIGNATURE PAGE 
Signatures below confirm that the Statistical Analysis Plan was developed in accordance with 
SOP-GDO-WW-019 and that it is approved for release. 
This document has been approved and signed electronically on the final page by the 
following: 
Signatory 
Project Role 
Author 
Vimalkumar Dave 
Biostatistics Lead 


PAREXEL International 
Apnimed  
  Apnimed IND 136752 
APN-002 (240495)                                                                                   
Statistical Analysis Plan 
TP-GDO-WW-133-01.a 
CONFIDENTIAL 
Project Document Version No. 1.0
Effective Date:  30 Jan 19 
Project Document Effective Date: 03Oct2019 
Related to:  SOP-GDO-WW-019 
Page 4 of 39 
TABLE OF CONTENTS 
1
INTRODUCTION ............................................................................................................. 8
2
STUDY OBJECTIVES ...................................................................................................... 8
2.1
Primary Objective(s) ................................................................................................. 8
3
INVESTIGATIONAL PLAN ............................................................................................ 9
3.1
Overall Study Design and Plan ................................................................................. 9
3.2
Endpoints and Associated Variables ....................................................................... 10
3.2.1
Primary Efficacy Endpoint .................................................................................. 10
3.2.2
Primary Safety & Functional Endpoints .............................................................. 10
3.2.3
Secondary Efficacy Endpoints ............................................................................. 11
3.2.4
Tertiary/Exploratory Endpoints ........................................................................... 11
3.2.5
Safety Variables ................................................................................................... 12
3.2.5.1 Adverse event....................................................................................................... 12
3.2.5.2 Serious Adverse Event (SAE) .............................................................................. 12
3.2.5.3 Suspected Unexpected Serious Adverse Reactions (SUSARs) ........................... 12
3.2.5.4 Clinical laboratory testing .................................................................................... 13
3.2.5.5 Cocaine Selective Severity Assessment (CSSA) ................................................. 13
3.2.5.6 Prospective Suicidality Assessment ..................................................................... 13
3.2.5.7 Pregnancy records ................................................................................................ 13
4
STATISTICAL METHODS ............................................................................................ 13
4.1
Data Quality Assurance .......................................................................................... 13
4.2
Study Subjects ......................................................................................................... 13
4.2.1
Disposition of Subjects ........................................................................................ 13
4.2.2
Protocol Deviations .............................................................................................. 14
4.3
Analysis Sets ........................................................................................................... 15
4.4
Demographics and Baseline Characteristics ........................................................... 16
4.5
General Presentation Considerations ...................................................................... 16
4.6
Medical History and Concomitant Therapy ............................................................ 17
4.7
Prior and Concomitant Medications ....................................................................... 18
4.8
Treatment Exposure / Compliance.......................................................................... 18
4.8.1
Treatment Exposure ............................................................................................. 18
4.8.2
Compliance .......................................................................................................... 18
4.9
Efficacy Evaluation ................................................................................................. 19
4.9.1
Analysis and Data Conventions ........................................................................... 19
4.9.1.1 Multi-center Studies ............................................................................................. 20
4.9.1.2 Adjustments for Covariates.................................................................................. 20
4.9.1.3 Handling of Dropouts or Missing Data ................................................................ 20
4.9.1.4 Multiple Comparisons/Multiplicity ..................................................................... 20
4.9.1.5 Interim Analyses .................................................................................................. 21
4.9.1.6 Examination of Subgroups ................................................................................... 21
4.9.2
Primary Efficacy Variable(s) ............................................................................... 21
4.9.3
Secondary Efficacy Variables .............................................................................. 22
4.9.4
Tertiary/Exploratory Variables ............................................................................ 24
4.10
Safety Evaluation .................................................................................................... 28
4.10.1
Adverse Events .................................................................................................... 28


PAREXEL International 
Apnimed  
  Apnimed IND 136752 
APN-002 (240495)                                                                                   
Statistical Analysis Plan 
TP-GDO-WW-133-01.a 
CONFIDENTIAL 
Project Document Version No. 1.0
Effective Date:  30 Jan 19 
Project Document Effective Date: 03Oct2019 
Related to:  SOP-GDO-WW-019 
Page 5 of 39 
4.10.2
Clinical Laboratory Evaluation ............................................................................ 29
4.10.3
Vital Signs, Physical Findings and Other Observations Related to Safety.......... 30
4.10.4
CSSA.................................................................................................................... 31
4.10.5
Prospective Suicidality Assessment ..................................................................... 31
4.10.6
Safety Monitoring ................................................................................................ 32
4.11
Other Analyses ........................................................................................................ 32
4.11.1
Digit Symbol Substitution Test (DSST) Results: ................................................ 32
4.11.2
Delayed Word Recall Test (DWRT) Results ....................................................... 33
4.11.3
PSG Parameters ................................................................................................... 33
4.12
Determination of Sample Size ................................................................................ 33
4.13
Changes in the Conduct of the Study or Planned Analysis .................................... 34
5
REFERENCES ................................................................................................................ 34
6
APPENDICES ................................................................................................................. 35
6.1
Schedule of Assessments ........................................................................................ 35


PAREXEL International 
Apnimed  
  Apnimed IND 136752 
APN-002 (240495)                                                                                   
Statistical Analysis Plan 
TP-GDO-WW-133-01.a 
CONFIDENTIAL 
Project Document Version No. 1.0
Effective Date:  30 Jan 19 
Project Document Effective Date: 03Oct2019 
Related to:  SOP-GDO-WW-019 
Page 6 of 39 
REVISION HISTORY 
Version 
No.
Date 
Author 
Summary of Change(s) 
1.0 
03 Oct 2019  
Vimalkumar Dave 
New document 


PAREXEL International 
Apnimed  
  Apnimed IND 136752 
APN-002 (240495)                                                                                   
Statistical Analysis Plan 
TP-GDO-WW-133-01.a 
CONFIDENTIAL 
Project Document Version No. 1.0
Effective Date:  30 Jan 19 
Project Document Effective Date: 03Oct2019 
Related to:  SOP-GDO-WW-019 
Page 7 of 39 
LIST OF ABBREVIATIONS 
Abbreviation / Acronym 
Definition / Expansion 
AHI 
Apnea-Hypopnea Index 
AE 
Adverse Event 
ATO 
Atomoxetine 
ATO/OXY 
Concurrent atomoxetine oxybutynin therapy 
Bang 
Body Mass Index, Age, Neck Circumference, And Gender Criteria 
BMI 
Body Mass Index 
CNS 
Central Nervous System 
CSP 
Clinical Study Protocol 
CSSA 
Cocaine Selective Severity Assessment 
ECG 
Electrocardiogram 
EEG 
Electroencephalogram 
eCRF 
Electronic Case Report Form(S) 
EDC 
Electronic Data Capture 
EOS 
End Of Study 
ESS 
Epworth Sleepiness Scale 
ICF 
Informed Consent Form 
IPSS 
International Prostate Symptom Score 
MedDRA 
Medical Dictionary for Regulatory Activities 
OSA 
Obstructive Sleep Apnea 
OXY  
Oxybutynin  
PGI-S 
Participant Global Impression Of Severity 
PK 
Pharmacokinetic(S) 
PSG 
Polysomnography 
REM 
Rapid Eye Movement 
SAE 
Serious Adverse Event 
SaO2
Oxygen Saturation 
SAP 
Statistical Analysis Plan 
SoA 
Schedule Of Activities 
STOP 
Snoring, Tiredness, Observed Apnea, And Blood Pressure Criteria 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 


PAREXEL International 
Apnimed  
  Apnimed IND 136752 
APN-002 (240495)                                                                                   
Statistical Analysis Plan 
TP-GDO-WW-133-01.a 
CONFIDENTIAL 
Project Document Version No. 1.0
Effective Date:  30 Jan 19 
Project Document Effective Date: 03Oct2019 
Related to:  SOP-GDO-WW-019 
Page 8 of 39 
1
INTRODUCTION 
The purpose of this Statistical Analysis Plan is to describe the planned analyses and 
reporting for Sponsor protocol APN-002 (240495), entitled “Phase 2, Placebo-Controlled, 
Parallel Group Dose-Finding Study to Evaluate the Efficacy and Safety of Three Fixed-
Dose Combinations of AD036 in Adults with Obstructive Sleep Apnea. 
This Phase 2B clinical study is designed to examine the efficacy and safety of AD036 
(combination of atomoxetine and oxybutynin) at concentrations that are both similar to the 
concentration used in the first in human study, and at 2 lower doses, versus placebo. 
Overall, the study is expected to provide dose selection guidance and a deeper 
understanding of repeat-dose safety and tolerability for the ongoing clinical development 
of AD036. 
The analyses described in this SAP are based upon the following study documents: 
Study Protocol, Version 1.4 (Dec 04, 2018) 
Electronic Case Report Form (eCRF), Version 1.0 (Jan 31, 2019) 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency 
(EMA), and International Conference on Harmonization (ICH) of Technical Requirements 
for Registration of Pharmaceuticals for Human Use: ICH Harmonized Tripartite Guideline 
Statistical Principles for Clinical Trials E9 [1] 
The SAP will be finalized prior to database lock and describes the statistical analysis as it 
is foreseen when the study is being planned. If circumstances should arise during the study 
rendering this analysis inappropriate, or if improved methods of analysis should arise, 
updates to the analyses may be made. Any deviations from the SAP after database lock, 
reasons for such deviations and all alternative or additional statistical analyses that may be 
performed, will be described in an SAP Addendum. In this SAP, terminologies like 
Subjects, Participant or Patients means participants enrolled in the study. 
2
STUDY OBJECTIVES 
2.1
Primary Objective(s) 
1. To assess the efficacy of 3 different fixed doses of AD036 (the combination of 
atomoxetine and oxybutynin) vs. placebo. 
2. To evaluate safety and tolerability of the combination AD036. 


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Apnimed  
  Apnimed IND 136752 
APN-002 (240495)                                                                                   
Statistical Analysis Plan 
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3
INVESTIGATIONAL PLAN 
3.1
Overall Study Design and Plan 
This is a phase 2, randomized, double blind, placebo-controlled, repeat-dose, parallel arm, 
outpatient and inpatient, multi-center, dose finding study of the combination of 
atomoxetine and oxybutynin in adults with obstructive sleep apnea (OSA) documented by 
polysomnography (PSG).  
Number of Participants and Randomization: Approximately 140 participants will be 
randomized to study treatment in equal ratio (1:1:1:1), at least 35 participants per arm, to 
1 of 4 parallel treatment groups. At a study site, multiple randomizations may occur within 
a single arm in a short period of time, temporarily leaving no investigational product 
available for the given study arm while resupply is sent from the depot. Consequently, if a 
subsequent randomization is to the same study arm, that randomization number will be 
skipped, and the patient will be randomly allocated to the next free number in the 
randomization list corresponding to one of the treatments in stock at the site, i.e. “forced 
randomization”.  Skipped randomization numbers will remain unallocated. 
Treatment Groups and Duration: There will be 4 parallel treatment groups, as follows: 
Group 
Atomoxetine/oxybutynin (mg) 
Subjects (n) 
1 
75/5 
35 
2 
75/1.5 
35 
3 
25/5 
35 
4 
Placebo 
35 
Overall study duration will be up to 8-9 weeks, with up to 28 days for screening and 
baseline PSG. All participants will receive placebo for 2 days to establish baseline 
measures. Participants assigned to active treatment will subsequently receive low dose (25 
mg atomoxetine/1.5 mg oxybutynin) for a 3-day dose-escalation period. Participants 
randomized to placebo will have a placebo run-in period. 
Following the dose-escalation period, participants will receive the dose level to which they 
were randomized (75/5; 75/1.5; 25/5; placebo) for 7 (±2) nights (6 nights at home, seventh 
night inpatient PSG). On the final night of dosing, participants will return for inpatient PSG 
(Visit 4). A follow-up safety visit will take place 2 weeks post study treatment dosing (±2 
days), or upon early withdrawal (figure 1). 
Dosing of the study treatment will occur approximately 30 minutes prior to bedtime. 
Participants who withdraw from the study will not be replaced. 


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Apnimed  
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APN-002 (240495)                                                                                   
Statistical Analysis Plan 
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CONFIDENTIAL 
Project Document Version No. 1.0
Effective Date:  30 Jan 19 
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Figure 1 – Overall Study design  
Abbreviations: ATO = atomoxetine; EoS = end of study; OXY = oxybutynin; PSG = polysomnography 
3.2
Endpoints and Associated Variables 
3.2.1
Primary Efficacy Endpoint 
Comparison of the proportion of participants with 
50% reduction in apnea-hypopnea 
index (AHI) from baseline to the second PSG visit in the atomoxetine 75 mg/oxybutynin 
5 mg dose group compared with placebo. 
3.2.2
Primary Safety & Functional Endpoints 
Safety Endpoints 
1. The number and percentage of participants reporting Adverse Events (AEs), including 
the post-dosing period  
2. Change from baseline in physical examination findings  
3. Change from baseline in clinical laboratory testing (hematology, serum chemistry, 
urinalysis, other tests) 
4. Cocaine Selective Severity Assessment (CSSA) results, Modified for study treatment 
5. Prospective Suicidality Assessment (item 17 “suicidality” of CSSA) results  


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Apnimed  
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APN-002 (240495)                                                                                   
Statistical Analysis Plan 
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CONFIDENTIAL 
Project Document Version No. 1.0
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6. Change from baseline in PSG parameters: heart rate, electrocardiogram (ECG), 
electroencephalogram (EEG), oximetry  
7. Change from baseline in vital signs, ECG 
Functional Endpoints  
1. Digit Symbol Substitution Test (DSST) results 
2. Delayed Word Recall Test (DWRT) results 
3.2.3
Secondary Efficacy Endpoints 
1. Percent change AHI, high-dose arm (atomoxetine 75 mg/oxybutynin 5 mg dose) vs. 
placebo. 
2. Proportion of participants with 50% reduction in AHI, measured in the supine sleeping 
position, from baseline to the second PSG visit in the 75/5 dose group compared with 
placebo.  
3. Proportion of participants with 50% reduction in Oxygen desaturation index from 
baseline (average of 2 baseline nights) to study treatment nights (average of 6 nights) 
for the 75/5 dose group compared with placebo. 
4. Change from baseline in the Epworth Sleepiness Scale (ESS) from baseline to the 
second PSG visit in the 75/5 dose group compared with placebo. 
5. Change from baseline in the Participant Global Impression of Severity (PGI-S) from 
baseline to the second PSG visit in the 75/5 dose group compared with placebo. 
6. Proportion of participants with 50% improvement in AHI from baseline to the second 
PSG visit in the 75/5 dose group compared with the lower treatment dose of 25/5. 
7. In the case that a statistically significant result for the AHI comparison of dose 75/5 to 
25/5 is observed, then the proportion of participants with 50% improvement in AHI 
from baseline to the second PSG visit in the 75/5 dose group compared with the lower 
treatment dose of 75/1.5. 
3.2.4
Tertiary/Exploratory Endpoints
1. Proportion of participants with 50% AHI decrease and final AHI<15/hour, PSG nights 
2. Total time with oxygen saturation (SaO2) <90%, PSG nights 
3. Total time with SaO2 <80%, PSG nights 
4. Snoring index, PSG nights  


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APN-002 (240495)                                                                                   
Statistical Analysis Plan 
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CONFIDENTIAL 
Project Document Version No. 1.0
Effective Date:  30 Jan 19 
Project Document Effective Date: 03Oct2019 
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5. Sleep stages distribution and % of time in the various sleep stages, PSG nights 
6. Arousal index, PSG nights 
7. Oxygen desaturation index, low-dose run in vs baseline, at home nights 
8. Proportion of apneas to hypopneas 
9. Proportion of participants with 50% improvement in AHI from baseline to the second 
PSG visit 
10. Correlation of phenotypic traits (Vpassive, Vactive, arousal threshold and Loop gain) 
with AHI response or subjective outcomes 
3.2.5
Safety Variables 
3.2.5.1 Adverse event 
An AE is any untoward medical occurrence in a participant or clinical study participant, 
temporally associated with the use of a study treatment, whether or not considered related 
to the medicinal product. 
AEs will be collected from the signing of the informed consent form (ICF) to the follow-
up visit (Visit 5/End of study). Each AE verbatim term will be coded to a system organ 
class and a preferred term using the latest version of  Medical Dictionary for Regulatory 
Activities (MedDRA).   
For patient level summaries, if more than one AE is coded to the same PT for the same 
patient, the patient will be counted only once in summary tables using the most serious 
grading on causal relationship to study treatment. 
3.2.5.2 Serious Adverse Event (SAE) 
An SAE is an AE occurring during any study phase (i.e., run-in, treatment, washout, 
follow-up), that fulfills one or more of the following criteria: 
Results in death 
Is life-threatening 
Requires inpatient hospitalization or prolongation of existing hospitalization 
Results in persistent disability or incapacity   
Is a congenital abnormality or birth defect 
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above 
3.2.5.3 Suspected Unexpected Serious Adverse Reactions (SUSARs) 
SUSAR is defined as an AE that is serious, associated with the use of the study treatment, 
and unexpected and has additional reporting requirements, as described in section 10.3 of 
the Clinical Study Protocol (CSP). 


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APN-002 (240495)                                                                                   
Statistical Analysis Plan 
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3.2.5.4 Clinical laboratory testing 
Laboratory data will be collected throughout the study, from screening to the follow-up 
visit as per the study plan described in the CSP. Hematology, serum chemistry, urinalysis, 
and others as clinically indicated will be collected as described in section 10.2 of the CSP.  
Missing laboratory data will not be imputed. However, laboratory assessment values of the 
form of “<x” (i.e., below the lower limit of quantification) or >x (i.e., above the upper limit 
of quantification) will be imputed as “x” in the calculation of summary statistics but 
displayed as “<x” or “>x” in the listings. 
3.2.5.5 Cocaine Selective Severity Assessment (CSSA) 
A modified version of the CSSA will be used to measure potential withdrawal signs and 
symptoms from the study treatment; “cocaine” will be replaced with “study drug”. The 
CSSA includes psychiatric symptoms of general safety interest such as changes in sleep, 
anxiety, energy level, activity level, tension, attention, paranoid ideation, anhedonia, 
depression, suicidality, and irritability. Items are rated on a scale of 0-7, and a total score 
is derived by summing the individual items.  
3.2.5.6 Prospective Suicidality Assessment 
The CSSA item 17, “suicidality”, will be used to monitor participants for suicidality during 
the study (whether or not abuse-related). A score of 
3 will be considered an AE. 
3.2.5.7 Pregnancy records 
Details of all pregnancies in female participants and female partners of male participants 
after the start of study treatment and until at least 5 terminal half-lives after the last dose 
will be collected. Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered to be SAEs. 
4
STATISTICAL METHODS 
4.1
Data Quality Assurance 
All tables, figures and data listings to be included in the report will be independently 
checked for consistency, integrity and in accordance with standard PAREXEL procedures. 
The data extraction will be set to appropriate date so that all data cleaning activities at site 
are taken care of. 
4.2
Study Subjects 
4.2.1
Disposition of Subjects 
A clear accounting of the disposition of all enrolled subjects who enter the study will be 
provided, from screening to study completion. 


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Statistical Analysis Plan 
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Screen failures are defined as subjects who consent to participate in the clinical study but 
are not subsequently randomized to study treatment/entered into the study.  
Summaries of subject disposition will be presented by treatment and overall.  
The following patient disposition summaries will be provided 
A summary of the number and percentage of subjects who were screened, screen 
failure, randomized, randomized but were not treated (not a single dose of the study 
treatment) will be provided. This summary will be based on total screened subjects. 
A separate summary table for subjects who completed, discontinued and the primary 
reason(s) for discontinuation will be provided for each treatment group. This summary 
will be based on mITT Population. 
Subject disposition including the subject status (completer, Yes/No), demographic data 
(age and race), screening date, study product start date and time, the duration in the 
study or trial, date of discontinuation and the specific reason for discontinuation, will 
be listed for randomized subjects by product group and center.  
4.2.2
Protocol Deviations 
Protocol deviations will be tracked by the study team throughout the conduct of the study. 
Data will be reviewed prior to un-blinding and closure of the database to ensure all 
important deviations are captured and categorized. Subjects with major protocol deviations 
(defined below) will be excluded from the PP population. 
Major protocol deviations are defined as those deviations from the protocol that are likely 
to have an impact on the subject’s rights, safety, well-being, and/or on the validity of the 
data for primary analysis. This will include all those deviations to be reported in the clinical 
study report (CSR). 
The impact of major protocol deviations on the efficacy and/or safety results will be 
investigated by assessing the robustness of the study results and conclusions to the choice 
of analysis population (see Section 4.4), both including and excluding data potentially 
affected by major protocol deviations. The final determination of major protocol deviations 
and the exclusion of patients from each of the analysis populations will be made prior to 
database lock. Please refer to the study protocol deviation specification for more 
information.  
In the event that a subject is allocated the incorrect study treatment as per the study 
randomization list, it will be considered as a protocol deviation.  
The number of subjects with protocol deviations will be summarized by category (Major 
or Minor) and deviation classification overall and by treatment group. Protocol deviations 
will be listed with date and study day of occurrence, deviation category, deviation 
description and analysis populations from which subject is excluded.   
The number of subjects included in each analysis population will be summarized. A listing 
of subjects included in each analysis population will also be provided. Subject exclusion 
from analysis sets will be listed with reasons for exclusions. 


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Statistical Analysis Plan 
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Blinding of the study will be maintained as per the Blinding Maintenance Plan which has 
been developed and approved on 13March2019. 
4.3
Analysis Sets 
Enrolled Population 
All participants who signed the ICF (including screening failures).  
Modified Intent to Treat (mITT) Population 
The efficacy summaries and analyses will be based on the mITT Population, which is based 
upon the Intention-to-Treat principle. The mITT Population comprises all participants who 
are randomized, take at least 1 dose of any of the study treatments, and have at least 1 
measurement on the primary endpoint.  The mITT population will therefore include 
patients who have a primary endpoint measurement at either Visit 2 (baseline) or Visit 4 
(on treatment), or both.  Participants will be analyzed for efficacy according to the 
treatment group into which they are randomized. 
If a subject is allocated the incorrect study treatment as per the study randomization list, 
subjects will be summarized and analyzed ‘as randomized’ i.e. by randomized treatment 
group. 
Safety Population 
The safety summaries and analyses will be based on the Safety Population.  The Safety 
Population consists of all participants who are randomized and receive at least 1 dose of 
any of the study treatments. Participants will be analyzed “as actually received" (i.e., 
according to the actual treatment received during randomization).  
Per Protocol (PP) Population 
The PP Population consists of all participants without any major protocol violations that 
could influence efficacy assessment, and who are at least 80% compliant with the study 
medication. Participants in this population will be analyzed according to the treatment they 
actually received. 
Upon database release, protocol deviation and analysis set outputs will be produced and 
will be sent to Apnimed for review. An analysis population classification meeting will be 
arranged to discuss the outputs and to decide which subjects and/or subject data will be 
excluded from certain analyses. Decisions made regarding the exclusion of subjects and/or 
subject data from analyses will be made prior to unblinding and will be documented and 
approved by Apnimed. 
Sensitivity analyses will be performed on the PP population for key primary and key 
secondary efficacy endpoints (key comparisons for which sequential order is specified, 
please refer section 9.4 of the protocol or 4.9.1.4 of the SAP) to understand the impact of 


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Apnimed  
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Statistical Analysis Plan 
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major protocol deviations on study results. Sensitivity analyses will separately be 
performed on the PP population excluding patients whose randomization was “forced”.  
4.4
Demographics and Baseline Characteristics 
Descriptive statistics (number of subjects [n], mean, median, standard deviation [SD], 
minimum and maximum) for the continuous variables and frequency (n) and percentages 
(%) for categorical variables will be provided for demographic variables. 
The continuous variable includes age (years) height (Meter), weight (kg), BMI,  
International Prostate Symptom Score (IPSS), AHI Score and categorical variables include 
gender, race, and Ethnicity, STOP BANG Score (5-8 [High risk of OSA], 3-4 [Intermediate 
OSA], 0-2[Low Risk]). 
Age will be calculated as the number of complete years between a subject's birth date and 
the date of informed consent. If age is missing but date of birth is present, age will be 
calculated as follows (without rounding): 
Age (years) = (study day 1 – date of birth) / 365.25 
This will be determined from the date of birth (birth date in the Demographics eCRF page) 
and baseline visit (‘visit 1’ in the Date of visit eCRF page). If the day of birth is missing, 
the first day of the month will be imputed and if day and month are missing January 1st 
will be imputed.  
4.5
General Presentation Considerations 
All statistical analyses will be performed using SAS® software Version 9.3 or later. 
Medical history and AEs will be coded using the latest version of MedDRA. The frequency 
count and percentage of subjects will be summarized according to the coded terms of 
system organ class (SOC) and preferred term (PT). Subject-wise data listing will be 
provided. 
For participants who are eligible and enroll in the study, the screening PSG night will serve 
as the baseline measure for AHI and other PSG efficacy and safety endpoints. Baseline 
measures for additional secondary and tertiary endpoints based on home oximetry will be 
recorded at home during the placebo period, and these endpoint measures will continue to 
be collected over the subsequent at-home study treatment dosing period. On the final night 
of dosing (Visit 4), participants will return for inpatient PSG. 
A participant is considered to have completed the study if he/she has completed all phases 
including Screening (visit 1), Baseline (visit 2), placebo baseline (2 night (Day 1-2 ), low 
dose run-in or placebo night (3 night [Day 3-5 +2]), ATO/OXY (mg) or placebo 7 night 
(Day 6-12 +/- 2 ) and the final Follow-up visit or the last scheduled procedure shown in 
the Schedule of Activities (SoA) (Appendix). 
The end of the study is defined as the date of the last visit of the last participant in the study 
or last scheduled procedure shown in the SoA for the last participant in the study globally. 


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Continuous data will be summarized in terms of the mean, standard deviation (SD), 
median, minimum, maximum and number of observations, unless otherwise stated.  
Continuous data that are expected to be skewed will be presented in terms of the maximum, 
upper quartile, median, lower quartile, minimum and number of observations. The 
minimum and maximum will be reported to the same number of decimal places as the raw 
data recorded in the database. The mean, median, lower quartile and upper quartile will be 
reported to one more decimal place than the raw data recorded in the database. The SD will 
be reported to two more decimal places than the raw data recorded in the database. In 
general, the maximum number of decimal places reported shall be four for any summary 
statistic. 
Categorical data will be summarized in terms of the number of subjects providing data at 
the relevant time point (n), frequency counts and percentages. Percentages will be 
presented to one decimal place. Percentages will be presented for zero counts along with 
95%confidence interval (CI) where applicable. Percentages will be calculated using 
n
(the total number of subjects providing data at the relevant time point) as the denominator. 
Percentages will not be presented for zero counts. Any planned collapsing of categories 
will be detailed in the SAP text and the data displays. 
In all summaries change from baseline variables will be calculated as 
Change from baseline = post-treatment value - baseline value.  
The percentage change from baseline will be calculated as  
Percent change from baseline = [(post-baseline value - baseline value) / baseline value] 
×100. 
P-values greater than or equal to 0.001, in general, will be presented to three decimal 
places.  P-values less than 0.001 will be presented as “<0.001”. 
Change from baseline and percent change from baseline will be calculated if both baseline 
and post-baseline data is available. 
Confidence intervals will be presented to one more decimal place than the respective point 
estimator. 
4.6
Medical History and Concomitant Therapy 
Relevant medical history (past and current) and relevant surgical history will be coded 
using the latest version of MedDRA. 
Concomitant procedures will be coded using the latest version of MedDRA, and will be 
summarized for the safety population by SOC and PT. 
Moreover, the prohibited or restricted concomitant therapies (see section 6.5 of the CSP) 
will be summarized. 


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4.7
Prior and Concomitant Medications 
The World Health Organization (WHO) Drug dictionary will be used for concomitant 
medication coding. 
Medication start and stop dates will be compared to the date of first dose of study 
medication to allow medications to be classified as either Prior only, both Prior and 
Concomitant, or Concomitant only. Medications starting after the completion/withdrawal 
date will be listed but will not be classified or summarized. 
Medications that start and stop prior to the date of first dose of study medication will be 
classified as Prior only. If a medication starts before the date of first dose of study 
medication and stops on or after the date of first dose of study medication, then the 
medication will be classified as both Prior and Concomitant. Medications will be classified 
as Concomitant only if they have a start date on or after the date of first dose of study 
medication. 
If medication start and/or stop dates are missing or partial, the dates will be compared as 
far as possible with the date of first dose of study medication. Medications will be assumed 
to be Concomitant only, unless there is clear evidence (through comparison of partial dates) 
to suggest that the medication started prior to the first dose of study medication. If there is 
clear evidence to suggest that the medication started prior to the first dose of study 
medication, the medication will be assumed to be both Prior and Concomitant, unless there 
is clear evidence to suggest that the medication stopped prior to the first dose of study 
medication. If there is clear evidence to suggest that the medication stopped prior to the 
first dose of study medication, the medication will be assumed to be Prior only. 
4.8
Treatment Exposure / Compliance 
4.8.1
Treatment Exposure  
Exposure to study treatment will be summarized by treatment group for the safety 
population by durations of drug exposure (days), total number of capsules received, and 
total number of capsules dispensed. Doses that were not given because the patient 
discontinued will not be summarized. 
4.8.2
Compliance  
Treatment compliance is calculated as the proportion in percentage of the scheduled 
expected number of doses, i.e. (Actual exposure/Expected exposure) *100. 
A table with proportion of subjects with compliance and Non-compliance (Subject would 
be considered non-compliant if the subject consumes less than 80% of the total amount of 
recommended dose.) will be presented. Non-compliance will be assessed on a subject by 
subject basis. Those subjects with treatment compliance less than 80% will be excluded 
from the PP analysis. Any subject excluded from PP analysis will be clearly documented. 
Treatment compliance listing will be presented  


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Apnimed  
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Statistical Analysis Plan 
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4.9
Efficacy Evaluation 
4.9.1
Analysis and Data Conventions 
The high-dose AD036 in this study is atomoxetine 75 mg/ oxybutynin 5 mg, similar to the dose 
used in initial human studies (atomoxetine 80 mg/oxybutynin 5 mg). To explore the potential 
efficacy and safety of lower atomoxetine and oxybutynin doses, the following 2 additional dose 
arms will be studied: atomoxetine 75 mg/oxybutynin 1.5 mg and atomoxetine 25 
mg/oxybutynin 5 mg. This Phase 2 clinical study will further examine the efficacy and safety 
of lower dose AD036 versus placebo.
The primary objective (s) of this study is to assess the efficacy of 3 different fixed doses of 
AD036 (the combination of atomoxetine and oxybutynin) vs. placebo. 
The primary endpoint is the proportion of participants with 
50% reduction in AHI from 
baseline to the second PSG visit (Visit 4). 
The primary comparison of the study is  
ATO 75 mg/OXY 5 mg vs placebo in the proportion of participants with 
50% 
reduction in AHI from baseline to the second PSG visit (Visit 4). 
Primary null hypothesis will be 
H0: Odds ratio for ATO 75 mg/OXY 5 mg versus placebo in participants with 50% 
reduction in AHI from baseline to the second PSG visit (Visit 4) = 1
Primary alternative hypothesis will be 
H1: Odds ratio for ATO 75 mg/OXY 5 mg versus placebo in participants with 50% 
reduction in AHI from baseline to the second PSG visit (Visit 4)
. 
The other efficacy comparisons of interest also will be tested using logistic regression 
similar to primary efficacy hypothesis. 
Participants that discontinue prior to the second PSG visit will not be replaced and will 
be considered non-responders. 
When change from baseline is assessed at a post-baseline visit, unless otherwise 
specified, only patients with both baseline and post-baseline measurements will be 
included in the analyses.  If baseline or post-baseline value is missing for a patient, then 
the change from baseline will be set to missing.   
For all PSG safety and efficacy endpoints the screening PSG night (Visit 2) will serve as 
the baseline. For additional secondary and tertiary endpoints based on home oximetry, 
the average of the two baseline nights (Placebo baseline two night) will serve as the 
baseline.  
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
will be set to missing. 


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For all efficacy endpoints, descriptive summary statistics for absolute values, change or 
percent change from baseline, if applicable, will be provided by analysis visits for mITT 
population and PP population. 
For primary and key secondary endpoint analysis based on logistic regression odds ratio 
and 95% Wald confidence limits will be presented. 
For primary and all key secondary endpoint line graph or bar graph will be created and 
details will be provided in the TLFs shell document. 
4.9.1.1
Multi-center Studies  
For the summaries and analyses purpose, the term ‘Center’ will be used to define 
each investigator site. 
4.9.1.2
Adjustments for Covariates 
Baseline values for all endpoint will be included as a covariate for all efficacy analysis.  
4.9.1.3
Handling of Dropouts or Missing Data 
Participants that discontinue prior to the second PSG visit will not be replaced and will 
be considered non-responders (<50% improvement in the AHI score). 
Subject with missing baseline data will also be consider as the non-responder. 
Score.   
For all other endpoint missing data will not be imputed.  
4.9.1.4
Multiple Comparisons/Multiplicity 
Hypothesis tests will be performed in a sequential manner to avoid the need to adjust 
type I error rates for multiplicity, at a 2-sided 0.05 significance level. The sequential order 
of hypothesis tests will occur as follows: 
baseline to the second PSG visit in the 75/5 dose group compared with placebo. 
Percent change AHI, high-dose arm vs. placebo. 
sleeping position, from baseline to the second PSG visit in the 75/5 dose group 
compared with placebo.  
from baseline (average of 2 baseline nights) to study treatment nights (average of 6 
nights) for the 75/5 dose group compared with placebo.  
Change from baseline in the Epworth Sleepiness Scale (ESS) from baseline to the 
second PSG visit in the 75/5 dose group compared with placebo.  
Change from baseline in the Participant Global Impression of Severity (PGI-S) from 
baseline to the second PSG visit in the 75/5 dose group compared with placebo.  


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second PSG visit in the 75/5 dose group compared with the lower treatment dose of 
25/5. 
In the case that a statistically significant result for the AHI comparison of dose 75/5 
AHI from baseline to the second PSG visit in the 75/5 dose group will be compared 
with the lower treatment dose of 75/1.5.  
4.9.1.5
Interim Analyses 
No formal interim analysis is planned. 
4.9.1.6
Examination of Subgroups 
As a part of the additional exploratory analysis the uniformity of the treatment effect for 
the primary efficacy variable will be examined for the following subgroups: 
1.
2.
The homogeneity of the treatment effect across subgroups will be investigated. In 
addition, a statistical test for the presence of a treatment-by-subgroup interaction will be 
performed, by including the interaction term in the primary analysis model. The 
treatment-by-subgroup interaction will be investigated at 10% level (p<0.10). 
Summaries of the primary efficacy variable by treatment group and subgroup will be 
produced. No formal statistical analysis will be performed within subgroup. 
4.9.2
Primary Efficacy Variable(s)  
baseline. 
Primary efficacy variable will be summarized by treatment group and visit. 
Summaries will include the total number of subjects with assessments, the number of 
participants with missing measurements, proportion of subjects with 
50% improvement 
in AHI from baseline and associated 95% confidence intervals. 
The primary efficacy endpoint will be analyzed using a logistic regression model with the 
treatment group as factor and baseline AHI score as a covariate. Estimate of the odds ratio 
along with associated 95% Wald confidence interval (CI) and two-sided p-value will be 
presented for primary comparison between 75 mg/5mg dose group and placebo.  
Odds ratio estimates, CIs, and p-values will also be presented for other efficacy 
comparisons under the primary objective: 
1. 75/1.5 dose arm vs Placebo arm 
2. 25/5 dose arm vs Placebo arm 
3. 75/5 dose arm vs. 75/1.5 dose arm 


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4. 75/5 dose arm vs. 25/5 dose arm 
5. 75/1.5 dose arm vs 25/5 dose arm 
In the situation of zero events (or < 5 participants) in treatment groups, the logistic model 
may fail to provide valid parameter estimates. In this situation exact logistic regression 
(Fisher’s exact test) can be used to compare the proportions across treatment groups. 
A by-subject listing of the primary efficacy data will be provided. 
The primary endpoint analysis will be based on mITT and PP population.
4.9.3
Secondary Efficacy Variables 
To control the type I error, a sequential testing procedure will be employed with the order 
of hypothesis defined as in Section 3.2.2 above. All comparisons will be carried out and 
their result will be interpreted carefully. 
Percent change AHI, high-dose arm vs. placebo. 
Percent change AHI will be compared between high-dose arm and placebo group using an 
analysis of covariance (ANCOVA) model with treatment group as factor and baseline AHI 
(Visit 2) as a covariate. In the ANCOVA model. 
Adjusted means, Standard error (SE) of Adjusted means, 95% confidence intervals, within 
treatment p-values for each treatment group, treatment group difference, 95% confidence 
interval of the difference and the between-treatment p-values based on the statistical model 
described above will also be presented 
Similar analysis will be carried out for the following treatment comparisons on the percent 
change AHI score at two-sided 0.05 level of significance. 
1. 75/1.5 dose arm vs Placebo arm 
2. 25/5 dose arm vs Placebo arm 
3. 75/5 dose arm vs. 75/1.5 dose arm 
4. 75/5 dose arm vs. 25/5 dose arm 
5. 75/1.5 dose arm vs 25/5 dose arm 
Proportion of participants with 
50% improvement in AHI, measured in the supine 
sleeping position, from baseline (Visit 2) to the second PSG visit (Visit 4) in the 75/5 dose 
group compared with placebo. 
position, from baseline to the second PSG visit between 75/5 dose and placebo group will 
be analyzed using a logistic regression model with the treatment group as factors and 
baseline AHI Score as a covariate.  
Estimate of the odds ratio along with associated 95% Wald confidence interval (CI) and 
two-sided p-value will be presented  


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Similar analysis will be carried out for the following treatment comparison on this efficacy 
variable at two-sided 0.05 level of significance. 
1. 75/1.5 dose arm vs Placebo arm 
2. 25/5 dose arm vs Placebo arm 
3. 75/5 dose arm vs. 75/1.5 dose arm 
4. 75/5 dose arm vs. 25/5 dose arm 
5. 75/1.5 dose arm vs 25/5 dose arm  
Proportion of participants with 
50% improvement in at-home Oxygen desaturation 
index from baseline (average of 2 baseline nights) to study treatment nights (average of 6 
nights) for the 75/5 dose group compared with placebo.  
The oxygen desaturation index is the average number of oxygen desaturations 4% or more 
below the baseline level per hour. 
baseline to study treatment nights (average of 6 nights) between 75/5 dose and placebo 
group will be analyzed using a logistic regression model with the treatment group as factors 
and baseline Oxygen desaturation index as a covariate.  
Estimate of the odds ratio along with associated 95% Wald confidence interval (CI) and 
two-sided p-value will be presented  
Similar analysis will be carried out for the each of following treatment comparison on this 
efficacy variable 
All statistical tests of hypotheses will be two-sided and will employ a level of significance 
1. 75/1.5 dose arm vs Placebo arm 
2. 25/5 dose arm vs Placebo arm 
3. 75/5 dose arm vs. 75/1.5 dose arm 
4. 75/5 dose arm vs. 25/5 dose arm 
5. 75/1.5 dose arm vs 25/5 dose arm 
Change in the ESS from baseline to the second PSG visit in the 75/5 dose group compared 
with placebo.  
Change from baseline in the ESS at second PSG visit (visit 4) will be compared between 
75/5 dose and placebo group using ANCOVA with treatment group as factor and baseline 
results as a covariate.  
Adjusted means, Standard error (SE) of Adjusted means, 95% confidence intervals, within 
treatment p-values for each treatment group, treatment group difference, 95% confidence 
interval of the difference and the between-treatment p-values based on the statistical model 
described above will also be presented 
Similar analysis will be carried out for the each of following treatment comparison on this 
efficacy variable. 


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All statistical tests of hypotheses will be two-sided and will employ a level of significance 
1. 75/1.5 dose arm vs Placebo arm 
2. 25/5 dose arm vs Placebo arm 
3. 75/5 dose arm vs. 75/1.5 dose arm 
4. 75/5 dose arm vs. 25/5 dose arm 
5. 75/1.5 dose arm vs 25/5 dose arm 
Change in the PGI-S from baseline to the second PSG visit in the 75/5 dose group 
compared with placebo.  
Change from baseline in the PGI-S at second PSG visit (visit 4) will be compared between 
75/5 dose and placebo group using ANCOVA with treatment group as factor and baseline 
results as a covariate. 
Adjusted means, Standard error (SE) of Adjusted means, 95% confidence intervals, within 
treatment p-values for each treatment group, treatment group difference, 95% confidence 
interval of the difference and the between-treatment p-values based on the statistical model 
described above will also be presented 
Similar analysis will be carried out for the each of following treatment comparison on this 
efficacy variable. 
All statistical tests of hypotheses will be two-sided and will employ a level of significance 
1. 75/1.5 dose arm vs Placebo arm 
2. 25/5 dose arm vs Placebo arm 
3. 75/5 dose arm vs. 75/1.5 dose arm 
4. 75/5 dose arm vs. 25/5 dose arm 
5. 75/1.5 dose arm vs 25/5 dose arm 
4.9.4 Tertiary/Exploratory Variables 
Proportion of participants with 
50% AHI decrease and final AHI<15/hour, PSG nights 
at Visit 4 will be analyzed using a logistic regression model with the treatment group as 
factors and baseline AHI score as a covariate. 
Estimate of the odds ratio along with associated 95% Wald confidence interval (CI) and 
two-sided p-value will be presented 
Similar analysis will be carried out for following treatment comparison  
1. 75/1.5 dose arm vs Placebo arm 
2. 25/5 dose arm vs Placebo arm 
3. 75/5 dose arm vs. 75/1.5 dose arm 
4. 75/5 dose arm vs. 25/5 dose arm 
5. 75/1.5 dose arm vs 25/5 dose arm  


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Total sleep time with SaO2 <90%, PSG nights 
A summary of the number and percentage of subjects who had total sleep time (minutes) 
with SaO2 <90% during PSG nights will be provided for each treatment group. 
Change from baseline in the total sleep time with SaO2<90 % at second PSG visit (visit 4) 
will be compared between 75/5 dose and placebo group using ANCOVA with treatment 
group as factor and baseline results as a covariate.  
Adjusted means, Standard error (SE) of Adjusted means, 95% confidence intervals, within 
treatment p-values for each treatment group, treatment group difference, 95% confidence 
interval of the difference and the between-treatment p-values based on the statistical model 
described above will also be presented 
Similar analysis will be carried out for following treatment comparison  
All statistical tests of hypotheses will be two-sided and will employ a level of significance 
1. 75/1.5 dose arm vs Placebo arm 
2. 25/5 dose arm vs Placebo arm 
3. 75/5 dose arm vs. 75/1.5 dose arm 
4. 75/5 dose arm vs. 25/5 dose arm 
5. 75/1.5 dose arm vs 25/5 dose arm  
Total sleep time with SaO2 <80%, PSG nights 
Similar analysis will be performed for this endpoint as specified for the endpoint “Total 
sleep time with SaO2 <90%, PSG nights” 
1. 75/1.5 dose arm vs Placebo arm 
2. 25/5 dose arm vs Placebo arm 
3. 75/5 dose arm vs. 75/1.5 dose arm 
4. 75/5 dose arm vs. 25/5 dose arm 
5. 75/1.5 dose arm vs 25/5 dose arm 
Snoring index, PSG nights  
Snoring index is defined as number of snores per hour of sleep. 
Descriptive statistics (n, mean, SD, median, minimum, maximum) for absolute values and 
changes from baseline of snoring index will be presented by study visits and treatment 
group. 
Change from baseline in the Snoring index at second PSG visit (visit 4) will be compared 
between 75/5 dose and placebo group using ANCOVA with treatment group as factor and 
baseline results as a covariate.  
Adjusted means, Standard error (SE) of Adjusted means, 95% confidence intervals, within 
treatment p-values for each treatment group, treatment group difference, 95% confidence 


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interval of the difference and the between-treatment p-values based on the statistical model 
described above will also be presented 
Similar analysis will be carried out for following treatment comparison  
All statistical tests of hypotheses will be two-sided and will employ a level of significance 
1. 75/1.5 dose arm vs Placebo arm 
2. 25/5 dose arm vs Placebo arm 
3. 75/5 dose arm vs. 75/1.5 dose arm 
4. 75/5 dose arm vs. 25/5 dose arm 
5. 75/1.5 dose arm vs 25/5 dose arm 
Percent of sleep time in the various sleep stages, PSG nights 
Descriptive statistics (n, mean, SD, median, minimum, maximum) for absolute values and 
changes from baseline of percent sleep time in each sleep stages (WASO, Stage N1, Stage 
N2, Stage N3, Stage REM) will be provided by study visits and treatment group. The 
percentage of time in each sleep stage will be calculated using two different denominators; 
1) amount of time the patient was asleep, 2) total recording time. 
Arousal index, PSG nights 
Arousal is defined as the total number of all arousals per hour of sleep. 
Descriptive statistics (n, mean, SD, median, minimum, maximum) for absolute values and 
changes from baseline of arousal index will be presented by treatment group. 
Change from baseline in the Arousal index at second PSG visit (visit 4) will be compared 
between 75/5 dose and placebo group using ANCOVA with treatment group as factor and 
baseline results as a covariate.  
Adjusted means, Standard error (SE) of Adjusted means, 95% confidence intervals, within 
treatment p-values for each treatment group, treatment group difference, 95% confidence 
interval of the difference and the between-treatment p-values based on the statistical model 
described above will also be presented 
Similar analysis will be carried out for following treatment comparison  
All statistical tests of hypotheses will be two-sided and will employ a level of significance 
1. 75/1.5 dose arm vs Placebo arm 
2. 25/5 dose arm vs Placebo arm 
3. 75/5 dose arm vs. 75/1.5 dose arm 
4. 75/5 dose arm vs. 25/5 dose arm 
5. 75/1.5 dose arm vs 25/5 dose arm  


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Oxygen desaturation index, low-dose run in (25/1.5) vs. placebo, or vs 75/5 final dose, at-
home nights 
The oxygen desaturation index is the average number of oxygen desaturations 4% or more 
below the baseline level per hour of sleep. 
presented for the following comparisons: 
1. Within the 75/5 dose arm, proportion of ODI responders in 75/5 dose period vs 
proportion of ODI responders 25/1.5 low dose run-in period. The responders in 75/5 
dose period will be calculated from average of 2 baseline nights to average of 6 
treatment nights and the responders in 25/1.5 dose period will be calculated from 
average of 2 baseline nights to average of 3 run-in nights. 
2. For all 3 active arms combined (i.e. 75/5;75/1.5;25/5) proportion of ODI responders 
in 25/1.5 low dose run-in period vs proportion of ODI responders in placebo period. 
The responders will be calculated from average of 2 baseline nights to average of 3 
run-in nights and then the comparison will be done between combined active 
treatments vs placebo. 
Estimate of the odds ratio along with associated 95% Wald confidence interval (CI) and 
two-sided p-value will be presented  
All statistical tests of hypotheses will be two-sided and will employ a level of significance 
Proportion of apneas to hypopneas 
Proportion of apneas to hypopneas is defined as = H/(A+H). 
Where,  
A-Number of Apnea with onset during TST 
H-Number of Hypopnea with onset during TST 
This variable will be derived for each individual subject at both PSG visit (Visit 2 and 
Visit 4)  
Change from baseline in the proportion of apneas to hypopneas at second PSG visit (visit 4) 
will be compared between 75/5 dose and placebo group using ANCOVA with treatment 
group as factor and baseline results as a covariate. 
Adjusted means, Standard error (SE) of Adjusted means, 95% confidence intervals, within 
treatment p-values for each treatment group, treatment group difference, 95% confidence 
interval of the difference and the between-treatment p-values based on the statistical model 
described above will also be presented 
Similar analysis will be carried out for following treatment comparison on this efficacy 
variable. 
All statistical tests of hypotheses will be two-sided and will employ a level of significance 


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1. 75/1.5 dose arm vs Placebo arm 
2. 25/5 dose arm vs Placebo arm 
3. 75/5 dose arm vs. 75/1.5 dose arm 
4. 75/5 dose arm vs. 25/5 dose arm 
5. 75/1.5 dose arm vs 25/5 dose arm  
Correlation of phenotypic traits (Vpassive, Vactive, arousal threshold and Loop gain) with 
AHI response or subjective outcomes 
Sponsor’s research team and scientific advisors will perform this exploratory analysis using 
the PSG data to quantify two key contributors to OSA—pharyngeal collapsibility and 
compensatory muscle responsiveness—that is applicable to diagnostic polysomnography. 
4.10
Safety Evaluation 
All safety summaries and analyses will be based upon the safety population as defined in 
Section 4.4. 
4.10.1 Adverse Events 
AEs will be coded using MedDRA. The final version used will be designated in the clinical 
study report.  For each AE, the severity level of the event (mild, moderate, or severe) will 
be determined by Investigator opinion. 
Summary information including the number and percentage of subjects for treatment and 
overall by SOC and PT will be tabulated for: 
All AEs 
Pre-Treatment AE 
All AEs causally related (Related or Possibly related) to study treatment (as 
determined by the reporting investigator e.g. Not Related, unlikely related, possibly 
related, related) 
All SAEs 
All SAEs causally related (Related or Possibly related) to study treatment (as 
determined by the reporting investigator) 
All SUSARs 
All TEAEs 
All TEAEs causally related (Related or Possibly related) to study treatment (as 
determined by the reporting investigator) 
AEs that lead to discontinuation of study treatment 
All adverse events of special interest (AESI) 
TEAEs leading to death 
AEs by severity  
TEAEs by severity 
A Pre-treatment AE will be defined as any AE with an onset date before the date of first 
administration of study treatment. 


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Adverse event summaries will be ordered in terms of decreasing frequency for SOC, and 
PT within SOC. 
For each subject and each adverse event, the worst severity recorded will be attributed and 
used in the by-severity summaries.  Similarly, the worst causality (most related to 
treatment) will be attributed and used in the by-causality summaries.  If severity or 
causality is missing, the worst case will be assumed. 
A by-subject listing of all adverse events will be provided.  This listing will be presented 
by treatment group and will include: center, subject identifier, age, sex, race, adverse event 
(SOC, PT, and verbatim term), date of onset, date of resolution, duration, severity, 
seriousness, action taken, outcome and causality. 
A summary of the number of subjects with TEAE outcome into “Not recovered/Not 
resolved”, 
“Recovered/Resolved”, 
“Recovered/Resolved 
with 
sequelae”, 
“Recovering/Resolving”, “Fatal”, and “Unknown” categories for number of events by 
treatment group and overall will be provided. 
Death will be summarized by cause of death by the number and percentage of subjects 
experiencing events by treatment group and overall. Death data will also be listed. 
Patients who experienced a SAE will be listed. 
Imputation of partial dates 
AE start date 
If year is missing (or completely missing), do not impute. 
If (year is present and month and day are missing) or (year and day are present and 
month is missing), impute as January 1st. 
If year and month are present and day is missing, impute day as first day of the 
month. 
AE end date 
If year is missing (or completely missing), do not impute. 
If (year is present and month and day are missing) or (year and day are present and 
month is missing, impute as December 31st. 
If year and month are present and day is missing, impute day as last day of the 
month. 
When the patient has died in the same month/year of partial stop date, use date of 
death. 
In addition, for AEs, if for a partial start date, the AE start date could (when also 
considering the AE end date) potentially be on the first dose of study treatment date, the 
AE start date will be imputed with the first dose of study treatment date to assume a “worst 
case” scenario; e.g. AE from UNK-Jun-2017 to 23-Jul-2017 with the first dose of study 
treatment date 21-Jun-2017, then the AE start date will be imputed to 21-Jun-2017. 
4.10.2 Clinical Laboratory Evaluation 
An absolute value change from baseline and percentage change from baseline for all 
continuous hematology, serum chemistry and urinalysis laboratory parameter will be 


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summarized by analysis visit and treatment group, including scheduled and unscheduled 
assessment on-study period which spans the time drug is administered until the day of the 
patient’s last contact date within the study, will be provided. 
All laboratory test results will be listed by subject and study time point including changes 
from baseline (with the exception of urinalysis).  
A separate listing will contain only values outside of normal ranges.  
The number and percent of patients with clinically relevant abnormal laboratory findings 
will be tabulated by treatment group. The abnormal values will be flagged with ‘L’ for 
values below the lower limit of the clinical reference range and ‘H’ for values above the 
upper limit of the clinical reference range and included in the listings. The Investigator will 
assess whether the values outside the clinical reference range are clinically significant and 
these will be reported as abnormal not clinically significant (NCS) or abnormal clinically 
significant (CS). Clinically significant laboratory values will be recorded by the 
Investigator as AEs. 
Shift tables from baseline for the following category will also be provided. 
Hematology: Hemoglobin, Platelet Count, RBC Count, White Cells Count 
Serum chemistry: Albumin, ALT, AST, Creatinine, Alkaline phosphatase, 
Potassium, Calcium, Sodium, Bilirubin, Total cholesterol, Glucose, Protein, Uric 
acid, Bicarbonate 
For all other lab tests listing will be provided. 
4.10.3 Vital Signs, Physical Findings and Other Observations Related to Safety 
Vital Signs 
The following vital signs measurements will be obtained: 
Systolic blood pressure (SBP) [mmHg]. 
Diastolic blood pressure (DBP) [mmHg]. 
Pulse rate (bpm). 
Body temperature (oral) [°C]. 
Respiratory rate. 
Vital signs data will be listed by subject including changes from baseline. The baseline for 
the vital signs measurements will be the measurement at screening. 
Absolute values and changes from baseline will be presented by study visit and treatment 
group. 
Participants who experience systolic blood pressure 
 160, or diastolic blood pressure 
100, or heart rate 
 120 beats per minute will be tabulated separately. If triplicate vital 
signs are taken at a time point, the average value of the three measurements will be used 
for the above cutoffs.  
Shift tables from baseline for the following category will also be provided. 
Systolic blood pressure (SBP) [mmHg]. 


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Diastolic blood pressure (DBP) [mmHg]. 
Pulse rate (bpm). 
12-Lead ECG 
The following ECG parameters will be recorded: 
PR-interval (msec). 
QRS-interval (msec). 
QT-interval (msec). 
QTcF-interval (msec). 
Heart rate (HR) (beats per minute [bpm]). 
The ECG will be evaluated by the Investigator as ‘Normal’, ‘Abnormal, NCS’ or 
‘Abnormal, CS’. 
All ECG parameters will be listed by subject for each study visit and treatment group 
including changes from baseline. The baseline for the ECG measurements will be obtained 
at screening. 
Descriptive statistics (n, mean, SD, median, minimum, maximum) for absolute values and 
changes from baseline will be presented by study visit and treatment group.  
A categorical summary for change from baseline for QT and QTcF interval (msec) will 
also be provided. 
Physical Examination 
Physical examination findings will be summarized by body system for each treatment 
group at screening/baseline. 
All individual physical examination findings will be listed. 
Pregnancy test 
Positive pregnancy test results will be listed only. 
4.10.4 CSSA 
Descriptive statistics (n, mean, SD, median, minimum, maximum) for absolute values and 
changes from baseline will be presented for each CSSA item and the total score by 
treatment group at visit 4, visit 5 and if data is available Post 1 week of EOS. Only absolute 
values will be presented for Questions 4 and 5. 
All individual CSSA data will be listed as well. 
4.10.5 Prospective Suicidality Assessment 
Descriptive statistics (n, mean, SD, median, minimum, maximum) for absolute values and 
changes from baseline will be presented by study visit and treatment group. 
suicidality assessment will be displayed in a frequency table by study visit and treatment 
group. 


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suicidality assessment will be displayed. 
4.10.6 Safety Monitoring  
Safety monitoring will be guided by the established safety profiles of atomoxetine and 
oxybutynin, and by Phase 1 safety data for the combination. Safety assessments will 
include physical examinations, measurement of vital signs, monitoring and recording of 
AEs, SAEs, and pregnancies, suicidality assessment, recording of study or treatment 
discontinuations, measurement of ECGs, clinical laboratory evaluations, and memory 
testing. Effects on OSA and sleep parameters (e.g., sleep time and sleep stages) will also 
be monitored by PSG. 
Adverse events of special interest include effects on urine outflow, as both atomoxetine 
and oxybutynin are associated with urinary retention. Effects of atomoxetine on heart rate 
and blood pressure are expected to be modest and will also be monitored. Participants with 
serious cardiac abnormalities will be excluded from the study. Suicidal ideation in children 
and adolescents is a boxed warning for atomoxetine; however, analysis in adult patients, 
the target population for the proposed OSA study, did not reveal an increased risk of 
suicidal ideation or behavior in association with atomoxetine. Safety monitoring in the 
dose-finding study will use an appropriate questionnaire to monitor for the potential 
emergence of suicidal ideation or behavior. 
Daytime sleepiness is both a potential safety outcome and efficacy outcome in OSA. Both 
atomoxetine and oxybutynin are associated with somnolence, and oxybutynin is 
additionally associated with anticholinergic central nervous system (CNS) effects such as 
memory difficulty. Safety monitoring will therefore include psychomotor vigilance testing 
and memory testing.  
4.11
Other Analyses 
4.11.1 Digit Symbol Substitution Test (DSST) Results: 
Descriptive statistics (n, mean, SD, median, minimum, maximum) for absolute values and 
changes from baseline will be presented for DSST score by treatment group. The 
participant’s DSST score is the number of correct items in 120 seconds, i.e. (the number of 
items were completed – the number of items were incorrect). 
Change from baseline in the DSST Score from baseline to the second PSG visit will be 
compared between 75/5 dose and placebo group using ANCOVA with treatment group as 
factor and baseline results as a covariate.  
Adjusted means, Standard error (SE) of Adjusted means, 95% confidence intervals, within 
treatment p-values for each treatment group, treatment group difference, 95% confidence 
interval of the difference and the between-treatment p-values based on the statistical model 
described above will also be presented 
This analysis will be carried out for following treatment comparison  
1. 75/1.5 dose arm vs Placebo arm 
2. 25/5 dose arm vs Placebo arm 


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3. 75/5 dose arm vs. 75/1.5 dose arm 
4. 75/5 dose arm vs. 25/5 dose arm 
5. 75/1.5 dose arm vs 25/5 dose arm  
4.11.2 Delayed Word Recall Test (DWRT) Results 
Summary information (the number and percentage of subjects by visit and treatment) will 
be tabulated for total number word recalled (0-10) and not recalled (0-10). 
Change from baseline in the total number of words recalled from baseline to the second 
PSG visit will be compared between 75/5 dose and placebo group using ANCOVA with 
treatment group as factor and baseline results as a covariate. 
Adjusted means, Standard error (SE) of Adjusted means, 95% confidence intervals, within 
treatment p-values for each treatment group, treatment group difference, 95% confidence 
interval of the difference and the between-treatment p-values based on the statistical model 
described above will also be presented 
1. 75/1.5 dose arm vs Placebo arm 
2. 25/5 dose arm vs Placebo arm 
3. 75/5 dose arm vs. 75/1.5 dose arm 
4. 75/5 dose arm vs. 25/5 dose arm 
5. 75/1.5 dose arm vs 25/5 dose arm  
4.11.3 PSG Parameters 
PSG parameters are measured in accordance with the American Academy of Sleep 
Medicine (AASM) scoring manual (Version 2.4).  
Descriptive statistics (n, mean, SD, median, minimum, maximum) for absolute values will 
be presented for the following PSG parameters by study visits and treatment group. 
Summary statistics based on change from baseline variable only provided for the key PSG 
parameter. (details will be provided in the TLFs shell document)  
Periodic limb movements per hour  
Total recording time, Time in Bed, Total Sleep Time, Sleep Onset Latency, REM 
Latency, Latency to Persistent Sleep, Wake After Persistent Sleep and Sleep 
Efficiency. 
Spontaneous arousals per hour during sleep, Respiratory arousals per hour of sleep, 
PLM arousals per hour of sleep, Total number of all arousals per hour. 
Average apnea duration, Central Apneas per hour, Mixed Apneas per hour, 
Obstructive Apneas per hour, Hypopneas per hour 
Average heart rate during TST, total time in minute that SaO2 is less than 90% 
during TST, total time in minute that SaO2 is less than 80% during TST, minimum 
oxygen saturation during TST, mean Sa O2 during TST 
4.12
Determination of Sample Size 
The effect of the drug combination in OSA has been investigated in preliminary academic 
studies that provide an estimate of effect size in a population similar to the planned Phase 2 
study population. Data from a single-night cross-over study showed that a high proportion 


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Statistical Analysis Plan 
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of participants, 8/9 (88.9%), with demographic characteristics matched to the planned 
[BMI] between 18.5 and 40 kg/m2, and age from 25 to 65 years) when treated with a 
combination of 80 mg atomoxetine and 5 mg oxybutynin achieved a clinically relevant 
threshold of at least a 50% improvement in AHI score. Using a proposed sample size of 
n=35 for each of the 4 treatment groups, given 90% power and 2-sided alpha of 0.05, the 
sample size is powered to detect a difference in proportion of responders between the 
high-dose group and placebo, assuming a response rate as low as 37% in the high-dose 
group (compared with the preliminary data that suggests response rate may be as high as 
90%) and 5% in the placebo group, estimated based on typical test-retest variability of PSG. 
Alternatively, if test-retest variability of PSG is higher, resulting in a higher placebo 
response rate of 10%, the study retains 90% power assuming a response rate in the 
high-dose group of 46%. Participants that discontinue prior to the second PSG visit will 
not be replaced and will be considered non-responders. 
4.13
Changes in the Conduct of the Study or Planned Analysis 
Not applicable. 
5
REFERENCES 
[1] American Academy of Sleep Medicine (AASM) scoring manual (Version 2.4) 
[2] Apnimed Delayed Word Recall Test  
[3] Digit Symbol Substitution Test 
[4] The Epworth Sleepiness Scale 


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Statistical Analysis Plan 
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CONFIDENTIAL 
Project Document Version No. 1.0
Effective Date:  30 Jan 19 
Project Document Effective Date: 03Oct2019 
Related to:  SOP-GDO-WW-019 
Page 35 of 39 
6
APPENDICES 
6.1
Schedule of Assessments 
Table 1 
Schedule of Assessments 
Procedures 
Screening and Baseline 
PSG1 
Treatment Period 
Visit 5 
EOS2
Notes 
Non-PSG 
Daytime 
Visit 1 
PSG night and 
next morning, 
Visit 2  
Blinded 
baseline 
placebo, 
at-home dosing 
Double-blind 
study 
treatment, 
at-home Dosing 
Daytime 
Visit 3 
Visit 4 
PSG 
Visit 
Trial Day (Visit Window) 
-28 to -3 
-7 to -13
1 to 24
3 – 11 ± 25
66
12 ± 27
26 ± 4
Pre-screening 
X8
Determination 
of 
basic 
eligibility for the study 
Informed consent9
X 
Consent for genetic testing 
for CYP2D6  
X 
Inclusion and exclusion 
criteria 
X 
Demography 
X 
STOP-Bang Questionnaire 
X 
Only used for participants 
without a history of diagnosis 
of OSA or CPAP use 
Physical exam  
X 
Medical and surgical 
history 
X 
Includes drug and substance 
usage and psychiatric history 
Blood sample for CYP2D6 
genotype 
X 
Serum pregnancy test 
(WOCBP only) 
X 
X 


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Procedures 
Screening and Baseline 
PSG1 
Treatment Period 
Visit 5 
EOS2
Notes 
Non-PSG 
Daytime 
Visit 1 
PSG night and 
next morning, 
Visit 2  
Blinded 
baseline 
placebo, 
at-home dosing 
Double-blind 
study 
treatment, 
at-home Dosing 
Daytime 
Visit 3 
Visit 4 
PSG 
Visit 
Trial Day (Visit Window) 
-28 to -3 
-7 to -13
1 to 24
3 – 11 ± 25
66
12 ± 27
26 ± 4
Urine drugs of abuse10
testing, ethanol testing  
X 
Randomization 
X 
Randomization takes place 
the morning after PSG testing 
for participants that qualify 
Medication distribution to 
participant, and study 
instructions and device 
X 
Prior to discharge morning 
after PSG 
QHS self-administration of 
baseline placebo  
X 
2 nights of QHS placebo, at 
home, 
all 
participants; 
administer ~30 minutes prior 
to bedtime 
International Prostate 
Symptom Scale 
X 
Male participants only 
QHS administration of 
randomized study treatment 
(combination drug or 
placebo) 
X 
X 
Total of 10 nights: 3 nights 
low dose (25 mg atomoxetine/ 
1.5 mg oxybutynin) followed 
by 7 nights randomized study 
treatment 
for 
participants 
randomized to active drug; 
10 nights 
placebo 
for 
participants randomized to 
placebo. 
“Reminder” telephone 
call/message 
X 
Day 10, participants reminded 
about study procedures and 
upcoming PSG visit11
Clinical laboratory 
assessments (hematology, 
X 
X 
X 


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Procedures 
Screening and Baseline 
PSG1 
Treatment Period 
Visit 5 
EOS2
Notes 
Non-PSG 
Daytime 
Visit 1 
PSG night and 
next morning, 
Visit 2  
Blinded 
baseline 
placebo, 
at-home dosing 
Double-blind 
study 
treatment, 
at-home Dosing 
Daytime 
Visit 3 
Visit 4 
PSG 
Visit 
Trial Day (Visit Window) 
-28 to -3 
-7 to -13
1 to 24
3 – 11 ± 25
66
12 ± 27
26 ± 4
clinical chemistry and 
urinalysis) 
12-lead ECG 
X 
X 
Vital signs12
X 
X 
X 
X 
Visit 4 measure both pre-dose 
and 
post-awakening 
from 
PSG 
AE/SAE monitoring 
X 
X 
X 
X 
X 
X 
Study Instruction Reminder 
X 
Oximeter Battery Change 
X 
Prior/concomitant 
medication monitoring 
X 
X 
Inpatient Polysomnography 
X 
X 
ESS 
X 
X 
X 
Measured 
to 
determine  
eligibility and as efficacy 
outcome on PSG nights
CSSA 
X 
X 
X13
Item 17 of the CSSA is used 
to assess suicidality
Patient Global Impression-
Severity 
X 
X 
Measured evening of baseline 
PSG and Visit 4 PSG 
Patient Global Satisfaction 
with Treatment 
X 
Home Oximetry  
X 
X 
Oximeter used all at-home 
dosing nights 


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Procedures 
Screening and Baseline 
PSG1 
Treatment Period 
Visit 5 
EOS2
Notes 
Non-PSG 
Daytime 
Visit 1 
PSG night and 
next morning, 
Visit 2  
Blinded 
baseline 
placebo, 
at-home dosing 
Double-blind 
study 
treatment, 
at-home Dosing 
Daytime 
Visit 3 
Visit 4 
PSG 
Visit 
Trial Day (Visit Window) 
-28 to -3 
-7 to -13
1 to 24
3 – 11 ± 25
66
12 ± 27
26 ± 4
Delayed Word Recall Test  
X 
X 
Administer at similar time 
after awakening after each 
PSG  
DSST 
X 
X 
Administer at similar time 
after awakening after each 
PSG 


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Abbreviations: AE = adverse event; CPAP = continuous positive airway pressure; CSSA = Cocaine Selective Severity Assessment; CYP2D6 = cytochrome 
P450 2D6; DSST = Digit Symbol Substitution Test; ECG = electrocardiogram; EOS = end of study; ESS = Epworth Sleepiness Scale; HIV = human 
immunodeficiency virus; ICF = informed consent form; IRB = Institutional Review Board; IRT = Interactive Response Technology; OSA = obstructive sleep 
apnea; PSG = polysomnography; QHS = 1 dose taken at bedtime; SAE = serious adverse event; STOP-Bang = Snoring, Tiredness, Observed apnea, Blood 
Pressure-Body mass index, Age, Neck circumference and Gender criteria; WOCBP = women of childbearing potential. 
1 
Following pre-screening, participants who meet basic eligibility requirements will be screened during a visit that includes non- PSG evaluations. Participants 
who otherwise are eligible will be scheduled for an overnight PSG study. 
2 
If a participant discontinues from the study, all EOS procedures should be performed at the discontinuation visit, within 48 hours of the last study dose. 
3 
Final study eligibility is determined the morning after the PSG exam, based on PSG and non-PSG findings, and enrolled participants are randomized and 
dispensed the study drug. The first dose of study drug should generally be taken that night; however, at the discretion of the investigator, the first night of 
study treatment dosing can occur up to 1 week later to accommodate scheduling of the on-drug PSG exam. 
4 
Trial day includes overnight through morning completion of endpoints.  
5 
Daily bedtime dosing (qhs in the protocol synopsis) continues through Visit 4 PSG night, i.e., through PSG visit window; final night of study treatment 
dosing is PSG night. 
6 
Can occur as late as day as Day 7, if necessary for scheduling. 
7 
Preference is for PSG Visit 4 to be on Day 12, but, if necessary to fit individual participant scheduling, may be ± 2 days. 
8 
Conducted prior to screening/PSG admission; per IRB-approved pre-screening procedures. 
9 
No trial-related assessment is to be carried out before the participant has signed the ICF. Any participant who provides informed consent will have a 
screening number assigned by the IRT system. 
10 Includes amphetamine; barbiturates; benzodiazepines; buprenorphine/metabolite; cannabinoids, cocaine/metabolites; Methylenedioxymethamphetamine; 
methadone/metabolite; opiates; oxycodone/oxymorphone; phencyclidine; by enzyme-linked immunosorbent assay method; test sample is urine.
11 Participants must return to PSG lab with study medication, pulse oximeter and study diary. 
12 Vital signs include the following: seated blood pressure, pulse, respiratory rate; AE collection refers to spontaneous AEs. Participants who experience 
13 If there are any responses to individual items at EOS Visit that are more than 4 points worse than baseline exam, CSSA is repeated by telephone at 1 week 
post EOS Visit.