Clinical trial NCT04631107
Conditions: Obstructive Sleep Apnea
Sponsor: Apnimed
Start date: 2020-12-22; Completion date: 2021-05-31
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a randomized, 3-period, placebo-controlled, crossover, phase 2 clinical study to examine the efficacy and safety of 2 doses of AD109 vs placebo in patients with mild obstructive sleep apnea.

Detailed description:
Participants underwent initial pre-screening to determine potential study eligibility. Participants selected for further screening had either a previous history of OSA of a severity consistent with enrollment criteria or were at high risk (e.g. as assessed by STOP-Bang Questionnaire score). Only participants who met all non polysomnography (PSG) enrollment criteria at Visit 1 were eligible for a screening PSG.

Arms: arm 1: AD109 Dose 1- 75 mg (A), then AD109 Dose 2- 37.5 mg (B), then Placebo (C). arm 2: AD109 Dose 1- 75 mg (A), then Placebo (C) then AD109 Dose 2- 37.5 mg (B) arm 3: AD109 Dose 2- 37.5 mg (B), then AD109 Dose 1- 75 mg (A), then Placebo (C) arm 4: AD109 Dose 2- 37.5 mg (B), then Placebo (C), then AD109 Dose 1- 75 mg (A) arm 5: Placebo (C), then AD109 Dose 1- 75 mg (A), then AD109 Dose 2- 37.5 mg (B) arm 6: Placebo (C), then AD109 Dose 2- 37.5 mg (B), then AD109 Dose 1- 75 mg (A)
Interventions: intervention 1: AD109 dose1- A intervention 2: AD109 dose2- B intervention 3: Placebo- C
Intervention descriptions: intervention 1: Oral administration at bedtime intervention 2: Oral administration at bedtime intervention 3: Oral administration at bedtime

Protocol documents:
Prot_000.pdf: 
 
Apnimed, Inc.
20 Holyoke Street
Cambridge, MA 02138
info@apnimed.com
Page 1 of 1 
CONFIDENTIAL. DO NOT DISTRIBUTE WITHOUT PERMISSION. 
August 1, 2022 
 
To: ClinicalTrials.gov 
 
This is a cover page to the redacted clinical protocol for APC-004 titled Phase 2 Randomized 
Double-Blind Placebo-Controlled 3-Period Single-Dose Crossover Study to Evaluate the Safety 
and Efficacy of Two Doses of AD-109 in Mild to Moderate Obstructive Sleep Apnea. 
 
The APC-004 clinical protocol is associated with NCT04631107.   
 
The following proprietary information was redacted from the clinical protocol for APC-004:  
 IND number 
 
Sincerely, 
 
 
 
Jeanne Brittain 
Director, Program Management 
 
 
Quality Approval:   
Name 
Title 
Signature 
Date 
Francesca 
Kelvy 
Senior Director, GXP 
Quality Assurance 
 
 
 
 




Apnimed, Inc.  
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Title Page 
Protocol Title: Phase 2 Randomized Double-Blind Placebo-Controlled 3-Period Single-Dose 
Crossover Study to Evaluate the Safety and Efficacy of Two Doses of AD-109 in Mild to 
Moderate Obstructive Sleep Apnea 
Protocol Number: APC-004 
Version Number: 2.0 
Compound Number: AD109 
Short Title: AD109 Dose Finding in Mild to Moderate OSA 
Sponsor Name and Legal Registered Address:  
Apnimed, Inc. 
20 Holyoke Street 
Cambridge, MA 02138 
Regulatory Agency Identifying Number: IND 141505 
Approval Date: 6 January 2021 
Date and Version of Previous Protocol:  12 November 2020 
 
 
 


Apnimed Inc.
Protocol APC-OO4/IND 141505
Sponsor Signatory:
RonaldFarkas, MD
ChiefMedical Officer
Clinical Sfudy Protocol
CONFIDENTIAL
/i;- 
LaL/
6 January 2021
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Table of Contents 
 
1 
Protocol Summary ....................................................................................................... 5 
1.1 
Synopsis ............................................................................................................................ 5 
1.2 
Schedule of Activities (SoA) ............................................................................................ 7 
2 
Introduction .................................................................................................................. 9 
2.1 
Study Rationale ................................................................................................................ 9 
2.2 
Background ...................................................................................................................... 9 
2.2.1 
Obstructive Sleep Apnea ................................................................................................ 9 
2.2.2 
Unmet Medical Need ................................................................................................... 10 
2.2.3 
Biological Rationale ..................................................................................................... 10 
3 
Endpoints ..................................................................................................................... 11 
4 
Study Design ................................................................................................................ 11 
4.1 
Overall Design ................................................................................................................. 11 
4.2 
Scientific Rationale for Study Design and Dose ............................................................ 14 
4.3 
End of Study Definition ................................................................................................. 14 
5 
Study Population ........................................................................................................ 14 
5.1 
Inclusion Criteria ............................................................................................................ 14 
5.2 
Exclusion Criteria ........................................................................................................... 16 
5.3 
Meals and Dietary Restrictions ...................................................................................... 18 
5.4 
Caffeine, Alcohol, and Tobacco ..................................................................................... 18 
5.5 
Activity ........................................................................................................................... 18 
5.6 
Screen Failures ............................................................................................................... 18 
6 
Study Treatment ......................................................................................................... 19 
6.1 
Study Treatment(s) Administered ................................................................................... 19 
6.2 
Preparation/Handling/Storage/Accountability ............................................................... 19 
6.3 
Measures to Minimize Bias: Randomization and Blinding ............................................ 20 
6.4 
Concomitant Therapy ..................................................................................................... 20 
6.5 
Discontinuation of Study Treatment ............................................................................... 22 
6.6 
Stopping Criteria ............................................................................................................ 23 
6.6.1 
Individual Participant Stopping Criteria ...................................................................... 23 
6.7 
Participant Discontinuation/Withdrawal from the Study ............................................... 23 
6.8 
Loss of Participants to Follow-Up .................................................................................. 24 
7 
Study Assessments and Procedures .......................................................................... 24 
7.1.1 
Polysomnography ......................................................................................................... 25 


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7.2 
Safety Assessments ......................................................................................................... 25 
7.2.1 
Physical Examinations ................................................................................................. 25 
7.2.2 
Vital Signs .................................................................................................................... 26 
7.2.3 
Electrocardiograms ...................................................................................................... 26 
7.2.4 
Clinical Safety Laboratory Assessments ...................................................................... 26 
7.3 
Adverse Events and Serious Adverse Events ................................................................. 27 
7.3.1 
Time Period and Frequency for Collecting AE and SAE Information ........................ 27 
7.3.2 
Method of Detecting AEs and SAEs ............................................................................ 27 
7.3.3 
Follow-up of AEs and SAEs ........................................................................................ 27 
7.3.4 
Regulatory Reporting Requirements for SAEs ............................................................ 28 
7.3.5 
Pregnancy ..................................................................................................................... 28 
7.4 
Treatment of Overdose ................................................................................................... 28 
7.5 
Pharmacokinetics ............................................................................................................ 29 
8 
Statistical Considerations .......................................................................................... 29 
8.1 
Sample Size Determination ............................................................................................ 29 
8.2 
Populations for Analyses ................................................................................................ 29 
8.3 
Interim Analyses ............................................................................................................. 30 
9 
Supporting Documentation and Operational Considerations ............................... 30 
9.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........................ 30 
9.1.1 
Regulatory and Ethical Considerations ........................................................................ 30 
9.1.2 
Financial Disclosure ..................................................................................................... 31 
9.1.3 
Informed Consent Process ........................................................................................... 31 
9.1.4 
Data Protection ............................................................................................................. 32 
9.1.5 
Data Quality Assurance ................................................................................................ 32 
9.1.6 
Source Documents ....................................................................................................... 33 
9.1.7 
Study and Site Closure ................................................................................................. 34 
9.1.8 
Publication Policy ........................................................................................................ 34 
9.1.9 
Protocol Approval and Amendment ............................................................................. 34 
9.1.10 
Liability and Insurance ................................................................................................. 35 
9.2 
Appendix 2: Clinical Laboratory Tests ........................................................................... 36 
9.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ............................................................................................ 37 
9.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information .......... 44 
9.5 
Appendix 5: List of Abbreviations ................................................................................. 48 
9.6 
Appendix 6: List of Amendment History ....................................................................... 49 
10 
References ................................................................................................................... 52 
 


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1 Protocol Summary 
1.1 Synopsis 
Protocol Title:  
Sponsor Study No.:  
Phase: 2 
Sponsor: Apnimed, Inc. 
Rationale: 
Apnimed is developing the combination of atomoxetine and oxybutynin for the treatment of 
obstructive sleep apnea (OSA). Initial Phase 2 studies of the combination were conducted with 
marketed oxybutynin (combination designated AD-036), which is a racemic mixture of R- and S-
oxybutynin. Subsequent development is being pursued with R-oxybutynin (combination 
designated AD-109), a new enantiomerically pure form of oxybutynin which is proposed to have 
an improved safety and efficacy profile in OSA compared to racemic oxybutynin.   
Previous studies of AD-036 provided dose-response efficacy and safety data across a broad 
spectrum of OSA disease severity. Study APC-004 is designed to extend and confirm these 
findings to AD-109 in a population with mild- to moderate OSA, in parallel with other studies of 
AD-109 planned by Apnimed in moderate- to severe OSA. 
Overall Design: 
Study APC-004 is a randomized, double blind, placebo-controlled, 3-period, single-dose 
crossover study in patients with mild- to moderate OSA. A screening visit and polysomnographic 
(PSG) exam will be conducted to establish that each participant meets study enrollment criteria. 
Each participant will then receive a single dose of each of the following during 3 overnight PSG 
exams, each separated by a one week washout period: 
• Atomoxetine 75 mg + R-oxybutynin 2.5 mg (i.e. 75/2.5) 
• Atomoxetine 37.5 mg + R-oxybutynin 2.5 mg (i.e. 37.5/2.5) 
• Placebo 
Primary efficacy and safety endpoints will compare the 75/2.5 and 37.5/2.5 doses to each other 
and to placebo.  
 


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Number of Participants: 
A total of 30 participants will be enrolled. 
Study Duration: 
The overall study duration will be up to 12 weeks, as follows:  
• Screening, up to 4 weeks; 
• 3-period crossover, up to 6 weeks; 
• End of Study Evaluation, 2 weeks post crossover period 


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1.2 Schedule of Activities (SoA)  
Table 1 
Schedule of Activities 
                                                 
1 Each washout period is a minimum of 7 days 
2 Includes ESS, PGI-S, and history of OSA symptoms 
3 WOCBP only 
4 Only patients who meet all non-PSG enrollment criteria at Visit 1 are eligible for a screening PSG  
5 Randomization occurs when participant meets enrollment criteria up to the time of the first crossover period. 
6 Study medication administered immediately before lights out 
7 Administer at similar time after awakening after each crossover PSG, approximately 1 hour after awakening 
8 Vital signs include the following: seated blood pressure, pulse, respiratory rate; vital signs on PSG nights taken after admission to PSG lab. 
Procedures 
 Screening 
3-Way Crossover Period 
End of Study 
Evaluation 
V1 
V2 
V3  
Wash-out 
1 
V4 
Wash-out  
V5 
Wash-out  
Trial Day (Visit Window) 
Up to 4 weeks 
Up to 6 weeks  
2 wks post V5 ± 3 d 
Informed consent 
X 
 
 
 
 
 
 
 
 
Non-PSG enrollment criteria2 
X 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Physical exam  
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Clinical laboratory testing  
X 
 
 
 
 
 
 
 
X 
Pregnancy test3 
X 
 
 
 
 
 
 
 
 
12 Lead ECG 
X 
 
 
 
 
 
 
 
 
PSG Exam 
 
X4 
X 
 
X 
 
X 
 
 
Randomization5 
 
 
X 
 
 
 
 
 
 
HS study treatment6  
 
 
X 
 
X 
 
X 
 
 
DSST, KSS, Sleep quality VAS7 
 
 
X 
 
X 
 
X 
 
 
Vital signs8 
X 
X 
X 
 
X 
 
X 
 
 
AE/SAE monitoring 
 
 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Abbreviations: AE = adverse event; DSST = Digit Symbol Substitution Test; ECG = electrocardiogram; ESS = Epworth sleepiness scale; KSS = Karolinska 
sleepiness scale; PGI-S = patient global impression of severity of OSA; PSG = polysomnography; SAE = serious adverse event; VAS = visual analog scale; 
WOCBP = women of childbearing potential. 


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2 Introduction 
2.1 Study Rationale 
Previous studies conducted by Apnimed (under IND 136752) and academic investigators support 
that the combination of atomoxetine and oxybutynin is safe and effective for the treatment of 
OSA. These initial Phase 2 studies of the combination were conducted with marketed oxybutynin 
(combination designated AD-036), which is a racemic mixture of R- and S-oxybutynin. 
Subsequent development (under IND 141505) is being pursued by Apnimed with R-oxybutynin 
(combination designated AD-109), a new enantiomerically pure form of oxybutynin which is 
proposed to have an improved safety and efficacy profile in OSA compared to racemic 
oxybutynin.   
Previous studies of AD-036 provided dose-response efficacy and safety data across a range of 
doses. Doses of atomoxetine ranged between 25 mg and 80 mg, and doses of racemic oxybutynin 
between 1.5 and 5 mg. Combinations with the highest doses were clearly more effective than 
combinations with the lowest doses, with mid-range doses retaining substantial efficacy. All 
doses were safe and well-tolerated, with suggestion of positive correlation between dose and 
generally mild adverse effects. Study APC-004 is designed to extend and confirm these findings 
to AD-109, combining a dose of 2.5 mg R-oxybutynin with either 75 mg or 37.5 mg 
atomoxetine. Study APC-004 will enroll patients with mild- to moderate OSA, in parallel with 
other studies of AD-109 planned by Apnimed in moderate- to severe OSA.  
 
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 


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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 
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 
AD109 is a new fixed dose drug combination of atomoxetine and R-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. R-oxybutynin has never 
been marketed, but racemic oxybutynin is approved as 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.  


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Efficacy of oxybutynin in overactive bladder may result both from antimuscarinic effects of 
oxybutynin and smooth muscle spasmolytic effects. The contribution to efficacy of oxybutynin in 
OSA is believed to be related to antimuscarinic effects, whereas spasmolytic effects may lead to 
effects on the bladder that are undesirable in typical OSA patients. The R-enantiomer of 
oxybutynin has been shown to confer the antimuscarinic effect of oxybutynin, whereas the 
spasmolytic effects (and other effects on calcium channel antagonism and local anesthetic effects) 
are non-stereoselective properties of both the enantiomers.  Apnimed therefore believes that the 
combination of the R-enantiomer of oxybutynin with atomoxetine may have an improved safety 
and efficacy profile in OSA compared to the combination with the racemate of oxybutynin.  
3 Endpoints 
 
4 Study Design 
4.1 Overall Design 
Study APC-004 is a randomized, double blind, placebo-controlled, 3-period, single-dose 
crossover study to evaluate the safety and efficacy of two different dose combinations of AD-109 
in patients with mild- to moderate OSA. Participants will undergo initial pre-screening to 
 
Endpoints 
Primary 
 
• 
Change in Hypoxic Burden (HB)  4% (scored in reference to AHI 4%), 75/2.5 
dose vs. placebo  
Secondary 
 
• 
Change in HB 4%, 37.5/2.5 dose vs. placebo and vs. 75.2.5 
• 
Change in Apnea Hypopnea Index (AHI) 4% 
• 
Change in Oxygen Desaturation Index (ODI) 
• 
Total time with SaO2 <90%, PSG nights 
• 
Proportion of participants with ≥50% reduction, AHI, HB and ODI 
Exploratory 
• 
Karolinska sleepiness scale 
• 
Sleep Quality VAS 
• 
AHI 3% (hypopnea scored when associated with 3% O2 desaturation or arousal) 
• 
OSA endotypes endpoints (Vpassive, Vactive, Muscle Compensation, Loop Gain)  
• 
PSG sleep and arousal parameters 
Safety Endpoints 
• 
Physical exam, vital signs, clinical laboratory assessment 
• 
Spontaneous adverse events, including the post-dosing period 
• 
DSST 
• 
PSG parameters: heart rate, ECG, EEG, oximetry 
Abbreviations: AHI = apnea-hypopnea index; DSST = Digit Symbol Substitution Test; ECG = electrocardiogram; 
EEG = electroencephalogram; HB = hypoxic burden; ODI = Oxygen Desaturation Index; OSA = obstructive sleep 
apnea; PSG = polysomnography; SaO2 = oxygen saturation. 


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determine potential study eligibility. Patients selected for further screening should either have a 
previous history of OSA of a severity consistent with enrollment criteria or be at high risk (e.g. 
as assessed by STOP-Bang Questionnaire score).  Only patients who meet all non-PSG 
enrollment criteria at Visit 1 are eligible for a screening PSG.  
Patients who meet all enrollment criteria will be randomized to receive the following 
experimental treatments, one treatment on each of 3 PSG night, separated by at least a one week 
washout period: 
• Atomoxetine 75 mg + R-oxybutynin 2.5 mg (i.e. 75/2.5) 
• Atomoxetine 37.5 mg + R-oxybutynin 2.5 mg (i.e. 37.5/2.5) 
• Placebo 
Dosing of the study treatment will occur immediately prior to lights out. The morning following 
each PSG exam in the crossover period the DSST, KSS, and sleep quality VAS will be 
administered approximately 1 hour after awakening.  
Each PSG night is followed by a 1-week washout period. AE/SAE information is recorded at 
each study visit and by telephone contact with participants during each washout period. 
Primary efficacy and safety endpoints will compare the 75/2.5 and 37.5/2.5 doses to each other 
and to placebo. AE/SAE information is recorded at each study visit and at the End of Study 
Evaluation. 
Participants who withdraw from the study will not be replaced. No subsequent open-label 
extension is planned following the study. 


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Figure 1: 
Overview of Study Design 
 
 PSG = polysomnography. 
 


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4.2 Scientific Rationale for Study Design and Dose 
Previous Phase 2 studies conducted by Apnimed and academic collaborators support that the 
combination of atomoxetine and racemic oxybutynin is effective for OSA over a wide range of 
disease severity.  This study will extend findings in patients with mild- to moderate OSA, 
whereas other planned studies will examine patients with moderate- to severe OSA. 
This study is designed to provide additional dose ranging efficacy and safety data for doses of 
atomoxetine in the middle- and higher-range of doses previously studied. Completed studies of 
AD036 support efficacy and safety of 5 mg racemic oxybutynin in combination with 
atomoxetine. Because the R-enantiomer of oxybutynin confers about 2-fold the anticholinergic 
activity of the racemate, with such activity thought to be the major contributor to efficacy in 
OSA, the dose of R-oxybutynin will be 2.5 mg in this study. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of AD109 is 
provided in the Investigator’s Brochure. 
4.3 End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of the 
study through 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 
Eligible participants will be recruited both from the existing clinic population at the study sites, 
including databases of previous subjects who participated in other studies, and through direct 
advertising to the community.  
Participants must be able to provide written consent and meet all the inclusion criteria and none 
of the exclusion criteria. 
5.1 Inclusion Criteria 
Age and Sex 
1. Between 25 to 65 years of age, inclusive, at the Screening Visit. 


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Disease Measures  
2. AHI 5 to 20 (hypopneas defined by 4% oxygen desaturation) 
3. PGI-S ≥ 1, or history of one or more of the following OSA symptoms:  
• Snoring or nighttime gasping/choking 
• Daytime sleepiness, fatigue, or decreased concentration 
• Nonrefreshing sleep, sleep fragmentation (including from nocturia), or morning 
headache  
• Irritability, decreased mood or libido  
Weight 
3. BMI between 18.5 and 40.0 kg/m2, inclusive, at the pre-PSG visit. 
Male participants: 
4. 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: 
5. 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.  
6. 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 
7. 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. 
8. Participant must be able to understand the nature of the study and must have the 
opportunity to have any questions answered. 


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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 (combination 
medications are considered as 1 medication for this purpose).  
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, urinary retention or 
insomnia. 
8. Medically unexplained positive screen for drugs of abuse (excluding THC/marijuana) or 
history of 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 as determined by investigator. 
11. Untreated narrow angle glaucoma.  
12. Women who are pregnant or nursing. 
Prior/Concomitant Therapy 
13. CPAP should not be used for at least 2 weeks prior to first study PSG and throughout the 
study. 
14. 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. 


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15. 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. 
16. History of oxygen therapy. 
17. Use of medications from the list of disallowed concomitant medications. 
18. 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 
19. Use of another investigational agent within 30 days or 5 half-lives, whichever is longer, 
prior to dosing.  
Diagnostic Assessments 
20. Hepatic transaminases >2X the upper limit of normal (ULN), total bilirubin >1.5X ULN 
(unless confirmed Gilbert syndrome), estimated glomerular filtration rate  < 60 ml/min.  
Other Exclusions 
21. <5 hours typical sleep duration.  
22. ESS > 18 
23. Night- or shift-work sleep schedule which causes the major sleep period to be during the 
day.  
24. Employment as a commercial driver or operator of heavy or hazardous equipment. 
25. Smoking more than 10 cigarettes or 2 cigars per day, or inability to abstain from smoking 
during overnight PSG visits. 
26. Unwilling to use specified contraception.  
27. Unwilling to limit during the study period alcohol consumption to no greater than 2 
units/day for men or 1 unit/day for women, not to be consumed within 3 hours of bedtime. 
28. Unwilling to limit during the study period 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. 


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29. 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. 
30. Participant considered by the investigator, for any reason, an unsuitable candidate to 
receive AD109 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. 
5.4 Caffeine, Alcohol, and Tobacco 
1. During the outpatient portions of the study, participants should refrain from more than 2 
standard units per day of alcohol for men or 1 unit/day for women, consumed no less than 
3 hours prior to bedtime. Alcohol should not be consumed on PSG nights. 
2. Moderate consumption of caffeinated beverages, containing up to a total of 400 mg 
caffeine per day, is permitted during the study period, 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). 


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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. 
6.1 Study Treatment(s) Administered 
One tablet of co-formulated atomoxetine and R-oxybutynin or matching placebo is taken 
immediately before the participant’s planned bedtime.  
Study Treatment Name: 
Atomoxetine 
hydrochloride/R-
oxybutynin 
chloride 
Atomoxetine 
hydrochloride/R-
Oxybutynin 
chloride 
Placebo 
 
Dosage Formulation: 
Tablet 
Tablet 
Tablet 
Dosage Level: 
37.5mg / 2.5mg 
75mg / 2.5mg  
N/A 
Route of Administration: 
Oral 
Oral 
Oral 
Dosing Instructions: 
1 tablet 
administered with 
up to 240 mL 
water  
1 tablet 
administered with 
up to 240 mL 
water  
1 tablet 
administered with 
up to 240 mL 
water 
Storage/Packaging/Labeling: 
 
Store at room 
temperature, in 
HDPE bottles 
Store at room 
temperature in 
HDPE bottles 
Store at room 
temperature in 
HDPE bottles 
 
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. 


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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, sites are 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 for the crossover phase of the study. Each 
participant will be assigned a unique number (randomization number) that encodes the 
participant’s assignment to 1 of the sequences of the study, according to the randomization 
schedule using a validated computer program.  
Returned study treatment should not be redispensed to the participants. 
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. 
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 Concomitant Therapy 
Concomitant therapy with the medications listed below is disallowed. For medication that is 
typically used as-needed for symptomatic conditions (e.g. occasional use of a sleep aid), the 
medication should not be used for at least one week prior to the first study PSG and for the 
duration of the study.  
• MAOIs or other drugs that affect monoamine concentrations (e.g., rasagiline) [MAOIs are 
contraindicated for use with atomoxetine] 


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• 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 including 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 


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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 1 month 
prior to enrollment, 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) 
• 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 
6.5 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). 


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6.6 Stopping Criteria 
6.6.1 
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 considered possibly related or related to study treatment. 
• 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. 
6.7 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. 
• 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 


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o Other 
6.8 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. 
7 Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA. 
• 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 approximately 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. 


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7.1.1 
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. 
• Scoring: All PSG studies (including screening PSG) will be scored by centralized PSG 
technologists, blinded to treatment assignment. Scoring will be conducted according to the 
American Academy of Sleep Medicine manual scoring criteria. 
7.2 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 and 2 safety data for the combination. Safety assessments will 
include physical examinations, measurement of vital signs, monitoring and recording of AEs, 
SAEs, and pregnancies, recording of study or treatment discontinuations. 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. Daytime sleepiness is both a potential safety outcome and efficacy outcome in 
OSA. Both atomoxetine and oxybutynin may be associated with somnolence, and oxybutynin 
is additionally associated with anticholinergic CNS effects such as memory difficulty.  
7.2.1 
Physical Examinations 
• The general physical examination at screening 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). 


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• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
7.2.2 
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.  
• 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). 
7.2.3 
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. The ECG will be recorded in the 
semi-supine position after the participant has rested in this position for at least 10 minutes. 
7.2.4 
Clinical Safety Laboratory Assessments 
• Refer to Section 9.2 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 and document this review. The laboratory 
reports must be filed with the source documents.  
• All protocol-required laboratory assessments 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. 


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7.3 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. 
7.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from randomization until the end of the study at the 
timepoints specified in the SoA. 
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 
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. 
7.3.2 
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. 
7.3.3 
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 


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event is otherwise explained, or the participant is lost to follow-up. Further information on 
follow-up procedures is given in Appendix 3. 
7.3.4 
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. 
7.3.5 
Pregnancy 
• Details of all pregnancies in female 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. 
7.4 Treatment of Overdose 
For this study, any dose of atomoxetine hydrochloride greater than 75 mg and of R-oxybutynin 
chloride greater than 2.5 mg more frequently than QHS will be considered an overdose. 


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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 R-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. 
7.5 Pharmacokinetics 
PK parameters are not evaluated in this study. 
8 Statistical Considerations 
8.1 Sample Size Determination 
A total of 30 patients will enter the 3-treatment crossover study. The study will have 80% power 
to detect a treatment difference on the primary endpoint at a two-sided 0.05 significance level, if 
the true difference between treatments on HB is at least -3.7 %min/h. This assumes that the 
within-subject standard deviation is 9 and a discontinuation rate of less than 20%. 
8.2 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. 
Participants in this population will be analyzed according to the 
treatment they actually received. 
 
8.3 Interim Analyses 
No interim analysis is planned.  
9 Supporting Documentation and Operational Considerations 
9.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
9.1.1 
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. 
• Applicable laws and regulations. 


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• 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. 
9.1.2 
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. 
9.1.3 
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. 
9.1.4 
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. 
9.1.5 
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. 


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• 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. 
• 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. 
9.1.6 
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. 


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9.1.7 
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. 
9.1.8 
Publication Policy 
• The Sponsor will generally support publication of multicenter studies only in their entirety 
and not as individual site data.  
• Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
• The Sponsor retains the right to disapprove any submission for publication, including any 
publication using trial data, including abstracts, presentations or manuscripts. 
• A summary of the study results will also be posted in a publicly accessible database (e.g., 
www.ClinTrials.gov).  
 
9.1.9 
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. 


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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. 
9.1.10 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. 
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. 
9.1.10.1 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 
the CRO and the Sponsor of the necessary support at all times. 


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9.2 Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 2 will be performed by the local laboratory. 
• 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. 
Table 2: Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Hematocrit 
Hemoglobin 
Platelet Count 
RBC Count 
RBC Indices (MCV, 
MCH, MCHC) 
 
WBC count with Differential 
 
Serum Chemistry Albumin 
BUN 
Creatinine 
Potassium 
Sodium  
Bilirubin (total) 
Total Protein  
Uric acid 
ALT 
AST 
Alkaline phosphatase 
Calcium 
Glucose  
Total cholesterol 
Chloride 
Bicarbonate 
Routine 
Urinalysis 
• Specific gravity, bilirubin, color, appearance, leukocyte esterase, 
nitrite, pH, protein (albumin), glucose, ketones, occult blood, 
urobilinogen 
• Reflex microscopy  
Other Tests 
• HbA1c (Screening Visit only) 
• Serum hCG pregnancy test at screening. Additional testing may be 
performed if needed in WOCBP. 
• Urine test of drugs of abuse (marijuana, cocaine, amphetamine, 
methamphetamine, opiates, phencyclidine)  
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
HbA1c = hemoglobin A1c (glycated hemoglobin); hCG = human chorionic gonadotropin; 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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9.3 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 CRO. 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 CRO. 
• 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 CRO. 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 CRO. 
• 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 the CRO 
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, the Investigator will provide the 
CRO with a copy of any post-mortem findings including histopathology. 


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• New or updated information will be recorded in the originally completed eCRF. 
• 
The Investigator will submit any updated SAE data to the CRO within 24 hours of 
receipt of the information. 
 
Reporting of SAE to CRO 
SAE Reporting to CRO 
Via EDC Tool 
• The Investigator must report any SAEs to the CRO 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/CRO 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 or by 
telephone. 
• 
Contacts for SAE reporting can be found in the Study Reference Manual. 
 
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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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 CRO 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/CRO 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. 


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9.4 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 
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: 


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• 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: 
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. 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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9.5 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 
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 
EOS 
end of study 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HB 
Hypoxic burden 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
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 
PK 
pharmacokinetic(s) 
PSG 
polysomnography 
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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9.6 Appendix 6: List of Amendment History 
Section 
Action 
Text 
Rationale for 
Change 
Revisions in Version 1.1 
Section 1.2 SoA 
Removed 
AE/SAE monitoring 
removed from V1 and V2  
AE/SAE 
monitoring begins 
with 
randomization; 
prior to that 
record as medical 
history 
Section 1.2 
Footnote 4 
Changed 
From 
“A PSG conducted by the 
study site within 6 
months that meets PSG 
enrollment criteria can 
take the place of a 
screening PSG” 
To 
“Only patients who meet 
all non-PSG enrollment 
criteria at Visit 1 are 
eligible for a screening 
PSG” 
Current PSG will 
be required to 
establish 
consistent 
baseline for all 
patients 
Section 4.1 
Overall Design 
Removed 
“A prior full night PSG 
conducted by the study 
site within 6 months of 
Visit 1 that meets PSG 
enrollment criteria can 
Current PSG will 
be required to 
establish 
consistent 
baseline for all 
patients 


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take the place of a 
screening PSG” 
Section 7.3.1 
Time Period 
and Frequency 
for Collecting 
AE and SAE 
Information 
Changed 
From 
“All AEs and SAEs will 
be collected from the 
signing of informed 
consent from (ICF) until 
the end of the study…” 
To 
“All AEs and SAEs will 
be collected from 
randomization until the 
end of the study…” 
AE/SAE 
monitoring begins 
with 
randomization; 
prior to that 
record as medical 
history 
Revisions in Version 2.0 
Section 3 
Endpoints 
Changed 
Primary hypothesis 
reflects HB as primary 
endpoint 
AHI changed to 
secondary endpoint 
Increasing 
evidence to 
support HB as a 
more meaningful 
and appropriate 
primary endpoint 
Section 5.2 
Exclusion 
Criteria 
Changed 
Exclusion criteria # 13 
now includes “…and 
throughout the study.” 
Added for further 
clarity 
Section 8.1 
Sample Size 
Determination 
Changed 
Power changed from 90 
to 80 
Treatment difference 
changed to - 3.7 % min/h 
Updated to reflect 
change in primary 
endpoint 


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10 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. 
Findley LJ, Unverzagt ME, Suratt PM. Automobile accidents involving patients with obstructive 
sleep apnea. Am Rev Respir Dis 1988;138:337-340. 
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. 
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. 


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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 Randomized Double-Blind Placebo-Controlled 3-Period Single-Dose Crossover 
Study to Evaluate the Safety and Efficacy of Two Doses of AD-109 in Mild to Moderate 
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. 
August 1, 2022 
 
To: ClinicalTrials.gov 
 
This is a cover page to the redacted SAP for APC-004 titled Phase 2 Randomized Double-
Blind Placebo-Controlled 3-Period Single-Dose Crossover Study to Evaluate the Safety and 
Efficacy of Two Doses of AD-109 in Mild to Moderate Obstructive Sleep Apnea. 
 
The APC-004 SAP is associated with NCT04631107.   
 
The following proprietary information was redacted from the SAP for APC-004:  
 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 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
Phase 2 Randomized Double-Blind Placebo-Controlled 3-Period Single-Dose Crossover Study to 
Evaluate the Safety and Efficacy of Two Doses of AD-109 in Mild to Moderate Obstructive 
Sleep Apnea 
 
 
Protocol Number:  APC-004 
Protocol Version:  2.0 
Protocol Date: 6 January 2021 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Version 2.0 
 
 
 


 
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Phase 2 Randomized Double-Blind Placebo-Controlled 3-Period Single-Dose Crossover 
Study to Evaluate the Safety and Efficacy of Two Doses of AD-109 in Mild to Moderate 
Obstructive Sleep Apnea 
 
STATISTICAL ANALYSIS PLAN 
Version 2.0 
 
 
 
 
 
 
Author: 
 
 
Bryce Weaver  
 
 
 
 
 
 
 
Biostatistician, CTI  
 
 
 
 
 
 
CTI Biostatistics 
Reviewer: 
 
 
Rachael Gilbert Runyan 
 
 
 
 
 
 
Manager, Biostatistics, CTI 
 
 
 
 
 
 
 
 
Sponsor Approval:  
 
 
 
Ronald Farkas  
 
 
 
 
 
 
 
Chief Medical Officer 
 
 
 
Apnimed, Inc. 
 
 
 
Note that the last signature date is the effective date of the plan. 
 


 
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Table of Contents 
LIST OF ABBREVIATIONS AND TERMS ............................................................................. 5 
1. 
INTRODUCTION ................................................................................................................. 7 
2. 
OBJECTIVES AND ENDPOINTS ...................................................................................... 7 
2.1. 
OBJECTIVES ....................................................................................................................... 7 
2.1.1. Primary Objective ......................................................................................................... 7 
2.2. 
ENDPOINTS ........................................................................................................................ 7 
2.2.1. Primary Endpoint ......................................................................................................... 7 
2.2.2. Secondary Endpoints .................................................................................................... 7 
2.2.3. Tertiary Endpoints ........................................................................................................ 8 
2.2.4. Safety Endpoints ........................................................................................................... 8 
3. 
INVESTIGATIONAL PLAN ............................................................................................... 9 
3.1. 
STUDY DESIGN .................................................................................................................. 9 
3.2. 
TREATMENT .................................................................................................................... 10 
3.2.1. Randomization Scheme and Treatment Arm Assignment ........................................... 10 
3.2.2. Blinding ...................................................................................................................... 11 
3.2.3. Dosing Schedule ......................................................................................................... 11 
3.2.4. Study Treatment Compliance...................................................................................... 11 
4. 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS ........................................... 11 
4.1. 
DATA QUALITY ASSURANCE ........................................................................................... 12 
4.2. 
ANALYSIS SETS ............................................................................................................... 12 
4.2.1. Enrolled Set ................................................................................................................ 12 
4.2.2. Modified Intent-To-Treat Analysis (mITT) Set ........................................................... 12 
4.2.3. Safety Set..................................................................................................................... 12 
4.2.4. Per Protocol (PP) Set ................................................................................................. 12 
4.3. 
ASSESSMENT WINDOWS .................................................................................................. 12 
4.4. 
HANDLING OF DROPOUTS OR MISSING DATA .................................................................. 12 
4.4.1. PSG Parameters ......................................................................................................... 12 
4.4.2. DSST Scores ............................................................................................................... 13 
4.5. 
MULTIPLE COMPARISONS ................................................................................................ 13 
4.6. 
DATA DERIVATIONS AND TRANSFORMATIONS ................................................................ 13 
4.7. 
MODELING FOR SELECT ENDPOINTS................................................................................ 14 
5. 
STUDY PARTICIPANTS ................................................................................................... 14 
5.1. 
DISPOSITION OF PARTICIPANTS ....................................................................................... 14 
5.2. 
PROTOCOL DEVIATIONS .................................................................................................. 14 
5.3. 
DEMOGRAPHIC ................................................................................................................ 14 
5.4. 
BASELINE CHARACTERISTICS .......................................................................................... 14 


 
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5.5. 
MEDICAL HISTORY .......................................................................................................... 15 
5.6. 
PRIOR AND CONCOMITANT MEDICATIONS ...................................................................... 15 
6. 
EFFICACY ANALYSIS ..................................................................................................... 15 
6.1. 
PRIMARY EFFICACY ANALYSIS – HB(4%) ...................................................................... 15 
6.2. 
SECONDARY EFFICACY ANALYSIS .................................................................................. 16 
6.2.1. HB(4%) ....................................................................................................................... 16 
6.2.2. AHI(4%)...................................................................................................................... 16 
6.2.3. ODI(4%) ..................................................................................................................... 16 
6.2.4. Total time with SaO2<90% ........................................................................................ 17 
6.3. 
TERTIARY EFFICACY ANALYSES ..................................................................................... 17 
6.3.1. KSS.............................................................................................................................. 17 
6.3.2. Sleep Quality VAS ....................................................................................................... 17 
6.3.3. PSG sleep and arousal parameters and alternate measures of AHI, ODI, and HB .. 18 
7. 
SAFETY ANALYSIS .......................................................................................................... 18 
7.1. 
EXTENT OF EXPOSURE..................................................................................................... 18 
7.2. 
ADVERSE EVENTS ........................................................................................................... 18 
7.2.1. Treatment-emergent Adverse Events .......................................................................... 18 
7.2.2. Adverse Event Intensity .............................................................................................. 19 
7.2.3. Adverse Event Relationship to Study Medication ....................................................... 19 
7.2.4. Serious Adverse Events ............................................................................................... 20 
7.2.5. Adverse Event Summaries .......................................................................................... 20 
7.3. 
VITAL SIGNS ................................................................................................................... 21 
7.4. 
CLINICAL LABORATORY VALUES ..................................................................................... 21 
7.5. 
DSST .............................................................................................................................. 21 
7.6. 
PSG PARAMETERS .......................................................................................................... 21 
8. 
INTERIM ANALYSIS ........................................................................................................ 22 
9. 
SAMPLE SIZE AND POWER CALCULATIONS ......................................................... 22 
10. APPENDICES ...................................................................................................................... 22 
10.1. APPENDIX A: SCHEDULE OF ACTIVITIES ......................................................................... 22 
10.2. APPENDIX B: PROTOCOL-REQUIRED SAFETY LABORATORY ASSESSMENTS .................... 23 
 
 


 
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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
AHI  
apnea-hypopnea index  
AE  
adverse event  
ATC 
anatomical, therapeutic, and chemical 
BMI 
body mass index 
CI 
confidence interval 
eCRF  
electronic case report form(s)  
CRO 
contract research organization 
CSR 
clinical study report  
DSST 
digit symbol substitution test 
EEG 
electroencephalogram 
ECG  
electrocardiogram  
HB 
hypoxic burden 
ICF  
informed consent form  
KSS 
Karolinska sleepiness scale 
LS 
least square 
MedDRA 
medical dictionary for regulatory activities 
mITT 
modified intent to treat 
NAW 
number of awakenings 
NREM 
non-rapid eye movement 
ODI 
oxygen desaturation index  
OSA  
obstructive sleep apnea  
PP 
per protocol 
PSG 
polysomnography  
PT 
preferred term 
REM 
rapid eye movement 
SAE  
serious adverse event  
SaO2 
oxygen saturation 
SAP  
statistical analysis plan 
SE 
sleep efficiency  


 
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Abbreviation 
Definition 
SOC 
system organ class 
SOL 
sleep onset latency  
TEAE 
treatment-emergent adverse event 
TST 
total sleep time  
WASO 
wake after sleep onset  
WHO 
world health organization 
 
 
 


 
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1. 
INTRODUCTION 
This statistical analysis plan (SAP) is based on the Protocol # APC-004 Version 2.0, dated 06 
January 2021, titled “Phase 2 Randomized Double-Blind Placebo-Controlled 3-Period Single-
Dose Crossover Study to Evaluate the Safety and Efficacy of Two Doses of AD-109 in Mild to 
Moderate Obstructive Sleep Apnea.” Apnimed is developing the combination of atomoxetine and 
oxybutynin for the treatment of obstructive sleep apnea (OSA). Initial Phase 2 studies of the 
combination were conducted with marketed oxybutynin (combination designated AD-036), which 
is a racemic mixture of R- and S-oxybutynin. Subsequent development is being pursued with R-
oxybutynin (combination designated AD-109), a new enantiomerically pure form of oxybutynin 
which is proposed to have an improved safety and efficacy profile in OSA compared to racemic 
oxybutynin.  
Previous studies of AD-036 provided dose-response efficacy and safety data across a broad 
spectrum of OSA disease severity. Study APC-004 is designed to extend and confirm these 
findings to AD-109 in a population with mild-to-moderate OSA, in parallel with other studies of 
AD-109 planned by Apnimed in moderate-to-severe OSA. Study APC-004 is a randomized, 
double blind, placebo-controlled, 3-period, single-dose crossover study in patients with mild-to-
moderate OSA.  
This document details the statistical methods planned to perform the final analyses of this study. 
The reader interested in detail on study rational, study design, and medical background is invited 
to refer to the study protocol.  
2. 
OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
The primary study objective is to compare the efficacy and safety of a higher dose (atomoxetine 
75 mg + R-oxybutynin 2.5 mg; 75/2.5) and lower dose (atomoxetine 37.5 mg + R-oxybutynin 
2.5 mg; 37.5/2.5) of AD109 to each other and to placebo in the treatment of mild-to-moderate 
OSA.  
2.2. 
Endpoints 
2.2.1. 
Primary Endpoint 
The primary efficacy endpoint is change in log10 of Hypoxic Burden (HB) 4% plus one (scored in 
reference to AHI[4%]), 75/2.5 dose vs. placebo  
2.2.2. 
Secondary Endpoints 
The secondary efficacy endpoints are as follows: 
 Change in log10(HB[4%] + 1), 37.5/2.5 dose vs. placebo and vs. 75/2.5 
 Change in Apnea Hypopnea Index (AHI) 4% 
 Change in Oxygen Desaturation Index (ODI) 4% 


 
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 Total time with SaO2 <90%, PSG nights 
 Proportion of participants with ≥50% reduction in AHI(4%), HB(4%), and ODI(4%) 
2.2.3. 
Tertiary Endpoints 
The tertiary efficacy endpoints are as follows: 
 Karolinska Sleepiness Scale (KSS) score 
 Sleep Quality VAS 
 OSA endotype endpoints (Vpassive, Vactive, Muscle Compensation, Loop Gain) 
 PSG sleep and arousal parameters 
o Sleep stages distribution and percentage of total sleep time (TST) in the various 
sleep stages 
▪ Sleep Efficiency (SE) 
▪ Wake After Sleep Onset (WASO) 
▪ Number of Awakenings (NAW) 
▪ Sleep Onset Latency (SOL) 
▪ Percentage of total sleep time (TST) spent in sleep stage N1 (Stage N1%) 
▪ Percentage of TST spent in sleep stage N2 (Stage N2%)  
▪ Percentage of TST spent in sleep stage N3 (Stage N3%) 
▪ Percentage of TST spent in sleep stage R (Stage R%) 
o Snoring index 
o Arousal indices (respiratory and spontaneous) 
o Fraction of hypopneas 
 Alternate measures of AHI, ODI and HB 
o AHI(4%) in non-rapid eye movement (NREM) sleep 
o AHI(4%) in rapid eye movement (REM) sleep 
o AHI(4%) adjusted for position 
o AHI(3% or arousal) 
o HB(3% or arousals)  
o HB(Total) 
o ODI(3%) 
2.2.4. 
Safety Endpoints 
The safety endpoints are as follows: 
 Vital signs, clinical laboratory assessment, electrocardiogram (ECG) 


 
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 Spontaneous adverse events, including the post-dosing period 
 Digit Symbol Substitution Test (DSST) 
 PSG parameters:  
o Heart rate (HR) 
o Total time with SaO2<90% 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Study Design 
Study APC-004 is a randomized, double blind, placebo-controlled, 3-period, single-dose crossover 
study in patients with mild-to-moderate OSA. A screening visit and polysomnographic (PSG) 
exam will be conducted to establish that each participant meets study enrollment criteria. Each 
participant will then receive a single dose of each of the following during 3 overnight PSG exams, 
each separated by a one week washout period: 
 A: Atomoxetine 75 mg + R-oxybutynin 2.5 mg (i.e., 75/2.5) 
 B: Atomoxetine 37.5 mg + R-oxybutynin 2.5 mg (i.e., 37.5/2.5) 
 C: Placebo 
Efficacy and safety endpoints will compare the 75/2.5 and 37.5/2.5 doses to each other and to 
placebo. 
Each PSG night is followed by a 1-week washout period. Adverse event (AE) and serious adverse 
event (SAE) information is recorded at each study visit and by telephone contact with participants 
during each washout period. The overall study duration will be up to 12 weeks (see Figure 1).  


 
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Figure 1: Overview of Study Design 
 
3.2. 
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. 
One tablet of co-formulated atomoxetine and R-oxybutynin or matching placebo is taken 
immediately before the participant’s planned bedtime. 
 
3.2.1. 
Randomization Scheme and Treatment Arm Assignment 
The planned randomization scheme will utilize randomly ordered blocks with 5 blocks of size 6, 
with each block randomizing one participant to each of the following 6 sequences: ABC, ACB, 
BAC, BCA, CAB, CBA. For example, a participant randomized to “ABC” will receive the 


 
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treatment sequence: 1.) Atomoxetine 75 mg + R-oxybutynin 2.5 mg; 2.) Atomoxetine 37.5 mg + 
R-oxybutynin 2.5 mg; 3.) Placebo. 
Participants who withdraw from the study will not be replaced. 
3.2.2. 
Blinding 
The investigator, study personnel and participant will be blinded to the identity of the study drug 
in all treatment periods. The CRO staff dealing with blinded site study staff will also be blinded. 
The Sponsor, Medical Monitor, CRO’s Drug Safety and Pharmacovigilance staff, as well as site 
personnel required for drug administration will also be blinded. The centralized PSG technologists 
will be blinded to treatment assignment.  
The CTI unblinded statistician who reviews the production randomization list will be unblinded to 
the treatment sequence a participant receives; however, this individual will not have access to 
study data prior to study completion. The investigational pharmacist and/or the study coordinator, 
depending on the site, will be unblinded to treatment assignment for the purposes of preparing, 
controlling, dispensing study product and documenting accountability of study product. 
3.2.3. 
Dosing Schedule 
There are 3 randomized crossover PSG nights. The participant will receive one treatment on each 
of the 3 PSG nights, separated by at least a one-week washout period. Dosing of the study treatment 
will occur immediately prior to lights out. 
3.2.4. 
Study Treatment Compliance 
Only participants enrolled in the study treatments and only authorized site staff may supply or 
administer study treatments.  
After receiving Sponsor approval in writing, sites are 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.  
4. 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS 
In general, continuous variables will be summarized by presenting the set sample size (N), number 
of participants with available data (n), mean, standard deviation (SD), median, minimum, and 
maximum. In summaries of change from baseline safety variables, only participants with both 
baseline and post baseline data will be included. Categorical variables will be summarized by 
presenting the number and percentage of participants within each category. Calculation of 
percentages will exclude missing data as a category. Where appropriate, descriptive statistics may 
be presented with 95% confidence intervals (CIs). 
All tabulations will be based on pooled data across centers. 
The data analyses will be performed using SAS for Windows, version 9.4 or higher (SAS, Cary, 
NC), except where other software may be deemed more appropriate.  
CTI Clinical Trial and Consulting Services (Covington, KY) will perform the efficacy and safety 
analyses described below. Apnimed, Inc., will perform the exploratory analysis pertaining to the 
OSA endotype endpoints mentioned in Section 2.2.3. Any changes to the analyses that are not 


 
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included in this SAP will be documented in the clinical study report (CSR). 
4.1. 
Data Quality Assurance 
Once all the source verification is complete, all queries are resolved, and the database has been 
updated appropriately, the database will be locked and made available to CTI Biostatistics for final 
analysis.  
Data may be made available to CTI Biostatistics for programming purposes prior to database lock 
at a time when source verification and query resolution is ongoing. 
All SAS programs used to create analysis data sets, tables, and listings will be independently 
programmed by two individuals. The independent SAS outputs produced will be compared, and 
the SAS programs will be updated until the outputs match. 
4.2. 
Analysis Sets 
4.2.1. 
Enrolled Set 
The Enrolled Set is defined as all participants who signed the informed consent form (ICF) 
(including screening failures). 
4.2.2. 
Modified Intent-To-Treat Analysis (mITT) Set 
The mITT Set 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 randomly assigned treatment for each 
period. 
4.2.3. 
Safety Set  
The Safety Set 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 
for each period. Treatment received is defined as the actual treatment taken during each period. 
4.2.4. 
Per Protocol (PP) Set 
The PP Set consists of all participants without any major protocol violations that could influence 
efficacy assessment. Participants in this set will be analyzed according to the treatment they 
received for each period. 
4.3. 
Assessment Windows 
Data will be summarized by the CRF (Study Visit) in which it was collected provided the data is 
within the windows specified.  
4.4. 
Handling of Dropouts or Missing Data 
Missing data will remain missing.  No imputation of missing data will be performed. 
4.4.1. 
PSG Parameters 
The criteria for use of PSG data will be as follows: 


 
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 When TST is < 120 minutes, only TST, time in bed, Stage N1%, Stage N2%, Stage 
N3%, and Stage R% will be reported. All other PSG indices will be excluded. 
 Any AHI and HB parameters during REM will be reported only when the time spent 
in REM is > 5 minutes. 
 Any AHI and ODI parameters in supine position will be reported only when the time 
spent supine is > 5 minutes. 
4.4.2. 
DSST Scores 
A DSST total correct of 0 will be dropped from the repeated measures model. 
4.5. 
Multiple Comparisons 
Each endpoint for this study implicitly contains three hypothesis tests based on comparisons 
between study treatments: i) 75/2.5 dose vs placebo, ii) 37.5/2.5 dose vs placebo, iii) 37.5/2.5 dose 
vs 75/2.5 dose. The sequential testing order of these hypotheses will be:  
1. 75/2.5 dose vs placebo for HB(4%), 
2. 37.5/2.5 dose vs placebo for HB(4%), 
3. 75/2.5 dose vs placebo for AHI(4%), 
4. 37.5/2.5 dose vs placebo for AHI(4%), 
5. 75/2.5 dose vs placebo for ODI(4%), 
6. 37.5/2.5 dose vs placebo for ODI(4%), 
7. 37.5/2.5 dose vs 75/2.5 dose for HB(4%), 
8. 37.5/2.5 dose vs 75/2.5 dose for AHI(4%), and 
9. 37.5/2.5 dose vs 75/2.5 dose for ODI(4%). 
All hypothesis tests will test that the two-sided p-value is less than 0.05. 
All hypothesis tests for secondary endpoints will be reported using the nominal 0.05 two-sided 
alpha level. 
4.6. 
Data Derivations and Transformations 
Study Day will be calculated as:  
 Date of assessment – date of randomization + 1 for assessments done on or after date of 
randomization 
 Date of assessment – date of randomization for assessments done before date of 
randomization 
For each efficacy and safety endpoint, the baseline value will be calculated as the last non-missing 
value prior to randomization (except where unscheduled assessments are performed the baseline 
value should be the value recorded at Screening). Where applicable, change from baseline values 
will be calculated as: 
Change from Baseline = assesment value −baseline value, 


 
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while the percent change from baseline values will be calculated as: 
percent change from baseline = change from baseline
baseline value
× 100%. 
For the endpoints that look for the proportion of participants with ≥50% reduction, participants 
will be assigned a visit level indicator:  
Indicator of ≥50% reduction = ቄ1
if percent change from baseline ≤−50%
0
otherwise
. 
4.7. 
Modeling for Select Endpoints 
In Section 6, modeling will be used for comparisons between study treatments with respect to 
given endpoints using the PROC GLIMMIX procedure in SAS.  The model will include study 
treatment and visit as fixed effects. Within participant variability (nested within treatment 
sequence) will be modeled using an unstructured (e.g., TYPE = UN, CHOL) covariance pattern. 
The unstructured covariance parametrized through its Cholesky root is to be used for logistic 
regression models and models in which convergence fails for the completely unstructured 
covariance. Point (e.g., mean, difference of means) and inferential (e.g., confidence interval, p-
values) statistics will provided be estimated using least squares (LS) methods. Unless otherwise 
stated, the link will be identity and the distribution gaussian.  
5. 
STUDY PARTICIPANTS 
5.1. 
Disposition of Participants 
A table of frequency counts and percentages of all participants who are enrolled, distributed study 
medication, and included in each analysis set will be provided. Participant disposition including 
study completion status and reasons for early termination will be tabulated overall. A by-
participant listing will be provided.  
5.2. 
Protocol Deviations 
Two separate by-participant listings for major and minor protocol deviations will be provided.   
5.3. 
Demographic  
Descriptive statistics will be used to summarize the demographic characteristics (age, gender, race, 
ethnicity, height, weight, and BMI) overall using the Safety Set. A by-participant listing will also 
be provided.   
5.4. 
Baseline Characteristics 
The results of the following assessments completed during the baseline PSG will be summarized 
overall using the Safety Set: 
 AHI(4%) 
 ODI(4%) 
 HB(4%) 
 Total time with SaO2 <90% 


 
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 Snoring index 
 Arousal indices (respiratory and spontaneous) 
 Fraction of hypopneas 
 WASO 
 Sleep stage (N1, N2, N3, R) separately in minutes and percent of total sleep time 
 Sleep efficiency 
 Number of awakenings 
 Sleep onset latency 
 Heart rate 
 Total sleep time  
 Systolic blood pressure 
 Diastolic blood pressure 
The baseline PSG parameters and vital signs will be included in their respective general listings. 
5.5. 
Medical History 
All medical conditions and surgical procedures will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) version 23.0. The number and percent of participants with each 
medical condition and surgical procedure will be presented by MedDRA system organ class 
(SOC), preferred term (PT) overall for the Safety Set. Each participant will be counted only once 
per SOC and PT. A by-participant listing will also be provided.   
5.6. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using September 2020 B3 Global World Health 
Organization (WHO) Drug Dictionary version.  The number and percent of participants using each 
medication will be tabulated by Anatomical Therapeutic Chemical (ATC) level 3, preferred name 
overall. Each prior or concomitant medication reported more than one time will only be counted 
once per participant for each ATC level and preferred name. A by-participant listing will also be 
provided.   
6. 
EFFICACY ANALYSIS 
The mITT Set will be used for all efficacy analyses. 
6.1. 
Primary Efficacy Analysis – HB(4%) 
Multiple comparisons will be performed as described in Section 4.5. A repeated measures model 
(see Section 4.7) will be used to model change in log10(HB[4%] + 1) from baseline. Model based 
LS mean estimates will be provided for the following: 
 mean change by study treatment (75/2.5 dose, 37.5/2.5 dose, placebo),  


 
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 difference in mean change between study treatments1 (75/2.5 dose vs placebo, 37.5/2.5 
dose vs placebo, and 75/2.5 dose vs 37.5/2.5 dose) with 95% confidence intervals and 
respective p-values (for null hypothesis).  
If the model shows there is a visit (i.e., period) effect, then ad hoc analyses will be performed. A 
sensitivity analysis will be performed using the PP Set on the primary efficacy endpoint using the 
same methods described above and using HB(4%) with identity transform (i.e., without transform) 
on the mITT set.  
Descriptive statistics for the reported value and change from baseline in log10(HB[4%] + 1) will 
be presented by study treatment. By taking the inverse transformations of the respective means, 
the geometric mean of HB(4%) + 1 and the ratio of the geometric mean to baseline will be reported. 
6.2. 
Secondary Efficacy Analysis  
6.2.1. 
HB(4%) 
The secondary outcomes of 37.5/2.5 dose vs placebo and vs. 75/2.5 dose are described in the 
primary efficacy analysis for log10(HB[4%] + 1). 
6.2.2. 
AHI(4%) 
Multiple comparisons will be performed as described in Section 4.5. A repeated measures model 
(see Section 4.7) will be used to model change in AHI(4%) from baseline. Model based LS mean 
estimates will be provided for the following: 
 mean change by study treatment (75/2.5 dose, 37.5/2.5 dose, placebo),  
 difference in mean change between study treatments (75/2.5 dose vs placebo, 37.5/2.5 dose 
vs placebo, and 75/2.5 dose vs 37.5/2.5 dose) with 95% confidence intervals and respective 
p-values (for null hypothesis).  
Descriptive statistics for the reported value and change from baseline in AHI(4%) will be presented 
by study treatment.   
6.2.3. 
ODI(4%) 
Multiple comparisons will be performed as described in Section 4.5. A repeated measures model 
(see Section 4.7) will be used to model change in ODI(4%) from baseline. Model based LS mean 
estimates will be provided for the following: 
 mean change by study treatment (75/2.5 dose, 37.5/2.5 dose, placebo),  
 difference in mean change between study treatments (75/2.5 dose vs placebo, 37.5/2.5 dose 
vs placebo, and 75/2.5 dose vs 37.5/2.5 dose) with 95% confidence intervals and respective 
p-values (for null hypothesis).  
Descriptive statistics for the reported value and change from baseline in ODI(4%) will be presented 
by study treatment. 
                                                 
1 Only 75/2.5 dose vs placebo is part of the primary outcome. The 37.5/2.5 dose vs placebo and 37.5/2.5 dose vs 
75/2.5 dose are secondary outcomes. 


 
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6.2.4. 
Total time with SaO2<90% 
Multiple comparisons will be performed as described in Section 4.5. A repeated measures model 
(see Section 4.7) will be used to model total time with SaO2<90%. Model based LS mean estimates 
will be provided for the following: 
 mean change by study treatment (75/2.5 dose, 37.5/2.5 dose, placebo),  
 difference in mean change between study treatments (75/2.5 dose vs placebo, 37.5/2.5 dose 
vs placebo, and 75/2.5 dose vs 37.5/2.5 dose) with 95% confidence intervals and respective 
p-values (for null hypothesis).  
Descriptive statistics for the reported value and change from baseline in total time with SaO2<90% 
will be presented by study treatment. 
6.2.5. 
Proportion of participants with ≥50% reduction 
Three separate repeated measures models (see section 4.7) will be used to model the probability 
of a ≥50% reduction in AHI(4%), hypoxic burden, and ODI(4%) values respectively. A logit link 
with binomial distribution will be employed. For each of the three endpoints, model based LS 
mean estimates will be provided for the following: 
 odds ratios for a ≥50% reduction between study treatments (75/2.5 dose vs placebo, 
37.5/2.5 dose vs placebo, and 75/2.5 dose vs 37.5/2.5 dose) with 95% confidence intervals 
and respective p-values (for null hypothesis).  
The proportion, with 95% CI, of participants with ≥50% reduction in AHI(4%), HB(4%), and 
ODI(4%) will be presented by study treatment in the same table as the models. 
6.3. 
Tertiary Efficacy Analyses 
6.3.1. 
KSS 
Two separate repeated measure models (see section 4.7) will be used to model the probability of 
being alert (KSS score ≤3) and of not being sleepy (KSS score ≤5). A logit link with binomial 
distribution will be employed. For each of the two endpoints, model-based LS mean estimates will 
be provided for the following: 
 odds ratios between study treatments (75/2.5 dose vs placebo, 37.5/2.5 dose vs placebo, 
and 75/2.5 dose vs 37.5/2.5 dose) with 95% confidence intervals and respective p-values 
(for null hypothesis).  
Descriptive statistic of the proportion, with 95% CI, of participants alert and not sleepy will be 
presented by study treatment separately in the same table as the model. Number and percentages 
of participants with the individual score values (1-9) will be given by study treatment. A by-
participant listing of the KSS scores will be given. 
6.3.2. 
Sleep Quality VAS 
A repeated measures model (see Section 4.7) will be used to model Sleep Quality VAS total score. 
Model based LS mean estimates will be provided for the following: 
 mean score by study treatment (75/2.5 dose, 37.5/2.5 dose, placebo),  


 
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 difference in mean score between study treatments (75/2.5 dose vs placebo, 37.5/2.5 dose 
vs placebo, and 75/2.5 dose vs 37.5/2.5 dose) with 95% confidence intervals and respective 
p-values (for null hypothesis).  
Summary statistics of Sleep Quality VAS total score by study treatment and a by-participant listing 
will also be provided. 
6.3.3. 
PSG sleep and arousal parameters and alternate measures of AHI, ODI, and HB 
Descriptive statistics for the reported value and change from baseline by study treatment will be 
reported for sleep stages distribution and percentage of time in the various sleep stages (SE, 
WASO, NAW, SOL, Stage N1%, Stage N2%, Stage N3%, Stage R%). A 95% confidence interval 
will be included for the change from baseline. 
Snoring index, arousal indices (respiratory and spontaneous), fraction of hypopneas (see below) 
and alternate measures of AHI, ODI, and HB (AHI[4%]: in NREM sleep, in REM sleep, AHI 
adjusted for position [see below]; AHI[3% or arousal]; HB[3% or arousal]; HB[Total]; ODI[3%]) 
and will have results provided similar to Section 6.1 (including the model of change from baseline 
and the descriptive statistics).  
Additional clarifying details for the analysis of some of these endpoints is as follows:  
 Fraction of hypopneas will be calculated by using the number of hypopneas divided by the 
total number of apneas plus hypopneas.  
 AHI adjusted for position: An additional covariate of % time supine (%TS) will be added 
to the repeated measures model for AHI(4%). 
7. 
SAFETY ANALYSIS 
Safety assessments will include measurement of adverse events (AEs) and serious AEs (SAEs).  
The analyses will be descriptive and will be based on the Safety Set. The safety assessments will 
be summarized by the study treatment the participant actually received within each period. 
7.1. 
Extent of Exposure 
The number and percentage of participants receiving study treatment will be summarized by study 
treatment and overall. A by-patient listing will be provided. 
7.2. 
Adverse Events 
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. 
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. 
7.2.1. 
Treatment-emergent Adverse Events 
A treatment-emergent adverse event (TEAE) is defined as any event not present prior to exposure 


 
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of study drug or an event already present that worsens in either severity or frequency following 
exposure. Each TEAE is assigned to the most recent study treatment administered on or before the 
TEAE’s date of onset.   
7.2.2. 
Adverse Event 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.  
7.2.3. 
Adverse Event Relationship to Study Medication 
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 CRO. 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 CRO.  
 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. 


 
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7.2.4. 
Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that, at any dose:  
 Results in death; 
 Is life-threatening; 
 Requires inpatient hospitalization or prolongation of existing hospitalization; 
 Results in persistent disability/incapacity; 
 Is a congenital anomaly/birth defect; 
 Other situations. 
7.2.5. 
Adverse Event Summaries 
Adverse event data will be displayed in listings by participant.  The number and percentage of 
participants with AEs will be tabulated by SOC and PT. A participant with multiple AEs within a 
SOC or PT will be counted once toward the total for the total for the SOC or PT.  
All AEs (serious and non-serious) occurring after completion of the informed consent process and 
before the end of study, regardless of relationship to study drug, will be included and presented by 
MedDRA SOC and PT. 
For TEAEs, the following will be summarized by study treatment and presented for the Safety Set. 
i. 
An overall summary of TEAEs, which includes:  
a. the number and percentage of participants experiencing any TEAE 
b. the number and percentage of participants experiencing any TEAE by strongest 
relationship to study medication 
c. the number and percentage of participants experiencing any TEAE by greatest 
intensity 
d. the number and percentage of participants experiencing any TESAE  
ii. 
the number and percentage of participants experiencing any TEAE by SOC, PT 
iii. 
the number and percentage of participants experiencing any TEAE by SOC, PT and the 
greatest intensity 
iv. 
the number and percentage of participants experiencing any TEAE by SOC, PT and the 
strongest relationship to study medication 
v. 
the number and percentage of participants experiencing any TEAE leading to study 
discontinuation by SOC and PT. 
In the overall summary of AEs table, besides tabulating the number and percentage of participants, 
the total number of AE episodes will also be provided. If a participant has repeated episodes of a 
particular AE within a treatment period, all episodes will be counted in the summary table and 
displayed by treatment.   
For displays by SOC and PT, each participant will be counted only once per SOC and PT within 
each treatment. 


 
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All occurrences of all AEs will be listed for each participant, grouped by treatment. The listing 
will contain the following information: treatment sequence, study treatment, SOC, PT, verbatim 
term,  intensity, relationship to study medication, date and study day of onset, date and study day 
of resolution, treatment given to treat the adverse event, action taken, the outcome, whether the 
event was an SAE, whether it led to withdrawal.  Listings will be sorted by treatment sequence, 
participant identification number, onset date, SOC, and PT. If onset year is non-missing but month 
and/or date is missing, then the day of the most recent study drug dose will be imputed as onset 
date.   
7.3. 
Vital Signs 
Vital sign data will be summarized by presenting descriptive statistics of actual values and changes 
from baseline by study treatment. Vital sign parameters include respiratory rate, temperature, 
systolic blood pressure, diastolic blood pressure, and heart rate. A by-participant listing of vital 
signs will also be provided. 
7.4. 
Clinical laboratory values 
Clinical laboratory values will be summarized by presenting descriptive statistics of actual values 
and changes from baseline for the end of study evaluation. Clinical laboratory values include 
urinalysis (dipstick and microscopic), hematology, and chemistry lab values. A by-participant 
listing of clinical laboratory values will also be provided. 
7.5. 
DSST 
A repeated measures model (see Section 4.7) will be used to model the natural log of total number 
of the correct symbol assignments2 (log (total completed - total incorrect)) from the DSST.  
Exponentiation of the model-based LS mean estimates of log values will be used to provide the 
following: 
 Geometric mean of DSST by study treatment (75/2.5 dose, 37.5/2.5 dose, placebo), and  
 Ratio of (geometric) mean of DSST between study treatments (75/2.5 dose vs placebo, 
37.5/2.5 dose vs placebo, and 75/2.5 dose vs 37.5/2.5 dose) with the 95% confidence 
intervals.  
Descriptive statistics of DSST and a by-participant listing (with both raw values and natural log of 
total complete) will also be provided. 
7.6. 
PSG Parameters 
PSG safety data will be summarized by presenting descriptive statistics of actual values and 
changes from baseline by study treatment.  PSG safety parameters include total sleep time, heart 
rate, and total time with SaO2<90%. A by-participant listing of PSG parameters (including baseline 
and efficacy parameters) will also be provided. 
                                                 
2 In the case that the total correct is 0, the participant will be dropped from the model. 


 
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8. 
INTERIM ANALYSIS 
No interim analysis is planned.  
9. 
SAMPLE SIZE AND POWER CALCULATIONS 
A total of 30 patients will enter the 3-treatment crossover study. The study will have 80% power 
to detect a treatment difference on the primary endpoint at a two-sided 0.05 significance level, if 
the true difference between treatments on HB is at least -3.7 % min/h. This assumes that the within-
participant standard deviation is 9 and a discontinuation rate of less than 20%.   
10. 
APPENDICES 
10.1. Appendix A: Schedule of Activities 
 


 
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10.2. Appendix B: Protocol-Required Safety Laboratory Assessments 
 


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