Clinical trial NCT04445688
Conditions: Obstructive Sleep Apnea
Sponsor: Apnimed
Start date: 2020-07-15; Completion date: 2020-12-01
Enrollment: 62 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 AD036 versus placebo or atomoxetine in patients with obstructive sleep apnea.

Detailed description:
The study is designed to examine the efficacy and safety of AD036 to treat obstructive sleep apnea. The study is a three-period single-dose randomized crossover design in which patients will undergo overnight Home Sleep Apnea Testing (HSAT) with dosing of one of the following 3 treatments: AD036, Atomoxetine, or Placebo. Participants will return 1 week after their final crossover HSAT for an end of study (EOS) Visit.

Arms: arm 1: AD036 oral capsule administered before sleep arm 2: Atomoxetine oral capsule administered before sleep arm 3: Placebo oral capsule administered before sleep
Interventions: intervention 1: AD036 intervention 2: Atomoxetine intervention 3: Placebo
Intervention descriptions: intervention 1: Oral administration before bed intervention 2: Oral administration before bed intervention 3: Oral administration before bed

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. 
 
June 21, 2023 
 
To: ClinicalTrials.gov 
 
This is a cover page to the redacted clinical protocol for APN-006 Phase 2, Randomized, 3-
Period, Placebo-Controlled Crossover Study to Evaluate the Efficacy and Safety in 
Obstructive Sleep Apnea of AD036 versus Placebo or Atomoxetine. 
 
The APN-006 clinical protocol is associated with NCT 04445688.   
 
The following proprietary information was redacted from the clinical protocol for APN-006:  
 IND number 
 
Sincerely, 
 
 
 
 
 
Jeanne Brittain 
Director, Program Management 
 


Apnimed, Inc.  
 Clinical Study Protocol 
Protocol APN-006/IND 
 
CONFIDENTIAL 
 
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Title Page 
Protocol Title: Phase 2, Randomized, 3-Period, Placebo-Controlled Crossover Study to Evaluate 
the Efficacy and Safety in Obstructive Sleep Apnea of AD036 versus Placebo or Atomoxetine 
Protocol Number: APN-006 
Compound Number: AD036 
Short Title: AD036 Crossover Study 
Sponsor Name and Legal Registered Address:  
Apnimed, Inc. 
20 Holyoke Street 
Cambridge, MA 02138 
 
Regulatory Agency Identifying Number: IND 
 
Approval Date: 15 September 2020 
Version: 3.0  
Date and Version of Previous Protocol:  13 April 2020, Version 2.0 
 
 
 
 


Apnimed, Inc.
Protocol APN-006flND 
Sponsor Signatoty:
Clinical Study Protocol
CONFIDENTIAL
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Ronald Farkas,MD, PhD
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15 September 2020
2 of45
v3.0


Apnimed, Inc.  
 Clinical Study Protocol 
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Table of Contents 
 
1 
Protocol Summary .................................................................................................................. 5 
1.1 
Synopsis ................................................................................................................................ 5 
1.2 
Schedule of Activities (SoA) ................................................................................................ 6 
2 
Introduction ............................................................................................................................. 7 
2.1 
Study Rationale..................................................................................................................... 7 
2.2 
Background ........................................................................................................................... 7 
2.2.1 
Obstructive Sleep Apnea ............................................................................................... 7 
2.2.2 
Unmet Medical Need .................................................................................................... 8 
2.2.3 
Biological Rationale ..................................................................................................... 8 
3 
Endpoints ................................................................................................................................. 9 
4 
Study Design ............................................................................................................................ 9 
4.1 
Overall Design ...................................................................................................................... 9 
4.2 
Scientific Rationale for Study Design .................................................................................11 
4.3 
Justification for Dose ...........................................................................................................11 
4.4 
End of Study Definition .......................................................................................................11 
5 
Study Population ................................................................................................................... 12 
5.1 
Inclusion Criteria ................................................................................................................ 12 
5.2 
Exclusion Criteria ............................................................................................................... 13 
5.3 
Meals and Dietary Restrictions........................................................................................... 15 
5.4 
Activity ............................................................................................................................... 15 
5.5 
Screen Failures ................................................................................................................... 15 
6 
Study Treatment ................................................................................................................... 15 
6.1 
Study Treatments ................................................................................................................ 15 
6.2 
Preparation/Handling/Storage/Accountability .................................................................... 16 
6.3 
Measures to Minimize Bias ................................................................................................ 16 
6.4 
Study Treatment Compliance ............................................................................................. 17 
6.5 
Concomitant Therapy ......................................................................................................... 17 
6.6 
Treatment After the End of the Study ................................................................................. 19 
7 
Discontinuation of Study Treatment ................................................................................... 19 
7.1 
Stopping Criteria................................................................................................................. 19 
7.1.1 
Individual Participant Stopping Criteria .................................................................... 19 
7.2 
Participant Discontinuation/Withdrawal from the Study.................................................... 19 
7.3 
Loss of Participants to Follow-Up ...................................................................................... 20 
8 
Study Assessments and Procedures ..................................................................................... 20 
8.1.1 
Home Sleep Apnea Testing (HSAT) ............................................................................. 21 


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8.2 
Safety Assessments ............................................................................................................. 21 
8.3 
Adverse Events and Serious Adverse Events ..................................................................... 21 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ........................ 21 
8.3.2 
Method of Detecting AEs and SAEs ............................................................................ 22 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................ 22 
8.3.4 
Regulatory Reporting Requirements for SAEs ............................................................ 22 
8.3.5 
Pregnancy ................................................................................................................... 23 
8.4 
Treatment of Overdose ....................................................................................................... 23 
8.5 
Pharmacokinetics ................................................................................................................ 23 
9 
Statistical Considerations and Sample Size Determination .............................................. 24 
9.1 
Populations for Analyses .................................................................................................... 24 
10 Supporting Documentation and Operational Considerations .......................................... 25 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............................. 25 
10.1.1 
Regulatory and Ethical Considerations ...................................................................... 25 
10.1.2 
Financial Disclosure ................................................................................................... 26 
10.1.3 
Informed Consent Process .......................................................................................... 26 
10.1.4 
Data Protection ........................................................................................................... 27 
10.1.5 
Dissemination of Clinical Study Data ........................................................................ 27 
10.1.6 
Data Quality Assurance .............................................................................................. 27 
10.1.7 
Source Documents ...................................................................................................... 28 
10.1.8 
Study and Site Closure ................................................................................................ 29 
10.1.9 
Publication Policy....................................................................................................... 29 
10.1.10 
Protocol Approval and Amendment ............................................................................ 29 
10.1.11 
Liability and Insurance ............................................................................................... 30 
10.2 Appendix 2: Clinical Laboratory Tests ............................................................................... 30 
Table 2: Protocol-Required Safety Laboratory Assessments ........................................................ 31 
10.3 Appendix 3: AE Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting ............................................................................................................................ 32 
10.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information .............. 38 
10.5 Appendix 5: List of Abbreviations ..................................................................................... 42 
11 References .............................................................................................................................. 44 
 


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1 Protocol Summary 
1.1 Synopsis 
Protocol Title: Phase 2, Randomized, 3-Period, Placebo-Controlled Crossover Study to Evaluate 
the Efficacy and Safety in Obstructive Sleep Apnea of AD036 versus Placebo or Atomoxetine 
Sponsor Study No.: APN-006 
Phase: 2 
Sponsor: Apnimed, Inc. 
Rationale: 
AD036 is a new fixed-dose combination of atomoxetine and oxybutynin being developed for the 
treatment of obstructive sleep apnea (OSA). Study APN-006 is designed to confirm and extend 
safety and efficacy findings from the Study APN-002, a Phase 2 study of AD036 in OSA.  
Overall Design: 
Patients who participated in Study APN-002 are eligible for enrollment, as are new patients who 
meet enrollment criteria. A total of 54 Patients with baseline characteristics that predict increased 
responsiveness to AD036 (based on Study APN-002 findings), will be planned for enrollment.  
The study is a three-period single-dose randomized crossover design in which patients will 
undergo overnight home sleep apnea testing (HSAT) with dosing of one of the following 3 
treatments:   
• Atomoxetine 80 mg + oxybutynin 5 mg  
• Atomoxetine 80 mg + placebo  
• Placebo + placebo  
A 1-week minimum washout period will occur between each of the 3 crossover HSAT nights. 
The primary hypothesis is that the AD036 combination of atomoxetine and oxybutynin is 
superior to placebo on apnea hypopnea index (AHI). Superiority of the AD036 combination to 
atomoxetine is a key secondary efficacy endpoint.  
Number of Participants: 
A total of 54 participants are planned for enrollment.  
Study Duration: 
The overall study duration will be up to 10 weeks, as follows:  
• Screening, up to 4 weeks;  
• 3-period crossover, approximately 5 weeks; 
• End of study evaluation, 1 week after end of crossover period 


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1.2 Schedule of Activities (SoA)  
Table 1 
Schedule of Activities 
Procedures 
 
3-Period Crossover at Home  
End of Study 
Evaluation1 
Notes 
Screen- 
ing 
HSAT 
1 
Wash-
out2  
HSAT 
2 
Wash-
out 
HSAT 
3 
Wash-
out 
Trial Day/Duration 
Up to 4 
weeks 
Up to 5 weeks 
1 week post 
crossover period 
Informed consent 
X 
 
 
 
 
 
 
 
 
Enrollment criteria 
X 
 
 
 
 
 
 
 
 
History and Physical  
X 
 
 
 
 
 
 
 
Includes vital signs and weight 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
Clinical laboratory and 
serum pregnancy test 
(WOCBP only) 
X 
 
 
 
 
 
 
 
CYP2D6 test only at Screening and only for patients not 
previously screened in Study APN-002 
Drugs of abuse  
X 
 
 
 
 
 
 
 
 
Instruct and remotely 
oversee HSAT use  
X3 
X 
 
X 
 
X 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Occurs after enrollment criteria met, prior to HSAT 1  
Dispense study drug 
 
X 
 
X 
 
X 
 
 
 
HSAT  
X3 
X4 
 
X 
 
X 
 
 
HSAT device provided prior to each HSAT night 
Study drug dosing 
 
X 
 
X 
 
X 
 
 
Dose at lights out; site verifies dosing remotely 
AE/SAE monitoring  
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior/concomitant 
medication monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: AE = adverse event; HSAT = home sleep apnea test; QHS = taken at bedtime; SAE = serious adverse event; WOCBP = women of childbearing potential. 
 
 
1 Can be conducted remotely 
2 Each washout period is at least 7 days 
3 Screening HSAT only for patients without prior qualifying sleep study, and only after other study enrollment criteria confirmed as met. Screening HSAT is conducted by site and 
reviewed by central reading center but the investigator is responsible for confirming patient eligibility. 
4 Remote instruction on use of HSAT and drug dosing confirmation provided by study site for each HSAT night 


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2 Introduction 
2.1 Study Rationale 
AD036 is a new fixed-dose combination of atomoxetine and oxybutynin being developed for the 
treatment of obstructive sleep apnea (OSA). Study APN-006 is designed to confirm and extend 
safety and efficacy findings from the Phase 2 Study APN-002 of AD036 in OSA, as follows:   
• In Study APN-002 efficacy of AD036 in reducing key measures of OSA severity 
including apnea-hypopnea index (AHI) and oxygen desaturation index (ODI) was 
correlated with certain patient baseline characteristics including those assessed by 
polysomnography (PSG). Study APN-006 will confirm this finding by enrolling patients 
from Study APN-002 who have baseline characteristics that predict increased 
responsiveness to AD036. New patients not previously screened in Study APN-002 who 
meet these criteria can also be enrolled in Study APN-006.  
• There was evidence that the higher-dose formulation of AD036 (atomoxetine 75 
mg/oxybutynin 5 mg) in Study APN-002 was superior to formulations of AD036 
composed of lower dose combinations of atomoxetine and oxybutynin. However, 
comparison was not made of the combination of atomoxetine and oxybutynin to the 
individual components (i.e. atomoxetine alone or oxybutynin alone) which would more 
clearly establish the contribution of each component drug to the efficacy of the 
combination. Study APN-006 will compare the efficacy of AD036 (composed of 
commercially available formulations of atomoxetine 80 mg and oxybutynin 5 mg) in 
OSA to the efficacy of atomoxetine 80 mg alone and to placebo, in a three-period single-
dose crossover design.  
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. 


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Research has shown that a number of pathogenic factors, or traits, contribute to the development 
of OSA (Eckert et al, 2013; Wellman et al, 2011; Wellman et al, 2013;Younes, 2003). The most 
important factors are the presence of an anatomically small, collapsible upper airway and a loss 
of pharyngeal muscle tone or responsiveness during sleep. 
Long-term, OSA is associated with increased mortality and a number of adverse cardiovascular, 
neurocognitive, metabolic, and daytime functional 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 has 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 
AD036 is a new fixed dose drug combination of atomoxetine and oxybutynin being developed for 
OSA. Atomoxetine is a pre-synaptic norepinephrine reuptake inhibitor indicated for the treatment 
of attention deficit hyperactivity disorder in children and adults. Oxybutynin is an antispasmodic 
drug that inhibits the muscarinic action of acetylcholine on smooth muscle and is indicated for the 
treatment of symptoms of bladder instability associated with voiding in patients with uninhibited 
neurogenic or reflex neurogenic bladder such as urgency, frequency, urinary leakage, urge 
incontinence and dysuria.  
Efficacy and safety of AD036 for the signs and symptoms of OSA was recently evaluated in 
Apnimed’s Phase 2 Study APN-002. There was evidence from this study that the high-dose 


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formulation of AD036 (atomoxetine 75 mg/oxybutynin 5 mg) was superior to formulations of 
AD036 composed of lower dose combinations of atomoxetine and oxybutynin, and to placebo. 
Efficacy of AD036 in OSA was correlated with certain patient baseline characteristics including 
those assessed by PSG. Study APN-006 will confirm and extend these findings by enrolling 
patients from Study APN-002 who have baseline characteristics that predict increased 
responsiveness to AD036. New patients not previously screened in Study APN-002 are also 
eligible for enrollment if all enrollment criteria are met.  
 
3 Endpoints 
4 Study Design 
4.1 Overall Design 
Patients who participated in Study APN-002 are eligible for enrollment, as are new patients who 
meet enrollment criteria. A total of 54 patients who have baseline characteristics that, based on 
study 002 findings, predict increased responsiveness to AD036, will be planned for enrollment.  
Objective OSA inclusion criteria for patients who participated in Study APN-002 will be 
determined based on the Study APN-002 baseline PSG exam (applies also to patients who were 
screened but did not meet the study PSG criteria).  Objective OSA inclusion criteria for new 
patients can be based on a previous full night PSG or HSAT conducted at the site within 4 
months prior to enrollment. If such results are not available, a screening HSAT may be conducted 
during the screening period, but such testing generally should be limited to patients with 
 
Endpoints 
Primary 
 
Primary Efficacy Endpoint 
• 
AHI(4%), AD036 vs. placebo 
Secondary 
 
• 
Hypoxic burden and ODI(4%), AD036 vs. placebo 
• 
Hypoxic burden, AHI(4%) and ODI(4%), AD036 vs. atomoxetine  
Tertiary  
 
Tertiary Efficacy Endpoints 
• 
Total time with SaO2 <90%  
• 
Snoring index 
• 
Sleep stages distribution and % of time in the various sleep stages 
• 
Arousal index 
• 
Proportion of participants with ≥50% reduction, AHI and ODI endpoints 
• 
Fraction of hypopneas 
• 
Alternative measures of AHI and ODI 
Abbreviations: AHI = apnea-hypopnea index; ODI = oxygen desaturation index; SaO2 = oxygen saturation. 


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documented previous sleep apnea test results (e.g. previous sleep study outside 4-month window) 
indicating the patient is still likely to meet objective OSA study enrollment criteria.  
There are 3 randomized crossover HSAT nights. Each HSAT night is followed by a 1-week 
washout period. Dosing of the study treatment will occur immediately prior to bedtime. Patients 
will be randomized to treatment sequence with one of the following experimental treatments on 
each HSAT night: 
• Atomoxetine 80 mg + oxybutynin 5 mg  
• Atomoxetine 80 mg + placebo  
• Placebo + placebo  
Site personnel will contact participants remotely via telephone or video-call each HSAT night to 
assist with HSAT equipment use and to confirm study drug dosing.  
Participants will be contacted by the site via telephone or video-call during each washout period 
to collect AE/SAE and concomitant medication information.  
Overall study duration will be up to 10 weeks. Participants who withdraw from the study will not 
be replaced. No subsequent open-label extension is planned following the study. 
Figure 1: 
Overview of Study Design 
 
 HSAT = home sleep apnea test. 
 
 


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4.2 Scientific Rationale for Study Design 
The completed Phase 2 Apnimed Study APN-002 provided evidence of efficacy and safety for 
AD036 in OSA. This Phase 2 clinical study will further examine the efficacy and safety of 
AD036 in patients with baseline characteristics thought to predict increased responsiveness to the 
drug.  
4.3 Justification for Dose 
The dose of AD036 in this study is the same or similar to the doses used in previous clinical 
studies that provided support for both the safety and efficacy of AD036 in OSA.   
The study uses a dose of 80 mg atomoxetine (either alone or in combination with 5 mg 
oxybutynin). Previous single-dose crossover studies of the PK, safety, and efficacy of AD036 
have demonstrated that this dosing is safe and well tolerated in the single-dose crossover setting.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of AD036 is 
provided in the Investigator’s Brochure. 
4.4 End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the final End of Study evaluation or the last scheduled procedure shown in the 
Schedule of Activities (SoA). 
The end of the study is defined as the date of the last evaluation of the last participant in the study 
or last scheduled procedure shown in the SoA for the last participant in the study globally. 
 
 


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5 Study Population 
The study population will consist both of participants from Study APN-002 and new patients 
who meet all enrollment criteria.  
Participants must be able to provide written consent and meet all the inclusion criteria and none 
of the exclusion criteria. 
5.1 Inclusion Criteria 
Individuals are eligible to be included in this study only if all of the following criteria apply: 
Age and Sex 
1. Male or Female, between 25 to 65 years of age, inclusive, at the Screening Visit. 
• Patients who participated in the APN-002 study can be enrolled if over the age of 65 
years of age, up to 67 years of age.  
• Patients who did not participate in the APN-002 study must be between 25 to 65 years 
of age at the Screening Visit.  
Objective Disease Measures  
2. AHI 10 to <20, or AHI ≥20 if any one of the following criteria are met: 
• Fraction of hypopneas (Fhypopnea) is >90% or 
• Mean oxygen desaturation of obstructive events is ≤4% or 
• Fraction of hypopneas is 50-90% and mean oxygen desaturation is 4-8%  
Note: Hypopneas defined by 4% oxygen desaturation 
Weight 
3. BMI between 18.5 and 40 kg/m2, inclusive.  
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 


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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 study-specific 
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. 
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. A 
medication for these purposes is defined by dosage form, such that a combination 
antihypertensive medication is considered 1 medication. 
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 current International 
Classification of Disease criteria. 
6. History of attempted suicide or suicidal ideation within 1 year prior to screening, or current 
suicidal ideation. 
7. History of clinically significant constipation, gastric retention, or urinary retention. 
8. Medically unexplained positive screen for drugs of abuse (excluding THC/marijuana) or 
substance use disorder as defined in DSM-V within 24 months prior to Screening Visit. 
9. A significant new illness or infection requiring medical treatment in the past 30 days. 


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10. Clinically significant cognitive dysfunction. 
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 HSAT. 
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. 
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 during study 
participation. 
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 prior to dosing, 
whichever is longer.  
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. Smoking more than 10 cigarettes or 2 cigars per day. 
23. Unwilling to use specified contraception.  
24. Unwilling to limit alcohol consumption to no greater than 2 units/day or less for men, or 1 
unit/day for women, not to be consumed within 3 hours of bedtime. 
25. Unwilling to limit caffeinated beverage intake (e.g., coffee, cola, tea) to 400 mg/day or less 
of caffeine, not to be used within 3 hours of bedtime. 


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26. 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. 
27. Participant considered by the investigator, for any reason, an unsuitable candidate to 
receive AD036 or unable or unlikely to understand or comply with the dosing schedule or 
study evaluations, including ability to use HSAT device. 
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 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). 
5.5 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized to study treatment/entered into the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants that 
meets the Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any serious adverse events (SAEs). 
Individuals who do not meet the criteria for participation in this study (screen failure) will not be 
rescreened, except if the opportunity for rescreening has been enabled by protocol amendment. 
6 Study Treatment 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 Study Treatments  
Study treatments include atomoxetine, oxybutynin, and placebo, taken immediately before the 
participant’s planned bedtime on HSAT nights, in randomized order: 


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• Atomoxetine 80 mg + oxybutynin 5 mg  
• Atomoxetine 80 mg + placebo  
• Placebo + placebo  
Study Treatment Name: 
Atomoxetine 
hydrochloride  
Oxybutynin 
chloride 
Placebo 
(Microcrystalline 
Cellulose) 
Dosage Formulation: 
Capsule 
Tablet 
Capsule 
Dosage Level: 
80 mg 
5 mg  
250mg 
Route of Administration: 
Oral 
Oral 
Oral 
Dosing Instructions: 
1 capsule 
administered with 
water  
1 tablet 
administered with 
water  
1 tablet 
administered with 
water 
Storage/Packaging/Labeling: Store per package 
insert.  
Store per package 
insert.  
Controlled room 
temperature. 
 
6.2 Preparation/Handling/Storage/Accountability 
• Only participants enrolled in the study may receive study treatments. Prior to 
distribution to participants 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. 
• 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). 
• 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. 
• Returned study treatment should not be re-dispensed to participants 
6.3 Measures to Minimize Bias 
All participants will be centrally randomized for the crossover study. Each participant will be 
assigned a unique number (randomization number) that encodes the participant’s assignment to 
one of the sequences of the study, according to the randomization schedule using a validated 
computer program.  


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6.4 Study Treatment Compliance 
Participants will be required to return any unused study drug. Unused study drug will be counted 
and recorded by study personnel to assess study treatment compliance.  
6.5 Concomitant Therapy 
Concomitant therapy with the following medications is disallowed: 
• MAOIs or other drugs that affect monoamine concentrations (e.g., rasagiline) [MAOIs are 
contraindicated for use with atomoxetine] 
• Selective Serotonin Reuptake Inhibitors (e.g., paroxetine) 
• Selective Norepinephrine Reuptake Inhibitors (e.g., duloxetine) 
• Norepinephrine Reuptake Inhibitors (e.g., reboxetine) 
• Alpha-1 antagonists (e.g., tamsulosin) 
• Tricyclic antidepressants (e.g., desipramine) 
• Centrally acting antihypertensives (e.g. clonidine, alpha-methyl-DOPA) 
• CYP2D6 inhibitors  
• Strong CYP3A4 inhibitors (e.g., ketoconazole) 
• Benzodiazepines and other anxiolytics 
• Opioids 
• Sedative hypnotics  
• 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) 


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• Antipsychotics 
• Anticholinergics and anticholinesterase inhibitors, including drugs with substantial 
anticholinergic side effects, (e.g., first generation antihistamines) 
• Sedating antihistamines 
• Pseudoephedrine, phenylephrine, oxymetazoline 
• Nicotine replacement products 
• Most drugs for Parkinson’s, Alzheimer’s, Huntington’s, Amyotrophic Lateral Sclerosis, or 
drugs for other neurodegenerative diseases 
Medications that do not have substantial effects on the central nervous system (CNS), 
respiration, or muscle activity are generally allowed if dose and frequency is stable2 for 1 month 
prior to enrollment and during the course of the study, including, but not necessarily limited to, 
the following drugs and drug classes: 
• Non-centrally acting 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) 
• Melatonin 
• Non-steroidal anti-inflammatory drugs and acetaminophen 
• Laxatives 
• Erectile dysfunction drugs 
• Inhaled corticosteroids (e.g., fluticasone) 
• Antidiabetics 
• Ocular hypotensives and other ophthalmics (e.g., timolol) 
• Hormonal therapy (e.g., estrogen replacement or anti-estrogens) and hormonal contraceptives 
 
2 Drugs that are used intermittently are considered to be used at a stable dose and frequency if the general pattern of 
use over time is consistent with the patient’s previous use. 


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• Thyroid medications 
• Anticoagulants 
• OTC topicals (e.g., topical pain relievers) 
• Osteoporosis drugs 
6.6 Treatment After the End of the Study 
Not applicable. No subsequent open-label extension is planned following the study. 
Study treatment will not be available after the end of study participation. 
7 Discontinuation of Study Treatment 
If a clinically significant finding is identified, the Investigator or qualified designee will 
determine if the participant can continue in the study and if any change in participant 
management is needed. Any new clinically relevant finding should be reported as an adverse 
event (AE). 
7.1 Stopping Criteria 
7.1.1 
Individual Participant Stopping Criteria 
• Incidents of abuse, diversion, or misuse of the study treatment. 
• Incidents of clinical significance: hallucinations, amnesia, delusional thinking, delirium, 
manic symptoms, aggressive behavior, suicidality, homicidality, agitation, confusion, or 
convulsions/seizures. 
• Participants reporting any SAE. 
• Acute urinary obstruction. 
• Any other AE that in the judgment of the Investigator necessitates the participant stopping to 
protect participant safety. 
7.2 Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, or 
administrative reasons. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 


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• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
• All participants who withdraw from the study with an ongoing AE must be followed until the 
event is resolved or deemed stable. 
• Participation may be terminated before completing the study and the reason recorded. 
7.3 Loss of Participants to Follow-Up 
A participant will be considered lost to follow-up if the study site is repeatedly unable to contact 
the participant. The following actions must be taken if a participant is lost to follow-up: 
• The site must attempt to contact the participant and resume study activities as soon as 
possible (and within the activity window, where one is defined) and counsel the participant 
on the importance of maintaining the assigned activity schedule and ascertain whether or not 
the participant wishes to and/or should continue in the study. 
• In cases in which the participant is deemed lost to follow-up, the Investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the participant’s 
medical record/eCRF. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8 Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA. 
• 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. 


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8.1.1 
Home Sleep Apnea Testing (HSAT) 
• Methods: Standard HSAT recording and data interpretation will be performed in accordance 
with the American Academy of Sleep Medicine (AASM) scoring manual for respiratory 
signals. EEG activity will be estimated from frontal derivations. Screening HSAT for new 
patients may be conducted without estimation of EEG activity. 
• Time of lights out will be according to the participants’ habitual schedule and kept constant 
across the HSAT study nights.  
• Sites will instruct participants on proper use of HSAT device at screening visit. 
• Sites will contact participants each night of study drug dosing to assist and confirm use of 
HSAT and study drug dosing. 
• Scoring: For uses other than establishing that the patients meets study enrollment criteria, all 
HSATs will be scored by centralized technologists who are separate from the clinical care 
team. 
8.2 Safety Assessments 
• Planned time points for all adverse events 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, and will include 
monitoring and recording of AEs, SAEs, and recording of study or treatment 
discontinuations. Effects on OSA will also be monitored by HSAT. 
8.3 Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Appendix 3. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for following 
up on AEs that are serious, considered related to the study treatment or the study, or that caused 
the participant to discontinue the study and/or study treatment (see Section 7). 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of informed consent form (ICF) until the 
end of the study.  


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All SAEs will be recorded and reported to the Sponsor or designee within 24 hours. 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. 
8.3.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrence. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each participant 
at subsequent contacts. All SAEs will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up. Further information on follow-up 
procedures is given in Appendix 3. 
8.3.4 
Regulatory Reporting Requirements for SAEs 
• Prompt notification (within 24 hours, see Appendix 3) by the Investigator to the Sponsor of 
an SAE is essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/Independent Ethics Committees (IEC), and 
Investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 


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• 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. 
8.3.5 
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. 
8.4 Treatment of Overdose 
For this study, any dose of atomoxetine greater than 80 mg and of oxybutynin greater than 5 mg 
more frequently than QHS will be considered an overdose. 
In the event of an overdose, the Investigator should refer to the approved product labels for 
atomoxetine and oxybutynin for advice on overdose and: 
1. Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF. 
2. Contact the Medical Monitor. 
3. Closely monitor the participant as clinically indicated for AE/SAE and laboratory 
abnormalities until atomoxetine and/or oxybutynin can no longer be detected systemically. 
4. Obtain a plasma sample for PK analysis, if clinically indicated, 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). 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5 Pharmacokinetics 
PK parameters are not evaluated in this study. 


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9 Statistical Considerations and Sample Size Determination 
The efficacy of AD036 in OSA was investigated in Apnimed Study APN-002. Patients in Study 
APN-006 will be selected based on baseline objective OSA criteria that, from the results of Study 
APN-002, are thought to enrich for patients more likely to be responders. A total of 54 patients (9 
per sequence) will enter the 3-treatment crossover study. The study will have 90% power to 
detect a treatment difference at a two-sided 0.05 significance level, if the true difference between 
treatments on AHI is -11.000 units. This assumes that the within-subject standard deviation is 12, 
estimated from Study APN-002 using a subset of 92 subjects with baseline Fhypopnea ≥65%. 
Subjects will be randomized to one of the following 6 sequences: A – B – C, B – C – A, C – B – 
A, A – C – B, B – A – C, C – A – B.  This design is both uniform within sequences (each 
treatment appears the same number of times within each sequence) and uniform within periods 
(each treatment appears the same number of times within each period).  These properties result in 
neither the sequence nor the period effects being aliased with the treatment effect. Furthermore, 
the inclusion of a washout period is believed to minimize any carryover effect, or at the 
minimum, the carryover effect is believed to be equal among all treatments and therefore would 
not be aliased with the estimation of the treatment effect. The above design also assures that each 
treatment is preceded by all other treatments at least once.  
 
9.1 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 take at least 
1 dose of any of the study treatments, and have at least 1 
measurement on the primary endpoint. Participants will be 
analyzed for efficacy according to the treatment group into which 
they are randomized. 
Safety Population 
The Safety Population consists of all participants who are 
randomized and receive at least 1 dose of any of the study 
treatments. Participants will be analyzed for safety based on the 
treatment received. A precise definition of “as actually received” 
will be added in the Statistical Analysis Plan (SAP). 
Per Protocol (PP) 
Population 
The PP Population consists of all participants without any major 
protocol violations that could influence efficacy assessment, and 
who are compliant with the study medication and HSAT in each 
crossover period. Participants in this population will be analyzed 
according to the treatment they actually received. 
 
10 Supporting Documentation and Operational Considerations 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with: 
o Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences International Ethical Guidelines. 
o Applicable International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines. 
o Applicable laws and regulations. 
• The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• The Investigator will be responsible for the following: 


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o 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. 
o Notifying the IRB/IEC of SAE or other significant safety findings as required 
by IRB/IEC procedures. 
o Overall conduct of the study at the site and adherence to requirements of 21 
Code of Federal Regulations (CFR), ICH GCP guidelines, the IRB/IEC 
guidelines, European regulation 536/2014 for clinical studies (if applicable), 
and all other applicable local regulations. 
10.1.2 Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 
10.1.3 Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study.  
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center. 
• 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. 


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• If a protocol amendment is required, the ICF may need to be revised to reflect the changes to 
the protocol. If the ICF is revised, it must be reviewed and approved by the appropriate 
IEC/IRB, and signed by all participants subsequently enrolled in the study as well as those 
currently enrolled in the study. 
10.1.4 Data Protection 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
• The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
• The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5 Dissemination of Clinical Study Data 
When the clinical study report is completed, the Sponsor will provide the major findings of the 
study to the Investigator. A summary of the study results will also be posted in a publicly 
accessible database (e.g., www.ClinTrials.gov). The results may also be submitted for 
publication.  
10.1.6 Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or eCRFs unless 
transmitted to the Sponsor or designee electronically. The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 


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• 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. 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. 
10.1.7 Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study.  
• Definition of what constitutes source data can be found in Section 10.1.11.1. 


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10.1.8 Study and Site Closure 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure evaluation 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. 
10.1.9 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. 
10.1.10 Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IEC/IRB/Competent Authorities, in accordance with local legal requirements. The 
Sponsor must ensure that all ethical and legal requirements have been met before the first 
participant is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/IEC/Competent Authority 
approval prior to implementation (if appropriate). Following approval, the protocol 
amendment(s) will be submitted to the US Investigational New Drug (IND) under which the 
study is being conducted. 


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Administrative changes (not affecting the participant benefit/risk ratio) may be made without the 
need for a formal amendment. All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
10.1.11 Liability and Insurance 
The Sponsor will take out reasonable third-party liability insurance cover in accordance with all 
local legal requirements. The civil liability of the Investigator, the persons instructed by him or 
her and the hospital, practice, or institute in which they are employed and the liability of the 
Sponsor with respect to financial loss due to personal injury and other damage that may arise as a 
result of the carrying out of this study are governed by the applicable law. 
The Sponsor will arrange for participants participating in this study to be insured against 
financial loss due to personal injury caused by the pharmaceutical products being tested or by 
medical steps taken in the course of the study. 
10.1.11.1 Access to Source Data 
During the study, a monitor will either make site visits or request documentation remotely 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. 
10.2 Appendix 2: Clinical Laboratory Tests 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• Laboratory testing is performed non-fasting. 
• Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations. 


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Table 2: Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Hematocrit 
Hemoglobin 
Platelet Count 
RBC Count 
RBC Indices 
 
WBC count with Differential 
 
Serum Chemistry Albumin 
BUN 
Creatinine 
Potassium 
Sodium  
Bilirubin 
Total Protein  
ALT 
AST 
Alkaline phosphatase 
Calcium 
Glucose  
Chloride 
Bicarbonate 
Routine 
Urinalysis 
Specific gravity 
pH, protein (albumin), glucose, ketones, blood (RBC), WBC by dipstick 
Microscopic examination (if blood or protein is abnormal) 
Other Tests 
• CYP 2D6 (only at Screening Visit, only for new patients not previously 
tested in Study 002) 
• HbA1c (Screening Visit only) 
• Serum hCG pregnancy test at screening. Additional testing may be 
performed if needed in WOCBP. 
• Urine drugs of abuse (marijuana, cocaine, amphetamine, 
methamphetamine, opiates, phencyclidine)  
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
CYP2D6 = cytochrome P450 2D6; γ-GTP = gamma guanosine-5’-triphosphate; HbA1c = hemoglobin A1c 
(glycated hemoglobin); hCG = human chorionic gonadotropin; MCH = mean corpuscular hemoglobin; MCV = 
mean corpuscular volume; RBC = red blood cell count; WBC= white blood cell; WOCBP = women of 
childbearing potential. 
Investigators must document their review of each laboratory safety report. 


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10.3 Appendix 3: AE 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. 
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 


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• 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. 
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’s. 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’s Clinical Studies Safety Center. 


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• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to one of the following categories: 
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with an SAE. Severe is a category utilized for rating the intensity 
of an event; and both AE and SAE can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• The Investigator is obligated to assess the relationship between study treatment and 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. 


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• 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. 
• 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. 


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• 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. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or by 
telephone. 
• 
Contacts for SAE reporting can be found in the Study Reference Manual. 
 
All SAEs will be recorded from signing of informed consent until the end of the study as defined 
in Section 4.4. 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. 
 
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. 


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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. 
 
10.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions 
WOCBP 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with one of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
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: 


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Male participants with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following during the protocol-defined time frame in Section 5.1: 
• Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent. 
• Agree to use a contraceptive method with a failure rate of <1% per year as described 
in the table below when having penile-vaginal intercourse with a WOCBP who is not 
currently pregnant. 
In addition, male participants must refrain from donating sperm for the duration of the study and 
for 3 months after the last dose of study treatment. 
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or to use a male condom during each episode of penile penetration 
during the protocol-defined time frame. 
Female Participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in the table 
below. 


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


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Female participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of a participant’s pregnancy. 
The participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect any follow up information on the participant and the neonate and the information 
will be forwarded to the Sponsor. Generally, follow up will not be required for longer than 6 
to 8 weeks beyond the estimated delivery date. Any termination of the pregnancy will be 
reported, regardless of fetal state (presence or absence of anomalies) or indication for the 
procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous 
abortion is always considered to be an SAE and will be reported as such. Any post-study 
pregnancy-related SAE considered reasonably related to the study treatment by the 
Investigator will be reported to the Sponsor as described in Section 8.3.4. While the 
Investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study. 
 
 


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10.5 Appendix 5: List of Abbreviations 
AHI 
apnea-hypopnea index 
AE 
adverse event 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CPAP 
continuous positive air pressure 
CSSA 
Cocaine Selective Severity Assessment 
CYP2D6 
cytochrome P450 2D6 
CYP3A4 
cytochrome P450 3A4 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
ECG 
electrocardiogram 
EEG 
electroencephalogram 
eCRF 
electronic case report form(s) 
EDC 
electronic data capture 
ESS 
Epworth Sleepiness Scale 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HRT 
hormone replacement therapy 
HSAT 
Home sleep apnea test 
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 
PGI-S 
Participant Global Impression of Severity 
PK 
pharmacokinetic(s) 
PSG 
polysomnography 
DWRT 
Delayed Word Recall Test 
QHS 
1 dose every night at bedtime 


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REM 
rapid eye movement 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SoA 
Schedule of Activities 
SUSAR 
suspected unexpected serious adverse reaction 
ULN 
upper limit of normal 
US 
United States 
WOCBP 
woman of childbearing potential 
 
 
 
 


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11 References 
Brooks D, Horner RL, Kozar LF, Render-Teixeira CL, Phillipson EA. Obstructive  sleep apnea as a cause of 
systemic hypertension. Evidence from a canine model. J Clin Invest 1997;99:106-109. 
Chan E, Steenland HW, Liu H, Horner RL. Endogenous excitatory drive modulating respiratory muscle activity 
across sleep-wake states. Am J Respir Crit Care Med 2006;174:1264-1273. 
Eckert DJ, White DP, Jordan AS, Malhotra A, Wellman A. Defining phenotypic causes of obstructive sleep apnea. 
Identification of novel therapeutic targets. Am J Respir Crit Care Med 2013;188:996-1004. 
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. 
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, 3-Period, Placebo-Controlled Crossover Study to Evaluate the 
Efficacy and Safety in Obstructive Sleep Apnea of AD036 versus Placebo or Atomoxetine  
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. 
 
June 21, 2023 
 
To: ClinicalTrials.gov 
 
This is a cover page to the redacted SAP for APN-006 titled Phase 2, Randomized, 3-Period, 
Placebo-Controlled Crossover Study to Evaluate the Efficacy and Safety in Obstructive Sleep 
Apnea of AD036 versus Placebo or Atomoxetine. 
 
The APN-006 SAP is associated with NCT 04445688.   
 
The following proprietary information was redacted from the SAP for APN-006:  
 IND number 
 Reference to the CRO (Contract Research Organization).   
 
Sincerely, 
 
 
 
 
 
Jeanne Brittain 
Director, Program Management 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
Phase 2, Randomized, 3-Period, Placebo-Controlled Crossover Study to Evaluate the Efficacy 
and Safety in Obstructive Sleep Apnea of AD036 versus Placebo or Atomoxetine 
 
 
Protocol Number:  APN-006 
Protocol Version:  3.0 
Protocol Date:  15 September 2020 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Version 1.1 
18 September 2020 
 
 
SIGN


 
 Apnimed Inc. APN-006 Statistical Analysis Plan v1.1 
 
CONFIDENTIAL  
 
Page 2 of 21 
 
Phase 2, Randomized, 3-Period, Placebo-Controlled Crossover Study 
to Evaluate the Efficacy and Safety in Obstructive Sleep Apnea of AD036 versus Placebo or 
Atomoxetine 
 
STATISTICAL ANALYSIS PLAN 
Version 1.1 
18 September 2020 
 
 
 
 
 
Author: 
 
 
Ying Li 
 
 
 
 
 
 
 
 
Biostatistician, CTI  
 
 
 
 
 
 
CTI Biostatistics 
Reviewer: 
 
 
Rachael Gilbert Runyan 
 
 
 
 
 
 
Manager, Biostatistics, CTI 
 
 
 
 
 
 
 
 
 
Sponsor Approval:  
 
 
 
Ronald Farkas  
 
 
 
 
 
 
 
Chief Medical Officer 
 
 
 
Apnimed, Inc. 
 
 


 
 Apnimed Inc. APN-006 Statistical Analysis Plan v1.1 
 
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SAP Revisions  
Version 1.0 of the SAP was finalized at the time of Protocol version 2.0 (13APR2020).  The 
following table details the changes made to the SAP due to subsequent protocol amendments.    
Protocol 
Version # 
Date 
SAP 
Section 
Modification 
Description and Rationale 
3.0 
15SEP2020 
2.1.3 
Removed endpoint ‘Fraction of 
apneas’. 
NA 
 
 
 


 
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Table of Contents 
SAP Revisions ....................................................................................................................................................... 3 
LIST OF ABBREVIATIONS AND TERMS ....................................................................................................... 6 
1. 
INTRODUCTION ............................................................................................................................................. 8 
2. 
OBJECTIVES AND ENDPOINTS ........................................................................................................................ 8 
2.1. 
OBJECTIVES ..................................................................................................................................................... 8 
2.1.1. Primary Objective .................................................................................................................................... 8 
2.1.2. Secondary Objectives .............................................................................................................................. 8 
2.1.3. Tertiary Objective .................................................................................................................................... 8 
2.2. 
ENDPOINTS ..................................................................................................................................................... 9 
2.2.1. Primary Endpoint .................................................................................................................................... 9 
2.2.2. Secondary Endpoints ............................................................................................................................... 9 
2.2.3. Tertiary Endpoints ................................................................................................................................... 9 
3. 
INVESTIGATIONAL PLAN .............................................................................................................................. 10 
3.1. 
STUDY DESIGN ............................................................................................................................................... 10 
3.2. 
TREATMENT .................................................................................................................................................. 11 
3.2.1. Randomization Scheme and Treatment Arm Assignment .................................................................... 11 
3.2.2. Blinding ................................................................................................................................................. 11 
3.2.3. Dosing Schedule .................................................................................................................................... 11 
3.2.4. Study Treatment Compliance ................................................................................................................ 11 
4. 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS ....................................................................................... 12 
4.1. 
DATA QUALITY ASSURANCE.............................................................................................................................. 12 
4.2. 
ANALYSIS SETS ............................................................................................................................................... 12 
4.2.1. Enrolled Population ............................................................................................................................... 12 
4.2.2. Modified Intent-To-Treat Analysis (mITT) Population ........................................................................... 12 
4.2.3. Safety Population .................................................................................................................................. 12 
4.2.4. Per Protocol (PP) Population ................................................................................................................. 13 
4.3. 
ASSESSMENT WINDOWS ................................................................................................................................. 13 
4.4. 
HANDLING OF DROPOUTS OR MISSING DATA ...................................................................................................... 13 
4.5. 
MULTIPLE COMPARISONS ................................................................................................................................ 13 
4.6. 
DATA DERIVATIONS AND TRANSFORMATIONS ...................................................................................................... 13 
5. 
STUDY PATIENTS ......................................................................................................................................... 13 
5.1. 
DISPOSITION OF PATIENTS ............................................................................................................................... 13 
5.2. 
PROTOCOL DEVIATIONS ................................................................................................................................... 13 
5.3. 
DEMOGRAPHIC .............................................................................................................................................. 13 
5.4. 
BASELINE SAFETY CHARACTERISTICS ................................................................................................................... 14 
5.5. 
MEDICAL HISTORY.......................................................................................................................................... 14 
5.6. 
PRIOR AND CONCOMITANT MEDICATIONS .......................................................................................................... 14 
6. 
EFFICACY ANALYSIS ..................................................................................................................................... 14 
6.1. 
PRIMARY EFFICACY ANALYSIS – AHI(4%) ........................................................................................................... 14 


 
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6.2. 
SECONDARY EFFICACY ANALYSIS ........................................................................................................................ 15 
6.2.1. AHI(4%) ................................................................................................................................................. 15 
6.2.2. Hypoxic burden(4%) .............................................................................................................................. 15 
6.2.3. ODI(4%) ................................................................................................................................................. 15 
6.5. 
TERTIARY EFFICACY ANALYSES .......................................................................................................................... 15 
7. 
SAFETY ANALYSIS ........................................................................................................................................ 16 
7.1. 
EXTENT OF EXPOSURE ..................................................................................................................................... 16 
7.2. 
ADVERSE EVENTS ........................................................................................................................................... 16 
7.2.1. Treatment-emergent Adverse Events ................................................................................................... 16 
7.2.2. Adverse Event Intensity ......................................................................................................................... 17 
7.2.3. Adverse Event Relationship to Study Medication ................................................................................. 17 
7.2.4. Serious Adverse Events ......................................................................................................................... 17 
7.2.5. Adverse Event Summaries ..................................................................................................................... 18 
8. 
INTERIM ANALYSIS ...................................................................................................................................... 19 
9. 
SAMPLE SIZE AND POWER CALCULATIONS .................................................................................................. 19 
10. APPENDICES ................................................................................................................................................ 20 
10.1. 
APPENDIX A: SCHEDULE OF ACTIVITIES ............................................................................................................... 20 
10.2. 
APPENDIX B: PROTOCOL-REQUIRED SAFETY LABORATORY ASSESSMENTS .................................................................. 21 
 
 


 
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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
AHI  
apnea-hypopnea index  
AE  
adverse event  
ATC 
anatomical, therapeutic, and chemical 
CSR 
clinical study report  
CYP2D6  
cytochrome P450 2D6  
ECG  
electrocardiogram  
eCRF  
electronic case report form(s)  
EDC  
electronic data capture  
HSAT  
Home sleep apnea test  
ICF  
informed consent form  
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  
PT 
preferred term 
REM 
rapid eye movement  
SAE  
serious adverse event  
SaO2 
oxygen saturation 


 
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Abbreviation 
Definition 
SAP  
statistical analysis plan 
SE 
sleep efficiency  
SOC 
system organ class 
SOL 
sleep onset latency  
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 # APN-006 Version 2.0, dated 13 
April, 2020, titled “Phase 2, Randomized, 3-Period, Placebo-Controlled Crossover Study to 
Evaluate the Efficacy and Safety in Obstructive Sleep Apnea of AD036 versus Placebo or 
Atomoxetine.”  AD036 is a new fixed-dose combination of atomoxetine and oxybutynin being 
developed for the treatment of obstructive sleep apnea (OSA). Study APN-006 is designed to 
confirm and extend safety and efficacy findings from Study APN-002, a Phase 2 study of AD036 
in OSA. See the study protocol for full details.  
This document details the statistical methods planned to perform the final analyses of this study.   
2. 
OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
The primary objective is to evaluate the efficacy of AD036 compared to placebo as measured by 
the 4% definition of apnea-hypopnea index (AHI).  
2.1.2. 
Secondary Objectives 
The secondary objectives include:  
 To evaluate the efficacy of AD036 compared to placebo as measured by hypoxic burden 
and the 4% definition of oxygen desaturation index (ODI).  
 To evaluate the efficacy of AD036 compared to atomoxetine on measures of hypoxic 
burden, AHI(4%), and ODI(4%). 
2.1.3. 
Tertiary Objective 
The tertiary objectives are to evaluate the effects of AD036 compared to both placebo and 
atomoxetine on: 
 Total time with SaO2 <90% 
 Snoring index  
 Sleep stages distribution and % of time in the various sleep stages 
 Arousal index 
 Proportion of participants with ≥50% reduction in AHI and ODI endpoints 
 Fraction of hypopneas 
 Alternative measures of AHI and ODI 


 
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2.2. 
Endpoints 
2.2.1. 
Primary Endpoint 
The primary efficacy endpoint is as follows: 
 AHI(4%), AD036 vs. placebo 
2.2.2. 
Secondary Endpoints 
The secondary efficacy endpoints are as follows: 
 Hypoxic burden(4%) and ODI(4%), AD036 vs. placebo 
 Hypoxic burden(4%), AHI(4%) and ODI(4%), AD036 vs. atomoxetine 
2.2.3. 
Tertiary Endpoints 
The tertiary efficacy endpoints are as follows: 
 Total time with SaO2 <90% 
 Snoring index 
 Sleep stages distribution and % of time in the various sleep stages 
o Total Sleep Time (TST) 
o Sleep Efficiency (SE) 
o Wake After Sleep Onset (WASO) 
o Number of Awakenings (NAW) 
o Sleep Onset Latency (SOL) 
o Percentage of TST spent in sleep stage N1 (Stage N1%) 
o Percentage of TST spent in sleep stage N2 (Stage N2%)  
o Percentage of TST spent in sleep stage N3 (Stage N3%) 
o Percentage of TST spent in sleep stage R (Stage R%) 
 Arousal index 
 Proportion of participants with ≥50% reduction, AHI and ODI endpoints 
 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(4%) in supine position 
o AHI(3% or arousal) 


 
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o HB(3%) 
o HB(total) 
o ODI(3%) 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Study Design 
Patients who participated in Study APN-002 are eligible for enrollment, as are new patients who 
meet enrollment criteria. A total of 54 Patients with baseline characteristics that, based on Study 
APN-002 findings, predict increased responsiveness to AD036, will be planned for enrollment. 
Objective OSA inclusion criteria for patients who participated in Study APN-002 will be determined 
based on the Study APN-002 baseline PSG exam (applies also to patients who were screened but did 
not meet the study PSG criteria). Objective OSA inclusion criteria for new patients can be based on a 
previous full night PSG or home sleep apnea test (HSAT) conducted at the site within 4 months prior 
to enrollment. If such results are not available, a screening HSAT may be conducted during the 
screening period, but such testing generally should be limited to patients with documented previous 
sleep apnea test results (e.g. previous sleep study outside 4-month window) indicating the patient is 
still likely to meet objective OSA study enrollment criteria. 
There are 3 randomized crossover HSAT nights. Each HSAT night is followed by a 1-week 
washout period. Dosing of the study treatment will occur immediately prior to bedtime. Patients 
will be randomized to treatment sequence with one of the following experimental treatments on 
each HSAT night:  
 A: Atomoxetine 80 mg + oxybutynin 5 mg 
 B: Atomoxetine 80 mg + placebo 
 C: Placebo + placebo 
Overall study duration will be up to 10 weeks, as follows:  
 Screening, up to 4 weeks; 
 3-period crossover, approximately 5 weeks; 
 End of study evaluation, 1 week after end of crossover period  


 
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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. 
Study treatments include atomoxetine 80 mg + oxybutynin 5 mg, atomoxetine 80 mg + placebo, 
and placebo + placebo, taken immediately before the participant’s planned bedtime on HSAT 
nights, in randomized order. 
3.2.1. 
Randomization Scheme and Treatment Arm Assignment 
The randomization scheme will allocate subjects to one of the following 6 treatment sequences: A 
– B – C, B – C – A, C – B – A, A – C – B, B – A – C, or C – A – B (using treatments A, B, and C 
as defined in Section 3.1). 
3.2.2. 
Blinding 
Not applicable. 
3.2.3. 
Dosing Schedule 
There are 3 randomized crossover HSAT nights. Each HSAT night is followed by a 1-week 
washout period. Dosing of the study treatment will occur immediately prior to bedtime. Patients 
will be randomized to treatment sequence with one of the experimental treatments taken on each 
HSAT night. 
3.2.4. 
Study Treatment Compliance 
Site personnel will contact participants remotely each HSAT night to assist with HSAT equipment 
use and to confirm study drug dosing. 
Participants will be required to return any unused study drug. Unused study drug will be counted 
and recorded by study personnel to assess study treatment compliance. 


 
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4. 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS 
In general, continuous variables will be summarized by presenting the population sample size (N), 
number of patients with available data (n), mean, standard deviation (SD), median, minimum, and 
maximum. In summaries of change from baseline safety variables, only patients with both baseline 
and post baseline data will be included. Categorical variables will be summarized by presenting 
the number and percentage of patients 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 all efficacy and safety 
analyses. Any changes to the analyses that are not 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 Population 
The Enrolled Population is defined as all participants who signed the informed consent form 
(ICF) (including screening failures). 
4.2.2. 
Modified Intent-To-Treat Analysis (mITT) Population 
The mITT Population comprises all participants who 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 sequence into which they are randomized 
4.2.3. 
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. Treatment received is defined as the actual treatment taken during each period. 


 
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4.2.4. 
Per Protocol (PP) Population 
The PP Population consists of all participants without any major protocol violations that could 
influence efficacy assessment, and who are compliant with the study medication. 
Participants in this population will be analyzed based on the treatment received. Treatment 
received is defined as the actual treatment taken during each period.  
4.3. 
Assessment Windows 
Data will be summarized by nominal study visit recorded in the database.  There will be no 
windowing of any endpoint. 
4.4. 
Handling of Dropouts or Missing Data 
Missing data will remain missing.  No imputation of missing data will be performed. 
4.5. 
Multiple Comparisons 
All hypothesis tests will be reported using the nominal 0.05 alpha level. There will be no 
adjustments for multiple comparisons of any endpoint. 
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 the assessment value minus the baseline value; percent change from baseline 
values will be calculated as the change from baseline value divided by the baseline value. 
5. 
STUDY PATIENTS 
5.1. 
Disposition of Patients 
A table of frequency counts and percentages of all patients who are enrolled, randomized, and 
included in each analysis population will be provided. Patient disposition including study 
completion status and reasons for early termination will be tabulated by treatment sequence and 
overall. A by-patient listing will be provided.  
5.2. 
Protocol Deviations 
Two separate by-patient 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, 


 
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ethnicity, height, weight, and BMI) by treatment sequence and overall using the Safety Population. 
A by-patient listing will also be provided.   
5.4. 
Baseline Safety Characteristics 
The results of the following assessments completed during the Screening visit will be 
summarized overall using the Safety Population: 
 Clinical laboratory assessments (hematology, serum chemistry, urinalysis, CYP 2D6, 
HbA1C, pregnancy test, and alcohol breath test and urine drugs of abuse). CYP 2D6 and 
pregnancy test will be in listings only.  
 Vital signs (respiratory rate, temperature, heart rate, and systolic and diastolic blood 
pressure) 
 ECG (heart rate, pulse rate, QRS, QT, and QTcF) 
 
A by-patient listing will also be provided for each baseline assessment above.  
 
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 patients with each 
medical condition and surgical procedure will be presented by MedDRA system organ class 
(SOC), preferred term (PT) overall for the Safety Population. Each patient will be counted only 
once per SOC and PT. A by-patient listing will also be provided.   
5.6. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using World Health Organization (WHO) Drug 
Dictionary version MAR2020.  The number and percent of patients 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 patient for 
each ATC level and preferred name. A by-patient listing will also be provided.   
6. 
EFFICACY ANALYSIS 
6.1. 
Primary Efficacy Analysis – AHI(4%) 
The primary efficacy endpoint is the AHI(4%) value.  The primary endpoint will be analyzed using 
a within-subject ANOVA model including treatment sequence, treatment, and visit as fixed effects. 
Robust variance estimates for the fixed effects will be used for testing treatment differences. 
Within subject variability (nested within treatment sequence) will be modeled using an 
unstructured (i.e., TYPE = UN) covariance pattern.  The primary comparison of interest will be 
the difference between the AD036 and placebo treatment conditions.  Model based point estimates 
(i.e., least square [LS] means for each treatment condition and the difference between conditions), 
95% confidence interval for the difference, and p-value will be reported. 
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 Population on the primary efficacy endpoint 
using the same methods described above.  


 
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6.2. 
Secondary Efficacy Analysis  
6.2.1. 
AHI(4%) 
The secondary comparison of interest between AD036 and atomoxetine will be the tested using 
the within-subject ANOVA model described in Section 6.1.  Model based point estimates of the 
difference between AD036 and atomoxetine, 95% confidence interval for the difference, and p-
value will be reported with the primary efficacy analysis. 
 
Descriptive statistics for the reported AHI(4%) value and change from baseline in AHI(4%) will 
be presented by treatment condition.   
6.2.2. 
Hypoxic burden(4%) 
Similar within-subject ANOVA methods as described for the primary analysis will be used for 
the analysis of hypoxic burden.  The comparisons of interest will be the differences between the 
AD036 and placebo treatment conditions and between the AD036 and atomoxetine treatment 
conditions. Model based point estimates (i.e., LS means for each treatment condition and the 
differences between conditions), 95% confidence interval for the differences, and p-values will 
be reported.  
Descriptive statistics for the reported hypoxic burden(4%) value and change from baseline in 
hypoxic burden(4%) will be presented by treatment condition.   
6.2.3. 
ODI(4%) 
Similar within-subject ANOVA methods as described for the primary analysis will be used for 
the analysis of ODI(4%).  The comparisons of interest will be the differences between the 
AD036 and placebo treatment conditions and between the AD036 and atomoxetine treatment 
conditions. Model based point estimates (i.e., LS means for each treatment condition and the 
differences between conditions), 95% confidence interval for the differences, and p-values will 
be reported.  
Descriptive statistics for the reported ODI(4%) value and change from baseline in ODI(4%) will 
be presented by treatment condition.   
6.5. 
Tertiary Efficacy Analyses 
Tertiary efficacy endpoints will be analyzed using similar methods as described for the primary 
analysis or by descriptive statistics by treatment condition (See Section 2.2.3), as appropriate for 
the endpoint. 
Additional clarifying details for the analysis of some of these endpoints is as follows: 
 ≥50% AHI reduction 
o Displays will be created for the AD036 and atomoxetine treatment conditions 
compared to the placebo condition (i.e., the % reduction will be defined as the 
difference in the AD036 and placebo values divided by the placebo value).    


 
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 ≥50% ODI reduction 
o  Displays will be created as above for ≥50% AHI reduction.   
 Fraction of hypopneas 
o 
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 
o Similar within-subject ANOVA methods as described before for the primary 
analysis will be used for a tertiary analysis of AHI(4%) including % time supine 
(%TS) as a covariate.  The comparison of interest will be the difference between 
the AD036 and placebo treatment conditions. Model based point estimates (i.e., 
LS means for each treatment condition and the difference between conditions), 
95% confidence interval for the difference, and p-value will be reported. The 
comparison of AD036 and atomoxetine treatment conditions will also be 
presented. 
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 Population. The safety assessments 
will be summarized by the treatment the subject actually received within each period. 
7.1. 
Extent of Exposure 
The number and percentage of patients receiving study treatment will be summarized by treatment 
condition and overall.  
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 
of study drug or an event already present that worsens in either severity or frequency following 
exposure. Each TEAE will be assigned to a treatment condition based on the treatment period it 
started in. There are a total of three (3) treatment periods. For example, a TEAE will be assigned 
to Treatment Period 1 if the AE start date/time is after the date/time of dosing in Treatment Period 
1 and prior to the date/time of dosing in Treatment Period 2.  


 
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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. 
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; 


 
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 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 patient.  The number and percentage of patients 
with AEs will be tabulated by SOC and PT.  A patient 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 treatment condition and presented for the Safety 
Population. 
i. 
An overall summary of TEAEs, which includes:  
a. the number and percentage of patients experiencing any TEAE 
b. the number and percentage of patients experiencing any TEAE by strongest 
relationship to study medication 
c. the number and percentage of patients experiencing any TEAE by greatest intensity 
d. the number and percentage of patients experiencing any TESAE  
ii. 
the number and percentage of patients experiencing any TEAE by SOC, PT 
iii. 
the number and percentage of patients experiencing any TEAE by SOC, PT and the 
greatest intensity 
iv. 
the number and percentage of patients experiencing any TEAE by SOC, PT and the 
strongest relationship to study medication 
v. 
the number and percentage of patients 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 patients, 
the total number of AE episodes will also be provided. If a patient has repeated episodes of a 
particular AE within a treatment period, all episodes will be counted in the summary table and 
displayed by treatment condition.   
For displays by SOC and PT, each subject will be counted only once per SOC and PT within each 
treatment condition. 
All occurrences of all AEs will be listed for each patient, grouped by treatment condition.  The 
listing will contain the following information: treatment sequence, treatment condition, verbatim 
term, SOC, PT, intensity, relationship to study medication, date and day of onset, date and day of 
resolution, treatment given to treat the adverse event, the outcome, whether the event was an SAE, 
whether it led to withdrawal.  Listings will be sorted by patient 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 


 
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most recent study drug dose will be imputed as onset date.   
8. 
INTERIM ANALYSIS 
No formal interim analysis is planned.  
9. 
SAMPLE SIZE AND POWER CALCULATIONS 
A total of 54 patients (9 per sequence) will enter the 3-treatment crossover study. The study will 
have 90% power to detect a treatment difference at a two-sided 0.05 significance level, if the true 
difference between treatments on AHI is -11.0 units. This assumes that the within-patient standard 
deviation is 12, estimated from Study APN-002 using a subset of 92 patients with baseline 
Fhypopnea ≥65%.  
 
 


 
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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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With Signing Reasons (on each tab): 
   I approve this document
Sent: 9/18/2020 11:49:01 AM
Viewed: 9/18/2020 12:19:30 PM 
Signed: 9/18/2020 12:22:20 PM
Electronic Record and Signature Disclosure: 
      Not Offered via DocuSign


Signer Events
Signature
Timestamp
Ronald Farkas
rfarkas@apnimed.com
Chief Medical Officer
Ron Farkas
Security Level: Email, Account Authentication 
(Required)
Signature Adoption: Pre-selected Style
Signature ID: 
2A5F46E3-93FC-40C7-8A20-AB4EF320DAB7
Using IP Address: 71.179.160.191
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I approve this document
Sent: 9/18/2020 12:22:23 PM
Resent: 9/22/2020 1:23:30 PM
Viewed: 9/22/2020 1:46:38 PM 
Signed: 9/22/2020 1:47:45 PM
Electronic Record and Signature Disclosure: 
      Accepted: 7/17/2020 9:40:08 AM
      ID: 7410fab0-c816-4828-a4ed-9fb902e0e97a
In Person Signer Events
Signature
Timestamp
Editor Delivery Events
Status
Timestamp
Agent Delivery Events
Status
Timestamp
Intermediary Delivery Events
Status
Timestamp
Certified Delivery Events
Status
Timestamp
Carbon Copy Events
Status
Timestamp
Witness Events
Signature
Timestamp
Notary Events
Signature
Timestamp
Envelope Summary Events
Status
Timestamps
Envelope Sent
Hashed/Encrypted
9/22/2020 1:23:30 PM
Certified Delivered
Security Checked
9/22/2020 1:46:38 PM
Signing Complete
Security Checked
9/22/2020 1:47:45 PM
Completed
Security Checked
9/22/2020 1:47:45 PM
Payment Events
Status
Timestamps
Electronic Record and Signature Disclosure


ELECTRONIC RECORD AND SIGNATURE DISCLOSURE  
From time to time, CTI Clinical Trial and Consulting Services (we, us or Company) may be 
required by law to provide to you certain written notices or disclosures. Described below are the 
terms and conditions for providing to you such notices and disclosures electronically through the 
DocuSign system. Please read the information below carefully and thoroughly, and if you can 
access this information electronically to your satisfaction and agree to this Electronic Record and 
Signature Disclosure (ERSD), please confirm your agreement by selecting the check-box next to 
‘I agree to use electronic records and signatures’ before clicking ‘CONTINUE’ within the 
DocuSign system. 
 
Electronic Signature Responsiblities  
You agree that your electronic signature is the equivalent of a hand-written signature and that 
you are responsible for actions initiated using your electronic signature. You agree to report 
unauthorized usage to CTI upon discovery of such usage via email to esign@ctifacts.com. 
Getting paper copies  
At any time, you may request from us a paper copy of any record provided or made available 
electronically to you by us. You will have the ability to download and print documents we send 
to you through the DocuSign system during and immediately after the signing session and, if you 
elect to create a DocuSign account, you may access the documents for a limited period of time 
(usually 30 days) after such documents are first sent to you. After such time, if you wish for us to 
send you paper copies of any such documents from our office to you, you will be charged a per-
page fee. You may request delivery of such paper copies from us by following the procedure 
described below. 
 
Withdrawing your consent  
If you decide to receive notices and disclosures from us electronically, you may at any time 
change your mind and tell us that thereafter you want to receive required notices and disclosures 
only in paper format. How you must inform us of your decision to receive future notices and 
disclosure in paper format and withdraw your consent to receive notices and disclosures 
electronically is described below. 
 
Consequences of changing your mind  
If you elect to receive required notices and disclosures only in paper format, it will slow the 
speed at which we can complete certain steps in transactions with you and delivering services to 
you because we will need first to send the required notices or disclosures to you in paper format, 
and then wait until we receive back from you your acknowledgment of your receipt of such 
paper notices or disclosures. Further, you will no longer be able to use the DocuSign system to 
Electronic Record and Signature Disclosure created on: 7/8/2020 8:22:51 AM
Parties agreed to: Ying Li, Ronald Farkas


receive required notices and consents electronically from us or to sign electronically documents 
from us. 
 
All notices and disclosures will be sent to you electronically  
Unless you tell us otherwise in accordance with the procedures described herein, we will provide 
electronically to you through the DocuSign system all required notices, disclosures, 
authorizations, acknowledgements, and other documents that are required to be provided or made 
available to you during the course of our relationship with you. To reduce the chance of you 
inadvertently not receiving any notice or disclosure, we prefer to provide all of the required 
notices and disclosures to you by the same method and to the same address that you have given 
us. Thus, you can receive all the disclosures and notices electronically or in paper format through 
the paper mail delivery system. If you do not agree with this process, please let us know as 
described below. Please also see the paragraph immediately above that describes the 
consequences of your electing not to receive delivery of the notices and disclosures 
electronically from us. 
 
How to contact CTI Clinical Trial and Consulting Services:  
You may contact us to let us know of your changes as to how we may contact you electronically, 
to request paper copies of certain information from us, and to withdraw your prior consent to 
receive notices and disclosures electronically as follows: 
Please send an email to esign@ctifacts.com  
 
To advise CTI Clinical Trial and Consulting Services of your new email address  
To let us know of a change in your email address where we should send notices and disclosures 
electronically to you, you must send an email message to us at esign@ctifacts.com and in the 
body of such request you must state: your previous email address, your new email address.   
If you created a DocuSign account, you may update it with your new email address through your 
account preferences.  
 
To request paper copies from CTI Clinical Trial and Consulting Services  
To request delivery from us of paper copies of the notices and disclosures previously provided 
by us to you electronically, you must send us an email to esign@ctifacts.com and in the body of 
such request you must state your email address, full name, mailing address, and telephone 
number.  
 
To withdraw your consent with CTI Clinical Trial and Consulting Services  


To inform us that you no longer wish to receive future notices and disclosures in electronic 
format you may: 
i. decline to sign a document from within your signing session, and on the subsequent page, 
select the check-box indicating you wish to withdraw your consent, or you may; 
ii. send us an email to esign@ctifacts.com and in the body of such request you must state your 
email, full name, mailing address, and telephone number.  
 
Required hardware and software  
The minimum system requirements for using the DocuSign system may change over time. The 
current system requirements are found here: https://support.docusign.com/guides/signer-guide-
signing-system-requirements.  
 
Acknowledging your access and consent to receive and sign documents electronically  
To confirm to us that you can access this information electronically, which will be similar to 
other electronic notices and disclosures that we will provide to you, please confirm that you have 
read this ERSD, and (i) that you are able to print on paper or electronically save this ERSD for 
your future reference and access; or (ii) that you are able to email this ERSD to an email address 
where you will be able to print on paper or save it for your future reference and access. Further, 
if you consent to receiving notices and disclosures exclusively in electronic format as described 
herein, then select the check-box next to ‘I agree to use electronic records and signatures’ before 
clicking ‘CONTINUE’ within the DocuSign system. 
By selecting the check-box next to ‘I agree to use electronic records and signatures’, you confirm 
that: 
 
You can access and read this Electronic Record and Signature Disclosure; and 
 
You can print on paper this Electronic Record and Signature Disclosure, or save or send 
this Electronic Record and Disclosure to a location where you can print it, for future 
reference and access; and 
 
Until or unless you notify CTI Clinical Trial and Consulting Services as described above, 
you consent to receive exclusively through electronic means all notices, disclosures, 
authorizations, acknowledgements, and other documents that are required to be provided 
or made available to you by CTI Clinical Trial and Consulting Services during the course 
of your relationship with CTI Clinical Trial and Consulting Services.