Conditions: Obstructive Sleep Apnea
Keywords: Apnea, Obstructive Sleep Sleep Apnea Syndromes Upper Airway Reistance Syndrome
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 15
Healthy volunteers: no

Brief summary:
The SEED study is designed to assess the safety and efficacy for Obstructive Sleep Apnea (OSA) of 3 escalating dose combinations of atomoxetine with AD313 compared to baseline and to atomoxetine alone.

Detailed description:
The SEED study is an open-label, 4 consecutive period dose-escalation study of combinations of AD313 vs. atomoxetine alone in participants with moderate- to severe OSA. A screening polysomnogram (PSG) will be conducted to establish that each participant meets study enrollment criteria and to serve as baseline. Each participant will then receive escalating doses of AD313 with on-drug PSGs to be conducted on the final night of dosing.

Arms:
arm 1: 3 days of atomoxetine 40 mg followed by 4 days of atomoxetine 80 mg. arm 2: Week 2: atomoxetine 40 mg/dronabinol 2.5 mg Week 3: atomoxetine 80 mg/dronabinol 5 mg Week 4: atomoxetine 80 mg/dronabinol 10 mg

Interventions: intervention 1: Dosing 1: Atomoxetine intervention 2: AD313
Intervention descriptions: intervention 1: Oral administration at bedtime intervention 2: Escalating dose of AD313; Oral administration at bedtime

Protocol document:
Prot_SAP_000.pdf: 
Apnimed, Inc.  
 Clinical Study Protocol 
Protocol: SEED 
CONFIDENTIAL 
 
 25 June 2021 
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Title Page 
Protocol Title: Open-Label 4-Period Dose-Escalation Safety and Efficacy Study of AD313 in 
Participants With Obstructive Sleep Apnea 
Protocol Name: SEED 
Version Number: 1.0 
Compound Number: AD313 
Short Title: Study for Efficacy and Dose Escalation of Dronabinol + Atomoxetine (SEED) 
Sponsor Name and Legal Registered Address:  
Apnimed, Inc. 
20 Holyoke Street 
Cambridge, MA 02138 
Approval Date:  25 June 2021 
Date and Version of Previous Protocol:  n/a 
 
 
 


Apnimed, Inc.
Protocol: SEED
Sponsor Signatory:
Clinical Study Protocol
CONFIDENTIAL
L i -Dnr- 1c-u I
Date
Ronald Farkasj MD
251we2021
2of47
v1.0


Apnimed, Inc.  
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Table of Contents 
 
1 
Protocol Summary ....................................................................................................... 5 
1.1 
Synopsis ............................................................................................................................ 5 
1.2 
Schedule of Activities (SoA) ............................................................................................ 7 
2 
Introduction .................................................................................................................. 8 
2.1 
Study Rationale ................................................................................................................ 8 
2.2 
Background ...................................................................................................................... 8 
2.2.1 
Obstructive Sleep Apnea ................................................................................................ 8 
2.2.2 
Unmet Medical Need ..................................................................................................... 8 
2.2.3 
Biological Rationale ....................................................................................................... 9 
3 
Endpoints .................................................................................................................... 10 
4 
Study Design ................................................................................................................ 11 
4.1 
Overall Design ................................................................................................................. 11 
4.2 
Scientific Rationale for Study Design and Dose ............................................................ 12 
4.3 
End of Study Definition ................................................................................................. 13 
5 
Study Population ........................................................................................................ 13 
5.1 
Inclusion Criteria ............................................................................................................ 13 
5.2 
Exclusion Criteria ........................................................................................................... 14 
5.3 
Meals and Dietary Restrictions ...................................................................................... 16 
5.4 
Caffeine, Alcohol, and Tobacco ..................................................................................... 16 
5.5 
Activity ........................................................................................................................... 17 
5.6 
Screen Failures ............................................................................................................... 17 
6 
Study Drug .................................................................................................................. 18 
6.1 
Study Treatment(s) Administered ................................................................................... 18 
6.2 
Preparation/Handling/Storage/Accountability ............................................................... 18 
6.3 
Concomitant Therapy ..................................................................................................... 19 
6.4 
Discontinuation of Study Treatment ............................................................................... 21 
6.5 
Stopping Criteria ............................................................................................................ 21 
6.5.1 
Individual Participant Stopping Criteria ...................................................................... 21 
6.6 
Participant Discontinuation/Withdrawal from the Study ............................................... 21 
6.7 
Loss of Participants to Follow-Up .................................................................................. 22 
7 
Study Assessments and Procedures .......................................................................... 23 
7.1.1 
Polysomnography ......................................................................................................... 23 
7.2 
Safety Assessments ......................................................................................................... 23 


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7.2.1 
Physical Examinations ................................................................................................. 24 
7.2.2 
Vital Signs .................................................................................................................... 24 
7.2.3 
Electrocardiograms ...................................................................................................... 24 
7.2.4 
Clinical Safety Laboratory Assessments ...................................................................... 24 
7.3 
Adverse Events and Serious Adverse Events ................................................................. 25 
7.3.1 
Time Period and Frequency for Collecting AE and SAE Information ........................ 25 
7.3.2 
Method of Detecting AEs and SAEs ............................................................................ 25 
7.3.3 
Follow-up of AEs and SAEs ........................................................................................ 26 
7.3.4 
Regulatory Reporting Requirements for SAEs ............................................................ 26 
7.3.5 
Pregnancy ..................................................................................................................... 26 
7.4 
Treatment of Overdose ................................................................................................... 27 
7.5 
Pharmacokinetics ............................................................................................................ 27 
8 
Statistical Considerations .......................................................................................... 28 
8.1 
Sample Size Determination ............................................................................................ 28 
8.2 
Populations for Analyses ................................................................................................ 28 
8.3 
Interim Analyses ............................................................................................................. 28 
9 
Supporting Documentation and Operational Considerations ............................... 28 
9.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........................ 28 
9.1.1 
Regulatory and Ethical Considerations ........................................................................ 29 
9.1.2 
Financial Disclosure ..................................................................................................... 29 
9.1.3 
Informed Consent Process ........................................................................................... 30 
9.1.4 
Data Protection ............................................................................................................. 30 
9.1.5 
Data Quality Assurance ................................................................................................ 30 
9.1.6 
Source Documents ....................................................................................................... 31 
9.1.7 
Study and Site Closure ................................................................................................. 31 
9.1.8 
Publication Policy ........................................................................................................ 32 
9.1.9 
Protocol Approval and Amendment ............................................................................. 32 
9.1.10 
Liability and Insurance ................................................................................................. 33 
9.2 
Appendix 2: Clinical Laboratory Tests ........................................................................... 33 
9.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ............................................................................................ 34 
9.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information .......... 40 
9.5 
Appendix 5: List of Abbreviations ................................................................................. 43 
10 
References ................................................................................................................... 45 
 


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1 Protocol Summary 
1.1 Synopsis 
Protocol Title: Open-Label 4-Period Dose-Escalation Safety and Efficacy Study of AD313 in 
Participants With Obstructive Sleep Apnea 
Sponsor Study Name.: SEED 
Sponsor: Apnimed, Inc. 
Rationale: 
Selective norepinephrine reuptake inhibitors (SNRIs) such as atomoxetine are thought to 
improve obstructive sleep apnea (OSA) by increasing pharyngeal muscle stiffness and 
responsiveness. 
Cannabinoids, including dronabinol, also have shown potential for reduction of OSA severity. 
The mechanism of beneficial action of dronabinol appears to be distinct from that of SNRIs, 
potentially involving stabilization of respiratory patterns and increased activation of upper 
airway dilating muscles during sleep.  
The SEED study is designed to assess the safety and efficacy for OSA of 3 escalating dose 
combinations of atomoxetine with dronabinol, compared to baseline and to atomoxetine alone. 
Overall Design: 
The SEED study is an open-label, 4 consecutive period dose-escalation study of combinations of 
atomoxetine with dronabinol vs. atomoxetine alone in participants with moderate- to severe 
OSA. A screening polysomnogram (PSG) will be conducted to establish that each participant 
meets study enrollment criteria and to serve as baseline. Each participant will then receive 
escalating doses of atomoxetine, then escalating doses of the combination of atomoxetine with 
dronabinol, as follows: 
• Week 1: atomoxetine 40 mg x 3 days, then atomoxetine 80 mg x 4 days 
• Week 2: atomoxetine 40 mg/dronabinol 2.5 mg 
• Week 3: atomoxetine 80 mg/dronabinol 5 mg 
• Week 4: atomoxetine 80 mg/dronabinol 10 mg 
 


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Dosing of study drug occurs at the participants usual bedtime. Dose escalation will be based on 
safety and tolerability, as assessed at weekly clinic visits and telephone contact with participants 
mid-week of each dosing period.  
In addition to the screening/baseline PSG, three on-drug PSGs will be conducted on the final 
night of the following dosing periods:  
• 1st week, dosing atomoxetine 80 mg alone 
• 3rd week, dosing atomoxetine 80 mg/dronabinol 5 mg 
• 4th week, dosing atomoxetine 80 mg/dronabinol 10 mg 
 
Number of Participants: 
A total of 15 participants will be enrolled. 
Study Duration: 
The overall study duration will be up to 9 weeks, as follows:  
• Screening, up to 3 weeks; 
• Atomoxetine alone: 1 week  
• Dronabinol dose escalation period: 3 weeks 
• End of Study telephone contact: 2 weeks 
 


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1.2 Schedule of Activities (SoA)  
Table 1 
Schedule of Activities 
Abbreviations: AE = adverse event; ATO = atomoxetine; DRO = dronabinol; DSST = Digit symbol substitution test; ECG = electrocardiogram; HS = Hora Somni; PGI-S = patient global impression of severity of OSA; PSG 
= polysomnography; SAE = serious adverse event; SAQLI = Sleep Apnea Quality of Life Index; WOCBP = women of childbearing potential; PROMIS = Patient Reported Outcomes Measurement Information System; PVT 
= psychomotor vigilance test; VOLT = visual object learning task 
 
1Study days shown represent case with no use of ± window days; study days shift cumulatively if window days are used 
2 WOCBP only 
3 On a case-by-case basis with agreement of Sponsor a PSG conducted at the site within 3 months may be used instead of the Screening PSG 
4 Study medication administered at lights out; dose on PSG nights is from supply dispensed to the participant if available, but can be provided from separate site supply. 
5 Administered at similar time on morning of each PSG visit 
6 Vital signs include seated blood pressure in triplicate, pulse, respiratory rate; vital signs on PSG nights taken morning after PSG.  
7 Site contacts participant by telephone mid-week of each at-home dosing period for safety evaluation and reminder of study activities 
Procedures 
Non-PSG 
Screening  
V1 
Screening/
Baseline 
PSG  
V2 
Dosing Period  
 
ATO 40 3d, ATO 80 4d 
ATO 40/DRO 2.5 
ATO 80/DRO 5 
ATO 80/DRO 10 
At home 
dosing 
V3 
PSG 
At home 
dosing 
V4 
At home 
dosing 
  
V5 
At home 
dosing 
PSG  
V6 
EoS Call 
Day1 
-21 to -1 
 1 - 7 ± 1  
7 ± 1 
8-14 ± 2  
14 ± 2 15 – 21 ± 2 21 ± 2 
21-28 ± 2  28 ± 2 
42± 2 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test2 
X 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory testing 
X 
 
 
 
 
 
 
 
 
 
 
12 Lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
PSG  
 
X3 
 
X 
 
 
 
X 
 
X 
 
Study drug dispense/return 
 
X 
 
X 
 
X 
 
X 
 
X 
 
HS study treatment4 
 
 
↔ 
↔ 
↔ 
↔ 
↔ 
↔ 
↔ 
↔ 
 
PGI-S, PROMIS sleep 
impairment, PROMIS sleep 
disturbance, PROMIS fatigue, 
DSST, VOLT, PVT 5 
 
X 
 
X 
 
 
 
X 
 
X 
 
Vital signs6  
X 
X 
 
X 
 
X 
 
X 
 
X 
 
AE/SAE monitoring7 
 
 
↔ 
↔ 
↔ 
↔ 
↔ 
↔ 
↔ 
↔ 
↔ 
Prior/concomitant medication 
 
 
↔ 
↔ 
↔ 
↔ 
↔ 
↔ 
↔ 
↔ 
↔ 


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2 Introduction 
2.1 Study Rationale 
Selective norepinephrine reuptake inhibitors (SNRIs) such as atomoxetine are thought to 
improve obstructive sleep apnea (OSA) by increasing pharyngeal muscle stiffness and 
responsiveness (1-4).  
Cannabinoids, such as dronabinol, have shown potential for reduction of OSA severity (21). The 
mechanism of beneficial action of dronabinol appears to be distinct from that of SNRIs, 
potentially involving stabilization of respiratory patterns and increased activation of upper 
airway dilating muscles during sleep.  
The SEED study is designed to assess the safety and efficacy for OSA of 3 escalating dose 
combinations of atomoxetine and dronabinol. 
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 (5). OSA is characterized by repetitive collapse or ‘obstruction’ of the 
pharyngeal airway during sleep, manifesting as repetitive episodes of hypopnea (i.e., shallow 
breathing) or apnea (i.e., paused breathing). These episodes of hypopnea or apnea may lead to 
arousal from sleep, sleep fragmentation, excessive daytime sleepiness, and/or 
neuropsychological impairment. 
Research has shown that a number of pathogenic factors, or traits, contribute to the development 
of OSA (6-9). The most important factors are the presence of an anatomically small, collapsible 
upper airway and a loss of pharyngeal muscle tone or responsiveness during sleep. 
Long-term, OSA is associated with increased mortality and a number of adverse cardiovascular, 
neurocognitive, metabolic, and daytime functioning consequences (10-19). 
2.2.2 
Unmet Medical Need 
Treatment for OSA changed little over the past 40 years, with the overwhelming majority of 
patients treated with positive airway pressure, the most common of which is continuous positive 
airway pressure (CPAP), provided by a machine that mechanically maintains an open airway. 


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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 (20). 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 
Atomoxetine is a pre-synaptic norepinephrine reuptake inhibitor indicated for the treatment of 
attention deficit hyperactivity disorder in children and adults. Dronabinol is synthetic delta-
9-tetrahydrocannabinol (delta-9-THC) indicated for the treatment of anorexia in patients with 
AIDS and nausea and vomiting associated with cancer chemotherapy. Apnimed believes that the 
combination of dronabinol and atomoxetine may have an improved efficacy profile in patients 
with OSA compared to either constituent alone.  
 


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3 Endpoints 
 
 
 
 
Endpoints 
Primary 
• 
AHI4%, ATO 80/DRO 10 vs. baseline  
Secondary 
 
• 
AHI4%, ATO 80/DRO 10 vs. ATO 80 
• 
AHI4%, ATO 80/DRO 5 vs. baseline 
• 
AHI4%, ATO 80/DRO 5 vs. ATO 80 
• 
HB4%, ODI4%, Total time with SaO2 <90%,  Proportion of participants with 
≥50% reduction in AHI4%, HB4%, ODI4% 
Exploratory 
• 
PGI-S 
• 
PROMIS sleep impairment 
• 
PROMIS sleep disturbance 
• 
PROMIS fatigue 
• 
AHI4%, highest dose achieved by patient (ie ATO 80/DRO 5 or ATO 80/DRO 10 
vs. baseline and vs. ATO 80 
• 
AHI3 (hypopnea scored when associated with 3% O2 desaturation) 
• 
AHI3a (hypopnea scored when associated with 3% O2 desaturation or arousal) 
• 
OSA endotype endpoints (Vpassive, Vactive, Muscle Compensation, Loop Gain)  
• 
PSG sleep and arousal parameters 
Safety Endpoints 
• 
Vital signs, Spontaneous adverse events, DSST, VOLT, PVT 
Abbreviations: AHI = apnea-hypopnea index; ATO = atomoxetine; DSST = digit symbol substitution test; DRO = 
dronabinol; HB = hypoxic burden; ODI = Oxygen Desaturation Index; OSA = obstructive sleep apnea; PROMIS = 
Patient Reported Outcome Measurement Information System; PGI-S = Patient Global Impression of Severity; PSG 
= polysomnography; PROMIS = Patient Reported Outcome Measurement Information System; PVT = 
psychomotor vigilance task; SaO2 = oxygen saturation; SAQLI = Sleep Apnea Quality of Life Index; VOLT = 
visual object learning task 


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4 Study Design 
4.1 Overall Design 
The SEED study is an open-label, 4 consecutive period dose-escalation study of combinations of 
atomoxetine and dronabinol in participants with moderate to severe OSA. Participants will 
undergo initial pre-screening to determine potential study eligibility. Participants selected for 
further screening should either have a previous history of OSA of a severity consistent with 
enrollment criteria or be at high risk (e.g. as assessed by STOP-Bang Questionnaire score).  Only 
participants who meet all non-PSG enrollment criteria at Visit 1 are eligible for a screening PSG. 
On a case by case basis and with agreement of the Sponsor a PSG conducted at the site within 3 
months may be used instead of the Screening PSG. 
Participants who meet all enrollment criteria will receive an escalating dose of atomoxetine the 
first week: 3 days of atomoxetine 40 mg followed by 4 days of atomoxetine 80 mg. Participants 
will then receive escalating dose combinations of atomoxetine and dronabinol for the next 3 
weeks. The weekly dose schedule is as follows: 
• Week 1: atomoxetine 40 mg x 3 days, then 80 mg x 4 days 
• Week 2: atomoxetine 40 mg/dronabinol 2.5 mg 
• Week 3: atomoxetine 80 mg/dronabinol 5 mg 
• Week 4: atomoxetine 80 mg/dronabinol 10 mg 
 
Dose escalation will be based on safety and tolerability, as assessed at weekly clinic visits and by 
telephone contact with participants mid-week of each at-home dosing period. Patients who do 
not tolerate dose escalation will discontinue dosing.  
Three on-drug PSGs will be conducted on the final night of the following dosing periods:  
• 1st week, dosing atomoxetine 80 mg alone 
• 3rd week, dosing atomoxetine 80 mg/dronabinol 5 mg 
• 4th week, dosing atomoxetine 80 mg/dronabinol 10 mg 
 
Study drug for Week 1 is dispensed to participants at Visit 2.. Any unused Week 1 study drug is 
returned at Visit 3. Similarly, study drug for Week 2, 3, and 4 is dispensed at Visits 3, 4 and 5, 
and unused study drug similarly returned at the subsequent visit.  
Dosing of the study treatment will occur each night at the participant’s usual bedtime, both 
during at-home nights and Visit 3, Visit 5 and Visit 6 PSG nights. Study drug dose on PSG nights 


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is from the supply dispensed to the participant if available, but can be provided from separate site 
supply. 
The morning of each PSG the PGI-S, PROMIS assessments, DSST, VOLT and PVT will be 
administered.  
An End-of-Study phone call will take place 2 weeks following the end of study drug dosing.  
Participants who discontinue from the study will not be replaced. No subsequent open-label 
extension is planned following the study. 
Figure 1: 
Overview of Study Design 
 
EoS = End of Study; PSG = polysomnography; 40 = atomoxetine 40 mg alone; 80 = atomoxetine 80 mg alone; 
40/2.5 = atomoxetine 40 mg/dronabinol 2.5 mg; 80/5 = atomoxetine 80 mg/dronabinol 5 mg; 80/10 = atomoxetine 
80 mg/dronabinol 10 mg 
 
4.2 Scientific Rationale for Study Design and Dose 
Selective norepinephrine reuptake inhibitors (SNRIs) such as atomoxetine are thought to 
improve obstructive sleep apnea (OSA) by increasing pharyngeal muscle stiffness and 
responsiveness.  
Cannabinoids, including dronabinol, also have shown potential for reduction of OSA severity 
(21). The mechanism of beneficial action of dronabinol appears to be distinct from that of 
SNRIs, potentially involving stabilization of respiratory patterns and increased activation of 
upper airway dilating muscles during sleep. Cannabinoids have also shown a hypnotic effect that 
may counteract the potential wakefulness induced by atomoxetine. 


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This study is designed to investigate if the combination of atomoxetine and dronabinol is safe 
and effective in participants with moderate to severe OSA.  
 
4.3 End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of the 
study through the last scheduled procedure shown in the Schedule of Activities (SoA). 
The end of the study is defined as the date of the last visit of the last participant in the study or last 
scheduled procedure shown in the SoA for the last participant in the study globally. 
 
5 Study Population 
Eligible participants will be recruited both from the existing clinic population at the study site, 
including databases of previous subjects who participated in other studies, and through direct 
advertising to the community.  
Participants must be able to provide written consent and meet all the inclusion criteria and none 
of the exclusion criteria. 
5.1 Inclusion Criteria 
Age and Sex 
1. 25 to 65 years of age, inclusive, at the Screening Visit. 
Disease Measures  
2. AHI 10 to 50 (hypopneas defined by 4% oxygen desaturation) 
3. ≤25% of apneas are central or mixed apneas at V2 baseline PSG 
Weight 
4. BMI between 18.5 and 40.0 kg/m2, inclusive, at the pre-PSG visit. 
Male participants: 
5. 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 


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the protocol specified contraception (see Appendix 4: Contraceptive Guidance and 
Collection of Pregnancy Information). 
Female participants: 
6. If a woman of childbearing potential (WOCBP), the participant must agree, from Study 
Day 1 through 1 week after the last dose of study drug, to practice the protocol specified 
contraception (See Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information). All WOCBP must have negative result of a serum pregnancy test performed 
at screening.  
7. 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 
8. Participant voluntarily agrees to participate in this study and signs an Institutional Review 
Board (IRB)-approved informed consent prior to performing any of the Screening Visit 
procedures. 
9. 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 clinically significant sleep disorder other than OSA. 
2. Clinically significant craniofacial malformation.  
3. Clinically significant cardiac disease (e.g., rhythm disturbances, coronary artery disease or 
cardiac failure) or hypertension requiring more than 2 medications for control (combination 
medications are considered as 1 medication for this purpose).  
4. Clinically significant neurological disorder, including epilepsy/convulsions. 
5. History of schizophrenia, schizoaffective disorder or bipolar disorder according to 
Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) or International 
Classification of Disease tenth edition criteria. 


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6. History of attempted suicide within 1 year prior to screening, or current suicidal ideation. 
7. Medically unexplained positive screen for drugs of abuse or history of substance use 
disorder as defined in DSM-V within 24 months prior to Screening Visit. 
8. A significant illness or infection requiring medical treatment in the past 30 days. 
9. Clinically significant cognitive dysfunction as determined by investigator. 
10. Women who are pregnant or nursing. 
Prior/Concomitant Therapy 
11. History of using devices for OSA treatment, including CPAP, oral or nasal devices, or 
positional devices, may enroll as long as the devices have not been used for at least 2 weeks 
prior to first study visit and are not used during participation in the study. 
12. History of chronic oxygen therapy. 
13. Use of medications from the list of disallowed concomitant medications. 
14. 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 
15. Use of another investigational agent within 30 days or 5 half-lives, whichever is longer, 
prior to dosing.  
Diagnostic Assessments 
16. 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.  
17. PLM arousal index >20 
Other Exclusions 
18. <5 hours typical sleep duration.  
19. ESS > 18 
20. Night- or shift-work sleep schedule which causes the major sleep period to be during the 
day.  
21. Employment as a commercial driver or operator of heavy or hazardous equipment. 


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22. Typically smoking more than 10 cigarettes or 2 cigars per day, or inability to abstain from 
smoking during overnight PSG visits. 
23. Unwilling to use specified contraception.  
24. History of regular alcohol consumption of more than 14 standard units per week (males) 
or more than 7 standard units per week (females), or unwillingness to limit alcohol 
consumption to no greater than 2 units/day (males),  1 unit per day (females), not to be 
consumed within 3 hours of bedtime or on PSG nights. 
25. Unwilling to limit during the study period caffeinated beverage intake (e.g., coffee, cola, 
tea) to 400 mg/day or less of caffeine, not to be used within 3 hours of bedtime. 
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 atomoxetine and/or dronabinol or unable or unlikely to understand or comply with 
the dosing schedule or study evaluations. 
5.3 Meals and Dietary Restrictions 
1. Participants should refrain from consumption of any nutrients known to modulate CYP 
enzyme activity (e.g., grapefruit or grapefruit juice, pomelo juice, star fruit, pomegranate, 
and Seville or Moro [blood] orange products) within 72 hours before the first dose of 
study drug and during the study.  
2. Diet should be generally stable during the study, e.g., new diet programs should not be 
initiated. 
5.4 Caffeine, Alcohol, and Tobacco 
1. During the outpatient portions of the study, participants should refrain from more than 2 
standard units per day of alcohol for men or 1 unit/day for women, consumed no less than 
3 hours prior to bedtime. Alcohol should not be consumed on PSG nights. 
2. Moderate consumption of caffeinated beverages, containing up to a total of 400 mg 
caffeine per day, is permitted during the study period, consumed no less than 3 hours prior 
to bedtime. 


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5.5 Activity 
There are no restrictions on physical activity during the study other than that physical activity 
should be generally stable during the study (e.g., new exercise programs should not be initiated). 
5.6 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned to receive 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. 
 
 


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6 Study Drug 
Study drug is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 Study Treatment(s) Administered 
One capsule of atomoxetine (week 1) or one capsule of atomoxetine and one capsule of 
dronabinol (weeks 2-4) is taken immediately before the participant’s planned bedtime.  
Study Treatment Name: 
Atomoxetine hydrochloride 
Dronabinol 
Dosage Formulation: 
Capsule 
Capsule 
Dosage Levels: 
40 mg, 80 mg 
2.5 mg, 5 mg, 10 mg 
Route of Administration: 
Oral 
Oral 
Dosing Instructions: 
1 capsule administered with 
up to 240 mL water  
1 capsule administered with 
up to 240 mL water  
Storage/Packaging/Labeling: 
 
Store at room temperature, in 
HDPE bottles 
Store at room temperature in 
HDPE bottles 
6.2 Preparation/Handling/Storage/Accountability 
1. The Investigator or designee must maintain a log to confirm appropriate temperature 
conditions have been maintained during transit for all study treatments received and any 
discrepancies are reported and resolved before use of the study treatment. 
2. Only participants enrolled in the study may receive study treatments and only authorized 
site staff may supply or administer study treatments. All study treatments must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the Investigator and 
authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). 


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4. After receiving Sponsor approval in writing, sites are responsible for returning all unused 
or partially used study treatment to the Sponsor or designated third party or for preparing 
the study treatment for destruction via incineration. 
6.3 Concomitant Therapy 
Concomitant therapy with the medications listed below is disallowed. For medication that is 
typically used as-needed for symptomatic conditions (e.g., occasional use of a sleep aid), the 
medication should not be used for at least one week prior to the first study PSG and for the 
duration of the study.  
• MAOIs or other drugs that affect monoamine concentrations (e.g., rasagiline) [MAOIs are 
contraindicated for use with atomoxetine] 
• Lithium  
• Cannabinoids  
• Selective Serotonin Reuptake Inhibitors (e.g., paroxetine) 
• Selective Norepinephrine Reuptake Inhibitors (e.g., duloxetine) 
• Norepinephrine Reuptake Inhibitors (e.g., reboxetine) 
• Alpha-1 antagonists (e.g., tamsulosin) 
• Tricyclic antidepressants (e.g., desipramine) 
• CYP2D6 inhibitors  
• Strong CYP3A4 inhibitors (e.g., ketoconazole) 
• Benzodiazepines and other anxiolytics 
• Opioids 
• Sedatives and sedative-hypnotics, including nonbenzodiazepine “Z-drugs” (zolpidem, 
zaleplon, eszopiclone) 
• Muscle relaxants  
• Pressor agents 
• Drugs with clinically significant cardiac QT-interval prolonging effects 
• Drugs known to lower seizure threshold (e.g., chloroquine) 
• Amphetamines 


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• Antiepileptics  
• Antiemetics 
• Modafinil or armodafinil 
• Beta2 agonists, (e.g., albuterol) 
• Antipsychotics 
• 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 including, but not necessarily limited to, the 
following drugs and drug classes: 
• Antihypertensives (angiotensin-converting-enzyme [ACE] /angiotensin II receptor blocker 
[ARB] inhibitors, calcium channel blockers, hydrochlorothiazide, etc.).  
• Statins 
• Proton pump inhibitors and histamine h2 receptor blockers 
• Over-the-counter (OTC) antacids 
• Non-sedating antihistamines (e.g., cetirizine, loratadine) 
• Acetaminophen  
• Laxatives 
• Erectile dysfunction drugs 
• Inhaled corticosteroids (e.g., fluticasone) 
• Anti-diabetics 
• Ocular hypotensives and other ophthalmics (e.g., timolol) 
• Hormonal therapy (e.g., estrogen replacement or anti-estrogens) and hormonal contraceptives 


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• Thyroid medications 
• Anticoagulants 
• Osteoporosis drugs 
6.4 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). 
6.5 Stopping Criteria 
6.5.1 
Individual Participant Stopping Criteria 
• Incidents of abuse, diversion, or misuse of the study treatment. 
• Incidents of clinical significance: hallucinations, amnesia, delusional thinking, delirium, 
manic symptoms, aggressive behavior, suicidality, homicidality, agitation, confusion, or 
convulsions/seizures. 
• Participants reporting any SAE considered possibly related or related to study treatment. 
• Any other AE that in the judgment of the Investigator necessitates the participant stopping to 
protect participant safety. 
Participants discontinued from dosing will undergo end of study procedures with follow-up 
monitoring of any AE(s) as clinically indicated. 
6.6 Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, or 
administrative reasons. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 


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• All participants who withdraw from the study with an ongoing AE must be followed until the 
event is resolved or deemed stable. 
• Participation may be terminated before completing the study and the reason recorded as 
follows: 
o Withdrawal due to AE 
o Withdrawal due to incident abuse, diversion, or misuse of the study treatment 
o Loss to follow-up 
o Participant withdrew consent at own request 
o Other 
6.7 Loss of Participants to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. The following actions must be 
taken if a participant fails to return to the clinic for a required study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible (and within the visit window, where one is defined) and counsel the participant on 
the importance of maintaining the assigned visit schedule and ascertain whether or not the 
participant wishes to and/or should continue in the study. 
• In cases in which the participant is deemed lost to follow-up, the Investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the participant’s 
medical record/eCRF. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
 
 


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7 Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA. 
• Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• The maximum amount of blood collected from each participant over the duration of the study 
will not exceed approximately 50 mL. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples, as per the Investigator or designee’s discretion. 
7.1.1 
Polysomnography 
• Methods: Standard overnight PSG recording and data interpretation will be performed in 
accordance with the American Academy of Sleep Medicine (AASM) scoring manual. 
Participants will be instrumented with standard PSG electrodes. Time of lights out will be 
established according to the participants’ habitual schedule and kept constant across the PSG 
study nights. The participants will be given 8 hours of time-in bed.  
• 
Participants should be actively encouraged to spend at least 1/3 of the night in the supine 
position and at least 1/3 of the night in the lateral position on each night of study. 
 
7.2 Safety Assessments 
• Planned time points for all safety assessments are provided in the SoA. 
• Safety monitoring will be guided by the established safety profiles of dronabinol and 
atomoxetine. Safety assessments will include physical examinations, measurement of vital 
signs, DSST, VOLT, PVT, monitoring and recording of AEs, SAEs, and pregnancies, 
recording of study or treatment discontinuations. Effects on OSA and sleep parameters (e.g., 
sleep time and sleep stages) will also be monitored by PSG. 


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7.2.1 
Physical Examinations 
• The general physical examination at screening includes an assessment of general appearance 
and a review of physical systems (dermatologic, head, eyes, ears, nose, mouth/throat/neck, 
thyroid, lymph nodes, respiratory, cardiovascular, gastrointestinal, extremities, 
musculoskeletal, neurologic, and psychiatric systems). Height and weight will also be 
measured and recorded (with shoes removed and wearing light indoor clothing).     
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
7.2.2 
Vital Signs 
• Assessment of vital signs (seated blood pressure, pulse rate, body temperature, respiratory 
rate) will be performed at the time points indicated in the SoA.  
• Vital signs will be measured at all visits in a seated position after 5 minutes rest and will 
include temperature, respiratory rate, systolic and diastolic blood pressure, and pulse. 
Measurements should be made in the same arm of the participant at each visit. 
• Systolic and diastolic blood pressure will be repeated for a total of 3 measurements, each at 
least 2 minutes apart. 
7.2.3 
Electrocardiograms 
• A 12-lead ECG will be obtained using an ECG machine that automatically calculates the 
heart rate and measures the PR, QRS, and QT intervals. The ECG will be recorded in the 
semi-supine position after the participant has rested in this position for at least 10 minutes. 
7.2.4 
Clinical Safety Laboratory Assessments 
• Refer to Section 9.2 for the list of screening clinical laboratory tests to be performed and to 
the SoA for the timing and frequency. 
• The Investigator must review the laboratory report and document this review. The laboratory 
reports must be filed with the source documents.  
• All protocol-required laboratory assessments must be conducted in accordance with the 
laboratory manual and the SoA. 


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• If laboratory values from laboratory assessments not specified in the protocol and performed 
at the institution’s local laboratory result in the need for a change in participant management 
or are considered clinically relevant by the Investigator (e.g., are considered to be an SAE or 
an AE or require dose modification), then the results must be recorded in the eCRF. 
7.3 Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Appendix 3.Adverse events will be reported by 
the participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for following 
up on AEs that are serious, considered related to the study treatment or the study, or that caused 
the participant to discontinue the study and/or study treatment. 
7.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from first dose of study drug until the end of the study at the 
timepoints specified in the SoA. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 3. The Investigator will submit any updated SAE data to the Sponsor within 
24 hours of it being available. 
Investigators are not obligated to actively seek AEs or SAEs after the conclusion of study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study treatment or study participation, the Investigator must promptly notify the 
Sponsor. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
7.3.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrence. 


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7.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, until the 
event is otherwise explained, or the participant is lost to follow-up. Further information on 
follow-up procedures is given in Appendix 3. 
7.3.4 
Regulatory Reporting Requirements for SAEs 
• Prompt notification (within 24 hours, see Appendix 3) by the Investigator to the Sponsor of 
an SAE is essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/Independent Ethics Committees (IEC), and 
Investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAE) from the Sponsor will file it 
along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according 
to local requirements. 
7.3.5 
Pregnancy 
• Details of all pregnancies in female participants after the start of study treatment and until at 
least 5 terminal half-lives after the last dose will be collected.  
• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered to be SAEs. 


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7.4 Treatment of Overdose 
For this study, any dose of atomoxetine hydrochloride greater than 80 mg or dronabinol greater 
than 10 mg more frequently than QHS will be considered an overdose. 
In the event of an overdose, the Investigator should refer to the approved product label for advice 
on overdose and: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for AE/SAE and laboratory abnormalities as medically 
indicated. 
3. Obtain a plasma sample for PK analysis within 1 day from the date of the last dose of study 
treatment if requested by the Medical Monitor (determined on a case- by- case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
7.5 Pharmacokinetics 
PK parameters are not evaluated in this study. 
 


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8 Statistical Considerations 
8.1 Sample Size Determination 
In Apnimed studies atomoxetine alone has decreased AHI by 65% or more, and dronabinol has 
been reported to decrease AHI by about 50% (21). Assuming that 12 participants will complete 
the trial, the study will have 90% power to detect a treatment difference with baseline at a two-
sided 0.05 significance level if the true difference is AHI is 12 units and the within-subject 
standard deviation 12. Considering an attrition rate of 25%, we will enroll 15 participants to 
complete the study. 
8.2 Populations for Analyses 
For the purposes of analysis, the following analysis sets are defined: 
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.  
Safety Population 
The Safety Population consists of all participants who receive at 
least 1 dose of any of the study treatments. Participants will be 
analyzed for safety based on the treatment received.  
Per Protocol (PP) 
Population 
The PP Population consists of all participants without any major 
protocol violations that could influence efficacy assessment. 
Participants in this population will be analyzed according to the 
treatment they actually received. 
 
8.3 Interim Analyses 
No interim analysis is planned.  
9 Supporting Documentation and Operational Considerations 
9.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
 


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9.1.1 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines. 
• Applicable International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
• Applicable laws and regulations. 
• The protocol, protocol amendments, ICF, and other relevant documents (e.g., advertisements) 
must be submitted to an IRB/IEC by the Investigator and reviewed and approved by the 
IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC. 
• Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures. 
• Overall conduct of the study at the site and adherence to requirements of 21 Code of 
Federal Regulations (CFR), ICH GCP guidelines, the IRB/IEC guidelines, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations. 
9.1.2 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 


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9.1.3 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorized representative and answer all questions regarding the study. 
• Participants must be informed that their participation is voluntary. Participants will be required 
to sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act requirements, 
where applicable, and the IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the signed ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the 
protocol. If the ICF is revised, it must be reviewed and approved by the appropriate IEC/IRB, and 
signed by all participants subsequently enrolled in the study as well as those currently enrolled in 
the study. 
9.1.4 
Data Protection 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred. 
• The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
• The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
9.1.5 
Data Quality Assurance 


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• All participant data relating to the study will be recorded on printed or eCRFs unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
• The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
• 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 recorded electronically at each study center 
using eCRFs. Data from external sources (such as laboratory data) will be entered into the 
database. 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. 
 
9.1.6 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
9.1.7 
Study and Site Closure 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 


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completion. A study site is considered closed when all required documents and study supplies have 
been collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are not 
limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines. 
• Inadequate recruitment of participants by the Investigator. 
• Discontinuation of further study treatment development. 
9.1.8 
Publication Policy 
• Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
• The Sponsor retains the right to disapprove any submission for publication, including any 
publication using trial data, including abstracts, presentations or manuscripts. 
• A summary of the study results will also be posted in a publicly accessible database (e.g., 
www.ClinTrials.gov).  
9.1.9 
Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IEC/IRB/Competent Authorities, in accordance with local legal requirements. The Sponsor 
must ensure that all ethical and legal requirements have been met before the first participant is 
enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments or exceptions must be 
written, receive approval from the appropriate personnel, and receive IRB/IEC/Competent 
Authority approval prior to implementation (if appropriate).  


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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. 
9.1.10 Liability and Insurance 
The Sponsor will take out reasonable third-party liability insurance cover in accordance with all 
local legal requirements. The civil liability of the Investigator, the persons instructed by him or her 
and the hospital, practice, or institute in which they are employed and the liability of the Sponsor 
with respect to financial loss due to personal injury and other damage that may arise as a result of 
the carrying out of this study are governed by the applicable law. 
The Sponsor will arrange for participants participating in this study to be insured against financial 
loss due to personal injury caused by the pharmaceutical products being tested or by medical steps 
taken in the course of the study. 
9.1.10.1 Access to Source Data 
Regulatory authorities of certain countries, IRBs, IECs, and/or the Sponsor may wish to carry out 
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 Sponsor of the necessary support at all 
times. 
9.2 Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 2 will be performed by local laboratory. 
• Laboratory testing is performed non-fasting. 
• Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Table 2: Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Hematocrit 
Hemoglobin 
Platelet Count 
RBC Count 
RBC Indices 
 
WBC count with Differential 
 


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Serum Chemistry Albumin 
BUN 
Creatinine 
Potassium 
Sodium  
Bilirubin 
Total Protein  
Uric acid 
ALT 
AST 
Alkaline phosphatase 
Calcium 
Glucose  
Total cholesterol 
Chloride 
Bicarbonate 
Other Tests 
• Urinalysis 
• HbA1c (Screening Visit only) 
• Serum hCG pregnancy test at screening. Additional testing may be 
performed if needed in WOCBP. 
• Urine test of drugs of abuse (marijuana, cocaine, amphetamine, 
methamphetamine, opiates, phencyclidine)  
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
HbA1c = hemoglobin A1c (glycated hemoglobin); hCG = human chorionic gonadotropin; RBC = red blood cell 
count; WBC= white blood cell; WOCBP = women of childbearing potential. 
 
Investigators must document their review of each laboratory safety report. 
9.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a participant or clinical study 
participant, temporally associated with the use of a study treatment, whether or not 
considered related to the medicinal product. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment. 
 
Events Meeting the AE Definition  
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the Investigator (i.e., not related to progression of 
underlying disease). 


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• 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. 
 
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 


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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 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Other situations 
• Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical treatment to prevent one 
of the other outcomes listed in the above definition. These events should usually be 
considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 


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Recording and Follow-up of AE and SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the eCRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s 
medical records in lieu of completion of the AE/SAE eCRF page. 
• There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. 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 Sponsor. 
• 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 


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• 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 Sponsor. 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 Sponsor. 
• 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 
Sponsor 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 
Sponsor with a copy of any post-mortem findings including histopathology. 


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• New or updated information will be recorded in the originally completed eCRF. 
• 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
 
Reporting of SAE to Sponsor 
SAE Reporting to Sponsor 
 
• The Investigator must report any SAEs to the Sponsor within 24 hours of becoming 
aware of the event. 
• When calling to report an SAE, state that you are reporting an SAE and give the 
Investigator’s name, your name, the telephone number where you can be reached, and 
the protocol number and title. 
• The Investigator and the Sponsor will review each SAE report and the Sponsor will 
evaluate the seriousness and the causal relationship of the event to study treatment. In 
addition, the Sponsor will evaluate the expectedness according to the reference 
documents (Investigator’s Brochure or US product labeling for atomoxetine or 
dronabinol). Based on the Investigator and Sponsor’s assessment of the event, a 
decision will be made concerning the need for further action. 
• After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form or by 
telephone. 
 
 
All SAEs will be recorded from signing of informed consent until the end of the study. Serious 
adverse events occurring after the end of the study and coming to the attention of the Investigator 
must be reported only if they are considered (in the opinion of the Investigator) causally-related to 
study treatment. 
 


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Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Any AE that is serious, associated with the use of the study treatment, and unexpected 
(SUSAR) has additional reporting requirements, as described below. 
• If the SUSAR is fatal or life-threatening, associated with study treatment, and 
unexpected, regulatory authorities and IECs will be notified within 7 calendar days 
after the Sponsor learns of the event. Additional follow-up (cause of death, autopsy 
report, and hospital report) information should be reported within an additional 8 days 
(15 days total). 
• If the SUSAR is not fatal or life-threatening but is otherwise serious, associated with 
study treatment, and unexpected, regulatory authorities and IECs will be notified 
within 15 calendar days after the Sponsor learns of the event. 
The Sponsor will notify the Investigators in a timely fashion of relevant information 
about SUSARs that could adversely affect the safety of participants. Follow-up 
information may be submitted if necessary. 
The Sponsor will also provide annual safety updates to the regulatory authorities and 
IECs responsible for the study. These updates will include information on SUSARs and 
other relevant safety findings. 
9.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions 
WOCBP 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with one of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 


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


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


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• 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. 
Collection of Pregnancy Information: 
Female participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate form 
and submitted to the Sponsor within 24 hours of learning of a participant’s pregnancy. The 
participant will be followed to determine the outcome of the pregnancy. The Investigator will 
collect any follow up information on the participant and the neonate and the information will 
be forwarded to the Sponsor. Generally, follow up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. Any termination of the pregnancy will be reported, 
regardless of fetal state (presence or absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous abortion 
is always considered to be an SAE and will be reported as such. Any post-study pregnancy-
related SAE considered reasonably related to the study treatment by the Investigator will be 
reported to the Sponsor. While the Investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study. 
 
9.5 Appendix 5: List of Abbreviations 
AHI 
apnea-hypopnea index 
AE 
adverse event 
Bang 
Body mass index, Age, Neck circumference, and Gender criteria 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CPAP 
continuous positive air pressure 
CYP2D6 
cytochrome P450 2D6 


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CYP3A4 
cytochrome P450 3A4 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
DSST 
Digit symbol substitution test 
ECG 
electrocardiogram 
EEG 
electroencephalogram 
eCRF 
electronic case report form(s) 
EDC 
electronic data capture 
EOS 
end of study 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HB 
hypoxic burden 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
OSA 
obstructive sleep apnea 
OTC 
over-the-counter 
MAOI 
monoamine oxidase inhibitor 
PK 
pharmacokinetic(s) 
PSG 
polysomnography 
PVT 
Psychomotor vigilance test 
QHS 
1 dose every night at bedtime 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SoA 
Schedule of Activities 
STOP 
Snoring, Tiredness, Observed apnea, and Blood pressure criteria 
SUSAR 
suspected unexpected serious adverse reaction 
ULN 
upper limit of normal 
US 
United States 
VOLT 
Visual object learning task 
WOCBP 
woman of childbearing potential 
 
 


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10 References 
1. 
Taranto-Montemurro L, Messineo L, Azarbarzin A, Vena D, Hess L, Calianese N, et al. 
Effects of the Combination of Atomoxetine and Oxybutynin on Obstructive Sleep Apnea 
Endotypic Traits. CHEST. 2020. 
2. 
Taranto-Montemurro L, Messineo L, Sands SA, Azarbarzin A, Marques M, Edwards BA, 
et al. The Combination of Atomoxetine and Oxybutynin Greatly Reduces Obstructive Sleep 
Apnea Severity. A Randomized, Placebo-controlled, Double-Blind Crossover Trial. American 
journal of respiratory and critical care medicine. 2019;199(10):1267-76. 
3. 
Taranto-Montemurro L, Messineo L, Wellman A. Targeting Endotypic Traits with 
Medications for the Pharmacological Treatment of Obstructive Sleep Apnea. A Review of the 
Current Literature. J Clin Med. 2019;8(11). 
4. 
Taranto-Montemurro L, Sands SA, Edwards BA, Azarbarzin A, Marques M, de Melo C, 
et al. Desipramine improves upper airway collapsibility and reduces OSA severity in patients 
with minimal muscle compensation. The European respiratory journal. 2016;48(5):1340-50. 
5. 
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):1006-14. 
6. 
Eckert DJ, White DP, Jordan AS, Malhotra A, Wellman A. Defining phenotypic causes of 
obstructive sleep apnea. Identification of novel therapeutic targets. American journal of 
respiratory and critical care medicine. 2013;188(8):996-1004. 
7. 
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. 2011;110(6):1627-37. 
8. 
Younes M. Contributions of upper airway mechanics and control mechanisms to severity 
of obstructive apnea. American journal of respiratory and critical care medicine. 
2003;168(6):645-58. 
9. 
Younes M. Role of arousals in the pathogenesis of obstructive sleep apnea. American 
journal of respiratory and critical care medicine. 2004;169(5):623-33. 
10. 
Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in 
obstructive sleep apnea. J Clin Invest. 1995;96(4):1897-904. 
11. 
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(14):1829-36. 
12. 
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(1):106-9. 
13. 
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(19):1378-84. 
14. 
Hung J, Whitford EG, Parsons RW, Hillman DR. Association of sleep apnoea with 
myocardial infarction in men. Lancet. 1990;336(8710):261-4. 
15. 
Wessendorf TE, Teschler H, Wang YM, Konietzko N, Thilmann AF. Sleep-disordered 
breathing among patients with first-ever stroke. J Neurol. 2000;247(1):41-7. 
16. 
Hoffstein V. Blood pressure, snoring, obesity, and nocturnal hypoxaemia. Lancet. 
1994;344(8923):643-5. 


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17. 
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. American journal of respiratory and critical care medicine. 2001;163(1):19-25. 
18. 
Redline S, Strauss ME, Adams N, Winters M, Roebuck T, Spry K, et al. 
Neuropsychological function in mild sleep-disordered breathing. Sleep. 1997;20(2):160-7. 
19. 
Findley LJ, Unverzagt ME, Suratt PM. Automobile accidents involving patients with 
obstructive sleep apnea. The American review of respiratory disease. 1988;138(2):337-40. 
20. 
Sawyer AM, Gooneratne NS, Marcus CL, Ofer D, Richards KC, Weaver TE. A 
systematic review of CPAP adherence across age groups: clinical and empiric insights for 
developing CPAP adherence interventions. Sleep Med Rev. 2011;15(6):343-56. 
21.  
Carley DW et al. Pharmacotherapy of apnea by cannabimimetic enhancement, the PACE 
clinical trial: effects of dronabinol in obstructive sleep apnea. SLEEP. 2018;41(1):1-13 
 
 


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Declaration of the Investigator 
Title: Open-Label 4-Period Dose-Escalation Safety and Efficacy Study of AD313 in Participants 
With Obstructive Sleep Apnea  
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence. This documentation includes this study 
protocol, Investigator's Brochure, EDC system/eCRF, and other scientific data. 
The study will not be commenced without the prior written approval of a properly constituted 
IRB or IEC. No changes will be made to the study protocol without the prior written approval of 
the Sponsor and the IRB or IEC, except where necessary to eliminate an immediate hazard to the 
participants. 
I have read and understood and agree to abide by all the conditions and instructions contained in 
this protocol. 
Responsible Investigator of the local study center 
 
_____________________________________ 
_____________________ 
Signature 
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number 
 

ICF_001.pdf: 
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SEED_ICF_v1.0 
1 
RESEARCH PARTICIPANT CONSENT FORM 
 
TITLE: 
Open-Label 4-Period Dose-Escalation Safety and Efficacy Study 
of AD313 in Participants With Obstructive Sleep Apnea  
 
 
(SEED Study) 
 
PROTOCOL NO.: 
SEED 
 
IRB Protocol #20213629 
 
SPONSOR: 
Apnimed, Inc. 
<<CF-Main Header Block - Investigator>> 
INVESTIGATOR: 
Name 
 
Address 
 
City, State Zip 
 
Country 
 
STUDY-RELATED 
PHONE NUMBER(S): 
<<CF-Main User Defined #1>> 
 
Phone Number 
 
Phone Number (24 hours) 
 
[24 hour number is required] 
 
RESEARCH CONSENT SUMMARY 
 
You are being asked for your consent to take part in a research study. This document provides a 
concise summary of this research. It describes the key information that we believe most people 
need to decide whether to take part in this research. Later sections of this document will provide 
all relevant details. 
 
What should I know about this research? 
 
• Someone will explain this research to you. 
• Taking part in this research is voluntary. Whether you take part is up to you. 
• If you don’t take part, it won’t be held against you. 
• You can take part now and later drop out, and it won’t be held against you 
• If you don’t understand, ask questions. 
• Ask all the questions you want before you decide. 
 
How long will I be in this research? 
 
We expect that your taking part in this research will last up to 9 weeks from the time of 
screening to the last phone call.  
 


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SEED_ICF_v1.0 
2 
Why is this research being done? 
 
You are being asked to participate in this research study because you have been diagnosed with 
or have obstructive sleep apnea (OSA). The purpose of this research study is to assess the safety 
and efficacy of two commercially available medications utilizing 3 increasing dose combinations 
of atomoxetine with dronabinol, compared to baseline and to atomoxetine alone. The use of 
atomoxetine with dronabinol or atomoxetine alone for the treatment of sleep apnea is 
investigational in the study. 
 
What happens to me if I agree to take part in this research? 
 
If you decide to take part in this research study, you will have a sleep study and lab tests to 
determine if you qualify for the study.  If you qualify, you will receive increasing dose 
combinations of two commercially available medications over a 4-week period.  Three sleep 
studies and office visits will be performed while taking the medication to assess their safety and 
efficacy.  
 
Could being in this research hurt me? 
 
The most important risks or discomforts that you may expect from taking part in this research 
include risks of the medications being taken (you will receive medication fact sheets), and any 
discomforts from the sleep study.   
 
Will being in this research benefit me? 
 
Since these two drugs have not been studied very much alone or together to treat OSA, there are 
no guaranteed benefits to you for participating in this research study. There is a possibility that 
these medications could assist your study doctor in the treatment of your OSA. In addition, other 
patients who suffer from the same condition could benefit from your participation in this 
research study. 
 
What other choices do I have besides taking part in this research? 
 
Taking part in this research study is voluntary. You don’t have to participate and you can stop at 
any time. If you decide not to take part in this study, you will continue to receive normal 
standard of care treatment. 
 
What else should I know about this research? 
 
Other information that may be important for you to consider so you can decide whether to take 
part in this research is the schedule of events.  We ask that you make your best effort to attend 
each visit.  Please also review the detailed consent for guidance on sexually active participants of 
childbearing potential and considerations regarding food and alcohol intake. 
 


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3 
DETAILED RESEARCH CONSENT 
 
You are being invited to take part in a research study.  A person who takes part in a research 
study is called a subject, research participant.  
 
In this consent form “you” generally refers to the research participant.  
 
Why is this research being done? 
 
You are being asked to participate in this research study because you have been diagnosed with 
or have moderate to severe obstructive sleep apnea (OSA) and you may qualify for this study to 
evaluate the treatment option of two commercially available medications for your OSA. 
 
OSA is a common and serious sleep disorder and it affects approximately 20 million people in 
the United States. OSA is the repetitive collapse or “obstruction” of the airway during sleep, 
creating repetitive episodes of hypopnea (shallow breathing) or apnea (paused breathing).  These 
episodes of shallow or paused breathing may lead to waking up from sleep, interrupted sleep, 
excessive daytime sleepiness and/or psychological disturbance. Long-term OSA is associated 
with increased risk of death and several adverse health consequences (e.g., heart disease, brain 
health, metabolism, functioning throughout the day). 
 
Treatment for OSA has changed little over the past 40 years. While common treatments such as 
CPAP and related therapies are effective in improving sleep characteristics and providing more 
oxygen, many patients find these devices uncomfortable or intolerable. Efforts to develop 
pharmacological therapies (drugs) for the treatment of OSA have been ongoing for at least 20 
years, with no success thus far. 
 
Selective norepinephrine reuptake inhibitors (SNRIs) such as atomoxetine are thought to 
improve OSA by increasing the stiffness and responsiveness of the airway muscles. 
Cannabinoids, such as dronabinol, have shown potential for reduction of OSA severity. The 
sponsor of this study (Apnimed) believes that the combination of dronabinol and atomoxetine 
may have an improved efficacy profile in patients with OSA compared to either option taken by 
itself. 
 
About 15 participants will take part in this research at up to 3 selected sites in the United States. 
 
What happens to me if I agree to take part in this research? 
 
If you agree to take part in this research study, a health screening will be conducted in order to 
confirm that you are eligible for the study.  The screening visit will be conducted at your study 
doctor’s office. The following assessments are not experimental, however will be performed 
solely for the purpose of this research study. 
 
• Your study doctor will assess your eligibility to participate in this study. You will be 
asked about your symptoms, your demographics, your medical history and any medicine 
that you are taking. 


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• You will have a brief physical exam and your vital signs (temperature, respiratory rate, 
blood pressure and heart rate) will be assessed. 
• Females of child-bearing potential, who are pre-menopausal and have not had a 
hysterectomy (uterus removed), you will have a blood pregnancy test.  
• You will complete clinical laboratory testing (blood and urine tests). 
• You will have a 12-Lead Electrocardiogram (EKG) to measure the electrical and 
muscular functions of your heart. 
• You will have a sleep study, unless you’ve already had one that qualifies for screening 
within the last three months that you can provide. 
• You will also perform the following questionnaires on an iPad or similar tablet: 
o Patient Global Impression of Severity of OSA (PGI-S) 
o Patient Reported Outcomes Measurement Information System (PROMIS) sleep 
impairment 
o PROMIS sleep disturbance 
o PROMIS fatigue 
o Digit Symbol Substitution Test (DSST) 
o Psychomotor Vigilance Test (PVT) 
 
If you qualify for the study, you will receive increasing dose combinations of atomoxetine and 
dronabinol. The weekly dose schedule is as follows: 
 
• Week 1: atomoxetine 40 mg x 4 days, then 80 mg x 3 days 
• Week 2: atomoxetine 40 mg/dronabinol 2.5 mg 
• Week 3: atomoxetine 80 mg/dronabinol 5 mg 
• Week 4: atomoxetine 80 mg/dronabinol 10 mg 
 
Dose escalation (increase) will be based on safety and tolerability, as assessed at weekly clinic 
visits and by telephone contact. If you do not tolerate dose escalation, you will be discontinued 
from the study.   
 
You will be asked to come to the study doctor’s office for office visits and additional sleep 
studies during the course of the study as follows: 
 
Activities 
Screening 
(May be 
performed over 
1-2 visits) 
Baseline Week 1 
(1-7 
days 
+/- 1) 
Week 2 
(8-14 
days 
+/- 2) 
Week 3 
(15-21 
days 
+/- 2) 
Week 4 
(21-28 
days 
+/- 2_ 
Week 6 
(42  
days 
+/- 2) 
Screening (Demographics, 
Exam, Labs, ECG) 
X 
 
 
 
 
 
 
Sleep Study (performed at 
the end of the week, Weeks 
1-4 when applicable) 
 
X 
X 
 
X 
X 
 
Office Visit 
 
 
 
X 
 
 
 
Phone Call 
 
 
 
 
 
 
X 
Vital Signs 
 
X 
X 
X 
X 
X 
 
Drug Receipt/Return 
 
X 
X 
X 
 
 
 


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Activities 
Screening 
(May be 
performed over 
1-2 visits) 
Baseline Week 1 
(1-7 
days 
+/- 1) 
Week 2 
(8-14 
days 
+/- 2) 
Week 3 
(15-21 
days 
+/- 2) 
Week 4 
(21-28 
days 
+/- 2_ 
Week 6 
(42  
days 
+/- 2) 
Questionnaires 
 
X 
X 
 
X 
X 
 
 
Description of Medications:  
 
Atomoxetine (STRATTERA®): 
 
Atomoxetine (STRATTERA®) has been FDA approved for over 18 years (approved in 2002) for 
the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) but not approved for your 
condition. The daily dose of atomoxetine that will be studied will be within the range typically 
recommended for adults, per the current U.S. prescribing information. Your study doctor will 
review this medication with you in detail and will answer any questions you may have.   
 
Dosing instructions: 1 capsule given by mouth with up to 240 mL (about 1 cup) of water. 
 
Dronabinol (Marinol®): 
 
Dronabinol (Marinol®) was initially approved by FDA in 1985 in adults for the treatment of: 
Anorexia associated with weight loss in patients with AIDS, Nausea and vomiting associated 
with cancer chemotherapy in patients who have failed to respond adequately to conventional 
antiemetic treatments but not approved for your condition. The daily dose of dronabinol that will 
be studied will be within the range typically recommended for adults, per the current U.S. 
prescribing information. Your study doctor will review this medication with you in detail and 
will answer any questions you may have.   
 
Dosing instructions: 1 capsule given by mouth with up to 240 mL (about 1 cup) of water. 
 
You will be instructed to keep a daily diary of the time at which you took your medications each 
day. 
 
What are my responsibilities if I take part in this research? 
 
If you take part in this research, your general responsibilities include: 
 
• Follow the instructions of the study doctor and the research staff. 
• Follow all your doctor and study doctor’s prescribed medication routine throughout the 
study period. If you have any questions, please contact your Study doctor or research staff. 
• If you have any kind of allergy to medications, please notify the study doctor and the 
research staff right away. 
• If you believe you are pregnant, please notify the study doctor and research staff. 
• Keep all of your study appointments. If you need to reschedule your missed research 
appointment, please contact the research staff to reschedule your visit as soon as you know 
that you will miss your originally scheduled appointment. 


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• Tell the study doctor or research study staff about any side effects, doctor visits and/or 
hospitalizations that you experience through the entire study period. 
• Ask questions as you think of them. 
• Tell the study doctor or research staff if you change your mind about staying in the study. 
 
For male participants:  
 
If you are sexually active with female partner(s) of childbearing potential, from Study Day 1 
through 1 week after the last dose of study drug, the participant must agree to ONE of the 
following during the protocol-defined time frame: 
 
• 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 less than 1% per year as 
described in the table below when having penile-vaginal intercourse with a woman of 
childbearing potential 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. 
 
For female participants:  
 
If you are a female of childbearing potential, from Study Day 1 through 1 week after the last 
dose of study drug, you are eligible to participate if you agree to use a highly effective method of 
contraception consistently and correctly as described in the table below. All females of 
childbearing potential must have a negative result of a blood (serum) pregnancy test performed at 
screening. If you become pregnant during this time, you will no longer be able to participate in 
the study, and the study doctor will ask to collect information about the pregnancy and its 
outcome. 
 
Highly Effective Contraceptive Methods That Are User Dependent* 
Failure rate of less than 1% per year when used consistently and correctly. 
Combined (estrogen- and progestin-containing) hormonal contraception associated with 
inhibition of ovulation: 
Oral (e.g., birth control pill) 
Intravaginal (e.g., NuvaRing)  
Transdermal (e.g., birth control patch) 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
Oral (e.g., birth control pill) 
Injectable (e.g., Depo-Provera) 
 
Highly Effective Contraceptive Methods That Are User Independent* 


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Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
IUD (e.g., copper IUD, ParaGard, or similar) 
Intrauterine hormone-releasing system (IUS) (e.g., Mirena, or similar)  
Bilateral tubal occlusion or ligation (e.g., “tubes tied”) 
 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the woman of childbearing potential and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception from the above list 
should be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from (not 
having) 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: 
*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. 
 
Meals and Dietary Restrictions:  
 
• Participants should not eat or drink anything containing the following foods within 72 
hours before the first dose of study drug and during the study: grapefruit or grapefruit 
juice, pomelo juice, star fruit, pomegranate, and Seville or Moro (blood) orange products.  
• You should not start any new diet programs during the study. 
 
Caffeine, Alcohol and Tobacco:  
 
• During the study, participants should not drink more than 2 standard units per day of 
alcohol for men or 1 unit/day for women (for example, 1 beer, 1 4 oz. glass of wine, or 1 
mixed drink), consumed no less than 3 hours prior to bedtime. You should not drink any 
alcohol the day of a sleep study.   
• Caffeinated beverages (such as soda, energy drinks or coffee), containing up to a total of 
400 mg caffeine per day is permitted during the study period.  Please do not drink them 
within 3 hours of bedtime. 
 
Physical Activity:  
 
• You should not start any new exercise programs during the study.  
 
Could being in this research hurt me? 
 
As with taking any type of medications, there are known potential risks with taking medications 
like these two, as well as potential risks that may be unknown.  Please review the medication fact 
sheets for more information.   


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Risks of atomoxetine: Constipation, dry mouth, nausea, decreased appetite, dizziness, erectile 
dysfunction, and urinary hesitation. 
 
Risks of dronabinol: abdominal pain, dizziness, euphoria, nausea, paranoid reaction, somnolence, 
thinking abnormal and vomiting.  
 
Precautions to be taken for atomoxetine and dronabinol: 
 
• Effects on heart rate and blood pressure; pulse and blood pressure will be measured at 
baseline and following dose increases. 
• Emergent psychiatric adverse events; do not to operate motor vehicles or other dangerous 
machinery until you are reasonably certain that mental or physical abilities are not 
impaired. 
• Nausea and vomiting; consult with the study doctor to consider discontinuation if 
symptoms continue or worsen 
• Dizziness, drowsiness; tolerance often develops to CNS adverse effects, and are less with 
nighttime dosing. 
• Rash; may be a symptom of hypersensitivity reaction, serious allergic reactions are rare 
but have been reported. 
 
Consult your study doctor if you experience any of these symptoms. 
 
In addition to these risks, taking part in this research may harm you in unknown ways. It is 
possible that your condition may not improve and could worsen if you take part in this study. 
 
Taking part in this study may hurt a pregnancy or fetus in unknown ways. 
 
Non-Experimental Study Procedures 
 
Risks of Blood Draws: You may experience swelling, bruising, bleeding where the needle 
enters the body. There is a risk of fainting, please let the study team know if this has happened to 
you in the past.  
 
Risks of Blood Pressure Measurements: The blood pressure cuff may cause some mild 
discomfort, bruising, or red spots on the arm. If this happens, it usually goes away shortly after 
the blood pressure cuff has been removed. 
 
Risks of Electrocardiogram (EKG) and Sleep Study: Skin irritation from the EKG and other 
sleep study electrode pads or pain when removing the pads can occur. If this happens, it is 
usually temporary. Difficulty sleeping in the study center may also occur. 
 
For more information about risks and side effects, ask the study research staff or doctor 
<<Investigator Full Name-Title>>[PI Name]. 
 


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Will it cost me money to take part in this research? 
 
Taking part in this research may lead to added costs to you, such as travel costs, and time away 
from work. You will be compensated fairly to cover these costs, see below.  The sponsor, 
Apnimed, Inc. will be paying for the services related to research, such as your office visits, sleep 
studies, and the study medication. 
 
Will I be paid for taking part in this research? 
 
<<CF-Main Payment for Part. Paragraph>>For taking part in this research, you may be paid up 
to a total of $[Amount]. Your compensation will be broken down as follows: 
 
• Completion of screening, if you do not qualify for the study: $[Amount] 
• Completion of screening and baseline, if you do qualify for the study: $[Amount] 
• Each research related sleep study: $[Amount] 
• Each office visit (without sleep study): $[Amount] 
 
If you withdraw from the study, you will only be compensated for the study visits or procedures 
completed. 
<<CF-Main Financial Disclosure>> 
Will being in this research benefit me? 
 
Since these two drugs have not been studied very much alone or together to treat OSA, there are 
no guaranteed benefits to you for participating in this research study. There is a possibility that 
these medications could assist your study doctor in the treatment of your OSA. In addition, other 
patients who suffer from the same condition could benefit from your participation in this 
research study. 
 
We cannot promise any benefits to you or others from your taking part in this research. However, 
possible benefits to you could include improvement of your OSA. 
 
We cannot promise any benefits to others from your taking part in this research. However, 
possible benefits to others include additional information on the use of these medications to treat 
OSA in the future. 
 
What other choices do I have besides taking part in this research? 
 
Your alternative is to not take part in the research. The other treatment options include use of 
continuous positive airway pressure (CPAP), pharyngeal surgery, mandibular advancement 
devices, and implantable nerve stimulators.  
 
What happens to the information collected for this research? 
 
Your private information and your medical record will be shared with individuals and 
organizations that conduct or watch over this research, including: 
 
• The research sponsor 
• Medical personnel associated with the study 


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• People who work with the research sponsor<<CF-Main SMO Company 1>><<CF-Main 
Affiliated IN Language 1>> 
• Government agencies, such as the Food and Drug Administration (FDA) 
• WCG IRB, the Institutional Review Board (IRB) that reviewed this research 
 
We may publish the results of this research. However, we will keep your name and other 
identifying information private. 
 
We protect your information from disclosure to others to the extent required by law. We cannot 
promise complete secrecy. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
Data collected in this research might be deidentified and used for future research or distributed to 
another investigator for future research without your consent. 
 
If you join this study, you should understand that you will not own your biospecimens or data.  
 
The information and biospecimens (samples of material such as urine, blood, etc.) obtained from 
this research study may be of commercial value, but you will not share in any potential profits 
from the commercialization of products developed from your participation in this study. 
 
Who can answer my questions about this research? 
 
If you have questions, concerns, or complaints, or think this research has hurt you or made you 
sick, talk to the research team at the phone number listed above on the first page of this 
document. 
 
This research is being overseen by WCG IRB. An IRB is a group of people who perform 
independent review of research studies. You may talk to them at 855-818-2289 or 
researchquestions@wcgirb.com if:  
 
• You have questions, concerns, or complaints that are not being answered by the research 
team. 
• You are not getting answers from the research team. 
• You cannot reach the research team. 
• You want to talk to someone else about the research. 
• You have questions about your rights as a research participant. 
 
What if I am injured because of taking part in this research? 
 
If you are injured or get sick because of being in this research, call the study doctor immediately. 
The study doctor will provide emergency medical treatment. Your insurance may be billed for 
this treatment. The sponsor will pay any charges that are not covered by your insurance policy or 


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the government, provided the injury was not due to your underlying illness or condition and was 
not caused by you or some other third party. No other payment is routinely available from the 
study doctor or sponsor. 
 
If you are a Medicare patient and receive payment for medical expenses from a study-related 
injury, the sponsor will need to know some information about you like your name, date of birth 
and social security number or Medicare Health Insurance Claim Number. This is because the 
sponsor has to report any study-related injury claim payments to Medicare. The sponsor will not 
use this information for any other purpose. The Centers for Medicare and Medicaid Services 
(CMS) is the agency that administers the Medicare program. The sponsor (or its delegate) must 
have certain private information about you, such as: 
 
• Your name 
• Date of birth 
• Social Security number 
• Medicare claim number 
• Date of injury 
• A description of the injury 
 
The sponsor normally would not receive such private information about you. However, the 
sponsor (or its delegate) has agreed to use this information only for the purposes described in this 
paragraph. The sponsor also agrees to use it as otherwise specified in the Authorization to Use 
and Disclose Protected Health Information section. This is included at the end of this consent 
document. 
 
Can I be removed from this research without my approval? 
 
The person in charge of this research can remove you from this research without your approval. 
Possible reasons for removal include: 
 
• It is in your best interest 
• You have a side effect that requires stopping the research 
• You need a treatment not allowed in this research 
• You become pregnant 
• The research is canceled by the FDA or the sponsor 
• You are unable to take the research medication 
• You are unable to keep your scheduled appointments 
• Other reasons we do not know at this time 
 
We will tell you about any new information that may affect your health, welfare, or choice to 
stay in this research. 
 


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What happens if I agree to be in this research, but I change my mind 
later? 
 
Participation is voluntary. You may refuse to participate or discontinue participation at any time 
without penalty or loss of benefits to which you are otherwise entitled. If you decide to leave this 
research, contact the research team so that the investigator can describe the procedures for 
leaving the study early. This will include returning of any unused study medication. 
 
Statement of Consent: 
 
Your signature below documents your consent to take part in this research<<CF-Main California 
Bill of Rights>>. 
 
 
 
Printed name of adult participant capable of consent 
 
 
 
 
 
 
Signature of adult participant capable of consent 
 
Date 
 
 
Signature of person obtaining consent 
 
Date 
<<CF-Main California HIPAA>> 


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**For Sites in California** 
AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR 
RESEARCH PURPOSES 
 
What information may be used and given to others? 
The study doctor will get your personal and medical information.  For example:  
• Past and present medical records 
• Research records 
• Records about phone calls made as part of this research 
• Records about your study visits. 
 
Who may use and give out information about you? 
The study doctor and the study staff.  [They may also share the research information 
with [enter SMO company name], an agent for the study doctor. delete if the site 
does not have an SMO] 
 
Who might get this information? 
The sponsor of this research.  “Sponsor” means any persons or companies that are: 
• working for or with the sponsor, or  
• owned by the sponsor. 
 
Your information may be given to:  
• The U.S. Food and Drug Administration (FDA), 
• Department of Health and Human Services (DHHS) agencies, 
• Governmental agencies in other countries,  
• The institution where the research is being done, 
• Governmental agencies to whom certain diseases (reportable diseases) must be 
reported, and 
• Institutional Review Board (IRB).  
 
Why will this information be used and/or given to others? 
• to do the research,  
• to study the results, and  
• to make sure that the research was done right.   
 
If the results of this study are made public, information that identifies you will not 
be used. 
 


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What if I decide not to give permission to use and give out my health 
information? 
Then you will not be able to be in this research study. 
 
May I review or copy my information? 
Yes, but only after the research is over.  
 
May I withdraw or revoke (cancel) my permission? 
This permission will be good until December 31, 2070. 
 
You may withdraw or take away your permission to use and disclose your health 
information at any time.  You do this by sending written notice to the study doctor.  
If you withdraw your permission, you will not be able to stay in this study. 
 
When you withdraw your permission, no new health information identifying you 
will be gathered after that date.  Information that has already been gathered may 
still be used and given to others.   
 
Is my health information protected after it has been given to others? 
There is a risk that your information will be given to others without your 
permission. 
 
Authorization: 
I have been given the information about the use and disclosure of my health 
information for this research study.  My questions have been answered. 
 
I authorize the use and disclosure of my health information to the parties listed in the 
authorization section of this consent for the purposes described above. 
 
AUTHORIZATION SIGNATURE: 
 
 
 
 
 
 
Signature of Subject 
 
Date