Study for Efficacy and Dose Escalation of AD313 + Atomoxetine (SEED)

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.

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.

Eligibility Criteria:
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 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.

Exclusion Criteria:

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.
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 \>15 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.
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.

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.

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.