DReAMzz- Dronabinol and Acetazolamide Medication for Sleep Apnea (ZZ). Dose Confirmation Crossover Study for IHL-42X in Subjects With Obstructive Sleep Apnea.

Phase II, Randomized, Double-Blind, Multidose Crossover Clinical Trial to Determine the Safety and Efficacy of IHL-42X in Subjects With Obstructive Sleep Apnea

The goal of this randomized, double-blind, multi-dose crossover clinical trial is to determine the safety and efficacy of IHL-42X in subjects with obstructive sleep apnea.

The primary endpoint is: Change in AHI4 at the end of each treatment period compared to baseline (each treatment period is 28 days).

The study will consist of three separate four-way crossover dose-comparison studies each comparing three dose strengths of IHL-42X to placebo. The double-blind four-way crossover will be conducted according to a Williams design. Each of the crossover studies will test different doses of dronabinol in combination with a distinct, set dose of acetazolamide. In total, nine different combinations of dronabinol and acetazolamide formulated as IHL-42X will be tested in the study. The optimal dose strength will be selected based on safety and efficacy over a 4-week treatment period.

Inclusion Criteria

Participants must satisfy all the following criteria at screening unless otherwise stated:

1. Aged ≥18 and ≤65 years of age at the time of consent.

2. Two screening PSG findings confirmed on central over-read that both must meet the below criteria:

   1. AHI4 ≥5
   2. ≤25% central or mixed apneas out of total AHI
   3. no Cheyne-Stokes respiration
   4. total sleep time ≥ 4 hours in each PSG
   5. < 30 periodic leg movement disorder arousals per hour.

3. A difference in AHI4 of ≤15 between screening PSG 1 and screening PSG 2.

4. A PROMIS-SRI 8a score of >16.

5. Intolerant or non-compliant to PAP, or has refused PAP after physician recommendation. Participants will be identified as intolerant or non-compliant to PAP devices by the following criteria (NB: OSA diagnosis must be entered in participant medical history):

   1. Participants are regarded as PAP-non-compliant if they do not use PAP for ≥ 4 hours for at least 63 nights during consecutive 90-day period based on data collected from the PAP device (e.g., SD storage cards) and/or a cloud-based repository of PAP device data.
   2. Participants are regarded as PAP-intolerant if they are former PAP users, i.e., a PAP device that they have not used for >90 days, have tried PAP and not continued to use it or refusal of PAP after prior positive sleep study or prior refusal of provider recommended sleep study due to unwillingness to consider PAP.

   NB: Participants will have the benefits and risks of PAP explained at screening, including that PAP is standard of care for OSA. Participants also have the option to withdraw from the study at any time if he/she elects to be treated with PAP or other alternative therapy such as an oral appliance or surgery.

6. Must agree not to take any form of cannabis or cannabinoid with the exception of the IP, or any other illicit or recreational drug while participating in this study.

7. A female participant of childbearing potential must agree to at least one approved highly effective method of contraception. Approved methods of contraception include the following:

   1. Intra-uterine device in place for at least 3 months prior to Day 1 through to 10 days following the last dose of the study drug.

   2. Stable hormonal contraceptive which includes oral, intravaginal, intrauterine, transdermal, injectable, or implantable methods of hormonal contraception for at least 3 months prior to Day 1 through to 10 days after the last dose of the study drug.

      NB: Barrier method (condom or diaphragm) is not considered 'highly effective' for the purpose of this study and should be used in combination with one of the approved highly effective methods listed above.

      A female will not be considered of childbearing potential if:

   3. 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels > 40 mIU/ml.

   4. Undergone bilateral tubal ligation, hysterectomy, or bilateral oophorectomy at least 6 months prior to Day 1.

8. A male participant must agree to use at least 1 approved method of contraception (or as required by local regulations) while engaging in sexual activity from study Day -1 through EOS follow-up and/or up to 10 days following the last administration of the study drug. Male participants must not donate sperm during this same period. Approved methods of contraception include the following:

   1. Barrier method (condom) from date of consent through to 10 days after the final dose of the study drug.
   2. Surgical sterilization (vasectomy) at least 6 months prior to Day 1 with proof of azoospermia.

9. Voluntarily written consent to participate in the study and be willing and able to participate in all scheduled visits, treatment plans, tests, and other study procedures according to the protocol.

Exclusion Criteria:

Participants will be excluded from the study if they satisfy any of the following criteria at screening, unless otherwise stated:

1. Body mass index (BMI) >40 kg/m2 (men) and >42 kg/m2 (women).

2. Diagnosed obesity hypoventilation syndrome or hypercapnia.

3. PAP-compliant, defined by use of PAP for ≥4 hours for at least 63 nights during the consecutive 90-day period.

4. Current use of custom-made oral appliances (mandibular advancement device, tongue retaining device, or mouth guard) or hypoglossal nerve stimulation devices. Devices must not be used for the duration of the study.

5. Maxillomandibular advancement, upper airway, or bariatric surgery within the last 6 months prior to first administration of the study drug; or participants who are planning surgical treatment.

6. Have commenced glucagon-like peptide-1 receptor agonist therapy within the last 6 months.

7. Use of benzodiazepines, sedative-hypnotics or stimulants (Anatomical Therapeutic Chemical [ATC] N06B, N05C, N05BA, N03AE, and N01AF categories) to treat insomnia, OSA, and other sleep disorders, or other disorders that require the drug to be taken prior to sleep.

8. Use of other prescription medications to treat insomnia.

9. Pierre Robin, Treacher Collins, or other craniofacial malformation syndrome, or grade ≥3 tonsillar hypertrophy.

10. Respiratory and neuromuscular diseases that could interfere with the results of the trial in the opinion of the investigator.

11. Known allergic or other severe reaction to cannabis products with previous use.

12. Known allergic reaction to sesame oil.

13. Known allergic reaction to acetazolamide.

14. Pregnant or breastfeeding.

15. Current illicit drug abuse (within the last 6 months prior to screening); "abuse" has some subsets that are objective and some that require investigator judgement; questions should be discussed with the medical monitor or with the sponsor

    1. An objective subset includes consumption of substances that are "illicit", i.e., not legal per local laws
    2. Investigator judgement is expected for legally marketed products ingested for other than the approved indication(s)
    3. Participants who test positive to THC should be screen failed and can be considered for rescreening after a >6-week washout period. Participants can only be rescreened once. Positive test results for all other substances shall be reviewed by the investigator and participants shall only be screen failed if the investigator believes the use of the substance may be clinically significant with regards to the participant's safe participation in this study or may confound this study's findings.

16. Severe depression, defined as a score of ≥30 on the Major Depression Inventory (MDI) questionnaire.

17. Severe anxiety, defined as score of >15 on the General Anxiety Disorder-7 (GAD-7) questionnaire.

18. Any of the following co-morbid conditions (NB: clarification on co-morbidities and inclusion/exclusion criteria may be discussed with the medical monitor and/or sponsor):

    1. Severe psychiatric disorder that might be aggravated or exacerbated by dronabinol's potential to cause anxiety/nervousness, depersonalization, hallucination, etc.
    2. Respiratory and neuromuscular diseases that could interfere with the results of the trial in the opinion of the investigator.
    3. Cardiac dysfunction and/or its treatment that might augment dronabinol's potential to cause tachycardia or vasodilation.
    4. Marked hepatic dysfunction as defined by elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 × the upper limit of normal (ULN), that would reduce dronabinol metabolism.

    i. One retest per participant is permitted at the discretion of the investigator; the participant may continue if BOTH repeat transaminase levels are within acceptable range (i.e., less than 3 × ULN).

    e. Current or history of encephalopathy or cirrhosis Child-Pugh category B or C (see Appendix 8) since acetazolamide can increase blood ammonia levels precipitating a bout of hepatic encephalopathy.

    f. Marked renal dysfunction that would reduce acetazolamide excretion, including eGFR <60 mL/min/1.73 m2, as determined using the National Kidney Foundation calculator (https://www.kidney.org/professionals /kdoqi/gfr_calculator) and instructions in Appendix 9.

    g. Hypokalemia (low blood potassium), hyponatremia (low blood sodium), hyperchloremic acidosis, and/or adrenal insufficiency that might be aggravated or exacerbated by acetazolamide's activity as a carbonic anhydrase inhibitor.

19. Known CYP2C9 poor metabolizers (NB: this is based on medical history and does not need to be tested genetically).

20. Other ongoing condition(s) that the investigator considers may be clinically significant with regards to the participant's safe participation in this study or may confound this study's findings; any consideration should be discussed with the medical monitor or with the sponsor (such as known alcohol abuse).

21. Shift workers whose shift pattern has the potential to disrupt sleep patterns.

22. Participation in any other interventional studies involving investigational or marketed products within 30 days or 5.5 half-lives, whichever is longer, prior to screening.