RePOSA-Revealing the Efficacy of IHL-42X Use in Patients With OSA

Study Overview
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Brief Summary
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The goal of this randomised, double-blind phase II/III clinical trial is to determine the safety and efficacy of IHL-42X in subjects with obstructive sleep apnoea who are intolerant, non-compliant, or naïve to positive airway pressure. Phase II study will be a 4-week dose-finding study comparing two dose strengths of IHL-42X to placebo. The optimal dose strength will be selected based on comparing the safety and efficacy of the two IHL-42X dose strengths to placebo over a 4-week treatment period. The three treatment groups are; IHL-42X Low dose (2.5mg dronabinol, 125mg acetazolamide), IHL-42X High dose (5mg dronabinol, 250mg acetazolamide) and Placebo. Each treatment group will enrol approximately 40 patients per treatment arm, for a total of approximately 120 patients. The safety and efficacy results of the Phase II study will be used to select the dose strength of IHL-42X and corresponding doses of dronabinol and acetazolamide in Phase III. Phase III study will use the optimal dose strength of IHL-42X identified in Phase II and will be compared to the component active pharmaceutical ingredients at equivalent dose strengths to those found in the IHL-42X optimal dose strength and placebo over 52 weeks. The four treatment groups are; IHL-42X (optimal dose from Phase II), Acetazolamide (equivalent dose strength to that in the IHL-42X optimal dose strength), Dronabinol (equivalent dose strength to that in the IHL-42X optimal dose strength) and placebo. The treatment groups will enrol approximately 165 patients in IHL-42X, approximately 55 patients in dronabinol, approximately 55 in acetazolamide, and approximately 165 in placebo, for a total of approximately 440 patients.

Official Title
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A Phase II/III, Randomised, Double-Blind Clinical Trial to Determine the Safety and Efficacy of IHL-42X in Subjects With Obstructive Sleep Apnoea Who Are Intolerant, Non-Compliant, or Naïve to Positive Airway Pressure

Conditions
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Obstructive Sleep Apnea

Intervention / Treatment
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* Drug: IHL-42X Low Dose
* Drug: IHL-42X High Dose
* Drug: Placebo
* Drug: IHL-42X (Optimal Dose)
* Drug: Dronabinol
* Drug: Acetazolamide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥18 years of age Screening polysomnography (PSG) findings confirmed on central over-read: AHI ≥15 ≤ 25% central or mixed apneas/hypopneas no Cheyne-Stokes respiration Intolerant, non-compliant, or naïve to PAP (Note: No more than 25% of the study population will consist of PAP-naïve patients). Patients will be identified as intolerant, non-compliant, or naïve to PAP devices by the following criteria: Patients are regarded as PAP-non-compliant if they do not use PAP for ≥ 4 hours for at least 21 nights during consecutive 30-day period based on data collected from the PAP device (eg, SD storage cards) and/or a cloud-based repository of PAP device data. Patients are regarded as PAP-intolerant if they are former PAP users, ie, a PAP device that they have not used for >30 days or who do not have access to PAP device Patients are regarded as PAP-naïve if they have no prior experience with PAP. Patients who have undergone a split-study, ie, a study of PAP during PSG, are not considered PAP- naïve and should be categorised according to a through b above. (Note: PAP-naïve patients will have the benefits and risks of PAP explained at screening, including that PAP is standard of care for OSA. These patients 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) Must agree not to take any form of cannabis or cannabinoid, or any other illicit or recreational drug with the exception of the investigational product (IP) while participating in this study. A female patient of childbearing potential must agree to use 2 approved methods of contraception. Approved methods of contraception include the following: 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 Barrier method (condom or diaphragm) for at least 3 months prior to Day 1 through to 10 days after the last dose of the study drug Stable hormonal contraceptive for at least 3 months prior to Day 1 and barrier method (condom or diaphragm) for at least 14 days prior to Day 1, through to 10 days after the last dose of the study drug. A female will not be considered of childbearing potential if: postmenopausal (defined as no menstruation for at least 12 months) with serum follicle-stimulating hormone levels >40 mIU/ml undergone bilateral tubal ligation, hysterectomy, or bilateral oophorectomy at least 6 months prior to Day 1 A male patient 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 End-of-Study (EOS) follow-up and/or up to 10 days following the last administration of the study drug. Male patients must not donate sperm during this same period. Approved methods of contraception include the following: Barrier method (condom) for at least 14 days prior to Day 1 through to 10 days after the final dose of the study drug Surgical sterilisation (vasectomy) at least 6 months prior to Day 1 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: Body mass index >45 kg/m2 PAP-compliant, defined by the use of PAP for ≥ 4 hours for at least 21 nights during the consecutive 30-day period Current use of oral appliances (eg, mandibular advancement device, tongue retaining device, or mouth guard) Maxillomandibular advancement, upper airway, or bariatric surgery within the last 6 months prior to first administration of the study drug; or patients who are considering surgical treatment Use of sedative-hypnotics (ATC N05C) or stimulants (ATC N06B) to treat insomnia, OSA, and other sleep disorders Pierre Robin, Treacher Collins, or other craniofacial malformation syndrome, or grade ≥3 tonsillar hypertrophy Chronic neuromuscular disorders such as motor neuron disease, muscular dystrophy, or myopathy Known allergic reaction to cannabis products with previous use Known allergic reaction to sesame oil Known allergic reaction to acetazolamide Pregnant or breast-feeding Current illicit drug abuse (within the last 6 months prior to screening) Severe depression, defined as a score of ≥30 on the Major Depression Inventory questionnaire Severe anxiety, defined as score of >15 on the General Anxiety Disorder-7 questionnaire Any of the following co-morbid conditions (Note: clarification on co-morbidities and inclusion/exclusion criteria may be discussed with the medical monitor and/or sponsor): severe psychiatric disorder that might be aggravated or exacerbated by dronabinol's potential to cause anxiety/nervousness, depersonalization, hallucination, etc; cardiac dysfunction and/or its treatment that might augment dronabinol's potential to cause tachycardia or vasodilation; marked hepatic dysfunction that would reduce dronabinol metabolism; current or history of encephalopathy or cirrhosis Child-Pugh category B or C (see Appendix 7) since acetazolamide can increase blood ammonia levels precipitating a bout of hepatic encephalopathy; marked renal dysfunction, including estimated glomerular filtration rate < 60 mL/min/1.73m2, that would reduce acetazolamide excretion; hypokalaemia (low blood potassium), hyponatremia (low blood sodium), hyperchloraemic acidosis, and/or adrenal insufficiency that might be aggravated or exacerbated by acetazolamide's activity as a carbonic anhydrase inhibitor Other ongoing condition(s) that the investigator considers may be clinically significant with regards to the patient'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 Participation in any other interventional studies involving investigational or marketed products within 30 days or 5.5 half-lives, whichever is longer, of the IP prior to screening. Patients in Phase II may enter screening (with a different identifier) for Phase III after 30 days from the last administration of the study drug in Phase II.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase 2 (3 arms) IHL-42X low dose (2.5mg dronabinol, 125mg acetazolamide) IHL-42X high dose (5mg dronabinol, 250mg acetazolamide) Placebo Phase 3 (4 Arms) IHL-42X (Optimal dose from phase 2) Dronabinol (equivalent dose strength to that in the IHL-42X optimal dose strength) Acetazolamide (equivalent dose strength to that in the IHL-42X optimal dose strength) Placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 2 Investigational Product - IHL-42X Low dose<br>IHL-42X (2.5 mg dronabinol + 125 mg acetazolamide), one capsule self-administered once daily every night approximately 1 hour prior to bed for 4 weeks. | Drug: IHL-42X Low Dose<br>* Softgel capsule<br>* Other names: Phase 2 Investigational Product - IHL-42X Low dose;|
| Experimental: Phase 2 Investigational Product - IHL-42X High dose<br>IHL-42X (5 mg dronabinol + 250 mg acetazolamide), one capsule self-administered once daily every night approximately 1 hour prior to bed for 4 weeks. | Drug: IHL-42X High Dose<br>* Softgel capsule<br>* Other names: Phase 2 Investigational Product - IHL-42X High dose;|
| Placebo Comparator: Phase 2 Placebo<br>One capsule self-administered once daily every night approximately 1 hour prior to bed for 4 weeks. | Drug: Placebo<br>* Softgel capsule<br>* Other names: Phase 2 Placebo;|
| Experimental: Phase 3 Investigational Product - IHL-42X<br>IHL-42X (dose will be identified based on the safety and efficacy results in Phase II), one capsule self-administered once daily every night approximately 1 hour prior to bed for 52 weeks. | Drug: IHL-42X (Optimal Dose)<br>* Softgel capsule<br>* Other names: Phase 3 Investigational Product - IHL-42X;|
| Active Comparator: Phase 3 Comparator - Reference Listed Drug/Dronabinol<br>One capsule of dronabinol (equivalent dose strength to that in the IHL-42X optimal dose strength) self-administered once daily every night approximately 1 hour prior to bed for 3 months then IHL-42X (optimal dose) one capsule self-administered once daily every night approximately 1 hour prior to bed for the remaining 9 months. | Drug: Dronabinol<br>* Softgel capsule<br>* Other names: Phase 3 Comparator - Reference Listed Drug/Dronabinol;|
| Active Comparator: Phase 3 Comparator - Reference Listed Drug/Acetazolamide<br>One capsule of acetazolamide (equivalent dose strength to that in the IHL-42X optimal dose strength) self-administered once daily every night approximately 1 hour prior to bed for 3 months then IHL-42X (optimal dose) one capsule self-administered once daily every night approximately 1 hour prior to bed for the remaining 9 months. | Drug: Acetazolamide<br>* Softgel capsule<br>* Other names: Phase 3 Comparator - Reference Listed Drug/Acetazolamide;|
| Placebo Comparator: Phase 3 Placebo<br>One capsule self-administered once daily every night approximately 1 hour prior to bed for 52 weeks. | Drug: Placebo<br>* Softgel capsule<br>* Other names: Phase 3 Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in apnea-hypopnea index (AHI) | Phase 2 - Assess the change in AHI compared to baseline | 4 weeks | 
| Change in apnea-hypopnea index (AHI) | Phase 3 - Assess the change in AHI compared to baseline | 52 weeks |