| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of excessive sleepiness in adult patients with obstructive sleep apnea; to increase the ability to stay awake throughout the day. |
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| E.1.1.1 | Medical condition in easily understood language |
| Treatment of excessive sleepiness in adult patients with obstructive sleep apnea; to increase the ability to stay awake throughout the day. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10055577 |
| E.1.2 | Term | Obstructive sleep apnea syndrome |
| E.1.2 | System Organ Class | 100000004855 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of JZP-110 administered once daily compared to placebo in the treatment of excessive sleepiness in adult subjects with OSA. |
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| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety and tolerability of JZP-110 administered once daily for up to 6 weeks in doses of 75, 150, and 300 mg compared to placebo in the treatment of excessive sleepiness in adult subjects with OSA. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria:
Each subject must meet the following criteria to be enrolled in the study.
1. Male or female between 18 and 75 years of age, inclusive.
2. Diagnosis of OSA according to ICSD-3 criteria.
3. Subject report (with clinician concurrence) of at least minimal use of a primary therapy for OSA or an attempt to use a primary therapy for OSA as follows:
a. Use of a primary therapy for OSA (e.g., positive airway pressure, oral appliance) on at least 1 night/week, or
b. History of at least 1 month of an attempt to use one or more primary OSA therapies with at least one documented adjustment that was made in an attempt to optimize the primary OSA therapy, or
c. History of a surgical intervention intended to treat OSA symptoms.
4. Subject report (with clinician concurrence) of a stable level of compliance with a primary OSA therapy for at least 1 month prior to the Titration Phase as follows:
a. A stable level of use of a primary OSA therapy, or
b. A lack of use of a primary OSA therapy following a history of attempted use, or
c. A history of a surgical intervention intended to treat OSA symptoms.
5. Epworth Sleepiness Scale (ESS) score ≥10 at the beginning of the Titration Phase.
6. Mean sleep latency ≤30 minutes as documented by the mean of the first four trials of the MWT at the beginning of the Titration Phase.
7. Usual nightly total sleep time of at least 6 hours.
8. Body mass index from 18 to <45 kg/m2.
9. Consent to use a medically acceptable method of contraception for at least 2 months prior to the first dose of study drug, throughout the entire study period, and for 30 days after the study is completed.
10. Willing and able to comply with the study design schedule and other requirements.
11. Willing and able to provide written informed consent.
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| E.4 | Principal exclusion criteria |
Exclusion Criteria:
Subjects who demonstrate any of the following will be excluded from the study.
1. Unwilling to attempt to use one or more primary OSA therapies.
2. Female subjects who are pregnant, nursing, or lactating.
3. Usual bedtime later than 1 AM (0100 hours).
4. Occupation requiring nighttime shift work or variable shift work.
5. Any other clinically relevant medical, behavioral, or psychiatric disorder other than OSA that is associated with excessive sleepiness.
6. History or presence of bipolar disorder, bipolar related disorders, schizophrenia, schizophrenia spectrum disorders, or other psychotic disorders according to DSM 5 criteria.
7.History or presence of any acutely unstable medical condition, behavioral or psychiatric disorder (including active suicidal ideation), or surgical history that could affect the safety of the subject or interfere with study efficacy or safety assessments or the ability of the subject to complete the trial per the judgment of the Investigator.
8. History of bariatric surgery within the past year or a history of any gastric bypass procedure.
9. Presence of renal impairment or creatinine clearance <60 mL/min.
10. Clinically significant ECG abnormality, in the opinion of the Investigator.
11. The criteria has been removed.
12. Presence of significant cardiovascular disease including but not limited to: myocardial infarction within the past year, unstable angina pectoris, symptomatic congestive heart failure (ACC / AHA stage C or D), revascularization procedures within the past year, ventricular cardiac arrhythmias requiring an automatic implantable cardioverter defibrillator (AICD) or medication therapy, uncontrolled hypertension, systolic blood pressure ≥155 mmHg or diastolic blood pressure ≥95 mmHg (at screening, or consistently across measures at Visit 2 according to protocol specifications), or any history of cardiovascular disease or any significant cardiovascular condition that in the investigator's opinion may jeopardize subject safety in the study.
13. Laboratory value(s) outside the laboratory reference range that are considered to be clinically significant by the Investigator (clinical chemistry, hematology, and urinalysis); NOTE: Screening labs may be repeated once.
14. Excessive caffeine use one week prior to the Titration Phase or anticipated excessive use during the study defined as >600 mg/day of caffeine.
15. Use of any over the counter (OTC) or prescription medications that could affect the evaluation of excessive sleepiness within 7 days prior to the Titration Phase, or planned use of such drug(s) at some point throughout the duration of the study. Examples of excluded medications include OTC sleep aids or stimulants (e.g., pseudoephedrine), methylphenidate, amphetamines, modafinil, armodafinil, sodium oxybate, pemoline, trazodone, hypnotics, benzodiazepines, barbiturates, and opioids. Medications should be discontinued such that the subject has returned to his/her baseline level of daytime sleepiness at least 7 days prior to the Titration Phase, in the opinion of the Investigator.
16. Use of a monoamine oxidase inhibitor (MAOI) in the past 14 days or five half-lives (whichever is longer) before the Titration Phase, or plans to use an MAOI during the study.
17. Received an investigational drug in the past 30 days or five half-lives (whichever is longer) before the Titration Phase assessments, or plans to use an investigational drug (other than the study drug) during the study.
18. Previous exposure to or participation in a clinical trial of JZP-110 (ADX-N05, R228060, or YKP10A).
19. Current or past (within the past 2 years) diagnosis of a moderate or severe substance use disorder according to DSM-5 criteria.
20. Nicotine dependence that has an effect on sleep (e.g., a subject who routinely awakens at night to smoke).
21. Current, past (within the past 2 years), or seeking treatment for a substance related disorder.
22. Urine drug screen positive for an illicit drug of abuse (including cannabinoids) at screening or at any point throughout the duration of the study, except for a prescribed drug (e.g., amphetamine) at screening.
23. History of phenylketonuria (PKU) or history of hypersensitivity to phenylalanine-derived products.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Co-primary Efficacy Endpoints:
• MWT: Change in the mean sleep latency time (in minutes) as determined from the first four trials of a 40 minute MWT from the end of the Stable Dose Phase (Week 4) to the end of the Double-blind Withdrawal Phase (Week 6)
• ESS: Change in ESS score from the end of the Stable Dose Phase (Week 4) to the end of the Double-blind Withdrawal Phase (Week 6)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Evaluation will be made at weeks 4 and 6 |
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| E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Endpoint:
• PGIc: Percentage of subjects reported as worse (minimally, much, or very much) on the PGIc at the end of the Double-blind Withdrawal Phase (Week 6)
Additional Secondary Endpoints
• CGIc: Percentage of subjects reported as worse (minimally, much, or very much) on the CGIc at the end of the Double-blind Withdrawal Phase (Week 6)
• FOSQ-10: Change in the total score from the beginning of the Titration Phase (Day 1) to the end of the Stable Dose Phase (Week 4) and from the end of the Stable Dose Phase (Week 4) to the end of the Double-blind Withdrawal Phase (Week 6)
Exploratory Endpoints
• Change in the frequency of use of primary OSA therapy from the beginning of the Titration Phase (Day -1) to the end of the Stable Dose Phase (Week 4) and from the end of the Stable Dose Phase (Week 4) to the end of the Double-blind Withdrawal Phase (Week 6)
• Change in PSG parameters including total sleep time (TST), time in Stages N1, N2, N3, wake after sleep onset (WASO), number of awakenings, AI, AHI, central apneas, SaO2 nadir, and SaO2 mean from the end of the Stable Dose Phase (Week 4) to the end of the Double-blind Withdrawal Phase (Week 6)
Safety Endpoints
To evaluate the safety and tolerability evaluations as determined by the occurrence of and/or changes in:
• Treatment-emergent adverse events
• Change in clinical laboratory tests (chemistry, hematology, and urinalysis)
• Vital signs
• 12-lead electrocardiograms (ECGs)
• Physical examination
• C-SSRS
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Evaluation will be made at weeks 4 and 6 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Finland |
| France |
| Germany |
| Sweden |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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