E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Impaired cognitive function in patients with excessive daytime sleepiness associated with obstructive sleep apnea |
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E.1.1.1 | Medical condition in easily understood language |
Impaired ability to understand, think and reason, in patients who have excessive daytime sleepiness due to their obstructive sleep apnoea (OSA - stopping breathing for short periods whilst sleeping) |
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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 | 21.1 |
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 solriamfetol on cognitive function in adult participants with EDS associated with OSA plus impaired cognitive functioning |
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E.2.2 | Secondary objectives of the trial |
To further evaluate the efficacy of solriamfetol on cognitive function in adult participants with EDS associated with OSA plus impaired cognitive functioning |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Age and Sex 1. Male or female between 18 (or the legal age of consent in the jurisdiction in which the study takes place) and 65 years of age, inclusive. Type of Participant and Disease Characteristics 2. Diagnosis of OSA according to International Classification of Sleep Disorders, Third Edition criteria. 3. Participant report (with clinician concurrence) of at least 1 of the following primary OSA therapy criteria: • Consistent number of hours of primary PAP therapy use (with downloadable history) for OSA on at least 5 nights/week for at least 1 month prior to Baseline (with or without prior OSA surgical intervention), OR • No current use of PAP therapy for at least 1 month prior to Baseline but a history of at least 1 month of attempting to use PAP as the primary OSA therapy with at least 1 documented adjustment that was made in an attempt to optimize the therapy (with or without prior OSA surgical intervention), OR • History of a surgical intervention intended to treat OSA symptoms (with or without current PAP use as primary OSA therapy). 4. The participant has an age-corrected scaled score ≤ 8 on the DSST Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) at the Screening visit. 5. British Columbia-Cognitive Complaints Inventory ≥ 9 at Screening and Baseline. 6. Epworth Sleepiness Scale (ESS) score > 10 at Screening and Baseline. 7. Usual nightly total sleep time of ≥ 6 hours. Weight 8. Body mass index from 18.5 to < 40 kg/m2. Sex and Contraceptive/Barrier Requirements 9. Male and female Participants a. Male participants: Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 14 days after the last dose of study intervention: • Refrain from donating sperm PLUS, either: • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent OR • Must agree to use contraception/barrier as detailed below • Agree to use a male condom with female partner use of an additional highly effective contraceptive method with a failure rate of < 1% per year as described in Appendix 5 Contraceptive and Barrier Requirements when having sexual intercourse with a women of childbearing potential (WOCBP) who is not currently pregnant. b. Female participants: • A female participant is eligible to participate if she is not pregnant or breastfeeding, and 1 of the following conditions applies: − Is a woman of nonchildbearing potential (WONCBP) as defined in Appendix 5 Contraceptive and Barrier Guidance OR − Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), as described in 0 Contraceptive and Barrier Guidance during the study intervention period and for at least 14 days after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study intervention. • A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within the Screening/Baseline period (once at the time of Screening for participation in the study and again at the time of the study Baseline assessment) before the first dose of study intervention, see Section 8.4.5 Pregnancy Testing. • Additional requirements for pregnancy testing during and after study intervention are located in Section 8.4.5. • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. Informed Consent 10. Capable of giving signed informed consent as described in Section 10.1.3, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. |
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E.4 | Principal exclusion criteria |
1. Female participants who are pregnant, nursing, or lactating. 2. Usual bedtime later than 1 AM (0100 hours). 3. Occupation requiring nighttime or variable shift work. 4. Unable to understand or perform DSST test per investigator’s judgement. 5. Use a PAP machine with no adherence data downloadable ability. 6. Diagnosis of another sleep disorder (other than OSA) including: circadian rhythm sleep disorders, narcolepsy, restless legs syndrome determined by participant sleep history. 7. Presence of acutely unstable major depression or current major depressive episode as based on the judgement of the investigator. 8. Participants with active clinically significant illness, including endocrine, neoplastic, gastrointestinal, hematological, hepatic, immunologic, metabolic, neurological, pulmonary, and/or renal disease, and/or surgical history which could interfere with the study efficacy, safety, conduct or the ability of the participant to complete the study based on the judgement of the investigator, or place the participant at risk during the trial or compromise the study objectives. 9. History or presence of any other clinically relevant medical, behavioral, or psychiatric disorder other than OSA that is associated with an impact on cognitive function; including history or presence of neurodegenerative condition (eg, mild cognitive impairment due to Alzheimer’s), autism, vascular dementia, active suicidal ideation, that could affect the safety of the participant or interfere with study efficacy, safety, conduct or the ability of the participant to complete the trial based on the judgment of the investigator. 10. History or presence of bipolar disorder, bipolar related disorders, schizophrenia, schizophrenia spectrum disorders, or other psychotic disorders according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. 11. History of bariatric surgery within the past year or a history of any gastric bypass procedure. 12. Participants with movement or motor disorders such as Parkinson’s disease, as they will not be able to complete the DSST. 13. Presence of renal impairment or calculated creatinine clearance < 60 mL/minute. 14. Clinically significant ECG abnormality in the opinion of the investigator. 15. Presence of significant cardiovascular disease including but not limited to: myocardial infarction within the past year, unstable angina pectoris, symptomatic congestive heart failure (ACC/American Heart Association stage C or D), revascularization procedures within the past year, uncontrolled atrial fibrillation, ventricular cardiac arrhythmias requiring automatic implantable cardioverter defibrillator or medication therapy, uncontrolled hypertension (as defined by Centers for Disease Control and Prevention), systolic blood pressure ≥ 155 mmHg or diastolic blood pressure ≥ 95 mmHg (at Screening or Baseline), or any history of cardiovascular disease or any significant cardiovascular condition that in the investigator’s opinion may jeopardize participant safety in the study. 16. Laboratory value(s) outside the laboratory reference range that is considered to be clinically significant by the investigator (clinical chemistry, hematology, and urinalysis). NOTE: Screening labs may be repeated once. 17. Hypothyroidism or hyperthyroidism, unless stabilized by appropriate medication for at least 3 months prior to Screening (a normal thyroid-stimulating hormone is required prior to Randomization at Baseline). Prior/Concomitant Therapy 18. Use of any over-the-counter (OTC) or prescription medications that could affect the evaluation of EDS within a time period prior to the Baseline visit corresponding to at least 5 half-lives of the drug(s) or planned use of such drug(s) at some point throughout the duration of the 5-week double-blind treatment period. Examples of excluded medications include OTC sleep aids, stimulants (eg methylphenidate, amphetamines, modafinil, and armodafinil), sodium oxybate, pemoline, pitolisant, bupropion, trazodone, vortioxetine, duloxetine, tricyclic antidepressants, hypnotics, benzodiazepines, pseudoephedrine, barbiturates, and opioids. Medications should be discontinued such that, in the opinion of the investigator, the participant has returned to his/her Baseline level of daytime sleepiness at least 7 days prior to the Baseline visit. 19. Current or recent (within the past 2 years) diagnosis of a moderate or severe substance use disorder (excluding caffeine) according to DSM-5 criteria, or seeking treatment for a substance-related disorder. Nicotine use disorder is excluded only if it has an effect on sleep (ie, a participant who routinely awakens at night to smoke). 25. History of phenylketonuria or history of hypersensitivity to phenylalanine-derived products. 26. Currently receiving MAO inhibitors or having had received MAO inhibitors for 14 days prior to the Baseline visit.
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E.5 End points |
E.5.1 | Primary end point(s) |
Difference in DSST means from the average of the 2- and 4-hour scores at Baseline (Visit 3) to the average of the 2- and 4-hour postdose scores (at Visit 5 and Visit 8) between solriamfetol and placebo |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
2- and 4-hour postdose scores (at Visit 5 and Visit 8) |
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E.5.2 | Secondary end point(s) |
1. Difference in overall BC-CCI score means from Baseline (Visit 3) to the end of double-blind treatment period (Visit 5 and Visit 8) between solriamfetol and placebo
2. Estimand 1: Difference in DSST means from the average of the 2-, 4-, 6-, and 8-hour scores at Baseline (Visit 3) to the average of 2-, 4-, 6-, and 8-hour scores postdose (at Visit 5 and Visit 8) between solriamfetol and placebo Estimand 2: Difference in DSST means from each of the 2-, 4-, 6-, and 8-hour DSST RBANS sores at Baseline (Visit 3) to each of the corresponding 2-, 4-, 6-, and 8-hour postdose (at Visit 5 and Visit 8) DSST RBANS scores between solriamfetol and placebo
3. Safety and tolerability evaluations will be determined by the occurrence of and/or changes in: • Incidence and severity of TEAEs • Vital signs • C-SSRS |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. End of double-blind treatment period (Visit 5 and Visit 8)
2. 2-, 4-, 6-, and 8-hour postdose (at Visit 5 and Visit 8)
3. End of the trial |
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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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 |
United States |
Italy |
Netherlands |
Spain |
United Kingdom |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
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 | 2 |