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The purpose of this study is to evaluate the tolerability, safety, pharmacokinetics (PK, or amount of drug over time in the body) and pharmacodynamics (PD, or effects on the body) of ACT-541468 following multiple ascending doses in healthy adults and following single ascending doses in healthy elderly subjects when administered in the morning. The safety, PK and PD of ACT-541468 will also be assessed after repeated evening administration of a selected dose in both healthy adults and elderly.
In the first-in-man study, single doses of ACT-541468 administered in healthy young adults were well tolerated up to the dose level of 200 mg (inclusive) and yielded results compatible with possible sleep facilitating effects of ACT-541468. So the present study aimed to further investigate the effects of ACT-541468 after multiple ascending doses in healthy young subjects as well as after single ascending doses in elderly subjects (morning administrations). The effects of repeated administrations of a selected dose administered in the evening in both healthy adults and elderly, will also be investigated.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part A: ACT-541468 multiple ascending doses | Experimental | Six young adults will receive ACT-541468 in the morning from Day 1 to Day 5 at each dose level in a sequential manner (total number of subjects = 18). Planned dose levels are 10, 25 and 75 mg per day |
|
| Part A: Placebo | Placebo Comparator | For each ACT-541468 dose level tested in Part A, 2 young adults will receive matching placebo in the same conditions (total number of subjects = 6) |
|
| Part B: ACT-541468 single ascending doses | Experimental | Six elderly will receive ACT-541468 in the morning of Day 1 at each dose level in a sequential manner (total number of subjects = 18). Planned dose levels are 5, 15 and 25 mg |
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| Part B: Placebo | Placebo Comparator | For each ACT-541468 dose level tested in Part B, 2 elderly will receive matching placebo in the same conditions (total number of subjects = 6) |
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| Part C: repeated dose of ACT-541468 | Experimental | Sixteen young adults and eight elderly will receive ACT-541468 (planned dose: 25 mg) in the evening for 7 days (8 days for 6 of the 16 young adults). |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| ACT-541468 (hydrochloride salt) | Drug | Hard-gelatin capsules (strength: 5 mg and 25 mg) |
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| Measure | Description | Time Frame |
|---|---|---|
| Number of participants with Adverse Events (AEs) | Treatment emergent adverse events and treatment emergent serious adverse events will be evaluated throughout the study | up to 72 hours post dosing |
| Changes from baseline in ECG variables and vital signs (heart rate and blood pressure) | 12-lead electrocardiogram variables including RR, PR, QRS, QT and QTc intervals at scheduled time points during Parts A, B and C | up to 72 hours post dosing |
| Changes from baseline in clinical laboratory parameters | Laboratory tests including hematology, blood chemistry and urinalysis at scheduled time points during PArts A, B and C | up to 72 hours post dosing |
| Measure | Description | Time Frame |
|---|---|---|
| Maximum plasma concentration (Cmax) of ACT-541468 after daytime and bedtime intake | Cmax will be determined after single (Parts A and B) and multiple morning doses (Part A) as well as after repeated evening doses to identify the nighttime PK profile (Part C) | Part A: Day 1 and Day 5; Part B: Day 1; Part C: evening of Day 8 (pre-dose) and Day 9 (nighttime samples) |
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Inclusion Criteria:
Exclusion Criteria:
Principal exclusion criteria common to young adults and elderly:
Exclusion criteria for young adults only:
Exclusion criteria for elderly only:
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| Name | Affiliation | Role |
|---|---|---|
| Clemens Mühlan, MSc | Actelion | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Investigator Site | Leiden | Netherlands |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31642731 | Derived | Muehlan C, Boehler M, Brooks S, Zuiker R, van Gerven J, Dingemanse J. Clinical pharmacology of the dual orexin receptor antagonist ACT-541468 in elderly subjects: Exploration of pharmacokinetics, pharmacodynamics and tolerability following single-dose morning and repeated-dose evening administration. J Psychopharmacol. 2020 Mar;34(3):326-335. doi: 10.1177/0269881119882854. Epub 2019 Oct 23. |
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| Part C: Placebo | Placebo Comparator | Four young adults and 2 elderly will receive matching placebo in the same conditions as subjects receiving the active compound in Part C |
|
| ACT-541468 (free base) | Drug | Soft capsules (strength: 25 mg) |
|
| Placebo | Drug | Placebo capsules matching the ACT-541468 formulations |
|
| Time to reach Cmax (tmax) of ACT-541468 after daytime and bedtime intake | tmax will be determined after single (Parts A and B) and multiple morning doses (Part A) as well as after repeated evening doses to identify the nighttime PK profile (Part C) | Part A: Day 1 and Day 5; Part B: Day 1; Part C: evening of Day 8 (pre-dose) and Day 9 (nighttime samples) |
| Terminal half-life [t(1/2)] after daytime and bedtime intake | t(1/2) will be determined after single (Parts A and B) and multiple morning doses (Part A) as well as after repeated evening doses (Part C) | Part A: Days 1 and 5, from pre-dose up to 72 h post-dose; Part B: Day 1, at pre-dose up to 72 h post-dose; Part C: from the morning of Day 8 up to 60 h post-dose and from the evening of Day 8 (pre-dose) until 36 h post-dose (with nighttime samples) |
| Areas under the plasma concentration-time curves [AUC(0-8), AUC(0-24)] of ACT-541468 after daytime and bedtime intake | AUC from time 0 to 8 hours after study drug administration [AUC(0--8)] and from time 0 to 24 hours after study drug administration [AUC(0--24)] will be determined after single (parts A and B) and multiple morning doses (Part A) as well as after multiple evening doses (Part C) | Part A: Days 1 and 5, from pre-dose up to 72 h post-dose; Part B: Day 1, at pre-dose up to 72 h post-dose; Part C: from the morning of Day 8 up to 60 h post-dose and from the evening of Day 8 (pre-dose) until 36 h post-dose (with nighttime samples) |
| Areas under the plasma concentration-time curves [AUC(0-t), AUC(0-inf)] of ACT-541468 after daytime and bedtime intake | AUC from time 0 to infinity [AUC(0--inf], AUC from time 0 to time of the last measured concentration above the limit of quantification [AUC(0--t)] will be determined after single (Part B) and multiple morning doses (Part A) as well as after multiple evening doses (Part C) | Part A: Day 5, from pre-dose up to 72 h post-dose; Part B: Day 1, at pre-dose up to 72 h post-dose; Part C: from the morning of Day 8 up to 60 h post-dose and from the evening of Day 8 (pre-dose) until 36 h post-dose (with nighttime samples) |
| Sedation as measured by saccadic peak velocity | saccadic eye movements (SEM) will be recorded by electrooculography and the average values of saccadic peak velocity of the SEM will be used as parameter of sedation | Part A: Day 1 and Day 5; Part B: Day 1; Part C: Day 2 and Day 14 |
| Visual motor coordination | Visual motor coordination will be assessed with the adaptive tracking test and the average tracking performance will be used as parameter of coordination | Part A: Day 1 and Day 5; Part B: Day 1; Part C: Day 2 and Day 14 |
| Change from baseline in body sway | Body sway will be assessed using a body sway meter | Part A: Day 1 and Day 5; Part B: Day 1; Part C: Day 2 and Day 14 |
| Change from baseline in subjective cognitive effects | Subjects will rate sleepiness, alertness and mood using questionnaires | Part A: every day from Day 1 to Day 6; Part B: Day 1; Part C: Day 1 to Day 8 |
| ID | Term |
|---|---|
| D007319 | Sleep Initiation and Maintenance Disorders |
| ID | Term |
|---|---|
| D020919 | Sleep Disorders, Intrinsic |
| D020920 | Dyssomnias |
| D012893 | Sleep Wake Disorders |
| D009422 | Nervous System Diseases |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| C000634383 | daridorexant |
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