Clinical trial NCT02571855: A Study to Investigate the Safety, Tolerability, Pharmacokinetics (PK), and Pharmacodynamics (PD) of ACT-541468 in Healthy Young Adults and Elderly Subjects
Official title: Double-blind, Placebo-controlled, Randomized Study to Investigate the Tolerability, Safety, Pharmacokinetics, and Pharmacodynamics of ACT-541468: Part A: Multiple-ascending Doses in Healthy Young Adults After Morning Administration Part B: Single-ascending Doses in Healthy Elderly Subjects After Morning Administration Part C: Repeated Doses in Both Healthy Young Adults and Elderly Subjects After Evening Administration
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Subjects
Keywords: insomnia
Pharmacokinetics
Safety
Pharmacodynamics
Healthy
Lead sponsor: Idorsia Pharmaceuticals Ltd.
Sponsor class: INDUSTRY
First posted: 2015-10-08
Enrollment: 85
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Signed informed consent.
* Adults aged from 18 to 45 years (inclusive) for Part A; elderly aged from 65 to 80 years (inclusive) for Part B; both adults from 18 to 45 years and elderly from 65 to 80 years (inclusive) for Part C.
* Regular sleep pattern of at least 6 hours nocturnal sleep.
* Young females must have negative pregnancy tests at screening and at pre-dose on Day 1 and use a reliable method of contraception
* Body mass index (BMI) between 18.0 and 30.0 kg/m2 (inclusive) at screening.
* Systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate (PR) between 100-145 mmHg, 50-90 mmHg and 45-90 bpm (all inclusive) for young adults, respectively; SBP, DBP and PR between 100-160 mmHg, 50-95 mmHg and 45-100 bpm (all inclusive) for elderly, respectively.
* Healthy on the basis of physical examination,electrocardiogram and laboratory tests.

Exclusion Criteria:

Principal exclusion criteria common to young adults and elderly:

* Pregnant or lactating women.
* Any contraindication to the study drugs.
* History or presence of any disease or condition or treatment, which may put the subject at risk of participation in the study or may interfere with the absorption, distribution, metabolism or excretion of the study drugs.
* History of narcolepsy or cataplexy or modified Swiss narcolepsy scale total score \< 0 at screening.
* Any circumstances or conditions, which, in the opinion of the investigator, may affect the subject's full participation in the study or compliance with the protocol.

Exclusion criteria for young adults only:

* Treatment with any prescribed medications or over-the-counter medications within 2 weeks prior to study drug administration.

Exclusion criteria for elderly only:

* Previous chronic treatment with any medication that is not given in stable doses and/or stable regimen within 2 months prior to screening.
* Previous treatment with CNS-active drugs or within 2 months prior to screening.
* Treatment with inhibitors of CYP3A4 (e.g., azole derivatives, ritonavir, clarithromycin) from 2 weeks prior to screening visit and up to EOS.

Primary outcomes:
measure: Number of participants with Adverse Events (AEs)
timeFrame: up to 72 hours post dosing
measure: Changes from baseline in ECG variables and vital signs (heart rate and blood pressure)
timeFrame: up to 72 hours post dosing
measure: Changes from baseline in clinical laboratory parameters
timeFrame: up to 72 hours post dosing
Secondary outcomes:
measure: Maximum plasma concentration (Cmax) of ACT-541468 after daytime and bedtime intake
timeFrame: Part A: Day 1 and Day 5; Part B: Day 1; Part C: evening of Day 8 (pre-dose) and Day 9 (nighttime samples)
measure: Time to reach Cmax (tmax) of ACT-541468 after daytime and bedtime intake
timeFrame: Part A: Day 1 and Day 5; Part B: Day 1; Part C: evening of Day 8 (pre-dose) and Day 9 (nighttime samples)
measure: Terminal half-life [t(1/2)] after daytime and bedtime intake
timeFrame: 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)
measure: Areas under the plasma concentration-time curves [AUC(0-8), AUC(0-24)] of ACT-541468 after daytime and bedtime intake
timeFrame: 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)
measure: Areas under the plasma concentration-time curves [AUC(0-t), AUC(0-inf)] of ACT-541468 after daytime and bedtime intake
timeFrame: 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)
measure: Sedation as measured by saccadic peak velocity
timeFrame: Part A: Day 1 and Day 5; Part B: Day 1; Part C: Day 2 and Day 14
measure: Visual motor coordination
timeFrame: Part A: Day 1 and Day 5; Part B: Day 1; Part C: Day 2 and Day 14
measure: Change from baseline in body sway
timeFrame: Part A: Day 1 and Day 5; Part B: Day 1; Part C: Day 2 and Day 14
measure: Change from baseline in subjective cognitive effects
timeFrame: Part A: every day from Day 1 to Day 6; Part B: Day 1; Part C: Day 1 to Day 8
Other outcomes:
Locations:
city: Leiden
country: Netherlands
facility: Investigator Site
Study officials:
affiliation: Actelion
name: Clemens Mühlan, MSc
role: STUDY_DIRECTOR
References:
citation: 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.