A Study to Investigate the Safety, Tolerability, Pharmacokinetics (PK), and Pharmacodynamics (PD) of ACT-541468 in Healthy Young Adults and Elderly Subjects

NCT02571855 | Completed Phase 1

• 1 other identifier: AC-078-102
• Study Type: interventional
• Target: 85
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy Subjects

Keywords

insomnia; Pharmacokinetics; Safety; Pharmacodynamics; Healthy

Outcome Measures

Primary Outcomes (3)

• 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

Secondary Outcomes (9)

• Maximum plasma concentration (Cmax) of ACT-541468 after daytime and bedtime intake

  Part A: Day 1 and Day 5; Part B: Day 1; Part C: evening of Day 8 (pre-dose) and Day 9 (nighttime samples)

• Time to reach Cmax (tmax) of ACT-541468 after daytime and bedtime intake

  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

  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

  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

  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)

Study Arms (6)

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

Drug: ACT-541468 (hydrochloride salt)

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)

Drug: Placebo

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

Drug: ACT-541468 (hydrochloride salt)

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)

Drug: Placebo

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).

Drug: ACT-541468 (free base)

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

Drug: Placebo

Interventions

ACT-541468 (hydrochloride salt) DRUG

Hard-gelatin capsules (strength: 5 mg and 25 mg)

Part A: ACT-541468 multiple ascending doses; Part B: ACT-541468 single ascending doses

ACT-541468 (free base) DRUG

Soft capsules (strength: 25 mg)

Part C: repeated dose of ACT-541468

Placebo DRUG

Placebo capsules matching the ACT-541468 formulations

Part A: Placebo; Part B: Placebo; Part C: Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

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

Sponsors & Collaborators

• Idorsia Pharmaceuticals Ltd.: lead

Study Sites (1)

Investigator Site

Leiden, Netherlands

Location

Related Publications (1)

• 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.

  PMID: 31642731 DERIVED

MeSH Terms

Conditions

Sleep Initiation and Maintenance Disorders

Interventions

daridorexant

Condition Hierarchy (Ancestors)

Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases; Mental Disorders

Study Officials

• Clemens Mühlan, MSc

  Actelion

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 2, 2015
• First Posted: October 8, 2015
• Study Start: October 1, 2015
• Primary Completion: February 1, 2016
• Study Completion: February 1, 2016
• Last Updated: July 10, 2018

Record last verified: 2018-07

Locations

NL (1)