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

Healthy Subjects Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02571855
• Other study ID #: AC-078-102
• Status: Completed
• Phase: Phase 1
• Start date: October 1, 2015
• Est. completion date: February 1, 2016

Study information

• Verified date: July 2018
• Source: Idorsia Pharmaceuticals Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 85
• Est. completion date: February 1, 2016
• Est. primary completion date: February 1, 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Healthy Subjects

Intervention

Drug:
• ACT-541468 (hydrochloride salt)
Hard-gelatin capsules (strength: 5 mg and 25 mg)
• ACT-541468 (free base)
Soft capsules (strength: 25 mg)
• Placebo
Placebo capsules matching the ACT-541468 formulations

Locations

Country	Name	City	State
Netherlands	Investigator Site	Leiden

Sponsors (1)

Lead Sponsor	Collaborator
Idorsia Pharmaceuticals Ltd.

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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