A Study to Evaluate the Pharmacokinetics of ACT-541468 in Subjects With Mild, Moderate, and Severe Hepatic Impairment

A Single-center, Open-label, Single-dose, Phase 1 Study to Evaluate the Pharmacokinetics of ACT-541468 in Subjects With Mild, Moderate, and Severe Hepatic Impairment

This is a prospective, single-center, open-label, single-dose, Phase 1 study, to assess the effect of mild, moderate, and severe hepatic impairment due to liver cirrhosis on the pharmacokinetics of ACT-541468.

Study Overview

• Status: Completed
• Conditions: Hepatic Impairment
• Intervention / Treatment: Drug: ACT-541468 25 mg; Drug: ACT-541468 25 mg (or 10 mg depending on interim results)

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • Basel, Switzerland, 4031
    • University Hospital Basel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed informed consent prior to any study-mandated procedure.
• Male and female subjects aged between 18 and 75 years (inclusive) at screening.
• Women of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test on Day -1. They must consistently and correctly use (from screening, during the entire study, and for at least one month after last study treatment intake) a highly effective method of contraception, be sexually inactive, or have a vasectomized partner.
• Women of non-childbearing potential.
• Body mass index of 18.0 to 35.0 kg/m2 (inclusive) at screening.

• For healthy subjects: Normal renal function confirmed by a creatinine clearance at screening according to Cockroft and Gault adjusted to age of:

  1. ≥ 80 mL/min/1.73 m2 for subjects ≤ 50 years of age.
  2. ≥ 70 mL/min/1.73 m2 for subjects 51-60 years of age.
  3. ≥ 60 mL/min/1.73 m2 for subjects 61-75 years of age.

• For subjects with hepatic impairment: Degree of liver function impairment due to liver cirrhosis according to the Child-Pugh classification:

  1. Group A: Mild hepatic impairment, Child-Pugh score 5-6.
  2. Group B: Moderate hepatic impairment, Child-Pugh score 7-9.
  3. Group C: Severe hepatic impairment, Child-Pugh score 10-15.

Exclusion Criteria:

• Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.
• For subjects with hepatic impairment: History of major medical or surgical disorders, which, in the opinion of the investigator, are likely to interfere with the absorption, distribution, metabolism, or excretion of the study treatment except for those related to liver cirrhosis (appendectomy and herniotomy allowed, cholecystectomy not allowed).

• For healthy subjects:

  1. History of alcoholism or drug abuse within the 3-year period prior to screening.
  2. Relevant history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: NON_RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Group A: ACT-541468 in subjects with mild hepatic impairment; Single oral dose administered on Day 1.	Drug: ACT-541468 25 mg; Administered as a tablet.
EXPERIMENTAL: Group B: ACT-541468 in subj. with moderate hepatic impairment; Single oral dose administered on Day 1.	Drug: ACT-541468 25 mg (or 10 mg depending on interim results); Administered as a tablet.
EXPERIMENTAL: Group C: ACT-541468 in subjects with severe hepatic impairment; Single oral dose administered on Day 1.	Drug: ACT-541468 25 mg (or 10 mg depending on interim results); Administered as a tablet.
EXPERIMENTAL: Group D: ACT-541468 in healthy subjects.; Single oral dose administered on Day 1.	Drug: ACT-541468 25 mg (or 10 mg depending on interim results); Administered as a tablet.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Treatment-emergent adverse events (AEs)	From study treatment administration up to EOS (duration: up to 4 days)
Treatment-emergent serious adverse events (SAEs)	From study treatment administration up to EOS (duration: up to 4 days)

Other Outcome Measures

Outcome Measure	Time Frame
Plasma pharmacokinetics: AUC(0-t)	At various timepoints (duration: up to 4 days)
Plasma pharmacokinetics: AUC(0-inf)	At various timepoints (duration: up to 4 days)
Plasma pharmacokinetics: AUC(0-24)	At various timepoints (duration: up to 4 days)
Plasma pharmacokinetics: Cmax	At various timepoints (duration: up to 4 days)
Plasma pharmacokinetics: Tmax	At various timepoints (duration: up to 4 days)
Plasma pharmacokinetics: T1/2	At various timepoints (duration: up to 4 days)
Plasma pharmacokinetics: Cu/C (extent of plasma protein binding)	At various timepoints (duration: up to 4 days)

Collaborators and Investigators

• Sponsor: Idorsia Pharmaceuticals Ltd.

Publications and helpful links

General Publications

• Berger B, Dingemanse J, Sabattini G, Delahaye S, Duthaler U, Muehlan C, Krahenbuhl S. Effect of Liver Cirrhosis on the Pharmacokinetics, Metabolism, and Tolerability of Daridorexant, A Novel Dual Orexin Receptor Antagonist. Clin Pharmacokinet. 2021 Oct;60(10):1349-1360. doi: 10.1007/s40262-021-01028-8. Epub 2021 May 18.

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 26, 2018
• Primary Completion (ACTUAL): February 27, 2020
• Study Completion (ACTUAL): February 27, 2020

Study Registration Dates

• First Submitted: October 18, 2018
• First Submitted That Met QC Criteria: October 18, 2018
• First Posted (ACTUAL): October 19, 2018

Study Record Updates

• Last Update Posted (ACTUAL): July 2, 2020
• Last Update Submitted That Met QC Criteria: July 1, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases
• Other Study ID Numbers: ID-078-112

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No