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

Hepatic Impairment Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03686995
• Other study ID #: 2018-01674;me18Kraehenbuehl
• Status: Not yet recruiting
• Phase: Phase 1
• Start date: November 5, 2018
• Est. completion date: June 1, 2019

Study information

• Verified date: October 2018
• Source: University Hospital, Basel, Switzerland
• Contact: Stephan Krähenbühl, Prof.,MD,Dr.
• Phone: +41 61 26547 35
• Email: Stephan.Kraehenbuehl[@]usb.ch
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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 (PK) of ACT-541468

Description:

Orexin receptor antagonist ACT-541468 is being evaluated for the treatment of insomnia disorders. This phase 1 study evaluates the effect of hepatic impairment on the Pharmacokinetics (PK) of ACT-541468.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 32
• Est. completion date: June 1, 2019
• Est. primary completion date: June 1, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Signed informed consent in a language understandable to the subject prior to any study-mandated procedure.

• 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 with a failure rate of ? 1% per year, be sexually inactive, or have a vasectomized Partner. If a hormonal contraceptive is used, it must have been initiated at least 1 month before treatment administration.

• Women of non-childbearing potential (i.e., postmenopausal [defined as 12 consecutive months with no menses without an alternative medical cause, confirmed by a follicle stimulating hormone (FSH) test], with previous bilateral salpingectomy, bilateral salpingo oophorectomy or hysterectomy, or with premature ovarian failure [confirmed by a specialist], XY genotype, Turner syndrome, uterine agenesis).

• Body mass index (BMI) of 18.0 to 35.0 kg/m2 (inclusive) at screening.

• Ability to communicate well with the investigator, in a language understandable to the subject, and to understand and comply with the requirements of the study.

• Normal renal function confirmed by a creatinine clearance at screening according to Cockroft & Gault adjusted to age of:

• = 80 mL/min/1.73 m2 for subjects = 50 years of age.

• = 70 mL/min/1.73 m2 for subjects 51-60 years of age.

• = 60 mL/min/1.73 m2 for subjects 61-75 years of age.

• 12-lead ECG without clinically relevant abnormalities, measured after 5 min in the supine position at screening.

• Negative results from urine drug screen and urine alcohol tests at screening and on Day -1.

Study-specific criteria for subjects with hepatic impairment

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

• Group A: Mild hepatic impairment, Child-Pugh score 5-6.

• Group B: Moderate hepatic impairment, Child-Pugh score 7-9.

• Group C: Severe hepatic impairment, Child-Pugh score 10-15. Child-Pugh score will be based on screening laboratory test results for bilirubin, serum albumin, Prothrombin time (PT), and the stage of hepatic encephalopathy, with or without ascites. Laboratory tests results obtained > 10 days before Day -1 must be reconfirmed.

• No clinically relevant findings in clinical laboratory tests (hematology, coagulation, clinical chemistry, and urinalysis) at screening and on Day -1 except for those related to liver cirrhosis.

• International normalized ratio (INR) ?5 at screening.

• Stable concomitant medications for at least 3 weeks prior to screening and up to Day 1 and expected to be stable during the conduct of the study.

• Systolic blood pressure (SBP) 95-180 mmHg, diastolic blood pressure (DBP) 50-105 mmHg, and pulse rate 45-100 beats per minute [bpm] (inclusive), measured on the dominant arm, after 5 min in the supine position at screening and on Day 1 pre-dose.

Additional criteria for healthy subjects

• Healthy subjects (Group D) individually matched to the group with the most severe hepatic impairment with regard to age (± 10 years difference allowed), both body weight and height (± 15 % difference allowed), and sex at screening.

• No clinically relevant findings on the physical examination at screening.

• No clinically relevant findings in clinical laboratory tests (hematology, coagulation, clinical chemistry, and urinalysis) at screening and on Day -1.

• SBP 100-145 mmHg, DBP 50-90 mmHg, and pulse rate 45-95 bpm (inclusive), measured on the dominant arm, after 5 min in the supine position at screening and on Day 1 pre-dose.

Exclusion Criteria:

General criteria for all subjects

• Known hypersensitivity to any excipients of the drug formulation.

• Veins unsuitable for intravenous puncture on either arm (e.g., veins that are difficult to locate, access, or puncture, veins with a tendency to rupture during or after puncture).

• Participation in a clinical study involving study treatment administration within 3 months prior to screening or in more than 4 clinical studies within 1 year prior to screening.

• Disease of the Central nervous system (CNS) (such as epilepsy, seizures), psychiatric disorders or neurological disorders.

• Chronic symptoms of pronounced constipation or diarrhea.

• Pregnant or lactating women.

• Excessive caffeine consumption, defined as 800 mg per day at screening.

• Inability to comply with smoking restrictions of the study site.

• Use of drugs which might reasonably influence results of the trial within 2 weeks prior to administration or during the trial. Comedication known to inhibit or induce CYP3A4 is not allowed.

• Loss of 250 mL or more of blood within 3 months prior to screening.

• Modified Swiss Narcolepsy Scale total score < 0 at screening or history of narcolepsy or cataplexy.

• Symptoms of a clinically relevant illness in the 4-week period preceding screening (e.g., bacterial, viral, or fungal infection).

• Positive results from the HIV serology at screening.

• Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.

• Legal incapacity or limited legal capacity at screening.

Study-specific criteria for subjects with liver 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).

• History, clinical evidence or suspicion of a hepatocellular carcinoma (HCC).

• Subjects with clinical evidence or suspected acute liver failure as judged by the investigator.

• Serum ammonia level > 200 µg/dL at screening or on Day -1.

• Gastrointestinal bleeding within the 2 weeks prior to the screening examination.

• Severe ascites and/or pleural effusion.

• Unstable disease making changes in concomitant medication probable, e.g., severe cardiac or renal organic disease or recurrent bleeding.

• Myocardial infarction within the 3 months prior to the screening visit.

• History of stroke (cerebral vascular accident) or indications of a clinically relevant stenosis of the vessels supplying the brain within the 6 months prior to the screening visit.

• History of heart, kidney or liver transplantation.

• Encephalopathy grade > 2.

• Clinical evidence of current alcoholism or drug abuse. Alcohol abuse is defined as regular intake of more than 60 g/day in males and more than 40 g/day in females.

• History or presence of rhythm disorders (e.g., sinoatrial heart block, sick-sinus syndrome, second- or third-degree atrioventricular block, long QT syndrome, symptomatic bradycardia, atrial flutter, or atrial fibrillation).

Additional criteria for healthy subjects

• History of alcoholism or drug abuse within the 3-year period prior to screening.

• Relevant history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions.

• Positive results from the hepatitis serology, except for vaccinated subjects or subjects with past but resolved hepatitis, at screening.

• Previous treatment with any prescribed medications (including vaccines) or over-the-counter (OTC) medications (including herbal medicines such as St John's Wort, homeopathic preparations, vitamins, and minerals) within 3 weeks or 5 half-lives (t½, whichever is longer) prior to first study treatment administration.

• History or clinical evidence of any disease and/or existence of any surgical or medical condition which might interfere with the absorption, distribution, metabolism or excretion of the study drug (e.g., appendectomy and herniotomy allowed, cholecystectomized subjects excluded).

Related Conditions & MeSH terms

• Hepatic Impairment
• Liver Diseases

Intervention

Drug:
• ACT-541468
single oral dose of 25 mg ACT-541468

Locations

Country	Name	City	State
Switzerland	University Hospital Basel, Division of Clinical Pharmacology & Toxicology	Basel

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Basel, Switzerland	Idorsia Pharmaceuticals Ltd.

Country where clinical trial is conducted

Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area under the plasma concentration-time curve (AUC) from time zero to time t of the last measured concentration above the limit of quantification (AUC0-t).	To assess the effect of mild, moderate, and severe hepatic impairment due to liver cirrhosis on the PK of ACT-541468 after administration of a single oral dose of ACT-541468 compared to healthy subjects.	Blood draw at 0 minutes, 15 minutes, 30 minutes,1 hour,1.5 hours (h), 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h,12 h, 24 h and 48 h after intake of ACT-541468
Secondary	time to reach plasma Cmax (tmax)	To assess the effect of mild, moderate, and severe hepatic impairment due to liver cirrhosis on the PK of ACT-541468 after administration of a single oral dose of ACT-541468 compared to healthy subjects.	Blood draw at 0 minutes, 15 minutes, 30 minutes,1 hour,1.5 hours (h), 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h,12 h, 24 h and 48 h after intake of ACT-541468
Secondary	maximum plasma concentration (Cmax)	To assess the effect of mild, moderate, and severe hepatic impairment due to liver cirrhosis on the PK of ACT-541468 after administration of a single oral dose of ACT-541468 compared to healthy subjects.	Blood draw at 0 minutes, 15 minutes, 30 minutes,1 hour,1.5 hours (h), 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h,12 h, 24 h and 48 h after intake of ACT-541468
Secondary	terminal elimination half-life (t½)	To assess the effect of mild, moderate, and severe hepatic impairment due to liver cirrhosis on the PK of ACT-541468 after administration of a single oral dose of ACT-541468 compared to healthy subjects.	Blood draw at 0 minutes, 15 minutes, 30 minutes,1 hour,1.5 hours (h), 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h,12 h, 24 h and 48 h after intake of ACT-541468
Secondary	ratio of free to plasma protein-bound concentrations (Cu/C) for ACT-541468 at 1.5 h post-dose	To assess the effect of mild, moderate, and severe hepatic impairment due to liver cirrhosis on the PK of ACT-541468 after administration of a single oral dose of ACT-541468 compared to healthy subjects.	Blood draw at 1.5 hours (h) after intake of ACT-541468