Clinical trial NCT04482270: A Study to Investigate the Effect of Mild and Moderate Hepatic Impairment on the Safety and Tolerability of Fezolinetant Compared to Participants With Normal Hepatic Function
Official title: A Phase 1 Study to Investigate the Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics, Safety and Tolerability of Fezolinetant Compared to Subjects With Normal Hepatic Function
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hepatic Impairment
Healthy Volunteers
Keywords: ES259564
Pharmacokinetics
fezolinetant
Healthy Volunteers
Hepatic Impairment
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2020-07-22
Enrollment: 26
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the pharmacokinetics of a single oral dose of fezolinetant and ES259564 (fezolinetant metabolite) in female participants with mild and moderate hepatic impairment compared to healthy female participants with normal hepatic function.

This study will also evaluate the safety and tolerability of a single oral dose of fezolinetant in female participants with mild and moderate hepatic impairment and healthy female participants with normal hepatic function.

Detailed description: The study will comprise of three groups based on hepatic function. Participants will be screened for up to 28 days prior to investigational product (IP) administration on Day 1. Eligible participants will be admitted to the clinical unit on Day -1 and will be residential for a single period of six days/five nights. On Day 1, participants will receive a single oral dose of fezolinetant under fasting conditions followed by a 96-hour in-house blood and urine sampling period. Participants are to remain semirecumbent for four hours postdose. Standard safety and tolerability assessments will be conducted. Participants will be discharged from the clinical unit on Day 5 on the condition that all required assessments have been performed and that there are no medical reasons for a longer stay in the clinical unit.

The study will be completed with an end-of-study visit (ESV). The ESV will take place five to nine days after the last pharmacokinetic sample is collected or at the time of early discontinuation from the study.

Eligibility criteria: Inclusion Criteria:

* Subject has a Body Mass Index (BMI) range of 18.5 to 36.0 kg/m\^2, inclusive and weighs at least 50 kg at screening.
* Female subject is not pregnant and at least one of the following conditions apply:

  * Not a woman of childbearing potential (WOCBP)
  * WOCBP who agrees to follow the contraceptive guidance for at least 30 days prior to day -1 through at least 30 days after IP administration.
* Female subject must agree not to breastfeed starting at screening and throughout the study period and for 30 days after IP administration.
* Female subject must not donate ova starting at first dose of IP and throughout the study period and for 30 days after IP administration.
* Subject agrees not to participate in another interventional study while participating in the present study.

Additional Criterion for Subjects with Hepatic Impairment:

* Subject has mild (Child-Pugh classification Class A, score 5 or 6) or moderate (Child-Pugh classification Class B, score 7 to 9) hepatic impairment.

Exclusion Criteria:

* Subject has received any investigational therapy within 28 days or five half-lives, whichever is longer, prior to Day -1.
* Subject has any condition which makes the subject unsuitable for study participation.
* Female subject who has been pregnant within six months prior to screening or breastfeeding within three months prior to screening.
* Subject has a known or suspected hypersensitivity to fezolinetant or any components of the formulation used.
* Subject has had previous exposure with fezolinetant.
* Subject has used any inducer of cytochrome P450 (CYP) 1A2 in the three months prior or inhibitors of CYP 1A2 in the two weeks or five half-lives of the inhibitor, whichever is longer, prior to Day -1.
* Subject has any clinically significant history of allergic conditions (including drug allergies, asthma, eczema or anaphylactic reactions, but excluding untreated, asymptomatic, seasonal allergies) prior to IP administration.
* Subject has/had febrile illness or symptomatic, viral (excluding chronic hepatitis B and C), bacterial (including upper respiratory infection) or fungal (noncutaneous) infection within one week prior to Day -1.
* Subject has smoked, used tobacco-containing products and nicotine or nicotine-containing products (e.g., electronic vapes) within six months prior to screening or the subject tests positive for cotinine at screening or on Day -1.
* Subject has had significant blood loss, donated ≥ 1 unit (450 mL) of whole blood or donated plasma within seven days prior to Day -1 and/or received a transfusion of any blood or blood products within 60 days.
* Subject is an employee of Astellas, the study-related contract research organizations (CROs) or the clinical unit.
* Subject has creatinine level outside normal limits on Day -1. In such a case, the assessment may be repeated once.

Additional Criteria for Subjects with Hepatic Impairment:

* Subject has any history or evidence of any clinically significant cardiovascular, gastrointestinal, endocrinologic, hematologic, immunologic, metabolic, dermatologic, psychiatric, renal and/or other major disease or malignancy, not related to current disease state.
* Subject has a history of consuming \> 7 units of alcoholic beverages per week within three months prior to screening or has a history of alcoholism or drug/chemical/substance abuse within one year prior to screening (note: 1 unit = 12 ounces of beer, 4 ounces of wine, 1 ounce of spirits/hard liquor) or the subject tests positive for alcohol at screening or on Day -1.
* Subject has a mean pulse \< 45 or \> 90 beats per minute (bpm); mean systolic blood pressure (SBP) \> 160 millimeters of mercury (mmHg); mean diastolic blood pressure (DBP) \> 100 mmHg (measurements taken in triplicate after subject has been resting in the supine position for at least five minutes; pulse will be measured automatically) on Day -1. If the mean blood pressure exceeds the limits above, one additional triplicate may be taken.
* Subject has a mean corrected QT interval using Fridericia's formula (QTcF) of \> 480 millisecond (msec) on Day -1. If the mean QTcF exceeds the limits above, one additional triplicate electrocardiogram (ECG) may be taken.
* Subject has used any drugs of abuse (amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine and/or opiates) within three months prior to Day -1 or the subject tests positive for drugs of abuse (amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine and opiates) at screening or on Day -1, unless the positive test is due to prescription drug use that is approved by the principal investigator and sponsor.
* Subject has a positive serology test for hepatitis A virus (HAV) antibodies (immunoglobulin M \[IgM\]) or antibodies to human immunodeficiency virus (HIV) type 1 and/or type 2 at screening.
* Subject has fluctuating or rapidly deteriorating hepatic function, as indicated by strongly varying or worsening of clinical and/or laboratory signs of hepatic impairment within the screening period (e.g., advanced ascites, infection of ascites, fever, active gastrointestinal bleeding).
* Subject who has had a change in dose regimen of medically required medication(s) in the two weeks prior to screening (permitted concomitant medications) and/or subject for whom dose changes are likely to occur during the study (minor dose changes are allowed in agreement with the sponsor) and/or subject has used nonpermitted concomitant medication(s) in the three weeks prior to admission to the clinical unit (nonpermitted concomitant medications include any known hepatic enzyme-altering agents or compounds known to restrict metabolism, vitamins, hormonal contraceptives, hormone replacement therapy \[HRT\] and natural and herbal remedies, e.g., St. John's Wort).
* Subject has a presence of a hepatocellular carcinoma, or an acute liver disease caused by an infection or drug toxicity.
* Subject has severe portal hypertension or surgical portosystemic shunts, including transjugular intrahepatic portosystemic shunt.
* Subject has biliary liver cirrhosis, biliary obstruction or other cause of hepatic impairment not related to parenchymal disorder and/or disease of the liver.
* Subject has signs of significant hepatic encephalopathy (hepatic encephalopathy Grade ≥ 2).
* Subject has severe ascites and/or pleural effusion.
* Subject has esophageal/gastric variceal bleeding in the past six months prior to screening, unless banded.
* Subject has thrombocyte level below 40 × 10\^9 per liter and /or hemoglobin \< 90 grams per liter.
* Subject has previous liver transplantation.

Additional Criteria for Healthy Subjects with Normal Hepatic Function:

* Subject has any of the liver function tests (alkaline phosphatase \[ALP\], alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\] and total bilirubin \[TBL\]) ≥ 1.5 × the Upper Limit of Normal (ULN) or international normalized ratio (INR) \> 1.1 on Day -1. In such a case, the assessment may be repeated once.
* Subject has any history or evidence of any clinically significant cardiovascular, gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal and/or other major disease or malignancy.
* Subject has a history of consuming \> 7 units of alcoholic beverages per week within six months prior to screening or has a history of alcoholism or drug/chemical/substance abuse within two years prior to screening (note: 1 unit = 12 ounces of beer, 4 ounces of wine, 1 ounce of spirits/hard liquor) or the subject tests positive for alcohol at screening or on Day -1.
* Subject has any clinically significant abnormality following the physical examination, ECG and protocol-defined clinical laboratory tests at screening or on Day -1.
* Subject has a mean pulse \< 45 or \> 90 bpm; mean SBP \> 140 mmHg; mean DBP \> 90 mmHg (measurements taken in triplicate after subject has been resting in the supine position for at least five minutes; pulse will be measured automatically) on Day -1. If the mean blood pressure exceeds the limits above, one additional triplicate may be taken.
* Subject has a mean QTcF of \> 450 msec on Day -1. If the mean QTcF exceeds the limits above, one additional triplicate ECG may be taken.
* Subject has used any prescribed or nonprescribed drugs (including vitamins, hormonal contraceptives, HRT and natural and herbal remedies, e.g., St. John's Wort) in the two weeks prior to IP administration, except for occasional use of acetaminophen (up to 2 g/day) and topical dermatological products, including corticosteroid products.
* Subject has used any drugs of abuse (amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine and/or opiates) within three months prior to Day -1 or the subject tests positive for drugs of abuse (amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine and opiates) at screening or on Day -1.
* Subject has a positive serology test for HAV antibodies (IgM), hepatitis B surface antigen, hepatitis C virus antibodies or antibodies to HIV type 1 and/or type 2 at screening.

Primary outcomes:
measure: Pharmacokinetics (PK) of Fezolinetant in Plasma: Area Under the Concentration-time Curve (AUC) From the Time of Dosing Extrapolated to Time Infinity (AUCinf)
timeFrame: Up to 5 days
measure: PK of Fezolinetant in Plasma: AUC From the Time of Dosing to the Last Measurable Concentration (AUClast)
timeFrame: Up to 5 days
measure: PK of Fezolinetant in Plasma: Maximum Concentration (Cmax)
timeFrame: Up to 5 days
measure: PK of Fezolinetant in Plasma: Apparent Clearance (CL/F)
timeFrame: Up to 5 days
measure: PK of Fezolinetant in Plasma: Apparent volume of Distribution During Terminal Phase After Non-intravenous Administration (Vz/F)
timeFrame: Up to 5 days
measure: PK of Fezolinetant Metabolite ES259564 in Plasma: AUCinf
timeFrame: Up to 5 days
measure: PK of Fezolinetant Metabolite ES259564 in Plasma: AUClast
timeFrame: Up to 5 days
measure: PK of Fezolinetant Metabolite ES259564 in Plasma: Cmax
timeFrame: Up to 5 days
Secondary outcomes:
measure: Number of Participants With Adverse Events (AEs)
timeFrame: Up to 14 days
measure: Number of Participants With Laboratory Value Abnormalities and/or Adverse Events (AEs)
timeFrame: Up to 14 days
measure: Number of Participants With Vital Sign Abnormalities and/or Adverse Events (AEs)
timeFrame: Up to 14 days
measure: Number of Participants With 12-lead Electrocardiogram (ECG) Abnormalities and/or Adverse Events (AEs)
timeFrame: Up to 14 days
Other outcomes:
Locations:
city: Clearwater
country: United States
facility: Clinical Research of West Florida, Inc.
state: Florida
city: Miami
country: United States
facility: Clinical Pharmacology of Miami, LLC
state: Florida
city: Orlando
country: United States
facility: Orlando Clinical Research Center
state: Florida
city: San Antonio
country: United States
facility: American Research Corporation
state: Texas
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Executive Medical Director
role: STUDY_DIRECTOR
References: