A Phase I, Open-label, Parallel-group Study to Evaluate the Single-dose Pharmacokinetics of Palovarotene in Male and Female Participants With Moderate and Severe Hepatic Impairment and Matched Participants With Normal Hepatic Function
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Ipsen
- 入组人数
- 31
- 试验地点
- 6
- 主要终点
- Maximum observed plasma drug concentration (Cmax)
研究概览
简要总结
The main aim of this study is to understand how moderate and severe liver impairment (based on the Child-Pugh classification) affects the body's processing of a single dose of 10 mg maximum of palovarotene, compared to healthy participants with normal liver function.
The study will also assess the safety and tolerability of the single dose of palovarotene.
Participants will be enrolled in stages and divided into three groups based on their liver function:
- Group 1: Healthy participants with normal liver function
- Group 2: Participants with moderate liver impairment
- Group 3: Participants with severe liver impairment (only enrolled if Group 2 results are safe and acceptable)
Blood samples will be taken to assess how the drug binds to proteins in the blood. Participants will undergo various safety checks and procedures. Participants will stay in the clinical unit until Day 5 for these assessments and will return on Day 10 for a final visit.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Male and female participants must be 18 to 70 years of age (inclusive) at the time of signing informed consent.
- •Body weight at least 60.0 kg with body mass index (BMI) within the range of 18.0 and 36.0 kg/m² (inclusive), at screening. BMI of >36.0 to ≤40.0 may be eligible if participant has moderate ascites scoring 3 points on the C-P criteria.
- •Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical trials
- •Clinical diagnosis of chronic hepatic disease (stable for more than 3 months) with a documented history of underlying hepatic insufficiency and no acute episodes of illness within 30 days prior to Day -1 (admission) and no significant change in disease status (i.e. up to 1 point in the C-P classification) from screening to Day -
- •A stable medication regimen, defined as not starting new therapy(ies) or significant changing dosage(s) within 30 days prior to dosing.
排除标准
- •Presence or significant history of cardiovascular, respiratory, hepatic (except for the hepatic impairment for those concerned), renal, gastrointestinal, biliary, mucocutaneous, endocrinological, haematological or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs, constituting a risk when taking the study intervention, or interfering with the interpretation of data.
- •Lymphoma, leukaemia or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years.
- •Breast cancer within the past 10 years.
- •Use of any medications (prescription or over the counter), herbal tea, energy drinks (including natural stimulants), herbal products (e.g. St. John's wort, garlic, milk thistle) or supplements/supratherapeutic doses of vitamins within 14 days prior to Day 1 and through discharge, apart from those approved by the investigator and the sponsor's medical monitor. Those with hepatic impairment may take concomitant medications
- •Use of any medications that are moderate or strong inhibitors or inducers of CYP3A4
- •Donation or loss (excluding volume drawn at screening or during menses) of more than 250 mL of blood or blood product within 3 months prior to screening. In addition, plan of blood donation within 8 weeks after the last PK sampling.
- •Presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to the dose of study intervention.
- •Positive hepatitis C antibody test result at screening or within 3 months prior to the dose of study intervention. Note: Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled if a confirmatory negative hepatitis C ribonucleic acid (RNA) test is obtained.
- •Positive hepatitis C RNA test result at screening or within 3 months prior to the dose of study intervention. Note: Test is optional and participants with negative hepatitis C antibody test are not required to also undergo hepatitis C RNA testing.
- •Sensitivity to the study intervention, or components thereof (including inactive ingredients), or drug or other allergy that, in the opinion of the investigator (or medical monitor), contraindicates participation in the study
- •Evidence of relevant active disease at screening, including gastroenterological (other than hepatic cirrhosis), cardiac (e.g. myocardial infarction in the past year, angina or congestive heart failure), renal, respiratory, haematological, neuropsychiatric or neoplastic (basal or squamous cell skin cancer is acceptable) disease.
- •Acute hepatitis B (positive for HBsAg) or acute hepatitis C (positive for anti-hepatitis C virus (HCV) for a duration of less than 6 months). Note: Participants with chronic HCV (positive for HCV RNA or anti-HCV for more than 6 months) are eligible for enrolment, if stable, as assessed by the investigator.
- •Primary sclerosing cholangitis or preliminary diagnosed biliary obstruction at screening.
- •Current or chronic history of liver disease. This includes (but is not limited to hepatitis virus infections), drug- or alcohol-related liver disease, non-alcoholic steatohepatitis, autoimmune hepatitis, hemochromatosis, Wilson's disease, α-1 antitrypsin deficiency, primary biliary cholangitis, primary sclerosing cholangitis, or any other liver disease considered clinically significant by the investigator.
研究组 & 干预措施
Group 1 Healthy participants
Evaluation of the pharmacokinetics of IPN60120 in control healthy participants matching the age, sex and weight with hepatic impaired participants
干预措施: Palovarotene (Drug)
Group 2 Moderate Hepatic impaired participants
Evaluation of the pharmacokinetics of IPN60120 in Moderate Hepatic impaired participants (Child-Pugh class B)
干预措施: Palovarotene (Drug)
Group 3 Severe Hepatic impaired participants
Evaluation of the pharmacokinetics of IPN60120 in Severe Hepatic impaired participants (Child-Pugh class C)
干预措施: Palovarotene (Drug)
结局指标
主要结局
Maximum observed plasma drug concentration (Cmax)
时间窗: Over 96 hours postdose
Measure of maximum observed plasma drug concentration (Cmax) (total and unbound) over 96 hours after dosing
Unbound fraction of drug in plasma (fu)
时间窗: Over 96 hours postdose
Measure of maximum observed plasma drug concentration (Cmax) (total and unbound) over 96 h after dosing
Time to maximum observed plasma concentration (Tmax)
时间窗: Over 96 hours postdose
Measure of AUC from time 0 to infinity (AUC0-∞) (total and unbound)
Area under the plasma concentration-time curve (AUC) from time 0 to infinity (AUC0-∞)
时间窗: Over 96 hours postdose
Measure of AUC from time 0 to infinity (AUC0-∞) (total and unbound)
AUC from 0 to time t corresponding to the last quantifiable concentration (AUC0-tlast)
时间窗: Over 96 hours postdose
Measure of AUC from 0 to time t corresponding to the last quantifiable concentration (AUC0-tlast) (total and unbound)
Apparent terminal elimination half life (T1/2)
时间窗: Over 96 hours postdose
Measure of apparent terminal elimination half-life over 96 hours post-dose
Apparent terminal elimination rate constant (λz).
时间窗: Over 96 hours postdose
Measure of apparent terminal elimination rate constant (λz) over 96 hours post-dose
次要结局
- Percentage of participants with Adverse Events (AEs)(From Baseline to Day 10)
- Percentage of Participants with clinically significant changes from baseline in Laboratory Parameters(At Day 2, Day 5 and Day 10)
- Percentage of participants with clinically significant change from baseline in physical examinations(At Day 1, 2 and 3, Day 5 and Day 10)
- Percentage of Participants With Clinically Significant Changes from baseline in Vital Signs(At Day 1, 2 and 3, Day 5 and Day 10)
- Percentage of participants with clinically significant change from baseline in 12-lead Electrocardiogram (ECG) readings(At Day 1, 2 and 3, Day 5 and Day 10)