NCT05891158已完成1 期
An Open-Label, Phase 1 Study to Evaluate the Pharmacokinetics, Safety, Tolerability, and Pharmacodynamics in Response to a Single Subcutaneous Dose of Fazirsiran (TAK-999) in Subjects With or Without Hepatic Impairment
Takeda5 个研究点 分布在 2 个国家目标入组 34 人开始时间: 2023年10月6日最近更新:
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 34
- 试验地点
- 5
- 主要终点
- Area Under the Plasma Concentration-time Curve from Time 0 to Infinity (AUC0-inf) for Fazirsiran
研究概览
简要总结
The main aim of this study is to learn how the body processes fazirsiran (pharmacokinetics [PK]) in people with mild, moderate, or severe liver problems, compared to people with normal liver function.
The study will include participants with liver scarring (cirrhosis) and mild, moderate, or severe liver problems, and participants with normal liver function. All participants will be given 1 injection of fazirsiran and will be followed up for 6 months after the fazirsiran injection.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •for All Participants
- •A 12-lead ECG at screening that, in the opinion of the investigator, has no abnormalities that compromise the participant's safety in this study.
- •No abnormal finding of clinical relevance at screening or before dosing that in the opinion of the investigator could adversely impact participant safety during the study or adversely impact study results.
- •Key Inclusion Criteria for Participants with Hepatic Impairment:
- •The participant is 18 to 75 years of age inclusive at the time of signing the informed consent form (ICF).
- •The participant has a body mass index (BMI) greater than or equal to (>=) 18.0 and less than or equal to (<=) 40.0 kilograms per square meter (kg/m^2) at screening.
- •Aside from HI, the participant must be sufficiently healthy for study participation based upon medical history, physical examination, vital signs, electrocardiograms (ECGs), and screening clinical laboratory profiles, as deemed by the investigator or designee.
- •Diagnosis of chronic (example, imaging, biopsy, etc.) stable hepatic insufficiency for at least 3 months before screening with features of cirrhosis due to any etiology according to medical history. HI must be stable, that is, no significant changes in hepatic function or clinical status in the 30 days preceding screening (or since the last visit if within 3 months before screening) and with treatment with stable doses of medication.
- •Has a Child-Turcotte-Pugh (CTP) score confirmed by 2 tests as follows:
- •Arm 1: Mild HI, CTP Class A: >=5 and <=6
- •Arm 2: Moderate HI, CTP Class B: >=7 and <=9
- •Arm 3: Severe HI, CTP Class C: >=10 and <=15
- •It must be confirmed that the participant does not have hepatocellular carcinoma (HCC).
- •Key Inclusion Criterion for Participants with Mild Hepatic Impairment • The participant has pulmonary status meeting criteria of percent predicted forced expiratory volume in the first second of expiration (ppFEV1) >=80 percent and percent predicted diffusing capacity of the lungs for carbon monoxide adjusted for hemoglobin (ppDLCOhgb) >=75%, based on pulmonary function test (PFT) at screening conducted as per American Thoracic Society (ATS)-European Respiratory Society (ERS) criteria.
- •Key Inclusion Criterion for Participants with Moderate and Severe Hepatic Impairment
- •The participant has pulmonary status meeting the criteria defined in the protocol based on PFT at screening conducted as per ATS-ERS criteria.
- •Key Inclusion Criteria for Participants with Normal Hepatic Function
- •The participant is 18 to 85 years of age inclusive, at the time of signing the ICF.
- •The participant has a BMI >=18.0 and <=40.0 kg/m^2, at screening. Participants will be matched to participants with HI by BMI (±15%).
- •AAT level at or above the lower end of the reference range (above or equal to 16.6 micromole (mcM) or 90 milligram per deciliter [mg/dL]) at screening.
- •The participant has normal liver tests including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBILI) <=1.2 x upper limit of the normal range (ULN) at screening and check-in.
- •The participant has pulmonary status meeting criteria of ppFEV1 >=80%, and ppDLCOhgb >=75%, based on PFT at screening conducted as per ATS- ERS criteria.
排除标准
- •for All Participants:
- •The participant has uncontrolled hypertension (systolic blood pressure [BP] >170 mm Hg and diastolic BP >100 millimeter of mercury [mmHg] at screening). Participants may be rescreened once BP is successfully controlled.
- •The participant has a history of torsades de pointes, ventricular rhythm disturbances (example, ventricular tachycardia or fibrillation), heart block (excluding first-degree block, being pulse rate [PR] interval prolongation only), congenital long QT syndrome or new ST segment elevation or depression or new Q wave on ECG. Participants with a history of atrial arrhythmias should be discussed with the medical monitor.
- •The participant has symptomatic heart failure (per New York Heart Association guidelines) or severe heart failure with reduced ejection fraction (EF <20%), unstable angina, myocardial infarction, transient ischemic attack, or cerebrovascular accident within 6 months before screening.
- •The participant is expected to have severe and unavoidable high-level exposure to inhaled pulmonary toxins during the study.
- •The participant has had a recent lower respiratory tract infection, such as pneumonia, within the last 6 months before screening.
- •The participant has a history of malignancy within the last 1 year, except for adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer. Participants with other curatively treated malignancies who have no evidence of metastatic disease and have been disease-free for >1 year may enter the study after approval by the medical monitor.
- •The participant has a history of thromboembolic disease (including deep vein thrombosis or pulmonary embolism) within 6 months of screening.
- •Key Exclusion Criteria for Participants with Hepatic Impairment:
- •The participant has a history of gastric or esophageal variceal bleeding within the past 6 months of dosing and for which varices have not been adequately treated with medication and/or endoscopic procedures.
- •The participant has grade >2 hepatic encephalopathy assessed using the West Haven criteria.
- •The participant has evidence of hepatopulmonary syndrome or portal-pulmonary hypertension.
- •The participant has portal vein thrombosis, transjugular intrahepatic portosystemic shunt (TIPS), or surgical portosystemic shunt.
- •The participant has required endoscopic treatment of esophageal or gastric varices or paracentesis to control ascites within the last 3 months of dosing.
- •The participant has chronic hepatitis B (hepatitis B surface antigen positive, or positive for both hepatitis B surface antibody and hepatitis B core antibody but negative for hepatitis B surface antigen); or has chronic or incompletely or unsuccessfully treated hepatitis C (as demonstrated by a positive hepatitis C antibody and positive polymerase chain reaction [PCR]).
- •The participant has any of the following clinically significant abnormal parameters at screening:
- •ALT or AST levels >250 units per liter (U/L) at screening.
- •Estimated glomerular filtration rate <45 milliliter per minute per 1.73 square meter (mL/min/1.73 m^2).
研究组 & 干预措施
Arm 1, Mild HI: Fazirsiran 200 mg
Experimental
Participants with mild hepatic impairment (HI) will receive fazirsiran 200 milligrams (mg) subcutaneous (SC) injection on Day 1.
干预措施: Fazirsiran (Drug)
Arm 2, Moderate HI: Fazirsiran 200 mg
Experimental
Participants with moderate HI will receive fazirsiran 200 mg SC injection on Day 1. The dose may be modified after review of available safety and PK data by the sponsor study team in consultation with the investigator.
干预措施: Fazirsiran (Drug)
Arm 3, Severe HI: Fazirsiran 200 mg
Experimental
Participants with severe HI will receive fazirsiran 200 mg SC injection on Day 1. The dose may be modified after review of available safety and PK data by the sponsor study team in consultation with the investigator.
干预措施: Fazirsiran (Drug)
Arm 4, Normal Hepatic Function: Fazirsiran 200 mg
Experimental
Participants with normal hepatic function will receive fazirsiran 200 mg SC injection on Day 1. The dose may be modified after review of available safety and PK data by the sponsor study team in consultation with the investigator.
干预措施: Fazirsiran (Drug)
结局指标
主要结局
Area Under the Plasma Concentration-time Curve from Time 0 to Infinity (AUC0-inf) for Fazirsiran
时间窗: From pre-dose up to Month 6 post-dose
Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for Fazirsiran
时间窗: From pre-dose up to Month 6 post-dose
Maximum Observed Plasma Concentration (Cmax) for Fazirsiran
时间窗: From pre-dose up to Month 6 post-dose
次要结局
- Number of Participants With Clinically Significant Abnormal Values for Laboratory Parameters(From the first dose of study drug up to end of follow-up (up to 6 months))
- Amount of Drug Excreted in Urine From Time 0 to Time 24 hours (Ae0-24hrs) for Fazirsiran(Pre-dose, 0 to 24 hours post-dose)
- Amount of Drug Excreted in Urine From Time 6 to Time 24 hours (Ae6-24h) for Fazirsiran(From 6 to 24 hours post-dose)
- Absolute Change in Serum AAT(From Day 1 Pre-dose Baseline and at Days 15, 29, 57)
- Percentage Change in Serum AAT(From Day 1 Pre-dose Baseline and at Days 15, 29, 57)
- Number of Participants With Injection Site Reaction(From the first dose of study drug up to end of follow-up (up to 6 months))
- Renal Clearance (CLr) for Fazirsiran(Pre-dose, 0 to 24 hours post-dose)
- Number of Participants With Treatment-emergent Adverse Events (TEAEs)(From the first dose of study drug up to end of follow-up (up to 6 months))
- Number of Participants With Clinically Significant Abnormal Values for Pulmonary Function Parameters(From the first dose of study drug up to end of follow-up (up to 6 months))
- Amount of Drug Excreted in Urine From Time 0 to Time 6 hours (Ae0-6hrs) for Fazirsiran(Pre-dose, 0 to 6 hours post-dose)
- Percent of Recovered Drug in Urine Compared With the Dose (%Dose [u])(Pre-dose, 0 to 24 hours post-dose)
- Percentage Change in Serum AAT at Nadir(From Day 1 Pre-dose Baseline up to end of follow up (up to 6 months))
- Number of Participants With Clinically Significant Abnormal Values for Vital Signs Parameters(From the first dose of study drug up to end of follow-up (up to 6 months))
- Number of Participants With Clinically Significant Abnormal Values for Electrocardiogram (ECG) Parameters(From the first dose of study drug up to end of follow-up (up to 6 months))
- Absolute Change in Serum Alpha-1 Antitrypsin (AAT) at Nadir(From Day 1 Pre-dose Baseline up to end of follow-up (up to 6 months))
研究者
研究点 (5)
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