A Study About Fazirsiran in People With and Without Liver Problems
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm 1, Mild HI: Fazirsiran 200 mg Participants with mild hepatic impairment (HI) will receive fazirsiran 200 milligrams (mg) subcutaneous (SC) injection on Day 1. |
Drug: Fazirsiran
Fazirsiran SC injection.
Other Names:
|
| Experimental: Arm 2, Moderate HI: Fazirsiran 200 mg 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. |
Drug: Fazirsiran
Fazirsiran SC injection.
Other Names:
|
| Experimental: Arm 3, Severe HI: Fazirsiran 200 mg 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. |
Drug: Fazirsiran
Fazirsiran SC injection.
Other Names:
|
| Experimental: Arm 4, Normal Hepatic Function: Fazirsiran 200 mg 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. |
Drug: Fazirsiran
Fazirsiran SC injection.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for Fazirsiran [From pre-dose up to Month 6 post-dose]
- Area Under the Plasma Concentration-time Curve from Time 0 to Infinity (AUC0-inf) for Fazirsiran [From pre-dose up to Month 6 post-dose]
- Maximum Observed Plasma Concentration (Cmax) for Fazirsiran [From pre-dose up to Month 6 post-dose]
Secondary Outcome Measures
- 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 Laboratory 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 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)]
- 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)]
- Number of Participants With Injection Site Reaction [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 0 to Time 6 hours (Ae0-6hrs) for Fazirsiran [Pre-dose, 0 to 6 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]
- Percent of Recovered Drug in Urine Compared With the Dose (%Dose [u]) [Pre-dose, 0 to 24 hours post-dose]
- Renal Clearance (CLr) for Fazirsiran [Pre-dose, 0 to 24 hours post-dose]
- 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)]
- Percentage Change in Serum AAT at Nadir [From Day 1 Pre-dose Baseline up to end of follow up (up to 6 months)]
- 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]
Eligibility Criteria
Criteria
Inclusion Criteria:
Key Inclusion Criteria for Participants with Hepatic Impairment and Participants with Normal Hepatic Function
-
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.
-
Normal lung function.
-
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:
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The participant is 18 to 75 years of age inclusive at the time of signing the informed consent form (ICF).
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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.
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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.
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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.
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Has a Child-Turcotte-Pugh (CTP) score confirmed by 2 tests as follows:
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Arm 1: Mild HI, CTP Class A: >=5 and <=6
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Arm 2: Moderate HI, CTP Class B: >=7 and <=9
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Arm 3: Severe HI, CTP Class C: >=10 and <=15
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It must be confirmed that the participant does not have hepatocellular carcinoma (HCC).
Key Inclusion Criteria for Participants with Normal Hepatic Function:
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The participant is 18 to 85 years of age inclusive, at the time of signing the ICF.
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The participant has a BMI >=18.0 and <=40.0 kg/m^2, at screening. Participants will be matched to participants with HI arms by BMI (±15%).
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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.
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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.
Exclusion Criteria:
Key Exclusion Criteria for Participants with Hepatic Impairment and Participants with
Normal Hepatic Function:
-
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.
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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.
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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.
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The participant is expected to have severe and unavoidable high-level exposure to inhaled pulmonary toxins during the study.
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The participant has had a recent lower respiratory tract infection, such as pneumonia, within the last 6 months before screening.
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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 surgical procedures.
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The participant has grade >2 hepatic encephalopathy assessed using the West Haven criteria.
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The participant has evidence of hepatopulmonary syndrome or portal-pulmonary hypertension.
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The participant has portal vein thrombosis, transjugular intrahepatic portosystemic shunt (TIPS), or surgical portosystemic shunt.
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The participant has required endoscopic treatment of esophageal or gastric varices or paracentesis to control ascites within the last 3 months of dosing.
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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]).
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The participant has any of the following clinically significant abnormal parameters at screening:
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ALT or AST levels >250 units per liter (U/L) at screening.
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Estimated glomerular filtration rate <45 milliliter per minute per 1.73 square meter (mL/min/1.73 m^2).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | CRU Hungary Kft | Kistarcsa | Hungary | 2143 | |
| 2 | Summit Clinical Research s.r.o. | Bratislava | Slovakia | 851 05 |
Sponsors and Collaborators
- Takeda
Investigators
- Study Director: Study Director, Takeda
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- TAK-999-1001
- 2023-503735-17