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A Study About Fazirsiran in People With and Without Liver Problems

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05891158
Recruitment Status : Recruiting
First Posted : June 6, 2023
Last Update Posted : December 1, 2023
Sponsor:
Information provided by (Responsible Party):
Takeda

Study Description
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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
Hepatic Impairment Drug: Fazirsiran Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 41 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : October 5, 2023
Estimated Primary Completion Date : April 15, 2025
Estimated Study Completion Date : April 15, 2025
Arms and Interventions
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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 Name: TAK-999
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 Name: TAK-999
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 Name: TAK-999
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 Name: TAK-999


Outcome Measures
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Primary Outcome Measures :
  1. Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for Fazirsiran [ Time Frame: From pre-dose up to Month 6 post-dose ]
  2. Area Under the Plasma Concentration-time Curve from Time 0 to Infinity (AUC0-inf) for Fazirsiran [ Time Frame: From pre-dose up to Month 6 post-dose ]
  3. Maximum Observed Plasma Concentration (Cmax) for Fazirsiran [ Time Frame: From pre-dose up to Month 6 post-dose ]

Secondary Outcome Measures :
  1. Number of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: From the first dose of study drug up to end of follow-up (up to 6 months) ]
  2. Number of Participants With Clinically Significant Abnormal Values for Laboratory Parameters [ Time Frame: From the first dose of study drug up to end of follow-up (up to 6 months) ]
  3. Number of Participants With Clinically Significant Abnormal Values for Vital Signs Parameters [ Time Frame: From the first dose of study drug up to end of follow-up (up to 6 months) ]
  4. Number of Participants With Clinically Significant Abnormal Values for Electrocardiogram (ECG) Parameters [ Time Frame: From the first dose of study drug up to end of follow-up (up to 6 months) ]
  5. Number of Participants With Clinically Significant Abnormal Values for Pulmonary Function Parameters [ Time Frame: From the first dose of study drug up to end of follow-up (up to 6 months) ]
  6. Number of Participants With Injection Site Reaction [ Time Frame: From the first dose of study drug up to end of follow-up (up to 6 months) ]
  7. Amount of Drug Excreted in Urine From Time 0 to Time 24 hours (Ae0-24hrs) for Fazirsiran [ Time Frame: Pre-dose, 0 to 24 hours post-dose ]
  8. Amount of Drug Excreted in Urine From Time 0 to Time 6 hours (Ae0-6hrs) for Fazirsiran [ Time Frame: Pre-dose, 0 to 6 hours post-dose ]
  9. Amount of Drug Excreted in Urine From Time 6 to Time 24 hours (Ae6-24h) for Fazirsiran [ Time Frame: From 6 to 24 hours post-dose ]
  10. Percent of Recovered Drug in Urine Compared With the Dose (%Dose [u]) [ Time Frame: Pre-dose, 0 to 24 hours post-dose ]
  11. Renal Clearance (CLr) for Fazirsiran [ Time Frame: Pre-dose, 0 to 24 hours post-dose ]
  12. Absolute Change in Serum Alpha-1 Antitrypsin (AAT) at Nadir [ Time Frame: From Day 1 Pre-dose Baseline up to end of follow-up (up to 6 months) ]
  13. Percentage Change in Serum AAT at Nadir [ Time Frame: From Day 1 Pre-dose Baseline up to end of follow up (up to 6 months) ]
  14. Absolute Change in Serum AAT [ Time Frame: From Day 1 Pre-dose Baseline and at Days 15, 29, 57 ]
  15. Percentage Change in Serum AAT [ Time Frame: From Day 1 Pre-dose Baseline and at Days 15, 29, 57 ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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:

  • 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 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 arms 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.

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.
  • 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 surgical 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).
Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05891158


Contacts
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Contact: Takeda Contact +1-877-825-3327 medinfoUS@takeda.com

Locations
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Hungary
CRU Hungary Kft Recruiting
Kistarcsa, Hungary, 2143
Principal Investigator: Geza Lakner         
Slovakia
Summit Clinical Research s.r.o. Recruiting
Bratislava, Slovakia, 851 05
Contact: Site Contact       kupcova@vnet.sk   
Principal Investigator: Viera Kupcova         
Summit Clinical Research s.r.o. Not yet recruiting
Malacky, Slovakia
Contact: Site Contact    00421 34 282 97 00      
Principal Investigator: Edita Kadlubiakova         
Summit Clinical Research s.r.o. Not yet recruiting
Nove Zamky, Slovakia, 940 34
Contact: Site Contact    00421 35 6912111      
Principal Investigator: Jozef Glassa         
Sponsors and Collaborators
Takeda
Investigators
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Study Director: Study Director Takeda
More Information
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Additional Information:

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Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT05891158    
Other Study ID Numbers: TAK-999-1001
2023-503735-17 ( Other Identifier: EU CTIS )
First Posted: June 6, 2023    Key Record Dates
Last Update Posted: December 1, 2023
Last Verified: November 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/ For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
URL: https://vivli.org/ourmember/takeda/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Liver Diseases
Digestive System Diseases