TAK-999-3001

Recruiting

Study to Check the Safety of Fazirsiran and Learn if Fazirsiran Can Help People With Liver Disease and Scarring (Fibrosis) Due to an Abnormal Version of Alpha-1 Antitrypsin Protein

Clinicaltrials.gov

EU CTIS

#2022-501943-34-00

EudraCT

#2022-501943-34

The main aim of this study is to learn if fazirsiran reduces liver scarring (fibrosis) compared to placebo. Other aims are to learn if fazirsiran slows down the disease worsening in the liver, to get information on how fazirsiran affects the body (called pharmacodynamics), to learn if fazirsiran reduces other liver injury (inflammation) and the abnormal Z-AAT protein in the liver, to get information on how the body processes fazirsiran (called pharmacokinetics), to test how well fazirsiran works compared with a placebo in improving measures of liver scarring including imaging and liver biomarkers (substances in the blood that the body normally makes and help show if liver function is improving, staying the same, or getting worse) as well as to check for side effects in participants treated with fazirsiran compared with those who received placebo. Participants will either receive fazirsiran or placebo. Liver biopsies, a way of collecting a small tissue sample from the liver, will be taken twice during this study.

12+

Interventional Phase 3 clinical trial.

For Healthcare Professionals

See if you qualify

What medical conditions are being studied?

Alpha1-Antitrypsin Deficiency

What is the clinical trial testing?

Placebo, Fazirsiran Injection

How many participants are being enrolled?

160

Are placebos part of the clinical trial?

Yes

When is the clinical trial being conducted?

Mar 2023 - Mar 2029

How long is participation in the clinical trial?

Participants will stay in the study for up to 230 weeks (approximately 4 years) and will receive treatment for up to 196 weeks (approximately 3.5 years).

Sexes

All

Age

18-75 years

Healthy volunteers?

Must be men and women from 18 to 75 years old

Must have the gene for abnormal Z-AAT protein and already have liver disease.

Liver biopsy must show stage F2, F3, or F4 fibrosis (scarring).

Lung (pulmonary) function or condition must meet some pre-defined criteria.

Cannot have a history of symptoms due to liver failure, such as enlarged veins that happen with severe scarring of the liver (as shown by endoscopy), have blood clots in the main vein going into the liver (portal vein), fluid build-up in the abdomen, or other types of chronic liver disease.

Additional entry criteria will be discussed with the study doctor.

Primary outcome measures

Reduction From Baseline of at Least 1 Stage of Histologic Fibrosis (METAVIR Staging) in the Centrally Read Liver Biopsy at Week 106 in AATD-LD With METAVIR Stage F2 and F3 Fibrosis [Time Frame: Baseline, Week 106]

Secondary outcome measures

Percent Change from Baseline in Intrahepatic Z-AAT Protein in Alpha-1 Antitrypsin Deficiency-Associated Liver Disease (AATD-LD) with METAVIR Stage F2 to F3 Fibrosis at Week 106 [Time Frame: Baseline, Week 106]

Reduction From Baseline of at Least 1 Stage of Histologic Fibrosis (METAVIR Staging) in the Centrally Read Liver Biopsy [Time Frame: Baseline, Week 106 and Week 202]

Number of Participants With Liver Related Clinical Events up to Week 202 [Time Frame: Baseline up to Week 202]

Change From Baseline in Serum Z-Alpha-1 Antitrypsin (Z-AAT) Protein [Time Frame: Baseline, Week 106, Week 202]

Change From Baseline in Intrahepatic Z-AAT Protein Polymer Burden Assessed by Periodic Acid Schiff Plus Diastase (PAS+D) Staining [Time Frame: Baseline, Week 106, Week 202]

Change From Baseline in Intrahepatic Portal Inflammation [Time Frame: Baseline, Week 106, Week 202]

Change From Baseline in Vibration-Controlled Transient Elastography (VCTE)/Magnetic Resonance Elastography (MRE)-derived Liver Stiffness [Time Frame: Baseline, Week 106, Week 196 and Week 202]

Change From Baseline in Model of End-Stage Liver Disease (MELD) Score [Time Frame: Baseline, Week 106, and Week 202]

Change From Baseline in Liver Injury [Time Frame: Baseline, Week 106 and Week 202]

Percent Change from Baseline in Intrahepatic Z-AAT Protein in AATD-LD With METAVIR Stage F2 to F4 Fibrosis [Time Frame: Baseline, Week 106 and Week 202]

Observed Plasma Concentrations of Fazirsiran [Time Frame: Pre-dose up to Week 196]

Number of Participants with Treatment-emergent adverse event (TEAE) and Serious TEAEs [Time Frame: From start of study drug administration up to end of the study (EOS) (Week 220)]

Number of Participants with Clinically Significant Declines in Lung Function Parameters [Time Frame: From start of study drug administration up to EOS (Week 220)]

Change From Baseline in Whole Lung PD15 (15th percentile point) Measured by CT lung Densitometry [Time Frame: Baseline up to EOS (Week 220)]

Number of Participants with Clinically Significant Change in Vital Signs [Time Frame: From start of study drug administration up to EOS (Week 220)]

Number of Participants with Clinically Significant Changes in Electrocardiogram (ECG) Parameters [Time Frame: From start of study drug administration up to EOS (Week 220)]

Number of Participants with Clinically Significant Changes in Clinical Laboratory Assessments [Time Frame: From start of study drug administration up to EOS (Week 220)]