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
Fazirsiran Injection: Participants will receive fazirsiran 200 mg/ml SC injection on Day 1, at Week 4, and Q12 W thereafter up to Week 196.
Placebo: Participants will receive placebo (sterile normal saline \[0.9% NaCl\]) SC injection on Day 1, at Week 4, and Q12 W thereafter up to Week 196.
Study summary
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.
Eligibility
Sex
ALL
Min age
18 Years
Max age
75 Years
Healthy volunteers
No
Inclusion criteria:
* The participant must have a diagnosis of the Z allele homozygotes (PiZZ) genotype AATD. PiZZ diagnosis from source verifiable medical records is permitted. Otherwise, participants must undergo PiZZ confirmatory testing (genotyping for PiS and PiZ alleles) at screening. PiMZ or PiSZ genotypes are not permitted.
* The participant, of any sex, is aged 18 to 75 years, inclusive.
* The participant's liver biopsy core sample collected should meet the requirements of the protocol.
* The participant has evidence of METAVIR stage F2, F3, or F4 liver fibrosis, evaluated by a centrally read baseline liver biopsy during the screening period; or confirmed as meeting all the entry criteria by central reading of a previous biopsy conducted within 6 months before the estimated enrollment date using an adequate liver biopsy and slides as defined in the study laboratory manual.
* The participant has a pulmonary status meeting the protocol's requirements.
* It must be confirmed that the participant does not have HCC. Participants will be screened for HCC with alpha-fetoprotein (AFP) and abdominal ultrasound. If the participant has any of the following, they will be required to have contrast-enhanced CT or MRI imaging to exclude HCC before randomization.
* An adult participant must have a body mass index (BMI) greater than or equal to (\>=) 18.0 kilograms per meter square (kg\^m2).
* The participant is a nonsmoker for at least 6 months before screening.
Exclusion Criteria
* The participant has a history of liver decompensating events (overt hepatic encephalopathy \[West Haven Grade \>=2\] documented by a physician or healthcare professional, clinically significant ascites, spontaneous bacterial peritonitis, GI bleeding from varices, hepatopulmonary syndrome, hepatorenal syndrome, portal pulmonary hypertension, or bleeding portal hypertensive gastropathy).
* The participant has a history of the presence of medium or large varices or varices with red wale signs based on a previous esophagogastroduodenoscopy (EGD) within 6 months before the estimated enrollment date. For certain participants, an EGD will be required at screening if there is no EGD available within 6 months before the estimated enrollment date. Presence of small varices with no red wale signs on EGD and no history of bleeding will be acceptable for study eligibility.
* The participant has evidence of chronic liver disease attributable to other diseases, including viral hepatitis B or C, primary biliary cholangitis, primary sclerosing cholangitis, Wilson disease, alcoholic hepatitis, hemochromatosis, liver cancer, history of biliary diversion, or autoimmune hepatitis.
* The participant has alanine transaminase (ALT) or aspartate transaminase (AST) levels \>250 units per liter (U/L).
* The participant has a platelet count \<60,000 per cubic millimeter (mm\^3) (\<60 × 10\^9 per liter \[10\^9/L\]).
* The participant has albumin \<=2.8 gram per deciliter (g/dL) (28 grams per liter \[g/L\]).
* The participant has international normalized ratio (INR) \>=1.7.
* The participant is expected to have severe and unavoidable high-level exposure to inhaled pulmonary toxins during the study such as may occur with occupational exposure to mineral dusts or metals.
* The participant has a history of drug abuse (such as cocaine, phencyclidine) within 1 year before the screening visit or has a positive urine drug screen at screening.
* The participant has previously been treated with fazirsiran or any other RNAi for AATD-LD.
* The participant has portal vein thrombosis.
* The participant has a prior transjugular portosystemic shunt procedure.
* The participant has a history of malignancy within the last 5 years, 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 a greater than 1-year disease-free interval may be entered after approval by the medical monitor.
Primary outcome measure(s)
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 — Baseline, Week 106 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 will be assessed.
Trial sites (89)
Facility
City
Region
Status
University of Alabama at Birmingham
Birmingham
Alabama
Recruiting
St. Joseph's Hospital and Medical Center
Phoenix
Arizona
Recruiting
Mayo Clinic
Phoenix
Arizona
Recruiting
University of Arizona Thomas D. Boyer Liver Institute
Tucson
Arizona
Withdrawn
Gastroenterology & Liver Institute
Escondido
California
Withdrawn
University of California San Diego, Altman Clinical and Translational Institute
La Jolla
California
Recruiting
UCLA Pulmonary and Critical Care
Los Angeles
California
Recruiting
Stanford University
Palo Alto
California
Recruiting
University of California Benioff Children's Hospital
San Francisco
California
Recruiting
Peak Gastroenterology Associates, PC
Colorado Springs
Colorado
Recruiting
University of Florida
Gainesville
Florida
Recruiting
Schiff Center for Liver Diseases/University of Miami
Miami
Florida
Recruiting
Children's Healthcare of Atlanta
Atlanta
Georgia
Withdrawn
Indiana University School of Medicine - Indianapolis
Indianapolis
Indiana
Recruiting
University of Iowa Hospitals and Clinics
Iowa City
Iowa
Recruiting
Ochsner Medical Center
New Orleans
Louisiana
Recruiting
University of Maryland Medical Center
Baltimore
Maryland
Recruiting
Brigham and Womens Hospital
Boston
Massachusetts
Recruiting
Boston Medical Center
Boston
Massachusetts
Recruiting
University of Michigan Hospital
Ann Arbor
Michigan
Recruiting
Henry Ford Medical Center - Columbus
Novi
Michigan
Recruiting
Mayo Clinic - PPDS
Rochester
Minnesota
Recruiting
Cardinal Glennon Children's Hospital
St Louis
Missouri
Recruiting
Washington University School of Medicine in St. Louis
St Louis
Missouri
Recruiting
NYU Langone Health
New York
New York
Recruiting
Morgan Stanley Childrens Hospital of New York Presbyterian (CHONY) - PIN
New York
New York
Withdrawn
Columbia University Irving Medical Center
New York
New York
Recruiting
University Hospitals Cleveland Medical Center
Cleveland
Ohio
Recruiting
Penn State Health Milton S. Hershey Medical Center
Hershey
Pennsylvania
Recruiting
Temple University Hospital
Philadelphia
Pennsylvania
Recruiting
Medical University of South Carolina
Charleston
South Carolina
Recruiting
Vanderbilt University Medical Center
Nashville
Tennessee
Recruiting
Texoma Liver Center
Denison
Texas
Recruiting
Baylor College of Medicine Medical Center
Houston
Texas
Recruiting
The Texas Liver Institute
San Antonio
Texas
Recruiting
Bon Secours St. Mary's Hospital
Richmond
Virginia
Recruiting
VCU Medical Center North Hospital
Richmond
Virginia
Recruiting
Royal Adelaide Hospital
Adelaide
South Australia
Withdrawn
St Vincents Hospital Melbourne - PPDS
Fitzroy
Victoria
Recruiting
LKH-Universitätsklinikum Graz
Graz
Austria
Recruiting
+ 49 more sites — see the full list on the official registry below.
This page summarises publicly available registry data for informational purposes — not medical advice. Eligibility is determined by each study team; patients should discuss participation with their clinician.
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