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

NCT05677971 | Recruiting Phase 3 DMC FDA Drug

• 2 other identifiers: TAK-999-30012022-501943-34-00
• Study Type: interventional
• Target: 160
• Locations: 18 countries
• Sites: 87

Brief 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.

Conditions

Alpha1-Antitrypsin Deficiency

Outcome Measures

Primary Outcomes (1)

• 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

  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.

  Baseline, Week 106

Secondary Outcomes (17)

• 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

  Baseline, Week 106

• Reduction From Baseline of at Least 1 Stage of Histologic Fibrosis (METAVIR Staging) in the Centrally Read Liver Biopsy

  Baseline, Week 106 and Week 202

• Number of Participants With Liver Related Clinical Events up to Week 202

  Baseline up to Week 202

• Change From Baseline in Serum Z-Alpha-1 Antitrypsin (Z-AAT) Protein

  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

  Baseline, Week 106, Week 202

Study Arms (2)

Fazirsiran

EXPERIMENTAL

Participants will receive fazirsiran 200 milligram per milliliter (mg/ml) subcutaneous (SC) injection on Day 1, at Week 4, and then every 12 weeks (Q12 W) thereafter up to Week 196.

Drug: Fazirsiran Injection

Placebo

PLACEBO COMPARATOR

Participants will receive placebo on Day 1, at Week 4, and Q12 W thereafter up to Week 196.

Other: Placebo

Interventions

Fazirsiran Injection DRUG

Participants will receive fazirsiran 200 mg/ml SC injection on Day 1, at Week 4, and Q12 W thereafter up to Week 196.

Also known as: TAK-999, ARO-AAT, ADS-001

Fazirsiran

Placebo OTHER

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.

Also known as: Sodium chloride

Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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) between 18.0 and 39.0 kilograms per meter square (kg\^m2), inclusive.
• The participant is a nonsmoker for at least 6 months before screening.

You may not qualify if:

• The participant has a history of liver decompensating events (overt hepatic encephalopathy \[West Haven Grade \>=2\] documented by a physician, 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 other forms of chronic liver 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 deciliter \[g/L\]).
• 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.

Sponsors & Collaborators

• Takeda: lead
• Takeda Development Center Americas, Inc.: collaborator

Study Sites (89)

University of Alabama at Birmingham

Birmingham, Alabama, 35233, United States

RECRUITING

St. Joseph's Hospital and Medical Center

Phoenix, Arizona, 85013, United States

RECRUITING

Mayo Clinic

Phoenix, Arizona, 85054-4502, United States

RECRUITING

University of Arizona Thomas D. Boyer Liver Institute

Tucson, Arizona, 85724-5136, United States

WITHDRAWN

Gastroenterology & Liver Institute

Escondido, California, 92025, United States

WITHDRAWN

University of California San Diego, Altman Clinical and Translational Institute

La Jolla, California, 92093, United States

RECRUITING

UCLA Pulmonary and Critical Care

Los Angeles, California, 90095-8344, United States

RECRUITING

Stanford University

Palo Alto, California, 94303, United States

RECRUITING

University of California Benioff Children's Hospital

San Francisco, California, 94143, United States

RECRUITING

Peak Gastroenterology Associates, PC

Colorado Springs, Colorado, 80907, United States

RECRUITING

University of Florida

Gainesville, Florida, 32611, United States

RECRUITING

Schiff Center for Liver Diseases/University of Miami

Miami, Florida, 33136-1051, United States

RECRUITING

Children's Healthcare of Atlanta

Atlanta, Georgia, 30329, United States

WITHDRAWN

Indiana University School of Medicine - Indianapolis

Indianapolis, Indiana, 46202, United States

RECRUITING

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

RECRUITING

Ochsner Medical Center

New Orleans, Louisiana, 70121-2429, United States

RECRUITING

University of Maryland Medical Center

Baltimore, Maryland, 21201-1504, United States

RECRUITING

Brigham and Womens Hospital

Boston, Massachusetts, 02115, United States

RECRUITING

Boston Medical Center

Boston, Massachusetts, 02118-2908, United States

RECRUITING

University of Michigan Hospital

Ann Arbor, Michigan, 48109, United States

RECRUITING

Henry Ford Medical Center - Columbus

Novi, Michigan, 48377-3600, United States

RECRUITING

Mayo Clinic - PPDS

Rochester, Minnesota, 55905-0001, United States

RECRUITING

Cardinal Glennon Children's Hospital

St Louis, Missouri, 63104-1003, United States

RECRUITING

Washington University School of Medicine in St. Louis

St Louis, Missouri, 63110, United States

RECRUITING

NYU Langone Health

New York, New York, 10016, United States

RECRUITING

Morgan Stanley Childrens Hospital of New York Presbyterian (CHONY) - PIN

New York, New York, 10032-1559, United States

WITHDRAWN

Columbia University Irving Medical Center

New York, New York, 10032-3722, United States

RECRUITING

University Hospitals Cleveland Medical Center

Cleveland, Ohio, 44106-1716, United States

RECRUITING

Penn State Health Milton S. Hershey Medical Center

Hershey, Pennsylvania, 17033, United States

RECRUITING

Temple University Hospital

Philadelphia, Pennsylvania, 19140-5103, United States

RECRUITING

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

RECRUITING

Vanderbilt University Medical Center

Nashville, Tennessee, 37232-0028, United States

RECRUITING

Texoma Liver Center

Denison, Texas, 75020, United States

RECRUITING

Baylor College of Medicine Medical Center

Houston, Texas, 77030-4202, United States

RECRUITING

The Texas Liver Institute

San Antonio, Texas, 78215, United States

RECRUITING

Bon Secours St. Mary's Hospital

Richmond, Virginia, 23226, United States

RECRUITING

VCU Medical Center North Hospital

Richmond, Virginia, 23298-5028, United States

RECRUITING

Royal Adelaide Hospital

Adelaide, South Australia, 5000, Australia

WITHDRAWN

St Vincents Hospital Melbourne - PPDS

Fitzroy, Victoria, 3065, Australia

RECRUITING

LKH-Universitätsklinikum Graz

Graz, 8036, Austria

RECRUITING

Medizinische Universität Innsbruck

Innsbruck, 6020, Austria

RECRUITING

Klinikum Klagenfurt Am Wörthersee

Klagenfurt, 9020, Austria

RECRUITING

Medizinische Universität Wien (Medical University of Vienna)

Vienna, 1090, Austria

RECRUITING

UZ Antwerpen

Antwerp, 2650, Belgium

RECRUITING

UZ Leuven

Leuven, 3000, Belgium

RECRUITING

Hospital de Base do Distrito Federal

Brasília, 71692-000, Brazil

RECRUITING

Hospital Sirio-Libanes

São Paulo, 01308-050, Brazil

RECRUITING

Universidade Estadual Paulista Julio de Mesquita Filho Faculdade de Medicina Campus de Botucatu

São Paulo, 18618-687, Brazil

RECRUITING

GI Research Institute

Vancouver, British Columbia, V6Z 2K5, Canada

RECRUITING

Queen Elizabeth II Health Sciences Center

Halifax, Nova Scotia, B3H 2Y9, Canada

RECRUITING

Inspiration Research Limited

Toronto, Ontario, M5T 3A9, Canada

RECRUITING

Institut klinicke a experimentalni mediciny

Prague, 140 21, Czechia

RECRUITING

Hvidovre Hospital

Hvidovre, 2650, Denmark

RECRUITING

Hôpital Beaujon

Clichy, 92110, France

RECRUITING

Hôpital de La Croix Rousse

Lyon, 69317, France

RECRUITING

Centre Francois Magendie

Pessac, 33064, France

RECRUITING

Hopital PONTCHAILLOU CHU de Rennes

Rennes, 35000, France

RECRUITING

Hospital Purpan

Toulouse, 31000, France

RECRUITING

Hôpital Paul Brousse

Val-de-Marne, 94805, France

RECRUITING

Universitätsklinikum der RWTH Aachen

Aachen, 52074, Germany

RECRUITING

Charité - Campus Virchow-Klinikum-Ostring 1

Berlin, 13353, Germany

RECRUITING

Hannover Medical School

Hanover, 30625, Germany

RECRUITING

Universitätsklinikum Schleswig-Holstein - Campus Kiel

Kiel, 24105, Germany

RECRUITING

Universitätsklinikum Tübingen

Tübingen, 72076, Germany

RECRUITING

Beaumont Hospital

Dublin, D09 YD60, Ireland

RECRUITING

Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico

Milan, 20122, Italy

RECRUITING

Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone

Palermo, 90127, Italy

RECRUITING

Fondazione IRCCS Policlinico San Matteo di Pavia

Pavia, 27100, Italy

RECRUITING

IRCCS Istituto Clinico Humanitas

Rozzano, 20089, Italy

RECRUITING

Amsterdam UMC - VUmc - De Boelelaan

Amsterdam, 1081 HV, Netherlands

WITHDRAWN

Leiden University Medical Center

Leiden, 2333 ZA, Netherlands

RECRUITING

ID Clinic Arkadiusz Pisula

Śląskie, 41-400, Poland

WITHDRAWN

WIP Warsaw IBD Point Profesor Kierkus

Warsaw, 00-728, Poland

RECRUITING

CCA Hospital Braga

Braga, 4710-243, Portugal

RECRUITING

Hospital Nélio Mendonça

Funchal, 9000-168, Portugal

RECRUITING

Centro Hospitalar do Porto

Porto, 4099-003, Portugal

RECRUITING

Hospital Universitario Vall d'Hebron - PPDS

Barcelona, 8025, Spain

RECRUITING

Hospital Universitario Virgen de la Victoria

Málaga, 29071, Spain

RECRUITING

Hospital Universitario Marques de Valdecilla

Santander, 39008, Spain

RECRUITING

Hospital Universitario Virgen del Rocio - PPDS

Seville, 41013, Spain

RECRUITING

Karolinska Universitetssjukhuset Huddinge

Huddinge, 14186, Sweden

RECRUITING

Universitetssjukhuset i Linköping

Linköping, 581 85, Sweden

RECRUITING

Inselspital Bern

Bern, 3010, Switzerland

RECRUITING

Addenbrooke's Hospital

Cambridge, CB2 0QQ, United Kingdom

RECRUITING

Royal Infirmary of Edinburgh

Edinburgh, EH16 4SA, United Kingdom

RECRUITING

Royal Free Hospital

London, NW3 2Q, United Kingdom

RECRUITING

King's College Hospital

London, SE5 9RS, United Kingdom

RECRUITING

Queen's Medical Centre

Nottingham, NG7 2UH, United Kingdom

WITHDRAWN

Derriford Hospital

Plymouth, PL6 8DH, United Kingdom

RECRUITING

Related Links

• To obtain more information on the study, click here/on this link

MeSH Terms

Conditions

alpha 1-Antitrypsin Deficiency

Interventions

Sodium Chloride

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Subcutaneous Emphysema; Emphysema; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Study Director

  Takeda

  STUDY DIRECTOR

Central Study Contacts

Takeda Contact

CONTACT

1-877-825-3327; medinfoUS@takeda.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 28, 2022
• First Posted: January 10, 2023
• Study Start: March 6, 2023
• Primary Completion (Estimated): February 17, 2028
• Study Completion (Estimated): August 14, 2030
• Last Updated: March 5, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, 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.

Locations

DE (5); BE (2); AU (4); PT (3); ES (4); FR (6); BR (3); IE (1); DK (1); PL (2); IT (4); CZ (1); US (37); SE (2); NL (2); GB (6); CH (1); CA (3)