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NCT05677971PHASE3Recruiting

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

Takeda

Start Date

3/6/2023

Completion Date

12/12/2031

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 Criteria

Age Range: 18 years to 75 years

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.

Interventions

DRUG

Fazirsiran Injection

OTHER

Placebo

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Conditions

Alpha1-Antitrypsin Deficiency

Locations

University of Alabama at Birmingham

Birmingham, Alabama 35233

United States

St. Joseph's Hospital and Medical Center

Phoenix, Arizona 85013

United States

Mayo Clinic

Phoenix, Arizona 85054-4502

United States

University of Arizona Thomas D. Boyer Liver Institute

Tucson, Arizona 85724-5136

United States

Gastroenterology & Liver Institute

Escondido, California 92025

United States

University of California San Diego, Altman Clinical and Translational Institute

La Jolla, California 92093

United States

UCLA Pulmonary and Critical Care

Los Angeles, California 90095-8344

United States

Stanford University

Palo Alto, California 94303

United States

University of California Benioff Children's Hospital

San Francisco, California 94143

United States

Peak Gastroenterology Associates, PC

Colorado Springs, Colorado 80907

United States

University of Florida

Gainesville, Florida 32611

United States

Schiff Center for Liver Diseases/University of Miami

Miami, Florida 33136-1051

United States

Children's Healthcare of Atlanta

Atlanta, Georgia 30329

United States

Indiana University School of Medicine - Indianapolis

Indianapolis, Indiana 46202

United States

University of Iowa Hospitals and Clinics

Iowa City, Iowa 52242

United States

Ochsner Medical Center

New Orleans, Louisiana 70121-2429

United States

University of Maryland Medical Center

Baltimore, Maryland 21201-1504

United States

Brigham and Womens Hospital

Boston, Massachusetts 02115

United States

Boston Medical Center

Boston, Massachusetts 02118-2908

United States

University of Michigan Hospital

Ann Arbor, Michigan 48109

United States

Henry Ford Medical Center - Columbus

Novi, Michigan 48377-3600

United States

Mayo Clinic - PPDS

Rochester, Minnesota 55905-0001

United States

Cardinal Glennon Children's Hospital

St Louis, Missouri 63104-1003

United States

Washington University School of Medicine in St. Louis

St Louis, Missouri 63110

United States

NYU Langone Health

New York, New York 10016

United States

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

New York, New York 10032-1559

United States

Columbia University Irving Medical Center

New York, New York 10032-3722

United States

University Hospitals Cleveland Medical Center

Cleveland, Ohio 44106-1716

United States

Penn State Health Milton S. Hershey Medical Center

Hershey, Pennsylvania 17033

United States

Temple University Hospital

Philadelphia, Pennsylvania 19140-5103

United States

Medical University of South Carolina

Charleston, South Carolina 29425

United States

Vanderbilt University Medical Center

Nashville, Tennessee 37232-0028

United States

Texoma Liver Center

Denison, Texas 75020

United States

Baylor College of Medicine Medical Center

Houston, Texas 77030-4202

United States

The Texas Liver Institute

San Antonio, Texas 78215

United States

Bon Secours St. Mary's Hospital

Richmond, Virginia 23226

United States

VCU Medical Center North Hospital

Richmond, Virginia 23298-5028

United States

Royal Adelaide Hospital

Adelaide, South Australia 5000

Australia

St Vincents Hospital Melbourne - PPDS

Fitzroy, Victoria 3065

Australia

LKH-Universitätsklinikum Graz

Graz, 8036

Austria

Medizinische Universität Innsbruck

Innsbruck, 6020

Austria

Klinikum Klagenfurt Am Wörthersee

Klagenfurt, 9020

Austria

Medizinische Universität Wien (Medical University of Vienna)

Vienna, 1090

Austria

UZ Antwerpen

Antwerp, 2650

Belgium

UZ Leuven

Leuven, 3000

Belgium

Hospital de Base do Distrito Federal

Brasília, 71692-000

Brazil

Hospital Sirio-Libanes

São Paulo, 01308-050

Brazil

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

São Paulo, 18618-687

Brazil

GI Research Institute

Vancouver, British Columbia V6Z 2K5

Canada

Queen Elizabeth II Health Sciences Center

Halifax, Nova Scotia B3H 2Y9

Canada

Inspiration Research Limited

Toronto, Ontario M5T 3A9

Canada

Institut klinicke a experimentalni mediciny

Prague, 140 21

Czechia

Hvidovre Hospital

Hvidovre, 2650

Denmark

Hôpital Beaujon

Clichy, 92110

France

Hôpital de La Croix Rousse

Lyon, 69317

France

Centre Francois Magendie

Pessac, 33064

France

Hopital PONTCHAILLOU CHU de Rennes

Rennes, 35000

France

Hospital Purpan

Toulouse, 31000

France

Hôpital Paul Brousse

Val-de-Marne, 94805

France

Universitätsklinikum der RWTH Aachen

Aachen, 52074

Germany

Charité - Campus Virchow-Klinikum-Ostring 1

Berlin, 13353

Germany

Hannover Medical School

Hanover, 30625

Germany

Universitätsklinikum Schleswig-Holstein - Campus Kiel

Kiel, 24105

Germany

Universitätsklinikum Tübingen

Tübingen, 72076

Germany

Beaumont Hospital

Dublin, D09 YD60

Ireland

Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico

Milan, 20122

Italy

Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone

Palermo, 90127

Italy

Fondazione IRCCS Policlinico San Matteo di Pavia

Pavia, 27100

Italy

IRCCS Istituto Clinico Humanitas

Rozzano, 20089

Italy

Amsterdam UMC - VUmc - De Boelelaan

Amsterdam, 1081 HV

Netherlands

Leiden University Medical Center

Leiden, 2333 ZA

Netherlands

ID Clinic Arkadiusz Pisula

Śląskie, 41-400

Poland

WIP Warsaw IBD Point Profesor Kierkus

Warsaw, 00-728

Poland

CCA Hospital Braga

Braga, 4710-243

Portugal

Hospital Nélio Mendonça

Funchal, 9000-168

Portugal

Centro Hospitalar do Porto

Porto, 4099-003

Portugal

Hospital Universitario Vall d'Hebron - PPDS

Barcelona, 8025

Spain

Hospital Universitario Virgen de la Victoria

Málaga, 29071

Spain

Hospital Universitario Marques de Valdecilla

Santander, 39008

Spain

Hospital Universitario Virgen del Rocio - PPDS

Seville, 41013

Spain

Karolinska Universitetssjukhuset Huddinge

Huddinge, 14186

Sweden

Universitetssjukhuset i Linköping

Linköping, 581 85

Sweden

Inselspital Bern

Bern, 3010

Switzerland

Addenbrooke's Hospital

Cambridge, CB2 0QQ

United Kingdom

Royal Infirmary of Edinburgh

Edinburgh, EH16 4SA

United Kingdom

Royal Free Hospital

London, NW3 2Q

United Kingdom

King's College Hospital

London, SE5 9RS

United Kingdom

Queen's Medical Centre

Nottingham, NG7 2UH

United Kingdom

Derriford Hospital

Plymouth, PL6 8DH

United Kingdom