Study to Learn About the Safety of Fazirsiran and if it Can Help People With Alpha-1 Antitrypsin Liver Disease With Mild Liver Scarring (Fibrosis)

NCT06165341 | Recruiting Phase 3 DMC FDA Drug

• 2 other identifiers: TAK-999-30022023-504198-19-00
• Study Type: interventional
• Target: 50
• Locations: 13 countries
• Sites: 41

Brief Summary

The liver produces a protein called alpha-1 antitrypsin (AAT). AAT is normally released into the bloodstream. In some people, the liver makes an abnormal version of the AAT protein, called Z-AAT. Making an abnormal version of the AAT protein can result in liver disease as Z-AAT builds up in liver cells, which leads to liver problems such as liver scarring (fibrosis), continuing liver damage (cirrhosis), and eventually end stage liver disease. Fazirsiran is a medicine that reduces the creation of the Z-AAT protein and thus the build-up of this abnormal protein in the liver. People with this type of liver disease who already have mild liver scarring will take part in the study. They will be treated with fazirsiran or a placebo for about 2 years. This study will check the long-term safety of fazirsiran, whether participants tolerate the treatment and if there are any effects on liver scarring. A liver biopsy, a way of collecting a small tissue sample from the liver, will be taken twice during the study.

Conditions

Alpha1-Antitrypsin Deficiency

Outcome Measures

Primary Outcomes (6)

• Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs)

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of the study intervention, whether or not it is considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study intervention. An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, congenital anomaly/birth defect, suspected transmission of any infectious agent, an important medical event. AEs and SAEs including any pulmonary AEs or SAEs indicative of worsening pulmonary condition (example, pulmonary exacerbation, respiratory infection, significant pulmonary function test decline) will be reported.

  From start of study drug administration up to End of study (EOS) (Week 124)

• Number of Participants With Clinically Significant Change From Baseline in Pulmonary Function Parameters

  Standard pulmonary function parameters will be used to study lung function. Clinical significance of pulmonary function parameters will be determined at the investigator's discretion.

  From start of study drug administration up to EOS (Week 124)

• Change From Baseline in Whole Lung 15th Percentile Density as Measured by Computed Tomography (CT) Lung Densitometry

  Change from baseline in whole lung 15th percentile density as measured by CT lung densitometry will be assessed.

  Baseline up to Week 100

• Number of Participants With Clinically Significant Changes in Vital Signs

  Vital signs include body temperature, respiratory rate, blood pressure (systolic and diastolic), pulse (beats per minute) and pulse oximetry. Clinical significance of vital signs will be determined at the investigator's discretion.

  From start of study drug administration up to EOS (Week 124)

• Number of Participants with Clinically Significant Changes in Electrocardiogram (ECG) Parameters

  12-lead ECG will be evaluated. Any clinically significant change in ECG assessments will be determined at the investigator's discretion.

  From start of study drug administration up to EOS (Week 124)

• Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters

  Laboratory parameters assessments include hematology, biochemistry including liver tests, coagulation, and urinalysis. Clinical significance of laboratory parameters will be determined at the investigator's discretion.

  From start of study drug administration up to EOS (Week 124)

Secondary Outcomes (9)

• Change From Baseline in Serum Z-AAT Protein Over Time to Week 106

  Baseline up to Week 106

• Percent Change From Baseline in Intrahepatic Liver Z-AAT Protein at Week 106

  Baseline up to Week 106

• Change From Baseline in Intrahepatic Z-AAT Protein Polymer Burden Assessed by Periodic Acid Schiff Plus Diastase (PAS+D) Staining in Liver Biopsy at Week 106

  Baseline up to Week 106

• Number of Participants with No Change or Decrease From Baseline in Intrahepatic Z-AAT Protein Polymer Burden Assessed by PAS+D staining at Week 106

  Baseline up to Week 106

• Change From Baseline in Intrahepatic Portal Inflammation Score in Liver Biopsy at Week 106

  Baseline up to Week 106

Study Arms (2)

Fazirsiran 200 mg

EXPERIMENTAL

Participants will receive fazirsiran 200 milligrams (mg), injection, subcutaneously on Day 1, at Week 4 and then every 12 weeks (Q12W) for up to Week 100.

Drug: Fazirsiran Injection

Placebo

PLACEBO COMPARATOR

Participants will receive fazirsiran matching placebo injection, subcutaneously on Day 1, at Week 4 and Q12W for up to Week 100.

Drug: Placebo

Interventions

Fazirsiran Injection DRUG

Fazirsiran will be injected subcutaneously.

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

Fazirsiran 200 mg

Placebo DRUG

Fazirsiran matching placebo.

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:

• In the opinion of the investigator, the participant is capable of understanding and fully complying with the protocol requirements and adhering to the protocol schedule.
• The participant is able to read, understand, and complete the study questionnaires electronically per the investigator's judgment.
• The participant signs and dates a written Informed Consent Form (ICF). Any required privacy authorization should also be signed before the initiation of any study procedures.
• The participant, of any sex, is aged 18 to 75 years, inclusive.
• The participant must have a diagnosis of the protease inhibitor Z mutation (PiZZ) genotype AATD. A diagnosis of PiZZ 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's liver biopsy core samples collected as per protocol requirements.
• The participant has evidence of METAVIR stage F1 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 from a previous biopsy conducted within 1 year 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 that meets the protocol requirements.
• It must be confirmed that the participant does not have hepatocellular carcinoma (HCC).
• Any participant who is taking statins, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, or beta-1 selective adrenergic receptor inhibitors must have been receiving a stable dose of these medications for at least 8 weeks before randomization. All attempts are to be made for the participant to continue the same dose of the medication for the duration of study participation.
• An adult participant must have a body mass index (BMI) between 18 and 39 kilogram per meter square (kg/m\^2), inclusive.
• The participant has a 12-lead electrocardiogram at screening that, in the opinion of the investigator, has no abnormalities that could compromise the participant's safety in this study.
• The participant is a nonsmoker.
• If the participant was being treated with any respiratory medications including inhaled bronchodilators, inhaled anticholinergics, inhaled corticosteroids, or low-dose systemic corticosteroids (prednisone less than or equal to \[\<=10\] milligrams per day \[mg/d\] or its equivalent), the doses of the participant's medications must have remained unchanged for greater than or equal to (\>=) 4 weeks before screening.
• The participant must have suitable venous access for blood sampling.

You may not qualify if:

• The participant has evidence of \>= F2 fibrosis based on liver biopsy during the screening period.
• The participant has a history of liver decompensating events.
• The participant has a history of varices based on a previous esophagogastroduodenoscopy.
• The participant has portal vein thrombosis.
• The participant has undergone a prior trans-jugular portosystemic shunt procedure.
• The participant has evidence of other forms of chronic liver diseases.
• 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 curatively treated malignancies who have no evidence of metastatic disease and disease-free interval greater than (\>) 1 year may be enrolled after approval by the medical monitor.
• The participant has an abnormal finding of clinical relevance at the screening evaluation and before administration of the first dose of study dosing that, in the opinion of the investigator, could adversely impact participant safety during the study or adversely impact study results.
• The participant has any laboratory abnormalities at screening and before the first dose of the study drug that meet protocol parameters.
• 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 recent lower respiratory tract infection, such as pneumonia, within the last 6 months before screening. The participant may be screened earlier based on principal investigator (PI) assessment of clinical recovery and return to baseline pulmonary function in discussion with the medical monitor.
• The participant has a history of frequent pulmonary exacerbations (\>=2 moderate or severe exacerbations within 52 weeks before screening).
• The participant is experiencing a pulmonary exacerbation at the time of screening (participant may be rescreened after the clinical resolution of an exacerbation).
• The participant is receiving long-term, around-the-clock oxygen supplementation or supplemental oxygen with continuous positive airway pressure (CPAP) or bilevel positive airway pressure for acute respiratory failure. The following conditions are allowable for the participant to enter screening: short-term use of oxygen supplementation (example, for the management of acute chronic obstructive pulmonary disease \[COPD\] exacerbation) or CPAP for obstructive sleep apnea.
• The participant has human immunodeficiency virus (HIV) infection as shown by the presence of anti-HIV antibody (seropositive).

Sponsors & Collaborators

• Takeda: lead

Study Sites (41)

St Joseph's Hospital and Medical Center

Phoenix, Arizona, 85013-4224, United States

RECRUITING

Mayo Clinic - PPDS

Phoenix, Arizona, 85054-4502, United States

RECRUITING

University of Arizona Thomas D. Boyer Liver Institute

Tucson, Arizona, 85724-0001, United States

RECRUITING

University of California San Diego

La Jolla, California, 92037-1337, United States

RECRUITING

UCLA Pulmonary and Critical Care

Los Angeles, California, 90095-3075, United States

RECRUITING

University of California Benioff Children's Hospital

San Francisco, California, 94143-2203, United States

RECRUITING

Peak Gastroenterology Associates

Colorado Springs, Colorado, 80907, United States

RECRUITING

Schiff Center for Liver Diseases/University of Miami

Miami, Florida, 33136, United States

RECRUITING

Indiana University School of Medicine-Indianapolis

Indianapolis, Indiana, 46202-2266, United States

RECRUITING

University Of Iowa Hospitals And Clinics

Iowa City, Iowa, 52242-1009, United States

RECRUITING

Boston Medical Center

Boston, Massachusetts, 02118-2335, United States

RECRUITING

University of Michigan Hospital - 1500 E Medical Center Dr

Ann Arbor, Michigan, 48109, United States

RECRUITING

Henry Ford Health System

Novi, Michigan, 48377-3600, United States

RECRUITING

Mayo Clinic PPDS

Rochester, Minnesota, 55905, United States

RECRUITING

NYU Langone Medical Center

New York, New York, 10016-6402, United States

RECRUITING

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, 17033-2360, United States

RECRUITING

Texas Liver Institute American Research Corporation

San Antonio, Texas, 78215, United States

RECRUITING

Bon Secours St. Mary's Hospital

Newport, Virginia, 23602-4414, United States

RECRUITING

LKH-Universitätsklinikum Graz

Graz, 8036, Austria

RECRUITING

KABEG - Klinikum Klagenfurt Am Wörthersee

Klagenfurt, 9020, Austria

RECRUITING

UZ Antwerpen

Antwerp, 2650, Belgium

RECRUITING

UZ Leuven

Leuven, 3000, Belgium

RECRUITING

Inspiration Research Limited

Toronto, Ontario, M5T 3A9, Canada

RECRUITING

Hôpital de La Croix Rousse

Lyon, 69317, France

RECRUITING

Hopital PONTCHAILLOU CHU de Rennes

Rennes, 35000, France

RECRUITING

Hôpital Paul Brousse

Val-de-Marne, 94800, France

RECRUITING

Universitätsklinikum der RWTH Aachen

Aachen, 52074, Germany

RECRUITING

Charité - Campus Virchow-Klinikum

Berlin, 13353, Germany

RECRUITING

Hannover Medical School

Hanover, 30625, Germany

RECRUITING

Universitätsklinikum Tübingen

Tübingen, 72076, Germany

RECRUITING

Fondazione IRCCS Policlinico San Matteo

Pavia, 27100, Italy

RECRUITING

ID Clinic Arkadiusz Pisula

Mysłowice, 41-400, Poland

WITHDRAWN

CCA Hospital Braga

Braga, 4710-243, Portugal

RECRUITING

Hospital Dr. Nélio Mendonça

Funchal, 9000-168, Portugal

RECRUITING

Centro Hospitalar de Universitário de Santo António E.P.E

Porto, 4099-001, Portugal

RECRUITING

Hospital Universitario Virgen del Rocio - PPDS

Seville, 41018, Spain

RECRUITING

Karolinska Universitetssjukhuset Huddinge

Huddinge, 14186, Sweden

RECRUITING

Universitätsspital Bern

Bern, 3010, Switzerland

RECRUITING

King's College Hospital

London, SE5 9RS, United Kingdom

RECRUITING

Related Links

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

MeSH Terms

Conditions

alpha 1-Antitrypsin Deficiency

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

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: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 1, 2023
• First Posted: December 11, 2023
• Study Start: March 1, 2024
• Primary Completion (Estimated): August 26, 2028
• Study Completion (Estimated): August 26, 2028
• 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

BE (2); IT (1); FR (3); US (20); DE (4); PT (3); PL (1); ES (1); SE (1); AU (2); CA (1); CH (1); GB (1)