An Extension Study to Learn About the Long-Term Safety of Fazirsiran and if Fazirsiran Can Help People With Alpha-1 Antitrypsin Liver Disease

NCT05899673 | Active Not Recruiting Phase 3 DMC FDA Drug

• 2 other identifiers: TAK-999-30032023-503497-21-00
• Study Type: interventional
• Target: 31
• Locations: 5 countries
• Sites: 10

Brief Summary

The main aim of this study is to learn if fazirsiran is safe during long-term use in people with liver disease caused by the abnormal Z-alpha-1 antitrypsin (Z-AAT) protein. People who have taken part in previous fazirsiran studies (AROAAT2001 \[NCT03945292\] or AROAAT2002 \[NCT03946449\]) can continue to receive fazirsiran every 3 months as long as they participate in this study, the study is ongoing or until health authorities in their country approve fazirsiran to be publicly available. The study may also provide information on whether fazirsiran has a long-term effect in reducing liver fibrosis or slowing down the progression of liver fibrosis in people with liver disease due to the abnormal Z-AAT protein.

Conditions

Alpha1-Antitrypsin Deficiency

Outcome Measures

Primary Outcomes (4)

• 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 (in current study) up to End of study (EOS) (current study [up to 10 years])

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

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

  Baseline (current study), up to EOS (current study up to 10 years])

• Number of Participants With Clinically Significant Changes in Vital Signs

  Vital signs include body temperature, respiratory rate, sitting blood pressure (systolic and diastolic, resting more than 5 minutes), pulse, oxygen saturation. Clinical significance of vital signs will be determined at the investigator's discretion.

  From start of study drug administration (in current study) up to EOS (current study [up to 10 years])

• Number of Participants With Clinically Significant Changes in Laboratory Parameters

  Laboratory parameters 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 (in current study) up to EOS (current study [up to 10 years])

Secondary Outcomes (6)

• Number of Participants With no Progression from Baseline of At least 1 Stage of Histologic Fibrosis on Liver Biopsy at Week 102

  At Week 102 (current study)

• Number of Participants With Reduction from Baseline of At least 1 Stage of Histologic Fibrosis on Liver Biopsy at Week 102

  At Week 102 (current study)

• 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 102

  Baseline (current study), Week 102 (current study)

• Change from Baseline in Intrahepatic Portal Inflammation Score at Week 102 in Liver Biopsy

  Baseline (current study), Week 102 (current study)

• Change from Baseline in Liver Stiffness Assessed by Magnetic Resonance Elastography (MRE)

  Baseline (current study), up to EOS (current study up to 10 years])

Study Arms (1)

Fazirsiran 200 mg

EXPERIMENTAL

Participants who are currently taking part in or who have completed their treatment in parent studies AROAAT2001 (NCT03945292) and AROAAT2002 (NCT03946449) may rollover in this study to receive fazirsiran, 200 milligrams (mg), injection, subcutaneously on Day 1 and once every 12 weeks (Q12W) thereafter until fazirsiran receives approval and is commercially available in the participant's country, until a participant withdraws from the study or the sponsor decides to terminate the study.

Drug: Fazirsiran Injection

Interventions

Fazirsiran Injection DRUG

Fazirsiran will be injected subcutaneously.

Also known as: TAK-999, ARO-AAT

Fazirsiran 200 mg

Eligibility Criteria

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

You may qualify if:

• The participant is willing and able to understand and fully comply with study procedures and requirements, in the opinion of the investigator.
• The participant is able to read, understand, and complete the study questionnaires electronically per investigator's judgment.
• The participant has provided informed consent (ICF) (that is, in writing, documented via a signed and dated ICF) and any required privacy authorization before the initiation of any study procedures.
• Note: For participants who comprehend, can provide informed consent, and are unable to sign the ICF, an impartial witness may sign the ICF on behalf of the participant after the participant has orally consented to the participant's participation in the study.
• The participant enrolling in this open-label extension (OLE) study will have participated in a previously qualifying study, and will be considered for eligibility based on the following study-specific criteria:
• AROAAT2001:
• Participants with fibrosis may roll over into this OLE study after they reach their next regularly scheduled, Q12W visit.
• Participants with fibrosis who have completed the AROAAT2001 study may be enrolled into the OLE study.
• AROAAT2002:
• Participants in Cohorts 1 and 1b may roll over after completing the 24-week primary study period.
• Participants in Cohort 2 may roll over after completing the 48-week primary study period.
• Participants who have completed the study may be enrolled into the OLE study.
• The participant is a nonsmoker (defined as: does not smoke cigarettes daily for at least 24 weeks) with current nonsmoking status confirmed by urine cotinine at Day 1.
• E-cigarettes (vapor) are not permitted.
• The participant may be on nicotine replacement (patch or gum). A positive urine cotinine result due to nicotine replacement is acceptable for enrollment at the discretion of the investigator.

You may not qualify if:

• The participant is likely to require major surgery. Major surgery typically requires at least 1 night in the hospital. Examples include laparoscopic surgery (except cholecystectomy and tubal ligation); Gastrointestinal tract (GI) tract surgery including 1 or more segments of the colon or terminal ileum; open resection of organs; large joint replacements; mastectomy with reconstruction; and spine, thoracic, vascular, or intracranial surgery.
• 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 abnormal finding(s) of clinical relevance during the evaluation before the first study dosing that, in the opinion of the investigator, could adversely impact participant safety during the study or adversely impact study results. For US only: Participants with baseline emphysema may be allowed into the OLE if their lung disease has been stable.
• The participant had major protocol deviation(s) in AROAAT2001 or AROAAT2002 that would affect the conduct of this study.
• The participant permanently discontinued investigational product because of an AE, adjudicated as related to the study intervention, in AROAAT2001 or AROAAT2002.
• Female participants who became pregnant during Study AROAAT2001 or AROAAT2002, female participants who are lactating or planning to become pregnant during the study period; or males or female participants of childbearing potential not agreeing to continue using appropriate contraception methods through the conclusion of study participation.
• The participant has a Child-Turcotte-Pugh (CTP) score \>=7 OR (Model for End-Stage Liver Disease) MELD score \>14.
• Participants who have a newly-diagnosed malignancy or recurrence of malignancy (except for resected cutaneous basal cell carcinoma, squamous cell carcinoma, superficial bladder tumors, or carcinoma in situ of the uterine cervix that has been treated with no evidence of recurrence).
• The participant is experiencing a pulmonary exacerbation at the time of enrollment (participant enrollment may be temporarily delayed after the clinical resolution of an exacerbation).
• The participant has unstable, poorly controlled, or severe hypertension. Participants may be reevaluated once their blood pressure is successfully controlled.
• The participant has a history of more than moderate alcohol consumption within 12 months before the Day 1 visit.
• The participant has a history of hypersensitivity or allergies to fazirsiran or any associated excipients.
• The participant has any concomitant medical or psychiatric condition or social situation that would make it difficult to comply with protocol requirements or put the participant at additional safety risk.
• The participant has a history of thromboembolic disease (including deep vein thrombosis or pulmonary embolism), within 24 weeks before enrollment; or is taking chronic anticoagulants. (Note: Participants taking stable doses of chronic anticoagulants may be allowed after consultation with the medical monitor, if they do not have cirrhosis or a history of liver decompensating events).
• The participant is unable to return for all scheduled study visits.

Sponsors & Collaborators

• Takeda: lead

Study Sites (10)

UCSD Altman Clinical and Translational Research Institute

La Jolla, California, 92037-1337, United States

Location

Stanford Medicine Outpatient Center

Redwood City, California, 94063, United States

Location

UF Clinical and Translational Science Institute

Gainesville, Florida, 32610-3010, United States

Location

University Of Iowa Hospitals And Clinics

Iowa City, Iowa, 52242-1009, United States

Location

Medical University of South Carolina - Hollings Cancer Center - PPDS

Charleston, South Carolina, 29425-8900, United States

Location

Medizinische Universitat Wien (Medical University of Vienna)

Vienna, A-1090, Austria

Location

Universitätsklinikum der RWTH Aachen

Aachen, North Rhine-Westphalia, 52074, Germany

Location

Hospital Nélio Mendonça

Funchal, 9000-168, Portugal

Location

Addenbrooke's Hospital

Cambridge, CB2 0QQ, United Kingdom

Location

Royal Infirmary of Edinburgh - PPDS

Edinburgh, EH16 4SA, United Kingdom

Location

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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 2, 2023
• First Posted: June 12, 2023
• Study Start: August 8, 2023
• Primary Completion (Estimated): May 2, 2033
• Study Completion (Estimated): May 2, 2033
• Last Updated: October 14, 2025

Record last verified: 2025-10

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

US (5); PT (1); DE (1); AU (1); GB (2)