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

• ClinicalTrials.gov Identifier: NCT05899673
• Recruitment Status: Enrolling by invitation
• First Posted: June 12, 2023
• Last Update Posted: March 15, 2024
• Sponsor: Takeda
• Information provided by (Responsible Party): Takeda

Study Description

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 are currently taking part in or have completed previous fazirsiran studies (AROAAT2001 [NCT03945292] or AROAAT2002 [NCT03946449]) can continue to receive fazirsiran in this study. Participants will receive fazirsiran every 3 months for almost 2 years and will then be followed for an additional 6 months. 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.

Condition or disease	Intervention/treatment	Phase
Alpha1-Antitrypsin Deficiency	Drug: Fazirsiran Injection	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 37 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Open-Label Extension Study to Evaluate the Long-Term Safety and Efficacy of Fazirsiran in Participants With Alpha-1 Antitrypsin Deficiency-Associated Liver Disease
• Actual Study Start Date: August 8, 2023
• Estimated Primary Completion Date: May 29, 2026
• Estimated Study Completion Date: May 29, 2026

Arms and Interventions

Arm

Intervention/treatment

Experimental: Fazirsiran 200 mg; 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 for up to 96 weeks or until participant withdraws from the study or the sponsor terminates the study.

Drug: Fazirsiran Injection; Fazirsiran will be injected subcutaneously.; Other Names: TAK-999; ARO-AAT

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) [ Time Frame: From start of study drug administration (in current study) up to End of study (EOS) (current study [up to Week 120]) ]
   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.
2. Number of Participants With Clinically Significant Changes From Baseline in Pulmonary Function Parameters [ Time Frame: Baseline (current study), Weeks 12, 24, 36, 48, 60, 72, 84, 96, EOS (current study [Week 120]) ]
   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.
3. Number of Participants With Clinically Significant Changes in Vital Signs [ Time Frame: From start of study drug administration (in current study) up to EOS (current study [up to Week 120]) ]
   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.
4. Number of Participants With Clinically Significant Changes in Laboratory Parameters [ Time Frame: From start of study drug administration (in current study) up to EOS (current study [up to Week 120]) ]
   Laboratory parameters include hematology, biochemistry including liver tests, coagulation, and urinalysis. Clinical significance of laboratory parameters will be determined at the investigator's discretion.

Secondary Outcome Measures :

1. Number of Participants With no Progression from Baseline of At least 1 Stage of Histologic Fibrosis on Liver Biopsy at Week 102 [ Time Frame: At Week 102 (current study) ]
   Number of participants with no progression from baseline of at least 1 stage of histologic fibrosis (by Meta-Analysis of Histological Data in Viral Hepatitis [METAVIR] staging) on liver biopsy at Week 102 will be reported.
2. Number of Participants With Reduction from Baseline of At least 1 Stage of Histologic Fibrosis on Liver Biopsy at Week 102 [ Time Frame: At Week 102 (current study) ]
   Number of participants with baseline fibrosis of F1 or higher, a decrease from baseline of at least 1 stage of histologic fibrosis (by METAVIR staging) on liver biopsy at Week 102 will be reported.
3. 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 [ Time Frame: Baseline (current study), Week 102 (current study) ]
   Change from baseline in intrahepatic Z-AAT protein polymer burden assessed by PAS+D staining in liver biopsy will be assessed.
4. Change from Baseline in Intrahepatic Portal Inflammation Score at Week 102 in Liver Biopsy [ Time Frame: Baseline (current study), Week 102 (current study) ]
   Change in portal inflammation score in liver biopsy, based on pathology slide reads. Inflammation will be assessed on a scale of 0-3, with higher scores showing more severe inflammation.
5. Change from Baseline in Hepatic Stiffness Assessed by Magnetic Resonance Elastography (MRE) at Weeks 48 and 96 [ Time Frame: Baseline (current study), Weeks 48 and 96 (current study) ]
   Change from baseline in MRE-derived liver stiffness will be assessed.
6. Change from Baseline in Vibration-Controlled Transient Elastography (VCTE) at 48 Week Intervals Through Week 102 [ Time Frame: Baseline (current study), at 48 Week intervals through Week 102 ]
   Change from baseline in VCTE-derived liver stiffness will be assessed.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Participants must meet all of the following criteria to be eligible for inclusion in the study:
• 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: A legally acceptable representative may sign an ICF in cases of participants who can give informed consent but are unable to sign for themselves. Persons incapable of giving informed consent are excluded from 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 roll over.

• 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.
• The participant must have suitable venous access for blood sampling.

• It must be confirmed that the participant does not have hepatocellular carcinoma (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 computed tomography (CT) or magnetic resonance imaging (MRI) imaging to exclude HCC before enrollment.

  • AFP >20 nanogram per milliliter (ng/mL).
  • AFP 15 to 19 ng/mL at enrollment if that is >2 times prestudy levels (if available).
  • Any liver lesion >10 millimeter (mm) (longest diameter) detected by ultrasound.
  • Poor visibility of liver on ultrasound.
• A person of childbearing potential (POCBP) must have a negative urine pregnancy test performed within 3 days prior to Day 1 dosing in this study (sensitive to 25 International Unit [IU] human chorionic gonadotropin [hCG]).
• The participant must use appropriate contraception methods (i.e., highly effective methods for female and medically appropriate methods for male study participants) for the entire duration of the study and for 24 weeks after the last dose of study medication. Males must not donate sperm for at least 24 weeks after the last dose of study medication.
• Sexual abstinence, for the purposes of this study, is only considered a highly effective method of contraception when considered to align with the preferred and usual lifestyle of the participant. It will be employed for the entire duration of the study and the 24 weeks after last dose of study medication.
• Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea methods are not considered "true" abstinence and are not acceptable methods of contraception.

Exclusion Criteria:

• The participant will be excluded from the study if any of the following exclusion criteria are met:
• 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 cirrhosis, 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.
• 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 drug, 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.
• The participant meets Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Creatinine criteria as per the protocol.
• 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 clinically significant hematologic, renal, hepatic, cardiovascular, infectious, pulmonary, neurologic, psychiatric, GI, systemic inflammatory, metabolic, or endocrine disorder or any other condition that, in the opinion of the investigator, rendered the participant a poor candidate for inclusion into the study.
• 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.
• The participant is unable to return for all scheduled study visits.
• The participant has known or suspected coronavirus disease 2019 (COVID-19) at enrollment. Positive antibody testing for COVID-19 without other evidence of current or recent active infection does not exclude participation. Enrollment of participants who fail inclusion due to COVID-19 infection may be temporarily delayed at the discretion of the sponsor and investigator.
• The participant is a study site employee, an immediate family member (example, spouse, parent, child, sibling), or is in a dependent relationship with a study site employee who is involved in conduct of this study, or may consent under duress.
• The participant who, in the opinion of the investigator or the sponsor, will be uncooperative or unable to comply with study procedures.
• The participant who participates in other studies involving an investigational product.

Contacts and Locations

Locations

United States, Alabama

UAB Hospital Clinical Research Unit

Birmingham, Alabama, United States, 35233-1900

United States, California

UCSD Altman Clinical and Translational Research Institute

La Jolla, California, United States, 92037-1337

Stanford Medicine Outpatient Center

Redwood City, California, United States, 94063

United States, Florida

UF Clinical and Translational Science Institute

Gainesville, Florida, United States, 32610-3010

United States, Iowa

University Of Iowa Hospitals And Clinics

Iowa City, Iowa, United States, 52242-1009

United States, New York

Columbia University Medical Center

New York, New York, United States, 10032-3725

United States, South Carolina

Medical University of South Carolina - Hollings Cancer Center - PPDS

Charleston, South Carolina, United States, 29425-8900

Austria

Medizinische Universitat Wien (Medical University of Vienna)

Vienna, Austria, A-1090

Germany

Universitätsklinikum der RWTH Aachen

Aachen, Nordrhein-Westfalen, Germany, 52074

Portugal

Hospital Nélio Mendonça

Funchal, Portugal, 9000-168

United Kingdom

Addenbrooke's Hospital

Cambridge, United Kingdom, CB2 0QQ

Royal Infirmary of Edinburgh - PPDS

Edinburgh, United Kingdom, EH16 4SA

Sponsors and Collaborators

Takeda

Investigators

• Study Director: Study Director; Takeda

More Information

Additional Information:

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

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT05899673
• Other Study ID Numbers: TAK-999-3003; 2023-503497-21 ( Registry Identifier: EU CTIS )
• First Posted: June 12, 2023
• Last Update Posted: March 15, 2024
• Last Verified: March 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (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.
• URL: https://vivli.org/ourmember/takeda/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:

Liver Diseases; Alpha 1-Antitrypsin Deficiency; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Subcutaneous Emphysema; Emphysema; Pathologic Processes