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Study of Fazirsiran (TAK-999, ARO-AAT) in Patients With Alpha-1 Antitrypsin Deficiency Associated Liver Disease (AATD)

Primary Purpose

Alpha 1-Antitrypsin Deficiency

Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Fazirsiran Injection (TAK-999, ARO-AAT)
Sponsored by
Arrowhead Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Alpha 1-Antitrypsin Deficiency

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Diagnosis of AATD
  • Women of childbearing potential must have a negative pregnancy test, cannot be breast feeding, and must be willing to use contraception
  • Willing to provide written informed consent and to comply with study requirements
  • Non-smoker for at least 1 year
  • No abnormal finding of clinical relevance at screening

Exclusion Criteria:

  • Clinically significant health concerns other than AATD
  • Previous diagnosis or diagnosis at Screening of definitive liver cirrhosis
  • Regular use of alcohol within one month prior to Screening
  • Use of an investigational agent or device within 30 days prior to dosing or current participation in an investigational study involving therapeutic intervention
  • Use of illicit drugs within 1 year prior to Screening

Note: additional inclusion/exclusion criteria may apply, per protocol

Sites / Locations

  • Medical University of Vienna Division of Gastroenterology and Hepatology
  • Universitatsklinikum Aachen, Anstalt des offentlich
  • Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust
  • Royal Infirmary of Edinburgh, NHS Lothian

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Fazirsiran (TAK-999, ARO-AAT) Cohort 1

Fazirsiran (TAK-999, ARO-AAT) Cohort 1b

Fazirsiran (TAK-999, ARO-AAT) Cohort 2

Arm Description

Administered on Day 1, Weeks 4 and 16 for a minimum of 3 doses. Treatment Extension (optional enrollment): Administered every 12 weeks for 12 additional doses.

Administered on Day 1, Weeks 4 and 16, for a minimum of 3 doses. Treatment Extension (optional enrollment): Administered every 12 weeks for 12 additional doses.

Administered on Day 1, Weeks 4, 16, 28 and 40 for a minimum of 5 doses. Treatment Extension (optional enrollment): Administered every 12 weeks for 12 additional doses.

Outcomes

Primary Outcome Measures

Change From Baseline Over Time in Total, Soluble, and Insoluble Z-Alpha 1 Antitrypsin (Z-AAT) Liver Concentrations

Secondary Outcome Measures

Change From Baseline Over Time in Circulating Levels of Z-AAT
Change From Baseline Over Time in Alanine Transaminase (ALT)
Change From Baseline Over Time in Gamma-Glutamyl Transferase (GGT)
Change From Baseline Over Time in Fibrosis-4 Index (FIB4)
Change From Baseline Over Time in Aspartate Transaminase (AST) to Platelet Ratio Index (APRI)
Change From Baseline Over Time in Plasma Collagen Type 3 (PRO-C3)
Change From Baseline Over Time in Hepatic Stiffness based on FibroScan (when available)
Change From Baseline Over Time in Histological Metrics of Liver Disease: Inflammation Score
Change in inflammation score, based on pathology slide reads. Inflammation was assessed on a scale of 0-3, with higher scores showing more severe inflammation.
Change From Baseline Over Time in Histological Metrics of Liver Disease: Steatosis Score
Change in steatosis score, based on pathology slide reads. Steatosis was assessed on a scale of 0-3, with higher scores showing more severe steatosis.
Change From Baseline Over Time in Histological Metrics of Liver Disease: Hepatocyte Cell Death Score
Change in hepatocyte cell death score, based on pathology slide reads. Hepatocyte cell death was assessed on a scale of 0-2, with higher scores showing more severe hepatocyte cell death.
Change From Baseline Over Time in Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Score
METAVIR scores range from F0 to F4 (F0=No Fibrosis, F1=Mild Fibrosis, F2= Significant Fibrosis, F3=Severe Fibrosis, F4=Cirrhosis). Higher scores indicate more severe fibrosis.
Number of Participants with Adverse Events (AEs) Possibly or Probably Related to Treatment
Incidence of Anti-Drug Antibodies (ADAs) to Fazirsiran
Titers of Anti-Drug Antibodies (ADAs) to Fazirsiran

Full Information

First Posted
May 8, 2019
Last Updated
June 3, 2023
Sponsor
Arrowhead Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT03946449
Brief Title
Study of Fazirsiran (TAK-999, ARO-AAT) in Patients With Alpha-1 Antitrypsin Deficiency Associated Liver Disease (AATD)
Official Title
A Pilot Open Label, Multi-dose, Phase 2 Study to Assess the Safety and Efficacy of Fazirsiran (TAK-999, ARO-AAT) in Patients With Alpha-1 Antitrypsin Deficiency Associated Liver Disease (AATD)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 19, 2019 (Actual)
Primary Completion Date
August 23, 2024 (Anticipated)
Study Completion Date
August 23, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Arrowhead Pharmaceuticals

4. Oversight

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
Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to evaluate the the safety and efficacy of the investigational product, fazirsiran (TAK-999, ARO-AAT), administered subcutaneously to patients with Alpha-1 Antitrypsin Deficiency.
Detailed Description
Participants will be enrolled to receive multiple subcutaneous injections of fazirsiran (TAK-999, ARO-AAT). All eligible participants will require a pre-dose biopsy completed as part of the study within the screening window. All participants will undergo an End of Study (EOS) biopsy. Treated participants will be offered the opportunity to continue treatment in an open label extension during which they will undergo a final biopsy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alpha 1-Antitrypsin Deficiency

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
16 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Fazirsiran (TAK-999, ARO-AAT) Cohort 1
Arm Type
Experimental
Arm Description
Administered on Day 1, Weeks 4 and 16 for a minimum of 3 doses. Treatment Extension (optional enrollment): Administered every 12 weeks for 12 additional doses.
Arm Title
Fazirsiran (TAK-999, ARO-AAT) Cohort 1b
Arm Type
Experimental
Arm Description
Administered on Day 1, Weeks 4 and 16, for a minimum of 3 doses. Treatment Extension (optional enrollment): Administered every 12 weeks for 12 additional doses.
Arm Title
Fazirsiran (TAK-999, ARO-AAT) Cohort 2
Arm Type
Experimental
Arm Description
Administered on Day 1, Weeks 4, 16, 28 and 40 for a minimum of 5 doses. Treatment Extension (optional enrollment): Administered every 12 weeks for 12 additional doses.
Intervention Type
Drug
Intervention Name(s)
Fazirsiran Injection (TAK-999, ARO-AAT)
Intervention Description
solution for subcutaneous (sc) injection
Primary Outcome Measure Information:
Title
Change From Baseline Over Time in Total, Soluble, and Insoluble Z-Alpha 1 Antitrypsin (Z-AAT) Liver Concentrations
Time Frame
Baseline and Week 24 (Cohort 1 &1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44
Secondary Outcome Measure Information:
Title
Change From Baseline Over Time in Circulating Levels of Z-AAT
Time Frame
Baseline through Week 24 (Cohort 1 & 1b) or through Week 48 (Cohort 2); Extension Cohort: Baseline through Extension Weeks 44 and 140
Title
Change From Baseline Over Time in Alanine Transaminase (ALT)
Time Frame
Baseline through Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Baseline through Extension Weeks 44 and 140
Title
Change From Baseline Over Time in Gamma-Glutamyl Transferase (GGT)
Time Frame
Baseline and Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Baseline and Extension Weeks 44 and 140
Title
Change From Baseline Over Time in Fibrosis-4 Index (FIB4)
Time Frame
Baseline through Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Baseline through Extension Weeks 44 and 140
Title
Change From Baseline Over Time in Aspartate Transaminase (AST) to Platelet Ratio Index (APRI)
Time Frame
Baseline through Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Baseline through Extension Weeks 44 and 140
Title
Change From Baseline Over Time in Plasma Collagen Type 3 (PRO-C3)
Time Frame
Baseline through Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Baseline through Extension Weeks 44 and 140
Title
Change From Baseline Over Time in Hepatic Stiffness based on FibroScan (when available)
Time Frame
Baseline and Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Extension Weeks 44 and 140
Title
Change From Baseline Over Time in Histological Metrics of Liver Disease: Inflammation Score
Description
Change in inflammation score, based on pathology slide reads. Inflammation was assessed on a scale of 0-3, with higher scores showing more severe inflammation.
Time Frame
Baseline and Week 24 (Cohort 1 &1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44
Title
Change From Baseline Over Time in Histological Metrics of Liver Disease: Steatosis Score
Description
Change in steatosis score, based on pathology slide reads. Steatosis was assessed on a scale of 0-3, with higher scores showing more severe steatosis.
Time Frame
Baseline and Week 24 (Cohort 1 &1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44
Title
Change From Baseline Over Time in Histological Metrics of Liver Disease: Hepatocyte Cell Death Score
Description
Change in hepatocyte cell death score, based on pathology slide reads. Hepatocyte cell death was assessed on a scale of 0-2, with higher scores showing more severe hepatocyte cell death.
Time Frame
Baseline and Week 24 (Cohort 1 &1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44
Title
Change From Baseline Over Time in Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Score
Description
METAVIR scores range from F0 to F4 (F0=No Fibrosis, F1=Mild Fibrosis, F2= Significant Fibrosis, F3=Severe Fibrosis, F4=Cirrhosis). Higher scores indicate more severe fibrosis.
Time Frame
Baseline and Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44
Title
Number of Participants with Adverse Events (AEs) Possibly or Probably Related to Treatment
Time Frame
Up to Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: up to Extension Week 140
Title
Incidence of Anti-Drug Antibodies (ADAs) to Fazirsiran
Time Frame
Day 1, Week 6, and Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Extension Weeks 24 and 44
Title
Titers of Anti-Drug Antibodies (ADAs) to Fazirsiran
Time Frame
Day 1, Week 6, and Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Extension Weeks 24 and 44

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of AATD Women of childbearing potential must have a negative pregnancy test, cannot be breast feeding, and must be willing to use contraception Willing to provide written informed consent and to comply with study requirements Non-smoker for at least 1 year No abnormal finding of clinical relevance at screening Exclusion Criteria: Clinically significant health concerns other than AATD Previous diagnosis or diagnosis at Screening of definitive liver cirrhosis Regular use of alcohol within one month prior to Screening Use of an investigational agent or device within 30 days prior to dosing or current participation in an investigational study involving therapeutic intervention Use of illicit drugs within 1 year prior to Screening Note: additional inclusion/exclusion criteria may apply, per protocol
Facility Information:
Facility Name
Medical University of Vienna Division of Gastroenterology and Hepatology
City
Vienna
ZIP/Postal Code
1090
Country
Austria
Facility Name
Universitatsklinikum Aachen, Anstalt des offentlich
City
Aachen
ZIP/Postal Code
52074
Country
Germany
Facility Name
Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust
City
Cambridge
ZIP/Postal Code
CB2 0QQ
Country
United Kingdom
Facility Name
Royal Infirmary of Edinburgh, NHS Lothian
City
Edinburgh
ZIP/Postal Code
EH19 3BJ
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
35748699
Citation
Strnad P, Mandorfer M, Choudhury G, Griffiths W, Trautwein C, Loomba R, Schluep T, Chang T, Yi M, Given BD, Hamilton JC, San Martin J, Teckman JH. Fazirsiran for Liver Disease Associated with Alpha1-Antitrypsin Deficiency. N Engl J Med. 2022 Aug 11;387(6):514-524. doi: 10.1056/NEJMoa2205416. Epub 2022 Jun 25.
Results Reference
derived

Learn more about this trial

Study of Fazirsiran (TAK-999, ARO-AAT) in Patients With Alpha-1 Antitrypsin Deficiency Associated Liver Disease (AATD)

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