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

Alpha 1-Antitrypsin Deficiency Clinical Trial

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03946449
• Other study ID #: AROAAT2002
• Secondary ID: 2019-000068-86
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: December 19, 2019
• Est. completion date: August 23, 2024

Study information

• Verified date: June 2023
• Source: Arrowhead Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 16
• Est. completion date: August 23, 2024
• Est. primary completion date: August 23, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Alpha 1-Antitrypsin Deficiency
• Liver Diseases

Intervention

Drug:
• Fazirsiran Injection (TAK-999, ARO-AAT)
solution for subcutaneous (sc) injection

Locations

Country	Name	City	State
Austria	Medical University of Vienna Division of Gastroenterology and Hepatology	Vienna
Germany	Universitatsklinikum Aachen, Anstalt des offentlich	Aachen
United Kingdom	Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust	Cambridge
United Kingdom	Royal Infirmary of Edinburgh, NHS Lothian	Edinburgh

Sponsors (1)

Lead Sponsor	Collaborator
Arrowhead Pharmaceuticals

Countries where clinical trial is conducted

Austria,  Germany,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline Over Time in Total, Soluble, and Insoluble Z-Alpha 1 Antitrypsin (Z-AAT) Liver Concentrations		Baseline and Week 24 (Cohort 1 &1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44
Secondary	Change From Baseline Over Time in Circulating Levels of Z-AAT		Baseline through Week 24 (Cohort 1 & 1b) or through Week 48 (Cohort 2); Extension Cohort: Baseline through Extension Weeks 44 and 140
Secondary	Change From Baseline Over Time in Alanine Transaminase (ALT)		Baseline through Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Baseline through Extension Weeks 44 and 140
Secondary	Change From Baseline Over Time in Gamma-Glutamyl Transferase (GGT)		Baseline and Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Baseline and Extension Weeks 44 and 140
Secondary	Change From Baseline Over Time in Fibrosis-4 Index (FIB4)		Baseline through Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Baseline through Extension Weeks 44 and 140
Secondary	Change From Baseline Over Time in Aspartate Transaminase (AST) to Platelet Ratio Index (APRI)		Baseline through Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Baseline through Extension Weeks 44 and 140
Secondary	Change From Baseline Over Time in Plasma Collagen Type 3 (PRO-C3)		Baseline through Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Baseline through Extension Weeks 44 and 140
Secondary	Change From Baseline Over Time in Hepatic Stiffness based on FibroScan (when available)		Baseline and Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Extension Weeks 44 and 140
Secondary	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.	Baseline and Week 24 (Cohort 1 &1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44
Secondary	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.	Baseline and Week 24 (Cohort 1 &1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44
Secondary	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.	Baseline and Week 24 (Cohort 1 &1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44
Secondary	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.	Baseline and Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44
Secondary	Number of Participants with Adverse Events (AEs) Possibly or Probably Related to Treatment		Up to Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: up to Extension Week 140
Secondary	Incidence of Anti-Drug Antibodies (ADAs) to Fazirsiran		Day 1, Week 6, and Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Extension Weeks 24 and 44
Secondary	Titers of Anti-Drug Antibodies (ADAs) to Fazirsiran		Day 1, Week 6, and Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Extension Weeks 24 and 44