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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03946449
Recruitment Status : Active, not recruiting
First Posted : May 10, 2019
Last Update Posted : May 4, 2022
Sponsor:
Information provided by (Responsible Party):
Arrowhead Pharmaceuticals

Study Description
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Brief Summary:
The purpose of this study is to evaluate the the safety and efficacy of ARO-AAT Injection (also referred to as ARO-AAT) administered subcutaneously to patients with alpha-1 antitrypsin deficiency.

Condition or disease Intervention/treatment Phase
Alpha 1-Antitrypsin Deficiency Drug: ARO-AAT Injection Phase 2

Detailed Description:
Participants will be enrolled to receive multiple subcutaneous injections of 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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 16 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Open Label, Multi-dose, Phase 2 Study to Assess the Safety and Efficacy of ARO-AAT in Patients With Alpha-1 Antitrypsin Deficiency Associated Liver Disease (AATD)
Actual Study Start Date : December 19, 2019
Estimated Primary Completion Date : August 23, 2024
Estimated Study Completion Date : August 23, 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: ARO-AAT Cohort 1

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.

 Drug: ARO-AAT Injection
solution for subcutaneous (sc) injection
Experimental: ARO-AAT Cohort 1b

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.

 Drug: ARO-AAT Injection
solution for subcutaneous (sc) injection
Experimental: ARO-AAT Cohort 2

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.

 Drug: ARO-AAT Injection
solution for subcutaneous (sc) injection


Outcome Measures
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Primary Outcome Measures :
  1. 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 Measures :
  1. 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 ]
  2. 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 ]
  3. 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 ]
  4. 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 ]
  5. 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 ]
  6. 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 ]
  7. 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 ]
  8. Change From Baseline Over Time in Histological Metrics of Liver Disease: Inflammation Score [ Time Frame: Baseline and Week 24 (Cohort 1 &1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44 ]
    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.

  9. Change From Baseline Over Time in Histological Metrics of Liver Disease: Steatosis Score [ Time Frame: Baseline and Week 24 (Cohort 1 &1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44 ]
    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.

  10. Change From Baseline Over Time in Histological Metrics of Liver Disease: Hepatocyte Cell Death Score [ Time Frame: Baseline and Week 24 (Cohort 1 &1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44 ]
    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.

  11. Change From Baseline Over Time in Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Score [ Time Frame: Baseline and Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44 ]
    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.

  12. 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 ]
  13. Incidence of Anti-Drug Antibodies (ADAs) to ARO-AAT [ Time Frame: Day 1, Week 6, and Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Extension Weeks 24 and 44 ]
  14. Titers of Anti-Drug Antibodies (ADAs) to ARO-AAT [ Time Frame: Day 1, Week 6, and Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Extension Weeks 24 and 44 ]

Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03946449


Locations
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Austria
Medical University of Vienna Division of Gastroenterology and Hepatology
Vienna, Austria, 1090
Germany
Universitatsklinikum Aachen, Anstalt des offentlich
Aachen, Germany, 52074
United Kingdom
Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust
Cambridge, United Kingdom, CB2 0QQ
Royal Infirmary of Edinburgh, NHS Lothian
Edinburgh, United Kingdom, EH19 3BJ
Sponsors and Collaborators
Arrowhead Pharmaceuticals
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Arrowhead Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03946449    
Other Study ID Numbers: AROAAT2002
2019-000068-86 ( EudraCT Number )
First Posted: May 10, 2019    Key Record Dates
Last Update Posted: May 4, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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