A Study in Adults to Learn About Inherited Alpha-1 Antitrypsin Deficiency (AATD) and AATD Related Liver Problems

Official title

Prospective Observational Study on the Natural History of Alpha-1 Antitrypsin Deficiency and Associated Liver Disease

Overview

The liver produces a protein called alpha-1 antitrypsin (AAT). AAT is normally released into the bloodstream. In some people, the liver makes an abnormal version of AAT, called Z-AAT. Z-AAT builds up in liver cells and also leads to low blood levels of AAT (called Alpha-1 Antitrypsin Deficiency or AATD). Over time, this build up leads to different stages of liver problems, if not treated. This is called natural history of AATD. The main aim of this study is to learn about liver problems caused by AATD in adults when not treated over 4 to 8 years. Other aims are to learn what can predict the AATD-liver condition starting and getting better or worse, describe how this condition is currently being diagnosed and watched in normal care, and describe how the AATD also affects an adult's lung function. Data in this study will be collected to include medical history of a participant, including the date AATD was first identified and/or the date on which the first AATD-related liver or lung problems were diagnosed. At study start and then every year until study end, participants will be asked to complete questionnaires (called patient-reported outcomes or PROs).

Interventions

• Other No Intervention
  This is an observational study.

Primary outcome measures

• Number of Participants With Liver Disease Progression [Time frame: Baseline up to 8 years]
• Time to Liver Disease Progression [Time frame: Baseline up to 8 years]
• Time to Liver Disease Trajectory [Time frame: Baseline up to 8 years]
• Probability of Transition in Liver Disease Trajectory [Time frame: Baseline up to 8 years]
• Percentage of Participants With Disease Regression [Time frame: Baseline up to 8 years]
• Time to Liver Disease Regression [Time frame: Baseline up to 8 years]
• Percentage of Participants With All-cause Mortality and Cause-specific Mortality [Time frame: Baseline up to 8 years]
• Time to Death (All-causes) and Cause-specific Death (Liver Disease-specific Causes) [Time frame: Baseline up to 8 years]

Secondary outcome measures (3)

• Percentage of Participants Who Develop Lung Disease [Time frame: Baseline up to 8 years]
• Proportion of Participants With Lung Disease at Baseline who Experience Lung Disease Progression at 4-8 Years [Time frame: Baseline up to 8 years]
• Characterize Diagnostic and Monitoring Patterns for Liver Disease (Invasive and Non-invasive Assessments) [Time frame: Baseline up to 8 years]

Eligibility criteria

Inclusion criteria

Participants who meet all the following criteria will be included in the study.

Cohorts 1 and 2:

• Willing to provide written informed consent to participate in the study.
• >=18 years of age at enrollment in this study.
• Participants with documented diagnosis of AATD, meeting the following criteria:

• Cohort 1 (AATD-Pi\*ZZ genotype/phenotype).

• Pi\*ZZ genotype as documented from rapid genetic assay, sequencing, or polymerase chain reaction (PCR), or Pi\*ZZ phenotype as documented from iso-electric focusing (IEF) electrophoresis.
• Cohort 2 (AATD-Pi\*SZ genotype/phenotype with liver disease manifestation).

• Pi\*SZ genotype as documented from rapid genetic assay, sequencing, or PCR, or Pi\*SZ phenotype as documented from IEF electrophoresis, and
• Moderate-advanced or severe liver disease manifestation as defined by either liver biopsy or surrogate laboratory or imaging measures.

Exclusion criteria

Participants who meet any following criteria will be excluded from the study.

• Documented AATD genotype/phenotype other than Pi\*ZZ or Pi\*SZ.
• History of liver transplant.
• No results for either biopsies, magnetic resonance elastography (MRE), FibroScan (vibration controlled transient elastography \[VCTE\]), or Aspartate aminotransferase to platelet ratio index (APRI) in the 24 months prior to the index/enrollment date and has none of these tests ordered during the index period (i.e., index date +90 days).
• Participants with prior participation in an interventional clinical trial evaluating liver or lung disease, or who have received an investigational AATD-directed therapy under a compassionate use program, will be excluded if they do not present one of the following:

• A minimum washout period of 6 months has elapsed since the last dose of the investigational product.
• A history of having received placebo in prior interventional trials (to be evaluated on a case-by-case basis).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

United States · 3 centers

• University of Florida — Gainesville
• University of South Carolina — Charleston
• Vanderbilt University Medical Center — Nashville

Austria · 1 center

• Vienna General Hospital (AKH Wien) — Vienna

Germany · 1 center

• Universitätsklinikum Aachen — Aachen

Ireland · 1 center

• Beaumont Hospital — Dublin

Spain · 1 center

• Hospital Universitari Vall d'Hebron — Barcelona

United Kingdom · 1 center

• Queen Elizabeth Hospital Birmingham — Birmingham

Identifiers

NCT: NCT06512454 · TAK-999-5008

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗