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

NCT06512454 | Recruiting

• 1 other identifier: TAK-999-5008
• Study Type: observational
• Target: 500
• Locations: 6 countries
• Sites: 8

Brief Summary

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).

Conditions

Alpha1-Antitrypsin Deficiency

Keywords

Natural History

Outcome Measures

Primary Outcomes (8)

• Number of Participants With Liver Disease Progression

  Liver disease progression will be defined as advancement in greater than or equal to (\>=)1 fibrosis stage: example any progression from fibrosis stage F0/F1 to F2, F1 to F2, F2 to F3 etc. and/or occurrence of any of these composite events: a) advancement in \>=1 fibrosis stage, b) development of a liver disease-related clinical event, c) model for end-stage liver disease (MELD) score increase, d) newly added on liver transplant list, e) receipt of a liver transplant. The fibrosis stages range from F0 to F4, with F0 indicating no fibrosis and F4 indicating cirrhosis. The MELD score ranges from 6 to 40 with higher scores indicating more severe liver disease and a worse outcome.

  Baseline up to 8 years

• Time to Liver Disease Progression

  Time to liver disease progression is defined as time to advancement in \>=1 fibrosis stage (example F0/F1 to F2, F2 to F3 etc.) and/or time to the earliest of: Advancement in \>=1 fibrosis stage, or development of a liver disease-related clinical event, or MELD score increase or receipt/newly added to transplant list of a liver transplant. The fibrosis stages range from F0 to F4, with F0 indicating no fibrosis and F4 indicating cirrhosis. The MELD score ranges from 6 to 40 with higher scores indicating more severe liver disease and a worse outcome.

  Baseline up to 8 years

• Time to Liver Disease Trajectory

  Time to liver disease trajectory is defined as time of transition from F0/F1 to F2, F2 to F3, F3 to F4, F4 to the first decompensating event or liver transplant/listing and first to second decompensating event and all subsequent decompensating events or liver transplant/listing. The fibrosis stages range from F0 to F4, with F0 indicating no fibrosis and F4 indicating cirrhosis.

  Baseline up to 8 years

• Probability of Transition in Liver Disease Trajectory

  Probability of liver disease trajectory is defined as probability of transition from F0/F1 to F2, F2 to F3, F3 to F4, F4 to the first decompensating event or liver transplant/listing and first to second decompensating event and all subsequent decompensating events or liver transplant/listing. The fibrosis stages range from F0 to F4, with F0 indicating no fibrosis and F4 indicating cirrhosis.

  Baseline up to 8 years

• Percentage of Participants With Disease Regression

  Disease regression is defined as decrease in \>=1 fibrosis staging. The fibrosis stages range from F0 to F4, with F0 indicating no fibrosis and F4 indicating cirrhosis.

  Baseline up to 8 years

• Time to Liver Disease Regression

  Time to liver disease regression is defined as time to decrease in \>=1 fibrosis stage. The fibrosis stages range from F0 to F4, with F0 indicating no fibrosis and F4 indicating cirrhosis.

  Baseline up to 8 years

• Percentage of Participants With All-cause Mortality and Cause-specific Mortality

  Cause-specific mortality is defined as mortality due to liver failure or complications of cirrhosis/portal hypertension or hepatocellular carcinoma, or infections secondary to liver failure.

  Baseline up to 8 years

• Time to Death (All-causes) and Cause-specific Death (Liver Disease-specific Causes)

  Cause-specific mortality is defined as mortality due to liver failure or complications of cirrhosis/portal hypertension or hepatocellular carcinoma, or infections secondary to liver failure.

  Baseline up to 8 years

Secondary Outcomes (3)

• Percentage of Participants Who Develop Lung Disease

  Baseline up to 8 years

• Proportion of Participants With Lung Disease at Baseline who Experience Lung Disease Progression at 4-8 Years

  Baseline up to 8 years

• Characterize Diagnostic and Monitoring Patterns for Liver Disease (Invasive and Non-invasive Assessments)

  Baseline up to 8 years

Study Arms (2)

Cohort 1: AATD-Pi*ZZ Genotype/Phenotype

Participants who have been diagnosed with Alpha-1 Antitrypsin Deficiency homozygous ZZ (AATD-Pi\*ZZ) genotype/phenotype with or without liver disease manifestations (fibrosis- F0-F4dc) will be enrolled and data will be prospectively collected per routine care throughout the follow-up period.

Other: No Intervention

Cohort 2: AATD-Pi*SZ Genotype/Phenotype

Participants who have been diagnosed with alpha-1 antitrypsin deficiency heterozygous SZ (AATD-Pi\*SZ) genotype/phenotype with moderate-advanced or severe liver disease (F2-F4dc) manifestations will be enrolled and data will be prospectively collected per routine care throughout the follow-up period.

Other: No Intervention

Interventions

No Intervention OTHER

This is an observational study.

Cohort 1: AATD-Pi*ZZ Genotype/Phenotype; Cohort 2: AATD-Pi*SZ Genotype/Phenotype

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Participants who have already been diagnosed with AATD of genotype/phenotype Pi\*ZZ, with or without liver disease manifestation (F0-F4dc), or with genotype/phenotype of Pi\*SZ with moderate-advanced or severe liver disease manifestation (F2-F4dc).

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Takeda: lead

Study Sites (8)

University of Florida

Gainesville, Florida, 32608, United States

RECRUITING

University of South Carolina

Charleston, South Carolina, 29425, United States

RECRUITING

Vanderbilt University Medical Center

Nashville, Tennessee, 37212, United States

RECRUITING

Vienna General Hospital (AKH Wien)

Vienna, 1090, Austria

RECRUITING

Universitätsklinikum Aachen

Aachen, 52074, Germany

RECRUITING

Beaumont Hospital

Dublin, Dublin 9, Ireland

RECRUITING

Hospital Universitari Vall d'Hebron

Barcelona, Spain

RECRUITING

Queen Elizabeth Hospital Birmingham

Birmingham, B15 2GW, United Kingdom

RECRUITING

Related Links

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MeSH Terms

Conditions

alpha 1-Antitrypsin Deficiency

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Subcutaneous Emphysema; Emphysema; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Study Director

  Takeda

  STUDY DIRECTOR

Central Study Contacts

Takeda Contact

CONTACT

+1-877-825-3327; medinfoUS@takeda.com

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 16, 2024
• First Posted: July 22, 2024
• Study Start: September 25, 2024
• Primary Completion (Estimated): December 31, 2031
• Study Completion (Estimated): December 31, 2031
• Last Updated: July 24, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, 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.

Locations

US (3); DE (1); IE (1); ES (1); GB (1); AU (1)