An observational study in Alpha1-Antitrypsin Deficiency, sponsored by Takeda. Recruiting at 8 sites in 6 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-07-24.
Sponsored by Takeda · Observational
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).
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).
Participants who meet all the following criteria will be included in the study.
Cohorts 1 and 2:
Participants with documented diagnosis of AATD, meeting the following criteria:
Cohort 1 (AATD-Pi*ZZ genotype/phenotype).
Cohort 2 (AATD-Pi*SZ genotype/phenotype with liver disease manifestation).
Exclusion Criteria:
Participants who meet any following criteria will be excluded from the study.
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:
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
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
This is an observational study.
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline up to 8 years
Percentage of Participants Who Develop Lung Disease
Development of lung disease will be defined as either a forced expiratory volume in 1 second (FEV1) percent (%) predicted of less than (\<) 70% or the diagnosis of at least 1 lung condition (chronic obstructive pulmonary disease \[COPD\], emphysema, bronchiectasis, chronic bronchitis) over the study duration or at specific timepoints.
Time frame: Baseline up to 8 years
Proportion of Participants With Lung Disease at Baseline who Experience Lung Disease Progression at 4-8 Years
Lung disease progression is defined as changes in pulmonary function (defined as \>=10% absolute change in FEV1, forced vital capacity \[FVC\], or diffusing capacity of the lungs for carbon monoxide \[DLCO\]) over the study duration or at specific timepoints.
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
Plan to share: Yes — Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
Supporting information: Study protocol, Sap, Icf, Csr
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alpha 1-Antitrypsin Deficiency
Takeda