Alpha1-Antitrypsin Deficiency
Conditions
Keywords
Natural History
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).
Interventions
OTHERNo Intervention
This is an observational study.
Sponsors
Takeda
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Participants who meet all the following criteria will be included in the study. Cohorts 1 and 2: 1. Willing to provide written informed consent to participate in the study. 2. \>=18 years of age at enrollment in this study. 3. Participants with documented diagnosis of AATD, meeting the following criteria: 1. 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. 2. 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. 1. Documented AATD genotype/phenotype other than Pi\*ZZ or Pi\*SZ. 2. History of liver transplant. 3. 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). 4. 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Liver Disease Progression | Baseline up to 8 years | 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 to Liver Disease Progression | Baseline up to 8 years | 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 to Liver Disease Trajectory | Baseline up to 8 years | 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. |
| Probability of Transition in Liver Disease Trajectory | Baseline up to 8 years | 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. |
| Percentage of Participants With Disease Regression | Baseline up to 8 years | 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 to Liver Disease Regression | Baseline up to 8 years | 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. |
| Percentage of Participants With All-cause Mortality and Cause-specific Mortality | Baseline up to 8 years | 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 to Death (All-causes) and Cause-specific Death (Liver Disease-specific Causes) | Baseline up to 8 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Develop Lung Disease | Baseline up to 8 years | 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. |
| Proportion of Participants With Lung Disease at Baseline who Experience Lung Disease Progression at 4-8 Years | Baseline up to 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. |
| Characterize Diagnostic and Monitoring Patterns for Liver Disease (Invasive and Non-invasive Assessments) | Baseline up to 8 years | — |
Countries
Austria, Germany, Ireland, Spain, United Kingdom, United States
Contacts
CONTACTTakeda Contact
STUDY_DIRECTORStudy Director
Takeda
Outcome results
None listed