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

Recruiting

• Conditions: Alpha1-Antitrypsin Deficiency
• Interventions: Other: No Intervention

• Registration Number: NCT06512454
• Lead Sponsor: Takeda

Brief Summary

The main aim of this study is to learn about liver problems caused by the lack of alpha-1 antitrypsin (called Alpha-1 Antitrypsin Deficiency or AATD) in adults when not treated (this is called the natural history of a condition) over 5 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 hospital care, and describe how the AATD also affects and 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 completed questionnaires (called patient-reported outcomes or PRO).

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2024-07-16
• Study First Submitted QC: 2024-07-16
• Study First Posted: 2024-07-22
• Status Verified: 2024-09
• Study Start: 2024-09-25
• Last Update Submitted: 2024-09-30
• Last Update Posted: 2024-10-01
• Primary Completion: 2032-04-06
• Study Completion: 2032-04-06

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1000

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 or currently enrolled in an ongoing participating AATD patient registry that does not require reconsenting 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 measures, as determined through:

        • Lab and imaging measures to define liver disease manifestation

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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), fibro scan (vibration controlled transient elastography [VCTE]), or Aspartate aminotransferase to platelet ratio index (APRI) in the 24 months prior to the study baseline date, and has none of these tests ordered in the current visit that will be available in the next 90 days.
4. Participants who had previously been treated or in an active participation in an interventional trial studying liver or lung disease.
5. Treatment with liver directed AATD investigational therapy as part of a compassionate use request.

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Cohort 2: AATD-Pi*SZ Genotype/Phenotype	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 manifestations will be enrolled and data will be prospectively collected per routine care throughout the follow-up period (up to 5 years).
Cohort 1: AATD-Pi*ZZ Genotype/Phenotype	No Intervention	Participants who have been diagnosed with Alpha-1 Antitrypsin Deficiency homozygote ZZ (AATD-Pi\*ZZ) genotype/phenotype with mild or without liver disease manifestations will be enrolled and data will be prospectively collected per routine care throughout the follow-up period (up to 5 years).

Primary Outcome Measures

Name	Time	Method
Number of Participants With Liver Disease Progression	Baseline up to 5 years	Liver disease progression will be defined as advancement in greater than or equal to (\>=1) fibrosis stage: example any progression from fibrosis stage (F) 1 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, or d) receipt of a liver transplant MELD score increase, or d) 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 Trajectory	Baseline up to 5 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 decompensating event or liver transplant and first to second decompensating event and all subsequent decompensating events or liver transplant. The fibrosis stages range from F0 to F4, with F0 indicating no fibrosis and F4 indicating cirrhosis.
Time to Death (All-causes) and Cause-specific Death (Liver Disease-specific Causes)	Baseline up to 5 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.
Probability of Transition in Liver Disease Trajectory	Baseline up to 5 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 decompensating event or liver transplant and first to second decompensating event and all subsequent decompensating events or liver transplant. The fibrosis stages range from F0 to F4, with F0 indicating no fibrosis and F4 indicating cirrhosis.
Time to Liver Disease Progression	Baseline up to 5 years	Time to liver disease progression is defined as time to advancement in \>=1 fibrosis stage (example 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 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 Regression	Baseline up to 5 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 5 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.
Percentage of Participants With Disease Regression	Baseline up to 5 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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants Who Develop Lung Disease	Baseline up to 5 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).
Proportion of Participants With Lung Disease at Baseline who Experience Lung Disease Progression at 5 Years	Baseline up to 5 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 \[DLCO\]).
Number of Participants With Invasive and Non-Invasive Assessment for Liver Disease	Baseline up to 5 years

Trial Locations

Locations (2)

University of Florida; 🇺🇸 Gainesville, Florida, United States

Universitätsklinikum Aachen AöR; 🇩🇪 Aachen, North Rhine-Westphalia, Germany