This site became the new ClinicalTrials.gov on June 19th. Learn more.
Show more
ClinicalTrials.gov Menu IMPORTANT: Listing of a study on this site does not reflect endorsement by the National Institutes of Health. Talk with a trusted healthcare professional before volunteering for a study. Read more...
ClinicalTrials.gov Menu IMPORTANT: Talk with a trusted healthcare professional before volunteering for a study. Read more...
ClinicalTrials.gov Menu
Give us feedback

Alpha-1 Antitrypsin Deficiency Adult Liver Study

This study is currently recruiting participants.
See Contacts and Locations
Verified January 2017 by Jeffrey Teckman M.D., St. Louis University
Sponsor:
Collaborators:
Alpha-1 Foundation
University of California
Boston University
University College, London
University of Massachusetts, Worcester
Information provided by (Responsible Party):
Jeffrey Teckman M.D., St. Louis University
ClinicalTrials.gov Identifier:
NCT02014415
First received: December 12, 2013
Last updated: January 3, 2017
Last verified: January 2017
  Purpose
The investigators hypothesize that there is liver injury (inflammation, fibrosis, cirrhosis) in adults with Alpha-1 Antitrypsin Deficiency (AATD), which is asymptomatic, under-recognized, and undiagnosed. In addition, the investigators believe that the genetic and environmental factors that play an important role in the development of alpha-1 antitrypsin (AAT) liver disease, can be identified by comparing a cohort database of clinical disease information to linked biospecimen and DNA samples.

Condition Intervention
Alpha-1 Antitrypsin Deficiency Procedure: Liver Biopsy (Biopsy Group Only)

Study Type: Observational [Patient Registry]
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 5 Years
Official Title: Alpha-1 Antitrypsin Deficiency Adult Clinical and Genetic Linkage Study

Resource links provided by NLM:


Further study details as provided by Jeffrey Teckman M.D., St. Louis University:

Primary Outcome Measures:
  • The risk and rate of histologic liver injury progression, as measured by liver biopsy, over a 5-year period. [ Time Frame: Liver biopsy performed in Year 1 and Year 5 ]

Secondary Outcome Measures:
  • Calculated Model for End-stage Liver Disease score (MELD) [ Time Frame: Calculated at baseline and annually through year 5 ]
  • Liver synthetic dysfunction defined by international normalized ratio (INR) > 1.3 or serum albumin < 3.2 gm/dL [ Time Frame: Measured at baseline and annually through year 5 ]
  • Presence of ascites (or treatment for ascites) [ Time Frame: Assessed at baseline and annually through year 5 ]
  • Development of complications of portal hypertension (e.g., variceal hemorrhage) [ Time Frame: Assessed at baseline and annually through year 5 ]
  • Jaundice (total serum bilirubin >2.0 mg/dl) [ Time Frame: Measured at baseline and annually through year 5 ]
  • Liver transplantation [ Time Frame: Assessed annually through year 5 ]
  • Listing for liver transplantation [ Time Frame: Assessed at baseline and annually through year 5 ]
  • Health related quality of life [ Time Frame: Measured at baseline and annually through year 5 ]
  • FEV1 % of Predicted [ Time Frame: Collected at baseline and annually through year 5 ]
  • Death [ Time Frame: Collected annually through year 5 ]

Biospecimen Retention:   Samples With DNA
Samples of serum, plasma, and blood for genetic testing (Induced Pluripotent Stem Cells (iPS cells), microRNA and DNA) will be collected from subjects at defined time points. In addition, samples of liver tissue will be collected from participants in the Liver Biopsy Group.

Estimated Enrollment: 120
Study Start Date: December 2013
Estimated Study Completion Date: August 2021
Estimated Primary Completion Date: August 2020 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Liver Biopsy
Participants will provide liver tissue specimens collected at the time of liver biopsy, to determine the rate of progression of liver injury in adults with Pi-ZZ Alpha-1 Antitrypsin Deficiency.
Procedure: Liver Biopsy (Biopsy Group Only)
A percutaneous (needle) liver biopsy will be performed on subjects in the Liver Biopsy Group, in Year 1 and Year 5 of the study.
Known Severe Liver Disease
Participants will provide samples of serum, plasma, and DNA at defined time points to determine what genetic and environmental modifiers and biomarkers are associated with severe clinical liver disease, such cirrhosis, portal hypertension and liver failure in adults with Pi-ZZ Alpha-1 Antitrypsin Deficiency.
Post Liver Transplant
Participants will provide a DNA sample to determine what genetic and environmental modifiers are associated with the need for liver transplantation in adults with Pi-ZZ Alpha-1 Antitrypsin Deficiency.

Detailed Description:

Alpha-1 Antitrypsin Deficiency (AATD) is a genetic disorder resulting in a low level of a protein called alpha-1 antitrypsin (AAT). This deficiency can cause life-threatening liver disease and/or lung disease at various ages. Some patients experience life-threatening liver disease in childhood or liver cancer as adults. There is no specific treatment for AAT related liver disease. Some patients develop emphysema as young adults, while some patients remain healthy throughout their lives. Differences in the environment or in other genes may explain such inconsistency in the disease.

The primary objective of this multi-center study is to assess the natural history of individuals with Pi-ZZ AAT deficiency, identify biomarkers for the progression of liver disease and construct a database capable of linking cohort data with repository biospecimens. The secondary objective is to analyze components of the demographic, social, and family history associated with more severe liver disease.

This study will examine the natural history of liver disease by recording participant's family history, medical history, current health, laboratory test results, and medical treatment(s). Participants may complete brief research questionnaires about their physical and mental health, diet, alcohol intake, and smoke, environmental and occupational (work) exposures.

At least 120 Pi-ZZ AAT deficient adults with no previous history of liver disease, moderate-severe liver disease, or post liver transplant, will be enrolled at one of three sites. Eligible subjects will participate in one of the following study arms:

  1. Liver Biopsy
  2. Known Severe Liver Disease - subjects not meeting Biopsy Group eligibility due to the presence of advanced liver disease
  3. Post Liver Transplant - subjects who have previously undergone a liver transplant

At the time of enrollment, each participant will be assigned a unique study identification (ID) number. All participant information recorded and samples collected for the study will be saved by this unique number. All blood, tissue and genetic samples collected will be sent to a secured repository for future retrieval and study. The process of coding data and samples lessens the chances of a breach in confidentiality.

The length of study participation, tests and activities performed specifically for research will be determined by the enrollment group. Subjects in the Biopsy and Known Severe Liver Disease groups participate in the study for 5 years (enrollment and four annual follow-up visits). Both groups undergo a physical exam, diagnostic abdominal ultrasound, pulmonary function testing and the collection of serum, plasma and blood for routine laboratory and genetic testing (Induced Pluripotent Stem Cells (iPS cells), microRNA and DNA). However, only the Biopsy Group participants undergo a liver biopsy and FibroScan at enrollment, and again in Year 5. The liver tissue samples will help the researchers learn what causes liver disease in some patients and how the liver disease progresses.

Subjects in the Post Liver Transplant group have a single study visit to record their history, complete questionnaires and perform pulmonary function testing. In addition, whole blood for DNA analysis will be collected from these participants.

Based on their study arm assignment, participants will receive copies of their diagnostic abdominal ultrasound, pulmonary function test, routine laboratory test and liver biopsy pathology results, to share with their primary care physician.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Pi-ZZ AAT deficient adults with either no previous history of liver disease, moderate-severe liver disease or post liver transplant. Biologic family members who are also Pi-ZZ and ≥ 18 years of age, will be offered enrollment into the study. The purpose of including family members is to determine if the natural history of the liver disease is consistent in a given family.
Criteria

Liver Biopsy Group:

Inclusion Criteria

  • Adults (≥ 18 years of age), with Alpha-1 Antitrypsin Deficiency
  • Documented evidence Pi-ZZ phenotype or genotype
  • Both genders, all races and ethnic groups
  • Willingness to be followed for up to 5 years

Exclusion Criteria:

  • Evidence of advanced liver disease defined by Child-Pugh Class B or C (score ≥ 7)
  • Known advanced lung disease defined as forced expiratory volume at one second (FEV1) < 40 % of Predicted
  • History of Organ Transplantation
  • Known congenital or metabolic liver disease (e.g.: Wilson's, glycogen storage, cystic fibrosis)or iron overload as evidenced by ≥ Grade 3 iron staining on a previous liver biopsy
  • Evidence of chronic hepatitis B (marked by the presence of HBsAg in serum) or Hepatitis C (marked by the presence of anti-hepatitis C virus (HCV) or HCV RNA in serum)
  • Vascular disorders of the liver (e.g.: cardiac sclerosis, acute or chronic Budd-Chiari, hepatoportal sclerosis, peliosis)
  • Known HIV positivity
  • Diagnosis of malignancy within the last 5 years
  • Active substance abuse, that in the opinion of the study investigator, would interfere with adherence to study requirements
  • Concomitant severe underlying systemic illness or medical condition which in the opinion of the investigator, would make the patient unsuitable for the study or would interfere with completion of follow-up
  • Inability to comply with the longitudinal follow-up as outlined in the protocol
  • Failure of the participant to sign informed consent or Health Insurance Portability and Accountability Act (HIPAA) documents

Known Severe Liver Disease Group:

Inclusion Criteria

  • Adults (≥ 18 years of age), with alpha-1-antitrypsin deficiency
  • Documented evidence PI-ZZ phenotype or genotype
  • Documented evidence of portal hypertension or evidence of advanced liver disease defined by Child-Pugh Class B or C (score ≥ 7), or previous liver biopsy with an Ishak Fibrosis Score ≥ 4
  • Both genders, all races and ethnic groups
  • Willingness to be followed for up to 5 years

Exclusion Criteria

  • History of Organ Transplantation
  • Known congenital or metabolic liver disease (e.g.: Wilson's, glycogen storage, cystic fibrosis) and iron overload as evidenced by ≥ Grade 3 iron staining on a previous liver biopsy
  • Evidence of chronic hepatitis B (marked by the presence of HBsAg in serum) or Hepatitis C (marked by the presence of anti-HCV or HCV RNA in serum)
  • Vascular disorders of the liver (e.g.: cardiac sclerosis, acute or chronic Budd-Chiari, hepatoportal sclerosis, peliosis)
  • Known HIV positivity
  • Diagnosis of malignancy within the last 5 years which in the opinion of the investigator, would make the patient's follow-up problematic or the results uninterpretable.
  • Active substance abuse, that in the opinion of the study investigator, would interfere with adherence to study requirements
  • Concomitant severe underlying systemic illness or medical condition which in the opinion of the investigator, would make the patient unsuitable for the study or would interfere with completion of follow-up
  • Inability to comply with the longitudinal follow-up as outlined in the protocol
  • Failure of the participant to sign informed consent or HIPAA documents.

Post Liver Transplant Group

Inclusion Criteria

  • Adults (≥ 18 years of age), with alpha-1-antitrypsin deficiency
  • Pre-transplant documented evidence of PI-ZZ phenotype or genotype
  • Documented evidence of liver transplantation
  • Both genders, all races and ethnic groups

Exclusion Criteria

  • Active substance abuse, that in the opinion of the study investigator, would interfere with adherence to study requirements
  • Concomitant severe underlying systemic illness or medical condition which in the opinion of the investigator, would make the patient unsuitable for the study or would interfere with completion of study requirements
  • Failure of the participant to sign informed consent or HIPAA documents.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02014415

Locations
United States, California
University of California Recruiting
San Diego, California, United States, 92103
Contact: Phirum Nguyen    619-471-0774    psnguyen@ucsd.edu   
Principal Investigator: David A. Brenner, MD         
Sub-Investigator: Rohit Loomba, MD, MHSc         
United States, Massachusetts
Boston University School of Medicine Recruiting
Boston, Massachusetts, United States, 02118
Contact: Mark Dodge    617-414-2968    mdodge1@bu.edu   
Principal Investigator: Andrew Wilson, MD         
United States, Missouri
Saint Louis University Recruiting
Saint Louis, Missouri, United States, 63104
Contact: Jackie Cerkoski, RN, BSN    314-577-5611    cerkoski@slu.edu   
Contact: Rosemary Nagy, RDN, LD, MBA    314-577-5608    rnagy@slu.edu   
Principal Investigator: Adrian M. Di Bisceglie, MD, FACP         
Sub-Investigator: Bruce R. Bacon, MD         
Sponsors and Collaborators
St. Louis University
Alpha-1 Foundation
University of California
Boston University
University College, London
University of Massachusetts, Worcester
Investigators
Study Chair: Jeffrey Teckman, MD St. Louis University
Study Director: Adam Wanner, MD Alpha-1 Foundation
Principal Investigator: David A. Brenner, MD The University of California, San Diego
Principal Investigator: Adrian M. Di Bisceglie, MD, FACP St. Louis University
Principal Investigator: Andrew Wilson, MD Boston University
  More Information

Responsible Party: Jeffrey Teckman M.D., Professor of Pediatrics and Professor of Biochemistry and Molecular Biology, St. Louis University
ClinicalTrials.gov Identifier: NCT02014415     History of Changes
Other Study ID Numbers: A1F-SLU-7113
Alpha-1 Foundation ( Other Grant/Funding Number: A1F-SLU-7113 )
Study First Received: December 12, 2013
Last Updated: January 3, 2017
Individual Participant Data  
Plan to Share IPD: Yes
Plan Description:

Based on study group assignment, participants will be given a copy of their test results as follows:

Liver Biopsy Group- liver biopsy pathology, diagnostic abdominal ultrasound, pulmonary function testing, and routine clinical laboratory testing.

Known Severe Liver Disease Group- diagnostic abdominal ultrasound, pulmonary function testing, and routine clinical laboratory testing.

Post Liver Transplant Group- pulmonary function testing.


Keywords provided by Jeffrey Teckman M.D., St. Louis University:
Alpha-1
AAT Deficiency
AATD
Liver
Fibrosis
Liver Transplant
Cirrhosis

Additional relevant MeSH terms:
Alpha 1-Antitrypsin Deficiency
Liver Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Subcutaneous Emphysema
Emphysema
Pathologic Processes
Liver Extracts
Alpha 1-Antitrypsin
Protein C Inhibitor
Hematinics
Trypsin Inhibitors
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on June 27, 2017