- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02014415
Alpha-1 Antitrypsin Deficiency Adult Liver Study
Alpha-1 Antitrypsin Deficiency Adult Clinical and Genetic Linkage Study
Study Overview
Status
Conditions
Intervention / Treatment
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:
- Liver Biopsy
- Known Severe Liver Disease - subjects not meeting Biopsy Group eligibility due to the presence of advanced liver disease
- 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.
Study Type
Enrollment (Estimated)
Contacts and Locations
Study Locations
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California
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San Diego, California, United States, 92103
- University of California
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Massachusetts
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Boston, Massachusetts, United States, 02118
- Boston University School of Medicine
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Missouri
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Saint Louis, Missouri, United States, 63104
- Saint Louis University
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Sampling Method
Study Population
Description
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.
Study Plan
How is the study designed?
Design Details
- Observational Models: Cohort
- Time Perspectives: Prospective
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
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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.
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A percutaneous (needle) liver biopsy will be performed on subjects in the Liver Biopsy Group, in Year 1 and Year 5 of the study.
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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.
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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.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
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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
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Liver biopsy performed in Year 1 and Year 5
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Secondary Outcome Measures
Outcome Measure |
Time Frame |
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Calculated Model for End-stage Liver Disease score (MELD)
Time Frame: Calculated at baseline and annually through year 5
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Calculated at baseline and annually through year 5
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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
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Measured at baseline and annually through year 5
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Presence of ascites (or treatment for ascites)
Time Frame: Assessed at baseline and annually through year 5
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Assessed at baseline and annually through year 5
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Development of complications of portal hypertension (e.g., variceal hemorrhage)
Time Frame: Assessed at baseline and annually through year 5
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Assessed at baseline and annually through year 5
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Jaundice (total serum bilirubin >2.0 mg/dl)
Time Frame: Measured at baseline and annually through year 5
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Measured at baseline and annually through year 5
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Liver transplantation
Time Frame: Assessed annually through year 5
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Assessed annually through year 5
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Listing for liver transplantation
Time Frame: Assessed at baseline and annually through year 5
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Assessed at baseline and annually through year 5
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Health related quality of life
Time Frame: Measured at baseline and annually through year 5
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Measured at baseline and annually through year 5
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FEV1 % of Predicted
Time Frame: Collected at baseline and annually through year 5
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Collected at baseline and annually through year 5
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Death
Time Frame: Collected annually through year 5
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Collected annually through year 5
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Study Chair: Jeffrey Teckman, MD, St. Louis University
- Study Director: Andrew A Wilson, MD, Alpha-1 Foundation
- Principal Investigator: David A. Brenner, MD, The University of California, San Diego
- Principal Investigator: Kamran Qureshi, MD, St. Louis University
- Principal Investigator: Andrew A Wilson, MD, Boston University
Study record dates
Study Major Dates
Study Start
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- A1F-SLU-7113
- Alpha-1 Foundation (Other Grant/Funding Number: A1F-SLU-7113)
- 22609 (Other Identifier: Saint Louis University IRB)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD 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.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Alpha-1 Antitrypsin Deficiency
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University of FloridaAlpha-1 FoundationEnrolling by invitation
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Thomayer University HospitalMasaryk UniversityRecruiting
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Grifols Therapeutics LLCCompletedAlpha₁-Antitrypsin DeficiencyUnited States
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Michael Campos, MDCSL BehringCompletedAlpha 1 Antitrypsin DeficiencyUnited States
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University of PittsburghNational Heart, Lung, and Blood Institute (NHLBI)CompletedAlpha 1 Antitrypsin Deficiency | AATDUnited States
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Washington University School of MedicineNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); N... and other collaboratorsTerminatedLiver Cirrhosis | Alpha-1-antitrypsin DeficiencyUnited States
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Alnylam PharmaceuticalsTerminatedZZ Type Alpha-1 Antitrypsin Deficiency Liver DiseaseUnited Kingdom
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Hospices Civils de LyonCompletedChildren With a Deficiency of Alpha-1 AntitrypsinFrance
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Heidelberg UniversityTerminatedHereditary Emphysema (Alpha 1-antitrypsin Deficiency)Germany
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Grifols Therapeutics LLCCompletedEmphysema | Alpha 1-antitrypsin Deficiency (AATD)United States
Clinical Trials on Liver Biopsy (Biopsy Group Only)
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The Cleveland ClinicCompleted
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Institute of Liver and Biliary Sciences, IndiaNot yet recruitingLiver CirrhosisIndia
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Brigham and Women's HospitalWithdrawn
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Asian Institute of Gastroenterology, IndiaCompletedNAFLD | Alcoholic HepatitisIndia
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Centre Hospitalier Universitaire de BesanconEuropean Network of Gynaecological Oncological Trial Groups (ENGOT); ARCAGY...RecruitingCervical CancerSpain, France, Germany, Czechia, Switzerland, China, Japan, Brazil, Italy, Canada, India, Norway, Slovakia
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M.D. Anderson Cancer CenterNational Cancer Institute (NCI)RecruitingLiver and Intrahepatic Bile Duct CarcinomaUnited States