Liver Fibrosis in Alpha-1 Antitrypsin Deficiency (AATD) - Full Text View

Purpose

We hypothesize that individuals with Alpha-1 Antitrypsin (AAT) deficiency have ongoing liver injury which is not detected by the usual blood tests used to look at liver function. This ongoing liver injury leads to cirrhosis in a significant number of adults with AAT deficiency.

Condition	Intervention	Phase
Liver Fibrosis Alpha-1 Antitrypsin Deficiency AAT Deficiency AATD	Device: Abdominal ultrasound Procedure: History and physical Procedure: Intravenous catheter Procedure: Blood draw Other: Liver questionnaire Procedure: Liver Biopsy Drug: Midazolam Drug: Fentanyl Drug: Lidocaine Drug: Acetaminophen	Phase 1

Study Type:	Interventional
Study Design:	Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Screening
Official Title:	Clinical Predictors and Epigenetic Markers for Liver Fibrosis in Alpha-1 Antitrypsin Deficiency

Resource links provided by NLM:

Genetics Home Reference related topics: alpha-1 antitrypsin deficiency North American Indian childhood cirrhosis

MedlinePlus related topics: Alpha-1 Antitrypsin Deficiency

Drug Information available for: Lidocaine hydrochloride Acetaminophen Lidocaine Fentanyl Fentanyl citrate alpha 1-Antitrypsin Midazolam hydrochloride

U.S. FDA Resources

Further study details as provided by University of Florida:

Primary Outcome Measures:

To estimate the prevalence and histologic spectrum of liver injury in an adult with Alpha-1 Antitrypsin deficiency and a genotype of ZZ. [ Time Frame: up to 30 days ] [ Designated as safety issue: No ]
An abdominal ultrasound will be done at the screening visit. A liver biopsy will be done on subjects who pass the screening process. The biopsy will be done within 30 days of the screening visit.

Secondary Outcome Measures:

To identify environmental and host risk factors for clinically significant liver fibrosis. [ Time Frame: At each study visit including screening, first liver biopsy, year 1, year 2, and year 3 visits. ] [ Designated as safety issue: No ]
A liver disease questionnaire will be done at the time of the first liver biopsy and at the year 3 study visit. A history and physical will also be completed at the screening visit, year 1 visit, year 2 visit, and year 3 visit.
To define the diagnostic accuracy of non-invasive markers of fibrosis in AAT liver disease. [ Time Frame: At the screening and year 3 visits. ] [ Designated as safety issue: No ]
An abdominal ultrasound will be completed at the screening visit and the year 3 visit.
To explore epigenetic markers for the development of liver fibrosis. [ Time Frame: Starting with the first liver biopsy and ending with the second liver biopsy done at year 3. ] [ Designated as safety issue: No ]
Liver tissue collected at the time of the first biopsy will be sent for testing which will evaluate for epigenetic markers of liver fibrosis. For subjects whose initial liver biopsy reveals liver fibrosis between stages 2 - 4, additional liver tissue will be collected at the time of the repeat biopsy done at the year 3 study visit.
To quantify liver fibrosis progression. [ Time Frame: At each study visit including screening, first liver biopsy, year 1, year 2, and year 3 visits. ] [ Designated as safety issue: No ]
The presence and progression of liver fibrosis will be evaluated by an abdominal ultrasound done at the screening visit, year 1 visit, year 2 visit, and year 3 visit. A liver biopsy will be done if a subject passes the screening visit and will be repeated at the year 3 study visit if the initial liver biopsy reveals liver fibrosis between stages 2 - 4.

Estimated Enrollment:	100
Study Start Date:	April 2013
Estimated Study Completion Date:	April 2017
Estimated Primary Completion Date:	April 2016 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: AATD ZZ Group AAT deficient people with genetic type ZZ will get a history and physical (H&P) and have an intravenous catheter (IV) placed, from which blood draws will be collected, at the screening and years 1-3 visits. An IV will also be placed at the liver biopsy visit(s) for the administration of medication. An abdominal ultrasound will be done at the screening and year 3 visits along with the completion of a liver questionnaire. Finally, participants will have a liver biopsy done, with the use of lidocaine, midazolam, and fentanyl, after the screening visit and potentially at the year 3 study visit, depending on the results of the first liver biopsy. Participants who experience pain after the liver biopsy may receive acetaminophen.	Device: Abdominal ultrasound Abdominal ultrasound will be done at the screening visit and year 3 visit. The purpose of the ultrasound is to evaluate for the presence of liver fibrosis. Other Name: SonoSite Edge Ultrasound System Procedure: History and physical Every study participant will be asked about their medical history and will have a physical exam done at the screening, year 1, year 2, and year 3 visits. Other Names: H&P exam medical history Procedure: Intravenous catheter Every study participant will have and intravenous catheter (IV) placed at every study visit. The IV will be used for the collection of blood at the screening, year 2, year 2, and year 3 visits. It will also be used for the administration of medication at the first liver biopsy, as well as the year 3 visit if the biopsy is repeated. Other Name: IV Procedure: Blood draw At the screening, year 1, year 2, and year 3 visits, every participant will have blood collected from the IV that is placed in one of their veins. Other Name: Phlebotomy Other: Liver questionnaire At the screening and year 3 visits, every subject will complete a questionnaire which involves questions regarding liver health. Other Name: Questionnaire Procedure: Liver Biopsy Every participating subject who passes the screening visit, will have a liver biopsy done with the use of lidocaine injected into skin where the biopsy will be collected. At the time of the biopsy, versed (a medicine used to cause sleepiness) and fentanyl (a medicine used to relieve pain) will be used. After the biopsy is done, participants who continue to have pain may receive Tylenol (a medicine used to relieve pain). Other Name: Biopsy Drug: Midazolam Every participating subject who passes the screening visit, will have a liver biopsy done with the use of lidocaine injected into skin where the biopsy will be collected. At the time of the biopsy, midazolam (a medicine used to cause sleepiness and amnesia) and fentanyl (a medicine used to relieve pain) will be used. After the biopsy is done, participants who continue to have pain may receive acetaminophen (a medicine used to relieve pain). Other Name: Versed Drug: Fentanyl Every participating subject who passes the screening visit, will have a liver biopsy done with the use of lidocaine injected into skin where the biopsy will be collected. At the time of the biopsy, midazolam (a medicine used to cause sleepiness and amnesia) and fentanyl (a medicine used to relieve pain) will be used. After the biopsy is done, participants who continue to have pain may receive acetaminophen (a medicine used to relieve pain). Other Names: Fentora Onsolis Drug: Lidocaine Every participating subject who passes the screening visit, will have a liver biopsy done with the use of lidocaine injected into skin where the biopsy will be collected. At the time of the biopsy, midazolam (a medicine used to cause sleepiness and amnesia) and fentanyl (a medicine used to relieve pain) will be used. After the biopsy is done, participants who continue to have pain may receive acetaminophen (a medicine used to relieve pain). Other Name: Xylocaine Drug: Acetaminophen Every participating subject who passes the screening visit, will have a liver biopsy done with the use of lidocaine injected into skin where the biopsy will be collected. At the time of the biopsy, midazolam (a medicine used to cause sleepiness and amnesia) and fentanyl (a medicine used to relieve pain) will be used. After the biopsy is done, participants who continue to have pain may receive acetaminophen (a medicine used to relieve pain). Other Name: Tylenol

Arms

Assigned Interventions

Experimental: AATD ZZ Group

AAT deficient people with genetic type ZZ will get a history and physical (H&P) and have an intravenous catheter (IV) placed, from which blood draws will be collected, at the screening and years 1-3 visits. An IV will also be placed at the liver biopsy visit(s) for the administration of medication. An abdominal ultrasound will be done at the screening and year 3 visits along with the completion of a liver questionnaire. Finally, participants will have a liver biopsy done, with the use of lidocaine, midazolam, and fentanyl, after the screening visit and potentially at the year 3 study visit, depending on the results of the first liver biopsy. Participants who experience pain after the liver biopsy may receive acetaminophen.

Device: Abdominal ultrasound

Abdominal ultrasound will be done at the screening visit and year 3 visit. The purpose of the ultrasound is to evaluate for the presence of liver fibrosis.

Other Name: SonoSite Edge Ultrasound System

Procedure: History and physical

Every study participant will be asked about their medical history and will have a physical exam done at the screening, year 1, year 2, and year 3 visits.

Other Names:

H&P
exam
medical history

Procedure: Intravenous catheter

Every study participant will have and intravenous catheter (IV) placed at every study visit. The IV will be used for the collection of blood at the screening, year 2, year 2, and year 3 visits. It will also be used for the administration of medication at the first liver biopsy, as well as the year 3 visit if the biopsy is repeated.

Other Name: IV

Procedure: Blood draw

At the screening, year 1, year 2, and year 3 visits, every participant will have blood collected from the IV that is placed in one of their veins.

Other Name: Phlebotomy

Other: Liver questionnaire

At the screening and year 3 visits, every subject will complete a questionnaire which involves questions regarding liver health.

Other Name: Questionnaire

Procedure: Liver Biopsy

Every participating subject who passes the screening visit, will have a liver biopsy done with the use of lidocaine injected into skin where the biopsy will be collected. At the time of the biopsy, versed (a medicine used to cause sleepiness) and fentanyl (a medicine used to relieve pain) will be used. After the biopsy is done, participants who continue to have pain may receive Tylenol (a medicine used to relieve pain).

Other Name: Biopsy

Drug: Midazolam

Every participating subject who passes the screening visit, will have a liver biopsy done with the use of lidocaine injected into skin where the biopsy will be collected. At the time of the biopsy, midazolam (a medicine used to cause sleepiness and amnesia) and fentanyl (a medicine used to relieve pain) will be used. After the biopsy is done, participants who continue to have pain may receive acetaminophen (a medicine used to relieve pain).

Other Name: Versed

Drug: Fentanyl

Every participating subject who passes the screening visit, will have a liver biopsy done with the use of lidocaine injected into skin where the biopsy will be collected. At the time of the biopsy, midazolam (a medicine used to cause sleepiness and amnesia) and fentanyl (a medicine used to relieve pain) will be used. After the biopsy is done, participants who continue to have pain may receive acetaminophen (a medicine used to relieve pain).

Other Names:

Fentora
Onsolis

Drug: Lidocaine

Every participating subject who passes the screening visit, will have a liver biopsy done with the use of lidocaine injected into skin where the biopsy will be collected. At the time of the biopsy, midazolam (a medicine used to cause sleepiness and amnesia) and fentanyl (a medicine used to relieve pain) will be used. After the biopsy is done, participants who continue to have pain may receive acetaminophen (a medicine used to relieve pain).

Other Name: Xylocaine

Drug: Acetaminophen

Every participating subject who passes the screening visit, will have a liver biopsy done with the use of lidocaine injected into skin where the biopsy will be collected. At the time of the biopsy, midazolam (a medicine used to cause sleepiness and amnesia) and fentanyl (a medicine used to relieve pain) will be used. After the biopsy is done, participants who continue to have pain may receive acetaminophen (a medicine used to relieve pain).

Other Name: Tylenol

Detailed Description:

Our overarching hypothesis is that liver disease in adults with AAT deficiency is the result of the accumulation of the abnormally folded protein within the endoplasmic reticulum of the hepatocyte. In some individuals, the intrinsic cellular mechanisms of the hepatocyte are sufficient to clear adequate amounts of the abnormally folded protein such that liver disease does not occur. In AAT deficient individuals who develop liver disease, environmental and other genetic factors stress the hepatocyte, and the normal cellular mechanisms that maintain homeostasis are disrupted, leading to liver disease.

For this proposal, our hypothesis is that the prevalence of liver disease in adults with AAT is higher than previously reported because liver injury and fibrosis is not accurately detected by available routine liver testing. Testing this hypothesis will require an initial evaluation for liver disease with liver function testing and imaging, and then histologic confirmation by liver biopsy.

Eligibility

Ages Eligible for Study:	21 Years to 70 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Alpha-1 Antitrypsin deficiency confirmed to be PI*ZZ by both genotype and phenotype who have serum AAT levels less than or equal to 11 µM;
Age range from 21-70;
Willingness to consent to liver biopsy;
Ability to travel to UF as necessary by protocol; and
Platelet count greater than or equal to 75,000/mm3 and an INR less than or equal to 1.5.

Exclusion Criteria:

Hemophilia, anticoagulant therapy that cannot be interrupted briefly, malignancy, or any other condition that would compromise the safety of a liver biopsy;
Any known pre-existing medical condition that might interfere with the patient's participation in and completion of the study or any condition, which in the opinion of the investigator would make the patient unsuitable for enrollment;
Active substance abuse including, but not limited to, alcohol, intravenous or, inhaled drugs;
History of adverse reactions or allergy to the local anesthetic, sedative, or pre-medication used for the percutaneous liver biopsy;
Poor venous access making the subject unable to complete the required laboratory testing schedule; and
Females who are pregnant or lactating at time of enrollment. Should a female subject become pregnant during the follow up period after the initial liver biopsy, continued participation would be allowed if the following conditions are met: the subject desires to continue; a discussion of risk and benefits of participation between the principal investigator and the subject has occurred; and no liver biopsy would be performed in the follow up period.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01810458

Contacts

Contact: Tracie L Kurtz, RN	866-229-6313	tlkurtz@ufl.edu
Contact: Virginia C Clark, MD	352-273-9491	Virginia.Clark@medicine.ufl.edu

Locations

United States, Florida
Shands at the University of Florida	Not yet recruiting
Gainesville, Florida, United States, 32610
Contact: Tracie L Kurtz, RN 866-229-6313 tlkurtz@ufl.edu
Contact: Virginia C Clark, MD 352-273-9491 Virginia.Clark@medicine.ufl.edu
Principal Investigator: Mark Brantly, MD
Sub-Investigator: Virginia C Clark, MD

Sponsors and Collaborators

University of Florida

Investigators

Principal Investigator:

Mark Brantly, MD

University of Florida

More Information

No publications provided

Responsible Party:	University of Florida
ClinicalTrials.gov Identifier:	NCT01810458 History of Changes
Other Study ID Numbers:	63-2013, 910
Study First Received:	March 6, 2013
Last Updated:	April 25, 2013
Health Authority:	United States: Food and Drug Administration

Keywords provided by University of Florida:

Liver
Fibrosis
Alpha-1
AAT
AATD

Additional relevant MeSH terms:

Alpha 1-Antitrypsin Deficiency
Alpha 1-Antitrypsin
Fibrosis
Liver Cirrhosis
Pathologic Processes
Liver Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Subcutaneous Emphysema
Emphysema
Acetaminophen
Fentanyl
Midazolam

Lidocaine
Protein C Inhibitor
Liver Extracts
Antipyretics
Physiological Effects of Drugs
Pharmacologic Actions
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Therapeutic Uses
Trypsin Inhibitors
Serine Proteinase Inhibitors
Protease Inhibitors

ClinicalTrials.gov processed this record on June 18, 2013