Liver Fibrosis in Alpha-1 Antitrypsin Deficiency (Liver AATD)

NCT01810458 | Completed DMC

• 3 other identifiers: IRB201601019910IRB201601019/ 63-2013
• Study Type: observational
• Target: 109
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Liver Fibrosis; Alpha-1 Antitrypsin Deficiency; AAT Deficiency; AATD

Keywords

Liver; Fibrosis; Alpha-1; AAT; AATD

Outcome Measures

Primary Outcomes (1)

• To estimate the prevalence and histologic spectrum of liver injury in an adult with Alpha-1 Antitrypsin deficiency having a ZZ genotype or other rare allele.

  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.

  up to 30 days

Secondary Outcomes (4)

• To identify environmental and host risk factors for clinically significant liver fibrosis.

  At each study visit including screening, first liver biopsy, year 1, year 2, and year 3 visits.

• To define the diagnostic accuracy of non-invasive markers of fibrosis in AAT liver disease.

  At the screening and year 3 visits.

• To explore epigenetic markers for the development of liver fibrosis.

  Starting with the first liver biopsy and ending with the second liver biopsy done at year 3.

• To quantify liver fibrosis progression.

  At each study visit including screening, first liver biopsy, year 1, year 2, and year 3 visits.

Study Arms (1)

AATD ZZ and Rare Alleles Group

Participants will get a history and physical (H\&P) and have an intravenous catheter (IV) placed, for blood draws, 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, lorazepam, or 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 or oxycodone/acetaminophen. Any subject experiencing nausea may receive ondansetron.

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; Drug: Lorazepam; Drug: Oxycodone/Acetaminophen; Drug: Ondansetron

Interventions

Abdominal ultrasound DEVICE

Abdominal ultrasound will be done at the liver biopsy visits. The purpose of the ultrasound is to evaluate for the presence of liver fibrosis and identify the biopsy site.

Also known as: SonoSite Edge Ultrasound System

AATD ZZ and Rare Alleles Group

History and physical PROCEDURE

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.

Also known as: H&P, exam, medical history

AATD ZZ and Rare Alleles Group

Intravenous catheter PROCEDURE

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.

Also known as: IV

AATD ZZ and Rare Alleles Group

Blood draw PROCEDURE

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.

Also known as: Phlebotomy

AATD ZZ and Rare Alleles Group

Liver questionnaire OTHER

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

Also known as: Questionnaire

AATD ZZ and Rare Alleles Group

Liver Biopsy PROCEDURE

Every participating subject who passes the screening visit, will have a liver biopsy done with the use of lidocaine (a numbing medicine) injected into skin where the biopsy will be collected. At the time of the biopsy, either lorazepam (a medicine used to treat anxiety and cause relaxation) or midazolam (a medicine used to cause sleepiness and amnesia) and fentanyl (a medicine used to relieve pain) will be used. Once the relaxation medication and numbing medicine have been given, a sample of liver tissue will be collected using a needle biopsy device.

Also known as: Biopsy

AATD ZZ and Rare Alleles Group

Midazolam DRUG

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, either lorazepam (a medicine used to treat anxiety and cause relaxation) or 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 either oxycodone/acetaminophen or acetaminophen (medicines used to relieve pain). Any participant who experiences nausea may receive ondansetron (a medicine used to relieve nausea).

Also known as: Versed

AATD ZZ and Rare Alleles Group

Fentanyl DRUG

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, either lorazepam (a medicine used to treat anxiety and cause relaxation) or 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 either oxycodone/acetaminophen or acetaminophen (medicines used to relieve pain). Any participant who experiences nausea may receive ondansetron (a medicine used to relieve nausea).

Also known as: Fentora, Onsolis

AATD ZZ and Rare Alleles Group

Lidocaine DRUG

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, either lorazepam (a medicine used to treat anxiety and cause relaxation) or 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 either oxycodone/acetaminophen or acetaminophen (medicines used to relieve pain). Any participant who experiences nausea may receive ondansetron (a medicine used to relieve nausea).

Also known as: Xylocaine

AATD ZZ and Rare Alleles Group

Acetaminophen DRUG

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, either lorazepam (a medicine used to treat anxiety and cause relaxation) or 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 either oxycodone/acetaminophen or acetaminophen (medicines used to relieve pain). Any participant who experiences nausea may receive ondansetron (a medicine used to relieve nausea).

Also known as: Tylenol

AATD ZZ and Rare Alleles Group

Lorazepam DRUG

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, either lorazepam (a medicine used to treat anxiety and cause relaxation) or 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 either oxycodone/acetaminophen or acetaminophen (medicines used to relieve pain). Any participant who experiences nausea may receive ondansetron (a medicine used to relieve nausea).

Also known as: Ativan

AATD ZZ and Rare Alleles Group

Oxycodone/Acetaminophen DRUG

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, either lorazepam (a medicine used to treat anxiety and cause relaxation) or 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 either oxycodone/acetaminophen or acetaminophen (medicines used to relieve pain). Any participant who experiences nausea may receive ondansetron (a medicine used to relieve nausea).

Also known as: Percocet, Tylox

AATD ZZ and Rare Alleles Group

Ondansetron DRUG

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, either lorazepam (a medicine used to treat anxiety and cause relaxation) or 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 either oxycodone/acetaminophen or acetaminophen (medicines used to relieve pain). Any participant who experiences nausea may receive ondansetron (a medicine used to relieve nausea).

Also known as: Zofran

AATD ZZ and Rare Alleles Group

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Pulmonary clinic, hepatology clinic, and the Alpha-1 Antitrypsin Tissue and Data Bank.

You may qualify if:

• Alpha-1 Antitrypsin deficiency confirmed to be PI\*ZZ by both genotype or another identified rare allele;
• Age range from 18-70;
• Willingness to consent to liver biopsy;
• Ability to travel to UF as necessary by protocol; and
• Platelet count greater than or equal to 50,000/mm3 and an INR less than or equal to 1.5.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Florida: lead

Study Sites (1)

Shands at the University of Florida

Gainesville, Florida, 32610, United States

Location

Related Publications (1)

• Clark VC, Marek G, Liu C, Collinsworth A, Shuster J, Kurtz T, Nolte J, Brantly M. Clinical and histologic features of adults with alpha-1 antitrypsin deficiency in a non-cirrhotic cohort. J Hepatol. 2018 Dec;69(6):1357-1364. doi: 10.1016/j.jhep.2018.08.005. Epub 2018 Aug 21.

  PMID: 30138687 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Liver tissue and whole blood.

MeSH Terms

Conditions

Liver Cirrhosis; alpha 1-Antitrypsin Deficiency; Fibrosis

Interventions

Health Records, Personal; Restraint, Physical; Blood Specimen Collection; Phlebotomy; Surveys and Questionnaires; Biopsy; Midazolam; Fentanyl; Lidocaine; Acetaminophen; Lorazepam; oxycodone-acetaminophen; Ondansetron

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Subcutaneous Emphysema; Emphysema

Intervention Hierarchy (Ancestors)

Medical Records; Records; Data Collection; Epidemiologic Methods; Investigative Techniques; Behavior Control; Therapeutics; Immobilization; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health; Cytodiagnosis; Cytological Techniques; Diagnostic Techniques, Surgical; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Piperidines; Heterocyclic Compounds, 1-Ring; Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Benzodiazepinones; Imidazoles; Azoles; Carbazoles; Indoles; Heterocyclic Compounds, 3-Ring

Study Officials

• Mark Brantly, MD

  University of Florida

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 6, 2013
• First Posted: March 13, 2013
• Study Start: October 1, 2013
• Primary Completion: September 1, 2019
• Study Completion: September 1, 2019
• Last Updated: August 21, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will share

Locations

US (1)