Altered Drug Disposition and Biomarkers for Diagnosis of Chronic Inflammatory Liver Disease

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2013 by University of North Carolina, Chapel Hill
Sponsor:
Collaborator:
University of North Carolina, Greensboro
Information provided by (Responsible Party):
Sidney Barritt, MD, University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier:
NCT01766960
First received: January 4, 2013
Last updated: August 14, 2013
Last verified: August 2013
  Purpose

One-third of the U.S. population suffers from non-alcoholic fatty liver disease (NAFLD). NAFLD is caused by diabetes and obesity, and is becoming more common. Although many people have this disease, the change in how the liver handles drugs and compounds in the body has not been studied. The purpose of this study is to investigate how advanced NAFLD changes the ability of the liver to handle both endogenous and exogenous compounds.


Condition Intervention Phase
Fatty Liver
Other: High fat meal
Drug: Morphine
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: Altered Drug Disposition and Biomarkers for Diagnosis of Chronic Inflammatory Liver Disease.

Resource links provided by NLM:


Further study details as provided by University of North Carolina, Chapel Hill:

Primary Outcome Measures:
  • Pharmacokinetic profile of morphine and its hepatically derived metabolites. [ Time Frame: 8 hours post dose ] [ Designated as safety issue: No ]
    Morphine will be administered as a 5-min IV infusion. Pharmacokinetic profiles of morphine and morphine metabolites will be quantified in the serum over the 8-hour sampling period. Non-compartmental analysis will be performed using Pharsight Phoenix software, comparing the following parameters between healthy subjects and patients with advanced NAFLD. The maximal concentration, time of maximal concentration, elimination half-life, area under the curve, and systemic and renal clearances will be calculated for both morphine and the glucuronide metabolites. Volume of distribution and metabolic clearance will be calculated for morphine.


Secondary Outcome Measures:
  • Bile acid profile [ Time Frame: Pre- and postprandially ] [ Designated as safety issue: No ]
    The bile acid profile in healthy and diseased subjects will be assessed following an 8 hour fast and every 30 min for 2 hours following a high fat breakfast. At each of the 5 time points, serum concentrations of total and selected individual bile acid species will be quantified and compared between healthy subjects and patients with advanced NAFLD. Comparison of the bile acid profile, comprised of all selected bile acids, between subjects and patients will pose as the primary endpoint for this outcome.

  • FibroScan with Controlled Attenuation Parameter (CAP) Software [ Time Frame: No preparation (fasting) required-consumption of large meals prior to the Fibroscan procedure is not advised ] [ Designated as safety issue: No ]
    FibroScan is more sensitive method to identify less severe scarring of liver tissue when compared to liver ultrasound and contrary to liver biopsy, it is not invasive. In this study, Fibroscan will be used to assess the extent of liver fibrosis in both healthy volunteers and patients diagnosed with NAFLD and the CAP software will be used to estimate fat liver content. These findings will be correlated with changes in morphine disposition and bile acid profile observed in the study participants as described above.


Estimated Enrollment: 30
Study Start Date: November 2012
Estimated Study Completion Date: November 2013
Estimated Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Healthy volunteers
Subjects will be asked to fast overnight. Upon presentation, FibroScan procedure with CAP will be conducted and baseline and postprandial bile acid profile will be assessed. Then, intravenous morphine will be administered and the pharmacokinetic profile will be assessed over 8 hours.
Other: High fat meal
A high fat breakfast will be administered to induce gall bladder emptying.
Drug: Morphine
Five milligrams of intravenous morphine will be administered.
Experimental: Advanced nonalcoholic fatty liver disease patients
Subjects will be asked to fast overnight. Upon presentation, FibroScan procedure with CAP will be conducted and baseline and postprandial bile acid profile will be assessed. Then, intravenous morphine will be administered and the pharmacokinetic profile will be assessed over 8 hours.
Other: High fat meal
A high fat breakfast will be administered to induce gall bladder emptying.
Drug: Morphine
Five milligrams of intravenous morphine will be administered.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

General:

  • Man or woman between 18 and 65 years of age
  • Negative pregnancy test for women of childbearing potential
  • Negative urine drug screen

Healthy Subjects:

  • Normal liver function tests
  • Normal kidney function and lipid panel

Nonalcoholic Steatohepatitis Patients:

  • Recent liver biopsy with nonalcoholic fatty liver disease activity score at least 4

Exclusion Criteria:

General:

  • History of significant alcohol use (>20 g/day) and/or illicit drug use
  • Inability to abstain from alcohol for 48 prior to study
  • Use of drugs associated with a clinical or histological picture consistent with fatty liver disease or NASH for more than 12 consecutive weeks in the year prior to screening; these include amiodarone, tamoxifen, methotrexate, glucocorticoids, anabolic steroids, tetracyclines, estrogens (at doses greater than those used for hormone replacement) or valproate/valproic acid
  • Type 2 diabetes treated with oral agents other than metformin; these include secretagogues, thiazolidinediones, alpha-glucosidase inhibitors, exenatide and pramlintide.
  • Current or recent use of bile acid sequestrants, bile acid derivatives (i.e. ursodiol) or fibric acid derivatives.
  • Current use of antioxidants such as silymarin, vitamin C, glutathione, or non-prescribed complementary alternative medications (including dietary supplements, megadose vitamins, herbal preparations, and special teas) within 30 days prior to screening.
  • Previous liver biopsy that demonstrated presence of cirrhosis.
  • Radiologic imaging consistent with cirrhosis or portal hypertension.
  • Serum creatinine of 2.0 mg/dL or greater, or on dialysis, at screening.
  • History of immunologically mediated disease (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, severe psoriasis, rheumatoid arthritis) that could affect the assessment of biomarkers (bile acids or inflammation).
  • History of bariatric surgery.
  • BMI > 45 kg/m^2 at screening.
  • Any known hypersensitivity to opiates, opiate antagonists, or ondansetron.

Healthy Subjects:

  • Taking concomitant medications, both prescription and non-prescription (including herbal products and over-the-counter medications), other than oral contraceptives and multivitamins (women stabilized on hormonal methods of birth control will be allowed to participate)
  • History or other evidence of liver disease in the opinion of the study investigators.
  • BMI > 30 kg/m^2 at screening.
  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: NCT01766960

Contacts
Contact: Brian C Ferslew, PharmD 9199620089 bferslew@unc.edu
Contact: Eleftheria Tsakalozou, PhD 9199620089 etsakal@email.unc.edu

Locations
United States, North Carolina
North Carolina Clinical and Translational Research Center Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Brian C Ferslew, PharmD    919-962-0089    bferslew@unc.edu   
Principal Investigator: Alfred S Barritt, MD, MSCR         
Principal Investigator: Kim LR Brouwer, PharmD, PhD         
Sub-Investigator: Brian C Ferslew, PharmD         
Sub-Investigator: Wei Jia, PhD         
Sub-Investigator: Curtis K Johnston, PharmD         
Sub-Investigator: Eleftheria Tsakalozou, PhD         
Sponsors and Collaborators
University of North Carolina, Chapel Hill
University of North Carolina, Greensboro
Investigators
Principal Investigator: Alfred S Barritt, MD University of North Carolina, Chapel Hill
Principal Investigator: Kim LR Brouwer, PharmD, PhD University of North Carolina, Chapel Hill
  More Information

No publications provided

Responsible Party: Sidney Barritt, MD, Assistant Professor of Medicine, University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT01766960     History of Changes
Other Study ID Numbers: 12-1599, 550KR41202
Study First Received: January 4, 2013
Last Updated: August 14, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by University of North Carolina, Chapel Hill:
Bile acids
Pharmacokinetics

Additional relevant MeSH terms:
Fatty Liver
Hepatitis
Liver Diseases
Digestive System Diseases
Morphine
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Pharmacologic Actions
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 18, 2014