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

NCT01766960 | Completed Phase 1

• 2 other identifiers: 12-1599550KR41202
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Fatty Liver

Keywords

Bile acids; Pharmacokinetics

Outcome Measures

Primary Outcomes (1)

• Pharmacokinetic profile of morphine and its hepatically derived metabolites.

  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.

  8 hours post dose

Secondary Outcomes (2)

• Bile acid profile

  Pre- and postprandially

• FibroScan with Controlled Attenuation Parameter (CAP) Software

  No preparation (fasting) required-consumption of large meals prior to the Fibroscan procedure is not advised

Study Arms (2)

Healthy volunteers

EXPERIMENTAL

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; Drug: Morphine

Advanced nonalcoholic fatty liver disease patients

EXPERIMENTAL

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; Drug: Morphine

Interventions

High fat meal OTHER

A high fat breakfast will be administered to induce gall bladder emptying.

Advanced nonalcoholic fatty liver disease patients; Healthy volunteers

Morphine DRUG

Five milligrams of intravenous morphine will be administered.

Advanced nonalcoholic fatty liver disease patients; Healthy volunteers

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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:

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• University of North Carolina, Greensboro: collaborator

Study Sites (1)

North Carolina Clinical and Translational Research Center

Chapel Hill, North Carolina, 27599, United States

Location

MeSH Terms

Conditions

Fatty Liver

Interventions

Morphine

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Study Officials

• Alfred S Barritt, MD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

• Kim LR Brouwer, PharmD, PhD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Study Record Dates

• First Submitted: January 4, 2013
• First Posted: January 11, 2013
• Study Start: November 1, 2012
• Primary Completion: March 1, 2014
• Study Completion: June 1, 2014
• Last Updated: March 3, 2016

Record last verified: 2016-03

Locations

US (1)