Development of Kinetic Biomarkers of Liver Fibrosis Measuring NAFLD

• ClinicalTrials.gov Identifier: NCT02124577
• Recruitment Status: Unknown
• First Posted: April 28, 2014
• Last Update Posted: December 19, 2014
• Sponsor: University of California, San Diego
• Collaborator: KineMed
• Information provided by (Responsible Party): Rohit Loomba, University of California, San Diego

Tracking Information

• First Submitted Date: April 24, 2014
• First Posted Date: April 28, 2014
• Last Update Posted Date: December 19, 2014
• Study Start Date: May 2014
• Estimated Primary Completion Date: May 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 24, 2014)

evaluate stable isotope/mass spectrometric methods [ Time Frame: Basline ]

Our primary aim is to evaluate stable isotope/mass spectrometric methods for measuring in vivo liver collagen synthesis (fibrogenesis) and liver lipogenesis rates using liver biopsy specimens from patients with Non-Alcoholic Steatohepatitis (NASH)/ Nonalcoholic fatty liver disease (NAFLD).

• Original Primary Outcome Measures: Same as current
• Change History: Complete list of historical versions of study NCT02124577 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: April 24, 2014)

serum or urine markers of liver fibrogenesis that can be measured by the same stable isotope/mass spectrometric approach [ Time Frame: Basline ]

Our secondary aim is to look for new serum or urine markers of liver fibrogenesis that can be measured by the same stable isotope/mass spectrometric approach in the same subjects. Subjects will drink the safe, non-toxic stable isotope heavy water (2H2O, deuterated water) prior to having a liver biopsy and providing urine and blood samples.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Development of Kinetic Biomarkers of Liver Fibrosis Measuring NAFLD
• Official Title: Development of Kinetic Biomarkers of Liver Fibrosis Based on Stable Isotope Mass Spectrometry Techniques for Measuring Nonalcoholic Fatty Liver Disease NAFLD)
• Brief Summary: This is a small preliminary study conducted to explore new methods for the potential of aiding in diagnosis of liver fibrotic disease as well as predicting disease progression. There will be a total of 4 visits spread out over approximately 8 weeks. You will be asked to drink "heavy water" during most of that time. "Heavy Water" also known as deuterated water, is physically and chemically very similar to ordinary drinking water. It tastes and feels exactly like regular water. It is odorless and has no known harmful effects at the doses given here. Heavy water occurs naturally, and is a minor component of the water we all ingest daily.

Detailed Description

Management of NASH and NAFLD remain a significant unmet medical challenge that is growing in importance as part of the obesity epidemic. Minimally invasive tools for monitoring disease progression and evaluating therapeutic interventions in NASH would be extremely valuable. Utilizing in vivo heavy water labeling, multiple pathways related to protein metabolism (fibrogenesis) and lipid metabolism can be quantified in human subjects. We have recently discovered that plasma lumicam synthesis represents a non-invasive kinetic biomarker of tissue fibrogenesis in patients with viral hepatitis. In addition, synthesis of fatty acids in plasma VLDL-triglycerides provide a window into hepatic lipid metabolism.

Stable isotopes have a long history as a safe, effective tracer for measuring synthesis of molecules in humans (1). Recently, new developments in stable isotope labeling techniques and advances in mass spectrometry have made in vivo kinetic measurement of slow metabolic processes possible. Through the use of 2H2O as the source of labeling, we and others have measured T-cell proliferation (2), mammary epithelial cell proliferation (3), prostate epithelial cell proliferation (4), triglyceride synthesis (5) and protein synthesis (6) in humans. We have recently evaluated this approach for the measurement of fibrogenesis patients with fibrotic liver disease.

Excess accumulation of collagen in the liver is termed fibrosis. Fibrosis is a common pathological feature of several chronic liver diseases (e.g. Hepatitis C, alcoholic liver disease, primary biliary sclerosis, drug/toxin induced liver disease, etc.). Currently, the standard method for detection of fibrosis is liver biopsy and histochemical analyses of tissue collagen content (8, 9). Although effective in diagnosing existing, advanced fibrosis, a single biopsy cannot measure current disease activity or predict rate of progression. To determine whether disease is progressing using current methods, a second biopsy is required. If significant additional collagen has accumulated since the first biopsy, this suggests that the disease is progressing. However, this measurement represents the history of the disease, not the current disease activity at the time of the second biopsy. There are also significant limitations in current methods, since changes in collagen pool size measurable by histochemistry cannot measure small changes in collagen content and intra-laboratory variability inherent in histochemical assays reduce their sensitivity (10, 11).

This stable isotope / mass spectrometry based method will be applied here for the quantification of fibrogenesis in vivo (from a bone marrow biopsy) and the identification of novel biomarkers of fibrogenesis in plasma in patients receiving investigational therapies.

If successful, this research will identify plasma proteins which can be easily measured by tandem mass spectrometry (LC/MS/MS) methods and whose synthesis rate reflects disease activity in the heart. Ideally, a set of markers related to NASH/ NAFLD will be developed that can detect and differentiate among multiple disease phenotypes, based on the kinetic signature measured in a single blood draw from a patient labeled with deuterated water.

The role of de novo lipogenesis (DNL) has been suggested by several clinical studies (Donnelly JCI 2005, Puri Hepatology 2009). DNL contributes significantly to the accumulation of lipid in NASH (Donnelly JCI 2005). Moreover DNL is elevated in many other inflammatory states and may be a useful marker of hepatic inflammation. DNL as well as hepatic TG assembly and cholesterogenesis are easily measured in plasma or dried blood spot samples from patients consuming 2H2O, after several days of labeling the plasma DNL reaches a steady state and reflects hepatic DNL rates.

• Study Type: Observational [Patient Registry]
• Study Design: Observational Model: Case Control; Time Perspective: Prospective
• Target Follow-Up Duration: 8 Weeks

Biospecimen

Retention:   Samples With DNA

Description:

Stored specimen The specimens (serum, plasma, urine, stool, saliva, liver tissue, and DNA) collected as part of this study will be kept in Dr. Loomba' s locked research freezer at the Clinical Teaching Facility (CTF-building A).All collected data and patient charts will be maintained at the CTF building in a locked computer file with access available to the principal and study investigators only.

All samples and data will be labeled with a code number. The name, address, social security number, date of birth and other personal identifiers will not be available on the sample, and we will not give out any information that identifies the patient to the researchers who use these samples and data.

• Sampling Method: Probability Sample
• Study Population: Adults, age 18 or above, may have NAFLD or NASH-related cirrhosis or may serve as a control participant without this condition.
• Condition: Non-alcoholic Fatty Liver Disease
• Intervention: Not Provided
• Study Groups/Cohorts: Not Provided
• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: April 24, 2014): 50
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 2019
• Estimated Primary Completion Date: May 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Adults (≥ 18 years of age)
2. Adult male and female subjects, all races, ethnic groups, social and economic backgrounds and health status who are scheduled to undergo a liver biopsy as part of routine medical care will be included in the research.
3. Willingness to follow-up for 8 weeks
4. Written inform consent.

Exclusion Criteria:

1. Children younger than 18 will be excluded, since growth of liver tissue may confound measurements of collagen synthesis and cell proliferation due to normal turnover or disease.
2. The eligibility of patients will be determined by Dr. Rohit Loomba, MD or a referring physician at the time the potential subject is recommended to undergo a liver biopsy procedure as part of their medical treatment.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02124577
• Other Study ID Numbers: 140338
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Rohit Loomba, University of California, San Diego
• Study Sponsor: University of California, San Diego
• Collaborators: KineMed

Investigators

• Principal Investigator: Rohit Loomba, MD; University of California, San Diego

• PRS Account: University of California, San Diego
• Verification Date: April 2014