Nonalcoholic Steatohepatitis
Conditions
Keywords
NASH, NAFLD, Steatohepatitis, Nonalcoholic, Fatty Liver Disease
Brief summary
The purpose of the study is to see if the drug colesevelam is a potential treatment for Nonalcoholic Steatohepatitis(NASH).
Detailed description
We plan to investigate the role of colesevelam, a bile-acid binding resin, in patients with NASH residing in the United States and assess liver fat changes during therapy using MRI of the liver. It can be hypothesized that colesevelam would lead to a greater improvement in insulin sensitivity and lipid profile compared with placebo and may lead to greater improvement in liver fat by MRI as compared to placebo. In this pilot study, we propose to randomize approximately 55 patients (1:1 ratio) to either colesevelam or placebo and treat them for 24-weeks to evaluate changes in baseline insulin sensitivity, serum biochemistry (ALT and AST), and liver fat by MRI during therapy. Liver histologic changes would also be examined as an exploratory outcome for future studies.
Interventions
DRUGColesevelam Hcl
3.75 gm/day (six 675 mg tablets)
Sponsors
Daiichi Sankyo
University of California, San Diego
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age at entry at least 18 years. 2. Serum alanine (ALT) or aspartate (AST) aminotransferase activities that are above the upper limits of normal. 19 or more in women and 30 or more in men. 3. Evidence of hepatic steatosis or liver fat (\>5%) by MRI. 4. Evidence of definite or suspected NASH 5. Written informed consent.
Exclusion criteria
1. Evidence of another form of liver disease. 2. History of excess alcohol ingestion. 3. Contraindications to liver biopsy. 4. Decompensated liver disease. 5. History of gastrointestinal bypass surgery or ingestion of drugs known to produce hepatic steatosis. 6. Recent initiation or change of anti-diabetic drugs. 7. Use of colesevelam or other agents in the same class. 8. Significant systemic or major illnesses other than liver disease that, in the opinion of the investigator would preclude treatment with colesevelam and adequate follow up. 9. Positive test for anti-HIV. 10. Active substance abuse, such as alcohol, inhaled or injection drugs within the previous one year. 11. Pregnancy or inability to practice adequate contraception in women of childbearing potential. 12. Evidence of hepatocellular carcinoma
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Outcome Will be Improvement in Hepatic Steatosis by Liver MRI | 24 weeks | To examine the efficacy of Colesevelam at 3.75 g/day orally versus placebo to decrease liver fat in patients with biopsy-proven nonalcoholic steatohepatitis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Sensitivity as Determined by HOMA-IR | 24 weeks | To examine the efficacy of Colesevelam at 3.75 g/day orally versus placebo to decrease HOMA-IR in patients with biopsy-proven nonalcoholic steatohepatitis. |
| Serum ALT and AST Values | 24 weeks | To examine the efficacy of Colesevelam at 3.75 g/day orally versus placebo to decrease serum ALT and AST in patients with biopsy-proven nonalcoholic steatohepatitis. |
| Lipid Profiles | 24 weeks | To examine the efficacy of Colesevelam at 3.75 g/day orally versus placebo to decrease improve the lipid profiles in patients with biopsy-proven nonalcoholic steatohepatitis. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo (Sugar) Pill Six tablets per day (identical to colesevelam)
Colesevelam Hcl: 3.75 gm/day (six 675 mg tablets) | 25 |
| Colesevelam Arm 3.75 grams per day
Colesevelam Hcl: 3.75 gm/day (six 675 mg tablets) | 25 |
| Total | 50 |
Baseline characteristics
| Characteristic | Placebo (Sugar) Pill | Total | Colesevelam Arm |
|---|---|---|---|
| Age, Continuous | 50.3 years STANDARD_DEVIATION 10.4 | 47.8 years STANDARD_DEVIATION 11.7 | 45.4 years STANDARD_DEVIATION 12.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 11 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants | 16 Participants | 9 Participants |
| Race (NIH/OMB) White | 8 Participants | 19 Participants | 11 Participants |
| Region of Enrollment United States | 25 participants | 50 participants | 25 participants |
| Sex: Female, Male Female | 12 Participants | 27 Participants | 15 Participants |
| Sex: Female, Male Male | 13 Participants | 23 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 25 |
| other Total, other adverse events | 2 / 25 | 1 / 25 |
| serious Total, serious adverse events | 0 / 25 | 0 / 25 |
Outcome results
Primary
The Primary Outcome Will be Improvement in Hepatic Steatosis by Liver MRI
To examine the efficacy of Colesevelam at 3.75 g/day orally versus placebo to decrease liver fat in patients with biopsy-proven nonalcoholic steatohepatitis.
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Sugar) Pill | The Primary Outcome Will be Improvement in Hepatic Steatosis by Liver MRI | 17.9 % of fat | Standard Deviation 7.7 |
| Colesevelam Arm | The Primary Outcome Will be Improvement in Hepatic Steatosis by Liver MRI | 14.2 % of fat | Standard Deviation 6.3 |
Secondary
Insulin Sensitivity as Determined by HOMA-IR
To examine the efficacy of Colesevelam at 3.75 g/day orally versus placebo to decrease HOMA-IR in patients with biopsy-proven nonalcoholic steatohepatitis.
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Sugar) Pill | Insulin Sensitivity as Determined by HOMA-IR | 8.3 units on a scale | Standard Deviation 9.8 |
| Colesevelam Arm | Insulin Sensitivity as Determined by HOMA-IR | 7.6 units on a scale | Standard Deviation 12.3 |
Secondary
Lipid Profiles
To examine the efficacy of Colesevelam at 3.75 g/day orally versus placebo to decrease improve the lipid profiles in patients with biopsy-proven nonalcoholic steatohepatitis.
Time frame: 24 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Sugar) Pill | Lipid Profiles | LDL | 115.8 mg/dL | Standard Deviation 31.2 |
| Placebo (Sugar) Pill | Lipid Profiles | Total Cholesterol | 202.4 mg/dL | Standard Deviation 36.5 |
| Colesevelam Arm | Lipid Profiles | LDL | 124.0 mg/dL | Standard Deviation 37.7 |
| Colesevelam Arm | Lipid Profiles | Total Cholesterol | 200.2 mg/dL | Standard Deviation 46 |
Secondary
Serum ALT and AST Values
To examine the efficacy of Colesevelam at 3.75 g/day orally versus placebo to decrease serum ALT and AST in patients with biopsy-proven nonalcoholic steatohepatitis.
Time frame: 24 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Sugar) Pill | Serum ALT and AST Values | ALT | 79.1 U/L | Standard Deviation 47.8 |
| Placebo (Sugar) Pill | Serum ALT and AST Values | AST | 49.9 U/L | Standard Deviation 32.1 |
| Colesevelam Arm | Serum ALT and AST Values | AST | 56.2 U/L | Standard Deviation 46.3 |
| Colesevelam Arm | Serum ALT and AST Values | ALT | 86.6 U/L | Standard Deviation 68.1 |