Diabetes Mellitus, Type II, Fatty Liver
Conditions
Keywords
Farnesoid X receptor agonist, Metabolic Disorder, Diabetes, NAFLD
Brief summary
The primary objectives of this study are to assess, in patients with Type 2 diabetes mellitus (DM) and presumed nonalcoholic fatty liver disease (NAFLD), the following: * The safety and tolerability of multiple doses of INT 747; * The effects of 2 dose levels (25 mg and 50 mg) of INT 747 on insulin resistance and glucose homeostasis; * Effects of INT-747 on hepatocellular function as measured by assessment of liver enzymes and biochemical markers of hepatic and metabolic function and inflammation, and; * Trough concentrations of INT-747 and its metabolites, glyco 6-ethyl chenodeoxycholic acid (6-EDCA) and tauro 6-ECDCA.
Detailed description
This is a multi-center, double-blind, randomized, placebo-controlled, multiple-dose, parallel-group study. Three (3) cohorts of 12 patients each will receive either placebo, 25 mg INT-747, or 50 mg INT-747 by mouth daily for 6 weeks. The primary objective of assessing changes in insulin resistance and glucose homeostasis will be attained by performing a euglycemic clamp procedure at baseline (Day 0) and at the end of 6 weeks of treatment (Day 43). Other endpoints will be evaluated by monitoring adverse experiences; vital signs; clinical laboratory values; plasma drug and metabolite concentrations; and general health and well-being.
Interventions
DRUGINT-747
25 mg by mouth once daily, 50 mg by mouth once daily
DRUGPlacebo
Placebo
Sponsors
Intercept Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes, defined by the American Diabetes Association (ADA), as one of the following criteria: * Symptoms of diabetes plus casual plasma glucose concentration \>200 mg/dL (11.1 mmol/L) or * Fasting plasma glucose \>126 mg/dL (7.0 mmol/L) or * 2-hour post-load glucose \>200 mg/dL (11.1 mmol/L) during a 75 g oral glucose tolerance test (GTT). * Presumed NAFLD, defined by one of the following criteria: * Alanine aminotransferase (ALT) ≥47 U/L for females and ≥56 U/L for males * Aspartate aminotransferase (AST) ≥47 U/L for females and ≥60 U/L for males * Enlarged liver (demonstrated by ultrasound or other imaging technique) * Diagnostic histological findings shown on prior biopsy (in the last 5 years).
Exclusion criteria
* Bilirubin \>2 × ULN * ALT \>155 U/L for females and \>185 U/L for males. * AST \>155 U/L for females and \>200 U/L for males. * Patients taking any antidiabetic medications, with the exception of metformin and sulfonylureas. If the HbA1c is \<11%, patients may be enrolled who have been withdrawn from all other diabetic medications as specified in the protocol, at the discretion of the Principal Investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Resistance and Glucose Homeostasis | baseline and 6 weeks | The primary objective of assessing changes in insulin resistance and glucose homeostasis will be attained by performing a euglycemic clamp procedure at baseline (Day 0) and at the end of 6 weeks of treatment (Day 43). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hepatocellular Function | baseline and 6 weeks | Hepatocellular function as measured by assessment of liver enzymes and biochemical markers of hepatic and metabolic function |
Countries
United States
Participant flow
Recruitment details
Sixty four subjects were enrolled in the study at 4 sites. Of the randomized subjects, 20 were randomized to INT-747 25 mg, 21 subjects to INT-747 50 mg, and 23 subjects to placebo. Study enrollment by center ranged from 4 to 31 subjects.
Pre-assignment details
A protocol amendment allowed for the enrollment of 14 replacement subjects (to enroll up to 56 subjects meeting eligibility requirements). The amendment pre-specified that the original 14 subjects being replaced would not be included in the efficacy analysis since they did not meet the protocol requirements.
Participants by arm
| Arm | Count |
|---|---|
| 25 mg INT-747 Once daily by mouth | 20 |
| 50 mg INT-747 Once daily by mouth | 21 |
| Placebo Once daily by mouth | 23 |
| Total | 64 |
Baseline characteristics
| Characteristic | 50 mg INT-747 | Placebo | 25 mg INT-747 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 3 Participants | 1 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 20 Participants | 19 Participants | 59 Participants |
| Age Continuous | 50.5 years STANDARD_DEVIATION 10.8 | 53.1 years STANDARD_DEVIATION 12.1 | 52.7 years STANDARD_DEVIATION 8.7 | 52.1 years STANDARD_DEVIATION 10.6 |
| Region of Enrollment United States | 21 participants | 23 participants | 20 participants | 64 participants |
| Sex: Female, Male Female | 12 Participants | 13 Participants | 6 Participants | 31 Participants |
| Sex: Female, Male Male | 9 Participants | 10 Participants | 14 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 20 | 15 / 21 | 13 / 23 |
| serious Total, serious adverse events | 0 / 20 | 0 / 21 | 0 / 23 |
Outcome results
Primary
Insulin Resistance and Glucose Homeostasis
The primary objective of assessing changes in insulin resistance and glucose homeostasis will be attained by performing a euglycemic clamp procedure at baseline (Day 0) and at the end of 6 weeks of treatment (Day 43).
Time frame: baseline and 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 25 mg INT-747 | Insulin Resistance and Glucose Homeostasis | Low Dose Insulin | .69 mg/kg/min | Standard Deviation 1.12 |
| 25 mg INT-747 | Insulin Resistance and Glucose Homeostasis | High Dose Insulin | .73 mg/kg/min | Standard Deviation 1.53 |
| 50 mg INT-747 | Insulin Resistance and Glucose Homeostasis | Low Dose Insulin | .24 mg/kg/min | Standard Deviation 1.62 |
| 50 mg INT-747 | Insulin Resistance and Glucose Homeostasis | High Dose Insulin | .42 mg/kg/min | Standard Deviation 1.42 |
| Placebo | Insulin Resistance and Glucose Homeostasis | Low Dose Insulin | -0.51 mg/kg/min | Standard Deviation 1.88 |
| Placebo | Insulin Resistance and Glucose Homeostasis | High Dose Insulin | -0.61 mg/kg/min | Standard Deviation 1.88 |
Comparison: The primary endpoints are calculated as the change (post minus pre treatment) during low dose and high dose insulin infusion periods. These are compared between placebo and INT-747 25 mg using t-tests for independent samples. These tests will be made without correction for multiple comparisons using 0.05 as the alpha criterion for significance. Results will be described with the corresponding means and standard deviations.p-value: 0.04t-test, 2 sided
Comparison: The primary endpoints are calculated as the change (post minus pre treatment) during low dose and high dose insulin infusion periods. These are compared between placebo and INT-747 50 mg using t-tests for independent samples. These tests will be made without correction for multiple comparisons using 0.05 as the alpha criterion for significance. Results will be described with the corresponding means and standard deviations.p-value: 0.28t-test, 2 sided
Secondary
Hepatocellular Function
Hepatocellular function as measured by assessment of liver enzymes and biochemical markers of hepatic and metabolic function
Time frame: baseline and 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 25 mg INT-747 | Hepatocellular Function | AST | -3 U/L | Standard Deviation 7 |
| 25 mg INT-747 | Hepatocellular Function | ALT | -9 U/L | Standard Deviation 14 |
| 25 mg INT-747 | Hepatocellular Function | GGT | -39 U/L | Standard Deviation 77 |
| 50 mg INT-747 | Hepatocellular Function | AST | 4 U/L | Standard Deviation 24 |
| 50 mg INT-747 | Hepatocellular Function | ALT | 9 U/L | Standard Deviation 47 |
| 50 mg INT-747 | Hepatocellular Function | GGT | -23 U/L | Standard Deviation 56 |
| Placebo | Hepatocellular Function | ALT | 11 U/L | Standard Deviation 48 |
| Placebo | Hepatocellular Function | GGT | 5 U/L | Standard Deviation 27 |
| Placebo | Hepatocellular Function | AST | 4 U/L | Standard Deviation 46 |
p-value: 0.0031t-test, 2 sided
p-value: >0.05t-test, 2 sided
p-value: 0.0001t-test, 2 sided
p-value: 0.0005t-test, 2 sided