Non-alcoholic Fatty Liver Disease (NAFLD), Non-alcoholic Steatohepatitis (NASH)
Conditions
Brief summary
Does the novel drug decrease liver fat in subjects with NASH or NAFLD as compared to placebo
Detailed description
We propose to evaluate hepatic fat and hepatic fibrosis using magnetic resonance elastography (MRE) liver (pre vs. post). We will also establish glucose tolerance status by our established labeled oral glucose tolerance test (OGTT) (6,6 ²H2 glucose). Following baseline evaluation subjects with biopsy/MRE proven NASH will be randomized to one of two groups and treated either with active drug (AZ compound) or placebo for 12 weeks (plus or minus 1 week). Subjects with history suggestive of non-alcoholic fatty liver disease (NAFLD) or NASH will be invited to participate. If they meet criteria following initial screening they will be included in the study. OGTT, liver MRE will be repeated. Liver enzymes \[aspartate aminotransferase (AST), alanine aminotransferase (ALT),alkaline phosphatase (ALP)\] as well as other safety tests \[creatine phosphokinase (CPK), thyroid stimulating hormone (TSH), international normalized ratio (INR),total bilirubin\] will be measured before, monthly during therapy and at one month following therapy. Furthermore, we will also do the subgroup analysis in NASH/NAFLD subjects with and without diabetes to see the effect of the drug.
Interventions
DRUGAZ compound
AZ compound 800 mg/day for 12 weeks (plus or minus 1 week) in two divided doses morning (400 mg) and evening (400 mg).
OTHERPlacebo
Placebo 800 mg/day for 12 weeks (plus or minus 1 week) in two divided doses morning (400 mg) and evening (400 mg).
Sponsors
AstraZeneca
University of Alabama at Birmingham
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Age: 21-75 * Body Mass Index (BMI) \>19 kg/m\^2 * Subjects with biopsy/MRE proven NASH \[MRE liver fat ≥ 5%, with elevated liver enzymes ALT \<5x upper limit normal (ULN)\]. * Subjects with NAFLD and MRE shows F0 or greater fibrosis * Subjects with history suggestive of NAFLD/NASH * Total bilirubin must be \< 1.5 x ULN and INR must be \< 1.3 at baseline screening. * TSH and CPK will be within normal limits (WNL) at screening. * Subjects with type 2 diabetes who are on stable doses of medications (except pioglitazone) to control hyperglycemia and have baseline HbA1c of 10% or lower. * Hemoglobin must be greater than or equal to 12.0 in males and 11.0 in females.
Exclusion criteria
* Medications that may affect glucose metabolism such as corticosteroids, opiates, barbiturates, and anticoagulants. * Subjects with anemia, and symptoms suggestive of undiagnosed illness, overt hepatic disease, stroke, Alzheimer's disease, autoimmune hepatitis, alcoholism or increased alcohol consumption over the American Diabetes Association (ADA) guidelines. * Any disorder that may potentially impact the outcome measures. * Pregnant women and children. * Subjects planning weight loss or in any weight loss program. * Subjects taking TZD's, Atazanavir, Indinavir, Ketoconazole, Valproic acid, Silybum marianum and Valeriana officinalis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Hepatic Fat | baseline, approximately 12 weeks | Percentage Hepatic fat measured using Magnetic Resonance Imaging (Proton Density Fat Fraction). A cut-off of \<5% is used to distinguish between normal and fatty liver. |
| Number of Participants With no Conversion of [13C] Cortisone to [13C] Cortisol | baseline, approximately 12 weeks | Hepatic conversion of \[13C\] cortisone to \[13C\] cortisol was assessed before and after the treatment in both groups using the triple tracer cortisol test. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Liver Fibrosis Measured With MRE in kPa | baseline, approximately 12 weeks | Liver fibrosis will be measured with Magnetic Resonance Enterography (MRE) at baseline and then compared after \ 12 weeks of treatment. A clinical cut-off of 2.93 kPa was used to classify the results as either normal or elevated liver stiffness. Change in Liver fibrosis (kPa) is compared in between the groups. |
| Total Insulin Sensitivity (Si) and Hepatic Insulin Sensitivity (Si Liver) | baseline, approximately 12 weeks | Total insulin sensitivity (Si) and hepatic insulin sensitivity (Si liver) will be measured with an Oral glucose Tolerance test at baseline and after \ 12 weeks of treatment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Active Drug AZ Compound AZ compound 800 mg/day for 12 weeks (plus or minus 1 week) in two divided doses morning (400 mg) and evening (400 mg).
AZ compound: AZ compound 800 mg/day for 12 weeks (plus or minus 1 week) in two divided doses morning (400 mg) and evening (400 mg). | 46 |
| Placebo Placebo 800 mg/day for 12 weeks (plus or minus 1 week) in two divided doses morning (400 mg) and evening (400 mg).
Placebo: Placebo 800 mg/day for 12 weeks (plus or minus 1 week) in two divided doses morning (400 mg) and evening (400 mg). | 47 |
| Total | 93 |
Baseline characteristics
| Characteristic | Active Drug AZ Compound | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 53.7 years STANDARD_DEVIATION 11.7 | 53.3 years STANDARD_DEVIATION 11.4 | 53.7 years STANDARD_DEVIATION 11.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 45 Participants | 43 Participants | 88 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Number of baseline particpants | 46 Participants | 47 Participants | 93 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 43 Participants | 45 Participants | 88 Participants |
| Region of Enrollment United States | 46 participants | 47 participants | 93 participants |
| Sex: Female, Male Female | 28 Participants | 29 Participants | 57 Participants |
| Sex: Female, Male Male | 18 Participants | 18 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 0 / 47 |
| other Total, other adverse events | 20 / 46 | 10 / 47 |
| serious Total, serious adverse events | 0 / 46 | 0 / 47 |
Outcome results
Primary
Number of Participants With no Conversion of [13C] Cortisone to [13C] Cortisol
Hepatic conversion of \[13C\] cortisone to \[13C\] cortisol was assessed before and after the treatment in both groups using the triple tracer cortisol test.
Time frame: baseline, approximately 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Drug AZ Compound | Number of Participants With no Conversion of [13C] Cortisone to [13C] Cortisol | 42 Participants |
| Placebo | Number of Participants With no Conversion of [13C] Cortisone to [13C] Cortisol | 0 Participants |
Primary
Percentage Change in Hepatic Fat
Percentage Hepatic fat measured using Magnetic Resonance Imaging (Proton Density Fat Fraction). A cut-off of \<5% is used to distinguish between normal and fatty liver.
Time frame: baseline, approximately 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Drug AZ Compound | Percentage Change in Hepatic Fat | -0.667 Percentage change in liver fat fraction | Standard Deviation 5.246 |
| Placebo | Percentage Change in Hepatic Fat | 0.139 Percentage change in liver fat fraction | Standard Deviation 4.323 |
Secondary
Liver Fibrosis Measured With MRE in kPa
Liver fibrosis will be measured with Magnetic Resonance Enterography (MRE) at baseline and then compared after \ 12 weeks of treatment. A clinical cut-off of 2.93 kPa was used to classify the results as either normal or elevated liver stiffness. Change in Liver fibrosis (kPa) is compared in between the groups.
Time frame: baseline, approximately 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Drug AZ Compound | Liver Fibrosis Measured With MRE in kPa | -0.639 kPa | Standard Deviation 0.991 |
| Placebo | Liver Fibrosis Measured With MRE in kPa | -0.662 kPa | Standard Deviation 0.977 |
Secondary
Total Insulin Sensitivity (Si) and Hepatic Insulin Sensitivity (Si Liver)
Total insulin sensitivity (Si) and hepatic insulin sensitivity (Si liver) will be measured with an Oral glucose Tolerance test at baseline and after \ 12 weeks of treatment.
Time frame: baseline, approximately 12 weeks
Population: Insulin Sensitivity was measured in the participants that completed the oral glucose tolerance test .
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Drug AZ Compound | Total Insulin Sensitivity (Si) and Hepatic Insulin Sensitivity (Si Liver) | Change in SI | -0.225 10^-4 dl/kg/min per uU/ml | Standard Deviation 1.918 |
| Active Drug AZ Compound | Total Insulin Sensitivity (Si) and Hepatic Insulin Sensitivity (Si Liver) | Change in Si liver | 0.075 10^-4 dl/kg/min per uU/ml | Standard Deviation 1.948 |
| Placebo | Total Insulin Sensitivity (Si) and Hepatic Insulin Sensitivity (Si Liver) | Change in SI | 0.719 10^-4 dl/kg/min per uU/ml | Standard Deviation 3.361 |
| Placebo | Total Insulin Sensitivity (Si) and Hepatic Insulin Sensitivity (Si Liver) | Change in Si liver | 0.126 10^-4 dl/kg/min per uU/ml | Standard Deviation 2.369 |