Use of a Novel Drug in People With Non-alcoholic Steatohepatitis (NASH) or Non-alcoholic Fatty Liver Disease (NAFLD)
Study Details
Study Description
Brief Summary
Does the novel drug decrease liver fat in subjects with NASH or NAFLD as compared to placebo
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2 |
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: 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). |
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).
|
Placebo Comparator: Placebo Placebo 800 mg/day for 12 weeks (plus or minus 1 week) in two divided doses morning (400 mg) and evening (400 mg). |
Other: Placebo
Placebo 800 mg/day for 12 weeks (plus or minus 1 week) in two divided doses morning (400 mg) and evening (400 mg).
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
Eligibility Criteria
Criteria
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.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Yogesh Yadav | Charlottesville | Virginia | United States | 22908 |
Sponsors and Collaborators
- University of Virginia
- AstraZeneca
Investigators
- Principal Investigator: Rita Basu, MD, University of Virginia
Study Documents (Full-Text)
More Information
Publications
None provided.- 15-000013
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail |
Arm/Group Title | Active Drug AZ Compound | Placebo |
---|---|---|
Arm/Group Description | 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). | 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). |
Period Title: Overall Study | ||
STARTED | 46 | 47 |
COMPLETED | 42 | 43 |
NOT COMPLETED | 4 | 4 |
Baseline Characteristics
Arm/Group Title | Active Drug AZ Compound | Placebo | Total |
---|---|---|---|
Arm/Group Description | 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). | 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). | Total of all reporting groups |
Overall Participants | 46 | 47 | 93 |
Age (years) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [years] |
53.7
(11.7)
|
53.3
(11.4)
|
53.7
(11.4)
|
Sex: Female, Male (Count of Participants) | |||
Female |
28
60.9%
|
29
61.7%
|
57
61.3%
|
Male |
18
39.1%
|
18
38.3%
|
36
38.7%
|
Ethnicity (NIH/OMB) (Count of Participants) | |||
Hispanic or Latino |
0
0%
|
3
6.4%
|
3
3.2%
|
Not Hispanic or Latino |
45
97.8%
|
43
91.5%
|
88
94.6%
|
Unknown or Not Reported |
1
2.2%
|
1
2.1%
|
2
2.2%
|
Race (NIH/OMB) (Count of Participants) | |||
American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
Asian |
1
2.2%
|
0
0%
|
1
1.1%
|
Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
Black or African American |
1
2.2%
|
0
0%
|
1
1.1%
|
White |
43
93.5%
|
45
95.7%
|
88
94.6%
|
More than one race |
0
0%
|
0
0%
|
0
0%
|
Unknown or Not Reported |
1
2.2%
|
2
4.3%
|
3
3.2%
|
Region of Enrollment (participants) [Number] | |||
United States |
46
100%
|
47
100%
|
93
100%
|
Number of baseline particpants (Count of Participants) | |||
Count of Participants [Participants] |
46
100%
|
47
100%
|
93
100%
|
Outcome Measures
Title | Percentage Change in Hepatic Fat |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Active Drug AZ Compound | Placebo |
---|---|---|
Arm/Group Description | 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). | 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). |
Measure Participants | 42 | 43 |
Mean (Standard Deviation) [Percentage change in liver fat fraction] |
-0.667
(5.246)
|
0.139
(4.323)
|
Title | Number of Participants With no Conversion of [13C] Cortisone to [13C] Cortisol |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Active Drug AZ Compound | Placebo |
---|---|---|
Arm/Group Description | 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). | 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). |
Measure Participants | 42 | 43 |
Count of Participants [Participants] |
42
91.3%
|
0
0%
|
Title | Liver Fibrosis Measured With MRE in kPa |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Active Drug AZ Compound | Placebo |
---|---|---|
Arm/Group Description | 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). | 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). |
Measure Participants | 42 | 43 |
Mean (Standard Deviation) [kPa] |
-0.639
(0.991)
|
-0.662
(0.977)
|
Title | Total Insulin Sensitivity (Si) and Hepatic Insulin Sensitivity (Si Liver) |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
Insulin Sensitivity was measured in the participants that completed the oral glucose tolerance test . |
Arm/Group Title | Active Drug AZ Compound | Placebo |
---|---|---|
Arm/Group Description | 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). | 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). |
Measure Participants | 29 | 32 |
Change in SI |
-0.225
(1.918)
|
0.719
(3.361)
|
Change in Si liver |
0.075
(1.948)
|
0.126
(2.369)
|
Adverse Events
Time Frame | 3 months | |||
---|---|---|---|---|
Adverse Event Reporting Description | ||||
Arm/Group Title | Active Drug AZ Compound | Placebo | ||
Arm/Group Description | 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). | 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). | ||
All Cause Mortality |
||||
Active Drug AZ Compound | Placebo | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/46 (0%) | 0/47 (0%) | ||
Serious Adverse Events |
||||
Active Drug AZ Compound | Placebo | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/46 (0%) | 0/47 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
Active Drug AZ Compound | Placebo | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 20/46 (43.5%) | 10/47 (21.3%) | ||
Endocrine disorders | ||||
Increased TSH | 3/46 (6.5%) | 0/47 (0%) | ||
Gastrointestinal disorders | ||||
Diarrhea | 9/46 (19.6%) | 6/47 (12.8%) | ||
General disorders | ||||
Headache | 8/46 (17.4%) | 4/47 (8.5%) |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Dr. Rita Basu |
---|---|
Organization | University of Virginia |
Phone | 434-924-5183 |
rb4vd@virginia.edu |
- 15-000013