Use of a Novel Drug in People With Non-alcoholic Steatohepatitis (NASH) or Non-alcoholic Fatty Liver Disease (NAFLD)

Sponsor
University of Virginia (Other)
Overall Status
Terminated
CT.gov ID
NCT02605616
Collaborator
AstraZeneca (Industry)
93
1
2
46
2

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
  • Drug: AZ compound
  • Other: Placebo
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

Study Type:
Interventional
Actual Enrollment :
93 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
A Randomized, Double-Blinded, Placebo-controlled Phase IIa Study to Assess the Efficacy and Safety of a Novel AstraZeneca Compound in Subjects With Non-alcoholic Steatohepatitis (NASH) or Non-alcoholic Fatty Liver Disease (NAFLD)
Study Start Date :
Nov 1, 2015
Actual Primary Completion Date :
Sep 1, 2019
Actual Study Completion Date :
Sep 1, 2019

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

  1. 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.

  2. 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

  1. 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.

  2. 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

Ages Eligible for Study:
21 Years to 75 Years
Sexes Eligible for Study:
All
Accepts 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.

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.
Responsible Party:
Rita Basu, MD, MD, University of Virginia
ClinicalTrials.gov Identifier:
NCT02605616
Other Study ID Numbers:
  • 15-000013
First Posted:
Nov 16, 2015
Last Update Posted:
Apr 4, 2022
Last Verified:
Mar 1, 2022
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:

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

1. Primary Outcome
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)
2. Primary Outcome
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%
3. Secondary Outcome
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)
4. Secondary Outcome
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

The study was stopped after enrolling 93 patients. The sponsor recalled the batch of AZD4017 /placebo that was provided to the study investigator after the batch of the investigational product failed a routine stability retest that was performed to support potential shelflife extension. Ten patients who were taking either AZD4017 or a placebo were asked to stop taking their drug. Since eight of the10 patients were close to reaching study completion, their data were included in the ITT analyses.

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
Email rb4vd@virginia.edu
Responsible Party:
Rita Basu, MD, MD, University of Virginia
ClinicalTrials.gov Identifier:
NCT02605616
Other Study ID Numbers:
  • 15-000013
First Posted:
Nov 16, 2015
Last Update Posted:
Apr 4, 2022
Last Verified:
Mar 1, 2022