Liver Diseases
Conditions
Keywords
Non alcoholic steatohepatitis, Steatohepatitis
Brief summary
The purpose of this study is to determine if therapy with pioglitazone or vitamin E will lead to an improvement in liver histology in non-diabetic adult patients with non-alcoholic steatohepatitis (NASH).
Detailed description
The purpose of this study is to determine if therapy with pioglitazone or vitamin E will lead to an improvement in liver histology in non-diabetic adult patients with non-alcoholic steatohepatitis (NASH).
Interventions
DRUGPioglitazone
30 mg daily
DIETARY_SUPPLEMENTVitamin E
800 IU daily
DRUGMatching placebo
Daily
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologic evidence of NASH based on a liver biopsy obtained within 6 months of randomization. * Age 18 years or older
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Improvement in Non-alcoholic Fatty Liver Disease (NAFLD) Activity Defined by Change in Standardized Scoring of Liver Biopsies at Baseline and After 96 Weeks of Treatment. | baseline and 96 weeks | Total nonalcoholic fatty liver disease (NAFLD) activity was assessed on a scale of 0 to 8, with higher scores indicating more severe disease; the components of this measure include steatosis (assessed on a scale of 0 to 3), lobular inflammation (assessed on a scale of 0 to 3), and hepatocellular ballooning (assessed on a scale of 0 to 2). The primary outcome was an improvement in histological findings from baseline to 96 weeks, which required an improvement by 1 or more points in the hepatocellular ballooning score; no increase in the fibrosis score; and either a decrease in the activity score for nonalcoholic fatty liver disease to a score of 3 or less or a decrease in the activity score of at least 2 points, with at least a 1-point decrease in either the lobular inflammation or steatosis score. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Improvement in Steatosis | baseline and 96 weeks | Steatosis is assessed on a scale of 0 to 3 with higher scores indicating more severe steatosis. This secondary outcome measure is the number of participants that experienced a decrease in steatosis score, which indicates improvement in steatosis. |
| Number of Participants With Improvement in Lobular Inflammation | baseline and 96 weeks | Lobular inflammation is assessed on a scale of 0 to 3 with higher scores indicating more severe lobular inflammation. This secondary outcome measure is the number of participants that experienced a decrease in lobular inflammation score, which indicates improvement in lobular inflammation. |
| Number of Participants With Improvement in Hepatocellular Ballooning | baseline and 96 weeks | Hepatocellular ballooning is assessed on a scale of 0 to 2 with higher scores indicating more severe hepatocellular ballooning. This secondary outcome measure is the number of participants that experienced a decrease in hepatocellular ballooning score, which indicates improvement in hepatocellular ballooning. |
| Number of Participants With Improvement in Fibrosis | baseline and 96 weeks | Fibrosis is assessed on a scale of 0 to 4 with higher scores indicating more severe fibrosis. This secondary outcome measure is the number of participants that experienced a decrease in fibrosis score, which indicates improvement in fibrosis. |
| Number of Participants With Resolution of Definite Nonalcoholic Steatohepatitis | baseline and 96 weeks | The criteria for nonalcoholic steatohepatitis was definite or possible steatohepatitis (assessed by a pathologist) with an activity score of 5 or more, or definite steatohepatitis (confirmed by two pathologists) with an activity score of 4. This secondary outcome measure is the number of participants who met this definition at baseline and did not meet this definition after 96 weeks of treatment and thus had a resolution of steatohepatitis. |
Countries
United States
Participant flow
Recruitment details
PIVENS enrollment started in January 2005 and ended in January 2007.
Pre-assignment details
A total of 339 patients were registered and screened for PIVENS trial, 92 of whom (27%) were found ineligible. The failure to meet histological entry criteria and fasting blood glucose \>125 mg/dL were the most frequent reasons for ineligibility.
Participants by arm
| Arm | Count |
|---|---|
| Pioglitazone Pioglitazone at a dose of 30 mg daily | 80 |
| Vitamin E Vitamin E at a dose of 800 IU daily | 84 |
| Placebo Placebo Pioglitazone and Placebo Vitamin E | 83 |
| Total | 247 |
Baseline characteristics
| Characteristic | Total | Pioglitazone | Placebo | Vitamin E |
|---|---|---|---|---|
| Age, Continuous | 46.3 years STANDARD_DEVIATION 11.9 | 47.0 years STANDARD_DEVIATION 12.6 | 45.4 years STANDARD_DEVIATION 11.2 | 46.6 years STANDARD_DEVIATION 12.1 |
| Region of Enrollment United States | 247 participants | 80 participants | 83 participants | 84 participants |
| Sex: Female, Male Female | 147 Participants | 47 Participants | 48 Participants | 52 Participants |
| Sex: Female, Male Male | 100 Participants | 33 Participants | 35 Participants | 32 Participants |
| Total nonalcoholic fatty liver disease (NAFLD) activity score | 4.9 scores on a scale STANDARD_DEVIATION 1.4 | 5.0 scores on a scale STANDARD_DEVIATION 1.4 | 4.8 scores on a scale STANDARD_DEVIATION 1.4 | 5.1 scores on a scale STANDARD_DEVIATION 1.4 |
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 | 41 / 80 | 46 / 84 | 40 / 83 |
| serious Total, serious adverse events | 2 / 80 | 7 / 84 | 10 / 83 |
Outcome results
Primary
Number of Participants With Improvement in Non-alcoholic Fatty Liver Disease (NAFLD) Activity Defined by Change in Standardized Scoring of Liver Biopsies at Baseline and After 96 Weeks of Treatment.
Total nonalcoholic fatty liver disease (NAFLD) activity was assessed on a scale of 0 to 8, with higher scores indicating more severe disease; the components of this measure include steatosis (assessed on a scale of 0 to 3), lobular inflammation (assessed on a scale of 0 to 3), and hepatocellular ballooning (assessed on a scale of 0 to 2). The primary outcome was an improvement in histological findings from baseline to 96 weeks, which required an improvement by 1 or more points in the hepatocellular ballooning score; no increase in the fibrosis score; and either a decrease in the activity score for nonalcoholic fatty liver disease to a score of 3 or less or a decrease in the activity score of at least 2 points, with at least a 1-point decrease in either the lobular inflammation or steatosis score.
Time frame: baseline and 96 weeks
Population: All randomized participants were included in the analysis of the primary outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone | Number of Participants With Improvement in Non-alcoholic Fatty Liver Disease (NAFLD) Activity Defined by Change in Standardized Scoring of Liver Biopsies at Baseline and After 96 Weeks of Treatment. | 27 participants |
| Vitamin E | Number of Participants With Improvement in Non-alcoholic Fatty Liver Disease (NAFLD) Activity Defined by Change in Standardized Scoring of Liver Biopsies at Baseline and After 96 Weeks of Treatment. | 36 participants |
| Placebo | Number of Participants With Improvement in Non-alcoholic Fatty Liver Disease (NAFLD) Activity Defined by Change in Standardized Scoring of Liver Biopsies at Baseline and After 96 Weeks of Treatment. | 16 participants |
Comparison: The proportions in each active-treatment group (pioglitazone and vitamin E) in whom there was improvement in non-alcoholic steatohepatitis were compared with the proportion of subjects in the placebo group in whom there was improvement.p-value: 0.001Mantel Haenszel
Comparison: The proportions in each active-treatment group (pioglitazone and vitamin E) in whom there was improvement in non-alcoholic steatohepatitis were compared with the proportion of subjects in the placebo group in whom there was improvement.p-value: 0.04Mantel Haenszel
Secondary
Number of Participants With Improvement in Fibrosis
Fibrosis is assessed on a scale of 0 to 4 with higher scores indicating more severe fibrosis. This secondary outcome measure is the number of participants that experienced a decrease in fibrosis score, which indicates improvement in fibrosis.
Time frame: baseline and 96 weeks
Population: Number of subjects with biopsy specimens at baseline and 96 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone | Number of Participants With Improvement in Fibrosis | 31 participants |
| Vitamin E | Number of Participants With Improvement in Fibrosis | 33 participants |
| Placebo | Number of Participants With Improvement in Fibrosis | 22 participants |
p-value: 0.24Fisher Exact
p-value: 0.12Fisher Exact
Secondary
Number of Participants With Improvement in Hepatocellular Ballooning
Hepatocellular ballooning is assessed on a scale of 0 to 2 with higher scores indicating more severe hepatocellular ballooning. This secondary outcome measure is the number of participants that experienced a decrease in hepatocellular ballooning score, which indicates improvement in hepatocellular ballooning.
Time frame: baseline and 96 weeks
Population: Number of subjects with biopsy specimens at baseline and 96 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone | Number of Participants With Improvement in Hepatocellular Ballooning | 31 participants |
| Vitamin E | Number of Participants With Improvement in Hepatocellular Ballooning | 40 participants |
| Placebo | Number of Participants With Improvement in Hepatocellular Ballooning | 21 participants |
p-value: 0.01Fisher Exact
p-value: 0.08Fisher Exact
Secondary
Number of Participants With Improvement in Lobular Inflammation
Lobular inflammation is assessed on a scale of 0 to 3 with higher scores indicating more severe lobular inflammation. This secondary outcome measure is the number of participants that experienced a decrease in lobular inflammation score, which indicates improvement in lobular inflammation.
Time frame: baseline and 96 weeks
Population: Number of subjects with biopsy specimens at baseline and 96 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone | Number of Participants With Improvement in Lobular Inflammation | 41 participants |
| Vitamin E | Number of Participants With Improvement in Lobular Inflammation | 43 participants |
| Placebo | Number of Participants With Improvement in Lobular Inflammation | 25 participants |
p-value: 0.02Fisher Exact
p-value: 0.004Fisher Exact
Secondary
Number of Participants With Improvement in Steatosis
Steatosis is assessed on a scale of 0 to 3 with higher scores indicating more severe steatosis. This secondary outcome measure is the number of participants that experienced a decrease in steatosis score, which indicates improvement in steatosis.
Time frame: baseline and 96 weeks
Population: Number of subjects with biopsy specimens at baseline and 96 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone | Number of Participants With Improvement in Steatosis | 48 participants |
| Vitamin E | Number of Participants With Improvement in Steatosis | 43 participants |
| Placebo | Number of Participants With Improvement in Steatosis | 22 participants |
p-value: 0.005Fisher Exact
p-value: <0.001Fisher Exact
Secondary
Number of Participants With Resolution of Definite Nonalcoholic Steatohepatitis
The criteria for nonalcoholic steatohepatitis was definite or possible steatohepatitis (assessed by a pathologist) with an activity score of 5 or more, or definite steatohepatitis (confirmed by two pathologists) with an activity score of 4. This secondary outcome measure is the number of participants who met this definition at baseline and did not meet this definition after 96 weeks of treatment and thus had a resolution of steatohepatitis.
Time frame: baseline and 96 weeks
Population: Number of subjects with biopsy specimens at baseline and 96 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone | Number of Participants With Resolution of Definite Nonalcoholic Steatohepatitis | 33 participants |
| Vitamin E | Number of Participants With Resolution of Definite Nonalcoholic Steatohepatitis | 29 participants |
| Placebo | Number of Participants With Resolution of Definite Nonalcoholic Steatohepatitis | 15 participants |
p-value: 0.05Fisher Exact
p-value: 0.001Fisher Exact