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Pioglitazone vs Vitamin E vs Placebo for Treatment of Non-Diabetic Patients With Nonalcoholic Steatohepatitis (PIVENS) (PIVENS)

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ClinicalTrials.gov Identifier: NCT00063622
Recruitment Status : Completed
First Posted : July 3, 2003
Results First Posted : August 1, 2012
Last Update Posted : April 6, 2018
Sponsor:
Information provided by (Responsible Party):
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Liver Diseases
Interventions Drug: Pioglitazone
Dietary Supplement: Vitamin E
Drug: Matching placebo
Enrollment 247
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.
Arm/Group Title Pioglitazone Vitamin E Placebo
Hide Arm/Group Description Pioglitazone at a dose of 30 mg daily Vitamin E at a dose of 800 IU daily Placebo Pioglitazone and Placebo Vitamin E
Period Title: Overall Study
Started 80 84 83
Completed 70 [1] 80 [1] 72 [1]
Not Completed 10 4 11
[1]
All randomized patients were included in analysis of primary outcome
Arm/Group Title Pioglitazone Vitamin E Placebo Total
Hide Arm/Group Description Pioglitazone at a dose of 30 mg daily Vitamin E at a dose of 800 IU daily Placebo Pioglitazone and Placebo Vitamin E Total of all reporting groups
Overall Number of Baseline Participants 80 84 83 247
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 80 participants 84 participants 83 participants 247 participants
47.0  (12.6) 46.6  (12.1) 45.4  (11.2) 46.3  (11.9)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 80 participants 84 participants 83 participants 247 participants
Female
47
  58.8%
52
  61.9%
48
  57.8%
147
  59.5%
Male
33
  41.3%
32
  38.1%
35
  42.2%
100
  40.5%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 80 participants 84 participants 83 participants 247 participants
80 84 83 247
Total nonalcoholic fatty liver disease (NAFLD) activity score   [1] 
Mean (Standard Deviation)
Unit of measure:  Scores on a scale
Number Analyzed 80 participants 84 participants 83 participants 247 participants
5.0  (1.4) 5.1  (1.4) 4.8  (1.4) 4.9  (1.4)
[1]
Measure Description: 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).
1.Primary Outcome
Title 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.
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants were included in the analysis of the primary outcome.
Arm/Group Title Pioglitazone Vitamin E Placebo
Hide Arm/Group Description:
Pioglitazone at a dose of 30 mg daily
Vitamin E at a dose of 800 IU daily
Placebo Pioglitazone and Placebo Vitamin E
Overall Number of Participants Analyzed 80 84 83
Measure Type: Number
Unit of Measure: participants
27 36 16
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vitamin E, Placebo
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments Given the fact that there were two planned primary comparisons, Bonferroni-adjusted P values of less than 0.025 were considered to indicate statistical significance.
Method Mantel Haenszel
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pioglitazone, Placebo
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.04
Comments Given the fact that there were two planned primary comparisons, Bonferroni-adjusted P values of less than 0.025 were considered to indicate statistical significance.
Method Mantel Haenszel
Comments [Not Specified]
2.Secondary Outcome
Title Number of Participants With Improvement in Steatosis
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Number of subjects with biopsy specimens at baseline and 96 weeks
Arm/Group Title Pioglitazone Vitamin E Placebo
Hide Arm/Group Description:
Pioglitazone at a dose of 30 mg daily
Vitamin E at a dose of 800 IU daily
Placebo Pioglitazone and Placebo Vitamin E
Overall Number of Participants Analyzed 70 80 72
Measure Type: Number
Unit of Measure: participants
48 43 22
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vitamin E, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.005
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pioglitazone, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
3.Secondary Outcome
Title Number of Participants With Improvement in Lobular Inflammation
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Number of subjects with biopsy specimens at baseline and 96 weeks
Arm/Group Title Pioglitazone Vitamin E Placebo
Hide Arm/Group Description:
Pioglitazone at a dose of 30 mg daily
Vitamin E at a dose of 800 IU daily
Placebo Pioglitazone and Placebo Vitamin E
Overall Number of Participants Analyzed 70 80 72
Measure Type: Number
Unit of Measure: participants
41 43 25
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vitamin E, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.02
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pioglitazone, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.004
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
4.Secondary Outcome
Title Number of Participants With Improvement in Hepatocellular Ballooning
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Number of subjects with biopsy specimens at baseline and 96 weeks
Arm/Group Title Pioglitazone Vitamin E Placebo
Hide Arm/Group Description:
Pioglitazone at a dose of 30 mg daily
Vitamin E at a dose of 800 IU daily
Placebo Pioglitazone and Placebo Vitamin E
Overall Number of Participants Analyzed 70 80 72
Measure Type: Number
Unit of Measure: participants
31 40 21
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vitamin E, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.01
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pioglitazone, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.08
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
5.Secondary Outcome
Title Number of Participants With Improvement in Fibrosis
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Number of subjects with biopsy specimens at baseline and 96 weeks
Arm/Group Title Pioglitazone Vitamin E Placebo
Hide Arm/Group Description:
Pioglitazone at a dose of 30 mg daily
Vitamin E at a dose of 800 IU daily
Placebo Pioglitazone and Placebo Vitamin E
Overall Number of Participants Analyzed 70 80 72
Measure Type: Number
Unit of Measure: participants
31 33 22
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vitamin E, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.24
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pioglitazone, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.12
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
6.Secondary Outcome
Title Number of Participants With Resolution of Definite Nonalcoholic Steatohepatitis
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Number of subjects with biopsy specimens at baseline and 96 weeks
Arm/Group Title Pioglitazone Vitamin E Placebo
Hide Arm/Group Description:
Pioglitazone at a dose of 30 mg daily
Vitamin E at a dose of 800 IU daily
Placebo Pioglitazone and Placebo Vitamin E
Overall Number of Participants Analyzed 70 80 72
Measure Type: Number
Unit of Measure: participants
33 29 15
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vitamin E, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.05
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pioglitazone, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Pioglitazone Vitamin E Placebo
Hide Arm/Group Description Pioglitazone at a dose of 30 mg daily Vitamin E at a dose of 800 IU daily Placebo Pioglitazone and Placebo Vitamin E
All-Cause Mortality
Pioglitazone Vitamin E Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Pioglitazone Vitamin E Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/80 (2.50%)   7/84 (8.33%)   10/83 (12.05%) 
General disorders       
Severe adverse event  2/80 (2.50%)  7/84 (8.33%)  10/83 (12.05%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Pioglitazone Vitamin E Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   41/80 (51.25%)   46/84 (54.76%)   40/83 (48.19%) 
Cardiac disorders       
Cardiovascular Event  10/80 (12.50%)  12/84 (14.29%)  12/83 (14.46%) 
Endocrine disorders       
Diabetes  0/80 (0.00%)  4/84 (4.76%)  0/83 (0.00%) 
General disorders       
Other mild and moderate adverse event  28/80 (35.00%)  26/84 (30.95%)  23/83 (27.71%) 
Hepatobiliary disorders       
Cirrhosis  0/80 (0.00%)  1/84 (1.19%)  0/83 (0.00%) 
Musculoskeletal and connective tissue disorders       
Bone fracture  3/80 (3.75%)  3/84 (3.57%)  5/83 (6.02%) 
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: Arun J. Sanyal
Organization: Virginia Commonwealth University
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier: NCT00063622     History of Changes
Other Study ID Numbers: NASH - ADULT (IND)
U01DK061730 ( U.S. NIH Grant/Contract )
First Submitted: July 1, 2003
First Posted: July 3, 2003
Results First Submitted: June 14, 2012
Results First Posted: August 1, 2012
Last Update Posted: April 6, 2018