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

• 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: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• 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

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.

Arm/Group Title	Pioglitazone	Vitamin E	Placebo
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

Baseline Characteristics

Arm/Group Title		Pioglitazone	Vitamin E	Placebo	Total
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
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).

Outcome Measures

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.
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

Outcome Measure Data

Analysis Population Description

All randomized participants were included in the analysis of the primary outcome.

Arm/Group Title	Pioglitazone	Vitamin E	Placebo
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

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]

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
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

Outcome Measure Data

Analysis Population Description

Number of subjects with biopsy specimens at baseline and 96 weeks

Arm/Group Title	Pioglitazone	Vitamin E	Placebo
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

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]

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
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

Outcome Measure Data

Analysis Population Description

Number of subjects with biopsy specimens at baseline and 96 weeks

Arm/Group Title	Pioglitazone	Vitamin E	Placebo
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

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]

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
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

Outcome Measure Data

Analysis Population Description

Number of subjects with biopsy specimens at baseline and 96 weeks

Arm/Group Title	Pioglitazone	Vitamin E	Placebo
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

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]

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
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

Outcome Measure Data

Analysis Population Description

Number of subjects with biopsy specimens at baseline and 96 weeks

Arm/Group Title	Pioglitazone	Vitamin E	Placebo
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

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]

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
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

Outcome Measure Data

Analysis Population Description

Number of subjects with biopsy specimens at baseline and 96 weeks

Arm/Group Title	Pioglitazone	Vitamin E	Placebo
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

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]

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]

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Pioglitazone	Vitamin E	Placebo
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	--/--	--/--	--/--
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%)
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%)

Limitations and Caveats

[Not Specified]

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: Arun J. Sanyal
• Organization: Virginia Commonwealth University
• EMail: asanyal@mcvh-vcu.edu

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Vilar-Gomez E, Gawrieh S, Liang T, McIntyre AD, Hegele RA, Chalasani N. Interrogation of selected genes influencing serum LDL-Cholesterol levels in patients with well characterized NAFLD. J Clin Lipidol. 2021 Mar-Apr;15(2):275-291. doi: 10.1016/j.jacl.2020.12.010. Epub 2020 Dec 27.

Maev IV, Samsonov AA, Palgova LK, Pavlov CS, Shirokova EN, Vovk EI, Starostin KM. Effectiveness of phosphatidylcholine as adjunctive therapy in improving liver function tests in patients with non-alcoholic fatty liver disease and metabolic comorbidities: real-life observational study from Russia. BMJ Open Gastroenterol. 2020 Mar 26;7(1):e000368. doi: 10.1136/bmjgast-2019-000368. eCollection 2020.

Kanwar P, Nelson JE, Yates K, Kleiner DE, Unalp-Arida A, Kowdley KV. Association between metabolic syndrome and liver histology among NAFLD patients without diabetes. BMJ Open Gastroenterol. 2016 Nov 9;3(1):e000114. doi: 10.1136/bmjgast-2016-000114. eCollection 2016.

Corey KE, Vuppalanchi R, Wilson LA, Cummings OW, Chalasani N; NASH CRN. NASH resolution is associated with improvements in HDL and triglyceride levels but not improvement in LDL or non-HDL-C levels. Aliment Pharmacol Ther. 2015 Feb;41(3):301-9. doi: 10.1111/apt.13035. Epub 2014 Nov 28.

Guy CD, Suzuki A, Abdelmalek MF, Burchette JL, Diehl AM; NASH CRN. Treatment response in the PIVENS trial is associated with decreased Hedgehog pathway activity. Hepatology. 2015 Jan;61(1):98-107. doi: 10.1002/hep.27235. Epub 2014 Aug 25.

Hoofnagle JH, Van Natta ML, Kleiner DE, Clark JM, Kowdley KV, Loomba R, Neuschwander-Tetri BA, Sanyal AJ, Tonascia J; Non-alcoholic Steatohepatitis Clinical Research Network (NASH CRN). Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2013 Jul;38(2):134-43. doi: 10.1111/apt.12352. Epub 2013 May 29.

Guerrerio AL, Colvin RM, Schwartz AK, Molleston JP, Murray KF, Diehl A, Mohan P, Schwimmer JB, Lavine JE, Torbenson MS, Scheimann AO. Choline intake in a large cohort of patients with nonalcoholic fatty liver disease. Am J Clin Nutr. 2012 Apr;95(4):892-900. doi: 10.3945/ajcn.111.020156. Epub 2012 Feb 15.

Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010 May 6;362(18):1675-85. doi: 10.1056/NEJMoa0907929. Epub 2010 Apr 28.

Chalasani NP, Sanyal AJ, Kowdley KV, Robuck PR, Hoofnagle J, Kleiner DE, Unalp A, Tonascia J; NASH CRN Research Group. Pioglitazone versus vitamin E versus placebo for the treatment of non-diabetic patients with non-alcoholic steatohepatitis: PIVENS trial design. Contemp Clin Trials. 2009 Jan;30(1):88-96. doi: 10.1016/j.cct.2008.09.003. Epub 2008 Sep 10.

• Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• ClinicalTrials.gov Identifier: NCT00063622
• 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