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

Primary Purpose

Liver Diseases

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Pioglitazone
Vitamin E
Matching placebo
Sponsored by
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Liver Diseases focused on measuring Non alcoholic steatohepatitis, Steatohepatitis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Histologic evidence of NASH based on a liver biopsy obtained within 6 months of randomization. Age 18 years or older

Sites / Locations

  • University of California, San Diego
  • University of California, San Francisco
  • Indiana University
  • St. Louis University
  • Duke University Medical Center
  • Case Western Reserve University
  • Virginia Commonwealth University
  • University of Washington

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Placebo Comparator

Arm Label

1

2

3

Arm Description

Pioglitazone

Vitamin E

Placebo Pioglitazone or Placebo Vitamin E

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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.

Full Information

First Posted
July 1, 2003
Last Updated
March 12, 2018
Sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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1. Study Identification

Unique Protocol Identification Number
NCT00063622
Brief Title
Pioglitazone vs Vitamin E vs Placebo for Treatment of Non-Diabetic Patients With Nonalcoholic Steatohepatitis (PIVENS)
Acronym
PIVENS
Official Title
Clinical Research Network in Nonalcoholic Steatohepatitis: Pioglitazone vs. Vitamin E vs. Placebo for the Treatment of Non-Diabetic Patients With Nonalcoholic Steatohepatitis (PIVENS)
Study Type
Interventional

2. Study Status

Record Verification Date
August 2012
Overall Recruitment Status
Completed
Study Start Date
January 2005 (undefined)
Primary Completion Date
June 2009 (Actual)
Study Completion Date
September 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Liver Diseases
Keywords
Non alcoholic steatohepatitis, Steatohepatitis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
247 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Active Comparator
Arm Description
Pioglitazone
Arm Title
2
Arm Type
Active Comparator
Arm Description
Vitamin E
Arm Title
3
Arm Type
Placebo Comparator
Arm Description
Placebo Pioglitazone or Placebo Vitamin E
Intervention Type
Drug
Intervention Name(s)
Pioglitazone
Other Intervention Name(s)
Actos
Intervention Description
30 mg daily
Intervention Type
Dietary Supplement
Intervention Name(s)
Vitamin E
Other Intervention Name(s)
Nature Made
Intervention Description
800 IU daily
Intervention Type
Drug
Intervention Name(s)
Matching placebo
Intervention Description
Daily
Primary Outcome Measure Information:
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
Secondary Outcome Measure Information:
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
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
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
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
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Histologic evidence of NASH based on a liver biopsy obtained within 6 months of randomization. Age 18 years or older
Facility Information:
Facility Name
University of California, San Diego
City
San Diego
State/Province
California
ZIP/Postal Code
92103
Country
United States
Facility Name
University of California, San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
Indiana University
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
St. Louis University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Case Western Reserve University
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44109
Country
United States
Facility Name
Virginia Commonwealth University
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298
Country
United States
Facility Name
University of Washington
City
Seattle
State/Province
Washington
ZIP/Postal Code
98195
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
33454241
Citation
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.
Results Reference
derived
PubMed Identifier
32337059
Citation
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.
Results Reference
derived
PubMed Identifier
27933201
Citation
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.
Results Reference
derived
PubMed Identifier
25429853
Citation
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.
Results Reference
derived
PubMed Identifier
24849310
Citation
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.
Results Reference
derived
PubMed Identifier
23718573
Citation
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.
Results Reference
derived
PubMed Identifier
22338037
Citation
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.
Results Reference
derived
PubMed Identifier
20427778
Citation
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.
Results Reference
derived
PubMed Identifier
18804555
Citation
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.
Results Reference
derived
Links:
URL
http://www.niddk.nih.gov/
Description
National Institute of Diabetes and Digestive and Kidney Diseases

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

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