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University of Texas H.S.C. San Antonio Pioglitazone in Non-Alcoholic Steatohepatitis Trial (UTHSCSA NASH Trial)

This study has been completed.
Sponsor:
Collaborator:
The University of Texas at San Antonio
Information provided by (Responsible Party):
University of Florida
ClinicalTrials.gov Identifier:
NCT00994682
First received: October 12, 2009
Last updated: February 20, 2017
Last verified: February 2017
Results First Received: September 6, 2016  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Participant, Care Provider, Investigator, Outcomes Assessor;   Primary Purpose: Treatment
Conditions: Nonalcoholic Steatohepatitis
Nonalcoholic Fatty Liver Disease
Type 2 Diabetes Mellitus
Interventions: Drug: Pioglitazone study drug
Drug: Placebo
Drug: Pioglitazone Open Label

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants were recruited from the general population of San Antonio, Texas, via newspaper advertisements and from the endocrinology and hepatology clinics at UTHSCSA and the Veterans Affairs Medical Center.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Once eligibility was met by histologically confirmed NASH, patients were randomized. The number of patients consented was 176, screen failed was 38, did not complete run-in phase was 37 (12 consent withdrawn, 9 lost to follow-up, 4 discontinued by PI decision, and 12 for other reasons). The remaining 101 patients were randomized.

Reporting Groups
  Description
Placebo After all participants receive dietary counseling at the research unit (CTSA), patients with prediabetes or type 2 diabetes mellitus (T2DM) and NASH will be started on placebo (or pioglitazone) in a randomized, double-blind,placebo-controlled study design by the research pharmacy. Participants were prescribed a hypocaloric diet (500– kcal/d deficit from the calculated weight maintaining diet) and received placebo pills with identical physical characteristics and in identical bottles to pioglitazone pills.
Pioglitazone After dietary counseling to all patients at the research unit (CTSA), patients with prediabetes or T2DM and NASH will be started on pioglitazone (or placebo) in a randomized, double-blind,placebo-controlled study design. Participants were prescribed a hypocaloric diet (500– kcal/d deficit from the calculated weight maintaining diet) and received pioglitazone 30mg/d (titrated after 2 months to 45 mg/d).

Participant Flow for 2 periods

Period 1:   Double Bilnd
    Placebo   Pioglitazone
STARTED   51   50 
COMPLETED   42   41 
NOT COMPLETED   9   9 
Withdrawal by Subject                5                6 
Lost to Follow-up                3                3 
Adverse Event                1                0 

Period 2:   Pioglitazone Open Label
    Placebo   Pioglitazone
STARTED   42   41 
COMPLETED   29   34 
NOT COMPLETED   13   7 
Withdrawal by Subject                4                4 
Lost to Follow-up                3                2 
Physician Decision                6                1 



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Placebo Participants were prescribed a hypocaloric diet (500– kcal/d deficit from the calculated weight maintaining diet) and received placebo pills with identical physical characteristics and in identical bottles to pioglitazone pills. After 18 months of treatment, metabolic measurements (OGTT and euglycemic insulin clamp), DXA, 1H-MRS, and liver biopsy were repeated, at which point the medication code was disclosed to investigators and patients. Patients whose NASH resolved after 18 months were instructed to discontinue the study because pioglitazone treatment or a repeated liver biopsy were considered unethical and were not indicated, whereas those with persistent disease were invited to start open-label pioglitazone therapy, titrated as described for the other arm.
Pioglitazone Participants were prescribed a hypocaloric diet (500– kcal/d deficit from the calculated weight maintaining diet) and received pioglitazone 30mg/d (titrated after 2 months to 45 mg/d). After 18 months of treatment, metabolic measurements (OGTT and euglycemic insulin clamp), DXA, 1H-MRS, and liver biopsy were repeated, at which point the medication code was disclosed to investigators and patients. Patients initially assigned to pioglitazone were asked to continue at the same dose.
Total Total of all reporting groups

Baseline Measures
   Placebo   Pioglitazone   Total 
Overall Participants Analyzed 
[Units: Participants]
 51   50   101 
Age 
[Units: Years]
Mean (Standard Deviation)
 49  (11)   52  (10)   50  (11) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
     
Female      16  31.4%      14  28.0%      30  29.7% 
Male      35  68.6%      36  72.0%      71  70.3% 
Ethnicity (NIH/OMB) 
[Units: Participants]
Count of Participants
     
Hispanic or Latino      37  72.5%      31  62.0%      68  67.3% 
Not Hispanic or Latino      14  27.5%      19  38.0%      33  32.7% 
Unknown or Not Reported      0   0.0%      0   0.0%      0   0.0% 
Weight 
[Units: Kg]
Mean (Standard Deviation)
 99.2  (17.0)   98.2  (16.5)   98.7  (16.7) 
Body mass index 
[Units: Kg/m^2]
Mean (Standard Deviation)
 34.5  (4.8)   34.3  (4.8)   34.4  (4.8) 
Total body fat [1] 
[Units: Percentage of fat mass]
Mean (Standard Deviation)
 34  (8)   33  (7)   33  (7) 
[1] Measured by DXA
Fasting plasma glucose 
[Units: Mg/dl]
Mean (Standard Deviation)
 121  (27)   124  (29)   122  (28) 
2-hour plasma glucose 
[Units: Mg/dl]
Mean (Standard Deviation)
 203  (64)   211  (78)   207  (71) 
Hemoglobin A1c 
[Units: Percentage]
Mean (Standard Deviation)
 6.3  (1.0)   6.4  (1.0)   6.3  (1.0) 
Fasting plasma insulin 
[Units: μU/mL]
Mean (Standard Deviation)
 16  (12)   15  (11)   16  (11) 
Fasting free fatty acids 
[Units: mmol/L]
Mean (Standard Deviation)
 0.54  (0.19)   0.49  (0.18)   0.52  (0.19) 
Use of diabetes medications 
[Units: Participants]
     
Metformin   17   19   36 
Sulfonylurea   16   12   28 
Insulin   6   5   11 
Use of statins 
[Units: Participants]
 19   19   38 
Plasma triglycerides 
[Units: Mg/dl]
Mean (Standard Deviation)
 179  (109)   224  (171)   201  (144) 
Plasma total cholesterol 
[Units: Mg/dl]
Mean (Standard Deviation)
 182  (42)   187  (46)   185  (44) 
Plasma LDL-C 
[Units: Mg/dl]
Mean (Standard Deviation)
 109  (33)   109  (44)   109  (38) 
Plasma HDL-C 
[Units: Mg/dl]
Mean (Standard Deviation)
 37  (9)   36  (9)   37  (9) 
Plasma AST 
[Units: U/L]
Mean (Standard Deviation)
 43  (22)   47  (21)   45  (22) 
Plasma ALT 
[Units: U/L]
Mean (Standard Deviation)
 57  (33)   62  (33)   60  (33) 
NAFLD activity score (NAS) Liver histology [1] 
[Units: Score on a scale]
Mean (Standard Deviation)
 4.5  (1.2)   4.5  (1.5)   4.5  (1.3) 
[1]

Steatosis: 0 = <5%; 1 = 5-33%; 2 = >33-66%; 3 = >66%. Lobular Inflammation: 0 = No foci 1 = <2 foci/200x; 2 = 2-4 foci/200x, 3 = >4 foci/200x.

Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning.

Total NAS score represents the sum of scores for steatosis, lobular inflammation, and ballooning. It is assessed on a scale of 0-8, with higher scores indicating more severe disease.

Steatosis grade [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 1.9  (0.8)   2.0  (0.8)   2.0  (0.8) 
[1] Steatosis: grade 0 = <5% of liver fat by histology; grade 1 = 5-33% liver fat; grade 2 = >33-66% liver fat; 3 = >66% liver fat, with higher scores indicating more severe disease.
Inflammation grade [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 1.7  (0.5)   1.7  (0.6)   1.7  (0.5) 
[1] Lobular Inflammation: grade 0 = No foci of inflammatory cells in the liver histology; grade 1 = <2 foci/200x; grade 2 = 2-4 foci/200x, grade 3 = >4 foci/200x, with higher scores indicating more severe disease.
Ballooning grade [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 0.9  (0.4)   0.8  (0.4)   0.9  (0.4) 
[1] Hepatocyte Ballooning: 0 = No ballooning cells observed in liver histology; 1 = Few balloon cells; 2 = Many cells/prominent ballooning, with higher scores indicating more severe disease.
Fibrosis stage [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 0.9  (0.9)   1.1  (1.1)   1.0  (1.0) 
[1] Fibrosis: 0 = No fibrosis in liver histology; 1 = Perisinusoidal or periportal, 1A = Mild, zone 3, perisinusoidal "delicate" fibrosis; 1B = Moderate, zone 3, perisinusoidal "dense" fibrosis; 1C = Portal/periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis, with higher scores indicating more severe disease.
Diagnosis of definite NASH 
[Units: Participants]
 45   42   87 


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Liver Histology (Using Kleiner et al Criteria, Hepatology 2005)   [ Time Frame: At 18 months ]

2.  Secondary:   Number of Participants With Resolution of NASH   [ Time Frame: Month 18 ]

3.  Secondary:   Mean Individual Histological Scores   [ Time Frame: Baseline and Month 18 ]

4.  Secondary:   Individual Histological Scores   [ Time Frame: Month 18 ]

5.  Secondary:   Mean Individual Histological Scores   [ Time Frame: Month 36 ]

6.  Secondary:   Liver Transaminases (AST and ALT).   [ Time Frame: 18 and 36 months ]

7.  Secondary:   Liver Fat by Magnetic Resonance and Spectroscopy (MRS).   [ Time Frame: 18 months ]

8.  Secondary:   Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)   [ Time Frame: 18 and 36 months ]

9.  Secondary:   Hepatic Insulin Sensitivity   [ Time Frame: 18 months ]

10.  Secondary:   Adipose Tissue Insulin Sensitivity   [ Time Frame: 18 months ]

11.  Secondary:   Skeletal Muscle Insulin Sensitivity   [ Time Frame: 18 months ]

12.  Secondary:   Body Mass Index (BMI)   [ Time Frame: Months 18 and 36 ]

13.  Secondary:   Total Body Fat   [ Time Frame: Months 18 ]

14.  Secondary:   Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (Adiponectin).   [ Time Frame: 18 and 36 months ]

15.  Secondary:   Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (CK-18).   [ Time Frame: 18 and 36 months ]

16.  Secondary:   Prevention of the Onset of T2DM and/or Reversal From IFG/IGT to NGT in Non-diabetics.   [ Time Frame: 18 months ]

17.  Secondary:   Osteoporotic Fractures   [ Time Frame: 18 and 36 months ]

18.  Secondary:   Molecular Pathways of Liver Glucose and Lipid Signaling; Inflammatory Pathways; Oxidative Stress; Other.   [ Time Frame: At 18 (2nd liver biopsy) and 36 (3rd liver biopsy) months. ]

19.  Secondary:   Bone Mineral Density   [ Time Frame: 18 and 36 months ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
The single-center nature of this study is a limitation that calls for additional work from a larger, longer-term (>3 years), multicenter trial.


  More Information
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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. Kenneth Cusi
Organization: University of Florida
phone: 352-273-8662
e-mail: kcusi@ufl.edu


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

Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT00994682     History of Changes
Other Study ID Numbers: HSC20070654
Study First Received: October 12, 2009
Results First Received: September 6, 2016
Last Updated: February 20, 2017