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Prevalence of Non-alcoholic Fatty Liver Disease (NAFLD) in Hispanics With Diabetes Mellitus Type 2 (T2DM) and Role of Treatment (VA NASH)

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ClinicalTrials.gov Identifier: NCT01002547
Recruitment Status : Completed
First Posted : October 27, 2009
Results First Posted : September 11, 2018
Last Update Posted : September 11, 2018
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition: Nonalcoholic Steatohepatitis
Interventions: Drug: pioglitazone-placebo
Drug: pioglitazone
Dietary Supplement: Vitamin E
Drug: Vitamin E-placebo

  Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Subjects were recruited from the endocrinology and hepatology clinics at two VA Medical Centers (i.e., Audie L. Murphy in San Antonio, TX and Malcom Randall in Gainesville, FL). The study was conducted between June 2010 and September 2016 (recruitment was completed in December 2014).

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
After initial screening (medical history, physical exam, laboratories, 75-gram oral glucose tolerance test [OGTT]), patients were instructed to keep physical activity and diet constant during the run-in phase (mean duration: 1 month).

Reporting Groups
  Description
Placebo

Patients with T2DM and biopsy-proven NASH.

Pioglitazone-placebo: This is a RCT in which all patients will be educated on a -500 kcal/day diet and a healthy lifestyle. Depending on randomization, subjects adjudicated to placebo will be started at the same time as the active (pioglitazone) arm and following the same up-titration. Placebo pills have the same characteristics as pills with active medication.

Vitamin E-placebo: Placebo of vitamin E will be given to arm 1.

Vitamin E

Patients with T2DM and biopsy-proven NASH.

Pioglitazone-placebo: This is a RCT in which all patients will be educated on a -500 kcal/day diet and a healthy lifestyle. Depending on randomization, subjects adjudicated to placebo will be started at the same time as the active (pioglitazone) arm and following the same up-titration. Placebo pills have the same characteristics as pills with active medication.

Vitamin E: All participants will receive vitamin E 400 IU orally twice daily.

Pioglitazone + Vitamin E

Patients with T2DM and biopsy-proven NASH.

Pioglitazone: This is a RCT in which all patients will be educated on a -500 kcal/day diet and a healthy lifestyle. Pioglitazone will be started on 30 mg/day, titrated to the maximal dose (45 mg/day) at two months and continued at this dose for the rest of the clinical trial.

Vitamin E: All participants will receive vitamin E 400 IU orally twice daily.


Participant Flow:   Overall Study
    Placebo   Vitamin E   Pioglitazone + Vitamin E
STARTED   32   36   37 
COMPLETED   24   33   29 
NOT COMPLETED   8   3   8 
Withdrawal by Subject                4                0                5 
Lost to Follow-up                2                1                1 
Physician Decision                1                0                0 
Death                0                2                2 
Adverse Event                1                0                0 



  Baseline Characteristics

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

Patients with T2DM and biopsy-proven NASH.

Pioglitazone-placebo: This is a RCT in which all patients will be educated on a -500 kcal/day diet and a healthy lifestyle. Depending on randomization, subjects adjudicated to placebo will be started at the same time as the active (pioglitazone) arm and following the same up-titration. Placebo pills have the same characteristics as pills with active medication.

Vitamin E-placebo: Placebo of vitamin E will be given to arm 1.

Vitamin E

Patients with T2DM and biopsy-proven NASH.

Pioglitazone-placebo: This is a RCT in which all patients will be educated on a -500 kcal/day diet and a healthy lifestyle. Depending on randomization, subjects adjudicated to placebo will be started at the same time as the active (pioglitazone) arm and following the same up-titration. Placebo pills have the same characteristics as pills with active medication.

Vitamin E: All participants will receive vitamin E 400 IU orally twice daily.

Pioglitazone + Vitamin E

Patients with T2DM and biopsy-proven NASH.

Pioglitazone: This is a RCT in which all patients will be educated on a -500 kcal/day diet and a healthy lifestyle. Pioglitazone will be started on 30 mg/day, titrated to the maximal dose (45 mg/day) at two months and continued at this dose for the rest of the clinical trial.

Vitamin E: All participants will receive vitamin E 400 IU orally twice daily.

Total Total of all reporting groups

Baseline Measures
   Placebo   Vitamin E   Pioglitazone + Vitamin E   Total 
Overall Participants Analyzed 
[Units: Participants]
 32   36   37   105 
Age 
[Units: Years]
Mean (Standard Deviation)
 57  (11)   60  (9)   60  (6)   59  (9) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
       
Female      2   6.3%      3   8.3%      7  18.9%      12  11.4% 
Male      30  93.8%      33  91.7%      30  81.1%      93  88.6% 
Race/Ethnicity, Customized 
[Units: Participants]
Count of Participants
       
White   23   27   26   76 
African American   2   4   3   9 
Hispanic   7   5   8   20 
Body mass index 
[Units: Kg/m2]
Mean (Standard Deviation)
 33.6  (4.0)   33.8  (4.6)   35.2  (4.3)   34.5  (4.2) 
Total body fat 
[Units: Percentage]
Mean (Standard Deviation)
 36  (5)   37  (6)   38  (6)   37  (6) 
Fasting plasma glucose 
[Units: Mg/dl]
Mean (Standard Deviation)
 153  (37)   158  (41)   144  (43)   152  (44) 
Hemoglobin A1c 
[Units: Percentage]
Mean (Standard Deviation)
 7.2  (1.2)   7.5  (1.3)   7.3  (1.1)   7.3  (1.2) 
Use of glucose-lowering medications 
[Units: Participants]
Count of Participants
       
Metformin   27   29   29   85 
Sulfonylurea   13   15   14   42 
Insulin   8   10   10   28 
Fasting plasma insulin 
[Units: uU/mL]
Mean (Standard Deviation)
 18  (13)   22  (14)   16  (10)   18  (13) 
Fasting free fatty acids 
[Units: Umol/ml]
Mean (Standard Deviation)
 0.41  (0.15)   0.39  (0.14)   0.41  (0.15)   0.40  (0.14) 
Intrahepatic triglyceride content 
[Units: Percentage]
Mean (Standard Deviation)
 10.5  (5.8)   11.7  (5.7)   13.8  (8.4)   12.2  (7.0) 
Plasma AST 
[Units: U/L]
Mean (Standard Deviation)
 40  (23)   41  (22)   32  (18)   37  (21) 
Plasma ALT 
[Units: U/L]
Mean (Standard Deviation)
 53  (33)   53  (32)   40  (25)   49  (31) 
Total cholesterol 
[Units: Mg/dl]
Mean (Standard Deviation)
 171  (40)   174  (44)   170  (53)   172  (46) 
LDL-cholesterol 
[Units: Mg/dl]
Mean (Standard Deviation)
 94  (33)   98  (39)   91  (44)   94  (39) 
HDL-cholesterol 
[Units: Mg/dl]
Mean (Standard Deviation)
 39  (10)   39  (9)   38  (10)   38  (9) 
Triglycerides 
[Units: Mg/dl]
Median (Inter-Quartile Range)
 154 
 (117 to 255) 
 156 
 (126 to 210) 
 163 
 (108 to 274) 
 158 
 (116 to 243) 
Statin use 
[Units: Participants]
Count of Participants
 25   26   29   80 
NAFLD activity score [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 4.2  (1.6)   3.9  (1.6)   3.7  (1.3)   4.0  (1.5) 
[1]

Calculated as the sum of steatosis grade (0 to 3), inflammation grade (0 to 3), and ballooning grade (0 to 2). Therefore, this score ranges from 0 to 8.

Steatosis: 0 = <5% fat; 1 = 5-33% fat; 2 = >33-66% fat; 3 = >66% fat.

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.

Fibrosis stage: 0 = None; 1 = Perisinusoidal or periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis.

Steatosis [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 1.8  (0.7)   1.7  (0.8)   1.6  (0.8)   1.7  (0.7) 
[1] Steatosis range 0-3, where: 0 = <5% fat; 1 = 5-33% fat; 2 = >33-66% fat; 3 = >66% fat.
Inflammation [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 1.6  (0.6)   1.3  (0.5)   1.4  (0.5)   1.4  (0.6) 
[1] Lobular Inflammation, range 0-3, where: 0 = No foci 1 = <2 foci/200x; 2 = 2-4 foci/200x, 3 = >4 foci/200x.
Hepatocyte ballooning [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 0.9  (0.8)   0.9  (0.8)   0.7  (0.6)   0.8  (0.7) 
[1] Hepatocyte Ballooning, range 0-2, where: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning.
Fibrosis [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 1.5  (1.0)   1.6  (1.2)   1.4  (1.1)   1.5  (1.1) 
[1] Fibrosis stage, range 0-4, where: 0 = None; 1 = Perisinusoidal or periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis.


  Outcome Measures

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

2.  Secondary:   Number of Participants With Resolution of NASH Without Worsening of Fibrosis   [ Time Frame: Month 18 ]

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

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

5.  Secondary:   Liver Fat by Magnetic Resonance Imaging and Spectroscopy (MRS).   [ Time Frame: Month 18 ]

6.  Secondary:   Weight   [ Time Frame: Month 18 ]

7.  Secondary:   Body Mass Index   [ Time Frame: Month 18 ]

8.  Secondary:   Total Body Fat by DEXA   [ Time Frame: Month 18 ]

9.  Secondary:   Plasma AST   [ Time Frame: Month 18 ]

10.  Secondary:   Plasma ALT   [ Time Frame: Month 18 ]

11.  Secondary:   Fasting Plasma Glucose   [ Time Frame: Month 18 ]

12.  Secondary:   Fasting Plasma Insulin   [ Time Frame: Month 18 ]

13.  Secondary:   Matsuda Index   [ Time Frame: Month 18 ]

14.  Secondary:   Total Cholesterol   [ Time Frame: Month 18 ]

15.  Secondary:   Triglycerides   [ Time Frame: Month 18 ]

16.  Secondary:   HDL-cholesterol   [ Time Frame: Month 18 ]

17.  Secondary:   LDL-cholesterol   [ Time Frame: Month 18 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats

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
Relative small sample size. A larger sample size could have resulted in significantly positive results for vitamin E alone in secondary outcomes. Because of this we acknowledge that vitamin E may still be an alternative for some patients.


  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: Dr. Kenneth Cusi
Organization: Malcom Randall VA Medical Center
phone: 352-273-8662
e-mail: Kenneth.Cusi@va.gov; Kenneth.Cusi@medicine.ufl.edu



Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT01002547     History of Changes
Other Study ID Numbers: CLIN-015-08F
HSC20090401H ( Other Identifier: IRB UTHSCSA )
VA-ORD#GRANT00508571 ( Other Grant/Funding Number: CSRD CSP )
610-2011 ( Other Identifier: University of Florida IRB-01 )
First Submitted: October 23, 2009
First Posted: October 27, 2009
Results First Submitted: August 13, 2018
Results First Posted: September 11, 2018
Last Update Posted: September 11, 2018