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

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ClinicalTrials.gov Identifier: NCT00994682
Recruitment Status : Completed
First Posted : October 14, 2009
Results First Posted : April 5, 2017
Last Update Posted : April 5, 2017
Sponsor:
Collaborator:
The University of Texas at San Antonio
Information provided by (Responsible Party):
University of Florida

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (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
Enrollment 176
Recruitment Details 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 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 The number of patients consented was 176, screen failed was 38, did not complete run-in phase was 37 (12 consent withdrawn, 9 lost to follow-up, 4 discontinued by PI decision, and 12 for other reasons).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.
Arm/Group Title Placebo Pioglitazone
Hide Arm/Group Description 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. 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).
Period Title: Double Bilnd
Started 51 50
Completed 42 41
Not Completed 9 9
Reason Not Completed
Withdrawal by Subject             5             6
Lost to Follow-up             3             3
Adverse Event             1             0
Period Title: Pioglitazone Open Label
Started 42 41
Completed 29 34
Not Completed 13 7
Reason Not Completed
Withdrawal by Subject             4             4
Lost to Follow-up             3             2
Physician Decision             6             1
Arm/Group Title Placebo Pioglitazone Total
Hide Arm/Group Description 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. 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 of all reporting groups
Overall Number of Baseline Participants 51 50 101
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 51 participants 50 participants 101 participants
49  (11) 52  (10) 50  (11)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 51 participants 50 participants 101 participants
Female
16
  31.4%
14
  28.0%
30
  29.7%
Male
35
  68.6%
36
  72.0%
71
  70.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 51 participants 50 participants 101 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  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 51 participants 50 participants 101 participants
99.2  (17.0) 98.2  (16.5) 98.7  (16.7)
Body mass index  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 51 participants 50 participants 101 participants
34.5  (4.8) 34.3  (4.8) 34.4  (4.8)
Total body fat   [1] 
Mean (Standard Deviation)
Unit of measure:  Percentage of fat mass
Number Analyzed 51 participants 50 participants 101 participants
34  (8) 33  (7) 33  (7)
[1]
Measure Description: Measured by DXA
Fasting plasma glucose  
Mean (Standard Deviation)
Unit of measure:  Mg/dl
Number Analyzed 51 participants 50 participants 101 participants
121  (27) 124  (29) 122  (28)
2-hour plasma glucose  
Mean (Standard Deviation)
Unit of measure:  Mg/dl
Number Analyzed 51 participants 50 participants 101 participants
203  (64) 211  (78) 207  (71)
Hemoglobin A1c  
Mean (Standard Deviation)
Unit of measure:  Percentage
Number Analyzed 51 participants 50 participants 101 participants
6.3  (1.0) 6.4  (1.0) 6.3  (1.0)
Fasting plasma insulin  
Mean (Standard Deviation)
Unit of measure:  μU/mL
Number Analyzed 51 participants 50 participants 101 participants
16  (12) 15  (11) 16  (11)
Fasting free fatty acids  
Mean (Standard Deviation)
Unit of measure:  mmol/L
Number Analyzed 51 participants 50 participants 101 participants
0.54  (0.19) 0.49  (0.18) 0.52  (0.19)
Use of diabetes medications  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 51 participants 50 participants 101 participants
Metformin 17 19 36
Sulfonylurea 16 12 28
Insulin 6 5 11
Use of statins  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 51 participants 50 participants 101 participants
19 19 38
Plasma triglycerides  
Mean (Standard Deviation)
Unit of measure:  Mg/dl
Number Analyzed 51 participants 50 participants 101 participants
179  (109) 224  (171) 201  (144)
Plasma total cholesterol  
Mean (Standard Deviation)
Unit of measure:  Mg/dl
Number Analyzed 51 participants 50 participants 101 participants
182  (42) 187  (46) 185  (44)
Plasma LDL-C  
Mean (Standard Deviation)
Unit of measure:  Mg/dl
Number Analyzed 51 participants 50 participants 101 participants
109  (33) 109  (44) 109  (38)
Plasma HDL-C  
Mean (Standard Deviation)
Unit of measure:  Mg/dl
Number Analyzed 51 participants 50 participants 101 participants
37  (9) 36  (9) 37  (9)
Plasma AST  
Mean (Standard Deviation)
Unit of measure:  U/L
Number Analyzed 51 participants 50 participants 101 participants
43  (22) 47  (21) 45  (22)
Plasma ALT  
Mean (Standard Deviation)
Unit of measure:  U/L
Number Analyzed 51 participants 50 participants 101 participants
57  (33) 62  (33) 60  (33)
NAFLD activity score (NAS) Liver histology   [1] 
Mean (Standard Deviation)
Unit of measure:  Score on a scale
Number Analyzed 51 participants 50 participants 101 participants
4.5  (1.2) 4.5  (1.5) 4.5  (1.3)
[1]
Measure Description:

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] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 51 participants 50 participants 101 participants
1.9  (0.8) 2.0  (0.8) 2.0  (0.8)
[1]
Measure Description: 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] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 51 participants 50 participants 101 participants
1.7  (0.5) 1.7  (0.6) 1.7  (0.5)
[1]
Measure Description: 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] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 51 participants 50 participants 101 participants
0.9  (0.4) 0.8  (0.4) 0.9  (0.4)
[1]
Measure Description: 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] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 51 participants 50 participants 101 participants
0.9  (0.9) 1.1  (1.1) 1.0  (1.0)
[1]
Measure Description: 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  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 51 participants 50 participants 101 participants
45 42 87
1.Primary Outcome
Title Liver Histology (Using Kleiner et al Criteria, Hepatology 2005)
Hide Description

Number of patients with reduction of at least 2 points in the nonalcoholic fatty liver disease activity score (NAS) (with reduction in at least 2 different histological categories) without worsening of fibrosis. NAS is the sum of the separate scores for steatosis (0–3), hepatocellular ballooning (0–2) and lobular inflammation (0–3), and ranges from 0-8 .

The scoring system is based on the following grading:

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

Time Frame At 18 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Pioglitazone
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 51 50
Measure Type: Count of Participants
Unit of Measure: Participants
9
  17.6%
29
  58.0%
2.Secondary Outcome
Title Number of Participants With Resolution of NASH
Hide Description Resolution of NASH was defined as absence of NASH after 18 months of therapy in patients with definite NASH (presence of zone 3 accentuation of macrovesicular steatosis of any grade, hepatocellular ballooning of any degree, and lobular inflammatory infiltrates of any amount) at baseline.
Time Frame Month 18
Hide Outcome Measure Data
Hide Analysis Population Description
Multiple imputation was used to impute missing histologic data for patients who did not complete 18 months of therapy.
Arm/Group Title Placebo Pioglitazone
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 51 50
Measure Type: Count of Participants
Unit of Measure: Participants
10
  19.6%
26
  52.0%
3.Secondary Outcome
Title Mean Individual Histological Scores
Hide Description Mean change in individual scores compared to baseline. 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. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis
Time Frame Baseline and Month 18
Hide Outcome Measure Data
Hide Analysis Population Description
Multiple imputation was used to impute missing histologic data for patients who did not complete 18 months of therapy.
Arm/Group Title Placebo Pioglitazone
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 51 50
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Steatosis
-0.2
(-1.8 to 1.4)
-1.1
(-2.7 to 0.5)
Inflammation
-0.1
(-1.7 to 1.5)
-0.6
(-2.2 to 1.0)
Ballooning
-0.2
(-1.8 to 1.4)
-0.6
(-2.2 to 1.0)
Fibrosis
0
(-1.568 to 1.568)
-0.5
(-2.1 to 1.1)
4.Secondary Outcome
Title Individual Histological Scores
Hide Description

Number of patients with improvement of at least 1 grade in each of the histological parameters.

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. Fibrosis: 0 = None; 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

Time Frame Month 18
Hide Outcome Measure Data
Hide Analysis Population Description
Multiple imputation was used to impute missing histologic data for patients who did not complete 18 months of therapy.
Arm/Group Title Placebo Pioglitazone
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 51 50
Measure Type: Count of Participants
Unit of Measure: Participants
Steatosis
13
  25.5%
35
  70.0%
Inflammation
11
  21.6%
25
  50.0%
Ballooning
12
  23.5%
25
  50.0%
Fibrosis
13
  25.5%
20
  40.0%
5.Secondary Outcome
Title Mean Individual Histological Scores
Hide Description 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. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis
Time Frame Month 36
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Pioglitazone
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 29 34
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Steatosis
1.56
(1.22 to 1.89)
0.97
(0.67 to 1.27)
Inflammation
1.30
(0.80 to 1.51)
0.81
(0.60 to 1.03)
Ballooning
0.33
(0.14 to 0.52)
0.22
(0.07 to 0.37)
Fibrosis
0.89
(0.49 to 1.29)
0.66
(0.32 to 0.99)
6.Secondary Outcome
Title Liver Transaminases (AST and ALT).
Hide Description [Not Specified]
Time Frame 18 and 36 months
Hide Outcome Measure Data
Hide Analysis Population Description
Data include 101 observations at baseline (51 in the placebo group and 50 in the pioglitazone group), 83 at month 18 (42 and 41, respectively), and 63 at month 36 (29 and 34, respectively).
Arm/Group Title Placebo Pioglitazone
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 51 50
Mean (Standard Deviation)
Unit of Measure: U/L
ALT at month 18 44  (33) 27  (12)
AST at month 18 38  (31) 29  (10)
ALT at month 36 32  (17) 27  (13)
AST at month 36 30  (10) 27  (8)
7.Secondary Outcome
Title Liver Fat by Magnetic Resonance and Spectroscopy (MRS).
Hide Description Liver fat content was calculated as the fat fraction: 100*(area under the curve [AUC] of fat peak / [AUC of fat peak + AUC of water peak]).
Time Frame 18 months
Hide Outcome Measure Data
Hide Analysis Population Description
Data include 101 observations at baseline (51 in the placebo group and 50 in the pioglitazone group) and 83 at month 18 (42 and 41, respectively).
Arm/Group Title Placebo Pioglitazone
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 42 41
Mean (Standard Deviation)
Unit of Measure: percentage of fat in liver
11  (7) 7  (5)
8.Secondary Outcome
Title Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)
Hide Description Homeostatic model assessment of insulin resistance (HOMA-IR) is a method for assessing insulin resistance (IR) from basal fasting plasma glucose (FPG) and fasting plasma insulin (FPI). It is calculated as (FPG x FPI)/405.
Time Frame 18 and 36 months
Hide Outcome Measure Data
Hide Analysis Population Description
Data include 101 observations at baseline (51 in the placebo group and 50 in the pioglitazone group), 83 at month 18 (42 and 41, respectively), and 63 at month 36 (29 and 34, respectively).
Arm/Group Title Placebo Pioglitazone
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 51 50
Mean (95% Confidence Interval)
Unit of Measure: Arbitrary units
HOMA-IR month 18 Number Analyzed 42 participants 41 participants
4.3
(2.9 to 5.7)
1.4
(1.0 to 1.8)
HOMA-IR month 36 Number Analyzed 29 participants 34 participants
2.3
(1.4 to 3.3)
1.6
(1.1 to 2.1)
9.Secondary Outcome
Title Hepatic Insulin Sensitivity
Hide Description Suppression of endogenous glucose production (Supp EGP) by low dose insulin (i.e., percentage of reduction of EGP with low dose insulin infusion compared to the baseline state). This was calculated as: 100*((EGP without insulin - EGP with insulin infusion)/EGP without insulin). All measurements are obtained at the same time point during an euglycemic insulin clamp.
Time Frame 18 months
Hide Outcome Measure Data
Hide Analysis Population Description
Data include 101 observations at baseline (51 in the placebo group and 50 in the pioglitazone group) and 83 at month 18 (42 and 41, respectively).
Arm/Group Title Placebo Pioglitazone
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 42 41
Mean (95% Confidence Interval)
Unit of Measure: % of suppression of EGP
37.7
(30.6 to 44.7)
55.3
(47.2 to 63.5)
10.Secondary Outcome
Title Adipose Tissue Insulin Sensitivity
Hide Description Suppression of free fatty acids by low dose insulin (i.e., percentage of reduction of plasma FFA with low dose insulin infusion compared to the baseline state). This was calculated as: 100*((plasma FFA without insulin - plasma FFA with insulin infusion)/plasma FFA without insulin). All measurements are obtained at the same time point during an euglycemic insulin clamp.
Time Frame 18 months
Hide Outcome Measure Data
Hide Analysis Population Description
Data include 101 observations at baseline (51 in the placebo group and 50 in the pioglitazone group) and 83 at month 18 (42 and 41, respectively).
Arm/Group Title Placebo Pioglitazone
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 42 41
Mean (95% Confidence Interval)
Unit of Measure: % of suppression of FFA
46.1
(38.8 to 53.5)
65.9
(60.6 to 71.3)
11.Secondary Outcome
Title Skeletal Muscle Insulin Sensitivity
Time Frame 18 months
Hide Outcome Measure Data
Hide Analysis Population Description
Data include 101 observations at baseline (51 in the placebo group and 50 in the pioglitazone group) and 83 at month 18 (42 and 41, respectively).
Arm/Group Title Placebo Pioglitazone
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 42 41
Mean (95% Confidence Interval)
Unit of Measure: mg/kgLBM/min
5.4
(4.6 to 6.2)
9.6
(8.2 to 11.1)
12.Secondary Outcome
Title Body Mass Index (BMI)
Hide Description [Not Specified]
Time Frame Months 18 and 36
Hide Outcome Measure Data
Hide Analysis Population Description
Data include 101 observations at baseline (51 in the placebo group and 50 in the pioglitazone group), 83 at month 18 (42 and 41, respectively), and 63 at month 36 (29 and 34, respectively).
Arm/Group Title Placebo Pioglitazone
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 51 50
Mean (Standard Deviation)
Unit of Measure: kg/m^2
BMI Month 18 Number Analyzed 42 participants 41 participants
34.6  (5.0) 34.6  (4.8)
BMI Month 36 Number Analyzed 29 participants 34 participants
36.7  (5.7) 35.2  (4.8)
13.Secondary Outcome
Title Total Body Fat
Hide Description Total body fat measured by dual-energy x-ray absorptiometry (DXA)
Time Frame Months 18
Hide Outcome Measure Data
Hide Analysis Population Description
Data include 101 observations at baseline (51 in the placebo group and 50 in the pioglitazone group), 83 at month 18 (42 and 41, respectively).
Arm/Group Title Placebo Pioglitazone
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 42 41
Mean (Standard Deviation)
Unit of Measure: Percentage of body weight that is fat
36  (8) 36  (7)
14.Secondary Outcome
Title Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (Adiponectin).
Hide Description [Not Specified]
Time Frame 18 and 36 months
Hide Outcome Measure Data
Hide Analysis Population Description
Data include 101 observations at baseline (51 in the placebo group and 50 in the pioglitazone group), 83 at month 18 (42 and 41, respectively), and 63 at month 36 (29 and 34, respectively).
Arm/Group Title Placebo Pioglitazone
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 51 50
Mean (95% Confidence Interval)
Unit of Measure: μg/ml
Adiponectin month 18 Number Analyzed 42 participants 41 participants
9.1
(7.1 to 11.1)
22.8
(19.0 to 26.5)
Adiponectin month 36 Number Analyzed 29 participants 34 participants
24.0
(14.5 to 33.5)
24.2
(18.6 to 29.8)
15.Secondary Outcome
Title Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (CK-18).
Hide Description [Not Specified]
Time Frame 18 and 36 months
Hide Outcome Measure Data
Hide Analysis Population Description
Data include 101 observations at baseline (51 in the placebo group and 50 in the pioglitazone group), 83 at month 18 (42 and 41, respectively), and 63 at month 36 (29 and 34, respectively).
Arm/Group Title Placebo Pioglitazone
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 51 50
Mean (95% Confidence Interval)
Unit of Measure: U/L
CK-18 month 18 Number Analyzed 42 participants 41 participants
314
(247 to 381)
186
(133 to 238)
CK-18 month 36 Number Analyzed 29 participants 34 participants
245
(184 to 305)
151
(114 to 189)
16.Secondary Outcome
Title Prevention of the Onset of T2DM and/or Reversal From IFG/IGT to NGT in Non-diabetics.
Hide Description Number of patients developing T2DM and number of patients regressing to NGT among patients with prediabetes (IFG/IGT).
Time Frame 18 months
Hide Outcome Measure Data
Hide Analysis Population Description
Only patients with prediabetes are included in this analysis
Arm/Group Title Pioglitazone Placebo
Hide Arm/Group Description:

After all patients receive dietary counseling at the research unit (CTSA), patients with prediabetes or type 2 diabetes mellitus (T2DM) and NASH will be started on pioglitazone (or placebo) in a randomized, double-blind,placebo-controlled study design. Pioglitazone will be given at 30 mg/day for the first 2 months and titrated to 45 mg/day thereafter (if well tolerated).

Pioglitazone study drug: 30 mg per day orally for 8 weeks, and if well tolerated, titrated to 45 mg per day until the end of 18 months

Pioglitazone Open Label: Patients in both arms were placed open label pioglitazone for an additional 18 months after successfully completing the double-blind, placebo-controlled portion of the study design.

After dietary counseling to all patients at the research unit (CTSA), patients with prediabetes or type 2 diabetes mellitus (T2DM) and NASH will be started on pioglitazone (or placebo) in a randomized, double-blind,placebo-controlled study design. Pioglitazone will be given at 30 mg/day for the first 2 months and titrated to 45 mg/day thereafter (if well tolerated).

Placebo: An oral tablet identical to pioglitazone will be given once daily but without active drug for 18 months.

Pioglitazone Open Label: Patients in both arms were placed open label pioglitazone for an additional 18 months after successfully completing the double-blind, placebo-controlled portion of the study design.

Overall Number of Participants Analyzed 26 23
Measure Type: Count of Participants
Unit of Measure: Participants
Patients developing T2DM
1
   3.8%
2
   8.7%
Patients regressing to NGT
10
  38.5%
1
   4.3%
17.Secondary Outcome
Title Osteoporotic Fractures
Hide Description Number of patients with osteoporotic fractures
Time Frame 18 and 36 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Pioglitazone Placebo
Hide Arm/Group Description:

After all patients receive dietary counseling at the research unit (CTSA), patients with prediabetes or type 2 diabetes mellitus (T2DM) and NASH will be started on pioglitazone (or placebo) in a randomized, double-blind,placebo-controlled study design. Pioglitazone will be given at 30 mg/day for the first 2 months and titrated to 45 mg/day thereafter (if well tolerated).

Pioglitazone study drug: 30 mg per day orally for 8 weeks, and if well tolerated, titrated to 45 mg per day until the end of 18 months

Pioglitazone Open Label: Patients in both arms were placed open label pioglitazone for an additional 18 months after successfully completing the double-blind, placebo-controlled portion of the study design.

After dietary counseling to all patients at the research unit (CTSA), patients with prediabetes or type 2 diabetes mellitus (T2DM) and NASH will be started on pioglitazone (or placebo) in a randomized, double-blind,placebo-controlled study design. Pioglitazone will be given at 30 mg/day for the first 2 months and titrated to 45 mg/day thereafter (if well tolerated).

Placebo: An oral tablet identical to pioglitazone will be given once daily but without active drug for 18 months.

Pioglitazone Open Label: Patients in both arms were placed open label pioglitazone for an additional 18 months after successfully completing the double-blind, placebo-controlled portion of the study design.

Overall Number of Participants Analyzed 50 51
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
18.Secondary Outcome
Title Molecular Pathways of Liver Glucose and Lipid Signaling; Inflammatory Pathways; Oxidative Stress; Other.
Hide Description [Not Specified]
Time Frame At 18 (2nd liver biopsy) and 36 (3rd liver biopsy) months.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Pioglitazone Placebo
Hide Arm/Group Description:

After all patients receive dietary counseling at the research unit (CTSA), patients with prediabetes or type 2 diabetes mellitus (T2DM) and NASH will be started on pioglitazone (or placebo) in a randomized, double-blind,placebo-controlled study design. Pioglitazone will be given at 30 mg/day for the first 2 months and titrated to 45 mg/day thereafter (if well tolerated).

Pioglitazone study drug: 30 mg per day orally for 8 weeks, and if well tolerated, titrated to 45 mg per day until the end of 18 months

Pioglitazone Open Label: Patients in both arms were placed open label pioglitazone for an additional 18 months after successfully completing the double-blind, placebo-controlled portion of the study design.

After dietary counseling to all patients at the research unit (CTSA), patients with prediabetes or type 2 diabetes mellitus (T2DM) and NASH will be started on pioglitazone (or placebo) in a randomized, double-blind,placebo-controlled study design. Pioglitazone will be given at 30 mg/day for the first 2 months and titrated to 45 mg/day thereafter (if well tolerated).

Placebo: An oral tablet identical to pioglitazone will be given once daily but without active drug for 18 months.

Pioglitazone Open Label: Patients in both arms were placed open label pioglitazone for an additional 18 months after successfully completing the double-blind, placebo-controlled portion of the study design.

Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
19.Secondary Outcome
Title Bone Mineral Density
Hide Description Bone mineral density measured at the levels of spine, femoral neck, hip, and wrist by DXA.
Time Frame 18 and 36 months
Hide Outcome Measure Data
Hide Analysis Population Description
Data analysis included 78 patients at month 18 and 62 at month 36 (based on DXA availability).
Arm/Group Title Pioglitazone Placebo
Hide Arm/Group Description:

After all patients receive dietary counseling at the research unit (CTSA), patients with prediabetes or type 2 diabetes mellitus (T2DM) and NASH will be started on pioglitazone (or placebo) in a randomized, double-blind,placebo-controlled study design. Pioglitazone will be given at 30 mg/day for the first 2 months and titrated to 45 mg/day thereafter (if well tolerated).

Pioglitazone study drug: 30 mg per day orally for 8 weeks, and if well tolerated, titrated to 45 mg per day until the end of 18 months

Pioglitazone Open Label: Patients in both arms were placed open label pioglitazone for an additional 18 months after successfully completing the double-blind, placebo-controlled portion of the study design.

After dietary counseling to all patients at the research unit (CTSA), patients with prediabetes or type 2 diabetes mellitus (T2DM) and NASH will be started on pioglitazone (or placebo) in a randomized, double-blind,placebo-controlled study design. Pioglitazone will be given at 30 mg/day for the first 2 months and titrated to 45 mg/day thereafter (if well tolerated).

Placebo: An oral tablet identical to pioglitazone will be given once daily but without active drug for 18 months.

Pioglitazone Open Label: Patients in both arms were placed open label pioglitazone for an additional 18 months after successfully completing the double-blind, placebo-controlled portion of the study design.

Overall Number of Participants Analyzed 39 39
Mean (Standard Deviation)
Unit of Measure: g/cm^2
Spine BMD at month 18 Number Analyzed 39 participants 39 participants
1.04  (0.17) 1.10  (0.17)
Femoral Neck BMD at month 18 Number Analyzed 39 participants 39 participants
0.84  (0.13) 0.86  (0.12)
Hip BMD at month 18 Number Analyzed 39 participants 39 participants
1.05  (0.13) 1.05  (0.13)
Wrist BMD at month 18 Number Analyzed 39 participants 39 participants
0.76  (0.08) 0.78  (0.09)
Spine BMD at month 36 Number Analyzed 34 participants 28 participants
1.06  (0.14) 1.10  (0.21)
Femoral Neck BMD at month 36 Number Analyzed 34 participants 28 participants
0.84  (0.14) 0.84  (0.12)
Hip BMD at month 36 Number Analyzed 34 participants 28 participants
1.02  (0.12) 1.06  (0.16)
Wrist BMD at month 36 Number Analyzed 34 participants 28 participants
0.75  (0.08) 0.77  (0.09)
Time Frame Adverse event data were collected for the entire study (36 months for each patient).
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo (First 18 Months) Pioglitazone (First 18 Months) Placebo (PIO Open-label) Pioglitazone (Months 18-36)
Hide Arm/Group Description 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. 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 being randomized to placebo for the first 18 months, 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. 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.
All-Cause Mortality
Placebo (First 18 Months) Pioglitazone (First 18 Months) Placebo (PIO Open-label) Pioglitazone (Months 18-36)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo (First 18 Months) Pioglitazone (First 18 Months) Placebo (PIO Open-label) Pioglitazone (Months 18-36)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   5/51 (9.80%)   5/50 (10.00%)   10/36 (27.78%)   9/40 (22.50%) 
Cardiac disorders         
Atypical chest pain *  1/51 (1.96%)  1/50 (2.00%)  0/36 (0.00%)  2/40 (5.00%) 
Pulmonary thromboembolism *  0/51 (0.00%)  0/50 (0.00%)  1/36 (2.78%)  0/40 (0.00%) 
Arrhythmia *  1/51 (1.96%)  0/50 (0.00%)  1/36 (2.78%)  0/40 (0.00%) 
Endocrine disorders         
Diagnosis of adrenal carcinoma *  0/51 (0.00%)  0/50 (0.00%)  1/36 (2.78%)  0/40 (0.00%) 
Gastrointestinal disorders         
Pancreatitis *  0/51 (0.00%)  1/50 (2.00%)  0/36 (0.00%)  0/40 (0.00%) 
Colelithiasis *  0/51 (0.00%)  0/50 (0.00%)  1/36 (2.78%)  2/40 (5.00%) 
Diverticulitis *  0/51 (0.00%)  0/50 (0.00%)  2/36 (5.56%)  0/40 (0.00%) 
Nervous system disorders         
Dissociative amnesia *  0/51 (0.00%)  1/50 (2.00%)  0/36 (0.00%)  0/40 (0.00%) 
Concussion *  0/51 (0.00%)  0/50 (0.00%)  1/36 (2.78%)  0/40 (0.00%) 
Renal and urinary disorders         
Diagnosis of prostate cancer *  0/51 (0.00%)  0/50 (0.00%)  0/36 (0.00%)  1/40 (2.50%) 
Urine retention *  0/51 (0.00%)  0/50 (0.00%)  2/36 (5.56%)  0/40 (0.00%) 
Kidney stones *  0/51 (0.00%)  0/50 (0.00%)  0/36 (0.00%)  2/40 (5.00%) 
Reproductive system and breast disorders         
Ovarian cyst rupture *  0/51 (0.00%)  0/50 (0.00%)  0/36 (0.00%)  1/40 (2.50%) 
Social circumstances         
Motor vehicle accident *  0/51 (0.00%)  1/50 (2.00%)  0/36 (0.00%)  0/40 (0.00%) 
Surgical and medical procedures         
Biopsy-related *  3/51 (5.88%)  1/50 (2.00%)  1/36 (2.78%)  1/40 (2.50%) 
*
Indicates events were collected by non-systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo (First 18 Months) Pioglitazone (First 18 Months) Placebo (PIO Open-label) Pioglitazone (Months 18-36)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   7/51 (13.73%)   15/50 (30.00%)   12/36 (33.33%)   10/40 (25.00%) 
Endocrine disorders         
Hypoglycemia *  4/51 (7.84%)  4/50 (8.00%)  7/36 (19.44%)  10/40 (25.00%) 
Vascular disorders         
Chronic lower limb edema *  3/51 (5.88%)  11/50 (22.00%)  5/36 (13.89%)  0/40 (0.00%) 
*
Indicates events were collected by non-systematic assessment
The single-center nature of this study is a limitation that calls for additional work from a larger, longer-term (>3 years), multicenter trial.
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
EMail: kcusi@ufl.edu
Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT00994682     History of Changes
Other Study ID Numbers: HSC20070654
First Submitted: October 12, 2009
First Posted: October 14, 2009
Results First Submitted: September 6, 2016
Results First Posted: April 5, 2017
Last Update Posted: April 5, 2017