Trial Outcomes & Findings for University of Texas H.S.C. San Antonio Pioglitazone in Non-Alcoholic Steatohepatitis Trial (UTHSCSA NASH Trial) (NCT NCT00994682)

Last Updated: 2017-04-05

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

176 participants

Primary outcome timeframe

At 18 months

Results posted on

2017-04-05

Participant Flow

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.

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 The number of patients consented was 176, screen failed was 38, did not complete run-in phase was 37 (12 consent withdrawn, 9 lost to follow-up, 4 discontinued by PI decision, and 12 for other reasons).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.

Participant milestones

Participant milestones
Measure	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).
Double Bilnd STARTED	51	50
Double Bilnd COMPLETED	42	41
Double Bilnd NOT COMPLETED	9	9
Pioglitazone Open Label STARTED	42	41
Pioglitazone Open Label COMPLETED	29	34
Pioglitazone Open Label NOT COMPLETED	13	7

Reasons for withdrawal

Reasons for withdrawal
Measure	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).
Double Bilnd Withdrawal by Subject	5	6
Double Bilnd Lost to Follow-up	3	3
Double Bilnd Adverse Event	1	0
Pioglitazone Open Label Withdrawal by Subject	4	4
Pioglitazone Open Label Lost to Follow-up	3	2
Pioglitazone Open Label Physician Decision	6	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=51 Participants 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 n=50 Participants 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 n=101 Participants Total of all reporting groups
Age, Continuous	49 years STANDARD_DEVIATION 11 • n=99 Participants	52 years STANDARD_DEVIATION 10 • n=107 Participants	50 years STANDARD_DEVIATION 11 • n=206 Participants
Sex: Female, Male Female	16 Participants n=99 Participants	14 Participants n=107 Participants	30 Participants n=206 Participants
Sex: Female, Male Male	35 Participants n=99 Participants	36 Participants n=107 Participants	71 Participants n=206 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	37 Participants n=99 Participants	31 Participants n=107 Participants	68 Participants n=206 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	14 Participants n=99 Participants	19 Participants n=107 Participants	33 Participants n=206 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Weight	99.2 kg STANDARD_DEVIATION 17.0 • n=99 Participants	98.2 kg STANDARD_DEVIATION 16.5 • n=107 Participants	98.7 kg STANDARD_DEVIATION 16.7 • n=206 Participants
Body mass index	34.5 kg/m^2 STANDARD_DEVIATION 4.8 • n=99 Participants	34.3 kg/m^2 STANDARD_DEVIATION 4.8 • n=107 Participants	34.4 kg/m^2 STANDARD_DEVIATION 4.8 • n=206 Participants
Total body fat	34 percentage of fat mass STANDARD_DEVIATION 8 • n=99 Participants	33 percentage of fat mass STANDARD_DEVIATION 7 • n=107 Participants	33 percentage of fat mass STANDARD_DEVIATION 7 • n=206 Participants
Fasting plasma glucose	121 mg/dl STANDARD_DEVIATION 27 • n=99 Participants	124 mg/dl STANDARD_DEVIATION 29 • n=107 Participants	122 mg/dl STANDARD_DEVIATION 28 • n=206 Participants
2-hour plasma glucose	203 mg/dl STANDARD_DEVIATION 64 • n=99 Participants	211 mg/dl STANDARD_DEVIATION 78 • n=107 Participants	207 mg/dl STANDARD_DEVIATION 71 • n=206 Participants
Hemoglobin A1c	6.3 percentage STANDARD_DEVIATION 1.0 • n=99 Participants	6.4 percentage STANDARD_DEVIATION 1.0 • n=107 Participants	6.3 percentage STANDARD_DEVIATION 1.0 • n=206 Participants
Fasting plasma insulin	16 μU/mL STANDARD_DEVIATION 12 • n=99 Participants	15 μU/mL STANDARD_DEVIATION 11 • n=107 Participants	16 μU/mL STANDARD_DEVIATION 11 • n=206 Participants
Fasting free fatty acids	0.54 mmol/L STANDARD_DEVIATION 0.19 • n=99 Participants	0.49 mmol/L STANDARD_DEVIATION 0.18 • n=107 Participants	0.52 mmol/L STANDARD_DEVIATION 0.19 • n=206 Participants
Use of diabetes medications Metformin	17 participants n=99 Participants	19 participants n=107 Participants	36 participants n=206 Participants
Use of diabetes medications Sulfonylurea	16 participants n=99 Participants	12 participants n=107 Participants	28 participants n=206 Participants
Use of diabetes medications Insulin	6 participants n=99 Participants	5 participants n=107 Participants	11 participants n=206 Participants
Use of statins	19 participants n=99 Participants	19 participants n=107 Participants	38 participants n=206 Participants
Plasma triglycerides	179 mg/dl STANDARD_DEVIATION 109 • n=99 Participants	224 mg/dl STANDARD_DEVIATION 171 • n=107 Participants	201 mg/dl STANDARD_DEVIATION 144 • n=206 Participants
Plasma total cholesterol	182 mg/dl STANDARD_DEVIATION 42 • n=99 Participants	187 mg/dl STANDARD_DEVIATION 46 • n=107 Participants	185 mg/dl STANDARD_DEVIATION 44 • n=206 Participants
Plasma LDL-C	109 mg/dl STANDARD_DEVIATION 33 • n=99 Participants	109 mg/dl STANDARD_DEVIATION 44 • n=107 Participants	109 mg/dl STANDARD_DEVIATION 38 • n=206 Participants
Plasma HDL-C	37 mg/dl STANDARD_DEVIATION 9 • n=99 Participants	36 mg/dl STANDARD_DEVIATION 9 • n=107 Participants	37 mg/dl STANDARD_DEVIATION 9 • n=206 Participants
Plasma AST	43 U/L STANDARD_DEVIATION 22 • n=99 Participants	47 U/L STANDARD_DEVIATION 21 • n=107 Participants	45 U/L STANDARD_DEVIATION 22 • n=206 Participants
Plasma ALT	57 U/L STANDARD_DEVIATION 33 • n=99 Participants	62 U/L STANDARD_DEVIATION 33 • n=107 Participants	60 U/L STANDARD_DEVIATION 33 • n=206 Participants
NAFLD activity score (NAS) Liver histology	4.5 score on a scale STANDARD_DEVIATION 1.2 • n=99 Participants	4.5 score on a scale STANDARD_DEVIATION 1.5 • n=107 Participants	4.5 score on a scale STANDARD_DEVIATION 1.3 • n=206 Participants
Steatosis grade	1.9 units on a scale STANDARD_DEVIATION 0.8 • n=99 Participants	2.0 units on a scale STANDARD_DEVIATION 0.8 • n=107 Participants	2.0 units on a scale STANDARD_DEVIATION 0.8 • n=206 Participants
Inflammation grade	1.7 units on a scale STANDARD_DEVIATION 0.5 • n=99 Participants	1.7 units on a scale STANDARD_DEVIATION 0.6 • n=107 Participants	1.7 units on a scale STANDARD_DEVIATION 0.5 • n=206 Participants
Ballooning grade	0.9 units on a scale STANDARD_DEVIATION 0.4 • n=99 Participants	0.8 units on a scale STANDARD_DEVIATION 0.4 • n=107 Participants	0.9 units on a scale STANDARD_DEVIATION 0.4 • n=206 Participants
Fibrosis stage	0.9 units on a scale STANDARD_DEVIATION 0.9 • n=99 Participants	1.1 units on a scale STANDARD_DEVIATION 1.1 • n=107 Participants	1.0 units on a scale STANDARD_DEVIATION 1.0 • n=206 Participants
Diagnosis of definite NASH	45 participants n=99 Participants	42 participants n=107 Participants	87 participants n=206 Participants

PRIMARY outcome

Timeframe: At 18 months

Outcome measures

Outcome measures
Measure	Placebo n=51 Participants 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 n=50 Participants 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.
Liver Histology (Using Kleiner et al Criteria, Hepatology 2005)	9 Participants	29 Participants

SECONDARY outcome

Timeframe: Month 18

Population: Multiple imputation was used to impute missing histologic data for patients who did not complete 18 months of therapy.

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.

Outcome measures

Outcome measures
Measure	Placebo n=51 Participants 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 n=50 Participants 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.
Number of Participants With Resolution of NASH	10 Participants	26 Participants

SECONDARY outcome

Timeframe: Baseline and Month 18

Population: Multiple imputation was used to impute missing histologic data for patients who did not complete 18 months of therapy.

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

Outcome measures

Outcome measures
Measure	Placebo n=51 Participants 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 n=50 Participants 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.
Mean Individual Histological Scores Steatosis	-0.2 units on a scale Interval -1.8 to 1.4	-1.1 units on a scale Interval -2.7 to 0.5
Mean Individual Histological Scores Inflammation	-0.1 units on a scale Interval -1.7 to 1.5	-0.6 units on a scale Interval -2.2 to 1.0
Mean Individual Histological Scores Ballooning	-0.2 units on a scale Interval -1.8 to 1.4	-0.6 units on a scale Interval -2.2 to 1.0
Mean Individual Histological Scores Fibrosis	0 units on a scale Interval -1.568 to 1.568	-0.5 units on a scale Interval -2.1 to 1.1

SECONDARY outcome

Timeframe: Month 18

Population: Multiple imputation was used to impute missing histologic data for patients who did not complete 18 months of therapy.

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

Outcome measures

Outcome measures
Measure	Placebo n=51 Participants 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 n=50 Participants 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.
Individual Histological Scores Steatosis	13 Participants	35 Participants
Individual Histological Scores Inflammation	11 Participants	25 Participants
Individual Histological Scores Ballooning	12 Participants	25 Participants
Individual Histological Scores Fibrosis	13 Participants	20 Participants

SECONDARY outcome

Timeframe: Month 36

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

Outcome measures

Outcome measures
Measure	Placebo n=29 Participants 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 n=34 Participants 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.
Mean Individual Histological Scores Steatosis	1.56 units on a scale Interval 1.22 to 1.89	0.97 units on a scale Interval 0.67 to 1.27
Mean Individual Histological Scores Inflammation	1.30 units on a scale Interval 0.8 to 1.51	0.81 units on a scale Interval 0.6 to 1.03
Mean Individual Histological Scores Fibrosis	0.89 units on a scale Interval 0.49 to 1.29	0.66 units on a scale Interval 0.32 to 0.99
Mean Individual Histological Scores Ballooning	0.33 units on a scale Interval 0.14 to 0.52	0.22 units on a scale Interval 0.07 to 0.37

SECONDARY outcome

Timeframe: 18 and 36 months

Population: 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).

Outcome measures

Outcome measures
Measure	Placebo n=51 Participants 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 n=50 Participants 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.
Liver Transaminases (AST and ALT). AST at month 18	38 U/L Standard Deviation 31	29 U/L Standard Deviation 10
Liver Transaminases (AST and ALT). ALT at month 18	44 U/L Standard Deviation 33	27 U/L Standard Deviation 12
Liver Transaminases (AST and ALT). ALT at month 36	32 U/L Standard Deviation 17	27 U/L Standard Deviation 13
Liver Transaminases (AST and ALT). AST at month 36	30 U/L Standard Deviation 10	27 U/L Standard Deviation 8

SECONDARY outcome

Timeframe: 18 months

Population: 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).

Liver fat content was calculated as the fat fraction: 100\*(area under the curve \[AUC\] of fat peak / \[AUC of fat peak + AUC of water peak\]).

Outcome measures

Outcome measures
Measure	Placebo n=42 Participants 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 n=41 Participants 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.
Liver Fat by Magnetic Resonance and Spectroscopy (MRS).	11 percentage of fat in liver Standard Deviation 7	7 percentage of fat in liver Standard Deviation 5

SECONDARY outcome

Timeframe: 18 and 36 months

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.

Outcome measures

Outcome measures
Measure	Placebo n=51 Participants 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 n=50 Participants 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.
Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) HOMA-IR month 18	4.3 Arbitrary units Interval 2.9 to 5.7	1.4 Arbitrary units Interval 1.0 to 1.8
Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) HOMA-IR month 36	2.3 Arbitrary units Interval 1.4 to 3.3	1.6 Arbitrary units Interval 1.1 to 2.1

SECONDARY outcome

Timeframe: 18 months

Population: 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).

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.

Outcome measures

Outcome measures
Measure	Placebo n=42 Participants 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 n=41 Participants 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.
Hepatic Insulin Sensitivity	37.7 % of suppression of EGP Interval 30.6 to 44.7	55.3 % of suppression of EGP Interval 47.2 to 63.5

SECONDARY outcome

Timeframe: 18 months

Population: 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).

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.

Outcome measures

Outcome measures
Measure	Placebo n=42 Participants 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 n=41 Participants 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.
Adipose Tissue Insulin Sensitivity	46.1 % of suppression of FFA Interval 38.8 to 53.5	65.9 % of suppression of FFA Interval 60.6 to 71.3

SECONDARY outcome

Timeframe: 18 months

Population: 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).

Rate of glucose disappearance (Rd) during high-dose insulin infusion. The rate of plasma glucose disappearance was calculated using Steele's non-steady-state equation.

Outcome measures

Outcome measures
Measure	Placebo n=42 Participants 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 n=41 Participants 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.
Skeletal Muscle Insulin Sensitivity	5.4 mg/kgLBM/min Interval 4.6 to 6.2	9.6 mg/kgLBM/min Interval 8.2 to 11.1

SECONDARY outcome

Timeframe: Months 18 and 36

Outcome measures

Outcome measures
Measure	Placebo n=51 Participants 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 n=50 Participants 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.
Body Mass Index (BMI) BMI Month 18	34.6 kg/m^2 Standard Deviation 5.0	34.6 kg/m^2 Standard Deviation 4.8
Body Mass Index (BMI) BMI Month 36	36.7 kg/m^2 Standard Deviation 5.7	35.2 kg/m^2 Standard Deviation 4.8

SECONDARY outcome

Timeframe: Months 18

Population: 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).

Total body fat measured by dual-energy x-ray absorptiometry (DXA)

Outcome measures

Outcome measures
Measure	Placebo n=42 Participants 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 n=41 Participants 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 Body Fat	36 Percentage of body weight that is fat Standard Deviation 8	36 Percentage of body weight that is fat Standard Deviation 7

SECONDARY outcome

Timeframe: 18 and 36 months

Outcome measures

Outcome measures
Measure	Placebo n=51 Participants 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 n=50 Participants 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.
Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (Adiponectin). Adiponectin month 18	9.1 μg/ml Interval 7.1 to 11.1	22.8 μg/ml Interval 19.0 to 26.5
Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (Adiponectin). Adiponectin month 36	24.0 μg/ml Interval 14.5 to 33.5	24.2 μg/ml Interval 18.6 to 29.8

SECONDARY outcome

Timeframe: 18 and 36 months

Outcome measures

Outcome measures
Measure	Placebo n=51 Participants 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 n=50 Participants 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.
Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (CK-18). CK-18 month 18	314 U/L Interval 247.0 to 381.0	186 U/L Interval 133.0 to 238.0
Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (CK-18). CK-18 month 36	245 U/L Interval 184.0 to 305.0	151 U/L Interval 114.0 to 189.0

SECONDARY outcome

Timeframe: 18 months

Population: Only patients with prediabetes are included in this analysis

Number of patients developing T2DM and number of patients regressing to NGT among patients with prediabetes (IFG/IGT).

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants 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 n=23 Participants 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.
Prevention of the Onset of T2DM and/or Reversal From IFG/IGT to NGT in Non-diabetics. Patients developing T2DM	1 Participants	2 Participants
Prevention of the Onset of T2DM and/or Reversal From IFG/IGT to NGT in Non-diabetics. Patients regressing to NGT	10 Participants	1 Participants

SECONDARY outcome

Timeframe: 18 and 36 months

Number of patients with osteoporotic fractures

Outcome measures

Outcome measures
Measure	Placebo n=50 Participants 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 n=51 Participants 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.
Osteoporotic Fractures	0 Participants	0 Participants

SECONDARY outcome

Timeframe: At 18 (2nd liver biopsy) and 36 (3rd liver biopsy) months.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 18 and 36 months

Population: Data analysis included 78 patients at month 18 and 62 at month 36 (based on DXA availability).

Bone mineral density measured at the levels of spine, femoral neck, hip, and wrist by DXA.

Outcome measures

Outcome measures
Measure	Placebo n=39 Participants 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 n=39 Participants 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.
Bone Mineral Density Spine BMD at month 36	1.06 g/cm^2 Standard Deviation 0.14	1.10 g/cm^2 Standard Deviation 0.21
Bone Mineral Density Femoral Neck BMD at month 36	0.84 g/cm^2 Standard Deviation 0.14	0.84 g/cm^2 Standard Deviation 0.12
Bone Mineral Density Hip BMD at month 36	1.02 g/cm^2 Standard Deviation 0.12	1.06 g/cm^2 Standard Deviation 0.16
Bone Mineral Density Wrist BMD at month 36	0.75 g/cm^2 Standard Deviation 0.08	0.77 g/cm^2 Standard Deviation 0.09
Bone Mineral Density Spine BMD at month 18	1.04 g/cm^2 Standard Deviation 0.17	1.10 g/cm^2 Standard Deviation 0.17
Bone Mineral Density Femoral Neck BMD at month 18	0.84 g/cm^2 Standard Deviation 0.13	0.86 g/cm^2 Standard Deviation 0.12
Bone Mineral Density Hip BMD at month 18	1.05 g/cm^2 Standard Deviation 0.13	1.05 g/cm^2 Standard Deviation 0.13
Bone Mineral Density Wrist BMD at month 18	0.76 g/cm^2 Standard Deviation 0.08	0.78 g/cm^2 Standard Deviation 0.09

Adverse Events

Placebo (First 18 Months)

Serious events: 5 serious events

Other events: 7 other events

Deaths: 0 deaths

Pioglitazone (First 18 Months)

Serious events: 5 serious events

Other events: 15 other events

Deaths: 0 deaths

Placebo (PIO Open-label)

Serious events: 10 serious events

Other events: 12 other events

Deaths: 0 deaths

Pioglitazone (Months 18-36)

Serious events: 9 serious events

Other events: 10 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo (First 18 Months) n=51 participants at risk 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 (First 18 Months) n=50 participants at risk 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).	Placebo (PIO Open-label) n=36 participants at risk 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.	Pioglitazone (Months 18-36) n=40 participants at risk 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.
Vascular disorders Chronic lower limb edema	5.9% 3/51 • Adverse event data were collected for the entire study (36 months for each patient).	22.0% 11/50 • Adverse event data were collected for the entire study (36 months for each patient).	13.9% 5/36 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/40 • Adverse event data were collected for the entire study (36 months for each patient).
Endocrine disorders Hypoglycemia	7.8% 4/51 • Adverse event data were collected for the entire study (36 months for each patient).	8.0% 4/50 • Adverse event data were collected for the entire study (36 months for each patient).	19.4% 7/36 • Adverse event data were collected for the entire study (36 months for each patient).	25.0% 10/40 • Adverse event data were collected for the entire study (36 months for each patient).

Additional Information

Dr. Kenneth Cusi

University of Florida

Phone: 352-273-8662

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Placebo (First 18 Months) n=51 participants at risk 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 (First 18 Months) n=50 participants at risk 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).	Placebo (PIO Open-label) n=36 participants at risk 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.	Pioglitazone (Months 18-36) n=40 participants at risk 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.
Cardiac disorders Atypical chest pain	2.0% 1/51 • Adverse event data were collected for the entire study (36 months for each patient).	2.0% 1/50 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/36 • Adverse event data were collected for the entire study (36 months for each patient).	5.0% 2/40 • Adverse event data were collected for the entire study (36 months for each patient).
Cardiac disorders Pulmonary thromboembolism	0.00% 0/51 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/50 • Adverse event data were collected for the entire study (36 months for each patient).	2.8% 1/36 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/40 • Adverse event data were collected for the entire study (36 months for each patient).
Cardiac disorders Arrhythmia	2.0% 1/51 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/50 • Adverse event data were collected for the entire study (36 months for each patient).	2.8% 1/36 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/40 • Adverse event data were collected for the entire study (36 months for each patient).
Gastrointestinal disorders Pancreatitis	0.00% 0/51 • Adverse event data were collected for the entire study (36 months for each patient).	2.0% 1/50 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/36 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/40 • Adverse event data were collected for the entire study (36 months for each patient).
Gastrointestinal disorders Colelithiasis	0.00% 0/51 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/50 • Adverse event data were collected for the entire study (36 months for each patient).	2.8% 1/36 • Adverse event data were collected for the entire study (36 months for each patient).	5.0% 2/40 • Adverse event data were collected for the entire study (36 months for each patient).
Gastrointestinal disorders Diverticulitis	0.00% 0/51 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/50 • Adverse event data were collected for the entire study (36 months for each patient).	5.6% 2/36 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/40 • Adverse event data were collected for the entire study (36 months for each patient).
Endocrine disorders Diagnosis of adrenal carcinoma	0.00% 0/51 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/50 • Adverse event data were collected for the entire study (36 months for each patient).	2.8% 1/36 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/40 • Adverse event data were collected for the entire study (36 months for each patient).
Nervous system disorders Dissociative amnesia	0.00% 0/51 • Adverse event data were collected for the entire study (36 months for each patient).	2.0% 1/50 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/36 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/40 • Adverse event data were collected for the entire study (36 months for each patient).
Reproductive system and breast disorders Ovarian cyst rupture	0.00% 0/51 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/50 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/36 • Adverse event data were collected for the entire study (36 months for each patient).	2.5% 1/40 • Adverse event data were collected for the entire study (36 months for each patient).
Renal and urinary disorders Diagnosis of prostate cancer	0.00% 0/51 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/50 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/36 • Adverse event data were collected for the entire study (36 months for each patient).	2.5% 1/40 • Adverse event data were collected for the entire study (36 months for each patient).
Renal and urinary disorders Urine retention	0.00% 0/51 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/50 • Adverse event data were collected for the entire study (36 months for each patient).	5.6% 2/36 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/40 • Adverse event data were collected for the entire study (36 months for each patient).
Renal and urinary disorders Kidney stones	0.00% 0/51 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/50 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/36 • Adverse event data were collected for the entire study (36 months for each patient).	5.0% 2/40 • Adverse event data were collected for the entire study (36 months for each patient).
Surgical and medical procedures Biopsy-related	5.9% 3/51 • Adverse event data were collected for the entire study (36 months for each patient).	2.0% 1/50 • Adverse event data were collected for the entire study (36 months for each patient).	2.8% 1/36 • Adverse event data were collected for the entire study (36 months for each patient).	2.5% 1/40 • Adverse event data were collected for the entire study (36 months for each patient).
Social circumstances Motor vehicle accident	0.00% 0/51 • Adverse event data were collected for the entire study (36 months for each patient).	2.0% 1/50 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/36 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/40 • Adverse event data were collected for the entire study (36 months for each patient).
Nervous system disorders Concussion	0.00% 0/51 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/50 • Adverse event data were collected for the entire study (36 months for each patient).	2.8% 1/36 • Adverse event data were collected for the entire study (36 months for each patient).	0.00% 0/40 • Adverse event data were collected for the entire study (36 months for each patient).