PERISCOPE: Efficacy Study of Pioglitazone Compared to Glimepiride on Coronary Atherosclerotic Disease Progression in Subjects With Type 2 Diabetes Mellitus

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00225277
• Collaborator: (none)
• Enrollment: 547
• Locations: 79
• Arms: 2
• Duration (Months): 51
• Patients Per Site: 6.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study was to determine the efficacy of pioglitazone, once daily (QD), compared to glimepiride on atherosclerotic disease measured by intravascular ultrasound.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus	Drug: Pioglitazone; Drug: Glimepiride	Phase 3

Detailed Description

Diabetes is a chronic disease with multiple metabolic defects that result in hyperglycemia arising from inadequate insulin activity. Type 2 diabetes is usually the result of a progression from reduced sensitivity of hepatic and peripheral tissue cells to circulating insulin (ie, insulin resistance) to a progressive inability of the body to produce adequate insulin to overcome insulin resistance (ie, insulin deficiency due to beta-cell insufficiency) resulting in impaired glucose tolerance and ultimately overt diabetes. In the United States, an estimated 21 million people have diabetes, with type 2 diabetes occurring in approximately 90% to 95% of cases. The goal of treating type 2 diabetes is to control blood glucose and thereby prevent long-term complications. Adequate glycemic control is paramount in attempting to avert chronic complications, including blindness; renal dysfunction resulting in dialysis or renal transplantation; neuropathy; non-traumatic amputations; and macrovascular complications, including myocardial ischemia and myocardial infarction, stroke, and peripheral arterial disease. Intensive glucose management in the early stages of diabetes may help forestall such complications.

Therapeutic agents have been developed to address each of the major functional metabolic defects associated with type 2 diabetes: decreased beta-cell function, elevated hepatic glucose output, and insulin resistance. Thiazolidinediones increase glucose utilization, decrease gluconeogenesis, and increase glucose disposal by binding to nuclear receptors known as peroxisome proliferator-activated receptors. Thiazolidinediones reduce insulin resistance by enhancing insulin sensitivity in muscle cells, adipose tissue, and hepatic cells (inhibiting hepatic gluconeogenesis), with no direct impact on insulin secretion. Thus, thiazolidinediones improve glycemic control and result in reduced levels of circulating insulin without predisposing patients to hypoglycemia. Peroxisome proliferator-activated receptors are found in tissues important for insulin action, such as adipose tissue, skeletal muscle, and the liver. The greatest concentration of peroxisome proliferator-activated receptors-gamma receptors is in adipose tissue.

This study was designed to compare the effects of pioglitazone compared to glimepiride on progression of atherosclerotic disease, as measured by intravascular ultrasound.

Study Design

• Study Type: Interventional
• Actual Enrollment: 547 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-Blind, Randomized, Comparator-Controlled Study In Subjects With Type 2 Diabetes Mellitus Comparing the Effects of Pioglitazone HCl Versus Glimepiride on the Rate of Progression of Coronary Atherosclerotic Disease as Measured by Intravascular Ultrasound
• Study Start Date: Jul 1, 2003
• Actual Primary Completion Date: Oct 1, 2007
• Actual Study Completion Date: Oct 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pioglitazone QD	Drug: Pioglitazone; Up to 45 mg pioglitazone (optimized for glucose control), tablets, orally, once daily for up to 72 weeks.; Other Names: ACTOS® AD4833
Active Comparator: Glimepiride QD	Drug: Glimepiride; Up to 4 mg of glimepiride (optimized for glucose control), tablets, orally, once daily for up to 72 weeks.

Outcome Measures

Primary Outcome Measures

1. Nominal Change From Baseline in Percent Atheroma Volume [Baseline and Final Visit (up to 72 weeks)]

   The nominal change from baseline in percent atheroma volume for all slices of anatomically comparable segments of the target coronary artery. Assessment completed at the Week 72 visit or Final Visit if treatment was prematurely discontinued.

Secondary Outcome Measures

1. Nominal Change From Baseline in Normalized Total Atheroma Volume [Baseline and Final Visit (up to 72 weeks)]

   The nominal change in normalized total atheroma volume as measured by the average of plaque areas for all slices of anatomically comparable segments of the target coronary artery multiplied by the mean number of matched slices in the population. Assessment completed at the Week 72 visit or Final Visit if treatment was prematurely discontinued.

2. Number of Subjects Experiencing Any of the Composite Endpoint A Cardiovascular Events [Up to 72 weeks]

   Due to low event rates, number of subjects experiencing any of the composite endpoint A cardiovascular events is being reported instead of time to first occurrence. Endpoint A conditions listed in Limitations and Caveats section.

3. Number of Subjects Experiencing Any of the Composite Endpoint B Cardiovascular Events [Up to 72 weeks]

   Due to low event rates, number of subjects experiencing any of the composite endpoint B cardiovascular events is being reported instead of time to first occurrence. Endpoint B conditions listed in Limitations and Caveats section.

4. Number of Subjects Experiencing Any of the Composite Endpoint C Cardiovascular Events [Up to 72 weeks]

   Due to low event rates, number of subjects experiencing any of the composite endpoint C cardiovascular events is being reported instead of time to first occurrence. Endpoint C conditions listed in Limitations and Caveats section.

Other Outcome Measures

1. Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee [Up to 72 weeks]

   The incidence of cardiovascular events and composite endpoints occurring within 30 days of last dose as adjudicated by the Clinical Endpoint Committee. Abbreviations: PCI: Percutaneous Coronary Intervention; CABG: Coronary Artery Bypass Graft; CHF: Congestive Heart Failure.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 35 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Females of childbearing potential who were sexually active agreed to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study.

• Had a diagnosis of type 2 diabetes mellitus

• Have received appropriate counseling on lifestyle modification for type 2 diabetes, including diet and exercise.

• naïve to or was not currently taking antidiabetic therapy, or were currently treated with monotherapy or combination therapy.

• Had a glycosylated hemoglobin level greater than or equal to 6.0% and less than 9% at screening if taking antidiabetic medication or greater than or equal to 6.5% and less than 10% at screening if naive to or not taking antidiabetic medication.

• Angiographic criteria:

• Entire Coronary Circulation: must have angiographic evidence of coronary heart disease as defined by at least 1 lesion in a native coronary artery that has greater than or equal to 20% reduction in lumen diameter by angiographic visual estimation.

• Left Main Coronary Artery: must not have greater than 50% reduction in lumen diameter by visual angiographic estimation.

• Target Coronary Artery:

• The target vessel, which includes the main artery and all of its side branches, had not undergone prior percutaneous coronary intervention or coronary artery bypass graft surgery.

• The target vessel, which includes the main artery and all of its side branches, was not currently a candidate for intervention or a likely candidate for intervention over the next 72 weeks.

• The target vessel was not a bypass graft.

• The target vessel was not infarct related.

• Had previous coronary artery bypass surgery at least six weeks prior to the qualifying intravascular ultrasound are eligible provided they are stable and meet all other entry criteria.

• Had an intravascular ultrasound tape deemed to be of acceptable intravascular ultrasound image quality and demonstrated adherence to the intravascular ultrasound interrogation protocol, as determined by the intravascular ultrasound Core Laboratory™ assessment.

Exclusion Criteria:

• Had type I diabetes mellitus.

• Had participated in another investigational study, or participated in an investigational study 30 days prior to the start of this study, or who were scheduled to participate in an investigational study during the time frame of this study.

• Male subjects who had a serum creatinine level greater than or equal to 2.0 mg/dL (greater than or equal to 177 µmol/L) (greater than or equal to 1.5 mg/dL; [greater than or equal to 133 µmol /L] if taking metformin) and female subjects who have serum creatinine greater than or equal to 1.8 mg/dL [greater than or equal to 159 µmol /L] (greater than or equal to 1.4 mg/dL [greater than or equal to 124 µmol /L] if taking metformin).

• Had unexplained microscopic hematuria greater than +1, confirmed by repeat testing.

• Had a history of drug abuse or a history of alcohol abuse (defined as regular or daily consumption of more than 4 alcoholic drinks per day) within the past 2 years.

• Had clinical cardiac failure as defined by New York Heart Association class III or IV, or known left ventricular dysfunction measured as left ventricular ejection fraction less than 40%, or by current use of diuretics or angiotensin converting enzyme inhibitors for treatment of heart failure.

• Had an alanine transaminase level of greater than 2.5 times the upper limit of normal active liver disease, or jaundice.

• Had a body mass index greater than 48 kg/m2 as calculated by weight (kg)/height (m2) or weight (pounds)/height (inches) 2 x 703.

• Was required to take or intended to continue taking any disallowed medication, any prescription medication, herbal treatment or over-the counter medication that may have interfered with evaluation of the study medication, including:

• Chronically used oral glucocorticoids (eg, prednisone, cortisone, hydrocortisone, dexamethasone)

• Niacin greater than100 mg a day, including niacin-containing products such as Advicor®

• Chronically used steroid-joint injections

• Thiazolidinediones

• Sulfonylureas

• Metformin/sulfonylurea combination

• Other oral antidiabetic medications (eg, nateglinide [Starlix®], acarbose [Precose®]) with the exception of metformin

• Had known or suspected malignancy or recurrence of malignancy within the past 5 years, with the exception of basal cell carcinoma and Stage 1 squamous cell carcinoma of the skin.

• Had any disease where, in the opinion of the investigator (or designee), survival is expected to be less than 72 weeks.

• Clinical status was unstable (ie, requiring vasopressors or intravenous inotropes, intra-aortic balloon pump, hypotension [systolic blood pressure less than 90 mm Hg]).

• Prior to the screening visit, was scheduled for a staged cardiac intervention (percutaneous coronary intervention), peripheral vascular intervention, or coronary artery bypass graft surgery following the screening angiography.

• In the opinion of the investigator (or designee) had clinically significant valvular heart disease likely to require surgical repair/replacement during the course of the study.

• Had persistent, uncontrolled hypertension (ie, sitting systolic blood pressure greater than 160 mm Hg or sitting diastolic blood pressure greater than 100 mm Hg) at randomization.

• Males who had hemoglobin less than 10.5 g/dL (less than 105 g/L) and female subjects who had hemoglobin less than 10.0 g/dL (less than 100 g/L).

• Had a triglyceride level greater than 500 mg/dL (greater than 5.6 mmol/L).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Phoenix	Arizona	United States
3		Huntington Beach	California	United States
4		Los Angeles	California	United States
5		Sacramento	California	United States
6		San Diego	California	United States
7		Torrance	California	United States
8		Bridgeport	Connecticut	United States
9		Farmington	Connecticut	United States
10		Washington	District of Columbia	United States
11		Bay Pines	Florida	United States
12		Jacksonville	Florida	United States
13		Decatur	Georgia	United States
14		Boise	Idaho	United States
15		Chicago	Illinois	United States
16		Edgewood	Kentucky	United States
17		Lexington	Kentucky	United States
18		Louisville	Kentucky	United States
19		New Orleans	Louisiana	United States
20		Bangor	Maine	United States
21		Baltimore	Maryland	United States
22		Detroit	Michigan	United States
23		Flint	Michigan	United States
24		Kalamazoo	Michigan	United States
25		Petoskey	Michigan	United States
26		Pontiac	Michigan	United States
27		Royal Oak	Michigan	United States
28		Ypsilanti	Michigan	United States
29		Duluth	Minnesota	United States
30		Minneapolis	Minnesota	United States
31		St. Cloud	Minnesota	United States
32		Columbia	Missouri	United States
33		Camden	New Jersey	United States
34		Albany	New York	United States
35		Bronx	New York	United States
36		Mineola	New York	United States
37		New York	New York	United States
38		Rochester	New York	United States
39		Troy	New York	United States
40		West Islip	New York	United States
41		Williamsville	New York	United States
42		Winston-Salem	North Carolina	United States
43		Cincinnati	Ohio	United States
44		Cleveland	Ohio	United States
45		Columbus	Ohio	United States
46		Westlake	Ohio	United States
47		Oklahoma City	Oklahoma	United States
48		Tulsa	Oklahoma	United States
49		Abington	Pennsylvania	United States
50		Bryn Mawr	Pennsylvania	United States
51		Hershey	Pennsylvania	United States
52		Pittsburgh	Pennsylvania	United States
53		Providence	Rhode Island	United States
54		Greenville	South Carolina	United States
55		Memphis	Tennessee	United States
56		Oak Ridge	Tennessee	United States
57		Amarillo	Texas	United States
58		Houston	Texas	United States
59		Lubbock	Texas	United States
60		San Antonio	Texas	United States
61		Charlottesville	Virginia	United States
62		Norfolk	Virginia	United States
63		Richmond	Virginia	United States
64		Everett	Washington	United States
65		Green Bay	Wisconsin	United States
66		Ciudad de Buenos Aires		Argentina
67		Cordoba		Argentina
68		Quilmes		Argentina
69		Edmonton	Alberta	Canada
70		Vancouver	British Columbia	Canada
71		Victoria	British Columbia	Canada
72		Winnepeg	Manitoba	Canada
73		Saint John	New Brunswick	Canada
74		London	Ontario	Canada
75		Ottawa	Ontario	Canada
76		Montreal	Quebec	Canada
77		Sainte Foy	Quebec	Canada
78		Saskatoon	Saskatchewan	Canada
79		Santiago		Chile

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: VP Clinical Science, Takeda

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• ACTOS® Package Insert

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT00225277
• Other Study ID Numbers: 01-01-TL-OPI-516; U1111-1114-0400
• First Posted: Sep 23, 2005
• Last Update Posted: Feb 28, 2012
• Last Verified: Feb 1, 2012

• Keywords provided by Takeda: Glucose Metabolism Disorder; Dysmetabolic Syndrome; Type II Diabetes; Diabetes Mellitus, Lipoatrophic; Dyslipidemia; Drug Therapy; Atherosclerosis
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Pioglitazone; Glimepiride

Study Results

Participant Flow

Recruitment Details	Subjects were enrolled at 97 sites in the United States, Canada, Argentina and Chile from 21 July 2003 to 18 October 2007.
Pre-assignment Detail	The participant flow results below do not include 4 subjects who were randomized but did not receive drug. Subjects participating in this study were enrolled in Pioglitazone or Glimepiride once daily (QD) treatment group.

Arm/Group Title	Pioglitazone QD	Glimepiride QD
Arm/Group Description	Subjects received up to 45 mg Pioglitazone (dose optimized for glucose control) for up to 72 weeks.	Subjects received up to 4 mg Glimepiride (dose optimized for glucose control) for up to 72 weeks.
Period Title: Overall Study
STARTED	274	273
COMPLETED	177	178
NOT COMPLETED	97	95

Baseline Characteristics

Arm/Group Title	Pioglitazone QD	Glimepiride QD	Total
Arm/Group Description	Subjects received up to 45 mg Pioglitazone (dose optimized for glucose control) for up to 72 weeks.	Subjects received up to 4 mg Glimepiride (dose optimized for glucose control) for up to 72 weeks.	Total of all reporting groups
Overall Participants	270	273	543
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	189 70%	193 70.7%	382 70.3%
>=65 years	81 30%	80 29.3%	161 29.7%
Sex: Female, Male (Count of Participants)
Female	84 31.1%	93 34.1%	177 32.6%
Male	186 68.9%	180 65.9%	366 67.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	63 23.3%	71 26%	134 24.7%
Not Hispanic or Latino	207 76.7%	202 74%	409 75.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
Native American	3 1.1%	10 3.7%	13 2.4%
Asian	12 4.4%	16 5.9%	28 5.2%
Black or African American	30 11.1%	27 9.9%	57 10.5%
White	225 83.3%	220 80.6%	445 82%
Family History of Coronary Artery Disease (Number) [Number]
Male Relative History	91 33.7%	77 28.2%	168 30.9%
Female Relative History	60 22.2%	59 21.6%	119 21.9%
No Family History	119 44.1%	137 50.2%	256 47.1%
Body Mass Index (Kg/m squared) [Mean (Full Range) ]
Mean (Full Range) [Kg/m squared]	32.08 (5.264)	32.03 (5.233)	32.05 (0)
Duration of Coronary Artery Disease (Months) [Mean (Full Range) ]
Mean (Full Range) [Months]	40.4 (65.10)	40.5 (67.20)	40.4 (0)
Duration of Diabetes Mellitus (Months) [Mean (Full Range) ]
Mean (Full Range) [Months]	98.0 (100.25)	96.3 (89.51)	97.1 (0)

Outcome Measures

1. Primary Outcome

Title	Nominal Change From Baseline in Percent Atheroma Volume
Description	The nominal change from baseline in percent atheroma volume for all slices of anatomically comparable segments of the target coronary artery. Assessment completed at the Week 72 visit or Final Visit if treatment was prematurely discontinued.
Time Frame	Baseline and Final Visit (up to 72 weeks)

Outcome Measure Data

Analysis Population Description

N at baseline included subjects who had both a baseline value and a final visit value. Baseline value is the last observation before first dose of study medication.

Arm/Group Title	Pioglitazone QD	Glimepiride QD
Arm/Group Description	Subjects received up to 45 mg Pioglitazone (dose optimized for glucose control) for up to 72 weeks.	Subjects received up to 4 mg Glimepiride (dose optimized for glucose control) for up to 72 weeks.
Measure Participants	179	181
Baseline	40.592 (0.6925)	40.016 (0.6663)
Nominal Change from Baseline	-0.161 (0.2095)	0.725 (0.2017)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone QD, Glimepiride QD
	Comments	2 Way analysis of covariance (ANCOVA), treatment and center effects with baseline value as covariate. Least Squares (LS) mean change and LS mean of the treatment difference reported.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.886
	Confidence Interval	() 95%; -1.4480 to -0.3250
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean Difference = Pioglitazone - Glimepiride

2. Secondary Outcome

Title	Nominal Change From Baseline in Normalized Total Atheroma Volume
Description	The nominal change in normalized total atheroma volume as measured by the average of plaque areas for all slices of anatomically comparable segments of the target coronary artery multiplied by the mean number of matched slices in the population. Assessment completed at the Week 72 visit or Final Visit if treatment was prematurely discontinued.
Time Frame	Baseline and Final Visit (up to 72 weeks)

Outcome Measure Data

Analysis Population Description

N at baseline included subjects who had both a baseline value and a final visit value. Baseline value is the last observation before first dose of study medication.

Arm/Group Title	Pioglitazone QD	Glimepiride QD
Arm/Group Description	Subjects received up to 45 mg Pioglitazone (dose optimized for glucose control) for up to 72 weeks.	Subjects received up to 4 mg Glimepiride (dose optimized for glucose control) for up to 72 weeks.
Measure Participants	179	181
Baseline	206.579 (7.2778)	217.619 (7.0030)
Nominal Change from Baseline	-5.528 (1.5989)	-1.480 (1.5370)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone QD, Glimepiride QD
	Comments	2 Way ANCOVA, treatment and center effects with baseline value as covariate. LS mean of the treatment difference reported.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.064
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.048
	Confidence Interval	() 95%; -8.3336 to 0.2374
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean Difference = Pioglitazone - Glimepiride

3. Secondary Outcome

Title	Number of Subjects Experiencing Any of the Composite Endpoint A Cardiovascular Events
Description	Due to low event rates, number of subjects experiencing any of the composite endpoint A cardiovascular events is being reported instead of time to first occurrence. Endpoint A conditions listed in Limitations and Caveats section.
Time Frame	Up to 72 weeks

Outcome Measure Data

Analysis Population Description

Kaplan-Meier methodology was used to estimate time to event for each composite endpoint. P-value comparing survival function between groups was based on log-rank test. Time to first occurrence of cardiovascular events/hospitalizations had non-estimable medians due to very low event rates. Number of participants experiencing events are presented.

Arm/Group Title	Pioglitazone QD	Glimepiride QD
Arm/Group Description	Subjects received up to 45 mg Pioglitazone (dose optimized for glucose control) for up to 72 weeks.	Subjects received up to 4 mg Glimepiride (dose optimized for glucose control) for up to 72 weeks.
Measure Participants	270	273
Number [Participants]	5 1.9%	6 2.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone QD, Glimepiride QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.744
	Comments	Kaplan-Meier methodology was used to estimate the time to event for each composite endpoint. The p-value was based on a log-rank test.
	Method	Log Rank
	Comments

4. Secondary Outcome

Title	Number of Subjects Experiencing Any of the Composite Endpoint B Cardiovascular Events
Description	Due to low event rates, number of subjects experiencing any of the composite endpoint B cardiovascular events is being reported instead of time to first occurrence. Endpoint B conditions listed in Limitations and Caveats section.
Time Frame	Up to 72 weeks

Outcome Measure Data

Analysis Population Description

Kaplan-Meier methodology was used to estimate time to event for each composite endpoint. P-value comparing survival function between groups was based on log-rank test. Time to first occurrence of cardiovascular events/hospitalizations had non-estimable medians due to very low event rates. Number of participants experiencing events are presented.

Arm/Group Title	Pioglitazone QD	Glimepiride QD
Arm/Group Description	Subjects received up to 45 mg Pioglitazone (dose optimized for glucose control) for up to 72 weeks.	Subjects received up to 4 mg Glimepiride (dose optimized for glucose control) for up to 72 weeks.
Measure Participants	270	273
Number [Participants]	40 14.8%	41 15%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone QD, Glimepiride QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.883
	Comments	Kaplan-Meier methodology was used to estimate the time to event for each composite endpoint. The p-value was based on a log-rank test.
	Method	Log Rank
	Comments

5. Secondary Outcome

Title	Number of Subjects Experiencing Any of the Composite Endpoint C Cardiovascular Events
Description	Due to low event rates, number of subjects experiencing any of the composite endpoint C cardiovascular events is being reported instead of time to first occurrence. Endpoint C conditions listed in Limitations and Caveats section.
Time Frame	Up to 72 weeks

Outcome Measure Data

Analysis Population Description

Kaplan-Meier methodology was used to estimate time to event for each composite endpoint. P-value comparing survival function between groups was based on log-rank test. Time to first occurrence of cardiovascular events/hospitalizations had non-estimable medians due to very low event rates. Number of participants experiencing events are presented.

Arm/Group Title	Pioglitazone QD	Glimepiride QD
Arm/Group Description	Subjects received up to 45 mg Pioglitazone (dose optimized for glucose control) for up to 72 weeks.	Subjects received up to 4 mg Glimepiride (dose optimized for glucose control) for up to 72 weeks.
Measure Participants	270	273
Number [participants]	11 4.1%	13 4.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone QD, Glimepiride QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.663
	Comments	Kaplan-Meier methodology was used to estimate the time to event for each composite endpoint. The p-value was based on a log-rank test.
	Method	Log Rank
	Comments

6. Other Pre-specified Outcome

Title	Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee
Description	The incidence of cardiovascular events and composite endpoints occurring within 30 days of last dose as adjudicated by the Clinical Endpoint Committee. Abbreviations: PCI: Percutaneous Coronary Intervention; CABG: Coronary Artery Bypass Graft; CHF: Congestive Heart Failure.
Time Frame	Up to 72 weeks

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Pioglitazone QD	Glimepiride QD
Arm/Group Description	Subjects received up to 45 mg Pioglitazone (dose optimized for glucose control) for up to 72 weeks.	Subjects received up to 4 mg Glimepiride (dose optimized for glucose control) for up to 72 weeks.
Measure Participants	270	273
Nonfatal Myocardial Infarction	2	4
Nonfatal Stroke	0	1
Coronary Revascularization: PCI/CABG counted once	29	30
Coronary Revascularization: PCI	25	28
Coronary Revascularization: CABG	5	2
Carotid Endarterectomy/Stenting	1	0
Hospitalization for Unstable Angina	4	2
CHF Hospitalization: new/exacerbated counted once	4	5
Hospitalization for New CHF	4	2
Hospitalization for Exacerbated CHF	0	3
Noncardiovascular Mortality	0	1
Cardiovascular Mortality	3	1
Composite Endpoint A	5	6
Composite Endpoint B	40	41
Composite Endpoint C	11	13

Adverse Events

Arm/Group Title	Pioglitazone QD		Glimepiride QD
Arm/Group Description	Subjects received up to 45 mg Pioglitazone (dose optimized for glucose control) for up to 72 weeks.		Subjects received up to 4 mg Glimepiride (dose optimized for glucose control) for up to 72 weeks.
All Cause Mortality
	Pioglitazone QD		Glimepiride QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Pioglitazone QD		Glimepiride QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	76/ (NaN)		77/ (NaN)
Blood and lymphatic system disorders
Anaemia	1/270 (0.4%)		0/273 (0%)
Cardiac disorders
Acute Coronary Syndrome	0/270 (0%)		3/273 (1.1%)
Acute Myocardial Infarction	2/270 (0.7%)		1/273 (0.4%)
Angina Pectoris	8/270 (3%)		4/273 (1.5%)
Angina Unstable	4/270 (1.5%)		3/273 (1.1%)
Atrial Fibrillation	2/270 (0.7%)		1/273 (0.4%)
Atrioventricular Block Complete	0/270 (0%)		1/273 (0.4%)
Cardiac Arrest	0/270 (0%)		1/273 (0.4%)
Cardiac Discomfort	0/270 (0%)		1/273 (0.4%)
Cardiac Failure Congestive	3/270 (1.1%)		5/273 (1.8%)
Cardiac Tamponade	0/270 (0%)		1/273 (0.4%)
Coronary Artery Atherosclerosis	1/270 (0.4%)		1/273 (0.4%)
Coronary Artery Disease	20/270 (7.4%)		16/273 (5.9%)
Coronary Artery Insufficiency	0/270 (0%)		1/273 (0.4%)
Coronary Artery Occlusion	0/270 (0%)		1/273 (0.4%)
Coronary Artery Stenosis	5/270 (1.9%)		5/273 (1.8%)
Myocardial Infarction	3/270 (1.1%)		2/273 (0.7%)
Ventricular Fibrillation	1/270 (0.4%)		0/273 (0%)
Ventricular Tachycardia	1/270 (0.4%)		0/273 (0%)
Ear and labyrinth disorders
Vertigo	1/270 (0.4%)		0/273 (0%)
Endocrine disorders
Hyperaldosteronism	1/270 (0.4%)		0/273 (0%)
Hyperthyroidism	1/270 (0.4%)		0/273 (0%)
Gastrointestinal disorders
Abdominal Hernia	0/270 (0%)		1/273 (0.4%)
Abdominal Pain	1/270 (0.4%)		1/273 (0.4%)
Abdominal Strangulated Hernia	1/270 (0.4%)		0/273 (0%)
Anal Haemorrhage	0/270 (0%)		1/273 (0.4%)
Appendiceal Mucocoele	0/270 (0%)		1/273 (0.4%)
Appendicitis Perforated	1/270 (0.4%)		0/273 (0%)
Colitis	0/270 (0%)		1/273 (0.4%)
Constipation	0/270 (0%)		1/273 (0.4%)
Dysphagia	1/270 (0.4%)		0/273 (0%)
Gastrointestinal Haemorrhage	0/270 (0%)		1/273 (0.4%)
Gastrooesophageal Reflux Disease	1/270 (0.4%)		0/273 (0%)
Ruptured Diverticulum of Colon	0/270 (0%)		1/273 (0.4%)
General disorders
Catheter Site Phlebitis	1/270 (0.4%)		0/273 (0%)
Non-Cardia Chest Pain	15/270 (5.6%)		5/273 (1.8%)
Hepatobiliary disorders
Biliary Colic	0/270 (0%)		1/273 (0.4%)
Chloelithiasis	1/270 (0.4%)		0/273 (0%)
Cholecystitis	1/270 (0.4%)		0/273 (0%)
Cholecystitis Acute	0/270 (0%)		1/273 (0.4%)
Hepatic Function Abnormal	0/270 (0%)		1/273 (0.4%)
Hepatitis	0/270 (0%)		1/273 (0.4%)
Infections and infestations
Bronchitis	1/270 (0.4%)		2/273 (0.7%)
Bronchitis Acute	1/270 (0.4%)		0/273 (0%)
Cellulitis	1/270 (0.4%)		2/273 (0.7%)
Diabetic Foot Infection	0/270 (0%)		1/273 (0.4%)
Diverticulitis	1/270 (0.4%)		2/273 (0.7%)
Gastroenteritis	0/270 (0%)		1/273 (0.4%)
Implant Site Infection	1/270 (0.4%)		0/273 (0%)
Lobar Pneumonia	1/270 (0.4%)		0/273 (0%)
Pneumonia	0/270 (0%)		5/273 (1.8%)
Pneumonia Primary Atypical	0/270 (0%)		1/273 (0.4%)
Upper Respiratory Tract Infection	0/270 (0%)		1/273 (0.4%)
Urinary Tract Infection	1/270 (0.4%)		1/273 (0.4%)
Wound Infeciton	1/270 (0.4%)		0/273 (0%)
Injury, poisoning and procedural complications
Accident at Work	1/270 (0.4%)		0/273 (0%)
Cerebrospinal Fluid Leakage	1/270 (0.4%)		0/273 (0%)
Device Malfunction	1/270 (0.4%)		0/273 (0%)
Fall	0/270 (0%)		1/273 (0.4%)
Incisional Hernia	0/270 (0%)		1/273 (0.4%)
Ligament Injury	0/270 (0%)		1/273 (0.4%)
Post Procedural Haematoma	1/270 (0.4%)		0/273 (0%)
Post Procedural Haemorrhage	1/270 (0.4%)		1/273 (0.4%)
Road Traffic Accident	0/270 (0%)		1/273 (0.4%)
Therapeutic Agent Toxicity	1/270 (0.4%)		0/273 (0%)
Investigations
Blood Creatinine Increased	0/270 (0%)		1/273 (0.4%)
Hepatitis C Antibody Positive	1/270 (0.4%)		0/273 (0%)
Metabolism and nutrition disorders
Dehydration	1/270 (0.4%)		0/273 (0%)
Diabetes Mellitus Inadequate Control	0/270 (0%)		1/273 (0.4%)
Diabetic Foot	1/270 (0.4%)		0/273 (0%)
Hyperglycaemia	1/270 (0.4%)		0/273 (0%)
Hypoclycaemia	0/270 (0%)		3/273 (1.1%)
Obesity	1/270 (0.4%)		0/273 (0%)
Synovial Cyst	0/270 (0%)		1/273 (0.4%)
Musculoskeletal and connective tissue disorders
Cervical Spinal Stenosis	1/270 (0.4%)		0/273 (0%)
Costochondritis	0/270 (0%)		1/273 (0.4%)
Flank Pain	1/270 (0.4%)		0/273 (0%)
Haemarthrosis	0/270 (0%)		1/273 (0.4%)
Localized Osteoarthritis	1/270 (0.4%)		1/273 (0.4%)
Osteoarthritis	2/270 (0.7%)		0/273 (0%)
Spinal Column Stenosis	1/270 (0.4%)		0/273 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma	0/270 (0%)		1/273 (0.4%)
Bladder Cancer	0/270 (0%)		1/273 (0.4%)
Nasal Sinus Cancer	1/270 (0.4%)		0/273 (0%)
Non-Small Cell Lung Cancer	1/270 (0.4%)		0/273 (0%)
Oesophageal Carcinoma	0/270 (0%)		1/273 (0.4%)
Renal Cell Carcinoma Stage Unspecified	1/270 (0.4%)		0/273 (0%)
Small Cell Carcinoma	0/270 (0%)		1/273 (0.4%)
Nervous system disorders
Carotid Artery Stenosis	1/270 (0.4%)		0/273 (0%)
Cerebrovascular Accident	0/270 (0%)		1/273 (0.4%)
Cerebrovascular Stenosis	0/270 (0%)		1/273 (0.4%)
Dizziness	0/270 (0%)		1/273 (0.4%)
Nystagmus	1/270 (0.4%)		0/273 (0%)
Syncope	1/270 (0.4%)		1/273 (0.4%)
Psychiatric disorders
Bipolar II Disorder	0/270 (0%)		1/273 (0.4%)
Mental Disorder	1/270 (0.4%)		0/273 (0%)
Mental Status Changes	0/270 (0%)		1/273 (0.4%)
Renal and urinary disorders
Renal Failure	0/270 (0%)		1/273 (0.4%)
Reproductive system and breast disorders
Benign Prostatic Hyperplasia	0/270 (0%)		2/273 (0.7%)
Respiratory, thoracic and mediastinal disorders
Acute Pulmonary Oedema	1/270 (0.4%)		0/273 (0%)
Astma	0/270 (0%)		2/273 (0.7%)
Chronic Obstructive Airways Disease Exacerbated	0/270 (0%)		3/273 (1.1%)
Interstitial Lung Disease	0/270 (0%)		1/273 (0.4%)
Pleural Effusion	1/270 (0.4%)		0/273 (0%)
Pulmonary Oedema	1/270 (0.4%)		0/273 (0%)
Surgical and medical procedures
Coronary Arterial Stent Insertion	1/270 (0.4%)		0/273 (0%)
Vascular disorders
Aortic Stenosis	1/270 (0.4%)		0/273 (0%)
Hypotension	1/270 (0.4%)		0/273 (0%)
Intermittent Claudication	0/270 (0%)		1/273 (0.4%)
Peripheral Vascular Disorder	1/270 (0.4%)		1/273 (0.4%)
Other (Not Including Serious) Adverse Events
	Pioglitazone QD		Glimepiride QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	226/ (NaN)		225/ (NaN)
Cardiac disorders
Angina Pectoris	12/270 (4.4%)		30/273 (11%)
Gastrointestinal disorders
Diarrhoea	11/270 (4.1%)		14/273 (5.1%)
Nausea	16/270 (5.9%)		18/273 (6.6%)
General disorders
Fatigue	17/270 (6.3%)		14/273 (5.1%)
Non-Cardiac Chest Pain	21/270 (7.8%)		27/273 (9.9%)
Oedema Peripheral	48/270 (17.8%)		30/273 (11%)
Infections and infestations
Influenza	14/270 (5.2%)		9/273 (3.3%)
Nasopharyngitis	13/270 (4.8%)		22/273 (8.1%)
Upper Respiratory Tract Infection	15/270 (5.6%)		16/273 (5.9%)
Urinary Tract Infection	17/270 (6.3%)		19/273 (7%)
Investigations
Weight Increased	28/270 (10.4%)		15/273 (5.5%)
Metabolism and nutrition disorders
Hyperglycaemia	15/270 (5.6%)		16/273 (5.9%)
Hypoglycaemia	41/270 (15.2%)		100/273 (36.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	17/270 (6.3%)		15/273 (5.5%)
Pain In Extremity	15/270 (5.6%)		19/273 (7%)
Nervous system disorders
Dizziness	26/270 (9.6%)		20/273 (7.3%)
Headache	19/270 (7%)		17/273 (6.2%)
Vascular disorders
Hypertension	13/270 (4.8%)		24/273 (8.8%)

Limitations/Caveats

Composite Endpoints A,B,C include cardiovascular mortality, nonfatal MI and nonfatal stroke. In addition, B: coronary revascularization, carotid endarterectomy/stenting, unstable angina hosp. or CHF; C: hospitalization for unstable angina or CHF.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The sponsor can review results communications prior to public release and can embargo trial results communications up to 150 days to permit actions necessary to preserve sponsor's intellectual property. Sponsor can request changes to the results communication only for the purpose of removing non study related information that is proprietary and confidential to sponsor. Sponsor can require delay of a results communication until the study has been completed at all participating sites.