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

Study Type:	Interventional
Study Design:	Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Parallel Assignment
Condition:	Diabetes Mellitus
Interventions:	Drug: Pioglitazone Drug: Glimepiride

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Subjects were enrolled at 97 sites in the United States, Canada, Argentina and Chile from 21 July 2003 to 18 October 2007.

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

	Pioglitazone QD	Glimepiride QD
STARTED	274^[1]	273^[2]
COMPLETED	177	178
NOT COMPLETED	97	95
Adverse Event	30	34
Lack of Efficacy	4	1
Lost to Follow-up	4	6
Physician Decision	6	8
Protocol Violation	6	3
Withdrawal by Subject	40	34
Other	7	9

[1]	274 subjects randomized, but four subjects did not receive drug.
[2]	Mean treatment durations were 56.3 weeks (glimepiride) and 56.5 weeks (pioglitazone).

	Pioglitazone QD	Glimepiride QD	Total
Number of Participants [units: participants]	270	273	543
Age [units: participants]
<=18 years	0	0	0
Between 18 and 65 years	189	193	382
>=65 years	81	80	161
Gender [units: participants]
Female	84	93	177
Male	186	180	366
Ethnicity (NIH/OMB) [units: Participants]
Hispanic or Latino	63	71	134
Not Hispanic or Latino	207	202	409
Unknown or Not Reported	0	0	0
Race/Ethnicity, Customized [units: participants]
Native American	3	10	13
Asian	12	16	28
Black or African American	30	27	57
White	225	220	445
Family History of Coronary Artery Disease^[1] [units: Participants]
Male Relative History	91	77	168
Female Relative History	60	59	119
No Family History	119	137	256
Body Mass Index^[2] [units: Kg/m squared] Mean ( Full Range )	32.08 ( 21.1 to 49.3 )	32.03 ( 19.7 to 47.9 )	32.05 ( 19.7 to 49.3 )
Duration of Coronary Artery Disease^[3] [units: Months] Mean ( Full Range )	40.4 ( 0 to 378 )	40.5 ( 0 to 468 )	40.4 ( 0 to 468 )
Duration of Diabetes Mellitus^[4] [units: Months] Mean ( Full Range )	98.0 ( 0 to 624 )	96.3 ( 0 to 556 )	97.1 ( 0 to 624 )

[1]	Was first degree male or female relative diagnosed with Coronary Artery Disease at age < 55 years or < 65 years, respectively?
[2]	The mean for total was calculated as the weighted average of the means of the two treatment arms.
[3]	The mean for total was calculated as the weighted average of the means of the two treatment arms.
[4]	The mean for total was calculated as the weighted average of the means of the two treatment arms.

Outcome Measures

1. Primary:

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

Measure Type	Primary
Measure Title	Nominal Change From Baseline in Percent Atheroma Volume
Measure 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)
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Pioglitazone QD	Subjects received up to 45 mg Pioglitazone (dose optimized for glucose control) for up to 72 weeks.
Glimepiride QD	Subjects received up to 4 mg Glimepiride (dose optimized for glucose control) for up to 72 weeks.

Measured Values

	Pioglitazone QD	Glimepiride QD
Number of Participants Analyzed [units: participants]	179	181
Nominal Change From Baseline in Percent Atheroma Volume [units: Percent volume] Least Squares Mean ± Standard Error
Baseline	40.592 ± 0.6925	40.016 ± 0.6663
Nominal Change from Baseline	-0.161 ± 0.2095	0.725 ± 0.2017

Statistical Analysis 1 for Nominal Change From Baseline in Percent Atheroma Volume

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.002
Mean Difference (Final Values) ^[4]	-0.886
95% Confidence Interval	( -1.4480 to -0.3250 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[4]	Other relevant estimation information:
	Mean Difference = Pioglitazone - Glimepiride

2. Secondary:

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

Measure Type	Secondary
Measure Title	Nominal Change From Baseline in Normalized Total Atheroma Volume
Measure 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)
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Pioglitazone QD	Subjects received up to 45 mg Pioglitazone (dose optimized for glucose control) for up to 72 weeks.
Glimepiride QD	Subjects received up to 4 mg Glimepiride (dose optimized for glucose control) for up to 72 weeks.

Measured Values

	Pioglitazone QD	Glimepiride QD
Number of Participants Analyzed [units: participants]	179	181
Nominal Change From Baseline in Normalized Total Atheroma Volume [units: Percent volume] Least Squares Mean ± Standard Error
Baseline	206.579 ± 7.2778	217.619 ± 7.0030
Nominal Change from Baseline	-5.528 ± 1.5989	-1.480 ± 1.5370

Statistical Analysis 1 for Nominal Change From Baseline in Normalized Total Atheroma Volume

Groups ^[1]	All groups
Method ^[2]	ANCOVA
P Value ^[3]	0.064
Mean Difference (Final Values) ^[4]	-4.048
95% Confidence Interval	( -8.3336 to 0.2374 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	2 Way ANCOVA, treatment and center effects with baseline value as covariate. LS mean of the treatment difference reported.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[4]	Other relevant estimation information:
	Mean Difference = Pioglitazone - Glimepiride

3. Secondary:

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

Measure Type	Secondary
Measure Title	Number of Subjects Experiencing Any of the Composite Endpoint A Cardiovascular Events
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Pioglitazone QD	Subjects received up to 45 mg Pioglitazone (dose optimized for glucose control) for up to 72 weeks.
Glimepiride QD	Subjects received up to 4 mg Glimepiride (dose optimized for glucose control) for up to 72 weeks.

Measured Values

	Pioglitazone QD	Glimepiride QD
Number of Participants Analyzed [units: participants]	270	273
Number of Subjects Experiencing Any of the Composite Endpoint A Cardiovascular Events [units: Participants]	5	6

Statistical Analysis 1 for Number of Subjects Experiencing Any of the Composite Endpoint A Cardiovascular Events

Groups ^[1]	All groups
Method ^[2]	Log Rank
P Value ^[3]	0.744

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	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.

4. Secondary:

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

Measure Type	Secondary
Measure Title	Number of Subjects Experiencing Any of the Composite Endpoint B Cardiovascular Events
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Pioglitazone QD	Subjects received up to 45 mg Pioglitazone (dose optimized for glucose control) for up to 72 weeks.
Glimepiride QD	Subjects received up to 4 mg Glimepiride (dose optimized for glucose control) for up to 72 weeks.

Measured Values

	Pioglitazone QD	Glimepiride QD
Number of Participants Analyzed [units: participants]	270	273
Number of Subjects Experiencing Any of the Composite Endpoint B Cardiovascular Events [units: Participants]	40	41

Statistical Analysis 1 for Number of Subjects Experiencing Any of the Composite Endpoint B Cardiovascular Events

Groups ^[1]	All groups
Method ^[2]	Log Rank
P Value ^[3]	0.883

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	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.

5. Secondary:

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

Measure Type	Secondary
Measure Title	Number of Subjects Experiencing Any of the Composite Endpoint C Cardiovascular Events
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Pioglitazone QD	Subjects received up to 45 mg Pioglitazone (dose optimized for glucose control) for up to 72 weeks.
Glimepiride QD	Subjects received up to 4 mg Glimepiride (dose optimized for glucose control) for up to 72 weeks.

Measured Values

	Pioglitazone QD	Glimepiride QD
Number of Participants Analyzed [units: participants]	270	273
Number of Subjects Experiencing Any of the Composite Endpoint C Cardiovascular Events [units: participants]	11	13

Statistical Analysis 1 for Number of Subjects Experiencing Any of the Composite Endpoint C Cardiovascular Events

Groups ^[1]	All groups
Method ^[2]	Log Rank
P Value ^[3]	0.663

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	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.

6. Other Pre-specified:

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

Measure Type	Other Pre-specified
Measure Title	Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee
Measure 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
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Population

Reporting Groups

	Description
Pioglitazone QD	Subjects received up to 45 mg Pioglitazone (dose optimized for glucose control) for up to 72 weeks.
Glimepiride QD	Subjects received up to 4 mg Glimepiride (dose optimized for glucose control) for up to 72 weeks.

Measured Values

	Pioglitazone QD	Glimepiride QD
Number of Participants Analyzed [units: participants]	270	273
Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee [units: Number of Events]
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

No statistical analysis provided for Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee

More Information

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Certain Agreements:

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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.

Results Point of Contact:

Name/Title: Sr. VP Clinical Sciences
Organization: Takeda Global Research and Development Center Inc.
phone: 800-778-2860
e-mail: clinicaltrialregistry@tpna.com

Publications of Results:

Nissen SE, Nicholls SJ, Wolski K, Nesto R, Kupfer S, Perez A, Jure H, De Larochellière R, Staniloae CS, Mavromatis K, Saw J, Hu B, Lincoff AM, Tuzcu EM; PERISCOPE Investigators. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA. 2008 Apr 2;299(13):1561-73. Epub 2008 Mar 31.

Responsible Party:	Takeda Global Research & Development Center, Inc. ( Sr. VP, Clinical Science )
Study ID Numbers:	01-01-TL-OPI-516
Study First Received:	September 21, 2005
Results First Received:	October 17, 2008
Last Updated:	September 23, 2009
ClinicalTrials.gov Identifier:	NCT00225277 History of Changes
Health Authority:	United States: Food and Drug Administration; Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica; Canada: Health Canada; Chile: Instituto de Salud Publica de Chile