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

Participant Flow

Recruitment Details

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

Pre-Assignment Details

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.

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.

Participant Flow: Overall Study

	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).

Baseline Characteristics

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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.

Baseline Measures

	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

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1. Primary:

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

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2. Secondary:

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

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3. Secondary:

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

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4. Secondary:

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

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5. Secondary:

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

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6. Other Pre-specified:

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

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Serious Adverse Events

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Other Adverse Events

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Frequency Threshold

Threshold above which other adverse events are reported	5%

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.

Other Adverse Events

	Pioglitazone QD	Glimepiride QD
Total, other (not including serious) adverse events
# participants affected	226	225
Cardiac disorders
Angina Pectoris ^†^A # participants affected / at risk	12/270 (4.44%)	30/273 (10.99%)
Gastrointestinal disorders
Diarrhoea ^†^A # participants affected / at risk	11/270 (4.07%)	14/273 (5.13%)
Nausea ^†^A # participants affected / at risk	16/270 (5.93%)	18/273 (6.59%)
General disorders
Fatigue ^†^A # participants affected / at risk	17/270 (6.30%)	14/273 (5.13%)
Non-Cardiac Chest Pain ^†^A # participants affected / at risk	21/270 (7.78%)	27/273 (9.89%)
Oedema Peripheral ^†^A # participants affected / at risk	48/270 (17.78%)	30/273 (10.99%)
Infections and infestations
Influenza ^†^A # participants affected / at risk	14/270 (5.19%)	9/273 (3.30%)
Nasopharyngitis ^†^A # participants affected / at risk	13/270 (4.81%)	22/273 (8.06%)
Upper Respiratory Tract Infection ^†^A # participants affected / at risk	15/270 (5.56%)	16/273 (5.86%)
Urinary Tract Infection ^†^A # participants affected / at risk	17/270 (6.30%)	19/273 (6.96%)
Investigations
Weight Increased ^†^A # participants affected / at risk	28/270 (10.37%)	15/273 (5.49%)
Metabolism and nutrition disorders
Hyperglycaemia ^†^A # participants affected / at risk	15/270 (5.56%)	16/273 (5.86%)
Hypoglycaemia ^†^A # participants affected / at risk	41/270 (15.19%)	100/273 (36.63%)
Musculoskeletal and connective tissue disorders
Arthralgia ^†^A # participants affected / at risk	17/270 (6.30%)	15/273 (5.49%)
Pain In Extremity ^†^A # participants affected / at risk	15/270 (5.56%)	19/273 (6.96%)
Nervous system disorders
Dizziness ^†^A # participants affected / at risk	26/270 (9.63%)	20/273 (7.33%)
Headache ^†^A # participants affected / at risk	19/270 (7.04%)	17/273 (6.23%)
Vascular disorders
Hypertension ^†^A # participants affected / at risk	13/270 (4.81%)	24/273 (8.79%)

^†	Indicates events were collected by systematic assessment.
^A	Term from vocabulary, MedDRA 7.1

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