IRIS: Insulin Resistance Intervention After Stroke Trial

• Sponsor: Yale University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00091949
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS) (NIH), Takeda Pharmaceuticals North America, Inc. (Industry)
• Enrollment: 3,876
• Locations: 183
• Arms: 2
• Duration (Months): 129
• Patients Per Site: 21.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if pioglitazone is effective in preventing future strokes or heart attacks among non-diabetic persons who have had a recent ischemic stroke.

Condition or Disease	Intervention/Treatment	Phase
Stroke; Myocardial Infarction; Diabetes	Drug: pioglitazone; Drug: placebo	Phase 3

Detailed Description

Among patients throughout the world who experience a transient ischemic attack (TIA)or ischemic stroke, subsequent stroke and heart attack are major causes of death and disability. Within 4 years of the initial TIA or ischemic stroke, 16 percent of patients will have a recurrent stroke and 9 percent will have a heart attack. Prevention of further vascular events, therefore, is critically important to the health of patients with stroke.

The IRIS trial will test a new treatment strategy based on evidence linking insulin resistance to increased risk for stroke and other vascular diseases. Insulin resistance is a condition in which insulin, a normal human hormone, does not work effectively because the body is resistant to its effects. This condition can lead to diabetes and is thought to cause blood vessel disease, including stroke and heart attack, in patients with and without diabetes.

Insulin resistance affects up to 50% of stroke patients and is effectively modified with thiazolidinedione (TZD) drugs used to treat type 2 diabetes. In addition to reducing insulin resistance, these drugs have other favorable effects on blood vessels, reduce blood vessel inflammation, and potentially prevent atherosclerosis. Currently marketed TZDs include rosiglitazone and pioglitazone.

The IRIS is a clinical trial that will enroll 3936 subjects at approximately 170 hospitals in Australia, Canada, Germany, Israel, Italy, the United Kingdom (UK) and the US. After an initial screening blood test, each participant will be randomly assigned to take either pioglitazone or placebo tablets. Recruitment will be completed during 2005-2012, and all participants will be followed for a minimum of 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3876 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Insulin Resistance Intervention After Stroke (IRIS) Trial
• Study Start Date: Feb 1, 2005
• Actual Primary Completion Date: Nov 1, 2015
• Actual Study Completion Date: Nov 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Pioglitazone pioglitazone	Drug: pioglitazone; a thiazolidinedione drug
Placebo Comparator: Placebo inactive substance	Drug: placebo; an inactive substance

Outcome Measures

Primary Outcome Measures

1. Recurrent Fatal or Non-fatal Stroke, or Fatal or Non-fatal Myocardial Infarction [Up to 5 years]

Secondary Outcome Measures

1. Fatal or Non-fatal Stroke Alone [5 years]

2. Acute Coronary Syndrome [5 years]

   Fatal or non-fatal acute myocardial infarction or unstable angina

3. Development of Overt Diabetes [5 years]

4. All Cause Mortality [5 years]

5. Decline in Cognitive Status [Annual measures from baseline to exit (up to 5 years)]

   Change in modified mental status examination (3MS) score from baseline to exit. Theoretical range of 3MS scores is 0-100. Baseline scores ranged from 22-100.

6. Composite Outcome of Fatal or Non-fatal Stroke, Fatal or Non-fatal MI or Episode of Serious Congestive Heart Failure [5 years]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

1. Ages 40 years or greater at the time of randomization.

2. Ischemic stroke or TIA no less than 14 days and no more than 6 months before randomization

3. Documentation of insulin resistance as defined by a value over 3.0 on the Homeostasis Model Assessment of insulin sensitivity (HOMA).

4. Both ability and willingness to provide informed consent.

5. Presence of none of the exclusion criteria.

Exclusion Criteria

Permanent Exclusions

1. Severely disabling stroke as indicated by an inability to participate in scheduled follow-up activities.

2. Persons whose ischemic stroke or TIA was related to structural cardiac lesion, significant head trauma, proximal arterial dissection or medical instrumentation.

3. Diabetes mellitus as defined by recent use of medication for diabetes as an out-patient (*see note below) or two fasting plasma blood sugars > 126 mg/dL.

4. HgbA1c > 7.0%.

5. Irreversible medical conditions likely to affect short-term survival or ability to participate in the study protocol. These include:

• Cancer or other chronic disease with poor prognosis (predicted survival of less than four years).

• Severe neurologic or psychiatric disease that would complicate the evaluation of study outcomes (e.g., dementia or schizophrenia).

1. History of intolerance to any thiazolidinedione.

2. Pregnancy or desire to become pregnant.

3. Oral contraceptive use.

4. Ongoing use of oral corticosteroids.

5. History of heart failure

6. Active liver disease as defined by known liver disease accompanied by cirrhosis, significant cholestasis, portal hypertension, hepatic encephalopathy, hepatic synthetic dysfunction, or expected significant loss of liver function over the course of the study.

7. History of bladder cancer.

8. Current participation in a conflicting clinical trial. A conflicting clinical trial is defined as a trial with any of following:

• Intervention that is known to affect the incidence of stroke or myocardial infarction.

• Intervention that is an experimental drug.

• Outcome that includes stroke or myocardial infarction.

• Exclusion for participation in another trial.

Temporary Exclusions Persons with temporary exclusions may be enrolled as soon as the exclusion has resolved.

1. Alanine aminotransferase (ALT) >2.5 times the upper limit of normal.

2. Hemoglobin <8.5 g/dl.

3. Moderate or severe pitting edema of the feet or legs (IRIS grade 3 or 4).

4. Carotid surgery or carotid stenting procedure scheduled (delay randomization until 2 weeks following procedure).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama	Birmingham	Alabama	United States	35294-0007
2	University of South Alabama	Mobile	Alabama	United States	36617-2293
3	University of Arizona	Tucson	Arizona	United States	85721-5023
4	Shanti Clinical Trials (NINDS-CRC site)	Colton	California	United States	92324
5	UCSF-Fresno	Fresno	California	United States	93702
6	Scripps Clinic	La Jolla	California	United States	92037
7	University of Southern California	Los Angeles	California	United States	90033
8	University of California	Los Angeles	California	United States	90095
9	Stanford University	Palo Alto	California	United States	94304
10	University of California-Davis	Sacramento	California	United States	95817
11	University of California	San Diego	California	United States	92103-8466
12	University of California	San Francisco	California	United States	94143-0114
13	Denver Health and Hospital Authority	Denver	Colorado	United States	80204-4507
14	Hartford	Hartford	Connecticut	United States	06102-5037
15	Yale University	New Haven	Connecticut	United States	06519
16	National Rehabilitation Hospital	Washington	District of Columbia	United States	20010-2949
17	University of Florida	Gainesville	Florida	United States	32610
18	University of Florida	Jacksonville	Florida	United States	32209
19	MIMA Century Research Associates	Melbourne	Florida	United States	32901
20	Pines Neurological Associates (NINDS-CRC site)	Pembroke Pines	Florida	United States	33026
21	Floria Neurovascular Institute	Tampa	Florida	United States	33606-3500
22	Cook County (Stroger) Hospital	Chicago	Illinois	United States	60612
23	Rush University	Chicago	Illinois	United States	60612
24	University of Illinois	Chicago	Illinois	United States	60612
25	Ingalls Memorial Hospital (NINDS-CRC site)	Harvey	Illinois	United States	60426
26	Loyola University Medical Center	Maywood	Illinois	United States	60153
27	OSF St. Francis Medical Center	Peoria	Illinois	United States	61637-0001
28	Tri-City Neruology (NINDS-CRC site)	Saint Charles	Illinois	United States	60175
29	Indiana Medical Research	Elkhart	Indiana	United States	46514
30	Associates In Neurology (NINDS-CRC site)	Valparaiso	Indiana	United States	46383
31	Iowa Health Des Moines Clinical Trials Office	Des Moines	Iowa	United States	50309
32	Ruan Neuroscience Center/Mercy Medical Center	Des Moines	Iowa	United States	50314
33	University of Iowa	Iowa City	Iowa	United States	52246
34	Northeast Iowa Medical Education Foundation (NINDS-CRC site)	Waterloo	Iowa	United States	50702
35	Via Christi Regional Medical Center	Wichita	Kansas	United States	67214
36	University of Kentucky Research Foundation	Lexington	Kentucky	United States	40536-0284
37	Louisiana State University Health Sciences Center	Shreveport	Louisiana	United States	71130-3932
38	Penobscot Bay Neurology	Rockport	Maine	United States	04856
39	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21209
40	Johns Hopkins	Baltimore	Maryland	United States	21287-6953
41	Massachusetts General Hospital	Boston	Massachusetts	United States	02114-2695
42	Boston University	Boston	Massachusetts	United States	02118
43	Caritas St. Elizabeth's Medical Center	Boston	Massachusetts	United States	02190
44	Beth Israel Deaconess	Boston	Massachusetts	United States	02215
45	Henry Ford Hospital	Detroit	Michigan	United States	48202
46	Michigan State University	East Lansing	Michigan	United States	48824
47	Minneapolis Clinic of Neurology	Robbinsdale	Minnesota	United States	55426
48	Hattiesburg Clinic (NINDS-CRC site)	Hattiesburg	Mississippi	United States	39401
49	St. Luke's Brain and Stroke Institute	Kansas City	Missouri	United States	64111
50	Washington University	Saint Louis	Missouri	United States	63110
51	St. John's Mercy Medical Center	Saint Louis	Missouri	United States	63141
52	St. Louis University	Saint Louis	Missouri	United States	63220
53	Billings Clinic	Billings	Montana	United States	59101
54	Advanced Neurology Specialists	Great Falls	Montana	United States	59405
55	University of Nebraska	Omaha	Nebraska	United States	68198
56	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
57	Cooper University Hospital	Camden	New Jersey	United States	08013
58	Kessler Medical Rehab Research Corp	West Orange	New Jersey	United States	07052
59	University of New Mexico	Albuquerque	New Mexico	United States	87108
60	Albany Medical Center	Albany	New York	United States	12208
61	SUNY Downstate	Brooklyn	New York	United States	11203
62	New York Methodist Hospital	Brooklyn	New York	United States	11215
63	SUNY Buffalo	Buffalo	New York	United States	14209
64	St. Vincent's Hospital Manhattan	New York	New York	United States	10011
65	Cornell University	New York	New York	United States	10021
66	University of Rochester	Rochester	New York	United States	14642
67	Southtowns Neurology of WNY (NINDS-CRC site)	West Seneca	New York	United States	14224
68	Burke Medical Research Institute	White Plains	New York	United States	10605
69	Clinical Research of Winston-Salem	Winston-Salem	North Carolina	United States	27103
70	Guilford Neurologic Associates	Winston-Salem	North Carolina	United States	27103
71	Altru Health System	Grand Forks	North Dakota	United States	58201
72	University of Cincinnati	Cincinnati	Ohio	United States	45267-0525
73	Case Western Reserve University	Cleveland	Ohio	United States	44106-4938
74	Metrohealth Medical Center	Cleveland	Ohio	United States	44109-1998
75	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
76	Ohio State University	Columbus	Ohio	United States	43210
77	University of Toledo	Toledo	Ohio	United States	43614
78	Oregon Health & Science University	Portland	Oregon	United States	97239-3098
79	Abington Memorial Hospital	Abington	Pennsylvania	United States	19001
80	Lankenau Institute for Medical Research	Bryn Mawr	Pennsylvania	United States	19010
81	Penn Stat-Hershey Medical Center (NINDS-CRC site)	Hershey	Pennsylvania	United States	17033
82	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107-5083
83	Temple University	Philadelphia	Pennsylvania	United States	19140
84	Allegheny Singer Research Institute	Pittsburgh	Pennsylvania	United States	15212
85	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213-2582
86	Rhode Island Hospital	Providence	Rhode Island	United States	02905
87	University of Tennessee	Memphis	Tennessee	United States	38163
88	Vanderbilt	Nashville	Tennessee	United States	37212
89	Baylor Research Institute	Dallas	Texas	United States	75246
90	University of Texas, Southwestern	Dallas	Texas	United States	75390-8897
91	Methodist Neurological Institute	Houston	Texas	United States	77030
92	University of Texas	San Antonio	Texas	United States	78229-3900
93	University of Utah	Salt Lake City	Utah	United States	84132
94	University of Vermont	Burlington	Vermont	United States	05405
95	University of Virginia	Charlottesville	Virginia	United States	22908
96	Sentara Medical Group	Norfolk	Virginia	United States	23507
97	University of Wisconsin	Madison	Wisconsin	United States	53792
98	Marshfield Clinic	Marshfield	Wisconsin	United States	54449
99	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226-3596
100	Flinders Medical Centre	Bedford Park	New South Wales	Australia	5042
101	Royal Prince Alfred	Camperstown	New South Wales	Australia	2050
102	John Hunter Hospital (University of Newcastle)	New Lambton Heights	New South Wales	Australia	2305
103	Box Hill Hospital (Eastern Health)	Box Hill	Victoria	Australia	3128
104	Western Hospital (University of Melbourne)	Footscray	Victoria	Australia	3011
105	Austin Health (National Stroke Research Institute)	Heidelberg Heights	Victoria	Australia	3801
106	Royal Melbourne Hospital	Parkville	Victoria	Australia	3050
107	Royal Perth	Perth	Western Australia	Australia	6000
108	University of Alberta	Edmonton	Alberta	Canada	T6G2B7
109	Center for Neurologic Research	Lethbridge	Alberta	Canada	T1J0N9
110	Vancouver Island Health Research Centre	Victoria	British Columbia	Canada	V8R4R2
111	Robarts Research Institute	London	Ontario	Canada	N6G2V2
112	Ottawa Hospital-General Campus	Ottawa	Ontario	Canada	k1Y 4E9
113	Intermountain Research Consultants	Thunder Bay	Ontario	Canada	P7B7C7
114	St. Michael's Hospital	Toronto	Ontario	Canada	M5B1W8
115	Hôpital Charles LeMoyne	Greenfield Park	Quebec	Canada	J4V 2H1
116	McGill-Montreal General	Montreal	Quebec	Canada	H3G1A4
117	McGill-Jewish General	Montreal	Quebec	Canada	H3T1E2
118	Centre Hospitalier Affilie Universitaire de Quebec	Quebec City	Quebec	Canada	G1J1Z4
119	CHUM-Centre de recherche, Hôpital Notre-Dame	Montreal		Canada	H2L4M1
120	Klinikum Altenburger Land	Altenburg		Germany	04600
121	Neurologische Klinik	Bad Neustadt		Germany	97616
122	University Hospital-Dresden	Dresden		Germany	01307
123	University Duesseldorf/Heinrich-Heine University	Duesseldorf		Germany	40225
124	University of Erlangen	Erlangen		Germany	91054
125	Alfried Krupp Hospital	Essen		Germany	45131
126	University Hospital Frankfurt	Frankfurt		Germany	60528
127	Freiburg University	Freiburg		Germany	79106
128	Ernst-Moritz-Arndt-University Greifswald	Griefswald		Germany	17475
129	Martin-Luther-Universitaet Halle-Wittenberg	Halle		Germany	06120
130	University Medical Center Hamburg-Eppendorf	Hamburg		Germany	20246
131	University Heidelberg	Heidelberg		Germany	69120
132	Friedrich Schiller-University Jena	Jena		Germany	07747
133	University Hospital Mainz	Mainz		Germany	55131
134	University Hospital Muenster	Muenster		Germany	48149
135	Klinikum der Universitat Muenchen	Munich		Germany	81377
136	University of Ulm	Ulm		Germany	89081
137	Soroka Medical Center	Beer Sheva		Israel	POB151
138	B'nai Zion Medical Center	Haifa		Israel	31048
139	Bnai-Zion Medical Center	Haifa		Israel	31048
140	Rambam Medical Center	Haifa		Israel	31096
141	Wolfson Medical Center	Holon		Israel	58100
142	Rabin Medical Center-Golda Campus	Petach Tikva		Israel	49372
143	Sheba Medical Center	Ramat Gan		Israel	52621
144	Tel Aviv Medical Center	Tel Aviv		Israel	64239
145	Genoa University Hospital	Genoa		Italy	16132
146	University of Laquila	Laquila		Italy	67100
147	University Vita Salute San Raffaele	Milan		Italy	20132
148	IRCCS FONdazione Istituto Neurologico C. Mondino	Pavia		Italy	27100
149	University of Perugia	Perugia		Italy	06100
150	University of Rome (S. Andrea Hospital)	Roma		Italy	00189
151	University of Rome La Sapienza	Rome		Italy	00161
152	Sacred Heart Catholic University	Rome		Italy	00168
153	Jazzolino Hospital	Vibo Valentia		Italy	89900
154	University of Puerto Rico	San Juan		Puerto Rico	00936
155	Royal Bournemouth	Bournemouth	Dorset	United Kingdom	BH7 7DW
156	Queen Elizabeth The Queen Mother Hospital	Margate	Kent	United Kingdom	CT9 4AN
157	Blackpool Victoria Hospital	Blackpool	Lancashire	United Kingdom	FY3 8NR
158	Wansbeck General Hospital	Ashington	Northumberland	United Kingdom	NE63 9JJ
159	Stobhill Hospital	Glasgow	Scotland	United Kingdom	G21 3UT
160	Glasgow Royal Infirmary	Glasgow	Scotland	United Kingdom	G4 0SF
161	Southern General Hospital	Glasgow	Scotland	United Kingdom	G51 4TF
162	Queen Elizabeth Hospital Gateshead	Gateshead	Tyne And Wear	United Kingdom	NE9 6SX
163	Aberdeen Royal Infirmary	Aberdeen		United Kingdom	AB25 2ZN
164	Monklands Hospital	Airdrie		United Kingdom	ML6 7UN
165	William Harvey Hospital	Ashford		United Kingdom	TN24 OLZ
166	Royal United Hospital	Bath		United Kingdom	BA1 3NG
167	Addenbrookes Foundation NHS Trust (Cambridge)	Cambridge		United Kingdom	CB2 2QQ
168	Countess of Chester Foundation Trust	Cheshire		United Kingdom	CH2 IUL
169	Dewsbury District Hospital	Dewsbury		United Kingdom	WF13 4HS
170	Southend University Hospital	Essex		United Kingdom	SS0 0RY
171	Devon PCT	Exeter		United Kingdom	EX2 5DW
172	Royal Devon and Exeter	Exeter		United Kingdom	EX2 5DW
173	Royal Surrey County Hospital	Guildford		United Kingdom	GU2 7XX
174	Calderdale Royal Hospital	Halifax		United Kingdom	HX3 0PW
175	The Royal Liverpool and Broadgreen University Hospitals	Liverpool		United Kingdom	L7 8XP
176	University Hospital Aintree	Liverpool		United Kingdom	L9 7AL
177	Kings College London	London		United Kingdom	SE5 9RS
178	Saint Georges University of London	London		United Kingdom	SW17 ORE
179	Luton and Dubstable Hospital	Luton		United Kingdom	LU4 0DZ
180	James Cook University Hospital	Middlesbrough		United Kingdom	TS4 3BW
181	Newcastle upon Tyne	Newcastle upon Tyne		United Kingdom	NE1 4LP
182	Torbay Hospital (South Devon Healthcare NHS Foundation Trust)	Torquay		United Kingdom	TQ2 7AA
183	North Tyneside General Hospital	Tyne And Wear		United Kingdom	NE29 2NH

Sponsors and Collaborators

• Yale University
• National Institute of Neurological Disorders and Stroke (NINDS)
• Takeda Pharmaceuticals North America, Inc.

Investigators

• Principal Investigator: Walter N. Kernan, M.D., Yale University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Kernan W, Viscoli C, Brass L, Amatangelo M, Birch A, Clark W, Conwit R, Furie K, Gorman M, Pesapane B, Kleindorfer D, Lovejoy A, Osborne J, Silliman S, Zweifler R, Horwitz R. Boosting enrolment in clinical trials: validation of a regional network model. Clin Trials. 2011 Oct;8(5):645-53. doi: 10.1177/1740774511414925. Epub 2011 Aug 8.
• Kernan WN, Viscoli CM, Demarco D, Mendes B, Shrauger K, Schindler JL, McVeety JC, Sicklick A, Moalli D, Greco P, Bravata DM, Eisen S, Resor L, Sena K, Story D, Brass LM, Furie KL, Gutmann L, Hinnau E, Gorman M, Lovejoy AM, Inzucchi SE, Young LH, Horwitz RI; IRIS Trial Investigators. Boosting enrollment in neurology trials with Local Identification and Outreach Networks (LIONs). Neurology. 2009 Apr 14;72(15):1345-51. doi: 10.1212/WNL.0b013e3181a0fda3.
• Viscoli CM, Brass LM, Carolei A, Conwit R, Ford GA, Furie KL, Gorman M, Guarino PD, Inzucchi SE, Lovejoy AM, Parsons MW, Peduzzi PN, Ringleb PA, Schwartz GG, Spence JD, Tanne D, Young LH, Kernan WN; IRIS Trial investigators. Pioglitazone for secondary prevention after ischemic stroke and transient ischemic attack: rationale and design of the Insulin Resistance Intervention after Stroke Trial. Am Heart J. 2014 Dec;168(6):823-9.e6. doi: 10.1016/j.ahj.2014.07.016. Epub 2014 Jul 28.

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT00091949
• Other Study ID Numbers: 0201013034; 5U01NS044876-10
• First Posted: Sep 22, 2004
• Last Update Posted: Apr 27, 2020
• Last Verified: Sep 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Yale University: stroke; heart attack; diabetes; pioglitazone; insulin resistance
• Additional relevant MeSH terms: Stroke; Myocardial Infarction; Insulin Resistance; Infarction; Pioglitazone

Study Results

Participant Flow

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	pioglitazone: a thiazolidinedione drug	placebo: an inactive substance
Period Title: Overall Study
STARTED	1939	1937
COMPLETED	1764	1786
NOT COMPLETED	175	151

Baseline Characteristics

Arm/Group Title	Pioglitazone	Placebo	Total
Arm/Group Description	pioglitazone: a thiazolidinedione drug	placebo: an inactive substance	Total of all reporting groups
Overall Participants	1939	1937	3876
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	63.5 (10.7)	63.5 (10.6)	63.5 (10.7)
Sex: Female, Male (Count of Participants)
Female	646 33.3%	692 35.7%	1338 34.5%
Male	1293 66.7%	1245 64.3%	2538 65.5%
Region of Enrollment (participants) [Number]
Canada	272 14%	271 14%	543 14%
Puerto Rico	9 0.5%	11 0.6%	20 0.5%
United States	1296 66.8%	1276 65.9%	2572 66.4%
United Kingdom	123 6.3%	133 6.9%	256 6.6%
Italy	22 1.1%	26 1.3%	48 1.2%
Israel	90 4.6%	88 4.5%	178 4.6%
Australia	53 2.7%	55 2.8%	108 2.8%
Germany	74 3.8%	77 4%	151 3.9%

Outcome Measures

1. Primary Outcome

Title	Recurrent Fatal or Non-fatal Stroke, or Fatal or Non-fatal Myocardial Infarction
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	pioglitazone: a thiazolidinedione drug	placebo: an inactive substance
Measure Participants	1939	1937
Number [participants]	175 9%	228 11.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	.0067
	Comments	P-value adjusted for interim looks.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.62 to 0.93
	Parameter Dispersion	Type: Value:
	Estimation Comments	Pioglitazone arm compared to placebo; CI adjusted for interim looks.

2. Secondary Outcome

Title	Fatal or Non-fatal Stroke Alone
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	pioglitazone: a thiazolidinedione drug	placebo: an inactive substance
Measure Participants	1939	1937
Number [participants]	127 6.5%	154 8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.19
	Comments	P-value adjusted for multiplicity (5 secondary outcomes).
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.61 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Pioglitazone arm compared to placebo; conference interval (CI) adjusted for multiplicity (5 secondary outcomes).

3. Secondary Outcome

Title	Acute Coronary Syndrome
Description	Fatal or non-fatal acute myocardial infarction or unstable angina
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	pioglitazone: a thiazolidinedione drug	placebo: an inactive substance
Measure Participants	1939	1937
Number [participants]	206 10.6%	249 12.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments	P-value adjusted for multiplicity (5 secondary outcomes).
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.52 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	Pioglitazone arm compared to placebo; CI adjusted for multiplicity (5 secondary outcomes).

4. Secondary Outcome

Title	Development of Overt Diabetes
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	pioglitazone: a thiazolidinedione drug	placebo: an inactive substance
Measure Participants	1939	1937
Number [participants]	73 3.8%	149 7.7%

5. Secondary Outcome

Title	All Cause Mortality
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	pioglitazone: a thiazolidinedione drug	placebo: an inactive substance
Measure Participants	1939	1937
Number [participants]	136 7%	146 7.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.52
	Comments	p-value adjusted for multiplicity (5 secondary outcomes)
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.73 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	Pioglitazone arm compared to placebo; CI adjusted for multiplicity (5 secondary outcomes).

6. Secondary Outcome

Title	Decline in Cognitive Status
Description	Change in modified mental status examination (3MS) score from baseline to exit. Theoretical range of 3MS scores is 0-100. Baseline scores ranged from 22-100.
Time Frame	Annual measures from baseline to exit (up to 5 years)

Outcome Measure Data

Analysis Population Description

Participants with baseline and at least 1 follow-up modified mini-mental examination score.

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	pioglitazone: a thiazolidinedione drug	placebo: an inactive substance
Measure Participants	1699	1699
Mean (Standard Error) [units on a scale]	0.27 (0.13)	0.29 (0.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone, Placebo
	Comments	Changes in modified mini-mental examination (3MS) score from baseline (to annual scores) were analyzed using a longitudinal repeated measures mixed effects model.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.88
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.023
	Confidence Interval	(2-Sided) 95%; -0.326 to 0.280
	Parameter Dispersion	Type: Value:
	Estimation Comments	Pioglitazone arm compared to placebo.

7. Secondary Outcome

Title	Composite Outcome of Fatal or Non-fatal Stroke, Fatal or Non-fatal MI or Episode of Serious Congestive Heart Failure
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	pioglitazone: a thiazolidinedione drug	placebo: an inactive substance
Measure Participants	1939	1937
Number [participants]	206 10.6%	249 12.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments	P-value adjusted for multiplicity (5 secondary outcomes).
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.65 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments	Pioglitazone arm compared to placebo; CI adjusted for multiplicity (5 secondary outcomes).

Adverse Events

Time Frame	Adverse event data collected during followup (2 to 5 years).
Arm/Group Title	Pioglitazone		Placebo
Arm/Group Description	pioglitazone: a thiazolidinedione drug		placebo: an inactive substance
All Cause Mortality
	Pioglitazone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Pioglitazone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	950/1939 (49%)		987/1937 (51%)
Cardiac disorders
Heart failure	51/1939 (2.6%)	61	42/1937 (2.2%)	55
General disorders
Hospitalization	908/1939 (46.8%)	1844	946/1937 (48.8%)	2023
Cancer	133/1939 (6.9%)	144	150/1937 (7.7%)	163
Bone fracture	99/1939 (5.1%)	178	62/1937 (3.2%)	99
Other (Not Including Serious) Adverse Events
	Pioglitazone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1007/1939 (51.9%)		724/1937 (37.4%)
General disorders
Bone fracture	133/1939 (6.9%)	198	94/1937 (4.9%)	126
Excessive weight gain	221/1939 (11.4%)	892	88/1937 (4.5%)	305
Edema	691/1939 (35.6%)	1093	483/1937 (24.9%)	731
Shortness of breath	342/1939 (17.6%)	444	292/1937 (15.1%)	379

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.