Insulin Resistance Intervention After Stroke Trial

Stroke Clinical Trial

— IRIS  

Official title:

Insulin Resistance Intervention After Stroke (IRIS) Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00091949
• Other study ID #: 0201013034
• Secondary ID: 5U01NS044876-10
• Status: Completed
• Phase: Phase 3
• Start date: February 2005
• Est. completion date: November 2015

Study information

• Verified date: September 2016
• Source: Yale University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3876
• Est. completion date: November 2015
• Est. primary completion date: November 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

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).

6. History of intolerance to any thiazolidinedione.

7. Pregnancy or desire to become pregnant.

8. Oral contraceptive use.

9. Ongoing use of oral corticosteroids.

10. History of heart failure

11. 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.

12. History of bladder cancer.

13. 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).

Related Conditions & MeSH terms

• Diabetes
• Infarction
• Insulin Resistance
• Myocardial Infarction
• Stroke

Intervention

Drug:
• pioglitazone
a thiazolidinedione drug
• placebo
an inactive substance

Locations

Country	Name	City	State
Australia	Flinders Medical Centre	Bedford Park	New South Wales
Australia	Box Hill Hospital (Eastern Health)	Box Hill	Victoria
Australia	Royal Prince Alfred	Camperstown	New South Wales
Australia	Western Hospital (University of Melbourne)	Footscray	Victoria
Australia	Austin Health (National Stroke Research Institute)	Heidelberg Heights	Victoria
Australia	John Hunter Hospital (University of Newcastle)	New Lambton Heights	New South Wales
Australia	Royal Melbourne Hospital	Parkville	Victoria
Australia	Royal Perth	Perth	Western Australia
Canada	University of Alberta	Edmonton	Alberta
Canada	Hôpital Charles LeMoyne	Greenfield Park	Quebec
Canada	Center for Neurologic Research	Lethbridge	Alberta
Canada	Robarts Research Institute	London	Ontario
Canada	CHUM-Centre de recherche, Hôpital Notre-Dame	Montreal
Canada	McGill-Jewish General	Montreal	Quebec
Canada	McGill-Montreal General	Montreal	Quebec
Canada	Ottawa Hospital-General Campus	Ottawa	Ontario
Canada	Centre Hospitalier Affilie Universitaire de Quebec	Quebec City	Quebec
Canada	Intermountain Research Consultants	Thunder Bay	Ontario
Canada	St. Michael's Hospital	Toronto	Ontario
Canada	Vancouver Island Health Research Centre	Victoria	British Columbia
Germany	Klinikum Altenburger Land	Altenburg
Germany	Neurologische Klinik	Bad Neustadt
Germany	University Hospital-Dresden	Dresden
Germany	University Duesseldorf/Heinrich-Heine University	Duesseldorf
Germany	University of Erlangen	Erlangen
Germany	Alfried Krupp Hospital	Essen
Germany	University Hospital Frankfurt	Frankfurt
Germany	Freiburg University	Freiburg
Germany	Ernst-Moritz-Arndt-University Greifswald	Griefswald
Germany	Martin-Luther-Universitaet Halle-Wittenberg	Halle
Germany	University Medical Center Hamburg-Eppendorf	Hamburg
Germany	University Heidelberg	Heidelberg
Germany	Friedrich Schiller-University Jena	Jena
Germany	University Hospital Mainz	Mainz
Germany	University Hospital Muenster	Muenster
Germany	Klinikum der Universitat Muenchen	Munich
Germany	University of Ulm	Ulm
Israel	Soroka Medical Center	Beer Sheva
Israel	B'nai Zion Medical Center	Haifa
Israel	Bnai-Zion Medical Center	Haifa
Israel	Rambam Medical Center	Haifa
Israel	Wolfson Medical Center	Holon
Israel	Rabin Medical Center-Golda Campus	Petach Tikva
Israel	Sheba Medical Center	Ramat Gan
Israel	Tel Aviv Medical Center	Tel Aviv
Italy	Genoa University Hospital	Genoa
Italy	University of Laquila	Laquila
Italy	University Vita Salute San Raffaele	Milan
Italy	IRCCS FONdazione Istituto Neurologico C. Mondino	Pavia
Italy	University of Perugia	Perugia
Italy	University of Rome (S. Andrea Hospital)	Roma
Italy	Sacred Heart Catholic University	Rome
Italy	University of Rome La Sapienza	Rome
Italy	Jazzolino Hospital	Vibo Valentia
Puerto Rico	University of Puerto Rico	San Juan
United Kingdom	Aberdeen Royal Infirmary	Aberdeen
United Kingdom	Monklands Hospital	Airdrie
United Kingdom	William Harvey Hospital	Ashford
United Kingdom	Wansbeck General Hospital	Ashington	Northumberland
United Kingdom	Royal United Hospital	Bath
United Kingdom	Blackpool Victoria Hospital	Blackpool	Lancashire
United Kingdom	Royal Bournemouth	Bournemouth	Dorset
United Kingdom	Addenbrookes Foundation NHS Trust (Cambridge)	Cambridge
United Kingdom	Countess of Chester Foundation Trust	Cheshire
United Kingdom	Dewsbury District Hospital	Dewsbury
United Kingdom	Southend University Hospital	Essex
United Kingdom	Devon PCT	Exeter
United Kingdom	Royal Devon and Exeter	Exeter
United Kingdom	Queen Elizabeth Hospital Gateshead	Gateshead	Tyne And Wear
United Kingdom	Glasgow Royal Infirmary	Glasgow	Scotland
United Kingdom	Southern General Hospital	Glasgow	Scotland
United Kingdom	Stobhill Hospital	Glasgow	Scotland
United Kingdom	Royal Surrey County Hospital	Guildford
United Kingdom	Calderdale Royal Hospital	Halifax
United Kingdom	The Royal Liverpool and Broadgreen University Hospitals	Liverpool
United Kingdom	University Hospital Aintree	Liverpool
United Kingdom	Kings College London	London
United Kingdom	Saint Georges University of London	London
United Kingdom	Luton and Dubstable Hospital	Luton
United Kingdom	Queen Elizabeth The Queen Mother Hospital	Margate	Kent
United Kingdom	James Cook University Hospital	Middlesbrough
United Kingdom	Newcastle upon Tyne	Newcastle upon Tyne
United Kingdom	Torbay Hospital (South Devon Healthcare NHS Foundation Trust)	Torquay
United Kingdom	North Tyneside General Hospital	Tyne And Wear
United States	Abington Memorial Hospital	Abington	Pennsylvania
United States	Albany Medical Center	Albany	New York
United States	University of New Mexico	Albuquerque	New Mexico
United States	Johns Hopkins	Baltimore	Maryland
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	Billings Clinic	Billings	Montana
United States	University of Alabama	Birmingham	Alabama
United States	Beth Israel Deaconess	Boston	Massachusetts
United States	Boston University	Boston	Massachusetts
United States	Caritas St. Elizabeth's Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	New York Methodist Hospital	Brooklyn	New York
United States	SUNY Downstate	Brooklyn	New York
United States	Lankenau Institute for Medical Research	Bryn Mawr	Pennsylvania
United States	SUNY Buffalo	Buffalo	New York
United States	University of Vermont	Burlington	Vermont
United States	Cooper University Hospital	Camden	New Jersey
United States	University of Virginia	Charlottesville	Virginia
United States	Cook County (Stroger) Hospital	Chicago	Illinois
United States	Rush University	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	University of Cincinnati	Cincinnati	Ohio
United States	Case Western Reserve University	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Metrohealth Medical Center	Cleveland	Ohio
United States	Shanti Clinical Trials (NINDS-CRC site)	Colton	California
United States	Ohio State University	Columbus	Ohio
United States	Baylor Research Institute	Dallas	Texas
United States	University of Texas, Southwestern	Dallas	Texas
United States	Denver Health and Hospital Authority	Denver	Colorado
United States	Iowa Health Des Moines Clinical Trials Office	Des Moines	Iowa
United States	Ruan Neuroscience Center/Mercy Medical Center	Des Moines	Iowa
United States	Henry Ford Hospital	Detroit	Michigan
United States	Michigan State University	East Lansing	Michigan
United States	Indiana Medical Research	Elkhart	Indiana
United States	UCSF-Fresno	Fresno	California
United States	University of Florida	Gainesville	Florida
United States	Altru Health System	Grand Forks	North Dakota
United States	Advanced Neurology Specialists	Great Falls	Montana
United States	Hartford	Hartford	Connecticut
United States	Ingalls Memorial Hospital (NINDS-CRC site)	Harvey	Illinois
United States	Hattiesburg Clinic (NINDS-CRC site)	Hattiesburg	Mississippi
United States	Penn Stat-Hershey Medical Center (NINDS-CRC site)	Hershey	Pennsylvania
United States	Methodist Neurological Institute	Houston	Texas
United States	University of Iowa	Iowa City	Iowa
United States	University of Florida	Jacksonville	Florida
United States	St. Luke's Brain and Stroke Institute	Kansas City	Missouri
United States	Scripps Clinic	La Jolla	California
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	University of Kentucky Research Foundation	Lexington	Kentucky
United States	University of California	Los Angeles	California
United States	University of Southern California	Los Angeles	California
United States	University of Wisconsin	Madison	Wisconsin
United States	Marshfield Clinic	Marshfield	Wisconsin
United States	Loyola University Medical Center	Maywood	Illinois
United States	MIMA Century Research Associates	Melbourne	Florida
United States	University of Tennessee	Memphis	Tennessee
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	University of South Alabama	Mobile	Alabama
United States	Vanderbilt	Nashville	Tennessee
United States	Yale University	New Haven	Connecticut
United States	Cornell University	New York	New York
United States	St. Vincent's Hospital Manhattan	New York	New York
United States	Sentara Medical Group	Norfolk	Virginia
United States	University of Nebraska	Omaha	Nebraska
United States	Stanford University	Palo Alto	California
United States	Pines Neurological Associates (NINDS-CRC site)	Pembroke Pines	Florida
United States	OSF St. Francis Medical Center	Peoria	Illinois
United States	Temple University	Philadelphia	Pennsylvania
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	Allegheny Singer Research Institute	Pittsburgh	Pennsylvania
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Minneapolis Clinic of Neurology	Robbinsdale	Minnesota
United States	University of Rochester	Rochester	New York
United States	Penobscot Bay Neurology	Rockport	Maine
United States	University of California-Davis	Sacramento	California
United States	Tri-City Neruology (NINDS-CRC site)	Saint Charles	Illinois
United States	St. John's Mercy Medical Center	Saint Louis	Missouri
United States	St. Louis University	Saint Louis	Missouri
United States	Washington University	Saint Louis	Missouri
United States	University of Utah	Salt Lake City	Utah
United States	University of Texas	San Antonio	Texas
United States	University of California	San Diego	California
United States	University of California	San Francisco	California
United States	Louisiana State University Health Sciences Center	Shreveport	Louisiana
United States	Floria Neurovascular Institute	Tampa	Florida
United States	University of Toledo	Toledo	Ohio
United States	University of Arizona	Tucson	Arizona
United States	Associates In Neurology (NINDS-CRC site)	Valparaiso	Indiana
United States	National Rehabilitation Hospital	Washington	District of Columbia
United States	Northeast Iowa Medical Education Foundation (NINDS-CRC site)	Waterloo	Iowa
United States	Kessler Medical Rehab Research Corp	West Orange	New Jersey
United States	Southtowns Neurology of WNY (NINDS-CRC site)	West Seneca	New York
United States	Burke Medical Research Institute	White Plains	New York
United States	Via Christi Regional Medical Center	Wichita	Kansas
United States	Clinical Research of Winston-Salem	Winston-Salem	North Carolina
United States	Guilford Neurologic Associates	Winston-Salem	North Carolina

Sponsors (3)

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

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Germany,  Israel,  Italy,  Puerto Rico,  United Kingdom, 

References & Publications (3)

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Recurrent Fatal or Non-fatal Stroke, or Fatal or Non-fatal Myocardial Infarction		Up to 5 years
Secondary	Fatal or Non-fatal Stroke Alone		5 years
Secondary	Acute Coronary Syndrome	Fatal or non-fatal acute myocardial infarction or unstable angina	5 years
Secondary	Development of Overt Diabetes		5 years
Secondary	All Cause Mortality		5 years
Secondary	Decline in Cognitive Status	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.	Annual measures from baseline to exit (up to 5 years)
Secondary	Composite Outcome of Fatal or Non-fatal Stroke, Fatal or Non-fatal MI or Episode of Serious Congestive Heart Failure		5 years