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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT00091949




Registration number
NCT00091949
Ethics application status
Date submitted
20/09/2004
Date registered
22/09/2004
Date last updated
27/04/2020

Titles & IDs
Public title
Insulin Resistance Intervention After Stroke Trial
Scientific title
Insulin Resistance Intervention After Stroke (IRIS) Trial
Secondary ID [1] 0 0
5U01NS044876-10
Secondary ID [2] 0 0
0201013034
Universal Trial Number (UTN)
Trial acronym
IRIS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Stroke 0 0
Myocardial Infarction 0 0
Diabetes 0 0
Condition category
Condition code
Stroke 0 0 0 0
Haemorrhagic
Stroke 0 0 0 0
Ischaemic
Cardiovascular 0 0 0 0
Coronary heart disease
Cardiovascular 0 0 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - pioglitazone
Treatment: Drugs - placebo

Active comparator: Pioglitazone - pioglitazone

Placebo comparator: Placebo - inactive substance


Treatment: Drugs: pioglitazone
a thiazolidinedione drug

Treatment: Drugs: placebo
an inactive substance
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Recurrent Fatal or Non-fatal Stroke, or Fatal or Non-fatal Myocardial Infarction
Timepoint [1] 0 0
Up to 5 years
Secondary outcome [1] 0 0
Fatal or Non-fatal Stroke Alone
Timepoint [1] 0 0
5 years
Secondary outcome [2] 0 0
Acute Coronary Syndrome
Timepoint [2] 0 0
5 years
Secondary outcome [3] 0 0
Development of Overt Diabetes
Timepoint [3] 0 0
5 years
Secondary outcome [4] 0 0
All Cause Mortality
Timepoint [4] 0 0
5 years
Secondary outcome [5] 0 0
Decline in Cognitive Status
Timepoint [5] 0 0
Annual measures from baseline to exit (up to 5 years)
Secondary outcome [6] 0 0
Composite Outcome of Fatal or Non-fatal Stroke, Fatal or Non-fatal MI or Episode of Serious Congestive Heart Failure
Timepoint [6] 0 0
5 years

Eligibility
Key inclusion criteria
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.
Minimum age
40 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/02/2005
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/11/2015
Sample size
Target
Accrual to date
Final
3876
Recruitment in Australia
Recruitment state(s)
NSW,VIC,WA
Recruitment hospital [1] 0 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [2] 0 0
Royal Prince Alfred - Camperstown
Recruitment hospital [3] 0 0
John Hunter Hospital (University of Newcastle) - New Lambton Heights
Recruitment hospital [4] 0 0
Box Hill Hospital (Eastern Health) - Box Hill
Recruitment hospital [5] 0 0
Western Hospital (University of Melbourne) - Footscray
Recruitment hospital [6] 0 0
Austin Health (National Stroke Research Institute) - Heidelberg Heights
Recruitment hospital [7] 0 0
Royal Melbourne Hospital - Parkville
Recruitment hospital [8] 0 0
Royal Perth - Perth
Recruitment postcode(s) [1] 0 0
5042 - Bedford Park
Recruitment postcode(s) [2] 0 0
2050 - Camperstown
Recruitment postcode(s) [3] 0 0
2305 - New Lambton Heights
Recruitment postcode(s) [4] 0 0
3128 - Box Hill
Recruitment postcode(s) [5] 0 0
3011 - Footscray
Recruitment postcode(s) [6] 0 0
3801 - Heidelberg Heights
Recruitment postcode(s) [7] 0 0
3050 - Parkville
Recruitment postcode(s) [8] 0 0
6000 - Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
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United States of America
State/province [2] 0 0
Arizona
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United States of America
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California
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Colorado
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Connecticut
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United States of America
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District of Columbia
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United States of America
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Florida
Country [8] 0 0
United States of America
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Illinois
Country [9] 0 0
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Indiana
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Iowa
Country [11] 0 0
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Kansas
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Kentucky
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Louisiana
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Maine
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Maryland
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Massachusetts
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Michigan
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Minnesota
Country [19] 0 0
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Mississippi
Country [20] 0 0
United States of America
State/province [20] 0 0
Missouri
Country [21] 0 0
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Montana
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Nebraska
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New Hampshire
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New Jersey
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New Mexico
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New York
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North Carolina
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North Dakota
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Ohio
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Oregon
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Pennsylvania
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Rhode Island
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Tennessee
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Texas
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Utah
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Vermont
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State/province [37] 0 0
Virginia
Country [38] 0 0
United States of America
State/province [38] 0 0
Wisconsin
Country [39] 0 0
Canada
State/province [39] 0 0
Alberta
Country [40] 0 0
Canada
State/province [40] 0 0
British Columbia
Country [41] 0 0
Canada
State/province [41] 0 0
Ontario
Country [42] 0 0
Canada
State/province [42] 0 0
Quebec
Country [43] 0 0
Canada
State/province [43] 0 0
Montreal
Country [44] 0 0
Germany
State/province [44] 0 0
Altenburg
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Germany
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Bad Neustadt
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Germany
State/province [46] 0 0
Dresden
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Germany
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Duesseldorf
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Germany
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Erlangen
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Germany
State/province [49] 0 0
Essen
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Germany
State/province [50] 0 0
Frankfurt
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Germany
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Freiburg
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Germany
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Griefswald
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Germany
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Halle
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Germany
State/province [54] 0 0
Hamburg
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Germany
State/province [55] 0 0
Heidelberg
Country [56] 0 0
Germany
State/province [56] 0 0
Jena
Country [57] 0 0
Germany
State/province [57] 0 0
Mainz
Country [58] 0 0
Germany
State/province [58] 0 0
Muenster
Country [59] 0 0
Germany
State/province [59] 0 0
Munich
Country [60] 0 0
Germany
State/province [60] 0 0
Ulm
Country [61] 0 0
Israel
State/province [61] 0 0
Beer Sheva
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Israel
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Haifa
Country [63] 0 0
Israel
State/province [63] 0 0
Holon
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Israel
State/province [64] 0 0
Petach Tikva
Country [65] 0 0
Israel
State/province [65] 0 0
Ramat Gan
Country [66] 0 0
Israel
State/province [66] 0 0
Tel Aviv
Country [67] 0 0
Italy
State/province [67] 0 0
Genoa
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Italy
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Laquila
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Italy
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Milan
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Italy
State/province [70] 0 0
Pavia
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Italy
State/province [71] 0 0
Perugia
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Italy
State/province [72] 0 0
Roma
Country [73] 0 0
Italy
State/province [73] 0 0
Rome
Country [74] 0 0
Italy
State/province [74] 0 0
Vibo Valentia
Country [75] 0 0
Puerto Rico
State/province [75] 0 0
San Juan
Country [76] 0 0
United Kingdom
State/province [76] 0 0
Dorset
Country [77] 0 0
United Kingdom
State/province [77] 0 0
Kent
Country [78] 0 0
United Kingdom
State/province [78] 0 0
Lancashire
Country [79] 0 0
United Kingdom
State/province [79] 0 0
Northumberland
Country [80] 0 0
United Kingdom
State/province [80] 0 0
Scotland
Country [81] 0 0
United Kingdom
State/province [81] 0 0
Tyne And Wear
Country [82] 0 0
United Kingdom
State/province [82] 0 0
Aberdeen
Country [83] 0 0
United Kingdom
State/province [83] 0 0
Airdrie
Country [84] 0 0
United Kingdom
State/province [84] 0 0
Ashford
Country [85] 0 0
United Kingdom
State/province [85] 0 0
Bath
Country [86] 0 0
United Kingdom
State/province [86] 0 0
Cambridge
Country [87] 0 0
United Kingdom
State/province [87] 0 0
Cheshire
Country [88] 0 0
United Kingdom
State/province [88] 0 0
Dewsbury
Country [89] 0 0
United Kingdom
State/province [89] 0 0
Essex
Country [90] 0 0
United Kingdom
State/province [90] 0 0
Exeter
Country [91] 0 0
United Kingdom
State/province [91] 0 0
Guildford
Country [92] 0 0
United Kingdom
State/province [92] 0 0
Halifax
Country [93] 0 0
United Kingdom
State/province [93] 0 0
Liverpool
Country [94] 0 0
United Kingdom
State/province [94] 0 0
London
Country [95] 0 0
United Kingdom
State/province [95] 0 0
Luton
Country [96] 0 0
United Kingdom
State/province [96] 0 0
Middlesbrough
Country [97] 0 0
United Kingdom
State/province [97] 0 0
Newcastle upon Tyne
Country [98] 0 0
United Kingdom
State/province [98] 0 0
Torquay

Funding & Sponsors
Primary sponsor type
Other
Name
Yale University
Address
Country
Other collaborator category [1] 0 0
Government body
Name [1] 0 0
National Institute of Neurological Disorders and Stroke (NINDS)
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/industry
Name [2] 0 0
Takeda Pharmaceuticals North America, Inc.
Address [2] 0 0
Country [2] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/study/NCT00091949
Trial related presentations / publications
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.
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.
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.
Spence JD, Viscoli CM, Inzucchi SE, Dearborn-Tomazos J, Ford GA, Gorman M, Furie KL, Lovejoy AM, Young LH, Kernan WN; IRIS Investigators. Pioglitazone Therapy in Patients With Stroke and Prediabetes: A Post Hoc Analysis of the IRIS Randomized Clinical Trial. JAMA Neurol. 2019 May 1;76(5):526-535. doi: 10.1001/jamaneurol.2019.0079. Erratum In: JAMA Neurol. 2019 May 1;76(5):625-626. doi: 10.1001/jamaneurol.2019.0475.
Young LH, Viscoli CM, Schwartz GG, Inzucchi SE, Curtis JP, Gorman MJ, Furie KL, Conwit R, Spatz ES, Lovejoy A, Abbott JD, Jacoby DL, Kolansky DM, Ling FS, Pfau SE, Kernan WN; IRIS Investigators. Heart Failure After Ischemic Stroke or Transient Ischemic Attack in Insulin-Resistant Patients Without Diabetes Mellitus Treated With Pioglitazone. Circulation. 2018 Sep 18;138(12):1210-1220. doi: 10.1161/CIRCULATIONAHA.118.034763.
Yaghi S, Furie KL, Viscoli CM, Kamel H, Gorman M, Dearborn J, Young LH, Inzucchi SE, Lovejoy AM, Kasner SE, Conwit R, Kernan WN; IRIS Trial Investigators. Pioglitazone Prevents Stroke in Patients With a Recent Transient Ischemic Attack or Ischemic Stroke: A Planned Secondary Analysis of the IRIS Trial (Insulin Resistance Intervention After Stroke). Circulation. 2018 Jan 30;137(5):455-463. doi: 10.1161/CIRCULATIONAHA.117.030458. Epub 2017 Oct 30.
Kernan WN, Viscoli CM, Dearborn JL, Kent DM, Conwit R, Fayad P, Furie KL, Gorman M, Guarino PD, Inzucchi SE, Stuart A, Young LH; Insulin Resistance Intervention After Stroke (IRIS) Trial Investigators. Targeting Pioglitazone Hydrochloride Therapy After Stroke or Transient Ischemic Attack According to Pretreatment Risk for Stroke or Myocardial Infarction. JAMA Neurol. 2017 Nov 1;74(11):1319-1327. doi: 10.1001/jamaneurol.2017.2136.
Stuart AC, Sico JJ, Viscoli CM, Tayal AH, Inzucchi SE, Ford GA, Furie KL, Cote R, Spence JD, Tanne D, Kernan WN. Taking care of volunteers in a stroke trial: a new assisted-management strategy. Stroke Vasc Neurol. 2016 Oct 25;1(3):108-114. doi: 10.1136/svn-2016-000029. eCollection 2016 Sep.
Furie KL, Viscoli CM, Gorman M, Ford GA, Young LH, Inzucchi SE, Guarino PD, Lovejoy AM, Conwit R, Tanne D, Kernan WN; IRIS Trial Investigators. Effects of pioglitazone on cognitive function in patients with a recent ischaemic stroke or TIA: a report from the IRIS trial. J Neurol Neurosurg Psychiatry. 2018 Jan;89(1):21-27. doi: 10.1136/jnnp-2017-316361. Epub 2017 Sep 22.
Young LH, Viscoli CM, Curtis JP, Inzucchi SE, Schwartz GG, Lovejoy AM, Furie KL, Gorman MJ, Conwit R, Abbott JD, Jacoby DL, Kolansky DM, Pfau SE, Ling FS, Kernan WN; IRIS Investigators. Cardiac Outcomes After Ischemic Stroke or Transient Ischemic Attack: Effects of Pioglitazone in Patients With Insulin Resistance Without Diabetes Mellitus. Circulation. 2017 May 16;135(20):1882-1893. doi: 10.1161/CIRCULATIONAHA.116.024863. Epub 2017 Feb 28.
Viscoli CM, Inzucchi SE, Young LH, Insogna KL, Conwit R, Furie KL, Gorman M, Kelly MA, Lovejoy AM, Kernan WN; IRIS Trial Investigators. Pioglitazone and Risk for Bone Fracture: Safety Data From a Randomized Clinical Trial. J Clin Endocrinol Metab. 2017 Mar 1;102(3):914-922. doi: 10.1210/jc.2016-3237.
Inzucchi SE, Viscoli CM, Young LH, Furie KL, Gorman M, Lovejoy AM, Dagogo-Jack S, Ismail-Beigi F, Korytkowski MT, Pratley RE, Schwartz GG, Kernan WN; IRIS Trial Investigators. Pioglitazone Prevents Diabetes in Patients With Insulin Resistance and Cerebrovascular Disease. Diabetes Care. 2016 Oct;39(10):1684-92. doi: 10.2337/dc16-0798. Epub 2016 Jul 27.
Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, Guarino PD, Lovejoy AM, Peduzzi PN, Conwit R, Brass LM, Schwartz GG, Adams HP Jr, Berger L, Carolei A, Clark W, Coull B, Ford GA, Kleindorfer D, O'Leary JR, Parsons MW, Ringleb P, Sen S, Spence JD, Tanne D, Wang D, Winder TR; IRIS Trial Investigators. Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. N Engl J Med. 2016 Apr 7;374(14):1321-31. doi: 10.1056/NEJMoa1506930. Epub 2016 Feb 17.
Kernan WN, Inzucchi SE. Metabolic rehabilitation: science gathers to support a new intervention to prevent stroke. Stroke. 2011 Dec;42(12):3333-5. doi: 10.1161/STROKEAHA.111.632489. Epub 2011 Oct 13. No abstract available. Erratum In: Stroke. 2012 Mar;43(3):e36.
Public notes

Contacts
Principal investigator
Name 0 0
Walter N. Kernan, M.D.
Address 0 0
Yale University
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT00091949