SPS3: Secondary Prevention of Small Subcortical Strokes Trial

Sponsor

University of British Columbia (Other)

Overall Status

Completed

CT.gov ID

NCT00059306

Collaborator

National Institute of Neurological Disorders and Stroke (NINDS) (NIH)

3,020

Enrollment

Locations

Arms

110

Duration (Months)

47.9

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The goal of this study is to learn if combination antiplatelet therapy (aspirin and clopidogrel) is more effective than aspirin alone for the prevention of recurrent stroke and cognitive decline, and if intensive blood pressure control is associated with fewer recurrent strokes and cognitive decline.

On July 21, 2011 the DSMB recommended terminating the anti platelet arm of the study due to an imbalance of overall and major non-CNS hemorrhagic SAE's and total deaths in the investigational anti platelet combination of aspirin + clopidogrel and an interim statistical analysis that demonstrated futility in the investigational anti platelet arm. It was recommended that patients be continued on standard care of aspirin mono therapy until their study close-out visit. Also, recommended the continuation and completion of the plood pressure arm following the protocol.

Condition or Disease	Intervention/Treatment	Phase
Cerebrovascular Accident Hypertension	Drug: aspirin Drug: clopidogrel Other: Target of Blood Pressure Other: placebo	Phase 3

Detailed Description

Stroke is damage to the brain caused by problems in the blood vessels. Strokes often cause paralysis, loss of sensation and speech, and other problems. A lacunar or small Subcortical stroke affects the inner part of the brain causing small "pea sized" areas of damage due to blockage of small blood vessels within the brain.

This multi-center study will recruit 3000 participants (20 percent of whom will be Hispanic) to find out if using aspirin and clopidogrel is more effective than using aspirin alone to prevent recurrent stroke in patients with lacunar stroke confirmed by MRI, and if lowering a patient's blood pressure below the usual limits will also help prevent recurrent stroke and maintain thinking ability. Both aspirin and clopidogrel are widely-used for blood clotting and stroke prevention. Investigators intend to find out if using the drugs together is more effective than using aspirin alone.

Participants will be randomly assigned to one of 2 types of treatment: either aspirin alone or the combination of aspirin and clopidogrel. In addition, participants will be assigned to one of 2 groups of blood pressure control. The difference between the two groups is the target level of systolic blood pressure-either 130-149 or below 130. The goal of the blood pressure aspect of this trial is to find out if lowering blood pressure after stroke helps to prevent recurrent stroke and preserves cognition.

Study Design

Study Type:

Interventional

Actual Enrollment :

3020 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

Secondary Prevention of Small Subcortical Strokes (SPS3) Trial

Study Start Date :

Feb 1, 2003

Actual Primary Completion Date :

Apr 1, 2012

Actual Study Completion Date :

Apr 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Antiplatelet Participants receive aspirin + placebo OR aspirin + clopidogrel	Drug: aspirin Participants receive aspirin + placebo, specifically: aspirin (325 mg) with placebo (an inactive substance). Participants will take 1 of each pill a day until the end of the study. Drug: clopidogrel Participants will receive aspirin + clopidogrel, specifically: aspirin (325 mg) with clopidogrel (75 mg)-- Participants will take 1 of each pill a day until the end of the study. Other: placebo an inactive substance
Active Comparator: Blood pressure The goal of the blood pressure aspect of this trial is to find out if lowering blood pressure after stroke helps to prevent recurrent stroke and preserves cognition.	Other: Target of Blood Pressure Participants will be assigned to one of 2 groups of blood pressure control. The difference between the two groups is the target level of systolic blood pressure-either 130-149 mmHg or below 130 mmHg; to do so, the scientists will use medications that are already in the market for blood pressure management.

Arm

Intervention/Treatment

Active Comparator: Antiplatelet

Participants receive aspirin + placebo OR aspirin + clopidogrel

Drug: aspirin

Participants receive aspirin + placebo, specifically: aspirin (325 mg) with placebo (an inactive substance). Participants will take 1 of each pill a day until the end of the study.

Drug: clopidogrel

Participants will receive aspirin + clopidogrel, specifically: aspirin (325 mg) with clopidogrel (75 mg)-- Participants will take 1 of each pill a day until the end of the study.

Other: placebo

an inactive substance

Active Comparator: Blood pressure

The goal of the blood pressure aspect of this trial is to find out if lowering blood pressure after stroke helps to prevent recurrent stroke and preserves cognition.

Other: Target of Blood Pressure

Participants will be assigned to one of 2 groups of blood pressure control. The difference between the two groups is the target level of systolic blood pressure-either 130-149 mmHg or below 130 mmHg; to do so, the scientists will use medications that are already in the market for blood pressure management.

Outcome Measures

Primary Outcome Measures

Evidence of clinically defined ischemic stroke (focal neurological deficits persisting for more than 24 hours) confirmed by non-investigational CT or MRI [Mean follow up of 4 years]
Evidence of hemorrhagic stroke; a neurologic deficit associated with intraparenchymal or subarachnoid space lesion on CT/MRI or cerebral hemorrhage demonstrated by surgery or autopsy. [within mean follow-up of 4 years]

Secondary Outcome Measures

The difference in the rate of cognitive decline among SPS3 participants assigned to receive aspirin alone versus combination of aspirin and clopidogrel, assessed through repeated neuropsychological tests; and major vascular events. [within mean follow-up of 4 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

30 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

INCLUSION:

Small subcortical ischemic stroke or subcortical TIA.

Inclusion criteria are based on TOAST criteria supplemented by required MRI data. All of the following criteria must be met:

One of the lacunar stroke clinical syndromes (adapted from Fisher) lasting > 24 hrs within the past 6 months
Absence of signs or symptoms of cortical dysfunction such as aphasia, apraxia, agnosia, agraphia, homonymous visual field defect, etc.
No ipsilateral cervical carotid stenosis (≥50%) by a reliable imaging modality done in an approved laboratory since the qualifying small subcortical stroke (S3), if hemispheric.
No major-risk cardioembolic sources requiring anticoagulation or other specific therapy. Minor-risk cardioembolic sources will be permitted if anticoagulation is not prescribed by the patient's primary care physician.
Subcortical TIA with corresponding lesion on DWI.
MRI evidence of S3: a. Presence of an S3 (1.5 and 2 cm in diameter corresponding to the qualifying event on DWI; when TIA, ADC image must confirm lesion or T2/FLAIR (hyperintense lesions) (required for all brainstem events) OR multiple S3s on FLAIR/TI(<1.5 cm in diameter) (hypointense lesions) b. Absence of cortical stroke and large subcortical stroke (recent or remote).

EXCLUSION:

To be eligible for entry into the study, the patient must not meet any of the criteria listed below:

Disabling stroke (Modified Rankin Scale less than or equal to 4)
Previous intracranial hemorrhage (excluding traumatic) or hemorrhagic stroke
Age under 30 years
High risk of bleeding (e.g. recurrent GI or GU bleeding, active peptic ulcer disease, etc)
Anticipated requirement for long-term use of anticoagulants (e.g. recurrent DVT) or other antiplatelets
Prior cortical stroke (diagnosed either clinically or by neuroimaging), or prior cortical or retinal TIA
Prior ipsilateral carotid endarterectomy
Impaired renal function: GFR <40
Intolerance or contraindications to aspirin or clopidogrel (including thrombocytopenia, prolonged INR)
A score < 24 (adjusted for age and education) on the Folstein Mini Mental Status Examination
Medical contraindication to MRI
Pregnancy or women of child-bearing potential who are not following an effective method of contraception
Geographic or social factors making study participation impractical
Unable or unwilling to provide informed consent
Unlikely to be compliant with therapy/unwilling to return for frequent clinic visits
Patients concurrently participating in another study with an investigational drug or device
Other likely specific cause of stroke (e.g. dissection, vasculitis, prothrombotic diathesis, drug abuse)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Southern Alabama Stroke Center	Mobile	Alabama	United States	36617
2	Catholic Healthcare West	Phoenix	Arizona	United States	85013
3	Mayo Clinic Scottsdale	Scottsdale	Arizona	United States	85259
4	University of Arizona, Department of Neurology	Tucson	Arizona	United States	85724
5	University of California San Diego Medical Center	San Diego	California	United States	92103-8466
6	University of California San Francisco-Fresno	San Francisco-Fresno	California	United States
7	Denver	Englewood	Colorado	United States
8	Melbourne	Melbourne	Florida	United States
9	Miami-University of Miami, Miller School of Medicine	Miami	Florida	United States	33136
10	Emory University, Grady Health System	Atlanta	Georgia	United States	30303
11	Mercy Medical Center-Ruan Neurology Clinical Research	Des Moines	Iowa	United States	50314
12	University of Kentucky, Aging/Stroke Program	Lexington	Kentucky	United States	40506-0230
13	Suburban Hospital	Bethesda	Maryland	United States
14	Boston University	Boston	Massachusetts	United States	02118
15	Wayne State	Detroit	Michigan	United States	48201
16	Henry Ford Hospital, Department of Neurology	Detroit	Michigan	United States	48202
17	Berman Center	Minneapolis	Minnesota	United States	55404
18	Mayo Stroke Center KA-SL-13	Rochester	Minnesota	United States	55905
19	University of Washington	Sant Louis	Missouri	United States
20	Tenet Health, St. Louis University	St. Louis	Missouri	United States	63110
21	St. John's Mercy	St. Louis	Missouri	United States	63141
22	Cooper University Hospital	Camden	New Jersey	United States	08103
23	Buffalo	Buffalo	New York	United States
24	Helen Hayes Hospital	Haverstraw	New York	United States	10993
25	Columbia University Medical Center	New York	New York	United States	10032
26	Rochester General Hospital	Rochester	New York	United States	14621
27	University of Rochester	Rochester	New York	United States	14642
28	Wake Forest University, Sciences-Neurology	Winston-Salem	North Carolina	United States	27157-1078
29	Case Western	Cleveland	Ohio	United States	44106
30	Metrohealth Medical Center	Cleveland	Ohio	United States	44109
31	Ohio State University, Division of Stroke	Columbus	Ohio	United States	43210
32	Oregon Health and Science University	Portland	Oregon	United States	97239
33	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
34	University of Texas Southwestern	Dallas	Texas	United States	75390-8897
35	Scurlock Stroke Center	Houston	Texas	United States	77030
36	University of Texas Health Science Center	San Antonio	Texas	United States	78229-3900
37	University of Washington	Seattle	Washington	United States	98104-2499
38	Marshfield Clinic, Department of Neurology	Marshfield	Wisconsin	United States	54449
39	Medical College of Wisconsin-Neurology	Milwaukee	Wisconsin	United States	53226
40	Calgary Health	Calgary	Alberta	Canada	T2N 2T9
41	SPS3 Coordinating Center	Vancouver	British Columbia	Canada	V6T 2B5
42	Halifax	Halifax	Nova Scotia	Canada	B3H 4V7
43	Ottawa Hospital General Campus	Ottawa	Ontario	Canada	K1H 8L6
44	Greenfield Park	Greenfield Park	Quebec	Canada	J4V 2H1
45	McGill-Jewish General	Montreal	Quebec	Canada	H37 1E2
46	McGill-Montreal General	Montreal	Quebec	Canada	H3G 1A4
47	CHA-Hospital de l'Enfant-Jesus	Quebec City	Quebec	Canada	G1J 1Z4
48	Hospital Clinico de la Universidad Católica de Chile	Santiago		Chile
49	Hospital Naval Almirante Nef, 'Subida Alessandri s/n, Hall A, Oficina 9	Viña del Mar		Chile	2530116
50	Hospital-Clinica Kennedy	Guayaquil		Ecuador
51	Hospital de La Universidad Autonoma de Nuevo Leon	Monterrey	Nuevo Leon	Mexico	644460
52	Antiguo Hospital Civil de Guadalajara	Guadalajara		Mexico	44280
53	Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zuibrán	Mexico City		Mexico	14000
54	Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez	Mexico City		Mexico	14269
55	Hospital Sabogal Essalud-Unidad de Investigacion	Bellavista-Callao	Lima	Peru
56	Hosp. Universitario Germans Trias I Pujol	Badalona		Spain	08916
57	Hospital Del Mar, Passeig Marítim 25-29	Barcelona		Spain	08003
58	Hospital de la Santa Creu I Sant Pau, c/Sant Antoni Maria Claret, 167	Barcelona		Spain	08025
59	Hospital del Sagrat Cor. Quinta de Salut I'Alianca, c/Viladomat 288	Barcelona		Spain	08029
60	Hosp. Parc Tauli de Sabadell	Barcelona		Spain	08208
61	Hosp. de Girona Dr. Josep Trueta	Girona		Spain	17007
62	Hospital La Paz	Madrid		Spain	28046
63	Universidad de Santiago de Compostela, Facultad de Medicina y Odontologia	Santiago de Compostela		Spain	15782