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Cerebrovascular AccidentPhase 3SPS3NCT00059306

Secondary Prevention of Small Subcortical Strokes Trial

A Phase 3 study testing aspirin, clopidogrel and Target of Blood Pressure in people with Cerebrovascular Accident and Hypertension, run by University of British Columbia at 63 sites in 7 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 30 years and older
Conditions the study is for
Cerebrovascular Accident, Hypertension
What is being tested?
aspirin, clopidogrel and Target of Blood Pressure
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
3,020 participants
Where
63 sitesin 7 countries
Study dates
Feb 2003to Apr 2012
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 30 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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).

Who cannot join

  • 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
Show all 18Show fewer
  • 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)

Trial locations and contacts

63 sites in 7 countries.

63 sites in 7 countries

United States39 sites

  • Emory University, Grady Health System

    Atlanta, Georgia, 30303

  • Suburban Hospital

    Bethesda, Maryland

  • Boston University

    Boston, Massachusetts, 02118

  • Buffalo

    Buffalo, New York

  • Cooper University Hospital

    Camden, New Jersey, 08103

  • Case Western

    Cleveland, Ohio, 44106

  • Metrohealth Medical Center

    Cleveland, Ohio, 44109

  • Ohio State University, Division of Stroke

    Columbus, Ohio, 43210

  • University of Texas Southwestern

    Dallas, Texas, 75390-8897

  • Mercy Medical Center-Ruan Neurology Clinical Research

    Des Moines, Iowa, 50314

  • Wayne State

    Detroit, Michigan, 48201

  • Henry Ford Hospital, Department of Neurology

    Detroit, Michigan, 48202

  • Denver

    Englewood, Colorado

  • Helen Hayes Hospital

    Haverstraw, New York, 10993

  • Scurlock Stroke Center

    Houston, Texas, 77030

  • University of Kentucky, Aging/Stroke Program

    Lexington, Kentucky, 40506-0230

  • Marshfield Clinic, Department of Neurology

    Marshfield, Wisconsin, 54449

  • Melbourne

    Melbourne, Florida

  • Miami-University of Miami, Miller School of Medicine

    Miami, Florida, 33136

  • Medical College of Wisconsin-Neurology

    Milwaukee, Wisconsin, 53226

  • Berman Center

    Minneapolis, Minnesota, 55404

  • University of Southern Alabama Stroke Center

    Mobile, Alabama, 36617

  • Vanderbilt University Medical Center

    Nashville, Tennessee, 37232

  • Columbia University Medical Center

    New York, New York, 10032

  • Catholic Healthcare West

    Phoenix, Arizona, 85013

  • Oregon Health and Science University

    Portland, Oregon, 97239

  • Mayo Stroke Center KA-SL-13

    Rochester, Minnesota, 55905

  • Rochester General Hospital

    Rochester, New York, 14621

  • University of Rochester

    Rochester, New York, 14642

  • University of Texas Health Science Center

    San Antonio, Texas, 78229-3900

  • University of California San Diego Medical Center

    San Diego, California, 92103-8466

  • University of California San Francisco-Fresno

    San Francisco-Fresno, California

  • University of Washington

    Sant Louis, Missouri

  • Mayo Clinic Scottsdale

    Scottsdale, Arizona, 85259

  • University of Washington

    Seattle, Washington, 98104-2499

  • Tenet Health, St. Louis University

    St Louis, Missouri, 63110

  • St. John's Mercy

    St Louis, Missouri, 63141

  • University of Arizona, Department of Neurology

    Tucson, Arizona, 85724

  • Wake Forest University, Sciences-Neurology

    Winston-Salem, North Carolina, 27157-1078

Other trials in United States

Canada8 sites

  • Calgary Health

    Calgary, Alberta, T2N 2T9

  • Greenfield Park

    Greenfield Park, Quebec, J4V 2H1

  • Halifax

    Halifax, Nova Scotia, B3H 4V7

  • McGill-Jewish General

    Montreal, Quebec, H37 1E2

  • McGill-Montreal General

    Montreal, Quebec, H3G 1A4

  • Ottawa Hospital General Campus

    Ottawa, Ontario, K1H 8L6

  • CHA-Hospital de l'Enfant-Jesus

    Québec, Quebec, G1J 1Z4

  • SPS3 Coordinating Center

    Vancouver, British Columbia, V6T 2B5

Other trials in Canada

Spain8 sites

  • Hosp. Universitario Germans Trias I Pujol

    Badalona, 08916

  • Hospital Del Mar, Passeig Marítim 25-29

    Barcelona, 08003

  • Hospital de la Santa Creu I Sant Pau, c/Sant Antoni Maria Claret, 167

    Barcelona, 08025

  • Hospital del Sagrat Cor. Quinta de Salut I'Alianca, c/Viladomat 288

    Barcelona, 08029

  • Hosp. Parc Tauli de Sabadell

    Barcelona, 08208

  • Hosp. de Girona Dr. Josep Trueta

    Girona, 17007

  • Hospital La Paz

    Madrid, 28046

  • Universidad de Santiago de Compostela, Facultad de Medicina y Odontologia

    Santiago de Compostela, 15782

Other trials in Spain

Mexico4 sites

  • Antiguo Hospital Civil de Guadalajara

    Guadalajara, 44280

  • Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zuibrán

    Mexico City, 14000

  • Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez

    Mexico City, 14269

  • Hospital de La Universidad Autonoma de Nuevo Leon

    Monterrey, Nuevo León, 644460

Other trials in Mexico

Chile2 sites

  • Hospital Clinico de la Universidad Católica de Chile

    Santiago

  • Hospital Naval Almirante Nef, 'Subida Alessandri s/n, Hall A, Oficina 9

    Viña del Mar, 2530116

Other trials in Chile

Ecuador1 site

  • Hospital-Clinica Kennedy

    Guayaquil

Other trials in Ecuador

Peru1 site

  • Hospital Sabogal Essalud-Unidad de Investigacion

    Bellavista-Callao, Lima

Other trials in Peru

About this study

Official title: Secondary Prevention of Small Subcortical Strokes (SPS3) Trial

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.

Read the 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.

Being tested
aspirin, clopidogrel, Target of Blood Pressure, placebo
Keywords
stroke, hypertension, high blood pressure, lacunar stroke, subcortical stroke, aspirin, clopidogrel
Medical subject headings
Stroke, Hypertension, Stroke, Lacunar

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • aspirinDrug

    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.

  • clopidogrelDrug

    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.

  • Target of Blood PressureOther

    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.

  • placeboOther

    an inactive substance

Study groups in NCT00059306
Study groupRoleWhat they receive
AntiplateletActive comparatorParticipants receive aspirin + placebo OR aspirin + clopidogrel
Receives: Drug: aspirin; Drug: clopidogrel; Other: placebo
Blood pressureActive comparatorThe 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.
Receives: Other: Target of Blood Pressure

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Evidence of clinically defined ischemic stroke (focal neurological deficits persisting for more than 24 hours) confirmed by non-investigational CT or MRI

    Measured: Mean follow up of 4 years

  2. 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.

    Measured: within mean follow-up of 4 years

Secondary outcomes (1)

  1. 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.

    Measured: within mean follow-up of 4 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Apr 2003 (estimated)
  2. Study startFeb 2003
  3. Primary completionApr 2012
  4. Study completionApr 2012

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
3,020 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00059306
Sponsor's protocol ID
H09-03016
Other IDs
CRC
Acronym
SPS3
Status last verified
Apr 2013
First submitted
23 Apr 2003
Last updated
4 Apr 2013
Results posted
No
Data monitoring committee
Yes

Publications

  • Goldstein ED, Liew SQR, Shu L, Yaghi S. The impact of pre-stroke aspirin exposure on radiographic appearance and disability outcomes: A post-hoc analysis of the SPS3 trial: Aspirin Use and Small Subcortical Stroke. J Stroke Cerebrovasc Dis. 2024 Mar;33(3):107566. doi: 10.1016/j.jstrokecerebrovasdis.2024.107566. Epub 2024 Jan 10.

    PubMed 38214239

  • Anadani M, Turan TN, Yaghi S, Spiotta AM, Gory B, Sharma R, Sheth KN, de Havenon A. Change in Smoking Behavior and Outcome After Ischemic Stroke: Post-Hoc Analysis of the SPS3 Trial. Stroke. 2023 Apr;54(4):921-927. doi: 10.1161/STROKEAHA.121.038202. Epub 2023 Mar 6.

    PubMed 36876480

  • Saiz LC, Gorricho J, Garjon J, Celaya MC, Erviti J, Leache L. Blood pressure targets for the treatment of people with hypertension and cardiovascular disease. Cochrane Database Syst Rev. 2022 Nov 18;11(11):CD010315. doi: 10.1002/14651858.CD010315.pub5.

    PubMed 36398903

  • Natale P, Palmer SC, Saglimbene VM, Ruospo M, Razavian M, Craig JC, Jardine MJ, Webster AC, Strippoli GF. Antiplatelet agents for chronic kidney disease. Cochrane Database Syst Rev. 2022 Feb 28;2(2):CD008834. doi: 10.1002/14651858.CD008834.pub4.

    PubMed 35224730

  • Shihab S, Boucher RE, Abraham N, Wei G, Beddhu S. Influence of Baseline Diastolic Blood Pressure on the Effects of Intensive Systolic Blood Pressure Lowering on the Risk of Stroke. Hypertension. 2022 Apr;79(4):785-793. doi: 10.1161/HYPERTENSIONAHA.121.18172. Epub 2022 Feb 4.

    PubMed 35114798

  • Cukierman-Yaffe T, McClure LA, Risoli T, Bosch J, Sharma M, Gerstein HC, Benavente O. The Relationship Between Glucose Control and Cognitive Function in People With Diabetes After a Lacunar Stroke. J Clin Endocrinol Metab. 2021 Mar 25;106(4):e1521-e1528. doi: 10.1210/clinem/dgab022.

    PubMed 33481011

  • Saiz LC, Gorricho J, Garjon J, Celaya MC, Erviti J, Leache L. Blood pressure targets for the treatment of people with hypertension and cardiovascular disease. Cochrane Database Syst Rev. 2020 Sep 9;9(9):CD010315. doi: 10.1002/14651858.CD010315.pub4.

    PubMed 32905623

  • Blum MR, Scherzer R, Ikeme JC, Benavente OR, McClure LA, Peralta CA, Odden MC. Functional health and white matter hyperintensities as effect modifiers of blood pressure-lowering on cognitive function and vascular events in older Secondary Prevention of Small Subcortical Strokes trial participants. J Hypertens. 2020 Aug;38(8):1578-1585. doi: 10.1097/HJH.0000000000002440.

    PubMed 32371759

  • Agarwal A, Cheung AK, Ma J, Cho M, Li M. Effect of Baseline Kidney Function on the Risk of Recurrent Stroke and on Effects of Intensive Blood Pressure Control in Patients With Previous Lacunar Stroke: A Post Hoc Analysis of the SPS3 Trial (Secondary Prevention of Small Subcortical Strokes). J Am Heart Assoc. 2019 Aug 20;8(16):e013098. doi: 10.1161/JAHA.119.013098. Epub 2019 Aug 19.

    PubMed 31423869

  • Ikeme JC, Pergola PE, Scherzer R, Shlipak MG, Catanese L, McClure LA, Benavente OR, Peralta CA. Cerebral White Matter Hyperintensities, Kidney Function Decline, and Recurrent Stroke After Intensive Blood Pressure Lowering: Results From the Secondary Prevention of Small Subcortical Strokes ( SPS 3) Trial. J Am Heart Assoc. 2019 Feb 5;8(3):e010091. doi: 10.1161/JAHA.118.010091.

    PubMed 30686103

  • Magvanjav O, McDonough CW, Gong Y, McClure LA, Talbert RL, Horenstein RB, Shuldiner AR, Benavente OR, Mitchell BD, Johnson JA; NINDS SiGN (Stroke Genetics Network). Pharmacogenetic Associations of beta1-Adrenergic Receptor Polymorphisms With Cardiovascular Outcomes in the SPS3 Trial (Secondary Prevention of Small Subcortical Strokes). Stroke. 2017 May;48(5):1337-1343. doi: 10.1161/STROKEAHA.116.015936. Epub 2017 Mar 28.

    PubMed 28351962

  • Wilson LK, Pearce LA, Arauz A, Anderson DC, Tapia J, Bazan C, Benavente OR, Field TS; SPS3 Investigators. Morphological classification of penetrating artery pontine infarcts and association with risk factors and prognosis: The SPS3 trial. Int J Stroke. 2016 Jun;11(4):412-9. doi: 10.1177/1747493016637366. Epub 2016 Mar 8.

    PubMed 26956031

  • Boehme AK, McClure LA, Zhang Y, Luna JM, Del Brutto OH, Benavente OR, Elkind MS. Inflammatory Markers and Outcomes After Lacunar Stroke: Levels of Inflammatory Markers in Treatment of Stroke Study. Stroke. 2016 Mar;47(3):659-67. doi: 10.1161/STROKEAHA.115.012166.

    PubMed 26888535

  • Peralta CA, McClure LA, Scherzer R, Odden MC, White CL, Shlipak M, Benavente O, Pergola P. Effect of Intensive Versus Usual Blood Pressure Control on Kidney Function Among Individuals With Prior Lacunar Stroke: A Post Hoc Analysis of the Secondary Prevention of Small Subcortical Strokes (SPS3) Randomized Trial. Circulation. 2016 Feb 9;133(6):584-91. doi: 10.1161/CIRCULATIONAHA.115.019657. Epub 2016 Jan 13.

    PubMed 26762524

  • Odden MC, McClure LA, Sawaya BP, White CL, Peralta CA, Field TS, Hart RG, Benavente OR, Pergola PE. Achieved Blood Pressure and Outcomes in the Secondary Prevention of Small Subcortical Strokes Trial. Hypertension. 2016 Jan;67(1):63-9. doi: 10.1161/HYPERTENSIONAHA.115.06480. Epub 2015 Nov 9.

    PubMed 26553236

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing aspirin, clopidogrel and Target of Blood Pressure in people with Cerebrovascular Accident and Hypertension, run by University of British Columbia at 63 sites in 7 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 4 Apr 2013. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 63 sites in United States, Canada, Spain, Mexico, Chile and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Evidence of clinically defined ischemic stroke (focal neurological deficits persisting for more than 24 hours) confirmed by non-investigational CT or MRI (time frame: Mean follow up of 4 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00059306, which also lists 35 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Apr 2013.

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