Prevention Trials

NIH STROKENET: PREVENTION STROKE TRIALS

Treatments for acute stroke include IV t-PA, stroke centers, stroke units, endovascular thrombectomy devices for selected patients, nimodipine for subarachnoid hemorrhage, and aneurysm coiling and clipping for ruptured aneurysms. Intracerebral hemorrhage has proven to be the most challenging for effective treatments; however recent research has shown promise.

CURRENT PREVENTION TRIAL WEBSITES

CLARITY Trial: Cilostazol for Prevention of Recurrent Stroke Trial		FOCAS Trial: Focal Cerebral Arteriopathy Steroids (FOCAS)

CAPTIVA Trial: Comparison of Anti-coagulation and Anti-platelet Therapies for Intracranial Vascular Atherostenosis		CAPTIVA-MRI: Observational multimodal MRI study, ancillary to the CAPTIVA trial.

ASPIRE: Anticoagulation for Stroke Prevention and Recovery after ICH		SLEEP SMART: Sleep for Stroke Management and Recovery Trial

CREST-H: Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis – Hemodynamics		SATURN: Statins Use in Intracerebral Hemorrhage Patient

CREST-2: Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis		ARCADIA: Atrial Cardiomyopathy and Antithrombotic Drugs in Prevention of Cryptogenic Stroke

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PRIMARY AND SECONDARY PREVENTION TRIAL SUMMARIES

ARCADIA: Atrial Cardiopathy and Antithrombotic Drugs in Prevention after Cryptogenic Stroke
Trial Summary: Enrollment is now closed.

In one-third of ischemic strokes, a specific cause cannot be identified. Many of these cryptogenic strokes appear to arise from a distant embolic source. Recent evidence suggests that some cryptogenic strokes arise from left atrial thromboembolism that goes unrecognized because it is not associated with atrial fibrillation/flutter (AF). Under the prevailing clinical paradigm, it is thought that AF is required for blood clots to form in the left atrium. Therefore, unless AF is apparent, patients do not receive anticoagulant therapy to prevent atrial thromboembolism. However, recent research indicates that embolization from the left atrium can occur when there are abnormal changes to atrial tissue and function even before there is AF. Such an “atrial cardiopathy” may explain many of the strokes that are currently of unknown cause. Since anticoagulant drugs such as apixaban have already proven more effective than standard aspirin therapy for preventing stroke from AF, the parallels between AF and atrial cardiopathy suggest that apixaban may also be more effective than aspirin for stroke prevention in patients with atrial cardiopathy and no AF.

ARCADIA is a randomized trial of apixaban versus aspirin specifically in patients with cryptogenic stroke who have evidence of atrial cardiopathy. This trial will address several important knowledge gaps. First, it will advance our understanding of stroke pathophysiology by assessing whether atrial cardiopathy is a valid therapeutic target, which may set the stage for a primary prevention trial. Second, this trial will advance our understanding of optimal secondary stroke prevention therapy.

Trial Design Summary:

ARCADIA is a multicenter, biomarker-driven, randomized, double-blind, active-control, phase 3 clinical trial of apixaban versus aspirin in patients who have evidence of atrial cardiopathy and a recent stroke of unknown cause. Atrial cardiopathy will be defined as one or more of the following biomarkers: P-wave terminal force in electrocardiogram lead V₁ >5,000 mV*ms, left atrial size index ≥3.0 cm/m² on echocardiogram, and serum NT-proBNP >250 pg/mL. The primary aim is to test the hypothesis that apixaban is superior to aspirin for the prevention of recurrent stroke in subjects with cryptogenic ischemic stroke and atrial cardiopathy.

ARCADIA will recruit 1,100 subjects over 2.5 years at 120 sites in the NINDS StrokeNet consortium. Subjects will be followed for a minimum of 1.5 years and a maximum of 4 years for the primary efficacy outcome of recurrent stroke and the primary safety outcomes of symptomatic intracranial hemorrhage and major hemorrhage other than intracranial hemorrhage.

ARCADIA trial methods paper Int J Stroke 2018

Sponsors and Collaborators:

Sponsor: Columbia University/Mitchell S.V. Elkind, MD, MS for the ARCADIA PIs
National Institute of Neurological Disorders and Stroke (NINDS)

Also supported by: BMS-Pfizer Partnership and Roche Diagnostics

Investigator Meetings:
ARCADIA Investigator Meeting November 17, 2017

Principal Investigators:
Mitchell S.V. Elkind, MD, MS, Columbia University
Hooman Kamel, MD, Cornell University
W.T. Longstreth Jr, MD, MPH, University of Washington
David L. Tirschwell, MD, MSC, University of Washington

FDA, CDRH: IDE: # G130221
- ARCADIA Website: Pending
- ClinicalTrials.gov Identifier: NCT03192215
- Trial WebSite Link: Pending
ARCADIA: Cognition and Silent Infarcts (CSI)

Study Summary:

Cognitive decline and dementia after stroke is a major public health problem, with risk of dementia more than doubling after stroke and affecting more the 2 million people in the United States alone. Yet, there are no effective treatments to prevent cognitive decline and dementia after stroke. Silent brain infarction has been associated with cognitive decline, especially among those at high risk for cardio-embolism. It is therefore likely that treatments that reduce the incidence of silent infarcts in stroke patients at high risk for cardio-embolism, will also reduce the rate of cognitive decline and dementia. To test this, we will conduct an ancillary study to the NINDS-sponsored ARCADIA trial. ARCADIA compares treatment with apixaban versus aspirin to prevent a recurrent clinical stroke in subjects with cryptogenic stroke and left atrial cardiopathy. We are taking advantage of the parent trial to address the possibility that apixaban might also reduce the incidence of silent infarction and be associated with better cognitive function over time compared to aspirin.

Study Design Summary:

We will enroll 500 subjects from the 1,100 that will participate in ARCADIA. Subjects who participate in the ancillary study (ARCADIA-CSI) will receive cognitive assessments at baseline and yearly thereafter using a telephone-based cognitive battery. We will test the hypothesis that subjects on apixaban experience less cognitive decline than subjects on aspirin therapy. We will also collect an initial MRI around the time of the qualifying stroke and a follow-up MRI at the time that the subject completes participation in the ARCADIA parent study. Based on these two MRI scans we will assess the incidence of new silent infarcts during the follow-up period and test the hypothesis that apixaban treatment results in a reduction in silent infarcts compared to aspirin therapy. An explorative analysis will also look for the relationship between new silent infarcts and cognitive change.

ARCADIA CSI: Payment Schedule

Sponsor: National Institute of Neurological Disorders and Stroke

Principal Investigators:
ASPIRE - Anticoagulation for Stroke Prevention and Recovery after ICH
STUDY SITE

Trial Summary:

ASPIRE is a randomized, double-blinded, phase 3 clinical trial designed to test the efficacy and safety of apixaban, compared with aspirin, in patients with a recent intracerebral hemorrhage (ICH) and non-valvular atrial fibrillation (AF). Seven hundred patients will be recruited at sites coordinated through the NIH/NINDS StrokeNet. Participants will be followed for outcomes over a median of 24 months (12 months minimum, 36 months maximum). Efficacy outcomes are stroke or death (primary) and change in modified Rankin Scale score (secondary). Tertiary outcomes include change in cognition and quality of life, major hemorrhage, myocardial infarction, venous thromboembolism, systemic embolism, and individual components of the primary outcome.

Objectives:
- Primary Aim: To determine if apixaban is superior to aspirin for prevention of the composite outcome of any stroke (hemorrhagic or ischemic) or death from any cause in patients with recent ICH and AF.
- Secondary Aim: To determine if apixaban, compared with aspirin, results in better functional outcomes as measured by the modified Rankin Scale.
- Tertiary Aims: To assess efficacy and safety of apixaban, compared with aspirin, on rates ischemic stroke, recurrent ICH, intracranial hemorrhage, major hemorrhage, thromboembolic events, measures of cognition and quality of life, and components of the primary outcome.
Population: 700 patients 18 years old - no upper age limit with non-valvular AF and a ICH 14-180 days before entry

Phase: Phase 3

Number of sites: 125

Study Agent:
- Active agent: Active agent: Apixaban (trade name Eliquis®) 5 mg by mouth twice daily (2.5 mg twice daily if standard criteria for reduced dose are met).
- Active control: Aspirin 81 mg by mouth once daily.
Study Duration: 5 years

Participant Duration: Minimum of 1 years and maximum of 3 years.

Sponsors and Collaborators:
Sponsor: Yale School of Medicine & Yale New Haven Hospital
National Institute of Neurological Disorders and Stroke (NINDS)

Principal Investigators:
Kevin Sheth, MD                       Hooman Kamel, MD
Yale School of Medicine            Weill Cornell Medicine
kevin.sheth@yale.edu               hok9010@med.cornell.edu

Send the ASPIRE team a message: ASPIRE@yale.edu

ClinicalTrials.gov NCT # 03907046
CAPTIVA: Comparison of Anti-Coagulation and Anti-Platelet Therapies or Intracranial Vascular Atherostenosis

Trial Summary:

CAPTIVA is a randomized, two-stage Phase III 3-arm, double-blind trial conducted in subjects age 30-80 with asymptomatic infarct attributed to 70-99% stenosis of a major intracranial artery (middle cerebral, intracranial carotid, intracranial vertebral, or basilar). The study will enroll 1,683 subjects at approximately 115 StrokeNet sites over a 4-year period. Subjects with will be randomized 1:1:1 to one year of treatment with:

1. ticagrelor (180 mg loading dose, then 90 mg twice daily) + aspirin (81 mg daily), or

2. low dose rivaroxaban (2.5 mg twice daily) + aspirin (81 mg daily), or

3. clopidogrel (600 mg loading dose, then 75 mg daily) + aspirin (81 mg daily)

All subjects will receive intensive risk factor management according to the SAMMPRIS protocol.

All subjects will be seen in person by the study coordinator and site neurologist for follow-up at 1 month, 4 months, 8 months, and 1 year after randomization when they will have their blood pressure checked, risk factors optimized, and will be assessed for study endpoints.

The main intent of CAPTIVA is to establish that at least one of the two novel therapies being evaluated is more effective than the current standard. CAPTIVA is not designed or powered to answer which of the two novel arms is more effective – that would require a much larger sample size. Nevertheless, CAPTIVA will provide important safety and efficacy data on both novel therapies.

Safety Aim: To identify an excess of intracerebral hemorrhage (ICH) or non-ICH major hemorrhage in the rivaroxaban or ticagrelor arms of the trial that could lead to an early termination of one or both of those arms. This aim will be evaluated in a prespecified safety analysis marking the conclusion of the first stage of the trial.

Efficacy Aim: To determine if the experimental arm(s) (rivaroxaban or ticagrelor or both) that progress to the second stage are superior to the clopidogrel arm for lowering the 1-year rate of the primary efficacy endpoint (ischemic stroke, ICH, or vascular death) in subjects with 70-99% symptomatic Intracranial Atherosclerotic Stenosis (sICAS).

Exploratory Aim: To estimate the impact of CYP2C19 loss-of-function (LOF) carrier status on any benefit that the ticagrelor or low dose rivaroxaban arms may have in lowering the primary endpoint compared with the clopidogrel arm.
CLARITY: Cilostazol for Prevention of Recurrent Stroke Trial

TRIAL SUMMARY:

Abstract: Clarity is a Phase 3, randomized, double-blind, placebo-controlled, clinical trial of cilostazol in patients with a history of a non-cardioembolic ischemic stroke or high-risk TIA. Participants will be recruited at approximately 100 sites. Participants will be followed for a maximum of 5 years for the primary outcome of a major adverse cardiovascular event (MACE).

Objective:  The primary goal of this trial is to determine if the addition of cilostazol to standard-of-care treatment with aspirin or clopidogrel reduces the risk of major adverse cardiovascular events in patients with a history of a non-cardioembolic ischemic stroke or high-risk TIA.

Endpoints: Primary: Time to first occurrence of ischemic stroke, acute myocardial infarction, or cardiovascular death (MACE). Secondary: Time to first occurrence of ischemic stroke Safety: Time to first occurrence of major hemorrhage.

Population:  Patients with a recent (within 180 days) non-cardioembolic ischemic stroke or high-risk TIA (defined by ABCD2 score ≥6) who are treated with standard-of-care single antiplatelet therapy with aspirin or clopidogrel.

Target sample size: 2,000 (final sample size may differ from the target based on the results of sample-size re-estimation and/or interim analyses)

Phase: 3
Number of site: Approximately 100
Investigational drug: Cilostazol
Control: Placebo tablets matched to the cilostazol tablets

Intervention: Participants will be randomized to the active treatment (cilostazol) or control (placebo) arm. All participants will start with a reduced dose (1 tablet daily) and will increase to the full dose (1 tablet twice daily) after having been on the reduced dose for 2 weeks. Participants will stay on the full dose for the remainder of their participation in the study.

Study duration: 6 years
Participant duration: Maximum of 5 years
Funding Source: NIH / NINDS

Clarity Contact Information: askclarity@stanford.edu

Principal Investigators:
Maarten Lansberg, Stanford University:  lansberg@stanford.edu
Adam de Havenon, Yale University:  adam.dehavenon@yale.edu
Kevin Sheth, Yale University:  kevin.sheth@yale.edu

Stanford Clarity Project Manager: Stephanie Kemp - skemp@stanford.edu
Yale Clarity Project Manager: Catherine Viscoli - catherine.viscoli@yale.edu

NCC Clarity Project Manager: tbn
CREST-2: Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial
Trial Summary:

Prevention of stroke involves managing and treating risk factors. Most strokes are caused when blood flow to a portion of the brain is blocked. One place this often happens is in the carotid artery. This blockage is called atherosclerosis or hardening of the arteries.

The purpose of this trial is to determine the best way to prevent strokes in people who have a high amount of blockage of their carotid artery but no stroke symptoms related to that blockage. Each eligible participant will be evaluated to determine which procedure(s) is best for him/her. All participants will receive intensive medical treatment. In addition, participants will be randomized to receive the selected procedure or not.

The trial will be conducted in the United States and Canada by physicians carefully selected on their ability to perform the procedures at low risk. Another key component of the trial is that important stroke risk factors, including hypertension, diabetes, high cholesterol, cigarette smoking, physical activity, and diet will be managed intensively. Participants will remain in the study for 4 years.

Trial Design Summary:

CREST-2 is two parallel multi-center randomized, observer-blinded endpoint clinical trials. One trial will assess treatment differences between intensive medical management alone compared to CEA plus intensive medical management. The parallel trial will assess treatment differences between intensive medical management alone compared to CAS plus intensive medical management. Intensive medical management will involve control of blood pressure, LDL cholesterol, cigarette smoking, and other vascular risk factors.

Sponsors and Collaborators:

Sponsor: Thomas G. Brott, M.D.
National Institute of Neurological Disorders and Stroke (NINDS), Cooperative Agreement U01 NS080168
Investigators:
Principal Investigator: Thomas Brott, MD, Mayo Clinic Florida

Principal Investigator: James Meschia, MD, Mayo Clinic Florida

Principal Investigator: Brajesh K. Lal, MD, University of Maryland

Principal Investigator: George Howard, DrPH University of Alabama at Birmingham

FDA, CDRH: IDE: # G130221

For More information:
- CREST-2 Website: www.crest2trial.org
- ClinicalTrials.gov Identifier: NCT02089217, Link: http://clinicaltrials.gov/ct2/show/NCT02089217
- Trial WebSite Link: Pending
CREST-H: Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial - Hemodynamics
Trial Summary:

The goal of this study is to determine whether a subset of CREST-2 patients with cerebral hemodynamic impairment on the side of high-grade (asymptomatic) stenosis and mild cognitive impairment will benefit cognitively from revascularization.

Prior studies show that patients with high-grade carotid stenosis may have cognitive impairment if they have lowered cerebral blood flow on the side of carotid occlusion. Case series suggest this may be reversible with revascularization, but this observation has never been demonstrated in a randomized clinical trial.

As an ancillary study to the CREST-2 clinical trial, CREST-H will assess cognitive outcomes in CREST-2 patients with cerebral hypoperfusion and mild cognitive impairment, comparing those who get revascularized (CEA or CAS) versus those who get Intensive Medical Management alone.

The main hypothesis is that patients with hemodynamic impairment due to the carotid stenosis have a reversible factor contributing to their mild cognitive impairment, and thus, compared with those who have no hemodynamic impairment, will benefit cognitively from reversing the hemodynamic impairment.

Trial Design Summary:

We will enroll 500 patients from 75 CREST-2 sites. All subjects enrolled in CREST-H will have an MRI perfusion scan to look for hemodynamic flow impairment by a time-to-peak delay on the side of stenosis. Scans will be performed locally and analyzed centrally for categorization of flow impairment. The primary outcome measure is change in cognition at 1 year. The group with cognitive impairment and flow asymmetry will be compared by treatment (revascularization vs medical management alone) with the group with cognitive impairment but no flow asymmetry. Silent infarcts, white matter hyperintensity volumes and microbleeds will also be obtained by MRI for secondary endpoint analysis.

Sponsors and Collaborators:

Sponsor: Randolph S Marshall, MD, MS
National Institute of Neurological Disorders and Stroke (NINDS), 1R01NS097876-01A1
Investigators:
Principal Investigator: Randolph Marshall, MD, MS, Columbia University Medical Center

Principal Investigator: Ronald Lazar, PhD, University of Alabama , Birmingham

Principal Investigator: E Sander Connolly, MD, Columbia University Medical Center

Principal Investigator: David Liebeskind, MD, UCLA Geffen School of Medicine

FDA, CDRH: IDE: # G130221

For More information:
- CREST-2 Website: www.crest2trial.org
- ClinicalTrials.gov Identifier: NCT03121209, Link: http://clinicaltrials.gov/ct2/show/NCT03121209
- Trial WebSite Link: Pending
CREST-H Training Webinar

January 2017
SATURN - Statins Use in Intracerebral Hemorrhage Patient
Trial Summary:

SATURN is a multi-center, prospective, randomized, phase 3, pragmatic, open-label, and blinded end-point assessment (PROBE) clinical trial to determine the effects of continuation vs. discontinuation of statins on the risk of intracerebral hemorrhage (ICH) recurrence in patients with lobar hemorrhage. A total of 1,456 patients will be recruited at ~ 140 sites in the United States and Canada coordinated through the NIH/NINDS StrokeNet. Participants presenting within 7 days of a spontaneous lobar ICH while taking statins will be randomized to one of two treatment strategies: discontinuation vs. continuation (restarting) of statin therapy (using the same agent and dose that they were using at ICH onset). Subjects will undergo baseline testing for APOE genotype and will be followed for 24 months to assess for the occurrence of recurrent symptomatic ICH and/or MACCE. Participants will also undergo repeated assessments of quality of life, modified Rankin Scale, and Montreal Cognitive Assessment during the 2-year follow-up period.

Primary Objectives:
- EFFICACY: To evaluate the effects of continuation vs. discontinuation of statins on the risk of ICH recurrence during 24 months of follow-up in patients presenting with a spontaneous lobar lCH while taking a statin drug.
- SAFETY: To determine the effects of discontinuation vs. continuation of statins on the occurrence of any of the following major adverse cerebro-cardiovascular events (MACCE), including: symptomatic ischemic stroke, symptomatic myocardial infarction, newly symptomatic arterial occlusive disease, revascularization procedures for coronary, carotid, or peripheral arterial disease, and vascular death.
Secondary Objective:
- To prospectively examine whether the presence vs. absence of APOE ε4 and APOE ε2 genotypes modifies the effects of statins on the risk of recurrent ICH.
Sponsors and Collaborators:
Sponsor: Beth Israel Deaconess Medical Center/Magdy Selim, MD, PhD
National Institute of Neurological Disorders and Stroke (NINDS)

Principal Investigator:
Magdy Selim, MD, PhD
Beth Israel Deaconess Medical Center
Harvard Medical School

ClinicalTrials.gov NCT # 03907046
Sleep SMART: Sleep for Stroke Management and Recovery Trial

STUDY SITE

Trial Summary:

The primary goals of this study are to determine whether treatment of obstructive sleep apnea (OSA) with positive airway pressure starting shortly after acute ischemic stroke or high risk TIA (1) reduces recurrent stroke, acute coronary syndrome, and all-cause mortality during 6 months after the event, and (2) improves stroke outcomes at 3 months in patients who experienced an ischemic stroke.

Prior studies have shown a clear independent association between OSA, which has a prevalence similar to hypertension among stroke patients, and development of stroke and poor outcomes after ischemic stroke. If the Sleep SMART hypotheses are confirmed, a new strategy to prevent stroke recurrence and improve stroke recovery will be available.

Trial Design Summary:

Sleep SMART has a prospective, randomized, open-label, blinded-endpoint (PROBE) design. This phase 3 multi-site, parallel-group superiority trial compares 6 months of OSA treatment to usual care. The 5-year study includes two trials: a prevention study with an embedded recovery trial.

Sleep SMART aims to randomize 3,062 subjects at 110 sites within StrokeNet. Subjects are followed for 6 months. The primary prevention outcome– recurrence of stroke, acute coronary syndrome, or all-cause mortality– is compared between subjects randomized to positive airway pressure vs. care as usual. The primary recovery outcome, assessed at 3 months, is functional neurologic status.

https://www.uofmhealth.org/news/archive/

Sponsors and Collaborators:
National Institute of Neurological Disorders and Stroke (NINDS)

Principal Investigators:
Devin Brown, MD, MS, University of Michigan
Ronald Chervin, MD, MS, University of Michigan

For more information:
Sleep SMART website: Pending
ClinicalTrails.gov Identifier: Pending