A Study of the Efficacy and Safety of Alteplase in Participants With Mild Stroke (PRISMS)

A Phase IIIB, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of Alteplase in Patients With Mild Stroke: Rapidly Improving Symptoms and Minor Neurologic Deficits (PRISMS)

PRISMS is a double-blind, multicenter, randomized, Phase IIIb study to evaluate the efficacy and safety of intravenous (IV) alteplase in participants with mild acute ischemic strokes that do not appear to be clearly disabling. Participants will be randomized in a 1:1 ratio to receive within 3 hours of last known well time either 1) one dose of IV alteplase and one dose of oral aspirin placebo or 2) one dose of IV alteplase placebo and one dose of oral aspirin 325 milligrams (mg).

Study Overview

• Status: Terminated
• Conditions: Stroke
• Intervention / Treatment: Drug: Alteplase Placebo; Drug: Aspirin; Drug: Alteplase; Drug: Aspirin Placebo

• Study Type: Interventional
• Enrollment (Actual): 313
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-3300
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Banner Good Samaritan Medical Center
    • Tucson, Arizona, United States, 85724-5030
      • University of Arizona
  • California
    • Fullerton, California, United States, 92835
      • St. Jude Medical Center
    • La Jolla, California, United States, 92093
      • University of California San Diego
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center
    • Newport Beach, California, United States, 92658
      • Hoag Memorial Hospital
    • Santa Monica, California, United States, 90404
      • University of California Los Angeles
  • Colorado
    • Englewood, Colorado, United States, 80113
      • Colorado Neurological Institute
    • Fort Collins, Colorado, United States, 80524
      • Poudre Valley Hospital
    • Loveland, Colorado, United States, 80538
      • Medical Center of the Rockies
  • Connecticut
    • Danbury, Connecticut, United States, 06810
      • Associated Neurologists PC
    • Fairfield, Connecticut, United States, 06824
      • Associated Neurologists of Southern CT PC
    • Hartford, Connecticut, United States, 06102
      • Hartford Hospital
  • Delaware
    • Newark, Delaware, United States, 19718-0002
      • Christiana Care Health Services; Sponsor Programs Ammon Education Center
  • Florida
    • Bradenton, Florida, United States, 34209
      • Nova Clinical Research, LLC
    • Fort Lauderdale, Florida, United States, 33308
      • Neurologic Consultants, P.A.
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine; Clinical Reseach Building
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60612-3244
      • Rush University Medical Center
    • Elk Grove Village, Illinois, United States, 60007
      • Alexian Brothers Neuroscience Institute
  • Indiana
    • Fort Wayne, Indiana, United States, 46845
      • Parkview Research Center
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Kentucky
    • Edgewood, Kentucky, United States, 41017
      • St. Elizabeth Edgewood; Cancer Care Center" for Account St. Elizabeth Edgewood
    • Elizabethtown, Kentucky, United States, 42791
      • University of Louisville
    • Florence, Kentucky, United States, 41042
      • St. Elizabeth Florence
    • Fort Thomas, Kentucky, United States, 41075
      • St. Elizabeth Fort Thomas
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky
  • Maryland
    • Baltimore, Maryland, United States, 21215
      • Sinai Hospital of Baltimore
    • Randallstown, Maryland, United States, 21133
      • Northwest Hospital Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Detroit Receiving Hospital
    • Lansing, Michigan, United States, 48909
      • Sparrow Health System
    • Pontiac, Michigan, United States, 48341
      • St Joesph Mercy Hospital Oakland
    • Royal Oak, Michigan, United States, 48073
      • Beaumont Hospital
  • Minnesota
    • Golden Valley, Minnesota, United States, 55422
      • The Minneapolis Clinic of Neurology
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Columbia, Missouri, United States, 65212
      • University of Missouri Health Care
    • Saint Louis, Missouri, United States, 63128
      • Washington University
  • Nevada
    • Reno, Nevada, United States, 89502
      • Renown Health; Renown Institute for Neurosciences
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
    • Summit, New Jersey, United States, 07902
      • Overlook Hospital
    • Toms River, New Jersey, United States, 08755
      • Shore Neurology
  • New York
    • Brooklyn, New York, United States, 11203
      • SUNY Downstate Medical Center.
    • Brooklyn, New York, United States, 11220
      • Lutheran Medical Center
    • Buffalo, New York, United States, 14203
      • Buffalo General Medical Center
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10029
      • Ichan School of Medicine at Mount Sinai
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina at Chapel Hill
    • Greensboro, North Carolina, United States, 27401
      • Guilford Neurologic Associates
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Medical Center
  • Ohio
    • Akron, Ohio, United States, 44307
      • Akron General Medical Center
    • Cincinnati, Ohio, United States, 45219
      • The Christ Hospital
    • Cincinnati, Ohio, United States, 45203-0542
      • University of Cincinnati
    • Cincinnati, Ohio, United States, 45211
      • West Hospital
    • Cincinnati, Ohio, United States, 45236
      • Jewish Hospital
    • Cincinnati, Ohio, United States, 45255
      • Anderson Hospital
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Cleveland, Ohio, United States, 44109
      • Case Western Reserve University
    • Columbus, Ohio, United States, 43214
      • Riverside Methodist Hospital
    • Dayton, Ohio, United States, 45409
      • Wright State University
    • Fairfield, Ohio, United States, 45014
      • Fairfield Hospital
    • Toledo, Ohio, United States, 43614
      • University of Toledo Medical Center
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Portland Medical Center
    • Portland, Oregon, United States, 97225
      • Providence Saint Vincent's Medical Center
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18105
      • LeHigh Valley Hospital
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Philadelphia, Pennsylvania, United States, 19141
      • Albert Einstein Healthcare Network
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
    • Pittsburgh, Pennsylvania, United States, 15219
      • University of Pittsburgh Cancer Institute
    • York, Pennsylvania, United States, 17403
      • York Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina; MSC 300
    • Columbia, South Carolina, United States, 29203-7606
      • University of South Carolina School of Medicine
    • Orangeburg, South Carolina, United States, 29118
      • The Neurology and Pain Clinic
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Chattanooga Center for Neurologic Research
    • Knoxville, Tennessee, United States, 37920
      • University of Tennessee Medical Center
  • Texas
    • Harlingen, Texas, United States, 78550
      • Valley Baptist Medical Center
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center Houston
    • Houston, Texas, United States, 77030
      • Methodist Neurological Institute
    • Lubbock, Texas, United States, 79430
      • Texas Tech Univ Health Sci Ctr
    • San Antonio, Texas, United States, 78229
      • University Hospital San Antonio
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Inova Fairfax Hospital
  • Washington
    • Seattle, Washington, United States, 98122
      • Swedish Medical Center
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University Hospital
  • Wisconsin
    • La Crosse, Wisconsin, United States, 54601
      • Gunderson Health System
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Mild ischemic stroke defined as the most recent pre-treatment NIHSS score of less than or equal to(</=) 5 and determined as not clearly disabling by the investigator
• Study treatment initiated within 3 hours of last time participant seen normal

Exclusion Criteria:

• Computed tomography (CT) or magnetic resonance imaging (MRI) findings of one of the following:

  1. CT with clear large hypodensity that is greater than (>) one-third middle cerebral artery (MCA) territory (or >100 cubic centimeter [cc] if not in MCA territory)
  2. MRI with clear large hyperintensity on concurrent diffusion-weighted (DW) and fluid-attenuated inversion recovery (FLAIR) that is greater than one-third MCA territory (or greater than 100 cc if not in MCA territory),
  3. Imaging lesion consistent with acute hemorrhage, or
  4. Evidence of intraparenchymal tumor
• Disability prior to the presenting stroke

• Standard contraindications to IV alteplase within 3 hours of symptom onset, including:

  1. Head trauma, myocardial infarction, or previous stroke within the previous 3 months
  2. Gastrointestinal or urinary tract hemorrhage within the previous 21 days
  3. Major surgery within the previous 14 days
  4. Arterial puncture at non-compressible site within the previous 7 days
  5. Any history of ICH with the exception of those less than (<) 5 chronic microbleeds on MRI
  6. Elevated blood pressure defined by systolic blood pressure >185 millimeters of mercury (mm Hg) or diastolic blood pressure >110 mm Hg, or treatments requiring aggressive measures to achieve acceptable levels
  7. Treatment with unfractioned heparin within past 48 hours and activated partial thromboplastin time outside normal range
  8. Blood glucose <50 milligrams per deciliter (mg/dL)
  9. International normalized ratio >1.7
  10. Platelet count <100,000 per cubic millimeter (/mm^3)
  11. Treatment with a direct thrombin inhibitor (dabigatran) or a factor Xa inhibitor (apixaban, rivaroxaban, edoxaban) within the last 48 hours
• Allergic reaction to study drug, aspirin, or nonsteroidal anti-inflammatory drugs (NSAIDs)
• Females of childbearing age who are known to be pregnant and/or lactating
• Inability to swallow, which would prevent oral intake of aspirin or aspirin placebo tablet
• Other serious, advanced, or terminal illness that would confound the clinical outcome at 90 days
• Current or recent (within 3 months) participation in another investigational drug treatment protocol
• Anticipated inability to obtain 3-month follow-up assessments
• Previous enrollment in PRISMS
• Any other condition deemed by the investigator that would pose hazard to the participant with alteplase treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Alteplase Placebo + Aspirin; Participants will receive single dose of IV alteplase placebo and aspirin orally.	Drug: Alteplase Placebo; Single dose of alteplase placebo will be administered as IV injection.; Drug: Aspirin; Single dose of aspirin will be administered at 325 mg orally.
Experimental: Alteplase + Aspirin Placebo; Participants will receive single dose of IV alteplase and aspirin placebo orally.	Drug: Alteplase; Single dose of alteplase will be administered at 0.9 milligrams per kilogram (mg/kg) IV (maximal dose of 90 mg).; Other Names: Activase; RO5532960; Drug: Aspirin Placebo; Single dose of aspirin placebo will be administered orally.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With a Modified Rankin Scale (mRS) Score of 0 or 1 at Day 90	mRS score was determined by the investigator. The mRS is a 7 point scale (0-6) with 0: No symptoms at all, 1: No significant disability despite symptoms, able to carry out all usual duties and activities, 2: Slight disability, unable to carry out all previous activities but able to look after own affairs without assistance, 3: Moderate disability requiring some help, but able to walk without assistance, 4: Moderately severe disability, unable to walk without assistance and unable to attend to own bodily needs without assistance, 5: Severe disability, bedridden, incontinent and requiring constant nursing care and attention, 6: death prior to Day 90. Reported is the percentage of participants with scores of 0 or 1 on the mRS.	Day 90

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Distribution of Participants Across the Ordinal mRS	mRS score was determined by the investigator. The mRS is a 7 point scale (0-6) with 0: No symptoms at all, 1: No significant disability despite symptoms, able to carry out all usual duties and activities, 2: Slight disability, unable to carry out all previous activities but able to look after own affairs without assistance, 3: Moderate disability requiring some help, but able to walk without assistance, 4: Moderately severe disability, unable to walk without assistance and unable to attend to own bodily needs without assistance, 5: Severe disability, bedridden, incontinent and requiring constant nursing care and attention, 6: death before Day 90. Reported are the percentages of participants for all scores on the mRS.	Day 90
Percentage of Participants With Global Favorable Recovery on mRS, NIHSS, BI, and GOS	Global favorable recovery is an integrated assessment of participants who meet the following: mRS Score 0-1, National Institutes of Health Stroke Scale (NIHSS) Score 0-1, Barthel Index [BI] greater than or equal to 95, and Glasgow Outcome Scale [GOS] equal to 1. mRS Score 0-1: 0= No symptoms at all, 1= No significant disability despite symptoms, able to carry out all usual duties and activities. NIHSS Score 0-1: 0= No stroke symptoms and 1= Minor stroke symptoms. BI is a 10 question index with a total score range of 0-100 with 100 being the best outcome. GOS =1: Good recovery. Reported here are the percentages of participants who achieved a favorable score on each of these scales.	Day 90
Percentage of Participants With Symptomatic Intracranial Hemorrhage (ICH )	ICH was considered symptomatic if it was not seen on computed tomography (CT) or magnetic resonance imaging (MRI) scan at baseline and any neurologic decline was attributed to it by the local investigator. To detect intracranial hemorrhage, neuroimaging (CT or MRI) scan was performed at 22 to 36 hours after study drug administration.	Within 36 hours after study drug administration on Day 1
Percentage of Participants With Any ICH	To detect ICH, neuroimaging (CT or MRI) scan was performed at 22 to 36 hours after study drug administration.	Within 36 hours after study drug administration on Day 1
Overall Mortality	Reported here is the percentage of participants who died due to any cause during the study.	From baseline to Day 90
Percentage of Participants Who Died Due to Stroke and Neurological Disorders	Reported here is the percentage of participants who died due to stroke and neurological disorders.	From baseline to Day 90
Percentage of Participants With Adverse Events	An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.	From baseline up to Day 90: Non-serious adverse events were collected through the Day 30 visit. Serious adverse events were collected through the end of study at Day 90.
Percentage of Participants With Serious Adverse Events	A serious adverse event (SAE) was defined as any experience that suggested a significant hazard, contraindication, side effect, or precaution, and fulfilled any of the following criteria: fatal (resulted in death), life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was medically significant or required intervention to prevent any of the other outcomes listed here.	From baseline to Day 90

Collaborators and Investigators

• Sponsor: Genentech, Inc.

Publications and helpful links

General Publications

• Khatri P, Kleindorfer DO, Devlin T, Sawyer RN Jr, Starr M, Mejilla J, Broderick J, Chatterjee A, Jauch EC, Levine SR, Romano JG, Saver JL, Vagal A, Purdon B, Devenport J, Pavlov A, Yeatts SD; PRISMS Investigators. Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits: The PRISMS Randomized Clinical Trial. JAMA. 2018 Jul 10;320(2):156-166. doi: 10.1001/jama.2018.8496.
• Zhao W, Mu Y, Tayama D, Yeatts SD. Comparison of statistical and operational properties of subject randomization procedures for large multicenter clinical trial treating medical emergencies. Contemp Clin Trials. 2015 Mar;41:211-8. doi: 10.1016/j.cct.2015.01.013. Epub 2015 Jan 29.
• Choi JC, Jang MU, Kang K, Park JM, Ko Y, Lee SJ, Cha JK, Kim DH, Park SS, Park TH, Lee KB, Lee J, Kim JT, Cho KH, Yu KH, Oh MS, Lee BC, Cho YJ, Kim DE, Lee JS, Lee J, Gorelick PB, Bae HJ. Comparative effectiveness of standard care with IV thrombolysis versus without IV thrombolysis for mild ischemic stroke. J Am Heart Assoc. 2015 Jan 27;4(1):e001306. doi: 10.1161/JAHA.114.000596.

Helpful Links

• PRISMS website

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2014
• Primary Completion (Actual): March 22, 2017
• Study Completion (Actual): March 22, 2017

Study Registration Dates

• First Submitted: February 24, 2014
• First Submitted That Met QC Criteria: February 24, 2014
• First Posted (Estimate): February 26, 2014

Study Record Updates

• Last Update Posted (Actual): July 3, 2018
• Last Update Submitted That Met QC Criteria: June 4, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Aspirin; Tissue Plasminogen Activator
• Other Study ID Numbers: ML29093

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No