NCT02072226: PRISMS

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

Terminated Phase 3 Results posted Last updated 3 July 2018

What this trial tests

Phase 3 trial testing Alteplase in Stroke in 313 participants. Terminated before completion.

Timeline

31 May 2014

Primary endpoint
22 March 2017

22 March 2017

Quick facts

Lead sponsor	Genentech, Inc.
Phase	Phase 3
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	313
Start date	31 May 2014
Primary completion	22 March 2017
Estimated completion	22 March 2017
Sites	88 locations across United States

Drugs / interventions tested

• Alteplase (ALTEPLASE) — full drug profile →
• Alteplase Placebo
• Aspirin — full drug profile →
• Aspirin Placebo — full drug profile →

Conditions studied

• Stroke — all drugs for Stroke →

Sponsor

Genentech, Inc. — full company profile →

Who can join

18 and older, any sex, with Stroke. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants With a Modified Rankin Scale (mRS) Score of 0 or 1 at Day 90 Primary · 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 consta

Group	Value	95% CI
Alteplase + Aspirin Placebo	78.2
Alteplase Placebo + Aspirin	81.5

Distribution of Participants Across the Ordinal mRS Secondary · 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 consta

mRS at Day 90 - 0

Group	Value	95% CI
Alteplase + Aspirin Placebo	44.9
Alteplase Placebo + Aspirin	50.3

mRS at Day 90 - 1

Group	Value	95% CI
Alteplase + Aspirin Placebo	33.3
Alteplase Placebo + Aspirin	31.2

mRS at Day 90 - 2

Group	Value	95% CI
Alteplase + Aspirin Placebo	11.5
Alteplase Placebo + Aspirin	11.5

mRS at Day 90 - 3

Group	Value	95% CI
Alteplase + Aspirin Placebo	2.6
Alteplase Placebo + Aspirin	3.2

mRS at Day 90 - 4

Group	Value	95% CI
Alteplase + Aspirin Placebo	5.1
Alteplase Placebo + Aspirin	2.5

mRS at Day 90 - 5 or 6 (death)

Group	Value	95% CI
Alteplase + Aspirin Placebo	2.6
Alteplase Placebo + Aspirin	1.3

Percentage of Participants With Global Favorable Recovery on mRS, NIHSS, BI, and GOS Secondary · Day 90

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 her

mRS 0 - 1 at Day 90

Group	Value	95% CI
Alteplase + Aspirin Placebo	78.2
Alteplase Placebo + Aspirin	81.5

NIHSS 0 - 1 at Day 90

Group	Value	95% CI
Alteplase + Aspirin Placebo	85.0
Alteplase Placebo + Aspirin	81.7

BI >= 95 at Day 90

Group	Value	95% CI
Alteplase + Aspirin Placebo	79.3
Alteplase Placebo + Aspirin	88.7

GOS = 1 at Day 90

Group	Value	95% CI
Alteplase + Aspirin Placebo	81.5
Alteplase Placebo + Aspirin	85.6

Percentage of Participants With Symptomatic Intracranial Hemorrhage (ICH ) Secondary · Within 36 hours after study drug administration on Day 1

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.

Group	Value	95% CI
Alteplase + Aspirin Placebo	3.2
Alteplase Placebo + Aspirin	0

Percentage of Participants With Any ICH Secondary · Within 36 hours after study drug administration on Day 1

To detect ICH, neuroimaging (CT or MRI) scan was performed at 22 to 36 hours after study drug administration.

Any ICH within 36 hours reported by site

Group	Value	95% CI
Alteplase + Aspirin Placebo	7.1
Alteplase Placebo + Aspirin	2.6

Any ICH within 36 hours reported by central reader

Group	Value	95% CI
Alteplase + Aspirin Placebo	7.1
Alteplase Placebo + Aspirin	3.3

Overall Mortality Secondary · From baseline to Day 90

Reported here is the percentage of participants who died due to any cause during the study.

Group	Value	95% CI
Alteplase + Aspirin Placebo	0.6
Alteplase Placebo + Aspirin	0

Percentage of Participants Who Died Due to Stroke and Neurological Disorders Secondary · From baseline to Day 90

Reported here is the percentage of participants who died due to stroke and neurological disorders.

Group	Value	95% CI
Alteplase + Aspirin Placebo	0
Alteplase Placebo + Aspirin	0

Percentage of Participants With Adverse Events Secondary · 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.

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.

Group	Value	95% CI
Alteplase + Aspirin Placebo	77.3
Alteplase Placebo + Aspirin	68.0

Percentage of Participants With Serious Adverse Events Secondary · From baseline to Day 90

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.

Group	Value	95% CI
Alteplase + Aspirin Placebo	26.0
Alteplase Placebo + Aspirin	13.1

Adverse events — posted to ClinicalTrials.gov

Time frame: Serious adverse events were collected from baseline through the end of study at Day 90. Non-serious adverse events were collected from baseline through the Day 30 visit.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Alteplase + Aspirin Placebo

Serious: 40/154 (26%)

Deaths: 1/154

Alteplase Placebo + Aspirin

Serious: 20/153 (13%)

Deaths: 0/153

Serious adverse events (61 terms)

Reaction	System	Alteplase + Aspirin Placebo	Alteplase Placebo + Aspirin
Ischaemic stroke	Nervous system disorders	—	—
Stroke in evolution	Nervous system disorders	—	—
Transient ischaemic attack	Nervous system disorders	—	—
Cardiac failure	Cardiac disorders	—	—
Cardiogenic shock	Cardiac disorders	—	—
Urinary tract infection	Infections and infestations	—	—
Seizure	Nervous system disorders	—	—
Haemorrhagic transformation stroke	Nervous system disorders	—	—
Cerebral haemorrhage	Nervous system disorders	—	—
Cerebrovascular accident	Nervous system disorders	—	—
Haemorrhage intracranial	Nervous system disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Splenic embolism	Blood and lymphatic system disorders	—	—
Sinus node dysfunction	Cardiac disorders	—	—
Acute left ventricular failure	Cardiac disorders	—	—
Acute myocardial infarction	Cardiac disorders	—	—
Cardiac aneurysm	Cardiac disorders	—	—
Cardiac failure acute	Cardiac disorders	—	—
Cardiac failure congestive	Cardiac disorders	—	—
Cardiomyopathy	Cardiac disorders	—	—
Vertigo	Ear and labyrinth disorders	—	—
Vertigo positional	Ear and labyrinth disorders	—	—
Retinal detachment	Eye disorders	—	—
Vitreous haemorrhage	Eye disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—

Other adverse events (6 terms — click to expand)

Reaction	System	Alteplase + Aspirin Placebo	Alteplase Placebo + Aspirin
Headache	Nervous system disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Hyperlipidaemia	Metabolism and nutrition disorders	—	—
Hypertension	Vascular disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—

Most-reported serious reactions: Ischaemic stroke, Stroke in evolution, Transient ischaemic attack, Cardiac failure, Cardiogenic shock, Urinary tract infection, Seizure, Haemorrhagic transformation stroke.

Data from ClinicalTrials.gov NCT02072226 adverse events section.

Sponsor's own description

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).

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits: The PRISMS Randomized Clinical Trial.
   Khatri P, Kleindorfer DO, Devlin T, Sawyer RN, et al · · 2018 · cited 293× · PMID 29998337 · DOI 10.1001/jama.2018.8496
2. Why are acute ischemic stroke patients not receiving IV tPA? Results from a national registry.
   Messé SR, Khatri P, Reeves MJ, Smith EE, et al · · 2016 · cited 156× · PMID 27629092 · DOI 10.1212/wnl.0000000000003198
3. Comparative effectiveness of standard care with IV thrombolysis versus without IV thrombolysis for mild ischemic stroke.
   Choi JC, Jang MU, Kang K, Park JM, et al · · 2015 · cited 34× · PMID 25628404 · DOI 10.1161/jaha.114.000596
4. Intravenous Thrombolysis in Chinese Patients with Different Subtype of Mild Stroke: Thrombolysis in Patients with Mild Stroke.
   Chen W, Pan Y, Zhao X, Liu L, et al · · 2017 · cited 16× · PMID 28536425 · DOI 10.1038/s41598-017-02579-2
5. Effect of alteplase within 6 hours of acute ischemic stroke on all-cause mortality (third International Stroke Trial).
   Whiteley WN, Thompson D, Murray G, Cohen G, et al · · 2014 · cited 15× · PMID 25370587 · DOI 10.1161/strokeaha.114.006890
6. Innovations in Acute Stroke Reperfusion Strategies.
   Vishnu VY, Padma Srivastava MV. · · 2019 · cited 10× · PMID 30692752 · DOI 10.4103/aian.aian_263_18
7. Controversies in Thrombolysis.
   Sandercock PAG, Ricci S. · · 2017 · cited 9× · PMID 28667504 · DOI 10.1007/s11910-017-0767-5
8. Comparison of statistical and operational properties of subject randomization procedures for large multicenter clinical trial treating medical emergencies.
   Zhao W, Mu Y, Tayama D, Yeatts SD. · · 2015 · cited 3× · PMID 25638754 · DOI 10.1016/j.cct.2015.01.013