The Spot Sign for Predicting and Treating ICH Growth Study

Study Overview
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Brief Summary
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The purpose of this study is to determine if computed tomography angiography can predict which individuals with intracerebral hemorrhage will experience significant growth in the size of the hemorrhage. For individuals who are at high risk for hemorrhage growth, the study will compare the drug recombinant activated factor VII (rFVIIa) to placebo to determine the effect of rFVIIa on intracerebral hemorrhage growth.

Detailed Description
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Intracerebral hemorrhage (ICH)-breakage of a blood vessel with bleeding in the brain-is a devastating form of stroke with a 40-50 percent fatality rate and no proven treatment. Because the majority of deaths from ICH occur within several days of the stroke, interventions for improving outcomes must occur early in the treatment course. Among the potentially modifiable determinants of ICH outcome, hematoma growth is a particularly attractive target for intervention and a major focus of this trial. The purpose of this study is to determine if an imaging test called computed tomography angiography (CTA) can predict which individuals with ICH will experience significant growth in the size of the hemorrhage. Growth of the hemorrhage can cause additional injury and may worsen the outcome. For individuals who are at high risk for hemorrhage growth based on CTA results (i.e., a positive CTA spot sign, evidence of contrast leakage within the hemorrhage), the study will compare the effects of a drug called recombinant activated factor VII (NovoSeven®) or rFVIIa with a placebo to determine which is better for reducing ICH growth. The primary goals of this trial are (1) to determine the sensitivity and specificity of the CTA spot sign for predicting hematoma growth; (2) to determine the feasibility of using CTA to identify individuals with ICH who are at high risk of hematoma growth and to select study participants for randomization to treatment with rFVIIa or placebo; and (3) to determine the rate of hematoma growth among spot-positive individuals at 24 hours-comparing individuals treated with rFVIIa to those treated with placebo. Approximately 184 persons with ICH will be enrolled in one of two study groups at 12 clinical sites across the United States and Canada. Participants with ICH who are determined by CTA to be at high risk for hemorrhage growth (CTA spot sign positive) will be randomized to receive either the active study medication, rFVIIa, at 80 mcg/kg, or to receive a placebo (an inactive substance). Participants with ICH who are determined by CTA not to be at high risk for hemorrhage growth (determined to be CTA spot sign negative) will be enrolled into a prospective observational group. Duration of the study for participants is approximately 3 months.

Official Title
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The Spot Sign for Predicting and Treating Intracerebral Hemorrhage Growth Study

Conditions
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Intracerebral Hemorrhage

Intervention / Treatment
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* Drug: recombinant activated factor VII
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute, spontaneous ICH (including bleeding in cerebellum) diagnosed by non-enhanced CT scan within five hours of symptom onset. (Time of onset is defined as the last time the patient was witnessed to be at baseline (i.e., subjects who have stroke symptoms upon awakening will be considered to have their onset at beginning of sleep) Age >/= 18 years through 80 years (candidates must have had their 18th birthday, but not had their 81st birthday) For spot positive patients, dosing of study drug within 90 minutes of enrolling CT scan Exclusion Criteria: Time of symptom onset of ICH is unknown or more than five hours prior to baseline CT scan, ICH secondary to known or suspected trauma, aneurysm, vascular malformation, hemorrhagic conversion of ischemic stroke, venous sinus thrombosis, thrombolytic treatment of any condition (e.g., myocardial infarction, cerebral infarction, etc.), central nervous system (CNS) tumor or CNS infection Brainstem location of hemorrhage (patients with cerebellar hemorrhage may be enrolled) Serum creatinine > 1.4 mg/dl (123 μmol/L). Sites that currently perform CTA as standard of care for ICH will follow their standard procedures regarding renal insufficiency. Known allergy to iodinated contrast media Intravenous or intra-arterial administration of iodinated contrast media within the previous 24 hours of baseline CT scan Known hereditary (e.g., hemophilia) or acquired hemorrhagic diathesis, coagulation factor deficiency, or anticoagulant therapy with international normalized ration (INR) > 1.2 Known or suspected thrombocytopenia (unless current platelet count documented above 50,000 / μl) Unfractionated heparin use with abnormal partial thromboplastin time (PTT) Low-molecular weight heparin use within the previous 24 hours GPIIb/IIIa antagonist use in the previous two weeks Direct thrombin inhibitor or factor Xa inhibitor within the previous 48 hours Glasgow Coma Scale score < 8 at time of proposed enrollment Pre-admission modified Rankin Scale score > 2 Baseline ICH volume of < 0.5 cc (Hematoma volume will be estimated by local investigators from the baseline CT using the ABC / 2 method.) Baseline ICH volume of > 90 cc Planned surgical evacuation of ICH within 24 hours of symptom onset (placement of intraventricular catheter is not a contraindication to study enrollment.) Evidence of acute or subacute ischemic stroke on baseline qualifying CT scan Clinical history of thromboembolism or ischemic vascular disease, including myocardial infarction, coronary artery bypass surgery, cardiac angina, transient ischemic attack, ischemic stroke, peripheral artery disease (vascular claudication), cerebral bypass surgery, carotid endarterectomy, deep venous thrombosis, pulmonary embolism, or coronary or cerebrovascular angioplasty or stenting. (Clinically silent evidence of old ischemia on EKG (Q waves) or CT scan (silent old infarct) will not be considered reasons for exclusion.) Baseline electrocardiogram shows evidence of acute cardiac ischemia (ST elevation in two contiguous leads, new left bundle branch block (LBBB), or ST depression) Clinical history suggestive of acute cardiac ischemia (e.g., chest pain) Abnormal baseline troponin Females of childbearing potential who are known to be pregnant and/or lactating or who have positive pregnancy tests on admission Advanced or terminal illness or any other condition the investigator feels would pose a significant hazard to the patient if rFVIIa were administered Recent (within 30 days) participation in any investigational drug or device trial or earlier participation in any investigational drug or device trial for which the duration of effect is expected to persist until the time of STOP-IT enrollment Planned withdrawal of care or comfort care measures Patient known or suspected of not being able to comply with trial protocol (e.g., due to alcoholism, drug dependency or psychological disorder) Informed consent cannot be obtained from the patient or legally authorized representative

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1-Recombinant activated factor VII<br>Participants with ICH determined by CTA to be high risk for hemorrhage growth (spot sign positive for contrast leakage within the brain hematoma) randomized to receive rFVIIa at 80 mcg/kg (max dose 21.3 mL). | Drug: recombinant activated factor VII<br>* Participants will receive rFVIIa at 80 mcg/kg (maximum dose volume 21.3 mL, equivalent to maximum weight of 160 kg).<br>|
| Placebo Comparator: Group 2 - Placebo<br>Participants with ICH determined by CTA to be high risk for hemorrhage growth (spot sign positive for contrast leakage within the brain hematoma) will be randomized to receive placebo. | Drug: placebo<br>* An inactive substance (maximum dose volume 21.3 mL, equivalent to maximum weight of 160 kg)<br>|
| No Intervention: Group 3 - Observation Only Arm<br>Participants with ICHdetermined by CTA not to be at high risk for hemorrhage growth (CTA spot sign negative) enrolled into a prospective observational group. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Study Subjects With Life-threatening Thromboembolic Complications | Thromboembolic complications are defined as development of (1) acute myocardial ischemia; or (2) acute cerebral ischemia; or (3) acute pulmonary embolism | through day 4 after completion of study drug administration | 
| Number of Subjects With Hematoma Growth Among Spot Sign Positive Subjects at 24 Hours. | Comparison of only the subjects with a positive spot sign with respect to a categorical measure of hematoma growth from baseline to 24 hours. the outcome of interest is the percent of subjects with hematoma growth > 33% or > 6 cc increase in volume, from baseline to 24 hours. | From baseline to 24 hours | 
| The Sensitivity of the Spot Sign for Predicting Hematoma Growth | The outcome measure is hematoma growth. Groups 2 and 3 only will be compared as Group 1 had administration of study drug which was hypothesized to reduce hematoma growth. Sensitivity was estimated. Sensitivity or true positive rate is defined as, the number of strokes correctly identified as spot positive according to the gold standard / the total number of strokes identified as spot positive | Baseline head CT scan within 5 hours of stroke, followed by a CT angiogram. Hematoma growth determined by comparison with a head CT scan performed at 24 hours. | 
| The Specificity of the Spot Sign for Predicting Hematoma Growth | The outcome measure is hematoma growth. Groups 2 and 3 only will be compared as group 1 had administration of study drug which was hypothesized to reduce hematoma growth. Specificity was estimated. Specificity or true negative rate is defined as, the number of non-spot positive (spot negative) strokes according to the gold standard / the total number of strokes identified as not spot positive. | Baseline head CT scan within 5 hours of stroke, followed by a CT angiogram. Hematoma growth determined by comparison with a head CT scan performed at 24 hours. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Other Potentially Study Drug Related Thromboembolic Complications Such as Deep Venous Thrombosis (DVT) and Elevations in Troponin Not Associated With ECG Changes | Evidence of a deep venous thrombosis or an elevation of troponin within 4 days of completion of study drug administration that are not associated with ECG changes that could be related to the study drug | through day 4 after completion of study drug | 
| Number of Spot Positive Subjects With 90-day Outcome of Modified Rankin Scale Score >= 5 | The modified Rankin Scale (0 is best, 5 is worst - non dead, 6 is dead) was used to define a bad outcome; categorized as a score >=5 versus <5. As the aim of the study was to examine the effect of rFIV!!a only the randomized groups, 1 and 2, defined as spot positive by CTA were compared. | 90 days (+/- 7 days) from time of study enrollment | 
| Number of Participants With Agreement Between the Clinical Site Radiologists and the Study Radiologist With Respect to Identification of a Positive Spot Sign or the Absence of Positive Spot Sign on CTA | The CTA was originally interpreted by the site radiologist so that subjects could be identified as having a positive spot sign for eligibility for randomization. The positive spot sign is indicative that there is potential for further hemorrhagic growth and these subjects were thus eligible to be randomized to receive investigational drug or placebo. The CTA scans were subsequently assessed by the study radiologist and compared for agreement. | Baseline head CT scan within 5 hours, followed by a CT angiogram. Hematoma growth determined by comparison with a head CT scan performed at 24 hours. | 
| Percent Change in Total Hemorrhage Volume (Intracerebral Hemorrhage (ICH) Plus Intraventricular Hemorrhage (IVH)). | Percent change in total volume (intracerebral hemorrhage (ICH) plus intraventricular hemorrhage (IVH)) from baseline CT to 24 hour CT. Percent change is expressed as difference between 24 hour total volume and baseline total volume divided by baseline total volume, expressed as a percentage. In order to examine the effect of rFIVIIa, the randomized groups, Group 1 and Group 2 only were statistically compared. | 24 hours (+/- 3 hours) from baseline CT scan | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ICH, intracerebral hemorrhage, computed tomography angiography, CTA, recombinant activated factor seven, rFVIIa, NovoSeven, recombinant activated factor VII