The Spot Sign for Predicting and Treating ICH Growth Study | NCT00810888

NCT00810888

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

No data available

No data is available for this block.

Derived Section

Miscellaneous Info Module

ID	Type	Description	Link
2P50NS044283	U.S. NIH Grant/Contract		View source

Status Module

Name	Class
National Institute of Neurological Disorders and Stroke (NINDS)	NIH

Description Module

Detailed Description

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.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Group 1-Recombinant activated factor VII	Active Comparator	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
Group 2 - Placebo	Placebo Comparator	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
Group 3 - Observation Only Arm	No Intervention	Participants with ICHdetermined by CTA not to be at high risk for hemorrhage growth (CTA "spot sign" negative) enrolled into a prospective observational group.

Interventions

Name	Type	Description	Arm Group Labels	Other Names
recombinant activated factor VII	Drug	Participants will receive rFVIIa at 80 mcg/kg (maximum dose volume 21.3 mL, equivalent to maximum weight of 160 kg).	Group 1-Recombinant activated factor VII

Outcomes Module

Primary Outcomes

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 Outcomes

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

Eligibility Module

Eligibility Criteria

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

Name	Affiliation	Role
Matthew L. Flaherty, MD	University of Cincinnati	Principal Investigator
Edward C. Jauch, MD, MS	Primary Emergency Medicine Investigator, Medical University of South Carolina	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
St. Joseph's Hospital and Medical Center		Phoenix	Arizona	85013	United States
University of California, San Diego

PubMed Identifier	Type	Citation	Retractions
31424491	Derived	Gladstone DJ, Aviv RI, Demchuk AM, Hill MD, Thorpe KE, Khoury JC, Sucharew HJ, Al-Ajlan F, Butcher K, Dowlatshahi D, Gubitz G, De Masi S, Hall J, Gregg D, Mamdani M, Shamy M, Swartz RH, Del Campo CM, Cucchiara B, Panagos P, Goldstein JN, Carrozzella J, Jauch EC, Broderick JP, Flaherty ML; SPOTLIGHT and STOP-IT Investigators and Coordinators. Effect of Recombinant Activated Coagulation Factor VII on Hemorrhage Expansion Among Patients With Spot Sign-Positive Acute Intracerebral Hemorrhage: The SPOTLIGHT and STOP-IT Randomized Clinical Trials. JAMA Neurol. 2019 Dec 1;76(12):1493-1501. doi: 10.1001/jamaneurol.2019.2636.

Label	URL
trial website	View source

Arm/Group Information

ID	Title	Description
FG000	Group 1 - Randomized to Study Drug	Participants with ICH who are determined by CTA to be at high risk for hemorrhage growth (or determined to be CTA "spot sign" positive for contrast leakage within the brain hematoma) will be randomized to receive either rFVIIa at 80 mcg/kg (maximum dose volume 21.3 mL, equivalent to maximum weight of 160 kg) or a placebo . Recombinant activated factor VII: Participants will receive rFVIIa at 80 mcg/kg (maximum dose volume 21.3 mL, equivalent to maximum weight of 160 kg).
FG001	Group 2 - Randomized to Placebo	Participants with ICH who are determined by CTA to be at high risk for hemorrhage growth (or determined to be CTA "spot sign" positive for contrast leakage within the brain hematoma) will be randomized to receive either rFVIIa at 80 mcg/kg or a placebo (maximum dose volume 21.3 mL, equivalent to maximum weight of 160 kg). Placebo: An inactive substance (maximum dose volume 21.3 mL, equivalent to maximum weight of 160 kg)
FG002	Group 3 - Observation Only Arm	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.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Group 1 - Randomized to Study Drug	Participants with ICH who are determined by CTA to be at high risk for hemorrhage growth (or determined to be CTA "spot sign" positive for contrast leakage within the brain hematoma) will be randomized to receive either rFVIIa at 80 mcg/kg (maximum dose volume 21.3 mL, equivalent to maximum weight of 160 kg) or a placebo . Recombinant activated factor VII: Participants will receive rFVIIa at 80 mcg/kg (maximum dose volume 21.3 mL, equivalent to maximum weight of 160 kg).

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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

The analysis population consists of 19 subjects diagnosed as "Spot Positive" on CT who were eligible for randomization within the clinical trial portion of the protocol, as well as 73 subjects diagnosed as "Spot Negative" on CT who were followed prospectively with no study intervention. Statistical comparison involves only Group1 and Group 2.

Posted

Count of Participants

Participants

through day 4 after completion of study drug administration

ID	Title	Description
OG000	Group 1 - Randomized to Study Drug	Participants with ICH who are determined by CTA to be at high risk for hemorrhage growth (or determined to be CTA "spot sign" positive for contrast leakage within the brain hematoma) will be randomized to receive either rFVIIa at 80 mcg/kg (maximum dose volume 21.3 mL, equivalent to maximum weight of 160 kg) or a placebo . Recombinant activated factor VII: Participants will receive rFVIIa at 80 mcg/kg (maximum dose volume 21.3 mL, equivalent to maximum weight of 160 kg).

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Group 1 - Randomized to Study Drug	Participants with ICH who are determined by CTA to be at high risk for hemorrhage growth (or determined to be CTA "spot sign" positive for contrast leakage within the brain hematoma) will be randomized to receive either rFVIIa at 80 mcg/kg (maximum dose volume 21.3 mL, equivalent to maximum weight of 160 kg) or a placebo . Recombinant activated factor VII: Participants will receive rFVIIa at 80 mcg/kg (maximum dose volume 21.3 mL, equivalent to maximum weight of 160 kg).

ID	Term
D020300	Intracranial Hemorrhages
D002561	Cerebrovascular Disorders
D001927	Brain Diseases
D002493	Central Nervous System Diseases