Clinical trial NCT00810888: The Spot Sign for Predicting and Treating ICH Growth Study
Official title: The Spot Sign for Predicting and Treating Intracerebral Hemorrhage Growth Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Intracerebral Hemorrhage
Keywords: intracerebral hemorrhage
ICH
computed tomography angiography
CTA
recombinant activated factor seven
rFVIIa
NovoSeven
recombinant activated factor VII
Lead sponsor: University of Cincinnati
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2008-12-18
Enrollment: 92
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

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

Primary outcomes:
measure: Number of Study Subjects With Life-threatening Thromboembolic Complications
timeFrame: through day 4 after completion of study drug administration
measure: Number of Subjects With Hematoma Growth Among Spot Sign Positive Subjects at 24 Hours.
timeFrame: From baseline to 24 hours
measure: The Sensitivity of the Spot Sign for Predicting Hematoma Growth
timeFrame: 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.
measure: The Specificity of the Spot Sign for Predicting Hematoma Growth
timeFrame: 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: 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
timeFrame: through day 4 after completion of study drug
measure: Number of Spot Positive Subjects With 90-day Outcome of Modified Rankin Scale Score >= 5
timeFrame: 90 days (+/- 7 days) from time of study enrollment
measure: 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
timeFrame: 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.
measure: Percent Change in Total Hemorrhage Volume (Intracerebral Hemorrhage (ICH) Plus Intraventricular Hemorrhage (IVH)).
timeFrame: 24 hours (+/- 3 hours) from baseline CT scan
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: St. Joseph's Hospital and Medical Center
state: Arizona
city: San Diego
country: United States
facility: University of California, San Diego
state: California
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Cincinnati
country: United States
facility: University of Cincinnati-Clinical Coordinating Center
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Toronto
country: Canada
facility: Sunnybrook Health Science Center
state: Ontario
Study officials:
affiliation: University of Cincinnati
name: Matthew L. Flaherty, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Primary Emergency Medicine Investigator, Medical University of South Carolina
name: Edward C. Jauch, MD, MS
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.