Phase 2 Proof-of-Concept Study of the Safety and Efficacy of Alfimeprase to Rapidly Open Arteries and Restore Brain Function Following a Stroke

Sponsor

ARCA Biopharma, Inc. (Industry)

Overall Status

Terminated

CT.gov ID

NCT00499902

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

0.3

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to identify a safe and effective bolus dose of intra-arterial/intra-thrombus alfimeprase in acute ischemic stroke (AIS) 3 to 9 hours from symptom onset.

Condition or Disease	Intervention/Treatment	Phase
Acute Ischemic Stroke	Drug: alfimeprase	Phase 2

Detailed Description

Currently approved drug therapy for AIS is limited by the need to treat within 3 hours of symptom onset. Alfimeprase acts to degrade fibrin directly and is inactivated locally by circulating alpha-2 macroglobulin. This study will determine whether treatment with alfimeprase facilitates rapid restoration of arterial blood flow with avoidance of symptomatic hemorrhagic conversion in subjects with AIS within 3 to 9 hours of symptom onset.

Study Design

Study Type:

Interventional

Actual Enrollment :

7 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase 2, Multicenter, Open-Label, Two-Stage Study to Evaluate the Safety and Efficacy of Intra-Arterial Catheter-Directed Alfimeprase for Restoration of Neurologic Function and Rapid Opening of Arteries in Stroke (CARNEROS-1)

Study Start Date :

Jun 1, 2007

Anticipated Primary Completion Date :

May 1, 2008

Anticipated Study Completion Date :

May 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Other: 2 stages This is a two-stage study. The first stage is in a three-tier dose escalation format, followed by a second stage during which subjects will be randomized in an equal proportion to up to 3 qualifying dose arms.	Drug: alfimeprase Alfimeprase will be given as a single bolus of 1mg/2mL, or a split bolus of 5mg/2mL or 10mg/2mL in a three-tier dose escalation format. The 5mg and 10mg doses will be administered as split doses with 1/2 of the total dose given initially and 1/2 of the total dose given 30 minutes after the initial dose.

Arm

Intervention/Treatment

Other: 2 stages

This is a two-stage study. The first stage is in a three-tier dose escalation format, followed by a second stage during which subjects will be randomized in an equal proportion to up to 3 qualifying dose arms.

Drug: alfimeprase

Alfimeprase will be given as a single bolus of 1mg/2mL, or a split bolus of 5mg/2mL or 10mg/2mL in a three-tier dose escalation format. The 5mg and 10mg doses will be administered as split doses with 1/2 of the total dose given initially and 1/2 of the total dose given 30 minutes after the initial dose.

Outcome Measures

Primary Outcome Measures

Symptomatic intracerebral hemorrhage (ICH) defined as a greater than or equal to 4-point increase in NIHSS compared to baseline at the time of CT evidence of ICH within 24 hours of study drug administration. []
Recanalization of primary arterial occlusive lesion (AOL) using the Thrombolysis in Myocardial Infarction (TIMI) classification; a score of II or III will be considered success. []

Secondary Outcome Measures

Relative hypotension requiring treatment (i.e. volume expanders and/or vasopressors) []
New cardiac events (e.g., cardiac ischemia, congestive heart failure, and dysrhythmia) []
Relative hypotension not requiring treatment []
Major bleeding events (TIMI definition) []
Hemorrhagic transformation: hemorrhagic infarction (Type 1 and 2), parenchymal hematoma formation (Type 1 and 2) []
Intracerebral hemorrhage outside of the stroke territory []
New AIS []
AEs/SAEs/All cause mortality []
Changes in chemistry, hematology, coagulation, and alpha-2-macroglobulin parameters based on central laboratory measurements []
Anti-alfimeprase antibody detection based on central laboratory measurements []
Recanalization of the primary AOL []
Global reperfusion of the primary AOL distal vascular bed defined by the Thrombolysis in Cerebral Infarction (TICI) score []
Neurological benefit as assessed by individual and combined analysis of NIHSS, mRS, and BI []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Clinical diagnosis of AIS defined as the sudden onset of an acute focal neurological deficit presumed to be due to cerebral ischemia
Arterial occlusion of the carotid T or a M1, M2, or M1-M2 branch of the middle cerebral artery (MCA) as documented by CT angiography or magnetic resonance angiography
Arteriographically confirmed occlusion of the carotid T or a M1, M2, or M1-M2 branch of the MCA
The subject (or legally acceptable representative) must give written informed consent
Age 18 years to 85 years
Onset of symptoms of AIS (i.e., last known well time) within 3-9 hours
Baseline NIHSS of 4 to 25
Available for follow-up assessments at 30 and 90 days

Exclusion Criteria:

Contraindication to systemic anticoagulation including any history of prior intracranial hemorrhage
Uncontrolled hypertension at study entry as defined by systolic blood pressure greater than 180 mmHg or diastolic blood pressure greater than or equal to 100 mmHg on repeated measures prior to study entry despite the use of IV antihypertensive agents
Expectation based on timing of presentation that alfimeprase administration will not be able to be completed by 9 hours after stroke onset
Inability to initiate alfimeprase within 120 minutes of the qualifying imaging scan
Coma
Rapidly improving neurological symptoms at the time of screening
Brain CT or MRI evidence of intracranial bleeding of any age
High clinical suspicion for subarachnoid hemorrhage despite a negative baseline CT or MRI
CT evidence of an acute and/or evolving hypodensity greater than 1/3 of the MCA territory in the vascular territory to be treated or Alberta Stroke Program Early CT Score (ASPECTS) of less than or equal to 5
MRI diffusion weighted imaging lesion greater than 1/3 of the MCA territory in the vascular distribution to be treated
Carotid artery and/or intracranial artery stenosis that precludes safe passage of a microcatheter to treat the primary AOL
Life expectancy of less than 6 months
History of significant acute or chronic kidney disease, including known nephrotic syndrome, that would preclude safe contrast angiography
Known allergy to contrast agents
History of immune deficiency
History of heparin-induced thrombocytopenia
Participation in any study of an investigational device, medication, biologic, or other agent within 30 days prior to enrollment (Stage I)/randomization (Stage II)
Any stroke, myocardial infarction, or use of thrombolytic therapy (including investigational thrombolytic therapy) within 3 months prior to enrollment (Stage I)/randomization (Stage II)
Past participation in any alfimeprase clinical trial
Pregnant, lactating, or actively menstruating women and women of child-bearing potential who are not using adequate contraceptive precautions
Current use of oral anticoagulants or an international normalized ratio (INR) greater than 1.4
Any non-atherosclerotic arteriopathy
Any prior neurologic event that would obscure the radiographic or clinical evaluation of the new index neurological deficits
Subjects with known renal insufficiency defined as a serum creatinine >2 mg/dL (>180 mmoL/L)
Subjects with known clinically significant hepatic disease defined as transaminase values > 3x upper limit of normal
Subjects with any malignant neoplasm diagnosed within five years prior to screening, with the exception of basal cell carcinoma of the skin and fully resected squamous cell carcinoma of the skin
Subjects with a platelet count less than 100,000/mm3
Subjects with a baseline serum glucose level less than 50 mg/dL or greater than 300 mg/dL
Subjects receiving any dose of a heparinoid or a non-prophylactic intensity dose of a low molecular weight heparin within the 24-hour period prior to study drug administration
Any other subject feature that in the opinion of the investigator should preclude study participation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA Medical Center	Los Angeles	California	United States	90024
2	Northwestern Medical Center	Chicago	Illinois	United States	60611
3	Ruan Neurology & Clinical Research Center	Des Moines	Iowa	United States	50314
4	University of Iowa Hospital	Iowa City	Iowa	United States	52242
5	University of Iowa Hospital	Iowa City	Iowa	United States	53342
6	University of Kansas School of Medicine, Via Christi Regional Medical Center	Wichita	Kansas	United States	67214
7	Norton Hospital	Louisville	Kentucky	United States	40202
8	Michigan State University, Sparrow Hospital	Lansing	Michigan	United States	48912
9	Albany Medical Center Hospital	Albany	New York	United States	12208
10	Kalieda Health, MFH	Buffalo	New York	United States	14203
11	Columbia Presbyterian Medical Center	New York	New York	United States	10032
12	University of Cincinnati	Cincinnati	Ohio	United States	45243
13	Riverside Methodist Hospital	Columbus	Ohio	United States	43214
14	Oregon Stroke Center	Portland	Oregon	United States	97239
15	University of Pittsburg Medical Center	Pittsburg	Pennsylvania	United States	15213
16	Baylor College of Medicine	Houston	Texas	United States	77030
17	St. Luke's Medical Center	Milwaukee	Wisconsin	United States	53215
18	University of Calgary, Foothills Medical Centre	Calgary	Alberta	Canada	T2N 2T9
19	Vancouver General Hospital	Vancouver	British Columbia	Canada	V52 1M9
20	Trilium Health Center	Mississauga	Ontario	Canada	L5B4A2
21	University Health Network Toronto	Toronto	Ontario	Canada	M5T 258
22	Montreal Neurological Institute	Montreal	Quebec	Canada	H3A 2B4