NeuroNEXT Human Activated Protein C with tPA in Ischemic Stroke

Principal Investigator: Peter Hannon
Keywords: Acute Stroke , activated protein C after tPA and/or IR Department: Neurology
IRB Number: 00073143 Co Investigator:  
Specialty: Neurology, Neurology
Sub Specialties: Neuro Critical Care, Stroke
Recruitment Status: Active, not recruiting

Contact Information

Crystal Neate
Crystal.neate@hsc.utah.edu
801.581.4258

Brief Summary

 

This is a multicenter, prospective, randomized, controlled, double-blinded Phase 2 study intended to evaluate the safety, PK and preliminary efficacy of 3K3A-APC following administration of tPA in subjects with moderately severe acute ischemic stroke. Approximately 100 subjects will be enrolled, which includes the planned 88 subjects in groups of four to either 3K3A-APC or placebo (in a 3:1 ratio) and the additional placebo subjects who will be enrolled during safety review pauses. This study will utilize a modified version of the CRM in order to establish a MTD.

Following completion of tPA infusion, eligible adult subjects will receive study treatment 60 minutes (+/- 30 minutes) later given as a 15-minute infusion. Subjects will receive another 15-minute infusion of 3K3A-APC every 12 hours (+/- 1 hour) for up to 5 total doses. The initial cohort dose of 3K3A-APC will be 120 μg/kg; the other dose levels that will be evaluated with the CRM are 240, 360, and 540 μg/kg. After the final group of subjects is enrolled, the final MTD will be defined as the dose with estimated toxicity probability closest to the target toxicity level of 10%.

Primary:

• To evaluate the safety of multiple ascending intravenous (IV) doses of 3K3A-APC following tPA administration in subjects who have experienced moderately severe acute hemispheric ischemic stroke.

Secondary:

• To investigate the pharmacokinetic (PK) properties of 3K3A-APC following administration of tPA in adults with acute ischemic stroke.

• To evaluate the effect of 3K3A-APC on all (symptomatic and asymptomatic) bleeding in the brain as determined by MRI at Day 7 (or discharge, whichever is sooner) and Day 30.

Exploratory:

• To collect the 7-day National Institute of Health Scale (NIHSS) scores as a predictor for 90-day modified Rankin Scale (mRS).

• To collect the 90-day mRS

• To collect the 90-day Barthel Index (BI)

• To collect infarct volume at 90 days (CT or T1 MRI)

• To assess the immunogenic potential of 3K3A-APC

Inclusion Criteria

Inclusion Criteria

1. Age 18 to 80 years, inclusive

2. Acute hemispheric ischemic stroke defined as focal, neurological deficit(s), secondary to a presumed vascular occlusive event

3. Able to receive IV tPA within 3 hours of stroke onset

4. National Institute of Health Stroke Scale (NIHSS) of 7 to 20

5. Signed informed consent by subject or authorized representative

6. Agreement to use effective birth control throughout the study:

a) Males - barrier method of contraception plus a spermicide

b) Females of childbearing potential (i.e., not surgically sterile or post-menopausal defined as age > 51 years without menses for ≥ 2 years) – hormonal contraception or barrier method of contraception plus a spermicide

7. Willing (subject and/or caretaker) to commit to follow-up assessments

Exclusion Criteria

Neurologic

1. Rapid spontaneous improvement of neurological signs during screening

2. History of stroke or penetrating head injury within 90 days prior to enrollment

3. History of previous or current diagnosis of intracranial hemorrhage (i.e., intracerebral, epidural, subdural or subarachnoid), moyamoya disease, cerebral arterio-venous malformation (AVM), known unsecured aneurysm, or intracranial neoplasm

4. Presence of other neurological or non-neurological co-morbidities (e.g., intracerebral neoplasm, metabolic encephalopathies, hemiplegic migraine, multiple sclerosis, convulsive disorder, monocular blindness) that, in the Investigator’s opinion, may lead, independently of the current stroke, to further deterioration in the subject’s neurological status during the trial period, or may render the study’s neurological assessments inconclusive for the purpose of evaluating the effect of investigational product on the stroke

5. Presence of premorbid neurological deficits and functional limitations assessed by a retrospective Modified Rankin Scale (mRS) score of ≥ 2

 Non-Neurological

6. Use of oral anticoagulants within 48 hours

7. Prolonged prothrombin time (INR >1.6)

8. Prolonged partial thromboplastin time (PTT) > 1.67 x upper limit of normal (ULN)

9. Use of heparin within the 48 hours prior to enrollment, except to maintain catheter patency

10. Gastrointestinal, respiratory or urinary tract hemorrhage within 30 days prior to enrollment

11. Major surgery within 30 days prior to enrollment

12. Severe hypertension (systolic blood pressure [BP] > 185 mm Hg or diastolic BP > 110 mm Hg) or hypotension (systolic BP < 90 mm Hg), as measured by at least 2 consecutive supine measurements 10 minutes apart, that does not respond to simple treatment (e.g., 1 dose of labetolol or nicardipine infusion)

13. Estimated glomerular filtration rate (GFR) <35 mL/min

14. Platelet count < 75,000/mm3

15. Blood glucose concentration < 50 mg/dL

16. Prior exposure to any exogenous form of APC (e.g., plasma-derived APC, 3K3A-APC, Xigris®)

General

17. Pregnancy or breastfeeding

18. Current abuse of alcohol or illegal drugs

19. Received treatment with an investigational drug or device within 30 days prior to enrollment

20. Any other condition that, in the opinion of the Investigator, may adversely affect the safety of the subject, the subject’s ability to complete the study, or the outcome of the study