(1) To study the safety of IV rt-PA in subjects with unwitnessed stroke onset with last known normal (LSN) time greater than 3h but who show MRI evidence of onset less than or equal to 3.5 h, and who otherwise meet American Heart Association (AHA) rt-PAguidelines.(2) To validate novel MRI profiles to improve the sensitivity while maintaining high specificity for detecting subjects with stroke durationless than or equal to 3.5 h using data from subjects whose stroke onset is determined by a reliable human witness(3) To explore imaging surrogates of clinical efficacy in subjects with unwitnessed stroke onset who are treated with thrombolysis
- Alteplase Drug
Intervention Desc: IV
open-label, single-arm, multi-center Phase IIa safety study
Consented patients who meet all inclusion criteria, and have imaging findings consistent with MR WITNESS classificationas being less than 3.5 h will be given 0.9 mg/kg of alteplase according to AHA guidelines, with a maximum dose of 90 mg. Alteplase will be reconstituted from a lyophilized powder in sterile water for injection. 10% of the total dose will be administered as an intravenous (IV) bolus over one minute. The remaining dosage will be given by continuous infusion over a period of 1h. We propose to investigate this in two stages - (1) we will first use a conservative diffusion positive-FLAIR negative definition shown by several centers to be indicative of patients in early stage stroke to decide which subjects are eligible for treatment, (2) after validation in multi-center datasets, a more sensitive decision-tree analysis approach will be used to identify potentially eligible subjects. We will evaluate safety outcomes and surrogates of clinical efficacy for subjects who were treated with rt-PA based on an MR “witness” vs. historical populations of patients treated with rt-PA based on a human witness. We will use a sequential boundary for the detection of an unacceptably high sICH rate to be the lower 92.5% exact confidence bound for the true hemorrhage rate. The trial will stop for a potential safety problem the first time this lower bound exceeds 5.3%, which was the rate ob-served in the ECASS 3 trial. With 100 subjects, and with a true rate of 5.3%, this will occur with probability 23%, and on average, after 83 subjects are observed. After every sICH, we will review the case to examine the imaging and clinical findings, and to ensure there were no protocol violations.
|Type||Measure||Time Frame||Safety Issue|
|Primary||No significant increase in symptomatic intracranial hemorrhage (SICH) rates at 24 h compared to those reported in ECASS3 using the ECASS II definition (any hemorrhage with neurologic deterioration as indicated by an NIHSS score that increased by 4 or more points over baseline value).|
|Secondary||we will monitor for other SAE, such as symptomatic edema or mortality, to investigate whether our rates are significantly higher than those reported by ECASS 3. For secondary outcomes, we will also examine rates of early reperfusion and lesion growth in rt-PA treated patients when evaluating for potential benefit.|