CLEAR-IVH (Clot Lysis Evaluating Accelerated Resolution of Intraventricular Hemorrhage) program overview:
Brain hemorrhage is the most fatal form of stroke. For patients with intracerebral hemorrhage (ICH) associated with IVH, the reported fatality rates range from 50 to 75%. No treatment with validated efficacy exists. Data on the removal of blood, the primary pathogenic element, did not exist until the funding of our safety trial. We have produced the only controlled, blinded data regarding clot lysis with thrombolytics in IVH. In producing this data we have performed a multicenter study demonstrating among the lowest reported mortalities for a disease where expected mortality remains well above 40%. In prior decades expected mortality for this group of patients was 80%. Furthermore, similarly aggressive neurointensive care centers not using thrombolytics still report a 75% or greater mortality.
The overall goal of this program is to develop an effective therapy for hematoma removal, validated by a Phase III clinical trial. Intraventricular hemorrhage occurs in about 40% of primary intracerebral hemorrhages and 15% of aneurismal subarachnoid hemorrhages (SAH). Epidemiological evidence strongly supports that IVH significantly and independently contributes to morbidity and mortality after cerebral hemorrhage. The clinical management of IVH requires a well-defined neurosurgical procedure-external ventricular drainage (EVD)-and seven to 14 days of integrated neurocritical care, including support of respiratory, hemodynamic, and nutritional needs. But, the current practice standard of external ventricular drainage via intraventricular catheter alone fails to prevent the morbidity and mortality of IVH. For this reason, in 1999, we proposed a safety and efficacy study of thrombolysis for all IVH patients. After external review (FDA Office of Orphan Product Development), our study investigators agreed to study the highest risk and most clinically uniform group of brain hemorrhage patients-individuals with small ICH and large IVH.
Our completed safety study demonstrates that thrombolytic drugs, particularly rt-PA, can be administered safely to patients with intraventricular hemorrhage. Presently, rt-PA therapy moderately shortens the time of blood clot resolution; our new study seeks the dosing regimen of rt-PA that will markedly shorten clot resolution time-one that minimizes the adverse consequences of blood exposed to brain tissue and optimizes the patient's response to therapy. With rapid clot removal, we create the opportunity to shorten ICU stay, decrease brain tissue damage from extravascular blood, and improve the long-term prognosis for functional recovery. Our preliminary data provides signals of efficacy in each of these areas. We propose to explore two lower doses of rt-PA to establish the lowest dose at which clot lysis occurs. Then, we propose to demonstrate the efficacy and safety of stepwise shortening of the rt-PA administration times. We will gather data to estimate the effect of these dose changes on clot resolution, 30-day mortality, and six-month morbidity in the IVH patient. Safety parameters will be evaluated simultaneously.
The Food and Drug Administration, Office of Orphan Product Development provides funding for the trial while Genentech, Inc. supplies study drug for our consortium.
For more information or for possible participation in this or future trials, please contact Tim Morgan at (410) 502-2946.