Study 201: GAMES-Pilot

Ischemic stroke due to occlusion of a major cerebral vessel is especially problematic, because it leads not only to loss of a large territory directly supplied by that vessel, but it also predisposes to “malignant infarction.” Malignant infarction occurs in 10–12% of stroke victims and is characterized by formation of rapidly accumulating cerebral edema. It is the syndrome of a large stroke causing progressive edema and tissue swelling that compromises arterial inflow to surrounding tissues, culminating in further ischemic damage, enlargement of the infarct, herniation, and death. Despite best available medical management, the prognosis for these patients is poor, with case fatality rates as high as 60–80%.

Decompressive craniectomy (DC) has improved the bleak outlook for these patients. However, numerous factors limit the usefulness of DC, including limited eligibility for surgery among patients who are gravely ill and have important co-morbidities, and reduced efficacy of DC in patients >60 years of age. Moreover, from a physiologic standpoint, preventing swelling is preferable to decompressing the already swollen brain. There is a clear and urgent need for innovative non-surgical medical strategies to reduce edema formation in patients with a large stroke.

At present, no specific pharmacotherapy is available to combat brain swelling secondary to stroke and no specific drug therapy has been rigorously investigated for patients with a high risk of developing malignant infarction. Given the paucity of experience enrolling subjects likely to develop malignant infarction, GAMES-Pilot was designed as a feasibility study to assess the potential of enrolling, evaluating, and treating such patients with RP-1127. GAMES-Pilot is a multi-center, prospective, open label, Phase 2a trial of RP-1127 in 10 patients with a severe anterior circulation ischemic stroke who are likely to experience clinically significant brain swelling. It is anticipated that the information gained in GAMES-Pilot will allow a much needed, randomized, double-blinded study to be designed for this patient population.

The GAMES-Pilot in patients with severe ischemic stroke is currently enrolling. Key eligibility criteria include:

• Patients with severe ischemic stroke, whether or not treated with standard of care intravenous tPA in the 0-4.5 hour timeframe
• Patients must be between 18-70 years of age
• Patients must have a baseline MRI diffusion weighted image lesion volume in the range of 82 – 210 cm³
• Time from symptom onset to start of study infusion must be ≤10 hours

Detailed information for this study is available at: http://clinicaltrials.gov/ct2/show/NCT01268683

Study 202: TBI

As with severe stroke, moderate and severe TBIs are particularly problematic because they lead not only to loss of a large territory directly injured, but also result in diffuse swelling and hemorrhage secondary to the initial injury. Moderate and severe injuries account for approximately 115,000 hospitalizations per year.

Despite best available medical management, the prognosis for these patients is poor, with case fatality rates as high as 39% in severe TBI. Decompressive craniectomy (DC) has improved the bleak outlook for a subset of these patients. However, numerous factors limit the usefulness of DC, including limited eligibility for surgery among patients who are gravely ill. Recently, early DC in TBI has been shown to be ineffective and potentially harmful. Moreover, from a physiologic standpoint, preventing swelling is preferable to decompressing the already swollen brain. There is a clear and urgent need for innovative non-surgical medical strategies to reduce edema formation in patients with moderate and severe TBI.

At present, no specific pharmacotherapy is available to combat brain swelling and hemorrhage secondary to TBI and no specific drug therapy has been rigorously investigated for its effect on brain swelling and hemorrhage.

Study 202 is a randomized, double-blind, placebo-controlled study of RP-1127 begun within eight hours of moderate or severe TBI, with a primary objective of assessing whether RP-1127 treated patients will show a decrease in MRI-defined edema and/or hemorrhage, compared to placebo treated patients. It is anticipated that the information gained in Study 202 will inform a Phase 3 study designed for this patient population.

Study 202 will begin enrolling in Q4 2011. Key eligibility criteria include:

• Patients must have closed head moderate or severe TBI
• Patients must be between 18-70 years of age
• Time from symptom onset to start of study infusion must be ≤8 hours

The study will enroll at two centers in the United States, the University of California at San Diego and University of Maryland Hospital. This study is being conducted by the INTRuST Consortium*, and is funded by the U.S. Department of Defense.

* The INTRuST Consortium is a group of clinical study sites funded by the Department of Defense to investigate promising new treatments for PTSD and traumatic brain injury. The INTRuST consortium coordination center is located at the University of California San Diego. Under this public-private agreement, Remedy holds the Investigational New Drug (IND) application, provides regulatory support and drug supplies. INTRuST runs all other aspects of the clinical study.