Effects of the bradykinin antagonist Bradycor (deltibant, CP-1027) in severe traumatic brain injury: results of a multi-center, randomized, placebo-controlled trial. American Brain Injury Consortium Study Group.

A phase II prospective, randomized, double blind clinical trial of Bradycor, a bradykinin antagonist, was conducted at 31 centers within North America in severely brain injured patients. Patients of Glasgow Coma Score (GCS) 3-8 (n = 139) with at least one reactive pupil were randomized to receive either Bradycor, 3 microg/kg/min or placebo as a continuous intravenous infusion for 5 days, with the infusion beginning within 12 h of the injury. The primary objective was to assess the efficacy of a continuous infusion of Bradycor (3.0 mc/kg/min) in preventing elevation of intracranial pressure (ICP). Other efficacy measures included the effect of Bradycor on the Therapy Intensity Level (TIL), mortality, and functional outcome. A secondary objective was to evaluate the safety of Bradycor in patients with severe brain injury. Randomization was carried out according to a computer generated randomization list. Patients were followed for the first 14 days of hospitalization with long-term outcome assessed at 3 and 6 months after injury. During the infusion and while the ICP monitor was in place, ICP measurements were recorded hourly along with blood pressure and heart rate. A modified version of the TIL was used to record therapeutic interventions hourly, while the ICP was being monitored. Outcome was assessed at 3 and 6 months after injury using the Glasgow Outcome Score (GOS). Bradycor was well tolerated in this patient population, and no adverse events were attributable to the compound. Although positive trends were seen for both ICP and TIL in the Bradycor group, these differences analyzed on a daily basis were not significant. However, a mixed model of variance which included treatment, day, treatment by day interaction, age and GCS revealed that the percentage time ICP of >15 mm Hg on days 4 and 5 was significantly lower in the Bradycor group compared to placebo (p = 0.035). There were fewer deaths in the Bradycor group, which had a 28-day all cause mortality of 20% versus 27% on placebo. Patients treated with Bradycor showed a 10.3% improvement in favorable outcome at 3 months and a 12% improvement in dichotomized GOS at 6 months (p = 0.26). The consistent positive trends seen in ICP, TIL, neuropsychological tests, and, most importantly, 3- and 6-month GOS provide supportive evidence that a bradykinin antagonist may play a neuroprotective role in severe brain injury.