A Single Dose, Three-Arm, Placebo-Controlled, Phase I Study of the Bradykinin B2 Receptor Antagonist Anatibant (LF16-0687Ms) in Patients with Severe Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) mortality and morbidity remains a public health challenge. Because experimental studies support an important role of bradykinin (BK) in the neurological deterioration that follows TBI, a double-blind, randomized, placebo-controlled study of Anatibant (LF16- 0687Ms), a selective and potent antagonist of the BK B(2) receptor, was conducted in severe (Glasgow Coma Scale [GCS] < 8) TBI patients (n = 25) at six sites in the United States. At 8-12 h after injury (9.9 +/- 2.8 h), patients received a single subcutaneous injection of Anatibant (3.75 mg or 22.5 mg, n = 10 each) or placebo (n = 5). The primary objective was to investigate the pharmacokinetics of Anatibant; general safety, local tolerability, levels of the bradykinin metabolite BK1-5 in plasma and cerebrospinal fluid (CSF), intracranial pressure (ICP), and cerebral perfusion pressure were also assessed. We observed a dose-proportionality of the pharmacokinetics, Cmax, and AUC of Anatibant. V(d)/F, Cl/F, and t(1/2) were independent on the dose and protein binding was >97.7%. Anatibant, administered as single subcutaneous injections of 3.75 g and 22.5 mg, was well tolerated in severe TBI patients with no unexpected clinical adverse events or biological abnormalities observed. Interestingly, plasma and CSF levels of BK1-5 were significantly and markedly increased after trauma (e.g., 34,700 +/- 35,300 fmol/mL in plasma vs. 34.9 +/- 5.6 fmol/mL previously reported for normal volunteers), supporting the use of Anatibant as a treatment of secondary brain damage. To address this issue, a dose-response trial that would investigate the effects of Anatibant on the incidence of raised ICP and on functional outcome in severe TBI patients is needed.

Role of the kallikrein–kinin system in traumatic brain injury

“…However, it remains questionable whether LF 16-0687 is effective within a clinically relevant time window (Plesnila et al, 2001). LF 16-0687 was investigated in a phase I clinical study (Marmarou et al, 2005) in patients with severe TBI. In this trial, patients with TBI and Glasgow Coma Scale <8 received LF 16-0687 as a single subcutaneous injection within 8–12 h after TBI, and Marmarou et al concluded that LF 16-0687 provides a potential therapeutic approach to treating cerebral edema following brain damage, as the compound was well tolerated.…”

A Method for Reducing Misclassification in the Extended Glasgow Outcome Score

“…The proposed system is an extension of the existing ABIC five-point GOS checklist, which was developed for the purpose of reducing inter-rater variation in GOS assessment in TBI trials . The GOS checklist has been shown to decrease interobserver variability in a pilot trial (Marmarou, 2001), and was used in two TBI clinical trials (Marmarou et al, 1999(Marmarou et al, , 2005. The current system adds additional criteria, while maintaining the five-point GOS rating criteria, to assess the use of the eight-point GOSE system, as directed by the guidelines .…”

Impact of Early Pharmacological Treatment on Cognitive and Behavioral Outcome After Traumatic Brain Injury in Adults

“…If different dosages of a drug were administered in the one study to separate treatment groups and compared to the same control group, these data were analyzed separately. On 3 occasions, 26,34,54 a single study was treated as 3 separate studies, and on 1 occasion, 58 a single study was treated as 2 separate studies because different dosages of a single drug were administered to different treatment groups. Thus, data from a total of 22 studies were analyzed.…”