Clinical Trials

Study TRA-204 – Phase 2a Trauma study (Europe & S. Africa)

Details
This multicenter, international, double-blind, phase 2a dose-finding study was conducted to evaluate the safety and efficacy of MP4OX plus standard of care in trauma patients with lactic acidosis due to severe hemorrhagic shock. Patients eligible for randomization had hemorrhagic shock, with evidence of lactic acidosis (serum lactate level ≥ 5 mmol/L; equivalent to ≥ 45 mg/dL) within 2 hours after arrival at study hospital and within 4 hours of traumatic injury. Two doses of MP4OX were evaluated (either 250-mL of MP4OX plus 250-mL of Ringer's Lactate, or 500-mL dose of MP4OX), and compared to a 500-mL infusion of Ringer's Lactate (Control). The main goal of this exploratory phase 2a study was to demonstrate reversal of lactic acidosis and to assess whether MP4OX treatment might also result in less hemorrhagic shock-induced organ failure.

Lactate was used in this study as a relevant biomarker for indicating potential improvement in organ dysfunction or failure, since an elevated serum lactate level indicates the presence of insufficient perfusion of tissues and anaerobic metabolism, and represents the level of oxygen debt and the severity of hemorrhage shock. The primary efficacy endpoint evaluated the clearance of lactate in the first 2 hours after dosing. The secondary objectives of this study included early and late mortality, time to transfer from ICU and discharge from hospital and the duration of organ failure as measured by serial SOFA and modified Denver Score and days on mechanical ventilation, renal replacement therapy or vasopressors, and a morbidity outcome composite endpoint of time to complete organ failure resolution (CTCOFR), defined as the last day on which the patient no longer needs any vasoactive agents, mechanical ventilation, or renal replacement support through study Day 14 or Day 21. Serious adverse events and mortality outcome were evaluated through Day 28. [Protocol details can be found at http://clinicaltrials.gov/ct/show/NCT01004198?order=3]

Summary of Results
The results of this study are being prepared for publication in a peer-reviewed critical care journal. Top-line efficacy and safety findings from this study have been presented and published in abstract form.

Brohi K, Plani F, Moeng M, Riou B, Goosen J, Pretorius J, Hardiman Y, Levy H, Multicenter randomized controlled trial TRA-204 to evaluate the safety and efficacy of MP4OX in lactate clearance following trauma. Crit Care Med 38: 749, 2010

A summary of the efficacy and safety findings from this study is provided below:

A total of 72 adult trauma patients with hemorrhagic shock causing lactic acidosis (lactate ≥5 mmol/L) were screened, and 51 of these patients (ranging in age from 20 to 73 years) were enrolled within 2 hours of arrival at hospital and within 4 hours of trauma at 11 centers in 4 countries (France, Germany, South Africa and the UK). In addition to standard care, the control patients (Control) received 500 mL Ringer’s lactate (RL) [N=18 patients], the MP4OX-250 group received 250 mL MP4OX + 250mL RL [N=18 patients], and the MP4OX-500 group received 500 mL MP4OX [N=15 patients], An unblinded independent Data Safety Monitoring

Board (DSMB) reviewed all serious adverse events (SAEs) and related laboratory safety data as they were reported during the course of the study.

Groups were well matched for age, sex, weight, mechanism or severity of injury, total fluids (colloids or crystalloids) and red blood cell (RBC) administration. MP4OX was effectively absent from the circulation if an additional 6 unit RBC transfusion was required. There was no significant difference in overall serious adverse events, cardiac events or mortality. There was no difference in AST, ALT, amylase, lipase, troponin I and creatinine to 28 days. Baseline lactates were similar - MP4OX: 6.6 mmol/L and Control: 7.0 mmol/L. There was immediate lactate decrease seen by the end of infusion (MP4OX: 5.3 mmol/L vs. Control: 8.5 mmol/L, P = 0.004) and this was sustained to Hour 2. More MP40X patients had a >10% lactate clearance between baseline and Hour 2 (86% vs. 56%; P = 0.035). There was no difference in lactate clearance between the MP4OX-250 and MP4OX-500 groups. Overall, for MP4OX-treated patients, there was a trend towards improved outcomes with reduction in median total hospital days (MP4OX vs. Control: 13 vs. 28 days; P = 0.089) and the proportion of patients discharged from hospital by Day 28 (MP4OX vs. Control: 48% vs. 28%; P = 0.234). Overall, MP4OX exhibited a satisfactory safety profile and was associated with an immediate and sustained lactate clearance. These positive results support further evaluation of MP4OX in larger trauma studies.