Clinical Trials

Study 6084 – Phase 3 Orthopedic Surgery (Europe)

Details
This multicenter, international, double-blind controlled Phase 3 study (Prevention Trial) was conducted in Europe in six countries (Belgium, Czech Republic, Netherlands, Poland, Sweden, and the UK). The primary objective was to evaluate the ability of MP4OX to prevent acute hypotension in orthopedic surgery patients undergoing first-time hip replacement procedures under spinal anesthesia. The efficacy endpoints were achieved, demonstrating superiority of MP4OX over Voluven (6% hydroxyethyl starch [HES 130/0.4] solution) for preventing hypotensive episodes during the operative and early postoperative period. The secondary objective was to determine whether MP4OX is superior to Voluven for reducing the incidence of operative and postoperative morbidity (based on composite outcomes for organ dysfunction and failure) associated with ischemia and/or tissue hypoxia, until follow-up at 1 month following surgery (postoperative day [POD] 30 ± 5 days). Adult female (surgically sterile or post-menopausal) or male patients, ≥ 50 years of age, who were scheduled to undergo elective primary hip arthroplasty (based on osteoarthritis diagnosis) with spinal anesthesia and who were classified with American Society of Anesthesiology Class II or III were eligible for enrollment.

A total of 394 patients consented to participate, and 376 patients (ages 50 – 86 years old) were randomized at 18 centers from February 2007 to May 2008 and were analyzed for safety (intent to treat [ITT] population). A total of 367 patients received at least a partial dose of investigational product (modified intent to treat [MITT] population) and were analyzed for efficacy. Patients were screened within 2 weeks prior to the day of primary hip arthroplasty surgery and baseline measurements were taken within 1 hour prior to insertion of the spinal needle. To help prevent patients from reaching the hypotension threshold, defined as a systolic blood pressure (SBP) < 90 mm Hg or below 75% of baseline level, the first 250-mL dose was administered at the time of spinal anesthesia induction. The second dose was administered only if the patient reached the protocol-defined trigger (i.e., a SBP < 100 mm Hg or below 80% of the baseline level, whichever was greater) at any time before the end of surgery (skin closure). After surgery, vasopressors, colloids or red blood cell transfusion were administered according to the site’s standard practice, when clinically indicated. [Protocol details can be found at http://clinicaltrials.gov/ct/show/NCT00421200]

Summary of Results
The results of this study have been accepted for publication in Anesthesiology.

Olofsson CI, Górecki AZ, Dirksen R, Kofranek I, Majewski JA, Mazurkiewicz T, Jahoda D, Fagrell B, Keipert PE, Hardiman YJ and Levy H for the Study 6084 Clinical Investigators. Evaluation of MP4OX for prevention of perioperative hypotension in patients undergoing primary hip arthroplasty with spinal anesthesia: A randomized, double-blind, multicenter study. Anesthesiology, 114: 1048-1063, 2011. [http://www.ncbi.nlm.nih.gov/pubmed?term=21455059]

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

The primary goal of this study was to investigate MP4OX for preventing hypotensive episodes. An additional goal was to establish the safety profile of MP4OX in a large, surgical population. A total of 367 patients from 18 active study sites in six countries, undergoing elective primary hip arthroplasty with spinal anesthesia, were randomized to receive MP4OX (active treatment) or hydroxyethyl starch (HES 130/0.4) solution (control). Patients received a 250 mL dose at induction of spinal anesthesia, and a second 250 mL dose if the protocol specified trigger (predefined drop in systolic blood pressure) was reached. The primary endpoint was the proportion of patients who developed ≥ 1 hypotensive episode.

The proportion of patients with ≥ 1 hypotensive episode was significantly lower (P < 0.0001) in the MP4OX group (66.1%) vs. controls receiving HES 130/0.4 (90.2%). More MP4OX-treated patients experienced adverse events compared to controls (72.7% vs. 61.4%; P = 0.026). Transient elevations in laboratory values (alanine aminotransferase, aspartate aminotransferase, lipase, and troponin) occurred more frequently in the MP4OX group. There were no significant differences in the incidence of serious adverse events, or in the composite morbidity and ischemia outcome endpoints, but nausea and hypertension (not seen during the infusion period) was reported more often in MP4OX-treated patients.

MP4OX significantly reduced the incidence of hypotensive episodes in hip arthroplasty patients, but the adverse event profile does not support use in routine low-risk surgical patients for the indication evaluated in this study. However, the safety data generated from this study has helped to establish the safety profile of MP4OX, to support further studies in high risk trauma patients with severe ischemia and tissue hypoxia where an oxygen therapeutic agent has a greater potential to demonstrate clinical benefit.