Clinical Trials

Study 6090 – Phase 3 Orthopedic Surgery (Europe)

Details
This multicenter, international, double-blind controlled Phase 3 study (Treatment Trial) was conducted in Europe in five countries (Belgium, Czech Republic, Netherlands, Poland and Sweden). The primary objective was to evaluate the ability of MP4OX to treat 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 treating acute 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 488 patients consented to participate, and 474 patients (ages 50 – 87 years old) were randomized at 21 centers from April 2007 to April 2008 and were analyzed for safety (Intent-to-Treat [ITT] population). A total of 405 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. Patients were randomized in a 1:1 ratio to receive up to two 250-mL units of either MP4OX or Voluven during surgery. The first 250-mL dose was given when patients reached the protocol-defined hypotension threshold (i.e., SBP < 90 mm Hg or below 75% of baseline level, whichever value was higher). The second 250-mL dose was administered only if the patient reached the same protocol-defined hypotension threshold level 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 clinical practice when clinically indicated.[Protocol details can be found at http://clinicaltrials.gov/ct/show/NCT00420277]

Summary of Results

The results of this study have been published recently in Anesthesia & Analgesia.

Van der Linden P, Gazdzik TS, Jahoda D, Heylen RJ, Skowronski JC, Pellar D, Kofranek I, Górecki AZ, T, Fagrell B, Keipert PE, Hardiman YJ, Levy H and the Study 6090 Study Investigators. A double-blind, randomized, multicenter study of MP4OX for treatment of perioperative hypotension in patients undergoing primary hip arthroplasty under spinal anesthesia. Anesth Analg, 112: 759-773, 2011. http://www.ncbi.nlm.nih.gov/pubmed?term=21317165]

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

The primary goal of this study this study was to investigates the ability of MP4OX to treat hypotensive episodes. In addition, the tolerability profile of MP4OX in a large surgical population was established. Patients from 21 study sites in five countries, scheduled to undergo primary hip arthroplasty under spinal anesthesia, were randomized in a double-blind manner to receive MP4OX or hydroxyethyl starch (HES) solution (Voluven®; HES 130/0.4). Patients received the first 250-mL dose of investigational product when systolic blood pressure (SBP) decreased to the predefined dosing trigger. A second 250-mL dose was given only if the SBP dropped to the same trigger level after administration of the first dose. The primary efficacy outcome was total duration of all hypotensive episodes during surgery and the first 6 h following skin closure.

Of the 474 patients randomized, 405 reached the dosing trigger and received at least one dose. The mean total duration of all hypotensive episodes was significantly shorter (P < 0.0001) in the MP4OX group (52.4 ± 71.50 min; range 3–442) compared with the HES group (137.6 ± 120.21; range 5–435). The overall incidence of adverse events (AEs) in the intent-to-treat population was similar between the MP4OX and HES groups (75.2% vs. 73.4%; P = 0.733). Transient elevations in laboratory values were reported in more patients in the MP4OX group vs. HES controls for aspartate aminotransferase (13.4% vs. 7.4%; P = 0.052), alanine aminotransferase (6.9% vs. 4.9%; P = 0.409, lipase (9.7% vs. 3.6%; P = 0.015) and troponin (8.1% vs. 2.0%; P = 0.006). There was no significant difference in the incidence of serious adverse events (SAEs) reported (6.4% in MP4OX group vs. 3.0% in HES controls; P = 0.106). Certain AEs did occur more frequently in the MP4OX group, including nausea (23.8% vs. 14.3%; P = 0.016), bradycardia (14.9% vs. 5.9%; P = 0.003), hypertension (not seen during the infusion period) (8.4% vs. 2.5%; P = 0.009) and oliguria (5.9% vs. 1.5%; P = 0.019). The composite morbidity and ischemia endpoints did not reveal any differences between the two treatment groups.

Administration of MP4OX achieved the endpoint of treating perioperative hypotension in patients undergoing primary hip arthroplasty under spinal anesthesia. The study was not powered to demonstrate clinical benefit based on the composite morbidity or ischemia outcomes. Although efficacy endpoints with sufficient power were met, MP4OX is not being proposed for use in routine surgery where the risk-benefit profile would not be favorable based on the safety profile demonstrated in this study.