Clinical Trials

Study 6055 – Phase 2 Orthopedic Surgery (Sweden)

Details
This multi-center, double blind, controlled, randomized phase 2 study to evaluate the safety and efficacy of 250 and 500 mL doses of MP4OX when administered in patients undergoing major orthopedic surgery with spinal anesthesia. The primary objective was to evaluate the safety and tolerability of MP4OX in this setting. The secondary objective was to obtain preliminary assessment of the efficacy of MP4OX to provide cardiovascular support (based on the incidence of hypotensive episodes and 24-hour Holter monitoring), and to measure the plasma persistence of MP4OX in surgical patients.

A total of 90 male and post-menopausal females, aged 50-89 years old, were enrolled at 6 centers in Sweden between August 2004 and March 2005. Patients were ASA class I to III patients, undergoing spinal anesthesia for elective hip replacement surgery or acute hip fracture (internal fixation or replacement). Patients were randomized (30 per arm) to receive either 250 mL, 500 mL of MP4OX, or Ringer's acetate (RA) just before induction of anesthesia. There were 12 cases of revision arthroplasty, with the majority (N=10) in the MP4OX groups (N=5 in 250-mL MP4OX; N=5 in 500-mL MP4OX; and N=2 in the control group). The incidence of hypotensive episodes was the primary efficacy endpoint, but to further evaluate hemodynamic stability, repeated electrocardiograms were taken and the cardiac rhythm was monitored with continuous Holter ECG recordings for 24 hours, starting 1 hour prior to infusion.

Summary of Results

Results from a subset analysis of those patients undergoing primary hip arthroplasty (N=74 of 90 randomized) in this study were published previously in Anesthesiology.

Olofsson C, Ahl T, Johansson T, Larsson S, Nellgård P, Ponzer S, Fagrell B, Przybelski R, Keipert PE, Winslow N, Winslow RM: A multicenter clinical study of the safety and activity of maleimide-polyethylene glycol-modified hemoglobin (Hemospan®) in patients undergoing major orthopedic surgery. Anesthesiology, 105: 1153-1163, 2006.http://www.ncbi.nlm.nih.gov/pubmed?term=17122578]

A summary of the key study findings for all randomized patients is provided below.

The primary goals of this study were to evaluate the safety and tolerability of MP4OX in this surgical patient population, and to obtain preliminary assessment of the efficacy of MP4OX to provide hemodynamic support based on the incidence of hypotensive episodes.

Overall, there were significantly fewer hypotensive episodes (P = 0.01317), and a lower incidence of hypotensive episodes (P = 0.0003) in the MP4OX-treated patients (48% in the 250-mL MP4OX group, 45% in the 500-mL MP4OX group, vs. 87% in the RA control group). Patients requiring vasopressor intervention to treat hypotension was also fewer in the MP4OX groups (21% in the 250 mL group; 23% in the 500 mL group) compared to 35% in RA controls.

Deaths and Serious Adverse Events: There were two SAEs, including massive food aspiration, and myocardial infarction that both resulted in death, and a third SAE of nonfatal silent myocardial infarction. One death (500-mL MP4OX patient) was due to massive food aspiration that occurred 36 hours after dosing in an 84-year old male patient who underwent revision hip arthroplasty. At autopsy, he was found to have a loop of colon incarcerated in an inguinal hernia.

The second death (250-mL MP4OX patient) occurred 9 days after surgery in an 89 year old female hip fracture patient with a history of chronic atrial fibrillation, hypertension, and stroke. Following IV clonidine (~12 hours after surgery) that excessively lowered her blood pressure, she suffered a myocardial infarction (detected on the Holter tracing) with elevated troponin levels. She was stable and asymptomatic for several days, receiving increasing doses of beta-blockers to lower an increasing heart rate, and was found dead in bed on POD 9.

The silent myocardial infarction (with no ST-segment elevation and no confirmatory symptoms or ECG changes) was reported in a 77-year old woman (500-mL MP4OX group) with a history of unstable angina and hypertension. She remained asymptomatic and recovered uneventfully.

Adverse Events: There were 216 AEs reported in 77 patients, and a high percentage reported at least 1 AE: 82.1%, 250-mL MP4OX group; 96.8%, 500-mL MP4OX group; and 77.4% in RA controls. The most commonly reported AEs were nausea, hypotension, bradycardia, and hypertension.

More patients in the 500-mL MP4OX group reported cardiac AEs (mostly bradycardia), GI events (mostly nausea) and hypertension compared to the 250-mL MP4OX and control groups. The majority of AEs were judged as mild or moderate. A total of 14 AEs in 8 patients were judged to be possibly related to study drug (8 events of hypertension and 1 event each of nausea, bradycardia, tachycardia, headache, polyuria and bleeding). Patients judged to have AEs possibly related to study drug were all treated with 500-mL MP4OX except an AE of nausea (250-mL MP4OX) and 2 AEs of hypertension (patients in 250-mL MP4OX and RA group, respectively).

Holter/ECG Findings: The results from the 24-hour Holter monitoring showed more rhythm abnormalities (mostly bradyarrhythmias) in MP4OX-treated patients vs. controls, but no evidence of myocardial ischemia (i.e., incidence of ST segment changes were similar across all 3 groups). There were no clinically significant ECG changes in the PR interval, RR interval, QRS-duration, QT-interval or QTc (Bazett) time observed during the study, and no significant differences between the MP4OX and RA control groups with regards to these parameters.

Laboratory Findings: There were no statistical differences between groups in maximum levels of any of the analytes with the exception of lipase (at 6 h in the 500-mL MP4OX group). Slight elevations in AST levels were seen in all treatment groups after surgery, but the elevation was greater in patients treated with MP4OX, as were LDH levels. There were no abnormal changes or between-group differences in platelet count or any coagulation parameters (except for aPTT which was increased in MP4OX treated patients. However, aPTT was artificially elevated due to a laboratory interference occurring at low levels of MP4OX caused by a specific assay reagent that was used in Sweden during the study.