Clinical Trials

Study 6055 – Phase II Orthopedic Surgery (Sweden)

Details
This phase II study was a multi-center, double blind placebo-controlled, randomized clinical 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.

Results

Results from a subset analysis of those patients undergoing primary hip arthroplasty (N = 74 of 90 randomized) in this study have been published by Olofsson et al., (2006) Anesthesiology, 105: 1153–1163. A summary of the study findings for all randomized patients is provided below.

Pharmacokinetics: Disappearance of MP4OX from plasma appeared to be exponential in both groups and exhibited an effective plasma t1/2 of ~20 hours for both dose levels, based on the plasma clearance curves. The level of plasma methemoglobin remained low and did not exceed 1.0 g/L, even at the 500-mL dose.

Efficacy findings: There was a significant difference between treatments in the number of hypotensive episodes (P <0.02), as well as the incidence of hypotensive episodes (P <0.001). The percentage of patients with any hypotensive episodes was approximately 48% (13 of 27) in the 250-mL MP4OX group, 45% (14 of 31) in the 500-mL MP4OX group, compared to 87% (27 of 31) in the RA control group.

The percentage of patients requiring vasopressor intervention to treat hypotension was also lower in patients receiving MP4OX (i.e., 21% in the 250 mL group; 23% in the 500 mL group) compared to 35% in the RA control group. Analysis of the fraction of patients who did not experience any hypotensive episode during the study monitoring period demonstrated better hemodynamic support with MP4OX treatment during surgery and the postoperative period.

During infusion, there was an increase in mean SBP and mean DBP in both MP4OX groups, whereas the RA control-treated patients showed an increase only in mean SBP. There was a decrease in both mean SBP and mean DBP for the RA controls from ~30 minutes after the start of infusion and during the post operative Days 1-3. The mean BP in this group was normalized at the follow-up visit. Overall, patients in the 500-mL MP4OX group had a more stable BP. There was a slight decrease in mean heart rates for all the treatments, which lasted from 15 minutes after start of infusion to 6 hours after start of infusion, followed by an increase in heart rate from 12 hours after start of infusion until follow-up.

Serious adverse events (SAEs): There were 3 SAEs (two of which resulted in death; massive food aspiration with incarcerated hernia, and iatrogenic complications of treatment of hypertension) and 1 myocardial infarction; all three SAE were considered by the investigators to be unrelated to MP4OX treatment. One of the deaths (500-mL MP4OX group) 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 also have a loop of colon incarcerated in an inguinal hernia.

The second death (250-mL MP4OX group) occurred 9 days after surgery for an internal fixation of a hip fracture in an 89 year old female patient with a history of chronic atrial fibrillation, hypertension, and stroke. Her baseline SBP was 195 mm Hg, and the lowest recorded SBP during surgery was 160 mm Hg. In the evening after surgery (~ 4 to 6 hours after dosing), her SBP was > 200 mmHg, which led to treatment with IV clonidine at ~12 hours after surgery to lower her blood pressure. At that time the patient's SBP fell to < 90 mmHg and was 110 mmHg the following morning. Later review documented a myocardial infarction based on the Holter ECG data and elevated cardiac troponin levels on POD 1 and 2. The patient was stable and asymptomatic for several days, but continued to receive additional higher doses of beta-blockers to lower a progressively increasing heart rate, and was subsequently found dead in bed on POD 9.

The third SAE that occurred in a 77-year old woman with a history of angina and hypertension undergoing a primary hip arthroplasty (500-mL MP4OX group), was a mild subendocardial "silent" myocardial infarction (no ST-segment elevation) that was discovered only during review of her lab data which showed elevated CK-MB and troponin levels, since there were no confirmatory symptoms or ECG changes. She was transferred to the intensive care unit for 24 hours for evaluation and monitoring (thereby prolonging her hospital stay), but she remained asymptomatic and recovered uneventfully. On later review of her medical records, it was noted that because of unstable angina she had been scheduled for coronary angiography 8 years earlier, but she refused as her symptoms abated at that time. The remainder of her hospitalization was unremarkable.

Adverse events: Overall, the incidence of adverse events in the 3 arms of the study was approximately equal. Some of the patients included in the study underwent repair of acute fractures or revision arthroplasties, and these surgery were longer and more complicated than the primary arthroplasties, as expected. There were 216 AEs reported in 77 patients during the study. A high percentage of patients reported at least 1 AE: 82.1% in the 250-mL MP4OX cohort, 96.8% in the 500-mL MP4OX cohort, and 77.4% in the RA control group. The most commonly reported AEs were nausea, hypotension, bradycardia, and hypertension. More patients in the 500-mL MP4OX group reported AEs in the cardiac disorder class (mostly bradycardia), the gastrointestinal disorders class (mostly nausea) and the vascular disorders class (mostly hypertension) compared to the 250-mL MP4OX and the RA control groups.

The majority of AEs were judged as mild or moderate. Seven AEs, in 4 patients, were reported as severe and included the following: 1 MP4OX 500-mL patient with hypertension, hypotension, dysuria and aspiration; 1 MP4OX 500-mL patient with 17 beats of ventricular tachycardia recorded on the Holter record at approximately 20 hours after surgery; 1 RA control patient who had an epileptic seizure; and 1 RA control patient with hypotension during cementing of the prosthesis. One event of local dermal reaction to infused fluid in a patient treated with MP4OX 500-mL was judged to have a definite relationship to the investigational product. A total of 14 AEs in 8 patients were judged to be possibly related to investigational product (8 events of hypertension and 1 event each of nausea, bradycardia, tachycardia, headache, polyuria and bleeding). Patients judged to have AEs possibly related to investigational product were all treated with 500-mL MP4OX except an AE of nausea (patient was treated with 250-mL MP4OX) and 2 AEs of hypertension (patients treated with 250-mL MP4OX and RA control, respectively).

Pharmacological intervention: The most frequently reported interventions used for cardiovascular support were atropine to treat bradycardia, and ephedrine for hypotension. A total of 6 patients were treated for hypertension. The recordings of these pharmacological interventions for cardiovascular support were equally distributed across treatments. A total of 11 patients were treated with diuretics (furosemide). Six of these patients received 250-mL MP4OX, 4 patients received 500-mL MP4OX, and 2 controls received RA. There were no significant differences in the use of pharmacological interventions when comparing the different sites. Overall, the use of ephedrine as a concomitant medication was higher in the RA control group than in the MP4OX groups (ephedrine was given to 6 patients in the 250-mL MP4OX group, 7 patients in the 500-mL MP4OX group, and 11 patients in the RA control group).

Holter/ECG findings: The results from the blinded analysis of the 24-hour Holter recordings showed that ventricular premature beats were observed in the majority of patients, with equal distribution across treatments. Supraventricular tachycardia was recorded in 5 patients (1 patient in the 250-mL MP4OX group, 3 patients in the 500-mL MP4OX group and 1 patient in the RA control group). A total of 9 patients recorded periods of couplets (1 patient in the 250-mL MP4OX group, 6 patients in the 500-mL MP4OX group and 2 patients in the RA control group). There were no recordings of R on T during the Holter monitoring. Pauses (defined as an RR interval > 2 seconds) were recorded for 3 patients in the 250-mL MP4OX group, 7 patients in the 500-mL MP4OX group and 3 patients in the RA control group. Three patients had single pauses with RR interval > 5 seconds (defined as asystole): 5.1 sec in 500-mL MP4OX group; and 5.7 and 15 seconds in 250-mL MP4OX group. AV-block was recorded in a total of 4 patients in the 500-mL MP4OX group. Supraventricular beats were recorded in the majority of patients and these were equally distributed across treatments. ST segment elevation (any channel) was recorded in 3 patients treated with 250-mL MP4OX, in 3 patients treated with 500-mL MP4OX and in 2 patients in the RA control group. ST segment depression (any channel) was recorded in 1 patient treated with 250 mL MP4OX and in 1 patient treated with 500-mL MP4OX.

There were 6 recordings of abnormal 12-lead ECGs judged to be clinically significant during post operative days 1-3. Two of these (ST-T-changes and ST-segment depression) were found in patients treated with 250-mL MP4OX and 4 recordings (3 recordings of atrial fibrillation and 1 recording of left ventricular hypertrophy and ST-segment depression) were found in patients treated with 500 mL MP4OX. No overall clinically significant changes in the PR interval, RR interval, QRS-duration, QT-interval or QTc (Bazett) time were seen during the study, and there were no significant differences between the MP4OX or RA control groups with regards to these parameters.

Laboratory findings: There were no abnormal changes or between-group differences in platelet count, INR, fibrinogen or D dimer, suggesting that MP4OX had no effect on the coagulation system. There was an increase in reticulocyte count in all treatment groups at the follow-up visit, indicating that the production of new RBCs was not affected by MP4OX.

There were no statistical differences between groups in maximum levels of any of the clinical chemistry analytes, with the exception of lipase. The greatest elevations in lipase were seen at 6 hrs in the 500-mL MP4OX group. Elevations in 4 additional patients were less and occurred only at a single time point. Elevated lipase values were also noted in 2 RA control patients. Amylase levels followed a similar pattern. There was a transient decrease in ALP after surgery that was more pronounced in MP4OX-treated patients, but levels increased to pre infusion levels or higher by the follow-up visit. Modest 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.

Coagulation did not appear to be adversely affected, although the aPTT time did appear to be significantly increased after surgery for MP4OX treated patients. However, this aPTT parameter is known to be 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.