Clinical Trials
Study 3002 – Phase Ib/II Orthopedic Surgery (Sweden)
Details
This phase Ib/II single-blind, controlled, safety and tolerability study was conducted at the Karolinska and Söder Hospitals in Stockholm, Sweden. A total of 30 orthopedic surgery patients (ages 27 – 76 years old) were given doses ranging from 200 to 1000 mL of either MP4OX or Ringer's acetate, in five cohorts of 6 patients (4 active and 2 control per cohort) , just prior to induction of spinal anesthesia. The primary objective was to evaluate the safety of increasing doses of MP4OX. Secondary objectives were to assess possible effectiveness of MP4OX to support tissue oxygenation, perfusion and hemodynamic stability. [Additional details about the protocol can be found at http://clinicaltrials.gov/ct/show/NCT00494949].
Results
The results of this study have been published by Olofsson et al., (2008) Transfusion Med, 18: 28-39. A summary of these findings is provided below.
Pharmacokinetics: The peak plasma MP4OX concentration in the 1000 mL group reached 1.3 g/dL. The plasma clearance t1/2 was dose-dependent, with t1/2 values of 14, 16, 18, 19 and 23 hours for doses of 200, 400, 600, 750 and 1000 mL, respectively. The plasma methemoglobin levels were independent of dose, reaching a maximum at 40 hours after dosing and never exceeded 0.125 g/dL. There was a transient disappearance of the plasma haptoglobin in patients on MP4OX on the day of surgery, with levels recovering by approximately postoperative Days 2-3. This was also seen in the phase I study (3001) and is due to MP4OX in plasma which binds with haptoglobin.
Vital signs and ECG findings: There was a transient increase in the mean SBP observed during the first hour following dosing in the 200-, 400-, 600- and 750-mL treatment groups. In the 1000 mL group, this increase in SBP was observed an hour later, likely because this dose was split into two 500-mL infusions to minimize volume overload (one was given just prior to spinal anesthesia and the second half was infused following induction). One patient in the 200-mL MP4OX cohort exhibited marked elevation of mean arterial pressure (MAP) after dosing, but there were no clinically relevant increases in MAP in any of the other patients. In all groups except the lowest dose cohort (200 mL), there was no increase in mean diastolic blood pressure (DBP) following infusion, suggesting that the increased SBP may be due to transient intravascular volume expansion because of the high oncotic pressure of the MP4OX solution. The lowest blood pressures during surgery were observed in the LR control group. There were no differences in heart rate between the 5 treatment groups.
No clinically significant changes in ECG parameters or differences between the MP4OX or control groups were seen in the study. All ECGs were judged as normal or with an abnormality that was not clinically significant, except for 1 LR control patient who had atrial fibrillation at baseline on the day of surgery. The QTc interval for this patient was prolonged according to Bazett's formula, and the atrial fibrillation persisted throughout the study.
Adverse events: There were no SAEs reported and no deaths in this study. Overall, the AE and safety data from this study suggest that MP4OX was tolerated at doses up to 1000 mL. The AEs were mild to moderate in intensity, with the most commonly reported AEs being nausea and pyrexia, which are expected events after anesthesia and surgery. The AE rate was similar between MP4OX-treated patients and controls; i.e., there were 30 AEs in the 20 patients receiving MP4OX (average of 1.5 AEs/patient) and 14 AEs in 10 control patients (average of 1.4 AEs/patient). All AEs were classified by the investigator to have either no connection with or an unlikely causal relationship to investigational product, with the exception of 1 AE (mild pruritis) reported in a control patient that was classified as being possibly related. None of the AEs led to the withdrawal of the patient, and all but 3 AEs resolved during the study.
Laboratory findings: Other than a transient rise in WBC and decreases in hemoglobin, hematocrit and RBC counts due to surgery, all hematology parameters remained stable throughout the study. Troponin T was transiently elevated in 2 patients receiving MP4OX (400-mL and 1000-mL cohorts), however, neither patient had CK-MB elevations outside the normal range. Moreover, these 2 patients had no symptoms or chest pain to suggest an MI, and there were no ECG abnormalities to suggest either myocardial ischemia or infarction.
A transient elevation in liver enzymes ALT, AST, and GGT was seen on the day of surgery and in the first few days afterwards in patients who received MP4OX, and a simultaneous decrease in ALP was noted. Measured bilirubin (total and conjugated) rose in a dose-dependent manner, as expected, because MP4OX in plasma interferes with these measurements. A possible treatment-emergent effect on liver enzymes could not be excluded, but the lack of a dose-dependent trend suggests that a clear mechanistic adverse effect on liver enzymes was not present.
One patient (600-mL MP4OX group) had a single lipase elevation at 6 hours, and 2 LR control patients had transient lipase elevations on POD 1. One patient (1000-mL MP4OX group) had an amylase elevation to 2X the upper level of normal (ULN) at 6 hours after dosing, which decreased to normal by POD 1. Amylase levels rose to the same extent in 2 LR control patients at Day 1 and also returned to normal 1 day later.
Renal function assessed by iohexol clearance at screening and at day 1 did not reveal any clinically relevant changes or differences between groups, suggesting there was no adverse effect of MP4OX on glomerular filtration and renal function. However, individual increases in urine β2-microglobulin levels were observed for some patients in the 1000-mL and 750-mL cohorts, as well as transiently elevated urine N-acetyl glucosamine (NAG) levels primarily in the 1000-mL MP4OX group. Urine NAG levels have been shown to rise when increased protein levels are presented to the tubular cells; hence, NAG activity in urine is thus a measure of altered function in the renal tubules and not simply an indicator of damage. There was no visible hemoglobinuria, but the dipstick method was positive for hemoglobin in urine samples post-infusion for patients treated with MP4OX. A dose-dependent relationship could be seen between hemoglobin levels detected by dipstick analyses and MP4OX doses, due to the high sensitivity of these dipsticks which measure peroxidase activity.
Coagulation: The prolongation of aPTT seen in some MP4OX-treated patients was explained by a change of reagent used by the laboratory for this analysis after the first phase I 3001 study had been performed, which resulted in a lab artifact. As a result, the prolonged aPTT results were not considered to be clinically relevant. This was supported by the fact that no abnormalities were noted in other coagulation parameters, including INR, fibrinogen and D-dimer. Mean plasma fibrinogen showed an increase on post-surgery Days 2-4 that was consistent between all treatment groups and most likely was due to the expected acute phase response that occurs following major invasive surgical procedures.
Antibody titers: Serum concentrations of anti-pegylated hemoglobin antibodies were measured using an immunoassay method. Analysis of serum samples showed that there were no treatment related elevations in antibody titer in samples from MP4OX-treated patients.