Clinical Trials

Study 6108 – Phase I Healthy Volunteers (Sweden)

Details
This was a phase I study that enrolled 18 healthy male volunteers (ages 18 – 48 years old) performed in Uppsala, Sweden. The main study objective was to compare the pharmacokinetic (PK) profile of 2 MP4OX lots made with raw materials sourced from different commercial vendors. Formal population-based PK analysis was performed at the University of Uppsala (Sweden) using a nonlinear, mixed effects modeling approach with the first-order conditional estimation method. A secondary objective of this study was to evaluate safety and to perform exploratory assessments of blood flow changes in the forearm in each volunteer using non-invasive strain-gauge plethysmography.

Results
Pharmacokinetics: As expected, plasma levels of hemoglobin increased with increasing doses (250, 500, and 750 mL) of MP4OX, and were best described using a single elimination phase (i.e., one-compartment model). Inspection of the goodness-of-fits plots revealed no significant differences between the two MP4OX preparations, and revealed plasma half-life values ranging from approximately 24 to 36 hours for the 3 doses tested. Infusion volume, time of day, and body weight were identified as important covariates to describe the differences in pharmacokinetics of MP4OX between individuals. Importantly, vendor formulation was not found as a statistically significant covariate, demonstrating that the 2 lots of MP4OX made with raw materials from different vendors behaved comparably.

Vital signs, ECG, and blood flow findings: No clinically relevant changes were observed in pulse rate, systolic or diastolic BP or in body temperature. No clinically significant abnormalities were observed in the physical examination. No clinically significant ECG abnormalities were found. Forearm blood flows, obtained from plethysmographic measurements, increased compared to baseline in the 750-mL cohort for both lots of MP4OX. In the 500-mL cohort, forearm blood flow was higher for one lot of MP4OX but lower after the other lot of MP4OX compared to baseline. Blood flow results from the 250 mL cohort could only be obtained from 1 subject due to technical problems with the plethysmography equipment.

Adverse events: There were no deaths, SAEs, severe AEs, or AEs that lead to discontinuation in this study. A total of 38 AEs were reported by 16 subjects in the study. Of those, 27 AEs were judged by the investigator to be related (possible, probable, or definite) to the treatment. Eight of the AEs were reported to have moderate intensity. The rest of all AEs were reported to have mild intensity. The most frequently occurring AEs were headache (7 episodes), pruritis (4 episodes) and constipation, nausea, fatigue, and nasopharyngitis (3 episodes each). Two events of dysphagia and 1 event of upper abdominal pain were reported. The results of this study indicated that administration of 2 MP4OX lots made with raw materials sourced from 2 vendors is safe in healthy subjects.

Laboratory findings: Most subjects had selected laboratory results outside the normal reference ranges. The presence of Hb in plasma may interfere with the spectrophotometric measurement of certain analytes. The assays most likely to be affected are LDH, ALP, AST, GGT, total protein, total bilirubin, and conjugated bilirubin However, the absence of a systematic change in any analytes among volunteers within each dose group or between dose cohorts suggests that there was no meaningful interference in the spectrophotometric analyses from the plasma Hb levels evaluated in this study.