Clinical Trials
Study 3001 – Phase I Healthy Volunteers (Sweden)
Details
This study was a first-in-man phase I safety study in 12 healthy volunteers (ages 19 – 30 yrs) performed at the Karolinska Hospital in Stockholm, Sweden. A full complement of safety assessments was performed to assess the tolerability of MP4OX in healthy volunteers. Two dose cohorts (4 active, 2 controls each) received either 50 mg/kg (~100 mL) or 100 mg/kg (~200 mL) of MP4OX or Lactated Ringers. Plasma concentrations of MP4OX were measured at various time points to evaluate the circulating half-life of MP4OX.
Results
The results of this study have been published by Björkholm et al., (2005) Haematologica 90: 505-15. A summary of these findings is provided below.
Pharmacokinetics: For the higher dose (100 mg/kg), the tmax occurred at approximately 52 minutes, which was in reasonable agreement with the expected tmax of approximately 40 minutes (i.e., the approximate time for infusion of this dose). The plasma t1/2 in both MP4OX groups was longer than what was observed in animal studies. The terminal elimination half-life values in the healthy volunteers were calculated to be 66 and 43 hours, for the 50 and 100 mg/kg cohorts, respectively. These data should be interpreted with caution since the number of subjects was low.
Vital signs and ECG findings: There were no clinically significant differences, between cohorts or between the 2 MP4OX dose cohorts and controls in systolic blood pressure. Some diastolic pressures were elevated compared to either baseline or controls, in the 50 mg/kg and 100 mg/kg MP4OX cohorts, but none occurred until after 2 hours post-dosing. Heart rates for both the MP4OX cohorts decreased compared to baseline for most of the 4-hour observation period. Continuous ECG monitoring was carried out for 4 hours post-dosing, and rhythm strips were recorded on Days 2, 3 and 4. No ECG abnormalities or rhythm disturbances were noted except for occasional sinus bradycardia.
Adverse events: There were no serious adverse events (SAEs) noted in this phase I study, and no AEs were attributable to MP4OX administration. The side effects frequently reported for earlier generation hemoglobin-based oxygen carriers (HBOCs) given at similar doses (i.e., gastrointestinal complaints, hypertension) were not observed. No subject reported loss of appetite, chest, abdominal or costovertebral pain. There were 5 mild AEs in the control group (2 cases of nausea, 2 cases of headaches, and hypersensitivity). In the MP4OX-treated patients, there were 2 AEs in the 50 mg/kg group (vomiting and dizziness) and 3 AEs in the 100 mg/kg group (nausea, pharyngolaryngeal pain, tooth ache); all were mild and unrelated to MP4OX administration.
Laboratory findings: There were no clinically significant changes in the laboratory assessments in this study. Troponin T, creatine kinase (CK) and cholesterol all remained within normal limits. One subject exhibited an elevation in amylase and lipase at a single time point (16 hours) after dosing with MP4OX (100 mg/kg group), but there were no associated GI symptoms, such as nausea, loss of appetite or pain. Serum haptoglobin decreased from baseline in all volunteers who received MP4OX infusion up to Day 2, but by Day 4 the haptoglobin values had recovered toward baseline values. No other hematologic changes occurred, and there were no between-group differences in hematocrit, hemoglobin, red cell indices, and leukocyte counts with differential blood smears. Coagulation parameters also remained unchanged, including platelet counts, plasma fibrinogen, INR, fibrin split products (D-dimer), PT, and aPTT.
Renal function, as measured by serum creatinine, glomerular filtration rate (GFR) using iohexol clearance, and urine output all remained normal in the MP4OX-treated subjects. There were no alterations noted in serum creatinine, β2 microglobulin, N-acetyl-β-D-glucosaminidase (NAG), or iohexol clearance, and there were no significant differences in creatinine clearance between the control and MP4OX groups during any measurement period.