Phase I trial of the recombinant soluble complement receptor 1 in acute lung injury and acute respiratory distress syndrome

Objective: To determine the safety, pharmacokinetics, biological effects, and immunogenicity of recombinant soluble complement receptor 1 (TP10) in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Design: Open label, ascending dosage, phase I trial. Setting: Two academic teaching hospitals. Patients: A total of 24 patients diagnosed with ALI/ARDS. Intervention: A single, 30-min intravenous infusion of 0.1, 0.3, 1, 3, or 10 mg/kg TP10. Measurements and Main Results: Serum levels of TP10 increased in proportion to the dose. Mean variable estimates (+/- SD) were half-life of disposition 69.7 +/- 39.7 hrs, plasma clearance 2.39 +/- 1.32 mL/hr/kg, and volume of distribution 190.6 +/- 135.0 mL/kg. Inhibition of complement activity, measured by CH50, was significant for the interaction of dose and time (p =.024). The C3a levels demonstrated a trend for dose which did not reach statistical significance (p = .090) and soluble C5b-9 levels were significant only for dose (p = .023). As expected by the proposed physiologic mechanism, C4a levels were not affected by TP10, dose, or time. The overall mortality rate was 33%. Neither the type nor the frequency rate of specific adverse events were substantially different between dose groups. Seven adverse events in four patients were thought to be possibly related to TP10. Conclusions:TP10 has a half-life of similar to 70 hrs and at doses greater than or equal to 1 mg/kg, significantly inhibits complement activity at the levels of C3 and C5 in patients with ALI/ARDS. Complement inhibition was more prolonged over time with TP10 doses of 3 and 10 mg/kg. TP10 appears to be safe at the doses tested. Further studies will be required to completely assess the impact of TP10 on pathophysiology and clinical outcome in patients with ALI/ARDS.