Sevuparin in children with severe malaria: a phase I safety and dose finding trial

Introduction: Mortality rates for African children with severe malaria remain high. Sevuparin, a heparin-like compound, as an adjunctive treatment, may improve outcomes due to its effects on Plasmodium falciparum-infected erythrocytes.

Methods: A Phase I dose-finding trial in Kenyan and Zambian children hospitalised with severe malaria aimed to identify the maximum tolerated dose (MTD) of sevuparin, given as three infusions (at 0, 8 and 16 hours post-enrolment) using the continual reassessment method. Safety was assessed as dose limiting toxicity (DLT) defined as Activated Partial Thromboplastin Time (APTT) >95 seconds (2.5x upper limit of normal) across 1.5-6mg/kg doses. Children were followed for 28 days. Grade 3 or 4 serious adverse events were recorded. Secondary endpoints were lactate clearance, parasite half-life, and APTT at 24 hours.

Results: Twenty-three children were enrolled; 20 were included in the primary analysis, across 10 cohorts. A data monitoring committee followed model recommendations, leading to dose escalation from 1.5mg/kg through all doses to 6mg/kg when 2 DLTs occurred. During de-escalation, DLTs occurred at 5mg/kg and 4mg/kg. The final dose was therefore 3mg/kg. There was 1 death (1/23 (4.3%)), 1 readmission and 1 grade 3 non-DLT adverse event: all judged unrelated to sevuparin.

Conclusion: MTD of 3mg/kg sevuparin in each of three infusions at 0, 8 and 16 hours was identified for future investigation.