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

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. A Phase I dose-finding trial in Kenyan and Zambian children with severe malaria aimed to identify the maximum tolerated dose (MTD) of sevuparin, given as three infusions (at 0, 8 and 16 h post-enrolment) using the continual reassessment method (ISRCTN32271864). The primary endpoint was dose limiting toxicity (DLT) defined as Activated Partial Thromboplastin Time (APTT) > 95 seconds (2.5x upper limit of normal) across 1.5-6 mg/kg doses. Secondary endpoints were lactate clearance, parasite half-life, APTT at 24 h and grade 3-4 serious adverse events. Twenty-three children were enroled; 20 were included in the primary analysis, across 10 cohorts. A data monitoring committee followed model recommendations, leading to dose escalation from 1.5 mg/kg through all doses to 6 mg/kg when 2 DLTs occurred. During de-escalation, DLTs occurred at 5 mg/kg and 4 mg/kg. The final dose was therefore 3 mg/kg. There was 1 death (1/23 (4.3%)), 1 readmission and 1 grade 3 non-DLT adverse event: all judged unrelated to sevuparin. MTD of 3 mg/kg sevuparin in each of three infusions at 0, 8 and 16 h was identified for future investigation.