Sevuparin as a potential adjunctive therapy in children with severe malaria: Phase I safety and dose-finding trial (SEVUSMAART)

A novel new drug candidate for adjunctive treatment of severe malaria,sevuparin, has been identified that can block merozoite invasion, prevent cytoadherence and transiently de-sequester infected erythrocytes in adults with uncomplicated P. falciparum malaria. If given, in addition to antimalarial treatment, early in the course of admission (<24 hours) this could result in improvements in the outcome from severe malaria for the subgroups at greatest risk and during the period of greatest risk (first day of hospitalisation). Sevuparin has been shown to be safe and well tolerated with only some mild effects on APTT levels at higher doses given over a longer period of time (3 days), which is not clinically relevant to the time period of greatest risk (first day of hospitalization). In this Phase I trial dose-finding paediatric study, we aim to use only 3 doses given at admission (0 hours), and then 8 and 16 hours subsequently, and will measure the key toxicity of interest, APTT, 1 hour after each dose (to assess maximum toxicity). The normal ranges of APTT in children have been shown to be the same those in as adults [53] so this study will learn from and build upon what has already been published on sevuparin in adults with malaria. A large comprehensive study of coagulation abnormalities in African children with severe malaria, mild malaria and healthy controls demonstrated that there are no derangements in APTT in children with severe malaria compared to mild malaria and healthy controls [52], providing reassurance that the comparison of APTT levels with normal ranges in this study is clinically meaningful in terms of identifying a maximal tolerated dose (MTD). Finally, if sevuparin resulted, in a future Phase III trial, in increased disability-free survival, then this may be a future suitable candidate to use in pre-referral management alongside parenteral or artesunate.

• Study design: Phase I safety and dose-finding trial

• Primary study design: Interventional

• Secondary study design: Non randomised study

• Trial setting: Hospitals

• Trial type: Treatment

ISRCTN project details

Drug-based Strategies

Feb 2019 — Jul 2023

Kenya

Severe Malaria Africa – A consortium for Research and Trials (SMAART)