Maitland, Kathryn;
Hamaluba, Mainga;
Obonyo, Nchafatso;
Oguda, Emmanuel;
Mogoka, Christabel;
Williams, Thomas N;
Chaponda, Mike;
... Severe Malaria in African Children A Research and Trials (SMAART; + view all
(2024)
SEVUparin as a potential Adjunctive Treatment in children with severe malaria: A phase I trial safety and dose finding trial (SEVUSMAART).
Wellcome Open Research
, 8
p. 484.
10.12688/wellcomeopenres.20111.2.
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Abstract
BACKGROUND: Even on the best antimalarial treatments (injectable artesunate) African children with severe malaria have poor outcomes with most deaths occurring early in the course of hospital admission (<24hours). Lactic acidosis, largely due to impairment of the microcirculatory flow due to parasite sequestration, is a main risk factor for poor outcome. There are no adjuvant treatments for severe malaria that target this complication. Sevuparin, a heparin-like drug, binds to Plasmodium falciparum erythrocyte membrane protein blocking merozoite invasion, preventing cytoadherence and transiently de-sequestering infected erythrocytes. Leading to improved microcirculatory flow by reversing/preventing parasite sequestration. If given early during admission this could result in improvements in outcomes. Sevuparin has been shown to be safe and well tolerated in adults with only some mild transient effects on activated partial thromboplastin time (APTT) were reported, without clinical consequences. METHODS: A Phase I trial designed to provide data on safety, dosing, feasibility of sevuparin as an adjuvant therapy in Kenya and Zambian children with severe malaria complicated by lactic acidosis (> 2mmol/l). Three intravenous doses will be given at admission (0 hours), 8 and 16 hours. APPT will be measured 1 hour after each dose (to assess maximum toxicity). Studying 20 children will allow sufficient data on safety to be generated across a range of doses to identify the maximum tolerated dose (MTD) using the Continual Reassessment Method, which adapts or informs subsequent doses for each child based on the data from previously enrolled children. The MTD will be identified based on the dose-toxicity model updated by each previous patient's APTT results using standard methods. CONCLUSIONS: The results of the Phase I trial will identify the final dose to be tested in a Phase II trial in terms of both efficacy and safety outcomes. REGISTRATION: PACTR number: 202007890194806 (date 20/07/2020) ISRCTN32271864 (date 28/07/2021).
| Type: | Article |
|---|---|
| Title: | SEVUparin as a potential Adjunctive Treatment in children with severe malaria: A phase I trial safety and dose finding trial (SEVUSMAART) |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.12688/wellcomeopenres.20111.2 |
| Publisher version: | http://dx.doi.org/10.12688/wellcomeopenres.20111.2 |
| Language: | English |
| Additional information: | Copyright: © 2024 Maitland K et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | adjunctive therapy, Africa, children, clinical trial, heparin-like molecule, severe malaria |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10196629 |
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