| Protocol No: | ECCT/20/06/05 | Date of Protocol: | 08-02-2019 |
| Study Title: | SEVUSMART TRIAL Sevuparin as a potential adjunctive therapy in children with severe malaria |
| This is the first protocol amendment,and the modification made to the protocol includes;
1) Carification on the inclusion criteria which states:
Current evidence of P. falciparum malaria (slide positive) rather than P. falciparum malaria (slide positive or RDT positive) since the drug targets children with parasitaemia and is not relevant for children who remain RDT positive and are slide negative.
2) Sample volume: Reduced and simplified the study sampling procedures so that there
a).Blood cultures are collected in line with routine care.
b) Reduction in volume and frequency of clotting tests.
c) Reduction in tubes collected for sample storage.
3) Reduction in the number of clotting tests and volume:
a) Clotting tests APTT and ACT will be measured at admission (0), 1, 9 and 24 hours (17 hours is dropped). 24 hours is retained as this is an endpoint (APTT 24H post enrolment is used as an assessment of normalization 8H after the final sevuparin dose.
b. Instead of 2.7 mls clotting tubes for test, 1.8 ml microtubes will be collected which will allow measurement of both APTT and ACT
4) PK sample storage: since this uses a clotting tube to collect this (before processing and storage) rather collecting in separated tubes, this will be collected all in one clotting tube (microtube as above) which will be processed to cover both APTT and plasma storage for later PK sample analysis. As well as harmonization of blood sampling to 9 hours only including PK sampling, APTT, stored red cells (Kilifi) and Lactate tests) rather than over 8- and 9-hour intervals and also a reduction in the number of lactate samples (hours 2,4 and 17 dropped)
5) Revision of the compensation rates from Ksh. 350 to 500 on the ICF
6) Update on the section of the informed consent on who should have access to the participant information collected
7) Update in the timelines (summary and timelines at the end)
8) Change in blood sample collection for coagulation tests from the previous fingerpick to venous blood mentioned in the ICF
9) Addition of Nchelenge in northern Zambia from a single site in Kilifi as well as inclusion of the new investigators in Zambia as amended in the protocol version 1.4 to version 2.0
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| Study Objectives: | The primary objective of this trial is to conduct a dose-finding study of intravenous sevuparin given in 3 doses over the first 18 hours from enrolment (within 24h of hospital admission), defining toxicity events as any APTT >2.5 upper limit of normal (ULN) (grade 3 toxicity) 1 hour after each dose to identify the maximum tolerated dose (MTD). The initial dosage (1.5 mg/kg) and the a priori dose-toxicity curve are based upon the results of the adult trial (where a dose of 1.5 mg/kg was associated with minimal risk of toxicity) and experimental evidence of dose-dependent efficacy i.e. inhibition of merozoite invasion and reversal of cytoadherence of infected erythrocytes [36]. Almost all adults enrolled in this trial experienced grade 2 toxicity after one or more sevuparin doses, but APTT rapidly normalized, hence the choice of grade 3 toxicity to define the MTD in this dose-finding trial.
The results of this Phase I trial will identify the final dosage selected for a subsequent Phase II that will include both efficacy and safety outcomes. The Phase II trial will be conducted by the SMAART consortium and plans to use change in lactate at 8 hours as its primary endpoint; likely secondary endpoints include neurological sequelae, day-28 and day-180 mortality, length of initial hospitalisation, re-admission to hospital, grade 3/4 and serious adverse events.
The primary endpoint for the future Phase II trial reflects the primary hypothesis that sevuparin improves microcirculatory flow by reversing and preventing parasite sequestration. Data collected in the Phase I trial will also assess whether lactate clearance at 8 hours is a realistic and feasible primary endpoint for a subsequent Phase II trial.
To identify the maximum tolerated dose (MTD) of intravenous sevuparin as an adjunctive therapy in children with severe malaria given as three infusions at 0, 8 and 16 hours using the Continual Reassessment Method (CRM) to adapt or inform subsequent doses for each child entering the trial, based on a toxicity event defined as any APTT >2.5 upper limit of normal (ULN) 1 hour after each dose, and updating the dose-toxicity model using the previous patients’ APTT results.
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| Laymans Summary: |
What is the problem/background? Even on the best antimalarial treatments (injectable artesunate) many African children with severe malaria have poor outcomes with most deaths occurring early in the course of hospital admission (<24hours). One of the bad things that happen in severe malaria is that red blood cells that are infected with malaria parasites that stick to the very deep parts of our blood vessels. This occurs throughout the body and therefore the blood flow is poor tissues which leads to a build-up of body acids (called lactate). Up to the present there have been no treatments available to prevent or reverse stop red cells sticking to the blood vessels when they have malaria parasites in them.
The SMAART: Severe Malaria in African children: A Research and Trials consortium have identified one key innovation which could improve this. A novel new drug candidate called sevuparin, has been identified and safely tested in adults with malaria in Thailand. Sevuparin acts by preventing malaria parasites getting into red cells in the first place (this means that the malaria parasite cannot survive); it also prevents red cells with infected with malaria parasites from sticking to the blood vessels and also able to ‘unstick’ red cells with infected with malaria parasites that are already sticking to the blood vessel and causing poor blood flow.
Given its potential to be transformative in improving current outcomes from severe malaria, a large group of specialist doctors in severe malaria research and clinical trials suggested that sevuparin should be tested in children with severe malaria. They have all helped to design this clinical trial, which will be conducted on the high dependency ward in Kilifi, Kenya.
What questions are we trying to answer? Study design: Phase I Safety and Dose Finding to assess the optimal dose of sevuparin given as a supportive therapy in severe malaria alongside of the usual antimalarial treatments to determine toxic level, adverse events and to identify the highest dose with an acceptable safety profile Study Population: 20 children hospitalised with severe malaria.
Sample Size: This is a Phase I trial designed to test safety and Dose Finding Trial of sevuparin as a supportive therapy in severe malaria; there is therefore no formal sample size calculation.
Where is the study taking place, how many people does it involve and how are they selected? The study will be carried out at Kilifi County Hospital, Kenya and plans to enroll 20 children. Children enrolled in the study will be aged 3 months to 12 years, and presenting to Kilifi County Hospital with severe malaria evidence of malaria (rapid diagnostic test positive or positive malaria slide). The carers of these children will be approached for consent and enrolment in the study. The study drug will be given on the first day of admission only alongside of usual treatments given for children with malaria.
What does the study involve for those who are in it?
What are the benefits and risks/costs of the study for those involved? Benefits: Close monitoring of all children on the high dependency unit during admission and follow up to day 28 after discharge. Hospital bills for participants older than 5 years will be covered by the study (covering the costs for standard treatment for severe malaria and related complications). Risks: One potential risk of sevuparin, as it is heparin-like drug is that it increases one of the blood clotting markers. This was seen in the study in Thailand but was short lived (ie only happened for a few hours only) and did not cause any side effects. We are monitoring carefully this blood clotting marker and this will help us make decisions about whether the child receives the next dose and as we are using a continuous reassessment method to monitor toxicity this will inform the dosages for the children enrolled in the trial.
How will the study benefit society? The study aims to improve the outcome from severe malaria. It will generate robust feasibility and safety data to support a future larger phase II trial with the aim of improving management of a vulnerable population of children and improving outcomes.
When does the study start and finish? Once we have received ethical approval. Enrolment will be over 12-15 months and study will end after 2 years.
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| Abstract of Study: | Severe Malaria In African Children: A Research and Trials Consortium (SMAART) was funded in 2018 by a collaboration award in science from the Wellcome Trust. Owing the continued high burden of malaria and poor outcomes of severe malaria, even on the best antimalarial, artesunate, the major objective of SMAART is to conduct better research faster across a collaborative platform to identify interventions to optimise the whole treatment pathway for children with severe malaria, and thus to achieve a step-change in improving their outcomes in the current era.
A novel new drug candidate for adjunctive treatment of severe malaria, sevuparin, has been identified that can blocks merozoite invasion, prevent cytoadherence and transiently de-sequesters infected erythrocytes in humans 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 outcomes 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 in adults with only some mild effects on activated partial thromboplastin time (APTT) at higher doses given over longer periods of time (3 days), which are not clinically relevant to the time of greatest risk.
In this Phase I trial dose-finding paediatric study, we aim to use only 3 doses given at admission (0 hours), and 8 and 16 hours later, and measure APTT 1 hour after each dose (to assess maximum toxicity based on adult data). The Phase I trial is designed to obtain data on safety, dosing, feasibility and potentially lactate clearance of sevuparin given as an adjuvant therapy in severe malaria in children. We aim to study 20 children admitted to hospital with severe malaria which 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 (CRM), which adapts or informs subsequent doses for each child entering the trial based on the data from previously enrolled children. The maximum tolerated dose (MTD) will be identified based on the dose-toxicity model being updated by each previous patient’s APTT results using standard methods.
The results of the Phase I trial will identify the final dosage to be tested in a Phase II trial in terms of both efficacy and safety outcomes. The primary endpoint for the future Phase II trial (lactate clearance) reflects the primary hypothesis that sevuparin improves microcirculatory flow by reversing and preventing parasite sequestration. The Phase I trial will also assess whether this endpoint, lactate clearance, is realistic; thus lactate will be collected along with other test results at baseline 4 hours and 8 hours, as well as other time points.
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