Pharmacy and Poisons Board: Applications

List Applications

Protocol No:

ECCT/24/04/03

Date of Protocol:

09-02-2024

Study Title:	Severe Malaria A Research and Trials consortium - Multisite Adaptive Platform trial
Study Objectives:	The SMAART-MAP trial aims to identify promising adjunctive therapies for advancement into a comprehensive Phase III trial focused on severe malaria with an emphasis on mortality outcomes. Utilizing an adaptive platform design, the trial is structured to incorporate multiple domains, enabling the evaluation of various adjunctive therapies across diverse clinical manifestations of severe malaria efficiently. Primary Objective The primary objective is to evaluate the therapeutic efficacy of each intervention within its respective domain. This evaluation will utilize early indicators such as biomarkers or clinical assessments conducted within 24-72 hours post-intervention. Secondary Objectives To determine the impact of the interventions on clinical outcomes, including readmission rates and mortality, assessed at 28 days and 90 days following randomization. To evaluate the incidence and severity of Grade 3 or 4 adverse events, as well as any adverse events associated with the interventions or their comparators. To explore the effects of defined severe malaria criteria, specifically platelet counts ≤150,000/μL and plasma pfHRP2 concentrations ≥800 ng/mL, on the differentiation between randomized groups. In a sub study, to assess the performance characteristics of a point-of-care (POC) pfHRP2 test in comparison with quantitative plasma pfHRP2 measurements. These objectives are designed to guide the systematic exploration and evaluation of adjunctive therapies in the treatment of severe malaria, thereby contributing to improved treatment strategies and outcomes.
Laymans Summary:	Children with severe malaria come to hospital very sick and need urgent care. Despite the introduction of the malaria vaccine in some areas of Africa and increased bednet use, severe malaria is still causing child deaths and hospitalisations. Even on the best anti-malarial treatments many African children with severe malaria have poor outcomes with including deaths which tend to occur on the first day of arrival to hospital. One of the bad things that happen in severe malaria is that red blood cells that are infected with malaria parasites stick to the very deep parts of our blood vessels. This occurs throughout the body and affects vital places such as the brain or kidneys. Thus, children come to hospital with different symptoms such as in a coma or with fits or with anaemia. They will be treated immediately with anti-malarials and may also receive antibiotics. Other treatments targeted at symptoms or specific areas of the body may also help them recover (called adjunctive therapy). The World Health Organisation has developed guidelines for treatment of severe malaria but much of the information used to develop the recommendations on adjunctive therapy are based on expert opinion and not data from clinical trials and studies which are a better source of evidence. The SMAART-MAP trial aims to identify adjunctive therapies that will help children with severe malaria get better faster in the short term (within 3 days of coming to hospital) and that could then be studied further in larger numbers to see if they are able to reduce the number of children who die or return to hospital. The trial has been designed to look at the impact of these adjunctive therapies on different symptoms or body areas. In the trial these different areas are called ‘domains’. One adjunctive therapy will be investigated within each domain of the trial. It is called an adaptive trial as new domains can be added to the structure of the trial after it has started, and all domains have some joint processes and will be run by the same staff. This document is the master protocol which outlines those joint processes and explains the main objective of the trial. Appendices describe the adjunctive therapies within each domain in more detail. A computer programme will assign a child to receive either the adjunctive treatment or the standard of care at that site within a domain at random (like the flip of a coin). Each child can only be enrolled to one domain and thus possibly receive one adjunctive treatment through the trial. Each child will be monitored through bedside observations and depending on the domain they may need some additional tests. This information will help us compare how children receiving the adjunctive therapy and receiving standard of care are responding to their treatment.
Abstract of Study:	The Severe Malaria Africa – A Consortium for Research and Trials (SMAART) aims to significantly improve outcomes for severe malaria through enhanced and accelerated research initiatives. SMAART serves as an efficient operational platform for coordinating future research, enabling continuous updates to disease definitions and treatment guidelines based on the latest evidence. During its 2-day inception meeting, SMAART assembled a multidisciplinary team including scientists from major Wellcome Trust programs (KEMRI in Kenya, Malawi-Liverpool-Wellcome Trust Unit in Malawi, Mahidol Oxford Tropical Medicine Research Unit in Thailand), clinical trial experts (MRC CTU at UCL), and African clinician scientists from multiple countries. The meeting focused on establishing the current burden of severe malaria through literature review, updating our understanding of the disease's clinical spectrum, identifying accurate diagnostic tools, and setting best practices to address research gaps. Key discussions revolved around refining practice guidelines in response to challenges like artemisinin resistance and persistently high mortality rates despite effective antimalarial treatments. The meeting also laid out plans for future clinical trials, emphasizing pathophysiological research and innovative trial methodologies. Despite various supportive therapies being explored through ongoing and planned clinical trials, the evidence remains sparse, underlining the urgent need for more comprehensive studies. The consortium stressed the necessity of an adaptive trial platform to properly evaluate potential beneficial adjunctive therapies and identified high-priority risk factors and interventions for a Phase II platform trial aimed at improving short and long-term outcomes. This structured approach aims to address severe malaria with targeted treatments and innovative research methodologies, with each intervention's background, justification, and rationale detailed in specific appendix protocols.