Abstract
BackgroundOnly one recommendation currently exists for the treatment of Lassa fever (LF), which is ribavirin administered in conjunction with supportive care. This recommendation is primarily based on evidence generated from a single clinical trial that was conducted more than 30 years ago–the methodology and results of which have recently come under scrutiny. The requirement for novel therapeutics and reassessment of ribavirin is therefore urgent. However, a significant amount of work now needs to be undertaken to ensure that future trials for LF can be conducted consistently and reliably to facilitate the efficient generation of evidence.MethodologyWe convened a consultation group to establish the position of clinicians and researchers on the core components of future trials. A Core Eligibility Criteria (CEC), Core Case Definition (CCD), Core Outcome Set (COS) and Core Data Variables (CDV) were developed through the process of a multi-stakeholder consultation that took place using a modified-Delphi methodology.ResultsA consensus position was achieved for each aspect of the framework, which accounts for the inclusion of pregnant women and children in future LF clinical trials. The framework consists of 8 core criteria, as well as additional considerations for trial protocols.ConclusionsThis project represents the first step towards delineating the clinical development pathway for new Lassa fever therapeutics, following a period of 40 years without advancement. Future planned projects will bolster the work initiated here to continue the advancement of LF clinical research through a regionally-centred, collaborative methodology, with the aim of delineating a clear pathway through which LF clinical trials can progress efficiently and ensure sustainable investments are made in research capacity at a regional level.
Highlights
A consensus position was achieved for each aspect of the framework, which accounts for the inclusion of pregnant women and children in future Lassa fever (LF) clinical trials
This project represents the first step towards delineating the clinical development pathway for new Lassa fever therapeutics, following a period of 40 years without advancement
Future planned projects will bolster the work initiated here to continue the advancement of LF clinical research through a regionally-centred, collaborative methodology, with the aim of delineating a clear pathway through which LF clinical trials can progress efficiently and ensure sustainable investments are made in research capacity at a regional level
Summary
Lassa fever (LF) is an acute viral haemorrhagic illness endemic to West Africa, causing an estimated 500,000 new infections and 10,000 deaths per year. [1] The main animal reservoir of the Lassa virus is the multimammate rat, Mastomys natalensis, through which transmission to humans can occur either from direct contact with the rat or indirect contact with contaminated food or household items. [2] Human-to-human transmission is most common in healthcare staff working in resource-limited settings where the supply of high quality protective equipment is suboptimal, preventing consistent adherence to infection prevention and control measures. [3]The incubation period of LF is wide-ranging, with the onset of symptoms occurring typically between 6 and 21 days. [2] Symptoms are often non-specific and most commonly include fever alongside headache, vomiting and abdominal pain, with a small proportion of patients presenting with clinically severe, life-threatening symptoms, such as seizure, breathing difficulty and shock. [4,5] In hospitalised cases, the case fatality rate (CFR) is reported to be 24– 27% [6,7] overall and 34% for pregnant women [8]– in a recent cohort study taking place in a research setting, the CFR for hospitalised cases was 13% for adults and 6% for children. [9]Despite a weak evidence base, the primary treatment for LF is ribavirin in conjunction with supportive care. [4,10] This recommendation is largely based on the results of a single prospective clinical trial that was conducted in the 1980s, which has since generated concern about its methods, analysis and the safety of ribavirin when used to treat mild cases of LF. [11–13] The requirement for novel therapeutics, a small number of which have been identified as candidates to be tested, is urgent. [14–16]before a new era of LF clinical trials can begin, robust methods must be developed to ensure that trials are conducted in a consistent way and can generate reliable, comparable data. The group were asked to consider the fundamental requirements that a Phase III pivotal trial should incorporate in its eligibility criteria, case definition, outcome measures and data variables to evaluate new and existing therapeutics (Box 1) This project represents the first step towards delineating the clinical development pathway for future LF therapeutics with the aim of guiding wider discussions within the West Africa Lassa fever Consortium (WALC). One recommendation currently exists for the treatment of Lassa fever (LF), which is ribavirin administered in conjunction with supportive care This recommendation is primarily based on evidence generated from a single clinical trial that was conducted more than 30 years ago– the methodology and results of which have recently come under scrutiny. A significant amount of work needs to be undertaken to ensure that future trials for LF can be conducted consistently and reliably to facilitate the efficient generation of evidence
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