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Mpox is caused by the monkeypox virus (MPXV), a double-stranded DNA orthopoxvirus with 2 known clades: clade I (formerly Congo Basin or Central African clade); and clade II (formerly West [...]

Background: Due to limited diagnostic capacity and availability of point-of-care tests, diagnosis of Clade I mpox in the geographical regions most affected is usually on clinical grounds. This may be complicated due to the similarity between mpox and varicella (chickenpox) lesions. Visual assessment of lesions is also used for determining clinical progress and to assess patient outcomes in clinical trials. However, there has been no investigation into whether clinicians can (i) identify Clade I mpox compared to other viral lesions (ii) differentiate between Clade I mpox lesion stages. Methodology/Principle findings: The objective of this study was to evaluate inter-rater reliability and agreement between clinicians assessing lesions in patients with Clade I mpox. We presented experienced clinicians with 17 images of Clade I mpox or varicella and asked them to independently indicate the most likely diagnosis–mpox or varicella–and to categorise the lesions according to their stage. When selecting the most likely diagnosis, accuracy varied across all images, the inter-rater reliability was poor (κ = 0.223; z = 10.1) and agreement was moderate (Po = 68%). When categorising lesions according to their type, if a single lesion type was present in the image, inter-rater reliability was moderate (κ = 0.671, z = 40.6) and agreement was good (Po = 78%), but when multiple lesion types were shown in an image, both inter-rater reliability (κ = 0.153, z = 10.5) and agreement (Po = 29%) decreased substantially. Conclusions: This study demonstrates that there are presently limitations in using visual assessment to diagnose Clade I mpox and evaluate lesion stage and treatment outcomes, which have an impact on clinical practice, public health and clinical trials. More robust indicators and tools are required to inform clinical, public-health, and research priorities, but these must be implementable in countries affected by mpox. Author summary: Mpox is a zoonotic illness caused by the monkeypox virus (MPXV), for which there are two distinct sub-clades. Clade I is typically found in central Africa and is associated with worse patient outcomes than Clade II. Diagnosis of mpox is most commonly performed using PCR, but in settings with limited laboratory capacity diagnosis is usually performed on clinical grounds taking lesion presentation in to account. Lesion presentation is also used to assess patient outcomes in both clinical and research settings. However, there has been no investigation into whether clinicians can (i) identify Clade I mpox compared to other viral lesions (ii) differentiate between Clade I mpox lesion stages, which has important implications for clinical practice, research and public health. Our study, which presented 16 clinicians with 17 sets of images of Clade I mpox or varicella and asked them to i) provide the most likely diagnosis and ii) categorise the lesions in to their stages, demonstrates that there are presently limitations in using visual assessment to diagnose Clade I mpox and evaluate lesion stage and treatment outcomes. Alternative methods and tools are therefore required that can be easily implemented in affected countries. [ABSTRACT FROM AUTHOR]

Background: Monkeypox is a viral zoonotic disease commonly reported in humans in parts of Central and West Africa. This protocol is for an Expanded Access Programme (EAP) to be implemented in the Central African Republic, where Clade I monkeypox virus diseases is primarily responsible for most monkeypox infections. The objective of the programme is to provide patients with confirmed monkeypox with access to tecovirimat, a novel antiviral targeting orthopoxviruses, and collect data on clinical and virological outcomes of patients to inform future research. Methods: The study will be conducted at participating hospitals in the Central African Republic. All patients who provide informed consent to enrol in the programme will receive tecovirimat. Patients will remain in hospital for the duration of treatment. Data on clinical signs and symptoms will be collected every day while the patient is hospitalised. Blood, throat and lesion samples will be collected at baseline and then on days 4, 8, 14 and 28. Patient outcomes will be assessed on Day 14 –end of treatment–and at Day 28. Adverse event and serious adverse event data will be collected from the point of consent until Day 28. Discussion: This EAP is the first protocolised treatment programme in Clade I MPXV. The data generated under this protocol aims to describe the use of tecovirimat for Clade I disease in a monkeypox endemic region of Central Africa. It is hoped that this data can inform the definition of outcome measures used in future research and contribute to the academic literature around the use of tecovirimat for the treatment of monkeypox. The EAP also aims to bolster research capacity in the region in order for robust randomised controlled trials to take place for monkeypox and other diseases. Trial registration: {2a & 2b}: ISRCTN43307947. [ABSTRACT FROM AUTHOR]

The article discusses the lack of progress in preventing and treating mpox, a virus that has caused 91,000 cases worldwide. There are significant inequalities in access to therapy and vaccination between high-income and low- and middle-income countries, particularly in Africa. The article highlights the challenges of conducting effective clinical research during short-lived outbreaks and the need for safe and effective treatments. It also emphasizes the importance of international collaborations, efficient regulatory processes, and equitable access to medical interventions. The article calls for action from all stakeholders to address these issues and improve clinical research in outbreak response. [Extracted from the article]

Background: Plague is a zoonotic disease that, despite affecting humans for more than 5000 years, has historically been the subject of limited drug development activity. Drugs that are currently recommended in treatment guidelines have been approved based on animal studies alone–no pivotal clinical trials in humans have yet been completed. As a result of the sparse clinical research attention received, there are a number of methodological challenges that need to be addressed in order to facilitate the collection of clinical trial data that can meaningfully inform clinicians and policy-makers. One such challenge is the identification of clinically-relevant endpoints, which are informed by understanding the clinical characterisation of the disease–how it presents and evolves over time, and important patient outcomes, and how these can be modified by treatment. Methodology/Principal findings: This systematic review aims to summarise the clinical profile of 1343 patients with bubonic plague described in 87 publications, identified by searching bibliographic databases for studies that meet pre-defined eligibility criteria. The majority of studies were individual case reports. A diverse group of signs and symptoms were reported at baseline and post-baseline timepoints–the most common of which was presence of a bubo, for which limited descriptive and longitudinal information was available. Death occurred in 15% of patients; although this varied from an average 10% in high-income countries to an average 17% in low- and middle-income countries. The median time to death was 1 day, ranging from 0 to 16 days. Conclusions/Significance: This systematic review elucidates the restrictions that limited disease characterisation places on clinical trials for infectious diseases such as plague, which not only impacts the definition of trial endpoints but has the knock-on effect of challenging the interpretation of a trial's results. For this reason and despite interventional trials for plague having taken place, questions around optimal treatment for plague persist. Author summary: Plague is an infectious disease that, despite affecting humans for more than 5000 years, has historically been the subject of limited drug development activity. In fact, the drugs currently used to treat plague have been approved based on experimental data alone–no major clinical trials have yet been completed that demonstrate the efficacy and safety of one treatment over another in humans. A major barrier to accomplishing this is that few research studies have taken place to date that can meaningfully inform the design of a clinical trial. We conducted this systematic review to gather and summarise all the existing information on the clinical profile of plague patients to understand whether sufficient information exists on which to design informative clinical trials that would provide clinicians and policy-makers with the information needed to make treatment decisions for patients. This study however found that, based on the existing literature, there is insufficient data that can be used to develop methodologies for future trials. Either time must be invested in to collecting robust clinical data or innovative trial designs need to be identified that can simultaneously collect much-needed observational data while also evaluating much-needed interventions. [ABSTRACT FROM AUTHOR]

Background: Only 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. Methodology: We 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. Results: A 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. Conclusions: 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. Author summary: Lassa fever (LF) is an acute viral haemorrhagic fever endemic to West Africa, causing an estimated 500,000 new infections and 10,000 deaths per year. At present, no treatment has been developed to specifically treat LF and only one prospective clinical trial has been conducted to evaluate the current treatment recommendation. Before a new era of LF clinical trials can begin, it is important to develop standardised methods and tools to ensure that trials are conducted in a consistent way and can generate reliable, comparable data. The aim of this project was initiate the first step to improve the comparability of LF studies by developing a standardised Phase III clinical trial methodology for LF therapeutics that could be applied in low-resource settings. Through multi-stakeholder consultation, we established a consensus position of clinicians and researchers on the core components of future Phase III clinical trials: Core Eligibility Criteria (CEC), Core Case Definition (CCD), Core Outcome Set (COS) and Core Data Variables (CDV). [ABSTRACT FROM AUTHOR]

Background: Among the many collaterals of the COVID-19 pandemic is the disruption of health services and vital clinical research. COVID-19 has magnified the challenges faced in research and threatens to slow research for urgently needed therapeutics for Neglected Tropical Diseases (NTDs) and diseases affecting the most vulnerable populations. Here we explore the impact of the pandemic on a clinical trial for plague therapeutics and strategies that have been considered to ensure research efforts continue. Methods: To understand the impact of the COVID-19 pandemic on the trial accrual rate, we documented changes in patterns of all-cause consultations that took place before and during the pandemic at health centres in two districts of the Amoron'I Mania region of Madagascar where the trial is underway. We also considered trends in plague reporting and other external factors that may have contributed to slow recruitment. Results: During the pandemic, we found a 27% decrease in consultations at the referral hospital, compared to an 11% increase at peripheral health centres, as well as an overall drop during the months of lockdown. We also found a nation-wide trend towards reduced number of reported plague cases. Discussion: COVID-19 outbreaks are unlikely to dissipate in the near future. Declining NTD case numbers recorded during the pandemic period should not be viewed in isolation or taken as a marker of things to come. It is vitally important that researchers are prepared for a rebound in cases and, most importantly, that research continues to avoid NTDs becoming even more neglected. Author summary: The COVID-19 pandemic has forced health systems to re-evaluate service provision, leading to the diversion of resources and widespread disruption of research activities. In particular, the pandemic has jeopardised the progress of research for Neglected Tropical Diseases (NTDs), which has historically faced considerable challenges. Many NTDs suffer a lack of robust clinical evidence to support current treatment recommendations and previous attempts to conduct clinical trials have been hampered by field conditions. This article presents the case of a randomised controlled trial for an NTD that was initiated at the start of the pandemic and explores the factors that may have influenced enrolment. Importantly, this article highlights mitigation strategies that have been considered by the trial team to ensure that trial activities can be maintained. The reduction in reporting of NTDs during the pandemic does not necessarily mean that there are fewer cases at the community level or that this trend will continue. As outbreaks of COVID-19 persist, strategies to mitigate the effect of continued disruption are critical to ensure that, even with a downward trend in NTD case notification, studies addressing an urgent research need can continue and NTDs don't become even more neglected than they already are. [ABSTRACT FROM AUTHOR]

Background: Research is urgently needed to reduce the morbidity and mortality of Lassa fever (LF), including clinical trials to test new therapies and to verify the efficacy and safety of the only current treatment recommendation, ribavirin, which has a weak clinical evidence base. To help establish a basis for the development of an adaptable, standardised clinical trial methodology, we conducted a systematic review to identify the clinical characteristics and outcomes of LF and describe how LF has historically been defined and assessed in the scientific literature. Methodology: Primary clinical studies and reports of patients with suspected and confirmed diagnosis of LF published in the peer-reviewed literature before 15 April 2021 were included. Publications were selected following a two-stage screening of abstracts, then full-texts, by two independent reviewers at each stage. Data were extracted, verified, and summarised using descriptive statistics. Results: 147 publications were included, primarily case reports (36%), case series (28%), and cohort studies (20%); only 2 quasi-randomised studies (1%) were found. Data are mostly from Nigeria (52% of individuals, 41% of publications) and Sierra Leone (42% of individuals, 31% of publications). The results corroborate the World Health Organisation characterisation of LF presentation. However, a broader spectrum of presenting symptoms is evident, such as gastrointestinal illness and other nervous system and musculoskeletal disorders that are not commonly included as indicators of LF. The overall case fatality ratio was 30% in laboratory-confirmed cases (1896/6373 reported in 109 publications). Conclusion: Systematic review is an important tool in the clinical characterisation of diseases with limited publications. The results herein provide a more complete understanding of the spectrum of disease which is relevant to clinical trial design. This review demonstrates the need for coordination across the LF research community to generate harmonised research methods that can contribute to building a strong evidence base for new treatments and foster confidence in their integration into clinical care. Author summary: Clinical research in difficult-to-study infectious diseases such as Lassa fever is challenging. Only one controlled clinical trial has been conducted to assess the safety and efficacy of therapeutic interventions for Lassa fever (LF). Further research to test new and repurposed therapies is needed and should be supported by a methodological framework in which clinical trials can be consistently conducted for LF. To establish a basis for a standardised clinical trial methodology, we carried out a systematic review to identify the clinical characteristics and outcomes of LF and describe how LF has historically been defined and assessed in the scientific literature. Our data corroborates the current characterisation of LF, and also highlights a broader range of other general symptoms that characterise the onset of LF, such as gastrointestinal illness and other nervous system and musculoskeletal disorders that are not commonly included as indicators of LF. These findings, however, should be tempered by the lack of systematic assessment and reporting of presenting signs and symptoms, their evolution following treatment, and outcomes at discharge in the historic literature. It is therefore evident that a standardised set of data variables and outcome measures should be developed and incorporated into future trials and reported to accelerate collective knowledge. [ABSTRACT FROM AUTHOR]

Background: Human mpox is a viral disease caused by an Orthopoxvirus, human mpox virus (hMPXV), typically causing fever and a rash. Mpox has historically been endemic to parts of Central and West Africa, with small numbers of imported cases reported elsewhere, but starting May 2022 an unprecedented global outbreak caused by clade IIb hMPXV was reported outside traditionally endemic countries. This prompted the initiation of MOSAIC, a cohort study implemented in Europe and Asia that aims to describe clinical and virologic outcomes of PCR-confirmed hMPXV disease, including those who receive antiviral therapy. The focus of this article, however, is on describing the study protocol itself with implementation process and operational challenges., Methods: MOSAIC recruits participants of any age with laboratory-confirmed mpox disease who provide informed consent. Participants enrol in the cohort for a total of six months. Blood, lesion and throat samples are collected at several timepoints from the day of diagnosis or the first day of treatment (Day 1) until Day 28 for PCR detection of hMPXV. Clinical data are collected by clinicians and participants (via a self-completion questionnaire) for six months to characterize the signs and symptoms associated with the illness, as well as short- and more long-term outcomes., Discussion: The design and prompt implementation of clinical research response is key in addressing emerging outbreaks. MOSAIC began enrolment within two months of the start of the international mpox epidemic. Enrolment has been stopped and the last follow-up visits are expected in January 2024., Ictrp Registration: EU CT number: 2022-501132-42-00 (22/06/2022)., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Pesonel E et al.)

Background : This is a standardized, pre-positioned protocol for the coordinated evaluation of Lassa fever therapeutics. The protocol is the product of discussions that took place in 2021 and 2022 among international investigators from a wide range of scientific and medical disciplines working together within the West Africa Lassa fever Consortium (WALC). Methods : This is a clinical Phase II/III multicentre randomised controlled platform trial using a superiority framework with an equal allocation ratio and a composite primary endpoint of all-cause mortality OR new onset of i) acute kidney failure (AKF), OR ii) acute respiratory failure (ARF), OR iii) shock assessed from enrolment (D0) to D28. Discussion : This pre-positioned protocol was developed by the WALC and made available for adaptation and implementation by the wider Lassa fever research community in order to generate efficient, reliable, and comparable evidence for Lassa fever therapeutics., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Bourner J et al.)