Gail Carson

Experimental Treatment of Ebola Virus Disease with TKM-130803: A Single-Arm Phase 2 Clinical Trial

Background TKM-130803, a small interfering RNA lipid nanoparticle product, has been developed for the treatment of Ebola virus disease (EVD), but its efficacy and safety in humans has not been evaluated. Methods and Findings In this single-arm phase 2 trial, adults with laboratory-confirmed EVD received 0.3 mg/kg of TKM-130803 by intravenous infusion once daily for up to 7 d. On days when trial enrolment capacity was reached, patients were enrolled into a concurrent observational cohort. The primary outcome was survival to day 14 after admission, excluding patients who died within 48 h of admission. After 14 adults with EVD had received TKM-130803, the pre-specified futility boundary was reached, indicating a probability of survival to day 14 of ≤0.55, and enrolment was stopped. Pre-treatment geometric mean Ebola virus load in the 14 TKM-130803 recipients was 2.24 × 109 RNA copies/ml plasma (95% CI 7.52 × 108, 6.66 × 109). Two of the TKM-130803 recipients died within 48 h of admission and were therefore excluded from the primary outcome analysis. Of the remaining 12 TKM-130803 recipients, nine died and three survived. The probability that a TKM-130803 recipient who survived for 48 h will subsequently survive to day 14 was estimated to be 0.27 (95% CI 0.06, 0.58). TKM-130803 infusions were well tolerated, with 56 doses administered and only one possible infusion-related reaction observed. Three patients were enrolled in the observational cohort, of whom two died. Conclusions Administration of TKM-130803 at a dose of 0.3 mg/kg/d by intravenous infusion to adult patients with severe EVD was not shown to improve survival when compared to historic controls. Trial registration Pan African Clinical Trials Registry PACTR201501000997429

Experimental Treatment of Ebola Virus Disease with Brincidofovir

Background The nucleotide analogue brincidofovir was developed to prevent and treat infections caused by double-stranded DNA viruses. Based on in vitro data suggesting an antiviral effect against Ebola virus, brincidofovir was included in the World Health Organisation list of agents that should be prioritised for clinical evaluation in patients with Ebola virus disease (EVD) during the West African epidemic. Methods and Findings In this single-arm phase 2 trial conducted in Liberia, patients with laboratory-confirmed EVD (two months of age or older, enrolment bodyweight ≥50 kg) received oral brincidofovir 200 mg as a loading dose on day 0, followed by 100 mg brincidofovir on days 3, 7, 10, and 14. Bodyweight-adjusted dosing was used for patients weighing <50 kg at enrolment. The primary outcome was survival at Day 14 after the first dose of brincidofovir. Four patients were enrolled between 01 January 2015 and 31 January 2015. The trial was stopped following the decision by the manufacturer to terminate their program of development of brincidofovir for EVD. No Serious Adverse Reactions or Suspected Unexpected Serious Adverse Reactions were identified. All enrolled subjects died of an illness consistent with EVD. Conclusions Due to the small sample size it was not possible to determine the efficacy of brincidofovir for the treatment of EVD. The premature termination of the trial highlights the need to establish better practices for preclinical in-vitro and animal screening of therapeutics for potentially emerging epidemic infectious diseases prior to their use in patients. Trial Registration Pan African Clinical Trials Registry PACTR201411000939962

Guidance on the use of respiratory and facial protection equipment

Summary Infectious micro-organisms may be transmitted by a variety of routes, and some may be spread by more than one route. Respiratory and facial protection is required for those organisms that are usually transmitted via the droplet/airborne route, or when airborne particles have been artificially created, such as during ‘aerosol-generating procedures’. A range of personal protective equipment that provides different degrees of facial and respiratory protection is available. It is apparent from the recent experiences with severe acute respiratory syndrome and pandemic (H1N1) 2009 influenza that healthcare workers may have difficulty in choosing the correct type of facial and respiratory protection in any given clinical situation. To address this issue, the Scientific Development Committee of the Healthcare Infection Society established a short-life working group to develop guidance. The guidance is based upon a review of the literature, which is published separately, and expert consensus.

Feasibility of Using Convalescent Plasma Immunotherapy for MERS-CoV Infection, Saudi Arabia.

Efficacy testing will be challenging because of the small pool of donors with sufficiently high antibody titers.

Open source clinical science for emerging infections

8 www.thelancet.com/infection Vol 14 January 2014 Emerging infections cause justifi able global concern. Current outbreaks of avian infl uenza A H7N9 and the Middle East respiratory syndrome (MERS) raise troubling memories of pandemic infl uenza and severe acute respiratory syndrome (SARS). With few mutations, these or other pathogens could evolve to cause widespread outbreaks. When new threats emerge, well established public health systems rapidly identify cases and evaluate sources, clinicians provide early descriptive case reports, and laboratories develop diagnostics and characterise pathogens. Clinical science is markedly less agile. We lack the tools to answer key questions rapidly. Who is susceptible, and why? What are the mechanisms of disease? What are the sites and dynamics of pathogen replication? How can early cases be identifi ed and stratifi ed? What is the clinical utility of new diagnostics? What treatments might work? Each emerging infection presents these fundamental questions. The method of answering them need not be reinvented from one infection to the next. If clinical scientists across the world were able to agree on methods and cooperate, the results of separate studies from diverse locations and conditions could be collated, allowing clinically useful conclusions to be reached from shared data. The International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) grew from the recognition that we have to do things diff erently, in the light of our experience during the epidemics of SARS, H5N1, and the 2009–10 infl uenza pandemic, but also regional epidemics of enterovirus 71, dengue, viral haemorrhagic fevers, and even during the rapid emergence of drug resistant malaria. We must motivate and equip individual investigators and networks around the world to work together to rapidly answer basic questions when new threats emerge. Academic credit and access to data and samples must be given to clinical investigators, who often recruit patients in extremely challenging circumstances. Unlike the existing model that prioritises independence, eff ective collaboration should be rewarded. The core materials needed to enrol patients must be freely available, making it as easy as possible for investigators at the front line. The core materials of clinical research—protocols, information sheets, consent forms, and case report forms—are analogous to the source code of computer software. In open-source software projects contributors receive recognition that builds their reputation within the software community. We propose a similar approach to clinical research, in parallel with the drive towards open access in academic publishing. Although community projects have a long history in other fi elds, individual recognition is required for scientists to obtain funding and promotion; to succeed, academic institutions, funders, journals, the clinical science and public health communities, and the public need to be in full support. To develop a consensus set of documentation, we engaged with investigators across countries and disciplines, in collaboration with WHO, in a systematic three-stage process: fi rst, to agree criteria by which to prioritise and stratify studies; second, to identify important unanswered questions relating to pathogenesis, susceptibility, and pharmacology in severe infection; and to allocate studies within a globally scalable framework. In the resulting protocol, research intensity is stratifi ed according to the local costs incurred. The lowest tiers have a minimum requirement for staff and resources to recruit a case (fi gure), enabling adaptation for use in places with diff ering resource levels, and also in diff erent phases of an outbreak. For example, early in an outbreak there are urgent questions that require Open source clinical science for emerging infections

Non-vector transmission of flaviviruses, with implications for the Zika virus

Objective To assess available evidence on non-vector modes of transmission of relevant flaviviruses to inform on potential transmission risks and preventive measures for Zika virus. Methods MEDLINE was searched for publications related to non-vector transmission of dengue, West Nile, Japanese encephalitis, yellow fever and Zika viruses, available before March 2016. The titles and abstracts were reviewed to select articles for full text reviews. The reference list of the articles chosen for full-text review were examined for other potentially relevant publications. Findings Vertical transmission has been demonstrated for dengue, Japanese encephalitis and Zika virus. Transmission through infected blood products and possibly through transplants has been reported for dengue and West Nile virus. Transmission in the healthcare setting through needle stick injures and other blood exposures has been reported for dengue, West Nile, yellow fever viruses and most recently with Zika. Transmission through sexual contact has been reported only for Zika virus. Conclusion The findings concerning non-vector transmission has major implications for daily lives of hundreds of thousands of people living in areas where Zika may become endemic and for travellers to the affected countries. The respective countries should improve surveillance and data collection to report these deviant cases and institute relevant policies and guidelines informed by those already available for other flaviviruses, customizing it to their settings.

Injectional anthrax at a Scottish district general hospital

This retrospective, descriptive case-series reviews the clinical presentations and significant laboratory findings of patients diagnosed with and treated for injectional anthrax (IA) since December 2009 at Monklands Hospital in Central Scotland and represents the largest series of IA cases to be described from a single location. Twenty-one patients who fulfilled National Anthrax Control Team standardized case definitions of confirmed, probable or possible IA are reported. All cases survived and none required limb amputation in contrast to an overall mortality of 28% being experienced for this condition in Scotland. We document the spectrum of presentations of soft tissue infection ranging from mild cases which were managed predominantly with oral antibiotics to severe cases with significant oedema, organ failure and coagulopathy. We describe the surgical management, intensive care management and antibiotic management including the first description of daptomycin being used to treat human anthrax. It is noted that some people who had injected heroin infected with Bacillus anthracis did not develop evidence of IA. Also highlighted are biochemical and haematological parameters which proved useful in identifying deteriorating patients who required greater levels of support and surgical debridement.

Ebola: controlling the nightmare

The unprecedented outbreak of Ebola virus disease (EVD) in West Africa is a true global public health emergency, requiring extraordinary measures and global cooperation. Throughout 2014 the world has observed a global health crisis unfold in a way that has never been seen before (Box 1). Multiple outbreaks of EVD have overwhelmed healthcare and humanitarian services in many areas, restricting the ability to perform contact tracing and efforts to limit onward transmission. Existing treatment centres struggle under the strain of large numbers of patients and the rapid and unchecked growth of cases witnessed in some areas means that new facilities reach their capacities almost as soon as they have opened. Tragically, scores of healthcare workers have died and affected countries are being stripped of their already limited medical workforce. Growing numbers of international workers who have helped to fill gaps are now being evacuated from affected countries, at the same time as calls are being made for more workers on the ground. Medecins Sans Frontieres (MSF), an organisation with a deep understanding of this epidemic and previous filovirus outbreaks, has told the UN that military support is required and in response the military has begun to deliver support. Other interventions, viewed by some as last resort measures, include the introduction of ‘cordons sanitaires’ and countrywide lock-downs. These are clear warning signs of an impending humanitarian catastrophe. In response, WHO, the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) and their partners are assisting with specific measures, but a concerted global effort is required if we are to win this battle. Fadela Chaib (WHO) recently said that beds are required for 50 Ebola Treatment Units across Guinea, Liberia and Sierra Leone. There is currently 1126 beds, which is only 25% of what is needed. This level of demand for clinical care is unprecedented in the context of viral haemorrhagic fever outbreaks. The previously held view of Ebola—as a deadly infection that affects remote villages and burns out before dissemination occurs—is now obsolete. We have no choice but to change the way we attempt to control outbreaks of EVD and treat infected patients. Armand Sprecher of MSF Belgium articulates this well, We [MSF] are being stretched thin by the multiplication of outbreak sites. Now it is a challenge of local scale. Monrovia will dwarf all our past experiences and require rethinking of what we do. For instance, we opened in Monrovia with insufficient medical staff before we were ready because patients were dying in the street and in cars outside our compound. We opened just to give them a bed to die in. Ordinarily, we would expect to bring up the level of care as our staffing levels increased. (A. Sprecher, personal communication, 2014).

Regulatory and Operational Complexities of Conducting a Clinical Treatment Trial During an Ebola Virus Disease Epidemic.

Abstract The first phase II and III clinical trials for Ebola virus disease treatments were conducted during the West Africa outbreak. We report the operational practicalities of conducting a phase II clinical trial of TKM-130803 to international standards during this outbreak.

Progress in promoting data sharing in public health emergencies

In February 2016, the World Health Organization (WHO) declared the Zika virus-related cluster of microcephaly cases and other neurological disorders reported in Brazil, a Public Health Emergency of International Concern (PHEIC). (1) Following the declaration, over 30 global health bodies issued a joint statement committing to data sharing to ensure that the global response to the Zika virus and future emergencies, could be informed by the best and most current evidence. (2) The statement represented a concerted effort by those involved to address past failures of timely access to relevant data. It also highlighted the lack of a clear path to implementation for data sharing during public health emergencies. In March 2016, the Global Research Collaboration for Infectious Disease Preparedness (GloPID-R) established a data-sharing working group which has been working in coalition with other stakeholders including WHO, scientists, nongovernmental organizations, journals and other agencies. (3) This group is working to identify barriers to data sharing in public health emergencies that should be addressed to better prepare for any future epidemic. We review the progress since the joint statement was made, outline the key challenges related to data sharing and summarize the groups activities to date. The experiences from the 2013-2016 Ebola virus disease outbreak and the 2015 Zika virus outbreak demonstrated the importance of research in public health emergencies and the difficulties associated with sharing research findings rapidly and outside of conventional scientific publications. (4-7) Research--whether epidemiological, genetic, preclinical, microbiological, behavioural or operational--can generate new knowledge about an outbreak in rapidly changing situations. Research can inform risk communication, surveillance, clinical care, product development and other interventions. The WHO consensus and policy statements called for a paradigm shift in information sharing in public health emergencies and described the particularities to consider in dealing with different data types. (8,9) Despite these efforts, rapid data sharing during public health emergencies remains challenging for various reasons. First, there are limited incentives for researchers and other people responding to the emergency to share data. Second, there is a lack of appropriate infrastructure for data sharing such as repositories and information technology platforms. Such rapid data sharing requires a clear governance structure that ensures a balance between privacy and access, as well as adheres to national and international ethical and legal requirements. Implementation of calls for data sharing is hampered by barriers, including: (i) inequity in capacity and funding between researchers in high-and low-income settings; (ii) varying concepts of data ownership by data providers and data users; (iii) no clear mechanism for attribution and academic recognition for data providers and data users related to published products; (iv) costs and varying degrees of access to data management systems within research groups or institutions; (v) reputational risk from premature sharing of data and results; (vi) ethical and regulatory issues related to privacy and consent in the context of experimental treatment and clinical care; (vii) access to the benefits of research; (viii) concerns about loss of potential financial benefits from eventual commercialization and intellectual property rights. …