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Are adaptive randomised trials or non-randomised studies the best way to address the Ebola outbreak in west Africa?

ABSTRACT: The Ebola outbreak that has devastated parts of west Africa represents an unprecedented challenge for research and ethics. Estimates from the past three decades emphasise that the present effort to contain the epidemic in the three most affected countries (Guinea, Liberia, and Sierra Leone) has been insufficient, with more than 24,900 cases and about 10,300 deaths, as of March 25, 2015. Faced with such an exceptional event and the urgent response it demands, the use of randomised controlled trials (RCT) for Ebola-related research might be both unethical and infeasible and that potential interventions should be assessed in non-randomised studies on the basis of compassionate use. However, non-randomised studies might not yield valid conclusions, leading to large residual uncertainty about how to interpret the results, and can also waste scarce intervention-related resources, making them profoundly unethical. Scientifically sound and rigorous study designs, such as adaptive RCTs, could provide the best way to reduce the time needed to develop new interventions and to obtain valid results on their efficacy and safety while preserving the application of ethical precepts. We present an overview of clinical studies registered at present at the four main international trial registries and provide a simulation on how adaptive RCTs can behave in this context, when mortality varies simultaneously in either the control or the experimental group.

SUBMITTER: Lanini S

PROVIDER: S-EPMC7129402 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Are adaptive randomised trials or non-randomised studies the best way to address the Ebola outbreak in west Africa?

Lanini Simone S Zumla Alimuddin A Ioannidis John P A JP Di Caro Antonino A Krishna Sanjeev S Gostin Lawrence L Girardi Enrico E Pletschette Michel M Strada Gino G Baritussio Aldo A Portella Gina G Apolone Giovanni G Cavuto Silvio S Satolli Roberto R Kremsner Peter P Vairo Francesco F Ippolito Giuseppe G

The Lancet. Infectious diseases 20150414 6

The Ebola outbreak that has devastated parts of west Africa represents an unprecedented challenge for research and ethics. Estimates from the past three decades emphasise that the present effort to contain the epidemic in the three most affected countries (Guinea, Liberia, and Sierra Leone) has been insufficient, with more than 24,900 cases and about 10,300 deaths, as of March 25, 2015. Faced with such an exceptional event and the urgent response it demands, the use of randomised controlled tria ...[more]

PMID: 25881871

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Project description:The Ebola virus (EBOV) outbreak in West Africa started in December 2013, claimed more than 11,000 lives, threatened to destabilize a whole region, and showed how easily health crises can turn into humanitarian disasters. EBOV genomic sequences of the West African outbreak revealed nonsynonymous mutations, which induced considerable public attention, but their role in virus spread and disease remains obscure. In this study, we investigated the functional significance of three nonsynonymous mutations that emerged early during the West African EBOV outbreak. Almost 90% of more than 1,000 EBOV genomes sequenced during the outbreak carried the signature of three mutations: a D759G substitution in the active center of the L polymerase, an A82V substitution in the receptor binding domain of surface glycoprotein GP, and an R111C substitution in the self-assembly domain of RNA-encapsidating nucleoprotein NP. Using a newly developed virus-like particle system and reverse genetics, we found that the mutations have an impact on the functions of the respective viral proteins and on the growth of recombinant EBOVs. The mutation in L increased viral transcription and replication, whereas the mutation in NP decreased viral transcription and replication. The mutation in the receptor binding domain of the glycoprotein GP improved the efficiency of GP-mediated viral entry into target cells. Recombinant EBOVs with combinations of the three mutations showed a growth advantage over the prototype isolate Makona C7 lacking the mutations. This study showed that virus variants with improved fitness emerged early during the West African EBOV outbreak.ImportanceThe dimension of the Ebola virus outbreak in West Africa was unprecedented. Amino acid substitutions in the viral L polymerase, surface glycoprotein GP, and nucleocapsid protein NP emerged, were fixed early in the outbreak, and were found in almost 90% of the sequences. Here we showed that these mutations affected the functional activity of viral proteins and improved viral growth in cell culture. Our results demonstrate emergence of adaptive changes in the Ebola virus genome during virus circulation in humans and prompt further studies on the potential role of these changes in virus transmissibility and pathogenicity.

Project description:Due to the lack of Ebola outbreak early warning alert, preparedness, surveillance and response systems, the most deadly, complex and largest ever seen Ebola war has been devastating West African communities. The unparalleled Ebola tsunami has prompted interrogations into, and uncertainties about, the effectiveness and efficiency of national, regional and international community's illed- responses using conventional humanitarian control and containment approaches and methods. The late humanitarian and local non-government organisations emergency responses and challenges to curb transmission dynamics and stop the ongoing spread in the Ebola outbreak in West Africa have led to an unprecedented toll of 14,413 reported Ebola cases in eight countries since the outbreak began, with 5,177 reported deaths including 571 health-care workers and 325 died as 14 November 2014. These indications the need of further evaluation of monitoring as substantial proportion of infections outside the context of Ebola epicentres, Ebola health centres treatment and care, infection prevention and control quality assurance checks in these countries. At the same time, exhaustive efforts should target ensuring an sufficient supply of optimal personal protective equipment (PPE) to all Ebola treatment facilities, along with the provision of training and relevant guidelines to limit to the minimum possible level of risk. The continent hosts a big proportion of the world's wealth, yet its people live in abject poverty, with governments unable to feed and govern them effectively, and who are condemned to endure even darker moments with the Ebola outbreak in West Africa. Institutionalisation of practical and operational non-conventional emergency response models efficient health systems, and tailored programmes can clearly support to prevent, control and eventually stamp out Ebola geo-distribution in addition to population mental health services that are requisite to address the massive range of the health, socio-psychological and economic consequences during and post Ebola associated crises. There is a critical need for a more pragmatic and robust scientific approach to transform and re-orient the huge natural and human resource potentials towards achieving universal coverage, the 2015-2030 Millennium Developing Goals (MDGs), sustainable growth and development in Africa.

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Are adaptive randomised trials or non-randomised studies the best way to address the Ebola outbreak in west Africa?

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Are adaptive randomised trials or non-randomised studies the best way to address the Ebola outbreak in west Africa?

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