Dataset Information

Design of a Randomized Controlled Trial for Ebola Virus Disease Medical Countermeasures: PREVAIL II, the Ebola MCM Study.

ABSTRACT:

Background

Unique challenges posed by emerging infectious diseases often expose inadequacies in the conventional phased investigational therapeutic development paradigm. The recent Ebola outbreak in West Africa presents a critical case-study highlighting barriers to faster development. During the outbreak, clinical trials were implemented with unprecedented speed. Yet, in most cases, this fast-tracked approach proved too slow for the rapidly evolving epidemic. Controversy abounded as to the most appropriate study designs to yield safety and efficacy data, potentially causing delays in pivotal studies. Preparation for research during future outbreaks may require acceptance of a paradigm that circumvents, accelerates, or reorders traditional phases, without losing sight of the traditional benchmarks by which drug candidates must be assessed for activity, safety and efficacy.

Methods

We present the design of an adaptive, parent protocol, ongoing in West Africa until January 2016. The exigent circumstances of the outbreak and limited prior clinical experience with experimental treatments, led to more direct bridging from preclinical studies to human trials than the conventional paradigm would typically have sanctioned, and required considerable design flexibility.

Results

Preliminary evaluation of the "barely Bayesian" design was provided through computer simulation studies. The understanding and public discussion of the study design will help its future implementation.

SUBMITTER: Dodd LE

PROVIDER: S-EPMC4878725 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Publications

Design of a Randomized Controlled Trial for Ebola Virus Disease Medical Countermeasures: PREVAIL II, the Ebola MCM Study.

Dodd Lori E LE Proschan Michael A MA Neuhaus Jacqueline J Koopmeiners Joseph S JS Neaton James J Beigel John D JD Barrett Kevin K Lane Henry Clifford HC Davey Richard T RT

The Journal of infectious diseases 20160211 12

<h4>Background</h4>Unique challenges posed by emerging infectious diseases often expose inadequacies in the conventional phased investigational therapeutic development paradigm. The recent Ebola outbreak in West Africa presents a critical case-study highlighting barriers to faster development. During the outbreak, clinical trials were implemented with unprecedented speed. Yet, in most cases, this fast-tracked approach proved too slow for the rapidly evolving epidemic. Controversy abounded as to ...[more]

PMID: 26908739

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Project description:BACKGROUND:Data from studies in nonhuman primates suggest that the triple monoclonal antibody cocktail ZMapp is a promising immune-based treatment for Ebola virus disease (EVD). METHODS:Beginning in March 2015, we conducted a randomized, controlled trial of ZMapp plus the current standard of care as compared with the current standard of care alone in patients with EVD that was diagnosed in West Africa by polymerase-chain-reaction (PCR) assay. Eligible patients of any age were randomly assigned in a 1:1 ratio to receive either the current standard of care or the current standard of care plus three intravenous infusions of ZMapp (50 mg per kilogram of body weight, administered every third day). Patients were stratified according to baseline PCR cycle-threshold value for the virus (?22 vs. >22) and country of enrollment. Oral favipiravir was part of the current standard of care in Guinea. The primary end point was mortality at 28 days. RESULTS:A total of 72 patients were enrolled at sites in Liberia, Sierra Leone, Guinea, and the United States. Of the 71 patients who could be evaluated, 21 died, representing an overall case fatality rate of 30%. Death occurred in 13 of 35 patients (37%) who received the current standard of care alone and in 8 of 36 patients (22%) who received the current standard of care plus ZMapp. The observed posterior probability that ZMapp plus the current standard of care was superior to the current standard of care alone was 91.2%, falling short of the prespecified threshold of 97.5%. Frequentist analyses yielded similar results (absolute difference in mortality with ZMapp, -15 percentage points; 95% confidence interval, -36 to 7). Baseline viral load was strongly predictive of both mortality and duration of hospitalization in all age groups. CONCLUSIONS:In this randomized, controlled trial of a putative therapeutic agent for EVD, although the estimated effect of ZMapp appeared to be beneficial, the result did not meet the prespecified statistical threshold for efficacy. (Funded by the National Institute of Allergy and Infectious Diseases and others; PREVAIL II ClinicalTrials.gov number, NCT02363322 .).

Project description:Background:The 2013-2016 outbreak of Ebola virus disease (EVD) in West Africa led to unprecedented morbidity and mortality. Although different classes of putative antiviral agents with supportive preclinical data were available for testing, and although several attempts to perform meaningful evaluation of these agents were undertaken during the epidemic, different research methods, a lack of appropriate controls in most studies, and formidable logistical challenges to completion of studies under field conditions hampered the success of these efforts. Ultimately only 1 randomized, placebo-controlled clinical trial (PREVAIL II) was performed in this setting, and, owing to a decrease in the number of new cases available for study, it, too, ended prior to reaching definitive results. Retrospective review of the lessons learned from this outbreak argues strongly for the need for much better preparedness in terms of selecting the trial design and drug(s) for use during the next outbreak. Methods:Using recent data provided by representatives from the pharmaceutical industry, clinical and laboratory subject matter experts from the National Institute of Allergy and Infectious Diseases, other US government agencies, and academic partners were consulted regarding the current state of knowledge about several lead compounds with putative activity against EVD. Consensus was sought on recommendations concerning the most promising treatment strategies against EVD that should be studied in the context of a randomized clinical trial during the next outbreak. Results:Four compounds from 2 different classes (monoclonal antibody [mAb] cocktails and direct-acting antiviral agents [DAAs]) were highlighted as lead candidates, limitations in the current knowledge base about these drug classes were reviewed, and recommendations about the optimal clinical research design for studying combinations of these different agents were made. Conclusions:Although achieving the desired sample size could be challenging, a randomized, controlled clinical trial based on a combination strategy of a mAb with a DAA was recommended as the most appropriate clinical trial design to be undertaken during the next outbreak of EVD.

Project description:BackgroundEbola virus disease (EVD) is an often-fatal infection where the effectiveness of medical countermeasures is uncertain. During the West African outbreak (2013-2016), several patients were treated with different types of anti-viral therapies including monoclonal antibody-based cocktails that had the potential to neutralise Ebola virus (EBOV). However, at the time, the efficacy of these therapies was uncertain. Given the scale of the outbreak, several clinical phenotypes came to the forefront including the ability of the same virus to cause recrudescence in the same patient-perhaps through persisting in immune privileged sites. Several key questions remained including establishing if monoclonal antibody therapy was effective in humans with severe EVD, whether virus escape mutants were selected during treatment, and what is the potential mechanism(s) of persistence. This was made possible through longitudinal samples taken from a UK patient with EVD.MethodsSeveral different sample types, plasma and cerebrospinal fluid, were collected and sequenced using Illumina-based RNAseq. Sequence reads were mapped both to EBOV and the human genome and differential gene expression analysis used to identify changes in the abundance of gene transcripts as infection progressed. Digital Cell Quantitation analysis was used to predict the immune phenotype in samples derived from blood.ResultsThe findings were compared to equivalent data from West African patients. The study found that both virus and host markers were predictive of a fatal outcome. This suggested that the extensive supportive care, and most likely the application of the medical countermeasure ZMab (a monoclonal antibody cocktail), contributed to survival of the UK patient. The switch from progression to a 'fatal' outcome to a 'survival' outcome could be seen in both the viral and host markers. The UK patient also suffered a recrudescence infection 10 months after the initial infection. Analysis of the sequencing data indicated that the virus entered a period of reduced or minimal replication, rather than other potential mechanisms of persistence-such as defective interfering genomes.ConclusionsThe data showed that comprehensive supportive care and the application of medical countermeasures are worth pursuing despite an initial unfavourable prognosis.

Dataset Information

Design of a Randomized Controlled Trial for Ebola Virus Disease Medical Countermeasures: PREVAIL II, the Ebola MCM Study.

Background

Methods

Results

Publications

Design of a Randomized Controlled Trial for Ebola Virus Disease Medical Countermeasures: PREVAIL II, the Ebola MCM Study.

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