Experimental Treatment of Ebola Virus Disease with Brincidofovir

Abstract

BackgroundThe 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 FindingsIn 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.ConclusionsDue 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 RegistrationPan African Clinical Trials Registry PACTR201411000939962

Post-exposure treatments for Ebola and Marburg virus infections

“…A single-arm phase II trial of brincidofovir was initiated in Liberia in January 2015 (REF. 184). The trial was stopped by the manufacturer after all four patients treated with brincidofovir died of EBOV haemorrhagic fever.…”

A Systematic Review of Ebola Treatment Trials to Assess the Extent to Which They Adhere to Ethical Guidelines

“…Authors were emailed up to three times with a request for missing information. Replies were received for 11 of the studies (69%) [28–30,35–39,41–43]. …”

“…The total number intended number of participants in the studies is approximately 1800 patients although actual enrolment is likely to be less as many trials were initiated as the incidence of Ebola was decreasing. As of the 27 th October 2016, only four of the trials had published results [28,29,39,41]. Eight studies have been completed [28,29,32–34,36–38], one is still recruiting [40], three others are enrolling by invitation only [35,42], one has been withdrawn [30], and one is not yet recruiting patients [31].…”

“…Upon completion of this study, physicians in Sierra Leone did not release reports of the treatment results and the study authors state that ‘it will be up to others to rigorously review and validate these findings’ [36]. One study is a Phase 1 clinical trial [35], four are listed as Phase 1/2 [31,32,34,43], five are Phase 2 clinical trials [29,33,39,41,42] and three were listed as Phase 2/3 trials [28,30,38]. Three studies did not state which phase they were in [36,37,40].…”

Intégrer la recherche clinique dans la réponse aux épidémies

“…Mais un point d'étape est apparu pour la priorisation des futures éva-luations per-épidémiques et la conception de modèles animaux prédictifs et pertinents. Certaines molécules ou classes médicamenteuses, initialement prometteuses, ont en effet été disqualifiées [10,15,16]. Néanmoins, les données de tolérance et d'efficacité préliminaires de certains agents encouragent la poursuite de leur évaluation, en particulier dans le cadre de combinaisons thérapeutiques (Tableau I) [10,17].…”