A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics.

BACKGROUND: Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial. METHODS: We conducted a trial of four investigational therapies for EVD in the Democratic Republic of Congo, where an outbreak began in August 2018. Patients of any age who had a positive result for Ebola virus RNA on reverse-transcriptase-polymerase-chain-reaction assay were enrolled. All patients received standard care and were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3. The REGN-EB3 group was added in a later version of the protocol, so data from these patients were compared with those of patients in the ZMapp group who were enrolled at or after the time the REGN-EB3 group was added (the ZMapp subgroup). The primary end point was death at 28 days. RESULTS: A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial; the recommendation was based on the results of an interim analysis that showed superiority of these groups to ZMapp and remdesivir with respect to mortality. At 28 days, death had occurred in 61 of 174 patients (35.1%) in the MAb114 group, as compared with 84 of 169 (49.7%) in the ZMapp group (P = 0.007), and in 52 of 155 (33.5%) in the REGN-EB3 group, as compared with 79 of 154 (51.3%) in the ZMapp subgroup (P = 0.002). A shorter duration of symptoms before admission and lower baseline values for viral load and for serum creatinine and aminotransferase levels each correlated with improved survival. Four serious adverse events were judged to be potentially related to the trial drugs. CONCLUSIONS: Both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality from EVD. Scientifically and ethically sound clinical research can be conducted during disease outbreaks and can help inform the outbreak response. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM ClinicalTrials.gov number, NCT03719586.).

Ebola Virus Disease Outbreak in Isiro, Democratic Republic of the Congo, 2012: Signs and Symptoms, Management and Outcomes.

Data collected during the 2012 Ebola virus disease (EVD) epidemic in the Democratic Republic of the Congo were analysed for clinical signs, symptoms and case fatality of EVD caused by Bundibugyo virus (BDBV), establishment of differential diagnoses, description of medical treatment and evaluation of the quality of clinical documentation. In a quantitative observational prospective study, global epidemiological data from 52 patients (34 patients within the community, 18 patients treated in the Ebola Treatment Centre) were entered anonymously into a database, subsequently matched and analysed. Relevant findings include an over-representation of females among community EVD cases (85.3%) and of community EVD cases in the age group of 15-54 years (82.4%). All ETC patients had fever (55.6% of all 18 ETC patients during their hospital stay) or self-reported fever (88.2% upon admission) at some point of time during their illness. Major symptoms of ETC patients during hospital stay included asthenia (82.4%), anorexia (82.4%), myalgia (70.6%), sore throat/difficulty swallowing (70.6%), arthralgia (76.5%) and nausea (70.6%). Gastrointestinal signs and symptoms (nausea, diarrhoea, vomiting) (76.4%) as well as general pain (94.1%) were frequent in ETC patients. The median duration of EVD was 18 days, while the mean incubation period was 11.3 days. Differential diagnosis of EVD included malaria (28.3%), intestinal parasitosis (10.9%), and infectious syndrome (10.9%). There was also an important variation in clinical evolvement. Quality of documentation was adversely affected by the way patient file contents were transferred from inside to outside the high-risk zone, entailing a mean mismatch value of 27.3% between patient file contents inside vs. outside the high-risk zone. This study adds further description of EVD (frequently non-specific signs and symptoms, non frequent bleeding, a long incubation period, long duration of disease) and emphasizes the need for improving clinical monitoring and documentation in EVD outbreak settings.