Anti-Ebola therapy for patients with Ebola virus disease: a systematic review.

BACKGROUND: Management of Ebola virus disease (EVD) has historically focused on infection prevention, case detection and supportive care. Several specific anti-Ebola therapies have been investigated, including during the 2014-2016 West African outbreak. Our objective was to conduct a systematic review of the effect of anti-Ebola virus therapies on clinical outcomes to guide their potential use and future evaluation. METHODS: We searched PubMed, EMBASE, Global Health, Cochrane Library, African Index Medicus, WHOLIS (inception-9 April 2018), and trial registries for observational studies or clinical trials, in any language, that enrolled patients with confirmed EVD who received therapy targeting Ebola virus and reported on mortality, symptom duration, or adverse effects. RESULTS: From 11,257 citations and registered trials, we reviewed 55 full-text citations, of which 35 met eligibility criteria (1 randomized clinical trial (RCT), 8 non-randomized comparative studies, 9 case series and 17 case reports) and collectively examined 21 anti-Ebola virus agents. The 31 studies performed during the West African outbreak reported on 4.8% (1377/28616) of all patients with Ebola. The only RCT enrolled 72 patients (0.25% of all patients with Ebola) and compared the monoclonal antibody ZMapp vs. standard care (mortality, 22% vs. 37%; 95% confidence interval for risk difference, - 36 to 7%). Studies of convalescent plasma, interferon-ß-1a, favipiravir, brincidofovir, artesunate-amodiaquine and TKM-130803 were associated with at least moderate risk of bias. CONCLUSIONS: Research evaluating anti-Ebola virus agents has reached very few patients with EVD, and inferences are limited by non-randomized study designs. ZMapp has the most promising treatment signal.

Time required to initiate a clinical trial in Canada at the onset of the COVID-19 pandemic: an observational research-in-motion study.

BACKGROUND: Randomized controlled trials (RCTs) provide essential evidence to inform practice, but the many necessary steps result in lengthy times to initiation, which is problematic in the case of rapidly emerging infections such as COVID-19. This study aimed to describe the start-up timelines for the Canadian Treatments for COVID-19 (CATCO) RCT. METHODS: We surveyed hospitals participating in CATCO and ethics submission sites using a structured data abstraction form. We measured durations from protocol receipt to site activation and to first patient enrolment, as well as durations of administrative processes, including research ethics board (REB) approval, contract execution and lead times between approvals to site activation. RESULTS: All 48 hospitals (26 academic, 22 community) and 4 ethics submission sites responded. The median time from protocol receipt to trial initiation was 111 days (interquartile range [IQR] 39-189 d, range 15-412 d). The median time between protocol receipt and REB submission was 41 days (IQR 10-56 d, range 4-195 d), from REB submission to approval, 4.5 days (IQR 1-12 d, range 0-169 d), from REB approval to site activation, 35 days (IQR 22-103 d, range 0-169 d), from protocol receipt to contract submission, 42 days (IQR 20-51 d, range 4-237 d), from contract submission to full contract execution, 24 days (IQR 15-58 d, range 5-164 d) and from contract execution to site activation, 10 days (IQR 6-27 d, range 0-216 d). Processes took longer in community hospitals than in academic hospitals. INTERPRETATION: The time required to initiate RCTs in Canada was lengthy and varied among sites. Adoption of template clinical trial agreements, greater harmonization or central coordination of ethics submissions, and long-term funding of platform trials that engage academic and community hospitals are potential solutions to improve trial start-up efficiency.

Establishing Healthcare Worker Performance and Safety in Providing Critical Care for Patients in a Simulated Ebola Treatment Unit: Non-Randomized Pilot Study.

Improving the provision of supportive care for patients with Ebola is an important quality improvement initiative. We designed a simulated Ebola Treatment Unit (ETU) to assess performance and safety of healthcare workers (HCWs) performing tasks wearing personal protective equipment (PPE) in hot (35 °C, 60% relative humidity) or thermo-neutral (20 °C, 20% relative humidity) conditions. In this pilot phase to determine the feasibility of study procedures, HCWs in PPE were non-randomly allocated to hot or thermo-neutral conditions to perform peripheral intravenous (PIV) and midline catheter (MLC) insertion and endotracheal intubation (ETI) on mannequins. Eighteen HCWs (13 physicians, 4 nurses, 1 nurse practitioner; 2 with prior ETU experience; 10 in hot conditions) spent 69 (10) (mean (SD)) minutes in the simulated ETU. Mean (SD) task completion times were 16 (6) min for PIV insertion; 33 (5) min for MLC insertion; and 16 (8) min for ETI. Satisfactory task completion was numerically higher for physicians vs. nurses. Participants' blood pressure was similar, but heart rate was higher (p = 0.0005) post-simulation vs. baseline. Participants had a median (range) of 2.0 (0.0-10.0) minor PPE breaches, 2.0 (0.0-6.0) near-miss incidents, and 2.0 (0.0-6.0) health symptoms and concerns. There were eight health-assessment triggers in five participants, of whom four were in hot conditions. We terminated the simulation of two participants in hot conditions due to thermal discomfort. In summary, study tasks were suitable for physician participants, but they require redesign to match nurses' expertise for the subsequent randomized phase of the study. One-quarter of participants had a health-assessment trigger. This research model may be useful in future training and research regarding clinical care for patients with highly infectious pathogens in austere settings.

Principles and Practices of Establishing a Hospital-Based Ebola Treatment Unit.

Outbreaks of Ebola virus disease and high-risk transmissible infections are increasing and pose threats to health care workers and global health systems. Previous outbreaks offer lessons for health system preparedness and response, including establishment of hospital-based high-risk pathogen treatment units. Their creation demands early preparation and interprofessional coordination; infection prevention and control; case management training; prepositioning of supplies; conversion of existing structures to treatment units; and strengthening communication and research platforms. Hospital-based Ebola and high-risk pathogen treatment units may improve case detection, interrupt transmission, and improve staff safety and patient care.