Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea

Abstract

BackgroundEbola virus disease (EVD) is a highly lethal condition for which no specific treatment has proven efficacy. In September 2014, while the Ebola outbreak was at its peak, the World Health Organization released a short list of drugs suitable for EVD research. Favipiravir, an antiviral developed for the treatment of severe influenza, was one of these. In late 2014, the conditions for starting a randomized Ebola trial were not fulfilled for two reasons. One was the perception that, given the high number of patients presenting simultaneously and the very high mortality rate of the disease, it was ethically unacceptable to allocate patients from within the same family or village to receive or not receive an experimental drug, using a randomization process impossible to understand by very sick patients. The other was that, in the context of rumors and distrust of Ebola treatment centers, using a randomized design at the outset might lead even more patients to refuse to seek care.Therefore, we chose to conduct a multicenter non-randomized trial, in which all patients would receive favipiravir along with standardized care. The objectives of the trial were to test the feasibility and acceptability of an emergency trial in the context of a large Ebola outbreak, and to collect data on the safety and effectiveness of favipiravir in reducing mortality and viral load in patients with EVD. The trial was not aimed at directly informing future guidelines on Ebola treatment but at quickly gathering standardized preliminary data to optimize the design of future studies.Methods and FindingsInclusion criteria were positive Ebola virus reverse transcription PCR (RT-PCR) test, age ≥ 1 y, weight ≥ 10 kg, ability to take oral drugs, and informed consent. All participants received oral favipiravir (day 0: 6,000 mg; day 1 to day 9: 2,400 mg/d). Semi-quantitative Ebola virus RT-PCR (results expressed in “cycle threshold” [Ct]) and biochemistry tests were performed at day 0, day 2, day 4, end of symptoms, day 14, and day 30. Frozen samples were shipped to a reference biosafety level 4 laboratory for RNA viral load measurement using a quantitative reference technique (genome copies/milliliter). Outcomes were mortality, viral load evolution, and adverse events. The analysis was stratified by age and Ct value. A “target value” of mortality was defined a priori for each stratum, to guide the interpretation of interim and final analysis.Between 17 December 2014 and 8 April 2015, 126 patients were included, of whom 111 were analyzed (adults and adolescents, ≥13 y, n = 99; young children, ≤6 y, n = 12). Here we present the results obtained in the 99 adults and adolescents. Of these, 55 had a baseline Ct value ≥ 20 (Group A Ct ≥ 20), and 44 had a baseline Ct value < 20 (Group A Ct < 20). Ct values and RNA viral loads were well correlated, with Ct = 20 corresponding to RNA viral load = 7.7 log10 genome copies/ml. Mortality was 20% (95% CI 11.6%–32.4%) in Group A Ct ≥ 20 and 91% (95% CI 78.8%–91.1%) in Group A Ct < 20. Both mortality 95% CIs i...

Post-exposure treatments for Ebola and Marburg virus infections

“…Importantly, the rVSV vaccine work in Guinea shows how a clinical trial can be done effectively during an outbreak, in contrast to clinical trials for ZMapp 151 , favipiravir 172 and TKM-130803 (REF. 156), which were important for compassionate use but were not wellconducted clinical studies.…”

“…For favipiravir, oral administration is a major benefit in resource-poor settings. Clinical trials of favipiravir in West Africa suggested some benefit in patients with lower viral loads when treatment was initiated 172 . Favipiravir was safe in phase I trials as well as in a clinical trial in patients with EBOV infection 172 .…”

“…Clinical trials of favipiravir in West Africa suggested some benefit in patients with lower viral loads when treatment was initiated 172 . Favipiravir was safe in phase I trials as well as in a clinical trial in patients with EBOV infection 172 . Favipiravir may also have some benefit in treating relapsed patients in whom the virus is present in immune-privileged tissues.…”

“…A historically controlled, single-arm, proof-of-concept trial of favipiravir, known as the JIKI trial, was conducted during the 2013-2016 EBOV epidemic in Guinea 172 . The trial enrolled 126 patients with EBOV infection, of whom 111 were analysed.…”

Neurological Complications of Ebola Virus Infection

“…The mortality rate of 54% in those who received favipiravir was not statistically different than the mortality rate of 58% among Bhistoric^controls from the same outbreak and area that the authors used for analysis [51]. The authors suggest that those who received favipiravir and had a higher pretreatment CT value had a lower mortality than historic controls; however, they also note that the study was not adequately powered or designed to detect such an effect.…”