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

Abstract

Background: Ebola 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 findings: Inclusion 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 included the predefined target value (30% and 85%, respectively). Baseline serum creatinine was ≥110 μmol/l in 48% of patients in Group A Ct ≥ 20 (≥300 μmol/l in 14%) and in 90% of patients in Group A Ct < 20 (≥300 μmol/l in 44%). In Group A Ct ≥ 20, 17% of patients with baseline creatinine ≥110 μmol/l died, versus 97% in Group A Ct < 20. In patients who survived, the mean decrease in viral load was 0.33 log10 copies/ml per day of follow-up. RNA viral load values and mortality were not significantly different between adults starting favipiravir within <72 h of symptoms compared to others. Favipiravir was well tolerated.

Conclusions: In the context of an outbreak at its peak, with crowded care centers, randomizing patients to receive either standard care or standard care plus an experimental drug was not felt to be appropriate. We did a non-randomized trial. This trial reaches nuanced conclusions. On the one hand, we do not conclude on the efficacy of the drug, and our conclusions on tolerance, although encouraging, are not as firm as they could have been if we had used randomization. On the other hand, we learned about how to quickly set up and run an Ebola trial, in close relationship with the community and non-governmental organizations; we integrated research into care so that it improved care; and we generated knowledge on EVD that is useful to further research. Our data illustrate the frequency of renal dysfunction and the powerful prognostic value of low Ct values. They suggest that drug trials in EVD should systematically stratify analyses by baseline Ct value, as a surrogate of viral load. They also suggest that favipiravir monotherapy merits further study in patients with medium to high viremia, but not in those with very high viremia.

Trial registration: ClinicalTrials.gov NCT02329054.

Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: SB, XdL, HR, and SG received a grant from St Luke International University (Tokyo, Japan) to perform research on favipiravir in non-human primates. YY declared board membership for AbbVie, BMS, Gilead, MSD, Roche, Johnson&Johnson, ViiV Healthcare, Pfizer, and consultancy for AbbVie, BMS, Gilead, MSD, Roche, Johnson&Johnson, ViiV Healthcare, and Pfizer. OP worked for Fab'entech biotechnology from 1st April to 13th November 2015. Between January 2014 and now, SC received a grant from the CHU de Québec research center, which had no relationship with the trial described in the paper. All other authors declared no conflict of interest.

Figures

Fig 1. JIKI trial settings.

The red stars indicate the four Ebola treatment centers that participated in the JIKI trial. Three were in the southern Guinean highlands (Gueckedou, Macenta, Nzerekore), and one was in coastal Guinea (Conakry). Source: Adapted from a Wikipedia map, derived from a United Nations map; public domain.

Fig 2. JIKI trial progress.

ALIMA, Alliance for International Medical Action; CRF, Croix Rouge Française (French Red Cross); EU, European Union; Inserm, Institut National de la Santé et de la Recherche Médicale; SSA, Service de Santé des Armées (French military health service).

Fig 3. JIKI trial flow chart.

*Including a pregnant woman. **Of the 15 patients excluded from the analysis, four died (received plasma: n = 3/10; missing Ct value, n = 1/5) and 11 survived. ***All aged ≥13 y because no child aged 7–12 y attended the trial centers during the study period.

Fig 4. JIKI trial mortality, according to age and baseline RT-PCR Ct value.

Histograms represent mortality percentages. Vertical bars represent 95% confidence intervals. Red bars represent target values. The RT-PCR assay was conducted using the RealStar Filovirus Screen RT-PCR Kit 1.0 (Altona Diagnostics).

Fig 5. JIKI trial: correlation between EBOV RT-PCR Ct value and RNA viral load at baseline in adolescents and adults.

The black line represents the regression line. The Spearman rank correlation coefficient was 0.88 (p < 0.001). A baseline Ct value of 20 corresponded to an RNA viral load of 5 × 107 genome copies/ml of plasma (7.7 log10 copies/ml). Of the 99 adolescents and adults, 84 had both an RT-PCR Ct and an RNA viral load measurement at baseline. Red dots represent patients who died. Blue dots represent patients who survived.

Fig 6. JIKI trial: evolution of RT-PCR Ct values and RNA viral load in adolescents and adults.

(A) Evolution of RT-PCR Ct values. (B) Evolution of RNA viral loads. The x-axis represents the time since first symptoms (for example, for a patient whose first symptom occurred 5 d before admission to the treatment center, the baseline value dot is positioned at 5 d). Each line represents one patient. Dots represent baseline values, X’s represent follow-up values, and asterisks represent values below the limit of quantification. Red symbols represent patients who died; blue symbols represent patients who survived.

Fig 7. JIKI trial: evolution of RNA viral load in adolescents and adults.

(A) Evolution of RNA viral load in adolescents and adults who survived. The x-axis represents the time since favipiravir initiation (day 0). Each blue line represents one patient (n = 48). Circles represent baseline and follow-up values. Asterisks represent values under the limit of detection (3.4 log10 copies/ml). The black line represents the mean log10 viral load decline estimated from a linear mixed effect model. The mean initial viral load was estimated at 6.65 log10 copies/ml (SD 0.86), and the mean slope of viral load evolution at −0.33 log10 copies/ml (SD 0.03) per day of follow-up. (B) Evolution of RNA viral load in adolescents and adults who died. The x-axis represents the time since favipiravir initiation (day 0). Each red line represents one patient (n = 49). Circles represent baseline and follow-up values. The black line represents the mean log10 viral load evolution estimated from a linear mixed effect model. The mean initial viral load was estimated at 8.54 log10 copies/ml (SD 0.21), and the mean slope of viral load evolution at −0.001 log10 copies/ml (SD 0.15) per day of follow-up.

Fig 8. JIKI trial: baseline serum creatinine in adolescents and adults and outcomes according to baseline values.

Creat, creatinine.

Fig 9. JIKI trial: evolution of serum creatinine, aspartate aminotransferase, alanine aminotransferase, and creatine phosphokinase in adolescents and adults.

The x-axis represents the time since first symptoms (for example, for a patient whose first symptom occurred 5 d before day 0, the baseline value dot is positioned at 5 d). Each line represents one patient. Dots represent baseline values, and X’s represent follow-up values. Red symbols represent patients who died; blue symbols represent patients who survived. Dark red lines represent patients with baseline Ct < 20 who died, light red lines represent patients with baseline Ct ≥ 20 who died, dark blue lines represent patients with baseline Ct < 20 who survived, and light blue lines represent patients with baseline Ct ≥ 20 who survived. Samples obtained more than 25 d after onset of symptoms are not represented.

Fig 10. JIKI trial: evolution of serum creatinine, transaminases, and creatine phosphokinase in the 11 adolescents and adults who had worsening in at least one biochemical parameter on favipiravir.

(A) Patients who survived (n = 7). (B) Patients who died (n = 4). Each line represents one patient. All patients are identified with an ID number (from 1 to 7) or letter (from a to d) throughout the figures. For all 11 patients, all available data are shown. Dots represent baseline values, and X’s represent follow-up values. Dark blue lines represent patients with baseline Ct < 20 who survived. Light blue lines represent patients with baseline Ct ≥ 20 who survived. Light red lines represent patients with baseline Ct ≥ 20 who died. The x-axis represents the time since first symptoms (for example, for a patient whose first symptom occurred 5 d before admission to the treatment center, the baseline value dot is positioned at 5 d). Samples obtained more than 25 d after onset of symptoms are not represented. All 11 patients continued favipiravir.