Efficacy of Favipiravir Against Ebola (JIKI)
Efficacy of Favipiravir Against Ebola (JIKI)
There is no specific treatment for Ebola Virus Disease (EVD). Current EVD care are
 supportive, and includes intravenous or oral rehydration, nutrition, pain killers, treatment
 of coinfections with antibacterial and antimalarial drugs, and blood transfusion when
 appropriate. Despite these interventions, mortality remains high since the ongoing Ebola
 outbreak in West Africa was declared in April.

 Potential anti-Ebola specific interventions include convalescent plasma, monoclonal and
 polyclonal antibodies, small inhibitory RNA (siRNA), synthetic adenosine analogues or RNA
 polymerase inhibitors. All these interventions are considered investigational due to lack of
 data in humans with EVD.

 In this study, the investigators chose to study the efficacy of favipiravir because this
 drug:

 -  showed anti-Ebola efficacy in immunodeficient murine models;

 -  has been studied in thousands of adult humans participating in anti-influenza trials,
 with good tolerance; it has been approved for treating novel or resistant influenza
 infections in Japan;

 -  is immediately available;

 -  can be used orally, and can be easily given in both adults and children because pills
 can be crushed and mixed in food or liquids;

 -  has recently been used in Europe for treating several patients with EVD; the French drug
 safety agency (ANSM) has reviewed published data as well as data provided by the firm
 (Toyama Chemical Co., Ltd), and approved its compassionate use in EVD.

 Here the investigators propose to assess the efficacy of high-dosed favipiravir in reducing
 mortality in humans with EVD.

 In the present trial "JIKI" (means "Hope" in "Kissi" language), investigators, sponsor,
 scientific advisory board and safety monitoring board will be coordinated in a very reactive
 way, so that any new fact can be discussed rapidly and the research plan can be adapted
 accordingly (change in drug dosage; use of drug combination; combination with another
 strategy such as passive immunization with convalescent plasma, etc.).
Hypotheses:

 1. The efficacy of antivirals in patients with EVD should correlate negatively with time
 since first symptoms. Thus, in this proof of concept trial, the main analysis will be
 done in adult patients with early symptoms in whom the efficacy is expected to be the
 highest;

 2. Favipiravir for EVD should be given at higher doses than that previously tested in
 studies in human with influenza. For this trial, the dose was calculated based on
 pharmacokinetics simulations, to rapidly reach plasma concentrations associated with
 anti-EBOV activity.

 3. A third assumption was made, given recent pre-trial data showing first a strong link
 between baseline viral load and mortality and second a higher mortality in children
 below 6 years: the efficacy of antivirals in patients with EVD should correlate
 negatively with viral load at start of treatment and with young age. Thus a secondary
 objective is the efficacy of favipiravir in adult patients and children >6 years with
 moderate baseline viral load (i.e. cycle threshold [Ct] ≥20 measured by RT-PCR) in whom
 the efficacy is expected to be the highest.

 A comparative trial of favipiravir against a standard package of care (with or without
 placebo) has been deemed not appropriate because of: i) the highly sensitive social and
 political context; ii) the need to collect rapidly basic phase II evidence on the efficacy of
 high dosed favipiravir on EVD before choosing the best intervention(s) to be tested in phase
 III (favipiravir alone or in combination with other drugs; other therapeutic options
 including convalescent plasma).

 Therefore, the investigators propose a non-comparative, proof-of-concept, phase II trial in
 patients with EVD, which will allow concluding within a few weeks:

 -  that mortality in patients starting favipiravir within 72 hours after the onset of first
 symptoms is inferior to mortality without treatment prior to the trial initiation;

 -  or that there is no trend that favipiravir brings significant benefit in terms of
 survival.

 Objectives Primary objective: to assess the efficacy of high-dosed favipiravir in reducing
 mortality in humans with EVD.

 Secondary objectives: to assess the evolution of EBOV plasma RNA and infectious loads under
 treatment; the tolerance of favipiravir; the viral micro-diversity of EBOV, the trough
 concentrations of favipiravir and factors associated with mortality and toxicity.

 Groups In this protocol, the investigators will refer to the following groups according to
 age and duration of symptoms*: Group A1: adults with time between first symptoms and first
 dose of favipiravir ≤72h; Group A2: adults with time between first symptoms and first dose of
 favipiravir >72h and Group C: all children >1 year and weighting ≥10kg. Time of first symptom
 refers to the time of the beginning of any symptom considered to be related to EVD.

 * Symptoms to be considered will be: acute onset of fever, severe headache, myalgia, extreme
 fatigue, vomiting, diarrhoea, abdominal pain, or unexplained hemorrhage.

 Given recent pre-trial data, a second definition of groups was also used: group AC1: adults
 and children >6 years with baseline Ct ≥20; group AC2: adults and children >6 years with
 baseline Ct values <20; group YC: young children ≤6 years and >1 year.

 Sample size: recruitment in the trial will be kept opened in all groups until group A1
 reaches 60 participants, unless early termination is recommended by the DSMB. Because we
 expect the efficacy of the treatment to be the maximum in patients with early symptoms, the
 sample size calculation was based on the analysis of mortality in group A1.

 The observed pre-trial mortality was estimated using the three months data (from 15/08/2014
 to 15/11/2014) of the MSF database in the Gueckedou EVD centre. Given those estimations, and
 to remain pragmatic and conservative, we set the pre-trial mortality to 55% for groups A1,
 A2, C.

 With 60 participants in group A1, the power to conclude that mortality in the trial will be
 -20% inferior to pre-trial mortality will be equal to 89%.

 Statistical analysis for primary outcome: mortality by Day-14 with 95% CI will be reported
 overall and in each group separately. Day-0 is the day of the first dose of favipiravir.

 In group A1, if the number of deaths is <24 (40%) out of 60 participants, the upper bound of
 the 95%CI will be <55%.

 In group A2, if the number of deaths is <54 (45%) out of 120 participants, the upper bound of
 the 95%CI will be <55%.

 In group C, if the number of deaths is <17 (38%) out of 45 participants, the upper bound of
 the 95%CI will be <55% In each group (A1, A2, C), the investigator will conclude that
 favipiravir decreases mortality if the upper bound of the 95% CI does not include the
 observed pre-trial mortality (55%) in untreated patients with same duration of symptoms prior
 to trial initiation.

 Statistical analysis for secondary outcomes: mortality by Day-14 with exact 95%CI will be
 reported according to the second group definition (AC1, AC2, YC). In each group, we will
 conclude that favipiravir decreases mortality if the upper bound of the 95% CI does not
 include the observed pre-trial mortality (30%, 85% and 70%, respectively) in untreated
 patients with same characteristics prior to trial initiation.

 All the following outcomes will be analysed overall and separately by the two group
 definitions (A1, A2, C or AC1, AC2, YC): the evolution of EBOV plasma RNA and infectious
 loads between Day-0 and the end of follow up will be described in each patient. The numbers,
 proportions and exact 95% CI will be described for grade 3-4 adverse events; resistance
 mutations; and patients reaching criteria for cure at Day-30. The distribution (median, IQR,
 min-max) of initial and maximal viral load, time to maximal viral load and to
 undetectability, and rate of increase/decrease will be reported. The distribution of trough
 concentrations of favipiravir at each point and the inter- and intra-patient variability of
 concentrations will be described.

 Factors associated with mortality by Day-14, cure at Day-30 and grade 3-4 clinical or
 biological adverse events (including time between first symptoms and treatment initiation,
 evolution of EBOV viral load, trough concentrations of favipiravir) will be studied.

 Stopping rules for futility: there will be intermediate analyses of mortality for futility
 only, performed every 20 adults in each group and every 10 children:

 -  Adults: recruitment in the two groups A1 and A2 will be prematurely stopped if the
 results show that the trial is unlikely to prove that mortality with favipiravir is
 <55%;

 -  Children: recruitment in the group C will be prematurely stopped if the results show
 that the trial is unlikely to prove that mortality with favipiravir is <55%.

 Toxicity: deaths will be reported to the sponsor and to the DSMB on a daily basis; SAE other
 than death will be reported to the sponsor and to the DSMB on a weekly basis.

 Sponsor and coordination The trial sponsor is the INSERM. The international coordinating,
 monitoring and data management centre will be the "Mereva" clinical trial unit (CTU), an
 international team with members affiliated to the Inserm 897 Unit, University of Bordeaux and
 to the "Pacci/ANRS" research site in Abidjan. Trial coordinating, monitoring and data
 management activities will be coordinated by an International Clinical Project Manager (CPM).
 In Guinea, where the trial will be conducted, a trial country coordination center (CCC) will
 be put in place, lead by a country CPM who will work in close collaboration with the
 international CPM and with the participating clinical centres.

 The trial will be conducted and monitored according to a Standard Operating Procedures (SOPs)
 manual.

 Monitoring

 In order to ensure the clinical trial is conducted properly, the CTU and CCC will coordinate
 all study activities of the Project Team. This includes in particular to:

 -  Set up and monitor workflows, timelines, milestones and tracking tools;

 -  Conduct regular team meetings to discuss project status, activities, and address issues;

 -  Maintain daily contact with principal investigators, sponsor and clinical sites;

 -  Provide status reports to principal investigator, DSMB, and SAB;

 -  Support the study sites with study related questions;

 -  Ensure that study drug is being stored, dispensed, and accounted for according to
 specifications;

 -  Check the completeness of patient records, the accuracy of entries in the database, the
 adherence to the protocol, SOPs and to Good Clinical Practice. Monitoring standards
 require full verification for the presence of informed consent, adherence to the
 inclusion/exclusion criteria, documentation of serious adverse events (SAEs), and the
 recording of data that will be used for all primary and safety variables.

 The investigator must give the CCC access to all relevant source documents to confirm their
 consistency with the CRF and database entries. For this particular trial, some documents
 filed in within the isolation ward will have to be destroyed in order to avoid contamination.
 Data recorded on a document that will have to be destroyed will be defined before study
 start.

 the investigators put particular focus on structured communication, and, together with the
 principal investigators and the partners, will define the communication plan which includes
 the key communication areas such as meetings, trainings, telephone conferences, internal
 project meetings, monitoring plan meetings and report updates.

 Investigators at each clinical site will keep a hard copy of the Trial Master File (TMF),
 containing all essential technical (protocol, SOPs, etc.), and regulatory (insurance, IRB
 approvals, task delegation descriptions, bio-sketches, agreements, etc.) trial documents. The
 country CPM will be responsible for checking that the files containing the hard copy of the
 TMF documents at each trial clinic and at the CCC are up-to-date. All TMF documents will also
 be made available online to investigators on a private website ("eTMF"). The international
 CPM will be responsible for routinely updating the documentation on the trial website.

 Data management

 The CTU will develop by December 1st, 2014:

 A case report form (CRF): data will be collected on hard copy CRF. The medical investigator
 or his/her designated representative will be responsible for filling out the forms.

 A database: Data will be entered online in a system that will ensure data encryption,
 restricted access to the database, daily back-up, and tracking of edits.

 A Data Management Plan (DMP) and Data Validation Plan (DVP), including the quality control
 process to ensure completeness, validity, consistency, timeliness and accuracy.

 Training will be provided to all members of the study team involved in data collection data
 entry, data check and monitoring.

 The CTU data managing team will conduct data review and handle queries on a weekly basis, and
 reconcile the safety database with the clinical database.
Inclusion Criteria:

 -  age >1 year and weighting ≥10kg,

 -  EVD confirmed by a positive qualitative PCR test,

 -  signed informed consent (signed by the parents/adults guardians in case of minor
 patient).

 Non inclusion-criteria:

 -  pregnancy*,

 -  inability to take the drug (encephalopathy, severe vomiting). * Emergency use of
 favipiravir in pregnant women outside of the trial is envisaged and under evaluation.

 In this protocol, the investigators will refer to the following groups according to age and
 duration of symptoms**:

 -  Group A1: adults with time between first symptoms and first dose of favipiravir ≤72h;

 -  Group A2: adults with time between first symptoms and first dose of favipiravir >72h;

 -  Group C: all children >1 year and weighting ≥10kg. Time of first symptom refers to the
 time of the beginning of any symptom considered to be related to EVD. **Symptoms to be
 considered will be: acute onset of fever, severe headache, myalgia, extreme fatigue,
 vomiting, diarrhoea, abdominal pain, or unexplained hemorrhage.

 The division in groups is a matter of analysis, and will not be perceptible by the patients
 during the trial process. Patients in the three groups will receive the same treatment and
 will be followed under the same procedures, with only two exceptions: the number of
 additional blood sample collections will be lower in group A2 and C (n=2) than in group A1
 (n=3) and daily dosages will be adapted to the body weight in group C.