Investigational Therapeutics for the Treatment of People With Ebola Virus Disease

Species Zaire ebolaviruses (EBOV) are members of the Filoviridae and are known primarily as
the underlying cause of severe viral hemorrhagic fevers with disturbingly high case fatality
rates. Between 1994 and the present, there have been many filovirus outbreaks affecting
mostly central Africa, with 2 large outbreaks in 1995 in Kikwit, Democratic Republic of Congo
(DRC), and in Gulu, Uganda in 2000-2001. The 2013-2016 West African outbreak significantly
exceeded all previous outbreaks in geographic range, number of patients affected, and in
disruption of typical activities of civil society. In 2018 there have been two additional
outbreaks of EBOV infection, both in the Democratic Republic of the Congo and constituting
the 9th and 10th recorded outbreaks of this infection in that country. The 10th outbreak is
currently ongoing in the DRC as of December 2018 and has raised great concern because of the
potential to expand greatly in scope and to spread to surrounding regions.

It has been suggested that one of the most important elements necessary to improve survival
from Ebola virus infection is the provision of supportive care inclusive of hemodynamic
support in the form of aggressive fluid replacement, ability to diagnose and correct severe
metabolic derangements, early treatment of sepsis, and other standards of modern medical
care. A small number of investigational therapeutics have been developed as putative
antiviral strategies for treating this infection. Unfortunately, phase 1/2 data supporting
the safety and efficacy of these agents are often limited, and thus there remains some degree
of equipoise as to which of these interventions should be prioritized in the treatment of
severe infection. The triple monoclonal antibody product ZMapp was studied through a
randomized controlled trial (RCT) in the 2014-2016 West African outbreak and remains perhaps
the best characterized of the available investigational products, but the end of that
outbreak forced the RCT to close prior to crossing pre-specified evidentiary boundaries.

A WHO Research and Development Ebola Therapeutics Committee has agreed that, given the
lethality of Ebola virus and the combination of human and non-human primate (NHP) efficacy
data for ZMapp, either ZMapp+oSOC or oSOC alone could potentially be positioned as the
control arm in comparative trials depending upon the preferences of the host countries. The
DRC has chosen to use ZMapp + oSOC in the current protocol. However, both the nature and
number of control and invegstigational arms may change over the course of the trial. Such
changes would require protocol amendments.

This multicenter, multi-outbreak, randomized controlled trial will study the comparative
safety and efficacy of additional investigational therapeutics compared to ZMapp in patients
with known EBOV disease (Zaire) receiving oSOC. The primary endpoint of this comparison will
be mortality by Day 28, with a number of secondary endpoints also planned that should
generate important knowledge about the safety, ease of administration, and antiviral activity
of all of these investigational interventions.

- INCLUSION CRITERIA:

- Males or females of any age with documented positive RT-PCR in blood for acute Ebola
virus infection within 3 days prior to enrollment and who have symptoms of any
duration.

- Willingness of study participant to accept randomization to any assigned treatment
arm.

- All males and females of childbearing potential must be willing to use effective
methods of contraception, from time of enrollment until Day 58 of study.

- Must agree not to enroll in another study of an investigational agent prior to
completion of Day 28 of study.

- Ability to provide informed consent personally, or by a legally acceptable
representative if the patient is unable to do so.

EXCLUSION CRITIERA:

- Patients who, in the judgment of the investigator, will be unlikely or unable to
comply with the requirements of this protocol through Day 28.

- Prior treatment with any investigational antiviral drug therapy against Ebola virus
infection within 5 half-lives or 30 days, whichever is longer, prior to enrollment.
(Patients who have received an experimental (or, in future, potentially a licensed)
immunization against Ebola virus remain eligible.)