Clinical trial NCT03719586: Investigational Therapeutics for the Treatment of People With Ebola Virus Disease
Official title: A Multicenter, Multi-Outbreak, Randomized, Controlled Safety and Efficacy Study of Investigational Therapeutics for the Treatment of Patients With Ebola Virus Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Ebola Virus
Keywords: EBOV
Viral Hemorrhagic Fever
Ebola Treatment Center
Filovirus
Zaire Ebola Virus
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2018-10-25
Enrollment: 681
Sex: ALL
Maximum age (years): 99
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Background:

Ebola virus can cause serious illness or death. No medicines are approved to treat it. Researchers need to test new medicines to see if they help people recover from Ebola and are safe to give. They need to test the drugs and compare them in a controlled way. Researchers want to test 4 drugs with people who have Ebola and are in treatment centers.

Objective:

To study the safety and effectiveness of 4 drugs for people with Ebola virus.

Eligibility:

People of any age with Ebola infection who are in treatment centers

Design:

Participants will be screened with questions, medical history, and blood tests.

Participants will be randomly assigned to get 1 of 3 study drugs:

* ZMapp by IV over about 4 hours. It will be given 3 times, 3 days apart.
* Remdesivir by IV over about 1 hour. It will be given once a day for 10 days.
* Mab114 by IV for 30-60 minutes. It will be given 1 time.
* REGN-EB3 by IV for about 2 hours. It will be given 1 time.

For at least a week, participants will stay in isolation in a clinic. They will:

* Get supportive care and be monitored
* Have a small plastic tube (IV) put in an arm vein for several days to give fluids and collect blood.
* Get their study drug.
* Be monitored for disease signs and drug side effects. They may get medicines for side effects.
* Have blood and urine tests.

Participants will stay in the clinic until they finish the study drug and are well enough to leave.

Participants will have 2 follow-up visits over 2 months. They will answer questions and give blood and semen samples.

...

Detailed description: 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.

Eligibility criteria: * 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.)

Primary outcomes:
measure: Mortality
timeFrame: 28 days
Secondary outcomes:
measure: Time in Days to First Negative Ebola Virus RT-PCR in Blood.
timeFrame: up to Day 28
measure: Viremia as Determined by CTnp Values on PCR
timeFrame: Days 1, 2, 3, 4, 6, 8, 10, 14, and 28.
measure: Incidence of Serious Adverse Events/AEs
timeFrame: up to Day 58
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
city: Kinshasa Gombe
country: Congo, The Democratic Republic of the
facility: Ebola Treatment Centers throughout the DRC
Study officials:
affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
name: Richard T Davey, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ottoni MP, Ricciardone JD, Nadimpalli A, Singh S, Katsomya AM, Pokoso LM, Petrucci R. Ebola-negative neonates born to Ebola-infected mothers after monoclonal antibody therapy: a case series. Lancet Child Adolesc Health. 2020 Dec;4(12):884-888. doi: 10.1016/S2352-4642(20)30278-9.
citation: Mulangu S, Dodd LE, Davey RT Jr, Tshiani Mbaya O, Proschan M, Mukadi D, Lusakibanza Manzo M, Nzolo D, Tshomba Oloma A, Ibanda A, Ali R, Coulibaly S, Levine AC, Grais R, Diaz J, Lane HC, Muyembe-Tamfum JJ; PALM Writing Group; Sivahera B, Camara M, Kojan R, Walker R, Dighero-Kemp B, Cao H, Mukumbayi P, Mbala-Kingebeni P, Ahuka S, Albert S, Bonnett T, Crozier I, Duvenhage M, Proffitt C, Teitelbaum M, Moench T, Aboulhab J, Barrett K, Cahill K, Cone K, Eckes R, Hensley L, Herpin B, Higgs E, Ledgerwood J, Pierson J, Smolskis M, Sow Y, Tierney J, Sivapalasingam S, Holman W, Gettinger N, Vallee D, Nordwall J; PALM Consortium Study Team. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. N Engl J Med. 2019 Dec 12;381(24):2293-2303. doi: 10.1056/NEJMoa1910993. Epub 2019 Nov 27.