Investigational Therapeutics for the Treatment of People With Ebola Virus Disease

• ClinicalTrials.gov Identifier: NCT03719586
• Recruitment Status: Completed
• First Posted: October 25, 2018
• Results First Posted: September 8, 2021
• Last Update Posted: September 8, 2021
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Tracking Information

• First Submitted Date: October 24, 2018
• First Posted Date: October 25, 2018
• Results First Submitted Date: December 30, 2020
• Results First Posted Date: September 8, 2021
• Last Update Posted Date: September 8, 2021
• Actual Study Start Date: November 21, 2018
• Actual Primary Completion Date: September 9, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 28, 2021)

Mortality [ Time Frame: 28 days ]

Number of Participants with Mortality by Day 28

• Original Primary Outcome Measures (submitted: October 24, 2018): Mortality [ Time Frame: Through 28 days ]

Current Secondary Outcome Measures (submitted: January 28, 2021)

• Time in Days to First Negative Ebola Virus RT-PCR in Blood. [ Time Frame: up to Day 28 ]
  This was a measure of the median number of days that it took for the serum PCR to first turn negative after having been positive throughout the patient's earlier course.
• Viremia as Determined by CTnp Values on PCR [ Time Frame: Days 1, 2, 3, 4, 6, 8, 10, 14, and 28. ]
  These are the median CTnp pCR values measured serially on the 4 treatment arms as per protocol. caveats: Undetectable ctNP values are imputed as ctNP=45.0 (the limit of detection). Missing values (due to gaps in sample collection, discharge, or death) are handled by carrying forward the last observation. The Day 28 visit includes a ±7-day visit window. The priority for defining the ctNP value for this timepoint, according to days post-randomization, is: 28, 27, 29, 26, 30, 25, 31, 24, 32, 23, 33, 22, 34, 21. For example, the ctNP result from the sample collected 26 days post-randomization will only be used for this timepoint if there are no sample results for 28, 27, or 29 days post-randomization.
• Incidence of Serious Adverse Events/AEs [ Time Frame: up to Day 58 ]
  The number of Serious Adverse Events that were tentatively ascribed to one of the four treatment arms by the site investigator and, upon extensive further review and adjudication by an independent Pharmacovigilance committee, were still felt potentially attributable to study drug as opposed to the underlying Ebola infection.

Original Secondary Outcome Measures (submitted: October 24, 2018)

• Time to first negative Ebola virus RT-PCR [ Time Frame: Throughout ]
• Viremia [ Time Frame: Days 1, 2, 3, 4, 6, 8, 10, 14, and 28. ]
• Incidence of AE/SAEs [ Time Frame: Throughout ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Ebola Virus

Intervention

• Drug: ZMapp
  Three doses of 50 mg/kg of body weight administered intravenously every third day beginning on Day 1
• Drug: Remdesivir
  Administered intravenously with a loading dose on Day 1 (200 mg for adults and pediatric patients with body weight >= 40 kg and for pediatric patients weighing < 40 kg one loading dose of remdesivir 5 mg/kg) followed by 9 to 13 days of once-daily maintenance dosing starting on Day 2 and extending through Day 10 to 14 (100 mg for adults and pediatric patients with body weight >= 40 kg and for pediatric patients weighing < 40 kg remdesivir 2.5 mg/kg)
• Drug: MAb114
  50 mg/kg of body weight administered intravenously on Day 1 as a single infusion
• Drug: REGN-EB3
  150 mg/kg of body weight administered intravenously on Day 1 as a single infusion

Study Arms

• Experimental: A
  Remdesivir plus optimized Standard of Care (oSOC)
  Intervention: Drug: Remdesivir
• Experimental: B
  MAb114 plus optimized Standard of Care (oSOC)
  Intervention: Drug: MAb114
• Experimental: C
  REGN-EB3 plus optimized Standard of Care (oSOC)
  Intervention: Drug: REGN-EB3
• Experimental: Control
  Zmapp plus optimized Standard of Care (oSOC)
  Intervention: Drug: ZMapp

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 30, 2020): 681
• Original Estimated Enrollment (submitted: October 24, 2018): 350
• Actual Study Completion Date: August 18, 2020
• Actual Primary Completion Date: September 9, 2019 (Final data collection date for primary outcome measure)

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.)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 99 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Congo, The Democratic Republic of the, United States

Administrative Information

• NCT Number: NCT03719586
• Other Study ID Numbers: 190003; 19-I-0003
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
• Original Responsible Party: Same as current
• Current Study Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Richard T Davey, M.D.; National Institute of Allergy and Infectious Diseases (NIAID)

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: November 2020