Putative Investigational Therapeutics in the Treatment of Patients With Known Ebola Infection

A Multicenter Randomized Safety and Efficacy Study of Putative Investigational Therapeutics in the Treatment of Patients With Known Ebola Infection

Background:

- Ebola is a viral infection that can spread quickly and causes life-threatening disease. Right now there is an Ebola outbreak in many countries in West Africa. There are no approved treatments for Ebola. But possible treatments are being developed. Researchers need to study these treatments to see if they help people get better.

Objective:

- To identify possible Ebola treatments. Also, to learn if adding 1 or more experimental drugs to advanced Ebola care can reduce the risk of death.

Eligibility:

- People who have recently been diagnosed with Ebola, usually by a test called the Polymerase Chain Reaction (PCR), and have been hospitalized in an isolation unit for treatment.

Design:

• Participants will be randomly assigned to Group A or B. Both groups will get advanced level care. One group will also get an experimental drug.
• Participants may have blood tests. They may have another PCR test.
• Researchers will try to learn how the participant got Ebola.
• Participants put in the experimental drug group may start taking medicine within 24 hours of enrollment. It may be given by mouth or intravenously. Additional doses may be needed.
• Participants may have a series of timed blood tests over the first 24 to 48 hours after they take the medicine.
• Blood will be drawn frequently. Other body fluids (urine, stool, vaginal fluid, etc.) may also be collected.
• Participants will be followed for up to 60 days. They may be evaluated for any long-term effects of the experimental treatment(s). They may be asked to return for 1 or more outpatient visits.
• For consenting participants, follow-up will be extended for up to one full year past Day 58 with contact/visits every 1-3 months to assess for a history of signs or symptoms potentially consistent with late onset of virologic relapse syndrome.

Study Overview

• Status: Completed
• Conditions: Ebola Virus Infection
• Intervention / Treatment: Other: A/Current Standard of Care Alone; Drug: B/Current Standard of Care Plus ZMapp

Detailed Description

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 EBOV 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. However, the 2014 West African outbreak significantly exceeds all previous outbreaks in geographic range, number of patients affected, and in disruption of typical activities of civil society.

There is strong consensus that the most important element necessary to improve survival from Ebola infection is the provision of full hemodynamic support in the form of aggressive fluid replacement, ability to diagnose and correct severe metabolic derangements, and other standards of modern medical care available in resource-rich environments. However, against this background, a small series of investigational agents or interventions have also been proposed as putative antiviral strategies of potential utility in treating this infection. Unfortunately, phase 1/2 data supporting the safety and efficacy of these agents is generally lacking, and thus there should be equipoise as to which, if any, of these interventions should be utilized in the treatment of severe infection.

In this multicenter randomized trial, we propose a flexible trial design with frequent interim monitoring to facilitate early elimination of poorly performing treatments as well as the introduction of new candidate therapies. The trial allows for a series of pairwise comparisons of novel interventions against a background of optimized medical care, with the goal of determining whether one or more of these interventions can improve the mortality over that achievable through optimized standard-of- care (oSOC) alone. The primary endpoint of this trial will be comparative mortality at Day 28, with a number of secondary endpoints that hopefully will generate generalizable knowledge about the relative safety and antiviral activity of these adjunctive interventions.

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Guinea
  • Forecariah, Guinea
    • CTE Forecariah
• Liberia
  • Monrovia, Liberia
    • Monrovia Medical Unit
  • Paynesville, Liberia
    • ELWA III Hospital
• Sierra Leone
  • Freetown, Sierra Leone
    • Police Training School 1 (PTS1), Western Rural District
  • Goderich, Sierra Leone
    • Emergency Ebola Treatment Unit
  • Hastings, Sierra Leone
    • Police Training School 2
  • Jui, Sierra Leone
    • Chinese Friendship Hospital
  • Kambia, Sierra Leone
    • International Medical Corps (IMC) Kambia
  • Port Loko, Sierra Leone
    • International Medical Corps (IMC) Lunsar
  • Waterloo, Sierra Leone
    • Adventist Development and Relief Ebola Treatment Unit
• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:
• Males or females with documented positive PCR for Ebola virus infection within 10 days of enrollment
• Willingness of study participant to accept randomization to any assigned treatment arm
• Access to oSOC
• All males and females of childbearing potential, must be willing to use highly effective methods of contraception [e.g. absolute abstinence from potentially reproductive sexual activity, hormonal, surgical or multiple barrier/combined], from time of enrollment for the duration of study participation.
• Must agree not to enroll in another study of an investigational agent prior to completion of last required protocol visit (Day 58)
• Ability to provide informed consent personally, or by a legally-authorized [per applicable local laws and regulations] representative [LAR] if the patient is unable to do so.

EXCLUSION CRITERIA:

• Any medical condition that, in the opinion of the site investigator, would place the patient at an unreasonably increased risk through participation in this study, including any past or concurrent conditions that would preclude randomization to one or more of the assigned treatment arms.
• Prior treatment with any investigational antiviral drug therapy against Ebola infection other than experimental vaccines, within 5 half-lives or 30 days, whichever is longer, prior to enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: A/Current Standard of Care Alone; A/Current Standard of Care Alone: Optimized standard of care to include aggressive fluid resuscitation, hemodynamic support, and other interventions available in an optimized care setting	Other: A/Current Standard of Care Alone; Optimized standard of care for Ebola virus infection
Experimental: B/Current Standard of Care Plus ZMapp; B/Current Standard of Care Plus ZMapp: ZMapp (Trademark) + Optimized standard of care to include aggressive fluid resuscitation, hemodynamic support, and other interventions available in an optimized care setting. ZMapp 50mg/kg IV administered every third day for 3 infusions.	Other: A/Current Standard of Care Alone; Optimized standard of care for Ebola virus infection; Drug: B/Current Standard of Care Plus ZMapp; Triple monoclonal cocktail of antibodies against Zaire species of Ebola virus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Death at Day 28	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With ZMapp Infusion-related Adverse Events	Adverse events related to ZMapp infusions	10 Days
Plasma Viral Load	Time to viral clearance	28 days

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Institut National de la Santé Et de la Recherche Médicale, France; The Ministry of Health and Social Welfare, Liberia; The Ministry of Health and Sanitation, Sierra Leone; The Ministry of Health and Public Hygiene, Guinea

Publications and helpful links

General Publications

• Joffe S. Evaluating novel therapies during the Ebola epidemic. JAMA. 2014 Oct 1;312(13):1299-300. doi: 10.1001/jama.2014.12867. No abstract available.
• Kanapathipillai R. Ebola virus disease--current knowledge. N Engl J Med. 2014 Sep 25;371(13):e18. doi: 10.1056/NEJMp1410741. No abstract available.
• Piot P, Muyembe JJ, Edmunds WJ. Ebola in west Africa: from disease outbreak to humanitarian crisis. Lancet Infect Dis. 2014 Nov;14(11):1034-1035. doi: 10.1016/S1473-3099(14)70956-9. Epub 2014 Oct 1. No abstract available.
• PREVAIL II Writing Group; Multi-National PREVAIL II Study Team; Davey RT Jr, Dodd L, Proschan MA, Neaton J, Neuhaus Nordwall J, Koopmeiners JS, Beigel J, Tierney J, Lane HC, Fauci AS, Massaquoi MBF, Sahr F, Malvy D. A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection. N Engl J Med. 2016 Oct 13;375(15):1448-1456. doi: 10.1056/NEJMoa1604330.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2015
• Primary Completion (Actual): December 31, 2017
• Study Completion (Actual): December 31, 2017

Study Registration Dates

• First Submitted: February 13, 2015
• First Submitted That Met QC Criteria: February 13, 2015
• First Posted (Estimate): February 16, 2015

Study Record Updates

• Last Update Posted (Actual): June 5, 2019
• Last Update Submitted That Met QC Criteria: May 23, 2019
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: VHF; EVD; Medical Countermeasures
• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Disease Attributes; Mononegavirales Infections; Hemorrhagic Fevers, Viral; Filoviridae Infections; Infections; Communicable Diseases; Hemorrhagic Fever, Ebola
• Other Study ID Numbers: 150083; 15-I-0083 (Other Identifier: NIH Office of Protocol Services)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No