Conditions: Ebola Virus
Keywords: EBOV Viral Hemorrhagic Fever Ebola Treatment Center Filovirus Zaire Ebola Virus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 681
Healthy volunteers: no

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.

Arms:
arm 1: Remdesivir plus optimized Standard of Care (oSOC) arm 2: MAb114 plus optimized Standard of Care (oSOC) arm 3: REGN-EB3 plus optimized Standard of Care (oSOC) arm 4: Zmapp plus optimized Standard of Care (oSOC)

Interventions: intervention 1: ZMapp intervention 2: Remdesivir intervention 3: MAb114 intervention 4: REGN-EB3
Intervention descriptions: intervention 1: Three doses of 50 mg/kg of body weight administered intravenously every third day beginning on Day 1 intervention 2: 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) intervention 3: 50 mg/kg of body weight administered intravenously on Day 1 as a single infusion intervention 4: 150 mg/kg of body weight administered intravenously on Day 1 as a single infusion

Protocol document:
Prot_SAP_ICF_000.pdf: 
2018 Ebola MCM RCT Protocol 
Page 1 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
 
A Multicenter, Multi-Outbreak, Randomized, Controlled 
Safety and Efficacy Study of Investigational Therapeutics for 
the Treatment of Patients with Ebola Virus Disease  
 
 
 
Short Title:  
2018 Ebola MCM RCT Protocol 
 
 
Sponsored by:  
Office of Clinical Research Policy  
 
and Regulatory Operations (OCRPRO) 
 
National Institute of Allergy and Infectious Diseases  
 
 
5601 Fishers Lane 
 
Bethesda, MD 20892 
 
 
 
 
NIH Protocol Number:  
19-I-0003 
Protocol IND #:  
125530 
ClinicalTrials.gov Number: NCT03719586 
 
 
 
 
 
Date: 
4 October 2019 
Version:  
7.0 
 
 
 
 
CONFIDENTIAL 
This document is confidential. No part of it may be transmitted, reproduced, published, or used by other 
persons without prior written authorization from the study sponsor and principal investigator. 
 
 


2018 Ebola MCM RCT Protocol 
Page 2 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
KEY ROLES 
 
DRC Principal Investigator: 
Jean-Jacques Muyembe-Tamfum, MD, PhD 
Director-General, DRC National Institute for 
Biomedical Research 
Professor of Microbiology, Kinshasa University 
Medical School 
Kinshasa Gombe 
Democratic Republic of the Congo 
Phone: +243 898949289 
 
Email: jjmuyembet@gmail.com 
 
 
Other International Investigators: 
see Appendix E 
 
Statistical Lead: 
Lori Dodd, PhD 
 
Biostatistics Research Branch, DCR, NIAID 
 
5601 Fishers Lane, Room 4C31 
 
Rockville, MD 20852 
 
Phone: 240-669-5247 
 
Email: doddl@niaid.nih.gov 
 
U.S. Principal Investigator: 
Richard T. Davey, Jr., MD 
 
Clinical Research Section, LIR, NIAID, NIH 
 
Building 10, Room 4-1479,  
 
Bethesda, MD 20892-1662  
 
Phone: +1-301-496-8029 
 
Email: rdavey@niaid.nih.gov 
 
 
Data Coordinating Center: 
Clinical Trials Research Section 
 
Biostatistics Research Branch 
 
Division of Clinical Research, NIAID 
5601 Fishers Lane, Room 4C31 
Rockville, MD 20852 
 
Federalwide assurance (FWA) numbers: 00005897 (NIH) 
 
00025422 (Kinshasa School of Public Health) 
 
Protocol Development Team 
see Appendix E 
 
Steering Committee 
see Appendix E 
 
DSMB 
see Appendix E 
 
Medical Monitors: 
see Appendix E 
 


2018 Ebola MCM RCT Protocol 
Page 3 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
TABLE OF CONTENTS 
 
KEY ROLES ................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 3 
PROTOCOL SUMMARY .............................................................................................................. 8 
PRÉCIS ......................................................................................................................................... 13 
1 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ............................. 14 
 
Background ....................................................................................................................... 14 
 Filoviruses ..................................................................................................................... 14 
 Transmission and Disease ............................................................................................. 14 
 Latest Outbreaks ........................................................................................................... 15 
 Therapy ......................................................................................................................... 16 
 RCT of ZMapp (PREVAIL II) ..................................................................................... 18 
 
Rationale for Study ........................................................................................................... 18 
2 
STUDY OBJECTIVES ......................................................................................................... 20 
 
Primary Objective ............................................................................................................. 20 
 
Secondary Objectives ........................................................................................................ 20 
 
Exploratory Objectives ..................................................................................................... 20 
3 
STUDY DESIGN.................................................................................................................. 20 
 
General .............................................................................................................................. 20 
 Extension Phase ............................................................................................................ 23 
 
Study Endpoints ................................................................................................................ 23 
 Primary Endpoint .......................................................................................................... 23 
 Secondary Endpoints .................................................................................................... 23 
 Exploratory Endpoints .................................................................................................. 24 
 
Overview of Study Drugs ................................................................................................. 24 
 
Considerations in Choice of Study Drugs ......................................................................... 24 
 
Definitions for the Purpose of this Study .......................................................................... 26 
4 
STUDY POPULATION ....................................................................................................... 26 
 
Research Subject Recruitment .......................................................................................... 26 
 Participation of Site Employees .................................................................................... 27 
 
Inclusion Criteria .............................................................................................................. 27 
 
Exclusion Criteria ............................................................................................................. 27 
 
Vulnerable Populations ..................................................................................................... 27 
 Pregnant Women ........................................................................................................... 27 
 Inclusion of Children and Neonates .............................................................................. 28 
 Adults Who Are Unable to Provide Initial or Ongoing Consent .................................. 28 
 
Subject Withdrawal ........................................................................................................... 28 
 
Discontinuation of Subject by Investigator ....................................................................... 28 
 
Discontinuation of Study .................................................................................................. 29 
5 
STUDY PROCEDURES ...................................................................................................... 29 
 
Personnel for Study Procedures ........................................................................................ 29 
 
Site-Specific Considerations ............................................................................................. 29 
 
Schedule of Evaluations (see also Table 2 below) ............................................................ 30 
 
Screening and Informed Consent ...................................................................................... 33 
 Demographics ............................................................................................................... 33 
Deleted:
Deleted:
Deleted:
Deleted:
Deleted
Deleted
Deleted
Deleted
Deleted
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted
Deleted:
Deleted
Deleted
Deleted
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted
Deleted:
Deleted:
Deleted:
Deleted
Deleted
Deleted
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted


2018 Ebola MCM RCT Protocol 
Page 4 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 Medical History ............................................................................................................ 33 
 Clinical Data ................................................................................................................. 33 
 Determination of Eligibility .......................................................................................... 33 
 
Day 1 ................................................................................................................................. 33 
 Baseline Evaluation ...................................................................................................... 33 
 Baseline Laboratory Testing ......................................................................................... 34 
 Randomization .............................................................................................................. 35 
 
Study Drug Administration and Pharmacokinetic Sampling ............................................ 35 
 Pharmacokinetic Sampling ........................................................................................... 35 
 
Follow-Up Study Days ..................................................................................................... 35 
 Follow-up Daily Assessment and oSOC....................................................................... 35 
 Clinical Safety Laboratory Testing ............................................................................... 36 
 
Special Follow-up Assessments ........................................................................................ 36 
 Day of Discharge .......................................................................................................... 36 
 Day 28 ........................................................................................................................... 36 
 Day 58 ........................................................................................................................... 37 
 Pregnancy ...................................................................................................................... 37 
 Extended Follow-Up ..................................................................................................... 37 
6 
STATISTICAL CONSIDERATIONS.................................................................................. 37 
 
Design overview ............................................................................................................... 37 
 
Less strict error rate control .............................................................................................. 37 
 
Study hypotheses and statistical analysis .......................................................................... 38 
 
Power and sample size ...................................................................................................... 39 
 
Interim monitoring ............................................................................................................ 41 
7 
RISKS AND BENEFITS ...................................................................................................... 42 
 
Potential Risks .................................................................................................................. 42 
 Unknown Risks ............................................................................................................. 42 
 Risks of Phlebotomy ..................................................................................................... 43 
 Risks to the Study Personnel and the Environment ...................................................... 43 
 
Potential Benefits .............................................................................................................. 43 
 
Alternatives ....................................................................................................................... 43 
8 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, AND DATA ........ 43 
 
Intended Use of the Samples/Specimens/Data ................................................................. 43 
 
Storage of Samples/Specimens/Data ................................................................................ 44 
 
Reporting Loss or Destruction of Samples/Specimens/Data ............................................ 44 
9 
REMUNERATION PLAN ................................................................................................... 44 
10 ASSESSMENT OF SAFETY ............................................................................................... 45 
 
Definitions ......................................................................................................................... 45 
 
Assessment of Safety ........................................................................................................ 46 
 
Investigator Assessment of Serious Adverse Events ........................................................ 47 
 
Causality ................................................................................................................... 47 
 
Timing and Scope of (S)AE Collection, and of Assessments and of Reporting 
Responsibilities to the Sponsor ..................................................................................................... 48 
 
Unanticipated Problems ............................................................................................ 48 
 
Pregnancy .................................................................................................................. 49 
 
Reporting Procedures to the IRB ...................................................................................... 49 
Deleted
Deleted
Deleted
Deleted:
Deleted
Deleted
Deleted
Deleted:
Deleted
Deleted:
Deleted
Deleted
Deleted:
Deleted
Deleted
Deleted
Deleted
Deleted
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted
Deleted
Deleted
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted
Deleted:
Deleted
Deleted
Deleted:


2018 Ebola MCM RCT Protocol 
Page 5 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
Annual Reporting to the IRB .................................................................................... 49 
 
Follow-Up of Serious Adverse Events ............................................................................. 50 
 
Sponsor’s Reporting Responsibilities ............................................................................... 50 
 
Safety Oversight ................................................................................................................ 50 
 
Investigator Safety Monitoring ................................................................................. 50 
 
Sponsor Medical Monitor (SMM) ............................................................................ 50 
 
Safety Review and Communications Plan ................................................................ 50 
 
Data and Safety Monitoring Board (DSMB) ............................................................ 50 
11 CLINICAL MONITORING STRUCTURE ......................................................................... 51 
 
Site Monitoring Plan ......................................................................................................... 51 
12 ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................ 51 
 
Informed Consent Process ................................................................................................ 51 
 
Subject Confidentiality ..................................................................................................... 52 
13 DATA MANAGEMENT AND MONITORING ................................................................. 52 
 
Data Management Responsibilities ................................................................................... 52 
 
Data Capture Methods ...................................................................................................... 52 
 
Types of Data .................................................................................................................... 53 
 
Source Documents and Access to Source Data/Documents ............................................. 53 
 
Record Retention .............................................................................................................. 53 
 
Data Sharing Plan ............................................................................................................. 53 
 
Trial Organization ............................................................................................................. 53 
14 PALM EXTENSION PHASE .............................................................................................. 54 
SELECTED REFERENCES ........................................................................................................ 57 
APPENDIX A. ZMAPP DRUG INFORMATION ...................................................................... 60 
APPENDIX B. REMDESIVIR DRUG INFORMATION ........................................................... 61 
APPENDIX C. MAB114 DRUG INFORMATION ..................................................................... 62 
APPENDIX D. REGN-EB3 DRUG INFORMATION ................................................................ 63 
APPENDIX E. OVERSIGHT AND/OR GOVERNANCE COMMITTEES: .............................. 64 
APPENDIX F:  SAMPLE INFORMED CONSENT AND ASSENT FOR THE RCT ............... 68 
APPENDIX G:  SAMPLE INFORMED CONSENT AND ASSENT FOR THE EXTENSION 
PHASE .......................................................................................................................................... 81 
 
LIST OF TABLES 
Table 1: Ebola Virus Outbreaks ..................................................... Error! Bookmark not defined. 
Table 2. Schedule of Evaluations (subject to individual site capabilities) .. Error! Bookmark not 
defined. 
Table 3. Sample sizes for 80%, 85%, and 90% power for two-sided 0.05 level Boschloo exact 
tests for 20%, 40%, and 50% reductions relative to that of the oSOC plus ZMapp control. Error! 
Bookmark not defined. 
Table 4. Power for sample sizes of 100, 112, and 132 per arm for two-sided 0.05 level Boschloo 
exact tests for 20%, 40%, and 50% reductions relative to that of the oSOC plus ZMapp control.
........................................................................................................ Error! Bookmark not defined. 
Table 5. Numbers of deaths by day 28 in each arm to cross the boundary at the first interim 
analysis with 20 patients per arm. .................................................. Error! Bookmark not defined. 
 
LIST OF FIGURES 
Deleted
Deleted:
Deleted:
Deleted:
Deleted
Deleted
Deleted
Deleted
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:
Deleted:


2018 Ebola MCM RCT Protocol 
Page 6 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Figure 1. Study Schema for Option 1. ........................................... Error! Bookmark not defined. 
Deleted:


2018 Ebola MCM RCT Protocol 
Page 7 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Term 
AE 
adverse event 
ALT 
alanine aminotransferase 
BDBV 
species Bundibugyo Ebolavirus 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CRF 
case report form 
DAIDS 
DCR 
Division of AIDS 
Division of Clinical Research 
DRC 
Democratic Republic of Congo 
EBOV 
species Zaire Ebolavirus 
EHF 
Ebola hemorrhagic fever 
ETU 
Ebola treatment unit 
EVD 
Ebola virus disease  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GP 
Glycoprotein 
HCW 
health care worker 
ICH 
International Council for Harmonisation  
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IND 
INRB 
Investigational New Drug Application 
Institut National de Recherche Biomédicale  
IRB/EC 
Institutional Review Board/Ethics Committee 
IV 
Intravenous 
kg 
Kilogram 
MAb 
monoclonal antibody 
MEURI 
Monitored Emergency Use of Unregistered and Investigational 
Interventions 
MoH 
Ministry of Health 
mg 
Milligram 
mL 
Milliliter 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
NHP 
oSOC 
non-human primate 
optimized standard of care 
PK 
REGN-EB3 
Pharmacokinetic 
Regeneron’s triple monoclonal cocktail REGN3470-3471-3479 
RESTV 
species Reston Ebolavirus 
RCT 
randomized controlled trial 
RNA 
ribonucleic acid 
RT-PCR 
reverse transcription-polymerase chain reaction 
SAE 
serious adverse event 


2018 Ebola MCM RCT Protocol 
Page 8 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Abbreviation 
Term 
SOC 
standard of care 
SUDV 
species Sudan Ebolavirus  
SUSAR 
serious and unexpected suspected adverse reaction 
TAFV 
species Taï Forest Ebolavirus 
UP 
unanticipated problem 
UPnonAE 
unanticipated problem that is not an adverse event 
WBC 
white blood cell 
WHO 
World Health Organization 
 
 


2018 Ebola MCM RCT Protocol 
Page 9 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
PROTOCOL SUMMARY 
 
Full Title: 
A Multicenter, Multi-Outbreak, Randomized, Controlled Safety and 
Efficacy Study of Investigational Therapeutics for the Treatment of 
Patients with Ebola Virus Disease 
 
Short Title: 
2018 Ebola MCM RCT Protocol 
Clinical Phase: 
2/3 
IND Sponsor: 
OCRPRO 
Conducted by: 
Multicenter Trial Consortium 
Principal Investigators: 
By participating countries 
Sample Size: 
N=725 for the Randomized Controlled Trial. 
Extension Phase will add up to 1500 patients. 
Accrual Ceiling: 
750, in order to enroll 725 to study treatment for the Randomized 
Controlled Trial.  
Extension Phase will accrue up to an additional 1500 patients. 
 
Study Population: 
Patients with known acute Ebola virus infection having symptoms of 
any duration 
 
Accrual Period: 
November 2018 – November 2023 
Study Design: 
Randomized controlled clinical trial.  While awaiting data analysis an 
Extension Phase will offer study treatment for new patients. 
 
Study Duration: 
Start Date: November 2018 
End Date: November 2023 (i.e., nominally up to 5 years, but could be 
shortened or lengthened depending upon the pace of subsequent 
outbreaks in order to reach desired sample size) 
 
Primary Objective: 
• To compare the mortality at 28 days in patients with Ebola 
virus disease who receive different investigational 
therapeutics relative to the control arm.  
Secondary Objectives: 
• To assess whether the mortality rates in the monoclonal arms 
support analysis of an antibody-class effect versus a direct-
acting antiviral product. 
• If pooling the monoclonal arms is justified based upon the 
analysis of heterogeneity outlined above, then compare the 
safety, tolerability, and efficacy of antibody-based products as 
a class with a direct-acting antiviral product in the treatment 
of Ebola. 


2018 Ebola MCM RCT Protocol 
Page 10 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
• To evaluate the safety and tolerability of investigational 
therapeutics. 
• To compare the change in viral load between study arms. 
• To compare mortality rates among patients whose baseline 
predictors of disease place them in high-risk versus low-risk 
categories for disease severity. 
• To compare mortality rates of investigational arms up to 58 
days after randomization. 
• When possible, to evaluate the presence of Ebola viral RNA 
in the semen of male survivors at ETU discharge or Day 28 
(whichever comes first) and Day 58. 
• To assess the relationship between change in viral load over 
time with survival. 
• To compare time to successful discharge from the ETU 
between participants receiving investigational therapeutics.  
• To compare time to death of participants receiving 
investigational therapeutics  
• To collect data on the oSOC available in each participating 
ETU and, when possible, on the oSOC provided to each 
participant. 
 
Exploratory Objectives: 
• To assess comparative ease of both preparation and 
administration of study agents. 
• Pharmacokinetic assessments of investigational agents, when 
possible. 
• Assessment of viral resistance over time, when possible. 
 
Primary Endpoint: 
• 28-day mortality.  
 
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 (see special provision for neonates). 
• 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. 


2018 Ebola MCM RCT Protocol 
Page 11 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Exclusion Criteria: 
• 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). 
 
 
Study Design 
• A randomized controlled trial with interim monitoring to 
introduce new arms and allow early stopping for futility, efficacy, 
or safety. Comparisons of safety and efficacy will be based on 
data from concurrently randomized participants. 
 
• It is assumed that this study will continue across more than one 
outbreak and in several countries. To allow for country specific 
preferences about what constitutes an ethical and scientifically-
acceptable control arm, there are two design options at present 
and as described below. In the event that both options enroll 
participants, analyses will be stratified by option for the common 
arms. 
 
o Option 1: Drug A as the control arm (4 arms, Drug 
A+oSOC vs Drug B+oSOC vs Drug C+oSOC vs Drug 
D+oSOC) 
 
o Option 2: oSOC as the control arm (5 arms, oSOC vs 
Drug A+oSOC vs Drug B+oSOC vs Drug C+oSOC vs 
Drug D+oSOC) 
       
This study will initially enroll participants in the Democratic 
Republic of Congo (DRC), which has chosen Option 1; therefore, 
the initial plan will randomize (1:1:1:1) enrolled participants to 
ZMappTM, remdesivir, MAb114, or REGN-EB3 each given with a 
backbone of oSOC. It is noted that a decision to explore Option 2 
in a future outbreak would require a major revision to the current 
study design and analysis plan that are not described within the 
current protocol. It is also noted that accrual of data in DRC as 
well as the availability of other investigational therapeutics may 
change the number and nature of arms.  
 
• Randomization will be stratified by: RT-PCR cycle threshold 
(≤22.0 vs >22.0), ETU site, and outbreak.  
 


2018 Ebola MCM RCT Protocol 
Page 12 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
• An independent data and safety monitoring board (DSMB) will 
actively monitor interim data to make recommendations about 
early study closure or changes to study arms. At the end of the 
outbreak, or if a predefined sample size is reached earlier, 
analyses will be presented to the DSMB. The DSMB will then 
recommend whether the results should be released or kept blinded 
until a stopping boundary is crossed or the study has fully 
enrolled.  
 
• Outbreaks with filovirus species other than Zaire ebolavirus will 
require reconsideration of design and study arms with agents that 
have known activity for that species. The monoclonal therapies 
currently targeted for study are specifically designed for Zaire 
ebolavirus variants.  
 
Study agents: 
Four arms for the DRC outbreak (all arms also receive oSOC): 
• ZMappTM, three doses of 50 mg/kg of body weight 
administered intravenously every third day beginning on Day 
1. 
• 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). The 
recommended remdesivir dosing duration is a total of 10 days, 
but dosing may be continued at the daily maintenance dosing 
levels described above for an additional 4 days if Ebola viral 
load remains detectable in blood at Day 10 of treatment. 
• MAb114, at 50 mg/kg of body weight administered 
intravenously on Day 1 as a single infusion. 
• REGN-EB3 at 150 mg/kg of body weight administered 
intravenously on Day 1 as a single infusion. 
 
Study Synopsis: 
• Informed consent for research participation upon admission 
into the treatment center. 
• Baseline determination of clinical status according to a 
standardized case report form (CRF). 
• Baseline collection of blood for quantitative Ebola viral load 
by RT-PCR to be processed by an appropriate laboratory 
facility. 
• Centralized randomization assignment made. 
• Provision of assigned study intervention, ideally immediately 
following randomization whenever possible, according to 


2018 Ebola MCM RCT Protocol 
Page 13 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
assigned treatment arm and the individual pharmacologic or 
logistical requirements of the treatment intervention. 
• 24- to 48-hour pharmacokinetic measurements of assigned 
intervention where appropriate and logistically feasible. 
• Daily assessments of clinical status (including oSOC provided 
within the capabilities of the site facility) according to 
standardized CRFs and the study flow sheet. 
• Serial collection of blood for quantitative viral load 
determination by RT-PCR for processing in an appropriate 
laboratory facility, as possible. 
• Longer-term follow-up up to Day 58, when feasible, for any 
late onset clinical history, seminal viral persistence, or 
symptoms possibly consistent with delayed virologic relapse 
or drug toxicity. 
 
 
 


2018 Ebola MCM RCT Protocol 
Page 14 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
PRÉCIS 
 
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 investigational 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 and exploratory endpoints also planned that 
should generate important knowledge about the safety, ease of administration, and antiviral 
activity of all of these investigational interventions. 
 
 
 


2018 Ebola MCM RCT Protocol 
Page 15 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
1 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
 
Background 
 
Filoviruses 
Ebolavirus is a large, negative-strand ribonucleic acid (RNA) virus composed of 7 genes 
encoding viral proteins, including a single glycoprotein (GP) (1-3). Ebolavirus is one of three 
genera in the Filoviridae family, which along with Marburgvirus, is known to induce viral 
hemorrhagic fever. Five distinct species, of which 4 have been implicated as etiologic agents of 
human Ebolavirus disease (EVD), formerly known as Ebola hemorrhagic fever (EHF), exist: 
Bundibugyo virus (BDBV), Reston virus (RESTV), Sudan virus (SUDV), Taï Forest virus 
(TAFV), and Zaire virus (EBOV) (4). The BDBV, EBOV, and SUDV species have been 
associated with large EVD outbreaks in Africa, with reported case fatality rates of up to 90% (5). 
Between 1994 and the present, there have been many filovirus outbreaks (Table 1) affecting 
mostly central Africa, with 2 large outbreaks in 1995 in Kikwit, DRC, and in Gulu, Uganda in 
2000-2001. The 2013-2016 West African outbreak (approximately 28,000 cases and over 11,000 
deaths) significantly exceeded all previous outbreaks in geographic range, number of patients 
affected, and in disruption of typical activities of civil society. EVD cases in persons who 
traveled from endemic areas were also reported in Italy, Spain, United States (US), and United 
Kingdom (UK) (6). While the World Health Organization (WHO) declared an end to the EVD 
public health emergency in March 2016, the risk that small outbreaks will continue to occur 
remains omnipresent (6). Given the frequency of international travel, EVD also remains a global 
threat to public health. 
 
Transmission and Disease 
Transmission of Ebolavirus to humans is not yet fully understood, but is likely due to incidental 
exposure to infected animals (7-9); through direct contact with blood, secretions, organs, or other 
bodily fluids of infected people (alive or dead); and through indirect contact with environments 
contaminated by such fluids (5). It is thought that people are infectious for as long as their blood 
and secretions contain the virus. Men who have recovered from the disease can potentially still 
transmit the virus through semen for an extended period of time after recovery from illness (5, 
10, 11). 
EVD has an incubation period of 2 to 21 days (7 days on average, depending on the species) 
followed by a rapid onset of non-specific symptoms such as fever, extreme fatigue, 
gastrointestinal complaints, abdominal pain, anorexia, headache, myalgias, and/or arthralgias. 
These initial symptoms, which last for about 2 to 7 days, are followed by more severe symptoms 
related to disease progression (e.g., hemorrhagic rash, epistaxis, hematuria, hemoptysis, 
hematemesis, melena, conjunctival hemorrhage, tachypnea, confusion, somnolence, and, in some 
cases, both internal and external bleeding) and are accompanied with low white blood cell 
(WBC) and platelet counts and elevated liver enzymes (5). These symptoms generally last for 
about 7 to 14 days. Death can occur at a variable time after the onset of symptoms, manifested by 
vomiting and diarrhea resulting in dehydration, shock, and then multi-organ failure (7, 12). 
Immunoglobulin M (IgM) antibodies to the virus appear 2 to 9 days after infection followed by 
immunoglobulin G (IgG) antibodies at approximately 17 to 25 days after infection; the latter 


2018 Ebola MCM RCT Protocol 
Page 16 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
coinciding with the recovery phase (13). In survivors of EVD, both humoral and cellular 
immunity are detected; however, their relative contribution to protection is unknown (13, 14). 
 
Latest Outbreaks 
On May 3, 2018, the Provincial Health Division of Equateur Province in the DRC alerted its 
Ministry of Health and Population (MoHP) of cases and community deaths clinically compatible 
with viral hemorrhagic fever (VHF) in the western region of that country. On May 8, 2018, an 
EVD outbreak (the 9th recorded outbreak in the DRC) was declared by the DRC MoHP. The 
epidemic spread geographically, including confirmation of cases reported in Mbandaka, the 
capital of Equateur province and a large urban area and center of trade. Overall, a total of 55 
cases of EBOV disease were reported in the region, including 38 confirmed, 15 probable, and 2 
suspected. The last confirmed case occurred on June 6, 2018, and 24 patients were reported to 
have been cured of their infections over the course of the epidemic. Through a series of 
coordinated public health interventions overseen by the MoHP (including the use of contact 
tracing, isolation, and safe burial practices), education, and possibly the use of Merck’s 
experimental rVSV-Ebola vaccine according to a ring vaccination strategy, the outbreak was 
declared officially ended as of July 24, 2018. 
Unfortunately, shortly after the outbreak in the western region of the DRC was declared over, on 
August 1, 2018, the Ministry of Health declared an outbreak of EVD following the confirmation 
of four cases of Ebola in the Mabalako health zone of the territory of Beni, North Kivu province, 
Eastern DRC. This is the first-time an Ebola outbreak was reported in this part of the country and 
constitutes the 10th known outbreak in DRC. As of August 3, 2018, a total of 49 cases had been 
reported across 7 health zones in two provinces, i.e., five health zones (Beni, Butembo, Oicha, 
Musienene and Mabalako) in North Kivu province and two health zones (Mandima and 
Mambasa) in Ituri province. As of 28 July 2019 – almost one year after the initial reports of the 
outbreak - a total of 2671 EVD cases, including 2577 confirmed and 94 probable cases, have 
been reported. A total of 1790 deaths have been reported (overall case fatality ratio 67%), 
including 1696 deaths among confirmed cases.  
Adding to the difficulty of controlling the outbreak is the fact that the affected territories have 
been beset by ongoing armed conflicts and, as a result, formidable security challenges exist in 
protecting deployed staff, providing investigational vaccine to at-risk populations, and ensuring 
safe delivery of medical treatment to those infected. 
Table 1: Ebola Virus Outbreaks 
 
Viral species 
Year 
Outbreak location 
# of human cases  
(% fatality) 
Zaire Ebolavirus 
1976 
Yambuku, Zaire (DRC) 
318 (88%) 
1977 
Tandala, Zaire (DRC) 
1 (100%) 
1994 
Ogooue-Ivindo province, Gabon 
52 (60%) 
1995 
Kikwit, DRC 
315 (79%) 
1996 
Mayibout 2, Gabon 
37 (57%) 
1996 
Booué, Gabon and Johannesburg, South 
Africa 
62 (74%) 
2001-02 
Mbomo-Kéllé, Republic of Congo 
59 (73%) 


2018 Ebola MCM RCT Protocol 
Page 17 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
2001-02 
La Zadie, Ivindo, and Mpassa districts, 
Gabon 
65 (81%) 
2002-03 
Cuvette region, Republic of Congo  
143 (89%) 
2003 
Mbomo and Mbandza, Republic of Congo 35 (83%) 
2005 
Etoumbi and Mbomo, Republic of Congo 12 (75%) 
2007 
Mweka, Kasai Occidental province, DRC 264 (71%) 
2008-09 
Mweka, Kasai Occidental province, DRC 32 (47%) 
2013-16 
West Africa (primarily 
Liberia, Sierra Leone, and Guinea) 
>28,000 (c. 40%) 
2014 
Boende, Western DRC 
69 (71%) 
2017 
Likati, Bas Uélé province, Northern DRC 8 (50%) 
2018 
Bikoro, Western DRC 
54 (61%) 
2018 
Beni-Mangina, Eastern DRC 
Ongoing as of 9/2018 
Sudan Ebolavirus 
1976 
Nzara, Maridi, Tembura, and Juba, Sudan 284 (53%) 
1979 
Nzara, Yambio, Sudan 
34 (65%) 
2000-01 
Gulu, Masindi, Uganda 
425 (53%) 
2004 
Yambio, Sudan 
17 (41%) 
2011 
Luwero District, Uganda 
1 (100%) 
Taï Forest Ebolavirus 
1994 
Taï Forest, Ivory Coast 
1 (0%) 
1995 
Liberia or Ivory Coast 
1 (0%) 
Reston Ebolavirus 
1989 
Philippines and VA and PA, USA 
3 asymptomatic (0%) 
1990 
Reston, VA, USA 
4 asymptomatic (0%) 
1992 
Siena, Italy 
0 
1996 
Philippines and Alice, TX, USA 
0 
2008 
Philippines 
6 asymptomatic (0%) 
Bundibugyo Ebolavirus 
2007-08 
Bundibugyo District, Uganda 
131 (32%) 
2012 
Isiro, Haut-Uélé province, DRC 
36 (36%) 
Adapted from: Ebola: Years of Ebola Virus Disease Outbreaks, 40 Years of Ebola Virus Disease around the World. Centers for 
Disease Control and Prevention website. https://www.cdc.gov/vhf/ebola/history/chronology.html. Updated August 31, 2018. 
Accessed September 10, 2018. 
 
Therapy 
Prior to the West African outbreak in 2013-2016, the standard treatment of EVD had been 
largely supportive, involving oral or intravenous fluid and electrolyte replenishment and pain 
reduction where possible. Due to the remote location of the outbreaks and the limited medical 
and logistical resources available in most of the affected regions, more aggressive treatment 
options usually had neither been available nor tested in most patients. However, some 
experimental interventions were explored in prior outbreaks. For example, during the Kikwit 
outbreak in 1995, 8 patients with EVD were treated with convalescent plasma harvested from 
EVD survivors; of those 8, 7 patients recovered from their acute illness (15). Overall, in certain 
centers where advanced treatment measures were able to be employed, a substantial reduction in 
mortality has sometimes been reported (16).  
Wherever possible, the standard treatment for EVD continues to focus on management of 
symptoms that includes supportive oral or IV fluids, electrolyte replacement, maintaining oxygen 
status and blood pressure, and pain reduction. Efforts continue to identify, standardize, and 
deploy the most successful standard-of-care (SOC) measures that potentially could be introduced 
into previously resource-poor areas. As one example, WHO published Clinical Management of 
patients with Viral Haemorrhagic Fever; A pocket guide for front-line health workers (February 
2016), which provides guidance for standard treatment of viral hemorrhagic diseases (16). 


2018 Ebola MCM RCT Protocol 
Page 18 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Evidence-based guidelines provide support for improved or “optimized” SOC measures (oSOC) 
to reduce the high mortality rates associated with the disease in the affected regions. 
In contrast, in the US and other developed nations to which a small number of infected HCWs 
had been medically evacuated during past outbreaks, aggressive IV fluid resuscitation, 
hemodynamic monitoring and support, point-of-care (POC) diagnostic modalities, and other 
aspects of critical care medicine have already been employed in the attempt to save these 
critically ill individuals. Against this background of oSOC has been the introduction of several 
different investigational therapeutics as adjunctive therapy, ranging from the administration of 
convalescent plasma from recovered patients to the use of direct antiviral agents provided under 
emergency IND as medical countermeasures (MCMs). As of 2015, investigational treatment data 
were available on a total of 27 HCWs or other individuals with documented Ebola infection who 
had been referred to special isolation units in the US or Europe after becoming infected while 
providing care in West Africa (17). The reported investigational agents used in these individuals 
were as follows: 
• ZMapp or MIL77 
• ZMab 
• TKM-Ebola 
• Favipiravir 
• Brincidofovir 
• FX06 
• Convalescent plasma 
• Convalescent whole blood 
• Amiodarone 
• Melanocortine 
 
Conclusions about possible benefits or toxicities from these treatments were limited because they 
were not administered in the context of a study. Furthermore, in many cases these patients 
received multiple different MCMs either together or over a short period of time, making 
differentiation of either a beneficial treatment effect or toxicity attributable to any single one of 
these agents almost impossible to discern. In addition, 6 medically evacuated HCWs were 
brought back to the United States following a serious percutaneous exposure to Ebola virus while 
in West Africa, but without documented infection at the time of transfer, and each received 1 
putative MCM each: Tekmira siRNA in one case and the investigational VSVΔG-ZEBOV 
vaccine in the remaining five (18). It should be emphasized that in almost all of these cases 
adequate phase 1 data to support the safety of the product in humans and/or data to support the 
safety and efficacy of the product in those with documented Ebola infection were either 
incomplete or lacking altogether. Also, while the use of these particular agents was facilitated in 
most cases by supportive preclinical data, it should be noted that several experimental treatment 
strategies were previously shown to be successful in in vitro or rodent models, but either failed 
testing or were not thoroughly tested in the NHP model, which is still considered the most 
accurate in modeling human disease. 
In regard to immune-based approaches to therapy, convalescent serum harvested from recovered 
patients has been one of the most widely used MCMs to date in the West African outbreak and, 
as noted above, was also used in a limited number of patients during the Kikwit 1995 ZEBOV 


2018 Ebola MCM RCT Protocol 
Page 19 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
outbreak. However, its earlier success remains a matter of dispute. Experimentally, passive 
immunization with horse serum resulted in protection of Hamadryl baboons (19), whereas it only 
delayed death in Cynomolgus macaques (20, 21). Certain monoclonal antibody treatments have 
also been successful in rodent models (22, 23) but have failed in preliminary NHP studies (24), 
indicating possible evasion of antibody neutralization as an escape mechanism of the virus. It is 
hoped that more recent monoclonal antibody products or cocktails may avoid this limitation. 
However, it remains fair to say, at least at this time, that a proven therapeutic role of 
convalescent plasma or monoclonal preparations as treatment adjuncts remains as yet 
unsubstantiated in this disease, as does the efficacy of direct antiviral agents that also appear 
promising in NHP studies. 
 
RCT of ZMapp (PREVAIL II) 
As an example of this uncertainty, beginning in March 2015 in West Africa, the Ministries of 
Health in Liberia, Guinea, and Sierra Leone collaborated with one another, the NIAID, and 
INSERM on a randomized, controlled trial of the triple monoclonal antibody product ZMapp 
(Mapp Biopharmaceuticals) plus SOC versus SOC alone in patients with EVD diagnosed by RT-
PCR assay (25). In this study, named PREVAIL II, eligible patients of any age were randomly 
assigned in a 1:1 ratio to receive either the current oSOC or the current oSOC plus three IV 
infusions of ZMapp (50 mg per kilogram of body weight, administered every third day). Patients 
were stratified according to their baseline RT-PCR cycle-threshold (CT) values for the virus 
(≤22 vs. >22) and by country of enrollment. Oral favipiravir was part of the current SOC in 
Guinea. The primary endpoint was mortality at 28 days. Due to curtailing of the outbreak in that 
region, a total of only 72 patients could be enrolled at sites in Liberia, Sierra Leone, Guinea, and 
the US out of a desired accrual of 100 patients per arm. Of the 71 patients who could be 
evaluated, 21 died, representing an overall case fatality rate of 30%. Death occurred in 13 of 35 
patients (37%) who received the current oSOC alone and in 8 of 36 patients (22%) who received 
the current SOC plus ZMapp. The observed posterior probability that ZMapp plus the current 
SOC was superior to the current oSOC alone was 91.2%, falling short of the prespecified 
threshold of 97.5%. Frequentist analyses yielded similar results (absolute difference in mortality 
with ZMapp, −15 percentage points; 95% confidence interval, −36 to 7). It was noted that 
baseline viral load was strongly predictive of both mortality and duration of hospitalization in all 
age groups. The authors concluded that although the estimated effect of ZMapp appeared to be 
beneficial, the result did not meet the prespecified statistical threshold for efficacy.  
 
Rationale for Study 
The current state of medical science with respect to the treatment of filovirus infections such as 
Ebola virus disease does not adequately address the role of therapeutic adjuncts beyond 
supportive care in the successful management of these infections. In some cases, our 
understanding of the role that these adjunctive therapies may play is greatly hampered by either 
incompleteness or lack of an adequate phase 1 safety and toxicity database of the lead drug 
candidates, or by lack of data concerning how the candidates in more advanced development 
may perform in this patient population. The tragic dimensions of the recent Ebola virus epidemic 
in West Africa afforded little time to explore these issues according to a more conventional time 
frame of traditional drug development, and argued strongly for an accelerated exploration of 
safety, toxicity, and potential efficacy of lead agents in a controlled research setting. 
Unfortunately, the recent advent of two more outbreaks in the DRC in 2018 has added further 


2018 Ebola MCM RCT Protocol 
Page 20 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
impetus to identify safe and effective drug treatments as quickly as possible so that case fatality 
rates associated with EVD can be reduced.  
Intrinsic to this rationale for expedited drug discovery in the current Ebola crisis are the 
following principles, which are by no means intended to be all-inclusive: 
• A multicenter, multinational randomized controlled study of lead therapeutic candidates 
is the best strategy for acquiring rigorous data about the safety and efficacy of 
investigational Ebola virus therapeutics. Single-use emergency IND, Emergency Use 
Authorization (EUA), Monitored Emergency Use of Unregistered and Investigational 
Interventions (MEURI), or similar mechanisms will not lead to generalizable evidence.  
• Randomization is essential to establishing efficacy results. EVD mortality rates vary 
considerably according to multiple factors, only some of which are known (e.g., CT, age,  
ETUs). Randomization is needed to balance these risk factors across treatment arms, and 
thereby reduce potential confounding of treatment outcomes with other factors not 
directly related to treatments received. 
• Collecting clinical and virologic data on enrolled patients according to standardized 
timelines and with a standardized collection instrument should provide valuable 
information about the clinical course, morbidities, and outcomes in these patients. 
• oSOC treatment options of fluid resuscitation, electrolyte monitoring and replacement, 
and other conventional approaches are a mainstay of therapy and must be the backbone to 
which experimental treatment modalities are added and compared. 
• Differences in oSOC may occur due to varying site resources and can obscure the 
potential additional contribution of experimental therapeutics. Therefore, every effort 
must be made to standardize the oSOC, both within and across treatment centers.  
• The number of EVD cases available for enrollment in this trial during the present 
outbreak is unpredictable and  potentially limited. Therefore, requirements for traditional 
levels of evidence must be reconsidered. Standards within other areas of rare diseases 
may provide guidance in this regard (26-28). 
• Limited, intermittent, or even absent drug supply may exist for some lead candidates 
proposed for study. Hence, a flexible, adaptive treatment design may be required. 
• At present, knowledge of the potential toxicity of lead candidates in this patient 
population may be limited. However, this toxicity risk is considered acceptable in the 
face of high individual mortality and community risk for continued Ebola virus 
transmission.  
• The use of a flexible platform design is recommended for the following reasons: 
o Efficiency: This design can accommodate the study of more than 1 investigational 
therapy using a shared control group. 


2018 Ebola MCM RCT Protocol 
Page 21 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
o Availability of study products: Some investigational products may be in limited, 
intermittent supply. The study design enables continuation of the study even if one 
product is not available. 
o A single trial allows a data and safety monitoring board (DSMB) to provide close 
oversight of safety and early efficacy signals.  
2 
STUDY OBJECTIVES 
 
Primary Objective 
• To compare the mortality at 28 days in patients with Ebola virus disease who receive 
different investigational therapeutics relative to the control arm. 
 
 
Secondary Objectives 
• To assess whether the mortality rates in the monoclonal arms support analysis of an 
antibody-class effect versus a direct-acting antiviral product. 
• If pooling the monoclonal arms is justified based upon the analysis of heterogeneity 
outlined above, then compare the safety, tolerability, and efficacy of antibody-based 
products as a class with a direct-acting antiviral product in the treatment of Ebola. 
• To evaluate the safety and tolerability of investigational therapeutics. 
• To compare the change in viral load between study arms. 
• To compare mortality rates among patients whose baseline predictors of disease place 
them in high-risk versus low-risk categories for disease severity. 
• To compare mortality rates of investigational arms up to 58 days after randomization. 
• When possible, to evaluate the presence of Ebola viral RNA in the semen of male 
survivors at ETU discharge or Day 28 (whichever comes first) and Day 58. 
• To assess the relationship between change in viral load over time with survival. 
• To compare time to successful discharge from the ETU between participants receiving 
investigational therapeutics.  
• To compare time to death of participants receiving investigational therapeutics  
• To collect data on the oSOC available in each participating ETU and, when possible, on 
the oSOC provided to each participant. 
 
Exploratory Objectives 
• To assess comparative ease both of preparation and administration of the individual study 
agents. 
• Pharmacokinetic assessments of investigational agents, when possible. 
• Assessment of viral resistance over time, when possible. 
3 
STUDY DESIGN  
 
General 
Study size:  Up to 725 randomized subjects. 


2018 Ebola MCM RCT Protocol 
Page 22 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Study duration: Nominally up to 5 years, but could be shortened or lengthened depending upon 
the pace of subsequent outbreaks and other contextual factors (i.e., intended to potentially span 
across several outbreaks in order to reach desired sample size). 
Study duration of individual subjects: Initially for 30 days following the primary endpoint 
(mortality at Day 28), or for a total of 58 days.  
[Under the auspices of a separate protocol yet to be developed, interested subjects may also be 
offered the opportunity, where and whenever feasible, to participate in longer-term follow-up 
(e.g., up to 1 year or more past Day 58 depending upon need) of their illness in order to 
determine whether they are at risk for late onset of any history or symptoms consistent with 
delayed virologic relapse potentially arising from immunologically-privileged sites (e.g., the 
central nervous system (CNS) or the male testes).] 
Sex distribution: Males and females. 
Age range: Unrestricted. 
Design: A multi-center, multi-outbreak, randomized, open-label, controlled clinical trial of 
experimental Ebola virus disease therapies, each administered with a backbone of oSOC. Figure 
1 provides a schema of the study. Interim monitoring is included to introduce new arms or allow 
early stopping for futility, efficacy, or safety. Guidelines for early stopping will be described in 
Table 5 in Section 6.5. This is a superiority design using a 28-day mortality endpoint. For the 
EBOV outbreak in the DRC, eligible patients will be randomized 1:1:1:1 to receive either 
ZMappTM as the control arm, remdesivir, REGN-EB3, or MAb114. The rationale for the 
selection of these specific drugs as the lead candidates is described in Section 3.4 below. This 
design assumes sufficient quantities of each drug will be available to initiate the trial. It also 
assumes that a sufficient quantity of ZMapp exists to complete the study as planned since ZMapp 
serves as the comparator or control arm. Should a treatment shortage occur in one of the 
investigational drug arms being compared to ZMapp, enrollment will continue to the remaining 
arms. Should a treatment shortage occur in any arm, enrollment will continue to the remaining 
arms. Comparisons will be limited to data from concurrently enrolled patients. Randomization 
will be stratified by PCR cycle threshold ≤22.0 vs >22.0, ETU, and outbreak. The selection of a 
threshold value of 22.0 was based on prior analysis of the distribution of CT values from a large 
cohort of Ebola virus-infected individuals during the West African crisis (25).  
The study will continue across outbreaks, unless a recommendation to modify or close the study 
is made by the DSMB. It may be amended per DSMB request to drop or replace poorly 
performing arms including a modification of the control arm. At the end of the outbreak and at 
predefined enrollment numbers, analyses will be presented to the DSMB to evaluate safety and 
efficacy of each arm. The DSMB will recommend to the Steering Committee if results should be 
released or kept blinded until a stopping boundary is crossed or the study has fully enrolled.  
It is understood that outbreaks with filovirus species other than the Zaire Ebola virus will require 
reconsideration of study drugs that have known activity for the circulating species. The 
monoclonal therapies currently targeted for study are specifically designed for the Zaire 
ebolavirus species. Therefore, future outbreaks not due to Zaire ebolavirus or its susceptible 
variants will require a new study design. If that were to occur, this would result in a separate new 


2018 Ebola MCM RCT Protocol 
Page 23 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
protocol with a new analysis plan and governance structure since the designs will not share the 
same drugs nor have a common control arm. 
Study Arms: Four arms (all given with oSOC): 
• ZMapp, three doses of 50 mg/kg of body weight administered intravenously every third 
day beginning on Day 1. 
• Remdesivir, administered intravenously with a loading dose of 200 mg on Day 1 
followed by 9 to 13 days (depending on Ebola viral load) of the 100-mg daily 
maintenance dose (see pediatric weight-based dosing adjustments). 
• MAb114, at 50 mg/kg of body weight administered intravenously on Day 1 as a single 
infusion. 
• REGN-EB3 at 150 mg/kg of body weight administered intravenously on Day 1 as a 
single infusion. 
 
Extensive discussions with primary stakeholders in ETU management have clearly revealed that 
there is not necessarily consensus on what standards of care should be considered the minimal 
standards that all patients should receive, much less how the term “oSOC” treatment should be 
defined for the purposes of this study as a whole. Accordingly, attempts to legislate across all 
ETUs what a uniform definition of oSOC must include in order for a given site to qualify for 
study participation carries the risk of unfairly disenfranchising some sites, and therefore some 
patients, and therefore should be discouraged. As a general rule, however, an attempt to 
implement oSOC at study sites should include, but not necessarily be limited to, the provision of 
appropriate fluid resuscitation, hemodynamic and respiratory support, metabolic corrections, and 
treatment of concurrent infections (e.g. malaria), seizures, and other acute co-morbidities. In the 
field setting where ETU resources may be severely constrained, for example, a minimum oSOC 
should usually include regular physician assessments including collection of vital signs, 
provision of rehydration (by either oral or IV fluids as feasible), serial measurement and 
correction of electrolytes, provision of empiric antibiotics when appropriate, and empiric 
treatment for malaria until confirmatory testing is available. However, it is acknowledged that 
the physician team in charge of a given ETU has the ultimate latitude to adjust these provisions 
based upon both ongoing resource considerations and their clinical judgment as to the suitability 
of a given provision for a specific patient. A deviation from the general oSOC measures 
described above in this circumstance will not constitute a protocol violation nor make the site 
ineligible for ongoing participation in the trial. 


2018 Ebola MCM RCT Protocol 
Page 24 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Figure 1. Study Schema for Option 1. 
Note: as stated above, this design assumes that a sufficient quantity of ZMapp will be provided 
to complete the study since that drug serves as the control arm. If there is insufficient supply of 
ZMapp for any reason, randomization to other arms will continue. Any instances of lack of 
supply for any reason will be reported and accounted for in the analyses. 
 
Extension Phase 
Refer to section 14.0 for PALM Extension Phase Plan. 
 
Study Endpoints 
Study endpoints will be evaluated by comparing randomized groups. 
 
Primary Endpoint 
• 28-day mortality.  
 
Secondary Endpoints 
• Incidence of serious adverse events (SAEs; see safety section for limitations on 
collection). 
• Incidence of infusion-related adverse events (AEs). 
• Frequency and characterization of clinically significant AEs related to study agent 
administration.  
• Incidence of other AEs as revealed by laboratory monitoring (see safety section for 
limitations on collection). 
• Mortality at Day 14 and Day 58. 
• Viremia at Days 1, 2, 3, 4, 5, 6, 8, 10, 14, and 28. 


2018 Ebola MCM RCT Protocol 
Page 25 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
• Ebola viral RNA in semen at ETU discharge or Day 28 (whichever comes first) and Day 
58. 
• Time to discharge from ETU. 
• Time to death over 58 days. 
• Time to first negative Ebola virus RT-PCR in blood. 
• Time to two consecutive negative Ebola virus RT-PCRs in blood.  
• oSOC provided to study participants at a site and, when possible, at an individual level 
• Delayed onset (after 28 days) of any clinical symptoms possibly consistent with virologic 
relapse or drug toxicity within 58 days after enrollment. 
 
Exploratory Endpoints 
• Comparative ease both of preparation and administration of the individual study agents 
including supply and storage constraints. 
• Pharmacokinetic assessments of investigational agents when possible.* 
• Assessment of viral resistance over time, when possible. 
 
* In general, pharmacokinetic measurements often involve processing (e.g., centrifugation) and testing of blood specimens with 
techniques or equipment not routinely available or safely performed in most point-of-care laboratory set-ups. These 
considerations, coupled with limitations on storage, transport, and analytical processing of infectious samples falling under Select 
Agent regulations, could limit these explorations outside the context of a high-containment laboratory such as a domestic BSL-4 
laboratory or similar in-country facility. 
 
Overview of Study Drugs 
Because each of the investigational study agents is provided under IND and each sponsor may 
have proprietary information concerning the products that is not in the public domain, the 
detailed descriptions of study agents are provided separately as Appendices to the protocol. For 
now, these agents include: Appendix A (ZMappTM), Appendix B (remdesivir), Appendix C 
(MAb114), and Appendix D (REGN-EB3). Each of these appendices contains preclinical, NHP, 
and human data in support of the choice of these products, information about how they should be 
administered, and their known side effect profiles.  
 
Considerations in Choice of Study Drugs 
Several factors influencing the choice of study drugs/interventions to be compared in this 
protocol were considered: 
• Willingness of both the pharmaceutical sponsors and the regulatory authorities to allow 
each of these drugs to be studied according to this proposed trial design. 
• Dedicated supply of agents to be made available for the study over the projected timeline 
of the trial. 
• Agreement on ongoing equipoise between study arms: 
o No available individual therapeutics candidate has yet been proven unequivocally 
to be superior to oSOC. 
o No therapeutics candidate has yet been demonstrated to be superior to another,  
o No compelling safety/toxicity concern has emerged with respect to individual 
therapeutics candidates to favor their removal from consideration as study 
interventions. 
• Given the consensus view on the value of this RCT and that MEURI access to 
interventions during the trial could preclude, or circumvent, interest in enrollment of 


2018 Ebola MCM RCT Protocol 
Page 26 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
patients into this RCT, the MEURI process will stop in participating sites where the trial 
is in progress, except for patients who cannot due to exceptional circumstances be 
enrolled in the study. Post-exposure prophylaxis activities will not be affected by the 
initiation of this RCT. 
 
As summarized above, ZMapp, remdesivir, REGN-EB3 and MAb114 are the experimental 
therapeutics chosen for the implementation of the protocol during the second 2018 outbreak in 
the DRC. The decision to include these products in the study was based on several factors: 1) a 
desire to link to the data from the prior RCT of ZMapp during the 2014-16 outbreak to the 
current study; 2) the desire to study a direct acting agent with a different mechanism of action 
from monoclonal antibodies both to determine comparative efficacy as well as an important 
prelude to potential future combination drug trials; 3) the positive in vitro, NHP data, and early 
phase I safety data for MAb114 coupled with the strong desire of the host country to evaluate an 
agent for which they played a seminal role in development. 
 
Initially the host country expressed a desire to restrict the study to no more than three arms 
(and limit the sample size to a total of 336 subjects) due to the complexity and feasibility of 
administering and accruing a study of this size. Accordingly, the initial version of the protocol 
that was designed, approved, and deployed was a three-arm design involving 1:1:1 
randomization of patients to ZMapp, Mab114, or remdesivir. However, on October 11, 2018, in 
Geneva the WHO convened an Ad-Hoc Consultation on Clinical Trials for Ebola Therapeutics 
that involved subject matter experts on Ebola therapeutics and whose purpose was to review all 
available therapeutic options and ensure that all stakeholders were comfortable that the study 
design was optimal. On November 9, 2018, the summary document from that consultation was 
finalized. Among other recommendations was the primary recommendation to add a fourth 
investigational treatment arm (i.e. REGN-EB3) to the current RCT. The specific rationale given 
for doing so was summarized as follows: 
“There was discussion of the trade-offs for including a fourth arm in the current RCT. Adding 
a fourth arm would spread enrolment across four arms and would increase the time required to 
accrue a sufficient number of patients in the trial. The trial could address the conceptual question 
of monoclonal antibody-based therapy vs. small molecule drug treatment without adding a fourth 
arm. It was also mentioned that each of the investigational products is different, have different 
dosing regimens and for the purposes of product licensure would be based on the available data 
for each of the products; a point in support of adding a fourth arm. The RCT will likely run over 
multiple outbreaks, so including each of the four investigational products (Mab 114, Regeneron, 
Remdesivir and ZMapp) provides a chance for data to be gathered on each using the current trial 
(as opposed to a future trial that might start at some point after the current trial has been 
completed). Also mentioned were the relative differences in the resources required to administer 
each of the products in the field with some products having single dose regimens. As noted above, 
taking these trade-offs into consideration, overall the group’s recommendation was to include the 
Regeneron product as a fourth arm in the current RCT.” 
 
Based upon this recommendation, in late November, 2018, a revised Protocol 
Development Team was assembled and supported amending the initial three-arm design of the 
RCT to become a four-arm design involving the addition of REGN-EB3. Randomization will 
occur on a 1:1:1:1 basis to the four study arms in this amended design, and the study sample size 
will be increased to 500 patients (in protocol version 3.0). 


2018 Ebola MCM RCT Protocol 
Page 27 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
Every attempt will be made to pre-position the investigational therapeutics under active study at 
the participating sites’ local or regional pharmacies in advance of anticipated enrollments. 
Randomization of an individual patient to a given study drug will only occur when there is 
sufficient quantity of each drug to complete a full treatment course for that individual. 
 
Definitions for the Purpose of this Study 
Enrolled 
For the purpose of collecting data and samples, and recording and grading of baseline 
SAEs/AEs, a subject will be considered enrolled beginning from when the informed consent 
form is signed and randomization to an assigned treatment has occurred, even if the subject 
expires before receipt of study drug, until the subject is considered either “discontinued” or 
“completed”. 
 
Discontinued 
Subjects are considered discontinued when they meet the following criterion: 
• Subject withdraws consent after being dosed and prior to the completion of Day 28 (see 
also Section 4.5).  
 
Completed 
Subjects are considered completed for the main study endpoint when they have died or are 
followed through Study Day 58 (i.e., 30 days past the primary endpoint measured at Day 28) and 
complete the final study follow-up visit or telephone contact scheduled for that time. If patients 
cannot be located or contacted (i.e., lost to follow-up) between the time of ETU discharge and 
study Day 58, their completion date will be considered the last known date of contact with them 
by study personnel. While no plans currently exist to do so, it is possible that a long-term follow-
up protocol may be developed to enable that protocol’s study personnel to collect additional 
information about the longer-term effects of EVD, the potential long-term effects of study drug 
administration, signs or symptoms possibly consistent with virologic relapse, and other relevant 
points of their clinical history for up to a year following ETU discharge. Patients will still be 
considered as having completed the current protocol if: 1) they decline this extended follow-up, 
or 2) they choose to discontinue extended follow-up prior to reaching 1-year past discharge. 
4 
STUDY POPULATION 
 
Research Subject Recruitment 
Persons with confirmed EBOV infection at participating health centers may participate in the 
trial as long as the site is willing to provide some measures of oSOC as described in Section 3.1 
above. Although ultimately subject to discretion by the treating physician team at a given site, in 
most cases this care would include the ability to provide regular physician assessments, 
collection and recording of vital signs, and provision of “systematic care” including oral (by 
mouth or by nasogastric tube) and/or IV fluids as needed, measurement and correction of 
electrolytes, use of empiric antibiotics when appropriate, and treatment for malaria until 
confirmatory testing is available. 


2018 Ebola MCM RCT Protocol 
Page 28 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
Participation of Site Employees 
Site employees who meet eligibility criteria may participate in this study, with the following 
conditions: 
• Neither participation nor refusal to participate in this protocol will have any effect on the 
subject’s subsequent employment or work situation nor in their accessibility to post-
exposure prophylaxis. 
 
Inclusion Criteria 
• Males or females of any age with documented positive RT-PCR for acute Ebola virus 
infection within 3 days prior to enrollment and who have symptoms of any duration 
(see special provision for neonates below). 
• 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 Criteria 
• 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.) 
 
Vulnerable Populations 
 
Pregnant Women 
A full understanding of the potential risks from the study medications to human fetuses is 
lacking at this time. However, given the mortality associated with Ebola virus infection and the 
likelihood that there is a greater risk to the fetus from severe EVD than from the study 
medications themselves, pregnant women will be permitted entry into the study. However, there 
may still be certain antiviral medications (e.g., favipiravir) with known teratogenic potential that 
pregnant women should generally not receive, and these considerations must be reviewed on a 
case-by-case basis with study investigators.  
The risks from the study medications to nursing infants are also unknown at this time. As women 
infected with Ebola will be quarantined in the ETU, breastfeeding will not be allowed. 
For women who are pregnant, every attempt will be made to track the pregnancy outcome 
through delivery in order to determine the outcome of the study intervention on the fetus. In 
many cases this may not be possible due to the challenges associated with tracking patients’ long 
term under difficult field conditions although every effort will be made to do so. 


2018 Ebola MCM RCT Protocol 
Page 29 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
Inclusion of Children and Neonates 
Similarly, the study medications have only been tested in limited fashion, or not at all, in 
children. Again, however, children of any age,will be eligible for enrollment given the likelihood 
that untreated Ebola infection may pose greater risk than exposure to the study medications. A 
neonate (defined as ≤ 7 days old) born to a mother who is RT-PCR positive for acute Ebola virus 
represents a special case. These neonates are presumed to be RT-PCR positive for acute Ebola 
virus at delivery, with untreated infection posing a greater risk than exposure to study 
medication. As such, neonates born to an infected mother who has not yet cleared the Ebola virus 
are eligible for enrollment even prior to RT-PCR confirmation (i.e. obtaining whose results could 
pose unnecessary delay). Neonates born to a mother who has cleared Ebola virus following a 
course of her assigned investigational medication may be enrolled prior to RT-PCR confirmation 
according to the discretion of the investigator regarding the likelihood that the neonate is infected 
(e.g., based on the interval between when the mother clears the virus and the baby is born). 
Regardless of when a neonate is enrolled, baseline blood for RT-PCR will be collected before 
study drug initiation. 
 
Adults Who Are Unable to Provide Initial or Ongoing Consent 
Adults who are unable to consent are eligible for enrollment in this protocol because of the high 
fatality rate with Ebola virus disease and the lack of other proven treatment options and the 
potential benefit provided by this study. Similarly, enrolled participants who lose the ability to 
provide ongoing consent during study participation may continue in the study. Capacity to 
provide initial and/or ongoing consent will be evaluated by the principal or associate 
investigator(s). Adults whose ability to consent is uncertain will be evaluated for the ability to 
consent according to local procedures. We will obtain assent for persons who are judged to have 
mental capacity above that of a 7-year-old. We will obtain permission for decisionally impaired 
adults via their appointed surrogate decision maker or another legally acceptable representative 
(such as a legal guardian). Local procedures will be followed for appointing a surrogate decision 
maker for adult participants who (a) are decisionally impaired, and (b) do not have a legal 
guardian. The risks of participation for adults unable to consent should be identical to those 
described for less vulnerable patients. The benefits for adults unable to consent are also the same 
because they will undergo the same procedures as participants who are able to provide consent. 
 
Subject Withdrawal 
Subjects can terminate full or partial study participation at any time without prejudice. If a 
subject terminates participation before completing the study, the reason for this decision will be 
recorded in the study record. Persons voluntarily withdrawing may elect to allow continued 
collection of outcome information. Subjects will continue clinical care per the local/site standard. 
Best efforts will be made to follow withdrawn subjects who have received study interventions for 
safety.  
 
Discontinuation of Subject by Investigator 
The investigator has the right to withdraw subjects from the study. Subjects may discontinue 
study treatment if, in his/her best judgment, the investigator believes that continuation in the 
study would be detrimental to the subject and therefore that discontinuation of the study drug 
would be in the participant’s best interests. In general, subjects withdrawn for AEs will still be 


2018 Ebola MCM RCT Protocol 
Page 30 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
followed for safety follow-up, if possible, as well as for ascertainment of the Day 28 mortality 
endpoint. 
  
The reason for discontinuation should be recorded in the study record. If an SAE is unresolved at 
the time of discontinuation, efforts should be made to follow up until the event resolves or 
stabilizes. Subjects will continue clinical care per the local/site standard. 
 
Discontinuation of Study 
The National Institute of Allergy and Infectious Diseases (NIAID), the Democratic Republic of 
Congo Ministry of Health, future countries who may join the study and their Ministries of 
Health, each institution’s Institutional Review Board (IRB), the Protocol Steering Committee, or 
the U.S. Food and Drug Administration (FDA) may request to terminate this study at any time 
upon notification of the other stakeholders. Reasons for terminating the study may include, but 
are not limited to, the following: 
• The incidence or severity of an SAE in this or other studies indicates a potential 
health hazard to subjects. 
• Subject enrollment is unsatisfactory. 
• Data recording is inaccurate or incomplete to the degree that objective evidence 
essential for determining the primary endpoint cannot be ascertained. 
• Investigators do not adhere to the protocol or applicable regulatory guidelines in 
conducting the study. 
5 
STUDY PROCEDURES 
 
Personnel for Study Procedures 
Assessments and study procedures may be performed by members of the investigative team and 
clinical team as assigned. 
The study will be conducted in accordance with the protocol, GCP, and all applicable US, INRB, 
and other host country regulations. 
 
Site-Specific Considerations 
Similar to prior outbreaks, the reality of the present outbreak of Ebola infection in the DRC is 
that patient care has been, and may likely continue to be, provided in a wide variety of different 
clinical settings, some of which may be fortunate to be comparatively resource-rich and others of 
which may face significant resource challenges. As long as sites will make every effort to fulfill 
the minimal standards of oSOC as outlined in Section 3.1 and obtain the necessary information 
to inform the primary endpoint, allowances should be made for differing site capabilities as a 
factor in study team expectations that sites collect and record both the full panel and complete 
frequency of data collection elements and safety assessments as outlined in the following 
sections. 
The protocol has defined minimal standards for assessment of efficacy and safety as well as 
defined the optimal scheduled assessments to obtain, if able, for the purpose of full longitudinal 
data collection. However, the inability of a site to collect the full optimal frequency of 
assessments as outlined below due to unavoidable resource limitations, and despite best 
efforts, will not constitute a protocol deviation. 


2018 Ebola MCM RCT Protocol 
Page 31 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
Schedule of Evaluations (see also Table 2 below) 
The day when the subject is enrolled and randomized to their assigned treatment arm is denoted 
as Study Day 1. The first day after randomization is Study Day 2. Subsequent days will be 
numbered chronologically through Day 58 of study. For each investigational agent being 
evaluated a unique schedule of assessments will be developed. The schedule of assessments will 
be harmonized across comparisons to provide the longitudinal data collection. Patients who 
agree to extended follow-up through Day 58 to help characterize potential late-onset symptoms, 
evidence of possible virologic relapse, or other clinical changes will either be seen in person or 
contacted via phone as permitted. If necessary, and with the patient’s verbal consent at the time 
they agree to this extended follow-up at time of ETU discharge, available medical staff and/or 
records at nearby treatment facilities may be consulted to determine whether the patient has 
recently been seen for any illnesses potentially consistent with any of these late-onset events. 
Performance of this extended follow-up will always remain subject to the patients’ wishes as 
well as the logistics and feasibility of being able to contact individual participants following 
discharge. 
 


2018 Ebola MCM RCT Protocol 
Page 32 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Table 2. Schedule of Evaluations (subject to individual site capabilities) 
 Evaluation / Procedure 
Screen 
Baseline 
Follow Upf 
Day +/- Window −1 to 1a 
1 
2 
3 
4 
5 
6 
7 
8 
9+ while 
hospitalized 
28±7 
58±7 
ELIGIBILITY/RANDOMIZATION 
  
  
  
  
  
  
  
  
  
  
  
  
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
Demographics and medical historyb 
X 
  
  
  
  
  
  
  
  
  
  
  
Ebola RT-PCR from blood with CT 
-3 to 1 
  
  
  
  
  
  
  
  
  
  
  
Randomize subject 
  
X 
  
  
  
  
  
  
  
  
  
  
STUDY DRUG ADMINISTRATION f 
  
  
  
  
  
  
  
  
  
  
  
  
ZMappTM (if randomized to receive ZMappTM) 
  
X (Day 1 if possible) 
  
+ 3 days 
from 1st dose 
  
+ 3 days 
from 2nd 
dose 
  
  
  
remdesivir (if randomized to receive remdesivir) 
 
Loading dose on Day 1 followed by 9 to 13 days of once-daily maintenance 
dosing.e 
 
 
MAb114 (if randomized to receive MAb114) 
 
Single infusion of 50mg/kg on Day 1 
 
 
REGN-EB3 (if randomized to receive REGN-EB3) 
 
Single infusion of 150mg/kg on Day 1 
 
 
MINIMUM STUDY PROCEDURESc (only obtained while in treatment unit) 
 
Vital signs and weight (actual or estimated) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record of oSOC 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Assessment of current symptoms/conditions, 
including AEs/SAEs 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ebola RT-PCR from blood with CTd 
X 
X 
 X 
X 
  
X 
Then every 2-3 days 
until negative x 2 
 
 
Creatinine, Potassium, Sodium 
X 
X 
 X 
X 
 X 
X 
X 
  
  
AST/ALT 
X 
X 
X 
X 
X 
X 
X 
 
 
Malaria status 
X 
 
 
 
 
 
 
 
 
OPTIMAL (Optional) STUDY PROCEDURES (In addition to the above. May include any or all of the below) 
 
CBC with differential 
  
X 
X 
X 
X 
X 
X 
X 
X 
Daily 
X 
X 
Ebola RT-PCR from blood with CT 
  
X 
X 
X 
X 
X 
X 
X 
X 
until 2 negatives 
X 
X 
Metabolic Panel 
  
X 
X 
X 
X 
X 
X 
X 
X 
Daily 
X 
X 
Hepatic Panel 
  
X 
X 
X 
X 
X 
X 
X 
X 
Daily 
X 
X 
Lactate 
  
X 
X 
X 
X 
X 
X 
X 
X 
Daily 
X 
X 
Albumin 
  
X 
X 
X 
X 
X 
X 
X 
X 
Daily 
X 
X 
ionized Calcium 
  
X 
X 
X 
X 
X 
X 
X 
X 
Daily 
X 
X 
PT / aPTT / INR 
  
X 
X 
X 
X 
X 
X 
X 
X 
Daily 
X 
X 
D-Dimer (and/or fibrinogen if available) 
  
X 
X 
X 
X 
X 
X 
X 
X 
Daily 
X 
X 
Urinalysis, dipstick 
  
X 
X 
X 
X 
X 
X 
X 
X 
Daily 
X 
X 
Serum or urine pregnancy test 
  
X 
 
 
 
 
 
 
 
 
 
X 


2018 Ebola MCM RCT Protocol 
Page 33 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Stored plasma, serum specimens 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Semen for Ebola viral RNA testing 
 
 
 
 
 
 
 
 
 
 
X 
X 
Pharmacokinetic sample (when possible) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CK-MB 
X 
 
 
 
 
 
 
 
 
 
 
 
a. 
All efforts should be made to screen, randomize, and initiate treatment as soon as a diagnosis has been made. 
b. It is the intent that a standardized CRF capturing expected disease symptoms will be completed at baseline and on each day that will guide the 
physician at bedside to conduct a consistent focused physical exam and history throughout the patient’s ETU stay. 
c. 
We will follow the minimal/optional laboratory assessments noted but will not interrupt study drug administration or make dose adjustments based 
on the results given the significant mortality associated with untreated (and likely partially treated) Ebola and the possible contribution of Ebola 
infection itself to these abnormalities. Also, the frequency and volume of blood draws is always subject to the clinical judgment of the site 
investigator as to safety and logistical considerations, and hence an inability to obtain the minimal laboratory assessments on a given day due to 
clinical or other extenuating circumstances will not constitute a protocol deviation. 
d. Ebola RT-PCR from blood with quantitative CT should be performed on Study Days 1, 2, 3, 4, 5, 6, 8, 10, 14, and 28. As above, inability to obtain 
this testing on a given day due to clinical or other extenuating circumstances will not constitute a protocol deviation. 
e. 
The recommended remdesivir dosing duration is a total of 10 days, but once-daily maintenance dosing may be continued for an additional 4 days if 
Ebola viral load remains detectable in blood at Day 10 of treatment. 
f. 
Following the completion of formal accrual into the RCT, an Extension Phase of the protocol will begin during which randomization to the 
treatment arms will continue but the data collected will not count towards the primary endpoint. For a listing of the abbreviated data to be collected 
during the Extension Phase, see Section 14.0 of the protocol. Only MAb114 and REGN-EB3 will be used in the Extension Phase. 
 
 


2018 Ebola MCM RCT Protocol 
Page 34 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
Screening and Informed Consent 
The investigator or a qualified and previously designated member of the study team will review 
informed consent with the subject. If a subject is incapable of reading the informed consent, the 
study will be explained in the local language preferred by the subject. Each consent will be 
witnessed, and the witness will also sign the informed consent. Each consent will include the 
date signed. A separate participant consent is required for a neonate born to a female study 
participant in order to enroll the neonate. The informed consent process will occur on or before 
Day 1. 
 
Demographics 
The following information should be recorded from the participant or surrogate: 
• Age 
• Sex 
• Ethnicity  
• Race 
• Country of birth 
• Contact information for patient and patient’s family 
 
Medical History 
The following information should be recorded: 
• Focused medical history regarding EVD, including all prior RT-PCR results if known 
• Current symptoms  
• Current participation in any recent research protocols 
 
Clinical Data  
• Vital signs (temperature, heart rate, respiratory rate, blood pressure) with oxygen 
saturation as possible  
• Weight (actual or estimated) 
 
Determination of Eligibility 
Once the screening evaluation is complete, eligibility will be determined based on the inclusion 
and exclusion criteria. Subjects that are found to be ineligible will be informed during the 
screening evaluation, and the reason for ineligibility will be discussed.  
 
Day 1 
 
Baseline Evaluation 
Within 24 hours prior to randomization, a baseline clinical evaluation will be performed with 
documentation of current targeted symptoms (below) and significant comorbid/pre-existing 
clinical conditions including vital signs. 
The list of targeted symptoms and signs to assess includes: fever, cough, mental state change, 
hearing loss, vision loss, headache, vomiting, diarrhea, abdominal pain, shortness of breath, 
hiccups, rash, edema, conjunctival injection, convulsions, and hemorrhage. 


2018 Ebola MCM RCT Protocol 
Page 35 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
Baseline Laboratory Testing 
When possible, the following tests will be performed and recorded as baseline determinations. 
Baseline laboratory testing shall be performed within 24 hours of study entry (randomization).  
5.5.2.1 
Minimum Baseline Requirements: 
• Creatinine 
• Potassium 
• Sodium 
• AST/ALT 
• Malaria test 
• Ebola virus RT-PCR with CT from blood sample 
o Although any positive Ebola virus RT-PCR from blood collected up to 3 days 
prior to informed consent provides eligibility, a baseline specimen should be 
collected on Day 1 if the prior specimen was collected >24 hours, as the viral load 
may have substantially changed. Baseline blood for RT-PCR will be collected for 
all neonates before study drug initiation, but results are not needed for eligibility 
as described in Section 4.4.2. 
o If a patient is a recent Merck rVSV-ZEBOV vaccine recipient (within 5 days prior 
to RT-PCR testing) then it is possible that a positive RT-PCR test for GP only 
could be due to GP expression from the VSV viremia that results from 
vaccination rather than to true Ebola infection. In such cases a secondary 
confirmatory test using a different Ebola gene target (e.g., NP gene) will be 
needed in order to document acute Ebola infection.  
5.5.2.2 
Optimal Baseline Laboratories 
• CBC with differential 
• Acute/hepatic/mineral chemistry panels as available via POC testing, defined as: 
o Metabolic Panel = Na, K, Cl, HCO3, blood urea nitrogen, creatinine, glucose, Ca, 
Mg 
o Hepatic Panel = AST/SGOT, ALT/SGPT, Alkaline phosphatase, t-Bilirubin 
o Lactate 
o Albumin 
o ionized Calcium 
• Ebola RT-PCR with CT and/or quantitative copies/mL from blood 
• PT/aPTT/INR 
• D-Dimer (and/or fibrinogen if available) 
• Urinalysis, dipstick 
• Serum or urine pregnancy test (females of childbearing potential only) if available as 
POC 
• Specimen storage if possible 
• CK-MB 


2018 Ebola MCM RCT Protocol 
Page 36 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
Randomization 
A randomization scheme will be generated by the Data Management Center prior to the initiation 
of the study. Randomization occurs on Day 1 with the site communicating with the regional 
operations center for the randomization. Randomization will only occur when a given individual 
has met all of the eligibility criteria as outlined above, including determination of their baseline 
PCR results necessary for stratification (see exception for neonates above). 
 
Study Drug Administration and Pharmacokinetic Sampling 
It is possible that Study Day 1 may be consumed by longitudinal determination of a patient’s 
overall clinical status, implementation of oSOC provisions, assessment for study eligibility, 
study randomization, and other exigencies. Therefore, while not preferable, it is possible that 
actual administration of the investigational study intervention (as part of the assigned treatment 
arm) might need to be deferred until Study Day 2. Refer to the Pharmacy SOP for specific 
administration details of each product. 
 
Pharmacokinetic Sampling 
Although not feasible in most settings, for those interventions where additional PK sampling 
may be of value and where sample processing can be performed safely and serial samples stored 
appropriately according to Select Agent regulations, as locally possible:  
• Collection of baseline drug level prior to assigned treatment intervention 
• Initiation of serial PK blood draws whose frequency and duration (24-48 hours) will be 
guided by anticipated PK profile based upon preclinical data. 
 
Follow-Up Study Days 
The plan for study drug administration, clinical assessments, and lab monitoring are outlined in 
the Schedule of Evaluations. Details on assessments are as follows:  
 
Follow-up Daily Assessment and oSOC 
This will include documentation of: 
• Current symptoms or conditions, including identification of any new or worsening 
(S)AEs compared to baseline or last prior status, focusing on: 
o targeted symptoms (above list) 
o organ dysfunction, failure, or possible drug toxicity 
o known or suspected study agent toxicities  
• Vital signs  
• oSOC received 
• Study agent administration, as applicable 
• Laboratory (as performed) 
• Urinalysis (as performed, optional) 
• Imaging and fluid resuscitation (as performed, optional) 
• Discharge/Outcome information, as appropriate 


2018 Ebola MCM RCT Protocol 
Page 37 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
Clinical Safety Laboratory Testing 
5.7.2.1 
Minimum Requirements 
The required minimum safety laboratory testing is as follows. For the frequency of this required 
testing, refer to the Schedule of Evaluations in Section 5.3. While every effort should be made to 
obtain these laboratories per the above schedule, note that the frequency and volume of blood 
draws is always subject to the clinical judgment of the site investigator as to safety and logistical 
considerations. Hence any inability to obtain the minimal laboratory assessments on a given day 
due to clinical or other extenuating circumstances will not constitute a protocol deviation. 
• Creatinine 
• Potassium 
• Sodium 
• AST/ALT 
• Ebola virus RT-PCR with CT from blood 
• Malaria test 
5.7.2.2 
Optimal Daily Laboratory Monitoring 
Refer to Schedule of Evaluations (Table 2) in Section 5.3. Testing should be performed during 
hospitalization and thereafter additionally as clinically indicated: 
• CBC with differential 
• Chemistry panels as available via POC testing 
• Ebola virus RT-PCR with CT from blood 
o After two negative Ebola virus RT-PCRs in blood, at least 24 hours apart, testing 
may be discontinued if consonant with local ETU testing policy. 
o Consideration of other bodily fluid sampling as clinically appropriate 
o Date of first RT-PCR negative result in blood 
• PT/aPTT/INR 
• D-Dimer (and/or fibrinogen if available) 
• Urinalysis, dipstick 
• Specimen Storage 
• CK-MB 
 
 
Special Follow-up Assessments 
 
Day of Discharge 
Additional information will be obtained on the day of discharge regarding the criteria for 
discharge and negative Ebola virus RT-PCR testing prior to discharge. 
 
Day 28 
As the primary endpoint is 28-day mortality, the Day 28 assessment provides the essential data 
needed for determining this endpoint. Accordingly, all efforts should be made to ensure the 
timely collection of data for this timepoint.  


2018 Ebola MCM RCT Protocol 
Page 38 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
Day 58 
Effort should be made to conduct a study visit or telephone contact at Day 58 whenever possible. 
Minimum and optional procedures for this visit are outlined in Table 2. 
 
Pregnancy 
As noted previously, whenever possible efforts will be made to follow any pregnant women 
enrolled into this study through delivery or end of pregnancy, for the express purpose of 
evaluating any reproductive impacts of study participation. 
 
Extended Follow-Up 
Under the auspices of a separate protocol yet to be developed and approved, survivors of EVD 
enrolled in this study may be contacted later either in person or by telephone to answer questions 
according to a special case report form dedicated to eliciting a history of signs or symptoms 
potentially consistent with late onset of a virologic relapse, possibly with a particular focus on 
ocular or neurologic symptoms (i.e., that may represent re-emergence of virus from a CNS 
source). 
6 
STATISTICAL CONSIDERATIONS 
 
Design overview 
This is a randomized platform trial of candidate Ebola therapies, as described above. Brief 
background about the two options is described here. Figure 1 provides a study schema of the 
design.  
 
As discussed above, results about ZMapp from PREVAIL II were promising, but not definitive 
at the traditional levels of evidence. Mortality rates were 37% and 22% (2-tailed p=0.18) for the 
oSOC and ZMapp arms respectively (25). NHP models showed a survival benefit (29). These 
results, in combination with concerns about the high mortality rate from EVD, have led many to 
conclude that ZMapp must be provided as a control treatment, at least until additional data is 
accrued. This was the reasoning for the DRC decision to select Option 1 for the current outbreak 
in the DRC. However, to anticipate the possibility that other options might be preferred in 
different countries or outbreaks, Option 2 is also included. Details about Option 2 will require 
further development, discussion, an approved protocol amendment, and possibly a different 
protocol and trial governance structure prior to implementation. See Section 1.2 for more details 
about the design rationale for DRC. 
 
Less strict error rate control 
Most clinical trials that intend to provide definitive evidence opt for strict control of the two-
tailed type 1 error rate at level 0.05, with adjustments for multiple comparisons of arms. This 
necessitates larger sample sizes to ensure high power. The current circumstances of high 
mortality, intermittent outbreaks, and the need to find effective treatments as quickly as possible 
argue for less austere statistical penalties.  As a result, the current trial will  use  Boschloo’s exact 
two-tailed tests at alpha=0.05 for each pairwise comparison. There will be no multiple 
comparison adjustment for the fact that multiple experimental arms are compared with the 
control. Similar reasoning has been used in other trials. For example, PREVAIL II allowed a 
type 1 error rate somewhat higher than the usual one-tailed level of 0.025, and trials involving 


2018 Ebola MCM RCT Protocol 
Page 39 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
rare cancers have allowed even higher one-tailed type 1 error rates such as 0.10 (26, 27). The 
need for multiple comparison adjustment has always been somewhat controversial. The products 
in this trial are made by different manufacturers, so one could view the comparisons almost like 
separate trials. The argument that no multiple comparison adjustment would be made in separate 
trials becomes even more compelling considering the special circumstances described above for 
this Ebola setting. 
 
Study hypotheses and statistical analysis 
Primary hypothesis 
The primary hypothesis is that the 28-day mortality rate of the investigational arms will be lower 
than that of the control arm. Boschloo’s test will be used to evaluate the primary hypothesis. For 
comparison of a given arm to control, two-tailed tests will be used. Note that an exact procedure 
was chosen in anticipation of early looks with limited numbers. Boschloo’s test was chosen over 
Fisher’s exact test due to less conservative small-sample performance. 
 
Secondary hypotheses 
Heterogeneity of mortality probabilities among antibody arms will be assessed using a global 
chi-squared test and separate pairwise chi-squared tests.  The antibody arms will be deemed 
combinable if the two-tailed p-values from the global and pairwise tests all exceed 0.10. 
 
If the antibody arms are deemed combinable using the criteria described above, mortality in the 
combined antibody arm will be compared to that of the DAA arm using Boschloo’s test, as 
described in the primary analysis.   
 
Safety will be evaluated by comparing the proportion of patients with at least one serious adverse 
event (SAE) for each arm relative to the control arm, using Boschloo’s test. Proportions of 
specific SAEs, to include infusion-related events, will be reported. 
 
Viremia hypothesis: Differences in median days to viral clearance will be tested using a rank-
based test, imputing deaths prior to day 28 as the worst ranks, with earlier deaths having a worse 
rank than later deaths.  
 
Propensity score analyses: Because some patients may be too sick to be saved by any treatment, 
principal stratification will be used to evaluate whether treatment effect differs by baseline risk 
of mortality. This risk (or propensity) of death will be evaluated using baseline predictors (e.g., 
CT, symptoms, age). Treatment effects will be evaluated stratifying participants according to 
low- and high-risk. Full details will be provided in the statistical analysis plan. 
 
Differences in mortality by day 14 and day 58 between relevant comparator arms will be tested 
with Boschloo’s test in the manner described for the primary hypothesis. 
 
Time-to-death: A log-rank test comparing time-to-death up to day 28 (and up to day 58) will be 
performed.  
 


2018 Ebola MCM RCT Protocol 
Page 40 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Time-to-discharge: Differences in median days to becoming eligible for discharge will be tested 
using a rank-based test, imputing deaths prior to day 28 as the worst rank, with earlier deaths 
having a worse rank than later deaths. Note that discharge decisions may not always be based on 
objective clinical data. For example, during PREVAIL II, some patients were not discharged if a 
caseload was low and a relative was still under current treatment at the ETU. For these reasons, 
time to meeting criteria for discharge will be analyzed rather than time to actual discharge. 
  
Proportions of patients with delayed onset of clinical symptoms possibly consistent with 
virologic relapse or drug toxicity within 58 days of enrollment will be summarized with 
descriptive statistics and 95% confidence intervals. 
 
Ease of preparation and administration of investigational products will be summarized according 
to mean preparation and infusion times for each arm, with 95% confidence intervals. 
 
Power and sample size 
The sample size will be 725 participants in total, with approximately 170 enrolled in the REGN-
EB3 arm and 185 enrolled in each of the ZMapp, MAb114 and remdesivir arms.  This target is 
updated in this protocol (version 4.0) to increase power for smaller effect sizes as outlined in 
Table 4.  
Comparisons will be made between each experimental arm and the ZMapp+oSOC control,using 
a two-sided type I error rate of 0.05. The initial mortality rate of 30% was based, in part, on a 
meta-analysis of eight clinical studies conducted during the 2014-2016 West African Ebola 
outbreak. This analysis indicated that the mortality rates within PREVAIL II were lower than 
other studies across both treatment and control arms. Hence, we expect the mortality rate with 
ZMapp may be higher than the point estimate from PREVAIL II, which was 22%. Table 3 gives 
sample sizes for 80%, 85%, and 90% power, and  
 
Deleted:


2018 Ebola MCM RCT Protocol 
Page 41 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Table 4 gives power for sample sizes of 125, 170 vs 185 and 185 per arm for various mortality 
rates in 2 arms (ZMapp vs 1 experimental arm).  
 
 
Deleted:


2018 Ebola MCM RCT Protocol 
Page 42 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
Table 3. Sample sizes for 80%, 85%, and 90% power for two-sided 0.05 level Boschloo 
exact tests for 20%, 40%, and 50% reductions relative to that of the oSOC plus ZMapp 
control. 
True mortality rates 
Sample size 
per arm: 
80% Power 
 
Sample size 
per arm: 
85% Power 
 
Sample size 
per arm: 
90% Power 
 
Control 
arm 
New 
experimental 
arm 
Relative 
reduction 
0.5 
0.4 
20%
392 
449 
520 
0.5 
0.3 
40%
95 
109 
127 
0.5 
0.25 
50%
60 
66 
78 
0.4 
0.32 
20%
570 
651 
758 
0.4 
0.24 
40%
135 
154 
181 
0.4 
0.2 
50%
84 
94 
112 
0.3 
0.24 
20%
870 
995 
1160 
0.3 
0.18 
40%
203 
230 
269 
0.3 
0.15 
50%
122 
139 
165 
0.2 
0.16 
20%
1465 
1676 
1954 
0.2 
0.12 
40%
341 
382 
445 
0.2 
0.1 
50%
205 
232 
271 
 
 
 


2018 Ebola MCM RCT Protocol 
Page 43 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Table 4. Power for sample sizes of 125 per arm, 170 REGN vs 185 ZMapp, and 185 per 
arm (for comparisons of ZMapp with either mAb114 or Remdesivir) for two-sided 0.05 
level Boschloo exact tests for 20%, 40%, and 50% reductions relative to that of the oSOC 
plus ZMapp control. 
True mortality rates 
125 per arm 
170  REGN-EB3 
185 ZMapp  
Control 
arm 
New 
experimental 
arm 
Relative 
reduction 
185 per arm (for 
comparisons of 
ZMapp with 
either mAb114 
or Remdesivir) 
0.5 
0.4 
20% 
35% 
46% 
48% 
0.5 
0.3 
40% 
90% 
97% 
98% 
0.5 
0.25 
50% 
98% 
>99% 
>99% 
0.4 
0.32 
20% 
26% 
34% 
35% 
0.4 
0.24 
40% 
78% 
90% 
91% 
0.4 
0.2 
50% 
94% 
99% 
99% 
0.3 
0.24 
20% 
18% 
23% 
24% 
0.3 
0.18 
40% 
60% 
75% 
76% 
0.3 
0.15 
50% 
81% 
92% 
93% 
0.2 
0.16 
20% 
12% 
16% 
16% 
0.2 
0.12 
40% 
39% 
52% 
54% 
0.2 
0.1 
50% 
58% 
74% 
76% 
 
Interim monitoring  
Interim efficacy monitoring: Interim monitoring  will use symmetric upper and lower 
boundaries for comparisons of a given arm to the control.  The O’Brien-Fleming alpha-spending 
procedure will truncate boundaries at a one-sided type I error rate of 0.001. Four interim looks 
(including the final analysis) are planned, roughly corresponding to endpoint data from 33, 65, 
100 and full enrollment (170 REGN-EB3 and 185 in each of the other 3 arms). The upper 
boundaries for the z-scores at these looks are 3.09, 3.09, 3.09, and 1.98. The timing of analyses 
might change depending on the size of the outbreak. A separate DSMB guidance document will 
be developed to address such issues as adding new therapeutics, changing the control group, 
dropping therapeutics due to futility, and sample size adjustments. 
 
Table 5 shows the numbers of deaths by day 28 in each arm to cross a boundary at the first 
interim analysis with 20 patients per arm. For example, if 8 out of 20 die within 28 days in one 
arm, and no-one dies by day 28 in the other arm, the boundary is crossed. The boundary is also 
crossed if there are 12 deaths by day 28 in one arm and 2 deaths or fewer in the other arm. 
 
 


2018 Ebola MCM RCT Protocol 
Page 44 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Table 5. Numbers of deaths by day 28 in each arm to cross the boundary at the first 
interim analysis with 20 patients per arm. 
 
Number of deaths out of 20 in one arm 
Number of deaths out of 20 in the other arm 
8 
0 
9 
0 
10 
1 or fewer 
11 
1 or fewer 
12 
2 or fewer 
13 
3 or fewer 
14 
4 or fewer 
15 
4 or fewer 
16 
6 or fewer 
17 
7 or fewer 
18 
8 or fewer 
19 
10 or fewer 
20 
12 or fewer 
 
 
Conditional power: Conditional power will be calculated under various assumptions about the 
treatment effect for future data. A rough guideline for futility is a conditional power of under 
20%, computed under the original assumption of a 50% relative reduction in mortality. Details 
about these calculations and the resulting boundaries will be provided in a statistical analysis 
plan and a DSMB guidance document. These calculations and boundaries are advisory, and the 
DSMB will consider them along with the totality of evidence when making recommendations. 
 
Final Analysis Plan: A data analysis plan developed and approved by all partners for evaluating 
the study endpoints will be formulated and presented to the DSMB for review and approval prior 
to locking of the study database and unblinding of the investigators before the first interim 
analysis. 
7 
RISKS AND BENEFITS 
 
Potential Risks  
 
Unknown Risks  
In addition to the underlying EVD itself, the primary risks to participants are due to study 
interventions whose human safety profile is very early and evolving in most cases. Animal 
and/or early/first in human clinical trials are ongoing, and changes to the risk/benefit profile for 
study interventions are anticipated during the course of this study. Known toxicity profiles of the 
included agents are summarized in the appendices. Safety profiles, risks, and other information 
relevant to participants decision to continue or to enroll in the study will be updated and provided 
under guidance of human subject protection oversight bodies and per regulatory bodies, 
requirements and guidance. The study may itself generate information that is relevant to human 
subjects, which will be provided under appropriate guidance standards and entities. Relevant 


2018 Ebola MCM RCT Protocol 
Page 45 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
current risks, to the degree they are known or reasonably suspected, have been outlined in the 
informed consent/assent documents. 
 
Risks of Phlebotomy 
The primary risks of phlebotomy include local discomfort, occasional bleeding or bruising of the 
skin at the site of needle puncture, hematoma and, rarely, infection or fainting. Because ongoing 
clinical care of participants may require frequent blood draws independent of actual study-related 
assessments, it will be important that study teams ensure that research blood draws do not exceed 
the guidelines set forth by each institution’s safety regulations.  
 
Risks to the Study Personnel and the Environment 
The principal risk for study personnel is exposure in the clinical setting to infectious pathogens 
from study subjects through various contact mechanisms (e.g., needlestick or mucous membrane 
exposure to blood borne pathogens or infected bodily fluids). Adherence to mandatory hygiene 
practices and infection control practices, including consistent and appropriate use of PPE, for 
working with patients infected with Ebola is of absolutely paramount importance throughout the 
conduct of this trial. Any perceived break in those practices must be reported immediately to the 
appropriate supervisory authorities in each institution per established algorithms. 
 
Potential Benefits 
There is no definite expectation of benefit to participants or to society at large. However, the 
agents planned for investigation in this study are all thought to have some potential to offer 
benefits to individual subjects, based upon previous pre-clinical and, in some cases, clinical 
investigation. Hence, while the potential benefits, if any, of a given medical intervention are 
presently unknown, it is possible that one or more interventions may subsequently be shown to 
offer evidence of a greater reduction in morbidity and mortality than that usually provided by 
oSOC alone. This may be manifested by a reduction in the length or the severity of disease, 
which may be life-saving in some cases given the nature of Ebola infection. If this is so, it is 
quite possible that this evidence will be suggestive, but not definitive, at this early stage of 
testing. However, even if no experimental treatment intervention is shown conclusively to 
provide this benefit, the knowledge gained from their study will provide important information 
that should help better inform what role such interventions should or should not play as 
adjunctive treatments in managing this disease. Thus, it is possible that both positive and 
negative results will help inform rapidly evolving treatment paradigms, and thus may offer a 
societal benefit.  
 
Alternatives 
The alternative to participating in this protocol is not to participate and to receive access either to 
supportive care measures alone or to experimental therapies available through MEURI or other 
similar mechanism in a non-participating ETU. 
8 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, AND DATA 
 
Intended Use of the Samples/Specimens/Data 
Samples and data collected under this protocol may be used to determine the interventional agent 
safety and efficacy, anti-viral effects, development of anti-drug antibodies, effects on immune 


2018 Ebola MCM RCT Protocol 
Page 46 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
response, pharmacokinetics, and related characterizations. Viral specific items of interest 
include: diagnostics and viral pathogenesis. 
 
Storage of Samples/Specimens/Data  
It is understood that blood, other bodily fluids, and tissue samples from this protocol will 
potentially be of great value in advancing our knowledge both of EVD pathogenesis and the 
treatment effects of investigational countermeasures. The first priority for samples collected in 
this study is to complete analyses outlined in this protocol. Accordingly, when possible, serial 
samples from the enrolled patients that may help address these important questions in Ebola 
research will be collected and stored. As part of this, reliable long-term storage in facilities 
capable of storing such samples safely and under appropriate storage conditions (e.g. having 
secure access, monitored freezer units, connection to a reliable electrical grid, etc.) will be 
arranged. Samples obtained in this study must adhere to national regulations for long term 
storage. Any export of samples outside of DRC will necessitate approval from the Ministry of 
Health of DRC.   
For any potential U.S. sites for sample storage, CDC regulations govern the storage of blood 
obtained from patients infected with Select Agents in other than BSL-4 containment facilities, 
which specifically require documentation of destruction of potentially infectious samples after 
more than 7 days’ time according to established CDC guidelines. Whenever possible, sites which 
have access to a secure BSL-4 laboratory repository should attempt to transfer samples to that 
repository for longer-term storage according to approved shipping regulations applicable to 
select agents. 
In the future, other non-protocol investigators (both locally in the affected countries, at NIH, and 
at other research centers) may wish to study these samples and/or data. In that case, IRB/ERB 
approval must be sought prior to any sharing of samples and/or data. Any clinical information 
shared about the sample with or without patient identifiers would similarly require prior 
IRB/ERB approval. 
The research use of stored, unlinked or unidentified samples from any US site may be exempt 
from the need for prospective IRB review and approval. Exemption requests will be submitted in 
writing to the NIH Office of Human Subjects Research, which is authorized to determine 
whether a research activity is exempt. 
 
Reporting Loss or Destruction of Samples/Specimens/Data  
Any loss or unanticipated destruction of locally maintained samples (for example, due to freezer 
malfunction) or data (for example, misplacing a printout of data with identifiers) that meets the 
definition of a protocol deviation, unanticipated problem, and/or compromises the scientific 
integrity of the data collected for the study, will be reported to the institution’s IRB or 
recognized ERB and to the protocol team. 
9 
REMUNERATION PLAN 
In general, subjects will not be compensated for the time and inconvenience of active study 
participation, including for any outpatient assessments that may occur within the first month 
following hospital discharge. However, individual participating institutions may choose to offer 


2018 Ebola MCM RCT Protocol 
Page 47 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
partial compensation for time and transportation costs associated with extended follow-up 
assessments. 
10 
ASSESSMENT OF SAFETY 
Regulatory requirements, including FDA regulations and ICH Guideline for Good Clinical 
Practice, set forth safety monitoring and reporting responsibilities of Sponsors and Investigators 
to ensure the safety and protection of human subjects participating in clinical trials.  
 
Definitions  
Adverse Event (AE): An AE is any untoward or unfavorable medical occurrence in a human 
subject, including any abnormal sign (e.g., abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the subject’s participation in the research, 
whether or not considered related to the research. 
 
Adverse Reaction: An AE that is caused by an investigational agent (drug or biologic). 
 
Suspected Adverse Reaction (SAR): An AE for which there is a reasonable possibility that the 
investigational agent caused the AE. “Reasonable possibility” means that there is evidence to 
suggest a causal relationship between the drug and the AE. An SAR implies a lesser degree of 
certainty about causality than AR, which implies a high degree of certainty. 
 
Serious Adverse Event (SAE): An SAE is an AE that results in one or more of the following 
outcomes: 
• death 
• a life-threatening event (places the participant at immediate risk of death from the event 
as it occurred) 
• an inpatient hospitalization or prolongation of an existing hospitalization 
• a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• a congenital anomaly/birth defect or fetal loss/miscarriage 
• a medically important event* 
*Medical and scientific judgment should be exercised in deciding events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed above. 
 
Unexpected Adverse Event: An AE is unexpected if it is not listed in the investigator’s 
brochure or package insert (for marketed products) or is not listed at the frequency, specificity or 
severity that has been observed. It is the responsibility of the IND sponsor to make this 
determination. 
 
Serious and Unexpected Suspected Adverse Reaction (SUSAR): A SUSAR is an SAR that is 
both serious and unexpected. 
 
Unanticipated Problem (UP): A UP is any event, incident, experience, or outcome that is 


2018 Ebola MCM RCT Protocol 
Page 48 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
1. unexpected in terms of nature, severity, or frequency in relation to 
a. the research risks that are described in the IRB-approved research protocol and 
informed consent document, Investigator’s Brochure, or other study documents; and 
b. the characteristics of the participant population being studied; and 
2. possibly, probably, or definitely related to participation in the research; and 
3. places participants or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized. (Per the IND 
sponsor, an AE with a serious outcome will be considered increased risk.) 
Unanticipated Problem that is not an Adverse Event (UPnonAE): A UP that does not fit the 
definition of an AE, but which may, in the opinion of the investigator, involve risk to the 
participant or others, or significantly impact the integrity of research data. For example, we will 
report occurrences of breaches of confidentiality, overdose, accidental destruction of study 
records, or unaccounted-for study drug. 
 
Protocol Deviation: A protocol deviation is defined as any change, divergence, or departure 
from the IRB approved study procedures in a research protocol. Protocol deviations are 
designated as serious or non-serious and further characterized as 
1. Those that occur because a member of the research team deviates from the protocol. 
2. Those that are identified before they occur, but cannot be prevented. 
3. Those that are discovered after they occur 
 
Serious Protocol Deviation: A deviation that meets the definition of an SAE or compromises 
the safety, welfare or rights of subjects or others. 
 
Non-compliance: The failure to comply with applicable NIH HRPP policies, IRB or ERB 
requirements, or national and international regulatory requirements for the protection of human 
subjects. Non-compliance is further characterized as 
1. Serious: Non-compliance that 
a. Increases risks, or causes harm, to participants 
b. Decreases potential benefits to participants 
c. Compromises the integrity of the NIH-HRPP 
d. Invalidates the study data 
2. Continuing: Non-compliance that is recurring 
3. Minor: Non-compliance that, is neither serious nor continuing. 
 
Assessment of Safety 
The primary purpose of safety data collection in a putative therapeutic study is to permit 
monitoring for the safety of those enrolled, and to gather data on study interventions to 
inform use and to protect other current and potential future users of the study-agents.   
The study population will generally be in hospital or will present due to symptoms of one of the 
most fulminant and deadly infections known. Signs and symptoms of Adverse Events are likely 
to progress through grade levels, and may achieve seriousness criteria in minutes to hours in 
many cases. This may occur prior to any study specific/investigational treatment. The highly 
infectious nature of the disease and characteristics of treatment facilities and the need to protect 


2018 Ebola MCM RCT Protocol 
Page 49 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
health care providers will each add layers of unavoidable challenge to the assessment and care 
process and to study activities.   
The above factors will limit, within reason, and for good cause, the nature and timing of 
data collected and reported for safety.   
Every attempt will be made to document the nature [name/type] and the severity [grade per 
DAIDS toxicity table version 2.1, July 2017] of conditions present at baseline, particularly as 
pertains to the status of Ebola infection and vital organ function, so that meaningful data can be 
collected on the safety and efficacy impact of study interventions. It is acknowledged at the 
outset that this effort will likely be incomplete, and there may be unavoidable inconsistencies 
over time and from place to place, due to harsh conditions at treatment/study sites. Nonetheless 
the study team is committed to working with the sponsor safety office and with all stakeholders 
to obtain the most complete and accurate dataset possible. 
Safety event assessment, recording, reporting, and cumulative evaluation will be aimed at 
achieving optimal safety for those enrolled in the study, and in pursuit of study objectives. Every 
attempt will be made to promptly identify relevant toxicity patterns that may require changes to 
the design or the conduct of the study, and to inform the use of these study interventions 
elsewhere.  
The Data Coordinating Center will grade the severity of laboratory values and other events 
according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events Version 2.1, July 2017 
(https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf). The “Common 
Terminology Criteria for Adverse Events (CTCAE)” version 5.0 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) will be used to 
grade drug infusion reactions. 
 
Investigator Assessment of Serious Adverse Events 
The Investigator will evaluate all SAEs with respect to Seriousness and Causality (relationship 
to study agent and relationship to research) as defined below. 
 
Causality  
Causality assessment is based on available information at the time of the assessment of the event. 
The investigator may revise the causality assessment as additional information becomes 
available. The likelihood that the SAE is related to the study agent will be assessed by the 
investigator according to the following simplified categorization. Due to the severity of Ebola 
illness and limitations of an ETU, further detailed breakdown will not occur:  
Reasonable Possibility 
 
• reasonable temporal relationship 
• little evidence for a more likely alternative etiology 
No Reasonable Possibility  
• does not have a reasonable temporal relationship  
OR 
• reasonable evidence for a more likely alternative etiology 


2018 Ebola MCM RCT Protocol 
Page 50 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
Timing and Scope of (S)AE Collection, and of Assessments and of Reporting 
Responsibilities to the Sponsor  
 SAE/AE data collection/recording, assessment/grading, reporting, and cumulative evaluation 
will be conducted/limited as follows: 
 
o At BASELINE, and as close to dosing as is feasible, there will be collection, recording, and 
grading of targeted symptoms and of significant baseline conditions prior to study agent 
administration. 
o BEGINNING AT INITIAL STUDY DOSING, AND DAILY, THROUGHOUT 
INPATIENT STAY there will be collection and recording (based upon both open-ended 
questioning and targeted solicitation) of targeted symptoms (see list), and of significant 
baseline conditions. During this period, ONLY the following SAEs are graded and are 
required to be individually reported to the Clinical Safety Office:  
§ New/worsening events considered unlikely or definitely unrelated to underlying 
Ebola infection, and/or  
§ New/worsening events considered possibly, probably, or definitely related to study 
interventions or to a non-Ebola condition, including any baseline comorbidity that has 
worsened. 
NOTE: ALL SAEs that are reportable per the above two bulleted criteria are to be reported 
to the Clinical Safety Office as follows, by the agreed upon reporting mechanism: 
§ Deaths and Immediately Life Threatening SAEs:   
• By close of the next business day after the day of site awareness. 
§ All other SAEs: 
• By close of the third next business day after the day of site awareness. 
o All other S/AEs (those not subject to the above criteria) that are recorded for the study will 
be included in a MONTHLY cumulative ‘line listing’ and summary report across all subjects, 
in a format to be agreed upon by the study team and the Clinical Safety Office, to enable 
regulatorily compliant safety monitoring of the overall study. 
o The study Principal Investigator, subject to review and confirmation by the Sponsor Medical 
Monitor, will recommend an initial determination of expectedness for all SAEs. 
 
Unanticipated Problems 
An Unanticipated Problem is any event, incident, experience, or outcome that is 
1. unexpected in terms of nature, severity, or frequency in relation to 
a. the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents; 
b. the characteristics of the subject population being studied (persons with life 
threatening Ebola infection); and 
2. possibly, probably, or definitely related to participation in the research; and 
3. places subjects or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized.  


2018 Ebola MCM RCT Protocol 
Page 51 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
Unanticipated Problems must be reported to the Data Coordinating Center and local IRB/ERB as 
per local institutional requirements. Unanticipated problems may include problems with protocol 
implementation, participant safety, and/or concerns regarding informed consent. Initial reports 
must be communicated no later than 7 calendar days of site awareness of the event. 
Report all Unanticipated Problems that are also SAEs on the SAE CRF. 
 
Pregnancy  
Pregnancy itself is not an AE. However, complications of pregnancies are AEs and may be 
SAEs. Any complications that are SAEs will be reported on the SAE CRF within the above 
timelines.  
If obtainable, pregnancy outcome data (e.g., delivery outcome, spontaneous or elective 
termination of the pregnancy) will be recorded on a protocol-specified form. Pregnant 
participants should be advised to notify their obstetrical care provider of study agent exposure, if 
applicable. In the event that the obstetrical care provider requires additional information on the 
pregnant participant, they will be referred to the study team for consultation. 
 
Reporting Procedures to the IRB  
As a general statement, SAEs, serious and non-serious UPs, and deaths will be reported per the 
institutional requirements of each participating entity.  Unanticipated problems, non-compliance, 
and other reportable events will be reported to the NIAID IRB according to Policy 801. 
 
Annual Reporting to the IRB 
• A high level summary of the following events will be reported to the NIAID IRB per 
NIH Policy 801at the time of continuing review: 
 
a. Major and minor deviations 
b. Noncompliance reported to the IRB that is not related to a protocol deviation 
c. Adverse events and serious adverse events (that do not meet the definition of a 
UP). Address if the expected frequency and severity of the events occurred as 
expected, or occurred in a manner that affected the safety assessment (i.e., rose to 
the level of a UP). 
d. UPs reported to the IRB 
• The following items will be reported to all other applicable IRB/ERBs in summary at the 
time of continuing review: 
a. Serious and non-serious UPs.  
b. SAEs that are possibly, probably, or definitely related to the research. 
c. SAEs that are not related to the research. 
d. All collected AEs, except expected AEs granted a waiver of reporting (e.g. the 
large number of AEs expected to be due to the underlying disease and judged not 
attributable to study drug).  
e. Serious and non-serious protocol deviations. Anticipated deviations in the conduct 
of the protocol will not be reported to the IRB unless they occur at a rate greater 
than anticipated by the study team. 
f. Serious, continuing, and minor non-compliance. 


2018 Ebola MCM RCT Protocol 
Page 52 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
g. Any trends or events which in the opinion of the investigator should be reported. 
 
Follow-Up of Serious Adverse Events 
Whenever possible, SAEs that have not resolved by the end of the initial follow-up period will be 
followed until final outcome is known. Pregnancy will be followed up as well as to outcome if 
feasible and if consent has been provided for such. If it is not possible to obtain a final outcome 
for an SAE (e.g., the subject is lost to follow-up), the reason a final outcome could not be 
obtained will be recorded by the investigator on the AE CRF (if the CRF is still open) and the 
SERF.  
 
Sponsor’s Reporting Responsibilities 
Serious and unexpected suspected adverse reactions (SUSARs) as defined in ICH E6 5.17 and as 
determined by the IND Sponsor will be reported to FDA, all participating country regulatory 
authorities, and all participating Investigators as IND Safety Reports. 
The IND Sponsor will also submit an IND Annual Report of the progress of the investigation to 
the FDA and all participating country regulatory authorities as defined in 21 CFR 312.  
AEs that are also UPs will be summarized by the IND Sponsor and distributed to investigators if 
they are relevant to other sites. 
 
Safety Oversight 
 
Investigator Safety Monitoring 
The Investigator or designee may interrupt the administration of study drug to an individual 
subject if indicated for unanticipated problems or SAEs. In addition, the Investigators are 
responsible for: 
• Protecting the safety and welfare of subjects 
• Evaluating subject safety 
• Notifying the sponsor of SAEs and immediately-reportable events 
• Informing the IRB/IEC of SAEs, as per institutional requirements 
 
Sponsor Medical Monitor (SMM) 
A Medical Monitor, representing the IND Sponsor, may be appointed for oversight of safety in 
this clinical study.  
 
Safety Review and Communications Plan 
A safety review and communications plan (SRCP) has been developed for the protocol. The 
SRCP is an internal communications document between the Principal Investigator and the 
Clinical Safety Office, which delineates the safety oversight responsibilities of the Principal 
Investigator, the Clinical Safety Office, and other stakeholders. The SRCP also includes the 
overall plan for conducting periodic safety surveillance assessments. 
 
Data and Safety Monitoring Board (DSMB) 
An independent DSMB with international representation of the host countries participating in the 
trial will review the study no less frequently than twice a year. The DSMB may convene 
additional reviews as necessary, dependent on the rate of subject accrual. The DSMB will review 


2018 Ebola MCM RCT Protocol 
Page 53 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
the study data to evaluate the safety, efficacy, study progress, and conduct of the study. All 
SAEs, all unanticipated problems, and all IND Safety Reports will be reported by the Data 
Coordinating Center to the DSMB at the same time they are submitted to the IRB or IND 
Sponsor. The Principal Investigator will submit the DSMB’s written summary open reports with 
the DSMB’s recommendations to the IRB. A specific DSMB charter will be put in place 
establishing the roles and responsibilities of members after review and approval by the Study 
Steering Committee. 
• The DSMB will monitor safety, efficacy, and quality of trial conduct measures closely 
throughout the trial and may pause enrollment in the event of unanticipated study-related 
deaths or SAEs that are considered study-related.  
• The DSMB will also review the completeness of follow-up and other aspects of study 
conduct.  
• After each meeting they will recommend that the study be continued as planned, 
modified, or terminated. 
11 
CLINICAL MONITORING STRUCTURE 
 
Site Monitoring Plan  
As per ICH-GCP 5.18 and FDA 21 CFR 312.50, clinical protocols are required to be adequately 
monitored by the study sponsor. This study monitoring will be conducted according to the 
“NIAID Intramural Clinical Monitoring Guidelines.” If feasible, monitors under contract to the 
NIAID/Office of Clinical Research Policy and Regulatory Operations (OCRPRO) or their 
designee may visit the clinical research site to monitor aspects of the study in accordance with 
the appropriate regulations and the approved protocol. The objectives of a monitoring visit would 
be: 1) to verify the existence of signed informed consent documents and documentation of the 
Informed Consent Form process for each monitored subject; 2) to verify the prompt and accurate 
recording of all monitored data points, and prompt reporting of all SAEs; 3) to compare data 
abstracts with individual subjects’ records and source documents (subjects’ charts, laboratory 
analyses and test results, medical progress notes, nurses’ notes, and any other relevant original 
subject information); and 4) to help ensure investigators are in compliance with the protocol. The 
monitors also may inspect the clinical site regulatory files to ensure that regulatory requirements 
(Office for Human Research Protections [OHRP]), FDA, and applicable guidelines (ICH-GCP) 
are being followed. During the monitoring visits, the investigator (and/or designee) and other 
study personnel should be available to discuss the study progress and monitoring visit. 
12 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
 
Informed Consent Process 
Informed consent is a process where information is presented to enable persons to voluntarily 
decide whether or not to participate as a research subject. It is an on-going conversation (in a 
language understood by the subject) between the human research subject and the researchers 
about the essential information about the study, which begins before consent is given and 
continues until the end of the subject's involvement in the research. Discussions of essential 
information about the research will include the study's purpose, duration, experimental 
procedures, alternatives, risks, and benefits, and subjects will have the opportunity to ask 
questions and have them answered. 


2018 Ebola MCM RCT Protocol 
Page 54 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Participants over 18 years of age will sign the informed consent document (in a language 
understood by the subject) prior to any procedures being done specifically for the study. The 
signature of a legally acceptable representative of the potential subject will be obtained for adults 
who are impaired and unable to provide informed consent. In the case of adults whose ability to 
consent is uncertain, capacity to consent will be evaluated by the principal or associate 
investigator(s). Parental/guardian permission and minor assent for children through 17 years of 
age will be obtained according to local standards and country-specific requirements. 
The participants may withdraw consent at any time throughout the course of the trial. If possible 
from an infection control standpoint, a copy of the informed consent document will be given to 
the participants for their records. The researcher will document the signing of the consent form in 
the subject’s medical record. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
Due to the biohazard of Ebola virus contaminated documents, special safety provisions must be 
made for how source documents are collected and stored. For example, it may be necessary for a 
photograph or scanned image of the informed consent signature page to be stored as an 
“electronic source document” rather than retaining a paper version. CRFs may also be used as 
source documents under these conditions. 
 
Subject Confidentiality 
All records will be kept confidential to the extent provided by federal, state and local laws in the 
jurisdictions in which the study is conducted. The study monitors and other authorized 
representatives of the Sponsor may inspect all documents and records required to be maintained 
by the Investigator, including but not limited to, medical records. Records will be kept locked 
and all computer entry and networking programs will be done with coded numbers only. Clinical 
information will not be released without written permission of the subject, except as necessary 
for monitoring by IRB, the FDA, the NIAID, the OHRP, the INRB, or the sponsor’s designee. 
13 
DATA MANAGEMENT AND MONITORING 
 
Data Management Responsibilities 
The site investigator is responsible for assuring that the data collected is complete, accurate, and 
recorded in a timely manner. Source documentation (the point of initial recording of information) 
should support the data transferred to the electronic data system and, when possible, should be 
signed and dated by the person recording and/or reviewing the data. All data should be reviewed 
by the Investigator and co-signed as required. 
 
Data Capture Methods 
Study data collected at the bedside at study sites will later be recorded as paper or electronic 
CRFs with subsequent transmission to the Data Coordinating Center. Data Coordinating Center 
personnel shall enter data into an electronic database. Corrections to electronic data systems will 
be tracked electronically (password protected and through an audit trail) with time, date, 
individual making the correction, and what was changed. 


2018 Ebola MCM RCT Protocol 
Page 55 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
Types of Data 
While greatly constrained within the physical setting of an ETU, source documents conceivably 
could include, but not be limited to, the subject’s medical records, laboratory reports, ECG 
tracings, x-rays, radiologist’s reports, subject’s diaries, biopsy reports, ultrasound photographs, 
progress notes, pharmacy records, and any other similar reports or records of procedures 
performed during the subject’s participation in the study. 
 
Source Documents and Access to Source Data/Documents 
Source documents include all recordings of observations or notations of clinical activities, and all 
reports and records necessary for the evaluation and reconstruction of the clinical trial.  
Due to the biohazard of Ebola virus contamination, any original written source documents 
created at the bedside (i.e. in the ‘hot zone’) must be treated as potentially infectious unless an 
effective means of decontamination can be instituted. Where possible, photographs, digital scans, 
or other electronic data capture methods may be obtained instead. 
 
Record Retention 
The protocol team is responsible for retaining all essential documents listed in the ICH Good 
Clinical Practice Guideline. All essential documentation for all study subjects is to be maintained 
by the investigators in a secure storage facility for a minimum of 3 years per NIAID policies or 
per in-country local or federal regulatory requirements (whichever is longer). The FDA requires 
study records to be retained for up to 2 years after marketing approval or disapproval (21 CFR 
312.62), or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational agent for a specific indication. These records are also to be 
maintained in compliance with IRB/EC, state, and federal medical records retention 
requirements, whichever is longest. All stored records are to be kept confidential to the extent 
required by federal, state, and local laws in the jurisdiction in which they are stored. 
 
Data Sharing Plan 
At the completion of the trial, a comprehensive study report will be prepared by the Data 
Coordination Center in concert with the Democratic Republic of Congo and other host countries 
and submitted for review to the DSMB, the FDA, study partners, and all other applicable 
regulatory and health agencies within the affected countries. The relevant primary and secondary 
outcome data from this trial will also be entered into ClinicalTrials.gov for access by other 
researchers. In addition, it is the intention of the extended protocol team that de-identified data 
from this trial will be made available upon request to outside investigators upon scientific review 
of the merits of their proposed research plan. This availability will be in accordance with the 
WHO Joint statement on public disclosure of results from clinical trials. To facilitate this, a 
Presentations and Publications subcommittee (which will include full representation of the DRC 
and any additional countries who may join the study as well as representation from the extended 
protocol team) will be created to receive, review for scientific merit, and, if appropriate, approve 
these requests for use of de-identified data arising from the trial. 
 
Trial Organization 
To be outlined according to the governance model in development.  
 


2018 Ebola MCM RCT Protocol 
Page 56 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
14 
PALM Extension Phase 
On August 9, 2019, the DSMB recommended stopping the PALM RCT and made a 
recommendation for the extension phase to commence with randomization to REGN-EB3 or 
MAb114.   These recommendations were based an interim analysis of 499 participants enrolled 
into the RCT, which revealed that REGN-EB3 crossed an early monitoring boundary for efficacy 
over ZMapp.  The DSMB also noted that mAb114 was close to crossing an early monitoring 
boundary for efficacy relative to ZMapp.  Furthermore, the mortality rates for MAb114 and 
REGN-EB3 were not statistically significantly different, justifying the continued randomization 
to these two therapies.   The final PALM RCT cohort will include 681 participants, the number  
enrolled up until the DSMB recommendation,  
 
While these results were strong enough to recommend immediate changes to the PALM RCT, 
the final analysis must wait until the primary outcome data have been collected on the remaining 
participants and the database has been locked, which could take 6-8 weeks.   During this period, 
the PALM Extension Phase will continue to randomize participants in order to generate 
additional safety and efficacy data related to these two therapies that may further inform the 
appropriate use of these investigational products. No formal hypothesis tests are planned.  
Confidence intervals on the 28-day mortality differences between the two arms will be 
computed.    
 
   
 
The PALM study team will continue to consent and randomize new cases of EVD to the 
remaining investigational treatments during the PALM Extension Phase of the trial. This phase  
will continue until the following conditions have BOTH been met: 
• study outcomes have been released and  
• a new revised treatment plan for future management of EVD, if needed, has been 
designed, approved, and implemented by the medical and regulatory authorities based 
upon those outcomes. It is expected that this revised plan will be formulated and 
communicated very quickly once the RCT outcomes are known. 
 
Depending upon those outcomes, for example,  
• a revised prioritization of the existing study drugs may be needed 
• combination therapies may be considered 
• other treatment strategies may be adopted 
 
During this Extension Phase, the existing stratification and randomization algorithm to determine 
treatment assignments (i.e. using hard-copy envelopes distributed to sites) of the present RCT 
will continue to be followed; HOWEVER two possible exceptions may apply: 
• not all drugs may be available at all times, in sufficient quantity, to support this, or 
• the DSMB, which will continue to monitor the PALM Extension,  may recommend that 
one of the two arms be stopped. 
 
 
There is a strong rationale for continuing to enroll and randomize new EVD patients during this 
Extension Phase: 


2018 Ebola MCM RCT Protocol 
Page 57 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
• The support that the RCT has been providing to the overall outbreak response, and to the 
ETUs in particular, has been viewed as critical to their ongoing operations and should be 
continued if possible. 
• It will be less disruptive for sites to continue the current enrollment process in which they 
have already been trained rather than switch back to a compassionate release (MEURI) 
drug allocation process. 
• Continued oversight of the trial by the current DSMB during the Extension Phase will 
provide an additional layer of safety to the provision of investigational agents to this 
vulnerable patient population. 
• Equipoise on the part of site investigators for the two study drugs will continue based on 
similar results during the interim analysis. 
• The Extension Phase will tend to make optimal use of the existing RCT infrastructure 
(data collection, data management, pharmacy support, etc.) already in place at the ETUs 
• Continuing the RCT enrollment process will facilitate more rapid transition to a new 
RCT if a decision to launch a new investigational study (e.g. a combination drug study) is 
undertaken based upon the RCT results. 
• The additional data collected about the study drugs during the Extension Phase will 
continue to contribute significant additional information to the overall efficacy and safety 
profiles of these agents that are still in early development, even if the data cannot be 
combined statistically with those data generated under the formal RCT for the primary 
endpoint. 
 
Inasmuch as the data collected under the Extension Phase cannot contribute directly to the 
primary endpoint of the RCT, a streamlined set of data elements will be collected during this 
phase that represents a pared-down version of those elements collected during the formal RCT. 
This reduced dataset will minimize the burden to the sites to continue to enroll and randomize 
patients during this period, and will also require only a minimum of additional staff training at 
the site level. While every effort will be made to determine the study outcomes as quickly as 
possible, the exact duration of the Extension Phase will depend upon the timing of such factors 
as when data on the Day 28 visits are collected, when the study team can be unblinded to 
perform primary outcome analyses, when the study results are ready for dissemination, and when 
a follow-up plan for overall future management of EVD is developed, approved, and 
implemented within the DRC (and potentially other affected countries). It is anticipated that the 
results of the RCT may greatly influence that follow-up plan, although the scope of that 
influence cannot be predicted at this time while the study results remain blinded.  
 
 
Similarly, the number of additional patients to be enrolled during the Extension Phase cannot be 
predicted with accuracy both because of the uncertain number of patients who may present to the 
four participating ETUs during this period as well as the unknown (but presumably brief) 
interval of time it may take to formulate and enact a new “open access” treatment plan once the 
RCT results are known and decisions have been made about the most appropriate treatments to 
be offered to future patients. For example, over the course of a 12-week period and at the current 
rate of new cases being identified, it is possible that between 100 and 200 new patients could 
present themselves to an ETU for admission and possible enrollment during this extension 
period. With this uncertainty in mind, there will be a generous ceiling of an additional 1500 
patients imposed upon the enrollment during this phase as long as: 


2018 Ebola MCM RCT Protocol 
Page 58 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
• adequate investigational drug supply, as defined in this protocol, exists to support 
provision of treatment under this mechanism, and 
• ETU resources remain adequate to conduct the Extension Phase, and  
• no recommendation to otherwise amend or halt the extension is made by the DSMB, the 
IRBs, or other regulatory bodies. 
 
As outlined above, a reduced data collection plan will be implemented during the Extension 
Phase. The case report forms that will still be completed (as applicable) and collected are: 
• Screening 
• Eligibility 
• Randomization Request 
• Randomization Assignment 
• Study Drug Infusion (modified) 
• Discharge (with Ebola RT-PCR) 
• A Revised Day 28/End of Study Composite Form 
• Death 
• SAEs 
• Pregnancy 
 
Accordingly, the following CRFs will not be collected: 
• Vital signs  
• Daily follow-up (daily chemistries may still be performed but those results will be 
recorded in source documents only) 
• Day 58 
• Optional Procedures 
• Semen Collection 
 
Other than the exceptions noted above, study conduct will proceed as described in prior sections 
of this protocol (e.g. safety oversight and reporting). 
 
 
 


2018 Ebola MCM RCT Protocol 
Page 59 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
SELECTED REFERENCES 
1. 
Hart MK. Vaccine research efforts for filoviruses. International journal for parasitology. 
2003;33(5-6):583-95. Epub 2003/06/05. PubMed PMID: 12782057. 
2. 
Sanchez A, Kiley MP, Holloway BP, Auperin DD. Sequence analysis of the Ebola virus 
genome: organization, genetic elements, and comparison with the genome of Marburg virus. 
Virus research. 1993;29(3):215-40. Epub 1993/09/01. PubMed PMID: 8237108. 
3. 
Sanchez A, Kiley MP, Klenk HD, Feldmann H. Sequence analysis of the Marburg virus 
nucleoprotein gene: comparison to Ebola virus and other non-segmented negative-strand RNA 
viruses. The Journal of general virology. 1992;73 ( Pt 2):347-57. Epub 1992/02/01. doi: 
10.1099/0022-1317-73-2-347. PubMed PMID: 1538192. 
4. 
Kuhn JH, Bao Y, Bavari S, Becker S, Bradfute S, Brister JR, Bukreyev AA, Chandran K, 
Davey RA, Dolnik O, Dye JM, Enterlein S, Hensley LE, Honko AN, Jahrling PB, Johnson KM, 
Kobinger G, Leroy EM, Lever MS, Muhlberger E, Netesov SV, Olinger GG, Palacios G, 
Patterson JL, Paweska JT, Pitt L, Radoshitzky SR, Saphire EO, Smither SJ, Swanepoel R, 
Towner JS, van der Groen G, Volchkov VE, Wahl-Jensen V, Warren TK, Weidmann M, Nichol 
ST. Virus nomenclature below the species level: a standardized nomenclature for natural variants 
of viruses assigned to the family Filoviridae. Archives of virology. 2013;158(1):301-11. Epub 
2012/09/25. doi: 10.1007/s00705-012-1454-0. PubMed PMID: 23001720; PMCID: 
PMC3535543. 
5. 
World Health Organization. Fact sheet: Ebola virus disease 2017. Available from: 
http://www.who.int/mediacentre/factsheets/fs103/en/. 
6. 
World Health Organization. Ebola Situation Report - 30 March 2016 2016. Available 
from: http://apps.who.int/ebola/current-situation/ebola-situation-report-30-march-2016. 
7. 
Geisbert TW, Jahrling PB. Exotic emerging viral diseases: progress and challenges. 
Nature medicine. 2004;10(12 Suppl):S110-21. Epub 2004/12/04. doi: 10.1038/nm1142. PubMed 
PMID: 15577929. 
8. 
Meslin FX. Global aspects of emerging and potential zoonoses: a WHO perspective. 
Emerging infectious diseases. 1997;3(2):223-8. Epub 1997/04/01. doi: 10.3201/eid0302.970220. 
PubMed PMID: 9204308; PMCID: PMC2627609. 
9. 
Okware SI, Omaswa FG, Zaramba S, Opio A, Lutwama JJ, Kamugisha J, Rwaguma EB, 
Kagwa P, Lamunu M. An outbreak of Ebola in Uganda. Tropical medicine & international health 
: TM & IH. 2002;7(12):1068-75. Epub 2002/12/04. PubMed PMID: 12460399. 
10. 
Bausch DG, Towner JS, Dowell SF, Kaducu F, Lukwiya M, Sanchez A, Nichol ST, 
Ksiazek TG, Rollin PE. Assessment of the risk of Ebola virus transmission from bodily fluids 
and fomites. The Journal of infectious diseases. 2007;196 Suppl 2:S142-7. Epub 2007/12/06. doi: 
10.1086/520545. PubMed PMID: 17940942. 
11. 
Kreuels B, Wichmann D, Emmerich P, Schmidt-Chanasit J, de Heer G, Kluge S, Sow A, 
Renne T, Gunther S, Lohse AW, Addo MM, Schmiedel S. A case of severe Ebola virus infection 
complicated by gram-negative septicemia. The New England journal of medicine. 
2014;371(25):2394-401. Epub 2014/10/23. doi: 10.1056/NEJMoa1411677. PubMed PMID: 
25337633. 
12. 
Hensley LE, Jones SM, Feldmann H, Jahrling PB, Geisbert TW. Ebola and Marburg 
viruses: pathogenesis and development of countermeasures. Current molecular medicine. 
2005;5(8):761-72. Epub 2005/12/27. PubMed PMID: 16375711. 


2018 Ebola MCM RCT Protocol 
Page 60 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
13. 
Broadhurst MJ, Brooks TJ, Pollock NR. Diagnosis of Ebola Virus Disease: Past, Present, 
and Future. Clinical microbiology reviews. 2016;29(4):773-93. Epub 2016/07/15. doi: 
10.1128/cmr.00003-16. PubMed PMID: 27413095; PMCID: PMC5010747. 
14. 
Sullivan N, Yang ZY, Nabel GJ. Ebola virus pathogenesis: implications for vaccines and 
therapies. Journal of virology. 2003;77(18):9733-7. Epub 2003/08/28. PubMed PMID: 
12941881; PMCID: PMC224575. 
15. 
Mupapa K, Massamba M, Kibadi K, Kuvula K, Bwaka A, Kipasa M, Colebunders R, 
Muyembe-Tamfum JJ. Treatment of Ebola hemorrhagic fever with blood transfusions from 
convalescent patients. International Scientific and Technical Committee. The Journal of 
infectious diseases. 1999;179 Suppl 1:S18-23. Epub 1999/02/13. doi: 10.1086/514298. PubMed 
PMID: 9988160. 
16. 
World Health Organization. Clinical management of patients with viral haemorrhagic 
fever: A pocket guide for the front-line health worker. Geneva: World Health Organization; 
2016. 
17. 
Uyeki TM, Mehta AK, Davey RT, Jr., Liddell AM, Wolf T, Vetter P, Schmiedel S, 
Grunewald T, Jacobs M, Arribas JR, Evans L, Hewlett AL, Brantsaeter AB, Ippolito G, Rapp C, 
Hoepelman AI, Gutman J. Clinical Management of Ebola Virus Disease in the United States and 
Europe. The New England journal of medicine. 2016;374(7):636-46. Epub 2016/02/18. doi: 
10.1056/NEJMoa1504874. PubMed PMID: 26886522; PMCID: PMC4972324. 
18. 
Wong KK, Davey RT, Jr., Hewlett AL, Kraft CS, Mehta AK, Mulligan MJ, Beck A, 
Dorman W, Kratochvil CJ, Lai L, Palmore TN, Rogers S, Smith PW, Suffredini AF, Wolcott M, 
Stroher U, Uyeki TM. Use of Postexposure Prophylaxis After Occupational Exposure to Zaire 
ebolavirus. Clinical infectious diseases : an official publication of the Infectious Diseases Society 
of America. 2016;63(3):376-9. Epub 2016/04/28. doi: 10.1093/cid/ciw256. PubMed PMID: 
27118786; PMCID: PMC4946014. 
19. 
Mikhailov VV, Borisevich IV, Chernikova NK, Potryvaeva NV, Krasnianskii VP. [The 
evaluation in hamadryas baboons of the possibility for the specific prevention of Ebola fever]. 
Voprosy virusologii. 1994;39(2):82-4. Epub 1994/03/01. PubMed PMID: 8017061. 
20. 
Jahrling PB, Geisbert TW, Geisbert JB, Swearengen JR, Bray M, Jaax NK, Huggins JW, 
LeDuc JW, Peters CJ. Evaluation of immune globulin and recombinant interferon-alpha2b for 
treatment of experimental Ebola virus infections. The Journal of infectious diseases. 1999;179 
Suppl 1:S224-34. Epub 1999/02/13. doi: 10.1086/514310. PubMed PMID: 9988188. 
21. 
Jahrling PB, Geisbert J, Swearengen JR, Jaax GP, Lewis T, Huggins JW, Schmidt JJ, 
LeDuc JW, Peters CJ. Passive immunization of Ebola virus-infected cynomolgus monkeys with 
immunoglobulin from hyperimmune horses. Archives of virology Supplementum. 1996;11:135-
40. Epub 1996/01/01. PubMed PMID: 8800795. 
22. 
Parren PW, Geisbert TW, Maruyama T, Jahrling PB, Burton DR. Pre- and postexposure 
prophylaxis of Ebola virus infection in an animal model by passive transfer of a neutralizing 
human antibody. Journal of virology. 2002;76(12):6408-12. Epub 2002/05/22. PubMed PMID: 
12021376; PMCID: PMC136210. 
23. 
Takada A, Ebihara H, Jones S, Feldmann H, Kawaoka Y. Protective efficacy of 
neutralizing antibodies against Ebola virus infection. Vaccine. 2007;25(6):993-9. Epub 
2006/10/24. doi: 10.1016/j.vaccine.2006.09.076. PubMed PMID: 17055127. 
24. 
Oswald WB, Geisbert TW, Davis KJ, Geisbert JB, Sullivan NJ, Jahrling PB, Parren PW, 
Burton DR. Neutralizing antibody fails to impact the course of Ebola virus infection in monkeys. 


2018 Ebola MCM RCT Protocol 
Page 61 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
PLoS pathogens. 2007;3(1):e9. Epub 2007/01/24. doi: 10.1371/journal.ppat.0030009. PubMed 
PMID: 17238286; PMCID: PMC1779296. 
25. 
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. The New England journal of medicine. 
2016;375(15):1448-56. Epub 2016/10/13. doi: 10.1056/NEJMoa1604330. PubMed PMID: 
27732819; PMCID: PMC5086427. 
26. 
O'Connor DJ, Hemmings RJ. Coping with small populations of patients in clinical trials. 
Expert Opinion on Orphan Drugs. 2014;2(8):765-8. 
27. 
Bogaerts J, Sydes MR, Keat N, McConnell A, Benson A, Ho A, Roth A, Fortpied C, Eng 
C, Peckitt C, Coens C, Pettaway C, Arnold D, Hall E, Marshall E, Sclafani F, Hatcher H, Earl H, 
Ray-Coquard I, Paul J, Blay JY, Whelan J, Panageas K, Wheatley K, Harrington K, Licitra L, 
Billingham L, Hensley M, McCabe M, Patel PM, Carvajal R, Wilson R, Glynne-Jones R, 
McWilliams R, Leyvraz S, Rao S, Nicholson S, Filiaci V, Negrouk A, Lacombe D, Dupont E, 
Pauporte I, Welch JJ, Law K, Trimble T, Seymour M. Clinical trial designs for rare diseases: 
studies developed and discussed by the International Rare Cancers Initiative. Eur J Cancer. 
2015;51(3):271-81. Epub 2014/12/30. doi: 10.1016/j.ejca.2014.10.027. PubMed PMID: 
25542058; PMCID: PMC4639696. 
28. 
Sposto R, Stram DO. A strategic view of randomized trial design in low-incidence 
paediatric cancer. Statistics in medicine. 1999;18(10):1183-97. Epub 1999/06/11. PubMed 
PMID: 10363339. 
29. 
Qiu X, Wong G, Audet J, Bello A, Fernando L, Alimonti JB, Fausther-Bovendo H, Wei 
H, Aviles J, Hiatt E, Johnson A, Morton J, Swope K, Bohorov O, Bohorova N, Goodman C, Kim 
D, Pauly MH, Velasco J, Pettitt J, Olinger GG, Whaley K, Xu B, Strong JE, Zeitlin L, Kobinger 
GP. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature. 
2014;514(7520):47-53. Epub 2014/08/30. doi: 10.1038/nature13777. PubMed PMID: 25171469; 
PMCID: PMC4214273. 
 
 
 


2018 Ebola MCM RCT Protocol 
Page 62 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Appendix A. ZMapp Drug Information 
See attached. 
 
 


2018 Ebola MCM RCT Protocol 
Page 63 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Appendix B. Remdesivir Drug Information 
See attached. 
 
 


2018 Ebola MCM RCT Protocol 
Page 64 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Appendix C. MAb114 Drug Information 
See attached. 
 
 


2018 Ebola MCM RCT Protocol 
Page 65 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Appendix D. REGN-EB3 Drug Information 
See attached. 
 
 
 


2018 Ebola MCM RCT Protocol 
Page 66 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Appendix E. Oversight and/or Governance Committees: 
 
As a multi-center, multilateral protocol whose full accrual may require extension of the trial over 
several EVD outbreaks that may arise in different countries over time, the complete listing of 
names of participating sites, investigators, and other members of the various governance 
committees may evolve over time. For this reason it is expected that this current list may change 
over time as new investigators and regional representatives are added or replaced as subsequent 
outbreaks occur that affect other regions. Accordingly, any changes in the current listings 
below will not constitute a protocol deviation. 
 
Original Protocol Team: 
Listed below are the names and brief contact information of the extended protocol team who 
were involved in the initial design and implementation of the original 3-arm trial launched on 
November 20, 2018, during the current (10th) outbreak in DRC. This list includes members of the 
DRC INRB and other investigators, various government and non-government representatives 
from the U.S. Department of Health and Human Services, various academic partners and subject 
matter experts, commercial drug manufacturers, the World Health Organization, Médecins Sans 
Frontières, and other NGO groups such as Alima and IMC  involved in conducting the trial at 
clinical sites. 
 
• Prof. Jean-Jacques Muyembe-Tamfum, MD, PhD, jjmuyembet@gmail.com 
• Dr. Mulangu Sabue, INRB, MOH, DRC sabuemulo@yahoo.fr  
• Prof Steve Ahuka, Head Department of Virology/INRB, amstev04@yahoo.fr   
• Dr. Olivier Tshiani, Clinician for Ebola patients in Mangina, pipombaya@hotmail.com   
• Placide Mbala,Ebola mobile lab, mbalaplacide@gmail.com   
• Prof Emile Okitolonda, Professeur of Clinical Trial, okitow@yahoo.fr   
• Prof Tona Lutete Gaston, Unit of Clinical Pharmacology and Pharmacovigilance, 
tonalutete@gmail.com   
• Prof Mesia, Unit of Clinical Pharmacology and Pharmacovigilance, 
mesia.kahunu@unikin.ac.cd   
• Prof Nsengi Ntwamabyaliro, clinical pharmacology, nsengi.ntama@unikin.ac.cd   
• Dr. William Fischer, WHO in Beni, william_fischer@med.unc.edu  
• Dr. Annick Antierens, MD MSF, Annick.Antierens@brussels.msf.org 
• Dr. Armand Sprecher, MSF Brussels, Armand.Sprecher@brussels.msf.org  
• Dr. Richard Kojan, ALIMA, richard.kojan@alima.ngo  
• Dr. Joseph Fair, PhD, IMC, jfair@internationalmedicalcorps.org 
• Dr. Tom Moench, MD MappBio, Thomas.moench@mappbio.com  
• Dr. Tomas Jensen MD, MSc, tomas.jensen@newyork.msf.org  
• Dr. Tomas Cihlar, PhD Gilead Science, Tomas.Cihlar@gilead.com  
• Dr. Huyen Cao, MD, Gilead Sciences, Huyen.Cao@gilead.com  
• Dr. Julie Ledgerwood, DO, Vaccine Research Center, NIAID, jumartin@niaid.nih.gov  
• Dr. Lori Dodd, PhD, Division of Clinical Research (DCR), NIAID, doddl@niaid.nih.gov  
• Dr. Rick Davey, MD, DCR, NIAID, rdavey@niaid.nih.gov  
• Dr. Jerry Pierson, PhD, DCR, NIAID, jpierson@niaid.nih.gov  
• Dr. Cliff Lane, MD, DCR, NIAID, clane@niaid.nih.gov  


2018 Ebola MCM RCT Protocol 
Page 67 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
• Dr. Libby Higgs, MD, DCR, NIAID, ehiggs@niaid.nih.gov 
• Dr. Michael Proschan, PhD, Division of Clinical Research (DCR), NIAID,  
proscham@niaid.nih.gov  
• Dr. Ian Crozier, MD, NIAID, ian.crozier@nih.gov 
• Risa Eckes, NIAID, reckes@niaid.nih.gov 
• Bridgette Jeanne Billioux, NIAID, Bridgette.billioux@nih.gov 
• Lisa Hensley, NIAID, lisa.hensley@nih.gov 
• Jamila Aboulhab, NIAID,  jamila.aboulhab@nih.gov 
 
 
This original team was then transitioned in late November, 2018 (see Section 3.4 of the protocol) 
to the following members of the Protocol Development Team who were involved in the redesign 
and implementation of the 4-arm protocol design that then became active in December, 2018: 
 
Protocol Development Team (PDT) RCT Ebola Therapeutics  
The scope of the PDT was to finalize the protocol and supporting documents and include 
amendments as pertinent.1 Membership is specific for each country and/or outbreak. This is a 
WHO-led (or a WHO-delegated entity) expert group, which includes international experts with 
expertise in Ebola clinical management; Ebola therapeutics; Ebola diagnostics/lab; RCTs; 
Statistics; Ethics; Regulatory; and Drug Development.  
The following experts were nominated by their institutions and agreed to serve as members of 
the Protocol Development Team:  
• Dr Richard Kojan - Alliance for International Medical Action (ALIMA)  
• Prof Jean-Jacques Muyembe - Institut National de la Recherche Biomédicale (INRB)  
• Prof Sabue Mulangu - Institut National de la Recherche Biomédicale (INRB)  
• Dr Nzolo Didier- Institut National de la Recherche Biomédicale (INRB)  
• Dr Adam Levine – International Medical Corps (IMC)  
• Dr Els Torreele - Médecins sans Frontières (MSF)*  
• Dr Rebecca Grais - Médecins sans Frontières (MSF)  
• Dr Pontiano Kalebuu - MRC/UVRI Uganda Research Unit  
• Dr Lori Dodd - National Institutes of Health (NIH)  
• Dr Richard Davey - National Institutes of Health (NIH)  
• Prof Ira Longini – Representative from the R&D Blueprint RCT expert group  
• Prof Peter Horby - Representative from the R&D Blueprint RCT expert group  
• Prof Richard Peto - Representative from the R&D Blueprint RCT expert group  
• Dr Janet Diaz – World Health Organization (WHO)  
• Dr Ana Maria Henao-Restrepo - World Health Organization (WHO)  
• Dr Marie-Pierre Preziosi - World Health Organization (WHO)  
• Dr Pierre Gsell - World Health Organization (WHO)  
• Ms Virginia Benassi - World Health Organization (WHO)  
 
 
 
 
 


2018 Ebola MCM RCT Protocol 
Page 68 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
 
The DRC RCT Protocol DSMB: 
 
The current DSMB membership overseeing the current version of the protocol consists of the 
following: 
 
DRC RCT Protocol DSMB Roster 
 
Name 
Affiliation 
Lisa A. Cooper, MD, MPH, FACP Chair Johns Hopkins University 
Baltimore, MD 
Salim Abdulla, PhD, MSc 
Ifakara Health Institute 
Ifakara, Tanzania 
Dave DeMets, PhD 
University of Wisconsin 
Madison, Wisconsin 
Albert Faye, PhD 
Robert Debré University Children’s Hospital 
Paris, France 
Scott M. Hammer, MD 
Columbia University Medical Center 
NY, NY 
Amadou Traore, MD, MSc 
Agence Nationale de Sécurité 
Sanitaire Conakry, Guinea 
Ann Sarah Walker, PhD, MSc 
NIHR Oxford Biomedical Research 
Centre Oxford, England 
Anita Katherine McElroy, MD, PhD 
University of 
Pittsburgh Pittsburgh, 
Pennsylvania 
Michael Jacobs, PhD 
Royal Free London NHS Foundation 
Trust London, England 
Thomas Fleming, PhD 
University of 
Washington Seattle, 
Washington 
Jean-Marie Denis Malvy, MD, PhD 
Centre Hospitalier Universitaire 
Bordeaux Bordeaux, France 
Aissatou Toure, PharmD, MSc 
Institut Pasteur 
Dakar Dakar, 
Senegal 
Hippolyte Situakibanza, MD 
University of Kinshasa 
Kinshasa, Democratic Republic of the Congo 
 
 


2018 Ebola MCM RCT Protocol 
Page 69 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
 
Steering Committee: 
 
The members of the trial Steering Committee are as follows: TBD 
 
 
 
 
 
Medical Monitors: 
 
Sponsor Medical Monitor: 
Marc J. Teitelbaum, MD, MS 
Clinical Monitoring Research Program Directorate 
 
Frederick National Laboratory for Cancer Research 
 
Leidos Biomedical Research, Inc.  
Support to: Regulatory Compliance & Human 
Subjects Protection Program / NIAID / NIH 
5705 Industry Lane  
Frederick, Maryland 21704 
Phone 301-228-4707 
Fax 301-846-6224 
Marc.Teitelbaum@nih.gov 
 
INRB Medical Monitor: 
Prof Tona Lutete Gaston, PhD. 
 
Head, Unit of Clinical Pharmacology and 
Pharmacovigilance 
 
University of Kinshasa 
 
Kinshasa, Democratic Republic of the Congo 
 
tonalutete@gmail.com 
 
 
 
 
 


2018 Ebola MCM RCT Protocol 
Page 70 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Appendix F:  Sample Informed Consent and Assent for the RCT 
 
RESEARCH PARTICIPANT INFORMED CONSENT 
AND PRIVACY AUTHORIZATION FORM 
 
NIAID Protocol #:  
19-I-0003 
 
Protocol Title:  
A Multicenter, Multi-Outbreak, Randomized, Controlled Safety and 
Efficacy Study of Investigational Therapeutics for the Treatment of 
Patients with Ebola Virus Disease 
 
Sponsors:  
United States National Institute of Allergy and Infectious Diseases 
(NIAID), National Institutes of Health (NIH) 
Democratic Republic of the Congo (DRC) National Institute for 
Biomedical Research 
 
Principal Investigators:  
Jean-Jacques Muyembe-Tamfum, MD, PhD (DRC) 
Richard T. Davey, Jr., MD (US)  
 
Site:  
Democratic Republic of the Congo (DRC), Central Africa 
 
 
1. 
What you should know about this study:   
• You are being asked to join a research study because you have Ebola. This consent 
form explains the research study and your part in the study. 
• Read this consent form carefully or have someone you trust read it to you. Take as 
much time as you need to understand the study. 
• Ask the study team to explain any words or information that you do not understand. 
• You are a volunteer and you do not have to join this study. You should talk to your 
doctor about what your options are if you do not want to be in this study.  
• If you join the study, you can change your mind later. You can decide not to take part 
or you can quit at any time. There will be no penalty or loss of benefits if you decide 
not to join or to quit the study. Your care within your community will not be affected.  
• During the study, we will tell you if we learn any new information that might affect 
whether you wish to continue to be in the study. 
• If you are signing for a person who cannot consent for themselves, such as a child or 
a person who is too sick to read and understand this, the word “you” in this consent 
form refers to that person. If you are signing for a baby born within the past 7 days to 
a mother who has Ebola, we will assume that the baby also has Ebola. In this case, we 
may not wait for the baby’s Ebola blood test result to confirm an Ebola infection 
before starting them on this study. 
 


2018 Ebola MCM RCT Protocol 
Page 71 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
2. 
What is this study about? 
We are looking for new treatments for Ebola virus disease. Ebola virus can make people 
very sick and some people can die from it. There are no approved medicines for Ebola. 
There are some possible Ebola medicines that are called experimental medicines because 
we are not sure if they work to treat Ebola. We need to test the experimental medicines to 
see if they help people recover from Ebola virus disease. To do this, we need the help of 
people who have Ebola and are in a treatment center where we can test these 
experimental drugs and compare them to each other in a controlled way. The 
experimental drugs that we are testing in this study (the “study drugs”) are described 
below. 
 
3. 
How many people will be in this study? 
We expect about 725 people to join the study in several Ebola treatment centers. 
 
4. 
What will happen if you join this study? 
Before you can join the study, we will ask you some questions, review your health 
history, assess your symptoms, and collect some of your blood to test for Ebola.  
 
If you are eligible and choose to join, you will be in the study for about 2 months. At the 
beginning, you will stay at the Ebola treatment center for treatment of your Ebola. How 
long you stay in the treatment center will depend on how sick you are. While you are in 
the treatment center, you will continue to get supportive care. This includes getting fluids 
to replace those you lose due to your illness. Your blood pressure and other vital signs 
will be measured to see if you are getting better or worse. We will take blood to check 
your health status and give you medicine to treat your symptoms. These specific steps are 
not experimental. This is standard care for Ebola patients in the treatment center. Any 
procedures done as part of this standard care will be explained to you as will the risks. 
 
We will use a needle to put a small plastic tube in your arm for several days. This is 
called an IV line. Fluids to help you, and also study drug, will be given through the IV.  
 
We will check you a few times each day to see if you are getting better or worse. We will 
need to read your medical records. We may ask you to give us some of your urine in a 
cup, and we will take some blood. We will use the blood and urine to guide your care, 
and for research tests. This will help us see how your body responds to Ebola and to the 
study drug.  
 
After you have recovered enough in the treatment center, you will be allowed to go 
home. We will contact you about 1 month and 2 months after you started the study. We 
will ask how you are feeling and if you have been sick. If possible, we will collect blood 
samples from all participants and semen samples from male participants for research and 
routine lab tests to check your health. After 2 months, you will be done with this study. 
For women who are or become pregnant during the study, we may ask you to let us know 
if there were any problems with your pregnancy or with your child.   
 


2018 Ebola MCM RCT Protocol 
Page 72 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
We may contact you and ask if you want to help us by being in other research studies in 
the future to learn more about how best to care for people who have survived Ebola.   
 
5. 
What are the study drugs and their side effects? 
Each person in this study will get 1 of the 4 study drugs described below. All study 
participants will also get routine medical care for Ebola. If you join the study, the study 
drug you get will be randomly assigned (that is, like throwing dice). Right now, nobody 
is sure if any of the study drugs are better than the others. There may be some side effects 
with the study drugs.  
 
The study team will tell you which study drug you will get, and will talk with you about 
it. You will only receive 1 of the study drugs while you are in this study. You will not be 
able to receive any other experimental drugs for 1 month. 
 
Study Drugs  
The 4 different study drugs we are using on this study are called  
• ZMapp 
• remdesivir 
• MAb114 
• REGN-EB3 
 
Information about how these drugs are given and their risks is given below. These 
experimental drugs have not been studied in very many people, so there may be risks that 
we do not know about. It is possible for people to have allergic reactions to any drug, 
including hives, trouble breathing, or other allergic responses. This is very rare. Severe 
allergic reactions (called anaphylaxis) can cause heart attacks and, if untreated, even 
death. The study doctors will be prepared to promptly and appropriately treat any severe 
allergic reaction to any of the study drugs.  
 
ZMapp: If you get ZMapp, we will give it to you 3 times, with about 3 days between 
each dose. Each dose is given through your IV line and will take about 4 hours to give. If 
you have side effects while we are giving the ZMapp, let us know. We can slow down 
how fast we give you the drug to help with the side effects. You will be monitored 
closely for side effects while you are getting the ZMapp, and we will have medicine and 
equipment available to treat side effects, including severe effects, if necessary. If you 
have severe side effects that do not get better, we will not give you any more doses. 
 
ZMapp has been tested in other studies in people with Ebola. Some of the side effects 
seen in people who received ZMapp were flushing (skin redness), fast heart rate, chills, a 
rise or fall in blood pressure, itchiness, swelling, fever, chest pain, shortness of breath, 
nausea and vomiting, a drop in blood sugar, seizures, and skin rash. These side effects 
may be caused by ZMapp and may be serious. We do not know if the drug caused all of 
these side effects. Some of them may have been caused by the Ebola infection. Some 
people have lived and some people have died after receiving ZMapp.  
 


2018 Ebola MCM RCT Protocol 
Page 73 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Risks of antihistamine and acetaminophen: If you have some kinds of side effects from 
ZMapp, we may give you antihistamine or acetaminophen to help treat it. Sedation is the 
major expected side effect of antihistamine and may last up to several hours after the 
antihistamine is given. Other common side effects of antihistamine include tiredness, 
sleepiness, dizziness, disturbed coordination, drying and thickening of oral and other 
respiratory secretions, and stomach upset. An antihistamine may also cause blurred 
vision, double vision, tremor, loss of appetite, or nausea. 
 
Significant side effects from a single dose of acetaminophen are uncommon but could 
include allergic-type reactions (for example, hives, rash, shortness of breath), minor 
stomach upset, and jaundice. 
 
Remdesivir: If you get remdesivir, we will give it to you through your IV line 1 time 
every day for 10 to 14 days in a row. Each dose takes about 30 to 60 minutes to give. We 
will monitor you closely for side effects while you are getting the remdesivir and will 
have medicine and equipment available to treat side effects, including severe effects, if 
necessary. If you have severe side effects that do not get better, we will not give you any 
more doses. 
 
Remdesivir has been given to a small number of people in other research studies, and 
some of these people had side effects. These included changes in laboratory tests that 
measure liver health. The liver changes lasted longer than a few days but came back to 
normal levels. Some people also had constipation, heartburn, itching, unusual feelings in 
the ear, dizziness, loss of appetite, nausea, vomiting, shaking of the leg and arm, 
headache, loose stool, or upset stomach. These side effects are temporary and should not 
last more than a few days. None of the side effects have been serious. 
 
Before drugs are tested in people, they are tested in animals first. When remdesivir was 
tested in animals, some of the animals had kidney damage. The animals’ kidneys went 
back to normal after the drug was stopped. Some of the animals also had redness around 
the spot of the drug infusion. We have not seen any kidney problems in the people who 
have taken this drug but since it is still being studied, it could still happen. We will be 
monitoring your blood during the study to check for kidney damage. 
 
Remdesivir has an ingredient called SBECD. When SBECD was given to animals in 
research studies, it caused changes in the kidneys but did not affect how well the kidneys 
worked. SBECD has been approved for use in the United States and is used to give other 
approved medications. 
 
You should not drink alcohol for 14 days after you start receiving remdesivir. You should 
also not take paracetamol (acetaminophen). 
 
MAb114: If you get MAb114, we will give you only 1 dose of MAb114 through your IV 
line. It will take about 30 to 60 minutes. If you have side effects while we are giving the 
MAb114, let us know. We can slow down how fast we give you the drug to help with the 
side effects. You will be monitored closely for side effects while you are getting the 


2018 Ebola MCM RCT Protocol 
Page 74 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
MAb114, and we will have medicine and equipment available to treat side effects, 
including severe effects, if necessary. 
 
MAb114 has been given to some healthy volunteers and some people with Ebola, and 
some people had side effects that included general discomfort, muscle pain, headache, 
chills, nausea, and joint pain. 
 
Since MAb114 has been given to very few people, we do not know all the side effects 
that could occur, but drugs that are made like MAb114 can cause side effects that can 
sometimes be serious. Most side effects occur within the first 24 hours. These may 
include fever, chills, shaking, nausea, vomiting, pain, headache, dizziness, trouble 
breathing, high or low blood pressure, itchiness, rash, hives, lip or face swelling, diarrhea, 
racing heart, or chest pain. 
 
Some drugs like MAb114 have a risk of more serious reactions or side effects like serum 
sickness. Serum sickness is a type of allergic reaction that may happen several days to 3 
weeks after this type of drug is given, but it has not been seen in anyone who has gotten 
MAb114. This reaction can include hives or rash, fever, enlarged lymph nodes, muscle 
pains, joint pains, chest discomfort, and shortness of breath. 
 
Some drugs like MAb114 contain larger amounts of an ingredient called sucrose. This 
may cause temporary damage to the kidneys. MAb114 contains less sucrose than those 
other drugs, but we will still monitor your kidneys closely with blood tests during this 
study. 
 
Some drugs like MAb114 attack human proteins and can increase the risk of serious 
infections. MAb114 is not expected to increase the risk of serious infections because it 
attacks the Ebola virus and not a human protein. 
 
REGN-EB3: If you get REGN-EB3, we will give you only 1 dose through your IV line. 
It will take about 2 hours. If you have side effects while we are giving the REGN-EB3, 
let us know. We can slow down how fast we give you the drug to help with the side 
effects. You will be monitored closely for side effects while you are getting the REGN-
EB3, and we will have medicine and equipment available to treat side effects, including 
severe effects, if necessary. 
 
REGN-EB3 has been given to some healthy volunteers in a clinical study and some 
people with Ebola, and some people had side effects. The most common side effects were 
headache and muscle pain. 
 
Since REGN-EB3 has been given to very few people, we do not know all the side effects 
that could occur, but drugs that are made like REGN-EB3 can cause side effects that can 
sometimes be serious. Most side effects occur within the first few hours of the infusion. 
These may include wheezing, trouble breathing, chills, shaking, dizziness, fainting, 
shortness of breath, cough, low blood pressure, rash, hives, or swelling around the mouth, 
throat, or eyes. 


2018 Ebola MCM RCT Protocol 
Page 75 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
Some drugs like REGN-EB3 have a risk of more serious reactions or side effects 
including allergic reactions. For example, there is a type of delayed allergic reaction that 
may happen several days to 3 weeks after this type of drug is given, although it has not 
been seen in anyone who has gotten REGN-EB3. This reaction could include hives or 
rash, fever, enlarged lymph nodes, joint pains, chest discomfort, and shortness of breath. 
 
Low levels of an antibiotic called doxycycline is used to make REGN-EB3. You should 
tell your study doctor or study staff if you have an allergy to doxycycline or any other 
medications. 
 
6. 
What are the other risks or discomforts of the study? 
The needle used to draw blood or place an IV line can hurt. You may get a black and blue 
mark where the needle went in. Sometimes drawing blood causes people to feel 
lightheaded or even to faint. There is a very small risk of getting an infection where the 
needle went into the vein.  
 
We will be careful to keep your study information confidential, but there is a small risk 
that someone not involved in the study could get this information. 
 
7. 
What do I need to know about pregnancy or breastfeeding during the 
study? 
Women: We do not know the effects of the study drugs on a developing fetus. If you can 
become pregnant, we may do pregnancy testing while you are on this study. If you are 
pregnant or become pregnant around the time you receive the study drug, there may be 
risks to you, the embryo, or fetus. These risks are not yet known. If you are a woman who 
can get pregnant, you must agree to use an effective method of birth control from the 
beginning of the study through the last study visit. If you find out that you were pregnant 
during the study, you must tell your doctor immediately. If you are breastfeeding or plan 
to breastfeed an infant, it is recommended by the World Health Organization that you 
avoid breast feeding for a period of time until your breast milk is tested to show that 
Ebola virus is not present. We also do not know if the study drugs can pass through in 
breast milk, and the risks to a nursing infant are not yet known. 
 
Men: The effects of the study drugs on sperm is not known. To protect against possible 
side effects, you should not get a sexual partner pregnant while taking part in this study. 
You must agree to use a condom from the beginning of the study through the last study 
visit. Research studies have found that Ebola virus can persist in the semen of Ebola 
survivors for extended periods after recovery from an Ebola infection, and might infect a 
sexual partner. Therefore, we recommend that you either don’t have sex or that you use 
condoms during sexual intercourse for as long is currently recommended by the World 
Health Organization, or until your semen is tested to show that Ebola virus is not present.  
We would like to test your semen for virus in this study when you leave the ETU and 
again about 2 months after you start the study. 
 


2018 Ebola MCM RCT Protocol 
Page 76 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
If you recover from Ebola, we will talk with you about precautions you should continue 
to take to prevent passing the virus to others through bodily fluids. 
 
8. 
Are there benefits to being in the study? 
We do not know if you will benefit from being in this study. It is possible that the study 
drug you receive will help treat your Ebola infection. But we do not yet know whether 
any of the treatments are effective. It is also possible that even if a drug is effective, it 
may cause serious side effects that make it more harmful than helpful. 
 
What we learn from this study may allow us to better understand Ebola and develop 
better ways of treating patients with Ebola in the future. 
 
9. 
What will happen to your samples and personal information? 
We will store your samples and data (information) for a very long time to use for future 
research on Ebola. Your stored samples and data will be marked with a code and not with 
your name. Only researchers linked to this study can get the codes. 
 
Your study information will be placed in a secure electronic system. It will not include 
your name. We must get approval from the DRC and US ethics boards that review this 
study before we share samples and data with other researchers. Other information, such 
as your sex, age, or health history might also be shared, but your name will not. This 
information cannot be traced back to you. You will not get any information about future 
research. Your sample will not be sold. You will not be paid for any products that result 
from this research. 
 
The only risk of allowing us to store your sample would be an accidental release of your 
identity. 
 
If you change your mind and decide you do not want us to store your sample or data, 
please let us know. We will do our best to follow your wishes but cannot promise that we 
will always be able to destroy your samples or data. 
 
10. 
Will it cost you anything to be in this study? 
It will not cost you anything to be in this study. 
 
11. 
Will you be paid if you join this study? 
No, you will not be paid. 
 
12. 
Who is watching over this study? 
A Data and Safety Monitoring Board (DSMB) will be looking at the study information 
very closely. The DSMB is made up of doctors and other people who are not directly 
involved in the study and who have a good understanding of Ebola and research studies. 
The DSMB may recommend changing the study drugs being used or stopping the study 
earlier than planned if they think it is not safe to continue or if they find out early that a 
drug is working better. The DRC and US ethics boards will also be watching over this 
study and have the authority to stop it at any time. 


2018 Ebola MCM RCT Protocol 
Page 77 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
13. 
How will your privacy be protected? 
We will keep your study information private. All files with information that could 
identify you will be kept in locked cabinets or secure computers. People responsible for 
making sure that the research is done properly may look at your study records. This might 
include people from the DRC and the US including the NIH and their designees. All of 
these people will also keep your identity private. Results from this study, but not your 
identity, may be shared with local medical providers or government health organizations 
to help them better understand Ebola virus infection. 
 
14. 
What other things should you know about this research study? 
a. ClinicalTrials.gov 
A description of this study will be on the internet at http://www.ClinicalTrials.gov. 
This website will not include information about you. At most, the website will 
include a summary of the results. You can search this website at any time. 
 
b. Conflict of Interest 
The policy of the NIH is to evaluate investigators at least yearly for any conflicts of 
interest. Research participants may review the system for assessing conflicts of 
interest by checking the web site link: http://ethics.od.nih.gov/forms/Protocol-
Review-Guide.pdf. Copies of the standards may also be requested by research 
patients. This study has investigators that are NIH employees and some that are not. 
All non-NIH investigators are required to follow the principles of the Protocol 
Review Guide but are not required to report their financial holdings to the NIH. 
 
The US NIH and the research team for this study have developed one of the drugs 
being used in this study. This means it is possible that the results of this study could 
lead to payments to NIH and Institut National de Recherche Biomédicale (INRB) 
scientists and to the NIH. By law, US government scientists are required to receive 
such payments for their inventions. You will not receive any money from the 
development of the drugs being used in this study. 
 
c. What is the Ethical Review Committee and how does it protect you? 
Your government’s ethics committee will review this study. It protects the rights and 
welfare of the people taking part in research studies. You can contact Patrick 
Kayembe Kalambayi, coordinator of the DRC ethics board (Tel: 0818111182) to 
answer questions you may have about being part of this study and your rights as 
someone who is in a study. The ethics committee at the US NIH has also reviewed 
and approved this research. 
 
d. What do you do if you have questions about the study? 
If you have questions about the study, you may contact the principal investigators. Dr. 
Jean-Jacques Muyembe-Tamfum (DRC) can be reached by phone +243 898949289, 
or by email jjmuyembet@gmail.com. Dr. Richard T. Davey, Jr. (US NIH) can be 
reached by email rdavey@niaid.nih.gov. 


2018 Ebola MCM RCT Protocol 
Page 78 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
e. What should you do if you are injured or ill as a result of being in this study? 
We do not expect any harm from participating in this study. However, unforeseeable 
risks may be present. The study doctors will give you short-term medical care if you 
are hurt by being in this study. 
 
 
If you agree to be in this study, please sign or put your fingerprint below. 
 
 
________________________________________                                  Date: _____/_____/_____ 
Signature or fingerprint of participant or guardian                                             dd       mm      yy 
 
 
________________________________________ 
Printed name of participant or guardian 
 
 
_____________________________________                                        Date: _____/_____/_____ 
Signature of investigator/designee                                                                      dd       mm      yy 
 
 
_____________________________________ 
Printed name of investigator/designee 
 
 
Complete if participant is illiterate: 
 
Witness to Consent Interview 
 
On the date given next to my signature, I witnessed the consent interview for the research study 
named above in this document. I attest that the information in this consent form was explained to 
the subject, and the subject indicated that his/her questions and concerns were adequately 
addressed. 
 
 
________________________________________                                  Date: _____/_____/_____ 
Signature of witness                                                                                           dd       mm      yy 
 
 
________________________________________ 
Printed name of witness 
 
 


2018 Ebola MCM RCT Protocol 
Page 79 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
MINOR ASSENT TO PARTICIPATE IN STUDY 
 
NIAID Protocol #:  
19-I-0003 
 
Protocol Title:  
A Multicenter, Multi-Outbreak, Randomized, Controlled Safety and 
Efficacy Study of Investigational Therapeutics for the Treatment of 
Patients with Ebola Virus Disease 
 
Sponsors:  
United States National Institute of Allergy and Infectious Diseases 
(NIAID), National Institutes of Health (NIH) 
Democratic Republic of the Congo (DRC) National Institute for 
Biomedical Research 
 
Principal Investigators:  
Jean-Jacques Muyembe-Tamfum, MD, PhD (DRC) 
Richard T. Davey, Jr., MD (US)  
 
Site:  
Democratic Republic of the Congo (DRC), Central Africa 
 
 
1 
Introduction 
You are being asked to be in this study because you have Ebola. Ebola can make 
people very sick. Some people can die from it. There are no approved medicines for 
treating Ebola, so we are trying to learn more about how best to treat it.  
 
First, we want to explain the study to you. Then, you can decide if you want to be in it. 
You do not have to be in this study if you do not want to. 
 
2 
What is this study about? 
This is a research study where we are testing possible medicines. We want to find out if 
any of these medicines could help treat Ebola. We call these medicines the “study 
drugs.” We do not know if any of them will be helpful. They have been given to some 
people before, but not many. We need to test them in more people, including kids, so 
we can make sure they are safe and see if any of them can help treat Ebola. 
 
3 
Do I have to be in this study? 
No. You can decide not to be in the study. You can talk to your family, friends, and 
doctor before you decide. Even if you want to be in the study now, you can change 
your mind later and stop being in the study at any time. 
 
4 
What will happen in this research study? 
If it is okay with you and you agree to join this study, we will give you 1 of the study 
drugs. There are 4 study drugs that we are testing. You will only get 1 of them, but we 
do not know which one yet. You cannot pick which one you want but we will tell you 
when we find out. 


2018 Ebola MCM RCT Protocol 
Page 80 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
During the study, you will stay in the Ebola treatment center for a while. You may stay 
up to a few weeks if you are very sick. You will continue to get regular care for Ebola. 
We will use a needle to put a small tube in your arm for several days. We will give you 
the study drug through the tube in your arm. We will also collect some blood and we 
may ask you to give us some urine in a cup for tests.  
 
After some time in the treatment center, when the doctor thinks it is safe for you, you 
can go home. We will contact you 2 more times to ask how you are feeling. If possible, 
we will give you a check up and take some more blood for tests. Then you will be done 
with the study. Your total time in the study will be about 2 months. 
 
5 
Will any part of the study hurt? 
Taking a study drug may make you feel sick, but you may also feel sick from the 
Ebola. The study drugs have not been given to a lot of people, so the study drug you get 
may cause changes that hurt or bother you that we do not know about. It may also not 
have been given to children before, so we may not know whether it may cause side 
effects in kids that were not seen in adults. In a very small number of people, the study 
drugs could cause something dangerous that people could die from. It is important that 
you always tell the study staff how you are feeling. 
 
If you get the study drug called “ZMapp,” you will get it 3 times. It might give you a 
fever or make you feel cold. It might make your skin red or itchy, give you a rash, or 
make your body swell. It might make you throw up or feel like you are about to throw 
up. You could feel like your heart is beating too fast or you are out of breath. You 
could feel a pain in your chest. You might get seizures. 
 
If you get the drug called “remdesivir,” you will get it 10 to 14 times. It might make 
you feel itchy, dizzy, or shaky. You might feel like your chest is warm or burning. It 
might make your head hurt. It might make your ears feel funny. It might make your 
stomach hurt, and it could make you have diarrhea, throw up, or feel like you might 
throw up. You could have trouble pooping for a while. 
 
If you get the drug called “MAb114,” you will get it 1 time. It might make you feel 
sick, cold, dizzy, or shaky, and it might give you a fever. It could make you have 
diarrhea, make you throw up or feel like you might throw up. It could make your head, 
muscles, or joints hurt. It could make you feel itchy, give you a rash or hives, or make 
your lips or face swell up. You could have trouble breathing. You could feel like your 
heart is beating too fast. It could give you a pain in your chest. 
 
If you get the drug called “REGN-EB3,” you will get it 1 time. It might make your 
head or muscles hurt. It could make you feel cold, shaky, or dizzy, or give you a fever, 
rash, or hives. It could make you cough or faint, make your joints hurt, or make your 
lips, face, or throat swell up. You could have trouble breathing. It could give you a pain 
in your chest. 
 


2018 Ebola MCM RCT Protocol 
Page 81 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
You will just get 1 of these drugs. You might have some of these things happen, or you 
might not feel any of them. We will watch you carefully when you get the study drug. 
If the drug makes you feel bad, we can sometimes give you medicines to help you feel 
better. 
 
It might hurt when we put a needle in your arm to draw blood or put in the plastic tube. 
Your arm may get swollen and sore where the needle goes in, and you might get a 
black and blue mark. These things should go away on their own. There is a very small 
chance that you could get an infection.  
 
6 
What do I need to know about pregnancy during the study? 
If you are female: We do not know the effects of the study drugs in pregnancy or in a 
nursing baby. If you can become pregnant, we may do pregnancy testing while you are 
on this study. If you are pregnant or get pregnant around the time you get the study 
drug, we don’t know if there may be effects on you or your baby. Therefore, you 
should avoid getting pregnant for 2 months after getting the study drug. You will need 
to use birth control if you are sexually active, unless you are not able to get pregnant. If 
you think that you have gotten pregnant during the study, tell the study team right 
away, and find medical care for your pregnancy. 
 
If you are male: The effects of the study drugs on sperm are not known. Therefore, you 
should not get a sexual partner pregnant for at least 2 months after getting the study 
drug. You should use a condom every time you have sex for 2 months after getting the 
study drug. 
 
7 
Will the study help me? 
We do not know if you will be helped by being in this study. We do not know if the 
study drug will make you feel better or get well sooner. It is possible that the study 
drug could make you worse. 
 
8 
Will the study help others? 
We might find out things from this study that will help other people with Ebola 
someday. 
 
9 
Do I have other choices? 
You do not have to be in this study. It is up to you. You can talk to your parents and 
your doctor about your options.  
 
No one will be upset if you don’t want to do this study. If you say okay now, but you 
want to stop later, that is okay too. If you decide to stop being in the study, all you have 
to do is tell your doctor or nurse that you don’t want to do the study anymore. No one 
will be mad at you if you change your mind. 
 
If you say no, you will still be given your regular care for Ebola. We will not give you 
the study drugs. 
 


2018 Ebola MCM RCT Protocol 
Page 82 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
10 
What if I have questions? 
If you want to talk to anyone about this research study because you think you have 
been hurt by being part of the study, or you if have any other questions about the study, 
you should tell the study team: Phone number +243 826792353. 
 
Also, you can contact Dr. Jean-Jacques Muyembe-Tamfum (Tel: +243 898949289) to 
answer questions you may have about being part of this study and your rights as 
someone who is in a study. 
 
If you have any questions at any time about this research study, you may ask someone 
on the study team. 
 
If you decide to be in the study, please write your name below. 
 
 
I have had this study explained to me in a way that I understand, and I have had the chance to 
ask questions. I agree to take part in this study. 
 
 
Signature or fingerprint of Minor Patient:  _____________________ 
Date: _____________ 
 
Print Name: _____________________________________________ 
 
 
Signature of Investigator/Designee:  _________________________ 
Date:  ____________ 
 
Print Name: _____________________________________________ 
 
 
 
 
 
 


2018 Ebola MCM RCT Protocol 
Page 83 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Appendix G:  Sample Informed Consent and Assent for the Extension Phase 
 
RESEARCH PARTICIPANT INFORMED CONSENT 
AND PRIVACY AUTHORIZATION FORM 
 
NIAID Protocol #:  19-I-0003 
 
Protocol Title:  
A Multicenter, Multi-Outbreak, Randomized, Controlled Safety and 
Efficacy Study of Investigational Therapeutics for the Treatment of Patients with Ebola Virus 
Disease 
 
Sponsors:  
United States National Institute of Allergy and Infectious Diseases (NIAID), 
National Institutes of Health (NIH) 
Democratic Republic of the Congo (DRC) National Institute for Biomedical Research 
 
Principal Investigators:  
Jean-Jacques Muyembe-Tamfum, MD, PhD (DRC) 
Richard T. Davey, Jr., MD (US)  
 
Site:  Democratic Republic of the Congo (DRC), Central Africa 
 
 
 
1. 
What you should know about this study:   
• You are being asked to join a research study because you have Ebola. This consent 
form explains the research study and your part in the study. 
• Read this consent form carefully or have someone you trust read it to you. Take as 
much time as you need to understand the study. 
• Ask the study team to explain any words or information that you do not understand. 
• You are a volunteer and you do not have to join this study. You should talk to your 
doctor about what your options are if you do not want to be in this study.  
• If you join the study, you can change your mind later. You can decide not to take part 
or you can quit at any time. There will be no penalty or loss of benefits if you decide 
not to join or to quit the study. Your care within your community will not be affected.  
• During the study, we will tell you if we learn any new information that might affect 
whether you wish to continue to be in the study. 
• If you are signing for a person who cannot consent for themselves, such as a child or 
a person who is too sick to read and understand this, the word “you” in this consent 
form refers to that person. If you are signing for a baby born within the past 7 days to 
a mother who has Ebola, we will assume that the baby also has Ebola. In this case, we 
may not wait for the baby’s Ebola blood test result to confirm an Ebola infection 
before starting them on this study. 
 
2. 
What is this study about? 
We are looking for new treatments for Ebola virus disease. Ebola virus can make people 
very sick and some people can die from it. There are no approved medicines for Ebola. 


2018 Ebola MCM RCT Protocol 
Page 84 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
There are some possible Ebola medicines that are called experimental medicines because 
we are not sure if they work to treat Ebola. We have recently been testing four 
experimental medicines to see if they help people recover from Ebola virus disease. To 
do this, we have needed the help of people who have Ebola and are in a treatment center 
where we can test these experimental medicines and compare them to each other in a 
scientific and precise way.  
 
Four study drugs were given in the Randomized Control Trial portion of this study which 
is now closed to people with known Ebola virus disease.  Some people have lived and 
some have died.   
 
From an early review of the study results we now know that 2 of the 4 study drugs were 
better at treating Ebola than the others.  We do not yet know if one of these 2 might be 
better than the other because we are still reviewing the data.  We wish to continue to offer 
these experimental medicines to people who might benefit from them. As soon as we 
analyze the final results, we will take standard steps to make that information public.  
 
The purpose of the current study is to offer you access to these experimental medicines. 
 
3. 
How many people will be in this study? 
We have set a limit of 1500 patients who can join the study while we are waiting for the 
final results of the comparison study to become available. We expect it may take a few 
weeks to a few months for those results to become available.   
 
4. 
What will happen if you join this study? 
Before you can join the study, we will ask you some questions, review your health 
history, assess your symptoms, and collect some of your blood to test for Ebola.  
 
If you are eligible and choose to join, you will be in the study for about 1 month. At the 
beginning, you will stay at the Ebola treatment center for treatment of your Ebola. How 
long you stay in the treatment center will depend on how sick you are. While you are in 
the treatment center, you will continue to get supportive care. This includes getting fluids 
to replace those you lose due to your illness. Your blood pressure and other vital signs 
will be measured to see if you are getting better or worse. We will take blood to check 
your health status and give you medicine to treat your symptoms. These specific steps are 
not experimental. This is standard care for Ebola patients in the treatment center. Any 
procedures done as part of this standard care will be explained to you as will the risks. 
 
We will use a needle to put a small plastic tube in your arm for several days. This is 
called an IV line. Fluids to help you, and also study drug, will be given through the IV.  
 
We will check you a few times each day to see if you are getting better or worse. We will 
need to read your medical records. We may ask you to give us some of your urine in a 
cup, and we will take some blood. We will use the blood and urine to guide your care, 
and for research tests. This will help us see how your body responds to Ebola and to the 
study drug.  


2018 Ebola MCM RCT Protocol 
Page 85 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
If you have recovered enough in the treatment center, you will be allowed to go home. 
We will contact you about 1 month after you started the study. We will ask how you are 
feeling and if you have been sick. If possible, we will collect blood samples from all 
participants and perform routine lab tests to check your health. After 1 month, you will be 
done with this study. For women who are or become pregnant during the study, longer 
follow-up may be needed during which we may ask you to let us know if there were any 
problems with your pregnancy or with your child.   
 
We may contact you and ask if you want to help us by being in other research studies in 
the future to learn more about how best to care for people who have survived Ebola.   
 
5. 
What are the study drugs and their side effects? 
Each person in this study will get 1 of the 2 study drugs described below. However, it is 
possible that both drugs will not be available at all times. All study participants will also 
get routine medical care for Ebola. If you join the study, the study drug you get will be 
randomly assigned (that is, like throwing dice). If we run out of one of the study drugs, 
you will be randomly assigned to the study drug that is available.  Right now, nobody is 
sure if one of the study drugs is better than the other. There may be some side effects 
with the study drugs.  
 
The study team will tell you which study drug you will get, and will talk with you about 
it. You will only receive 1 of the study drugs while you are in this study. You will not be 
able to receive any other experimental medicines for 1 month. 
 
Study Drugs  
The 2 different study drugs we are using on this study are called  
• mAb114 
• REGN-EB3 
 
Information about how these drugs are given and their risks is given below. As of now 
these experimental medicines have only been studied in a few hundred people each, so 
there may be risks that we do not know about. It is possible for people to have allergic 
reactions to any drug, including hives, trouble breathing, or other allergic responses. This 
is very rare. Severe allergic reactions (called anaphylaxis) can cause heart attacks and, 
possibly, death. The study doctors will be prepared to promptly treat any severe allergic 
reaction to any of the study drugs.  
 
If you have side effects while we are giving the study drug, let us know. We can slow 
down how fast we give you the drug to help with the side effects. 
 
mAb114: If you get mAb114, we will give you only 1 dose of MAb114 through your IV 
line. It will take about 30 to 60 minutes. You will be monitored closely for side effects 
while you are getting the mAb114, and we will have medicine and equipment available to 
treat side effects, including severe effects, if necessary. 
 


2018 Ebola MCM RCT Protocol 
Page 86 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
mAb114 has been given to some healthy volunteers and some people with Ebola, and 
some people had side effects that included general discomfort, muscle pain, headache, 
chills, nausea, and joint pain. 
 
Since mAb114 has been given to very few people, we do not know all the side effects 
that could occur, but drugs that are made like mAb114 can cause side effects that can 
sometimes be serious. Most side effects occur within the first 24 hours. These may 
include fever, chills, shaking, nausea, vomiting, pain, headache, dizziness, trouble 
breathing, high or low blood pressure, itchiness, rash, hives, lip or face swelling, diarrhea, 
racing heart, or chest pain. 
 
Some drugs like mAb114 have a risk of more serious reactions or side effects like serum 
sickness. Serum sickness is a type of allergic reaction that may happen several days to 3 
weeks after this type of drug is given, but it has not been seen in anyone who has gotten 
mAb114. This reaction can include hives or rash, fever, enlarged lymph nodes, muscle 
pains, joint pains, chest discomfort, and shortness of breath. 
 
Some drugs like mAb114 contain larger amounts of an ingredient called sucrose. This 
may cause temporary damage to the kidneys. mAb114 contains less sucrose than those 
other drugs, but we will still monitor your kidneys closely with blood tests during this 
study. 
 
Some drugs like mAb114 attack human proteins and can increase the risk of serious 
infections. mAb114 is not expected to increase the risk of serious infections because it 
attacks the Ebola virus and not a human protein. 
 
REGN-EB3: If you get REGN-EB3, we will give you only 1 dose through your IV line. 
It will take about 2 hours. You will be monitored closely for side effects while you are 
getting the REGN-EB3, and we will have medicine and equipment available to treat side 
effects, including severe effects, if necessary. 
 
REGN-EB3 has been given to some healthy volunteers in a clinical study and some 
people with Ebola, and some people had side effects. The most common side effects were 
headache and muscle pain. 
 
Since REGN-EB3 has been given to very few people, we do not know all the side effects 
that could occur, but drugs that are made like REGN-EB3 can cause side effects that can 
sometimes be serious. Most side effects occur within the first few hours of the infusion. 
These may include wheezing, trouble breathing, chills, shaking, dizziness, fainting, 
shortness of breath, cough, low blood pressure, rash, hives, or swelling around the mouth, 
throat, or eyes. 
 
Some drugs like REGN-EB3 have a risk of more serious reactions or side effects 
including allergic reactions. For example, there is a type of delayed allergic reaction that 
may happen several days to 3 weeks after this type of drug is given, although it has not 


2018 Ebola MCM RCT Protocol 
Page 87 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
been seen in anyone who has gotten REGN-EB3. This reaction could include hives or 
rash, fever, enlarged lymph nodes, joint pains, chest discomfort, and shortness of breath. 
 
Low levels of an antibiotic called doxycycline is used to make REGN-EB3. You should 
tell your study doctor or study staff if you have an allergy to doxycycline or any other 
medications. 
 
6. 
What are the other risks or discomforts of the study? 
The needle used to draw blood or place an IV line can hurt. You may get a black and blue 
mark where the needle went in. Sometimes drawing blood causes people to feel 
lightheaded or even to faint. There is a very small risk of getting an infection where the 
needle went into the vein.  
 
We will be careful to keep your study information confidential, but there is a small risk 
that someone not involved in the study could get this information. 
 
7. 
What do I need to know about pregnancy or breastfeeding during the 
study? 
Women: We do not know the effects of the study drugs on a developing fetus. If you can 
become pregnant, we may do pregnancy testing while you are on this study. If you are 
pregnant or become pregnant around the time you receive the study drug, there may be 
risks to you, the embryo, or fetus. These risks are not yet known. If you are a woman who 
can get pregnant, you must agree to use an effective method of birth control from the 
beginning of the study through the last study visit. If you find out that you were pregnant 
during the study, you must tell your doctor immediately. If you are breastfeeding or plan 
to breastfeed an infant, it is recommended by the World Health Organization that you 
avoid breast feeding for a period of time until your breast milk is tested to show that 
Ebola virus is not present. We also do not know if the study drugs can pass through in 
breast milk, and the risks to a nursing infant are not yet known. 
 
Men: The effects of the study drugs on sperm is not known. To protect against possible 
side effects, you should not get a sexual partner pregnant while taking part in this study. 
You must agree to use a condom from the beginning of the study through the last study 
visit. Research studies have found that Ebola virus can persist in the semen of Ebola 
survivors for extended periods after recovery from an Ebola infection, and might infect a 
sexual partner. Therefore, we recommend that you either don’t have sex or that you use 
condoms during sexual intercourse for as long is currently recommended by the World 
Health Organization, or until your semen is tested to show that Ebola virus is not present.   
If you recover from Ebola, we will talk with you about precautions you should continue 
to take to prevent passing the virus to others through bodily fluids. 
 
8. 
Are there benefits to being in the study? 
We do not know if you will benefit from being in this study. It is possible that the study 
drug you receive will help treat your Ebola infection. But we do not yet know which 
study drug is more effective. It is also possible that even if a drug is effective, it may 
cause serious side effects that make it more harmful than helpful. 


2018 Ebola MCM RCT Protocol 
Page 88 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
What we learn from this study may allow us to better understand Ebola and develop 
better ways of treating patients with Ebola in the future. 
 
9. 
What will happen to your samples and personal information? 
We will store your samples and data (information) for a very long time to use for future 
research on Ebola. Your stored samples and data will be marked with a code and not with 
your name. Only researchers linked to this study can get the codes. 
 
Your study information will be placed in a secure electronic system. It will not include 
your name. We must get approval from the DRC and US ethics boards that review this 
study before we share samples and data with other researchers. Other information, such 
as your sex, age, or health history might also be shared, but your name will not. This 
information cannot be traced back to you. You will not get any information about future 
research. Your sample will not be sold. You will not be paid for any products that result 
from this research. 
 
The only risk of allowing us to store your sample would be an accidental release of your 
identity. 
 
If you change your mind and decide you do not want us to store your sample or data, 
please let us know. We will do our best to follow your wishes but cannot promise that we 
will always be able to destroy your samples or data. 
 
10. 
Will it cost you anything to be in this study? 
It will not cost you anything to be in this study. 
 
11. 
Will you be paid if you join this study? 
No, you will not be paid. 
 
12. 
Who is watching over this study? 
A Data and Safety Monitoring Board (DSMB) will be looking at the study information 
very closely. The DSMB is made up of doctors and other people who are not directly 
involved in the study and who have a good understanding of Ebola and research studies. 
The DSMB may recommend changing the study drugs being used or stopping the study 
earlier than planned if they think it is not safe to continue or if they find out early that a 
drug is working better. The DRC and US ethics boards will also be watching over this 
study and have the authority to stop it at any time. 
 
13. 
How will your privacy be protected? 
We will keep your study information private. All files with information that could 
identify you will be kept in locked cabinets or secure computers. People responsible for 
making sure that the research is done properly may look at your study records. This might 
include people from the DRC and the US including the NIH and their designees. All of 
these people will also keep your identity private. Results from this study, but not your 


2018 Ebola MCM RCT Protocol 
Page 89 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
identity, may be shared with local medical providers or government health organizations 
to help them better understand Ebola virus infection. 
 
14. 
What other things should you know about this research study? 
a. ClinicalTrials.gov 
A description of this study is on the internet at http://www.ClinicalTrials.gov. This 
website will not include information about you. At most, the website will include a 
summary of the results. You can search this website at any time. 
 
b. Conflict of Interest 
The policy of the NIH is to evaluate investigators at least yearly for any conflicts of 
interest. Research participants may review the system for assessing conflicts of 
interest by checking the web site link: http://ethics.od.nih.gov/forms/Protocol-
Review-Guide.pdf. Copies of the standards may also be requested by research 
patients. This study has investigators that are NIH employees and some that are not. 
All non-NIH investigators are required to follow the principles of the Protocol 
Review Guide but are not required to report their financial holdings to the NIH. 
 
The US NIH and the research team for this study have developed one of the drugs 
being used in this study. This means it is possible that the results of this study could 
lead to payments to NIH and Institut National de Recherche Biomédicale (INRB) 
scientists and to the NIH. By law, US government scientists are required to receive 
such payments for their inventions. You will not receive any money from the 
development of the drugs being used in this study. 
 
c. What is the Ethical Review Committee and how does it protect you? 
Your government’s ethics committee will review this study. It protects the rights and 
welfare of the people taking part in research studies. You can contact Patrick 
Kayembe Kalambayi, coordinator of the DRC ethics board (Tel: 0818111182) to 
answer questions you may have about being part of this study and your rights as 
someone who is in a study. The ethics committee at the US NIH has also reviewed 
and approved this research. 
 
d. What do you do if you have questions about the study? 
If you have questions about the study, you may contact the principal investigators. Dr. 
Jean-Jacques Muyembe-Tamfum (DRC INRB) can be reached by phone +243 
898949289, or by email jjmuyembet@gmail.com. Dr. Richard T. Davey, Jr. (US 
NIH) can be reached by email rdavey@niaid.nih.gov. 
 
e. What should you do if you are injured or ill as a result of being in this study? 
We do not expect any harm from participating in this study. However, unforeseeable 
risks may be present. The study doctors will give you short-term medical care if you 
are hurt by being in this study. 
 


2018 Ebola MCM RCT Protocol 
Page 90 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
If you agree to be in this study, please sign or put your fingerprint below. 
 
 
________________________________________                                  Date: _____/_____/_____ 
Signature or fingerprint of participant or guardian                                             dd       mm      yy 
 
 
________________________________________ 
Printed name of participant or guardian 
 
 
_____________________________________                                        Date: _____/_____/_____ 
Signature of investigator/designee                                                                      dd       mm      yy 
 
_____________________________________ 
Printed name of investigator/designee 
 
 
Complete if participant is illiterate: 
 
Witness to Consent Interview 
 
On the date given next to my signature, I witnessed the consent interview for the research study 
named above in this document. I attest that the information in this consent form was explained to 
the subject, and the subject indicated that his/her questions and concerns were adequately 
addressed. 
________________________________________                                  Date: _____/_____/_____ 
Signature of witness                                                                                           dd       mm      yy 
 
 
________________________________________ 
Printed name of witness 
 
 


2018 Ebola MCM RCT Protocol 
Page 91 of 92 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
 
MINOR ASSENT TO PARTICIPATE IN STUDY 
 
NIAID Protocol #:  
19-I-0003 
 
Protocol Title:  
A Multicenter, Multi-Outbreak, Randomized, Controlled Safety and 
Efficacy Study of Investigational Therapeutics for the Treatment of 
Patients with Ebola Virus Disease 
 
Sponsors:  
United States National Institute of Allergy and Infectious Diseases 
(NIAID), National Institutes of Health (NIH) 
Democratic Republic of the Congo (DRC) National Institute for 
Biomedical Research 
 
Principal Investigators:  
Jean-Jacques Muyembe-Tamfum, MD, PhD (DRC) 
Richard T. Davey, Jr., MD (US)  
 
Site:  
Democratic Republic of the Congo (DRC), Central Africa 
 
 
1 
Introduction 
You are being asked to be in this study because you have Ebola. Ebola can make 
people very sick. Some people can die from it. There are no approved medicines for 
treating Ebola, so we are trying to learn more about how best to treat it.  
 
First, we want to explain the study to you. Then, you can decide if you want to be in it. 
You do not have to be in this study if you do not want to. 
 
2 
What is this study about? 
We recently completed a research study where we tested 4 possible medicines to find 
out if any of these medicines could help treat Ebola.  From an early review of the study 
results we now know that 2 of the 4 study drugs were better at treating Ebola than the 
others.  We do not yet know if one of these 2 might be better than the other because we 
are still reviewing the data.  While we are waiting to learn the results of the research 
study, we wish to make these medicines available to more people, including kids, who 
have Ebola.  
 
3 
Do I have to be in this study? 
No. You can decide not to be in the study. You can talk to your family, friends, and 
doctor before you decide. Even if you want to be in the study now, you can change 
your mind later and stop being in the study at any time. 
 


2018 Ebola MCM RCT Protocol 
Page 92 of 93 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
4 
What will happen in this research study? 
If it is okay with you and you agree to join this study, we will give you 1 of the study 
drugs. There are 2 study drugs that we are testing. You will only get 1 of them, but we 
do not know which one yet. You cannot pick which one you want but we will tell you 
when we find out which study drug you will receive. 
 
During the study, you will stay in the Ebola treatment center for a while. You may stay 
up to a few weeks if you are very sick. You will continue to get regular care for Ebola. 
We will use a needle to put a small tube in your arm for several days. We will give you 
the study drug through the tube in your arm. We will also collect some blood and we 
may ask you to give us some urine in a cup for tests.  
 
After some time in the treatment center, when the doctor thinks it is safe for you, you 
can go home. We will contact you at least one more time to ask how you are feeling. If 
possible, we will give you a check up and take some more blood for tests. Then you 
will be done with the study. Your total time in the study will be about 1 month. 
 
5 
Will any part of the study hurt? 
Taking a study drug may make you feel sick, but you may also feel sick from the 
Ebola. The study drugs have not been given to a lot of people, so the study drug you get 
may cause changes that hurt or bother you that we do not know about. It may also not 
have been given to many children before, so we may not know whether it may cause 
side effects in kids that were not seen in adults. In a very small number of people, the 
study drugs could cause something dangerous that people could die from. It is 
important that you always tell the study staff how you are feeling. 
 
If you get the drug called “mAb114,” you will get it 1 time. It might make you feel 
sick, cold, dizzy, or shaky, and it might give you a fever. It could make you have 
diarrhea, make you throw up or feel like you might throw up. It could make your head, 
muscles, or joints hurt. It could make you feel itchy, give you a rash or hives, or make 
your lips or face swell up. You could have trouble breathing. You could feel like your 
heart is beating too fast. It could give you a pain in your chest. 
 
If you get the drug called “REGN-EB3,” you will get it 1 time. It might make your 
head or muscles hurt. It could make you feel cold, shaky, or dizzy, or give you a fever, 
rash, or hives. It could make you cough or faint, make your joints hurt, or make your 
lips, face, or throat swell up. You could have trouble breathing. It could give you a pain 
in your chest. 
 
You will just get 1 of these drugs. You might have some of these things happen, or you 
might not feel any of them. We will watch you carefully when you get the study drug. 
If the drug makes you feel bad, we can sometimes give you medicines to help you feel 
better. 
 
It might hurt when we put a needle in your arm to draw blood or put in the plastic tube 
to give you the study drug. Your arm may get swollen and sore where the needle goes 


2018 Ebola MCM RCT Protocol 
Page 93 of 94 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
in, and you might get a black and blue mark. These things should go away on their 
own. There is a very small chance that you could get an infection.  
 
6 
What do I need to know about pregnancy during the study? 
If you are female: We do not know the effects of the study drugs in pregnancy or in a 
nursing baby. If you can become pregnant, we may do pregnancy testing while you are 
on this study. If you are pregnant or get pregnant around the time you get the study 
drug, we don’t know if there may be effects on you or your baby. Therefore, you 
should avoid getting pregnant for 2 months after getting the study drug. You will need 
to use birth control if you are sexually active, unless you are not able to get pregnant. If 
you think that you have gotten pregnant during the study, tell the study team right 
away, and find medical care for your pregnancy. 
 
If you are male: The effects of the study drugs on sperm are not known. Therefore, you 
should not get a sexual partner pregnant for at least 2 months after getting the study 
drug. You should use a condom every time you have sex for 2 months after getting the 
study drug. 
 
7 
Will the study help me? 
We do not know if you will be helped by being in this study. We do not know which 
study drug will make you feel better or get well sooner. It is possible that the study 
drug could make you worse. 
 
8 
Will the study help others? 
We might find out things from this study that will help other people with Ebola 
someday. 
 
9 
Do I have other choices? 
You do not have to be in this study. It is up to you. You can talk to your parents and 
your doctor about your options.  
 
No one will be upset if you don’t want to do this study. If you say okay now, but you 
want to stop later, that is okay too. If you decide to stop being in the study, all you have 
to do is tell your doctor or nurse that you don’t want to do the study anymore. No one 
will be mad at you if you change your mind. 
 
If you say no, you will still be given your regular care for Ebola. We will not give you 
the study drugs. 
 
10 
What if I have questions? 
If you want to talk to anyone about this research study because you think you have 
been hurt by being part of the study, or if have any other questions about the study, you 
should tell the study team: Phone number +243 826792353. 
 


2018 Ebola MCM RCT Protocol 
Page 94 of 94 
IND#: 125530 
         CONFIDENTIAL 
4 October 2019, version 7.0 
Also, you can contact Dr. Jean-Jacques Muyembe-Tamfum (Tel: +243 898949289) to 
answer questions you may have about being part of this study and your rights as 
someone who is in a study. 
 
If you have any questions at any time about this research study, you may ask someone 
on the study team. 
 
If you decide to be in the study, please write your name below. 
 
 
I have had this study explained to me in a way that I understand, and I have had the chance to 
ask questions. I agree to take part in this study. 
 
 
Signature or fingerprint of Minor Patient:  _____________________ 
Date: ____________ 
 
Print Name: _____________________________________________ 
 
 
Signature of Investigator/Designee:  _________________________ 
Date:  ____________ 
 
Print Name: _____________________________________________