Conditions: Ebola Virus Infection
Keywords: Medical Countermeasures VHF EVD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 72
Healthy volunteers: no

Brief summary:
Background:

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

Objective:

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

Eligibility:

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

Design:

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

Detailed description:
Ebolaviruses (EBOV) are members of the Filoviridae and are known primarily as the underlying cause of severe viral hemorrhagic fevers with disturbingly high case fatality rates. Between 1994 and the present, there have been many EBOV outbreaks affecting mostly central Africa, with 2 large outbreaks in 1995 in Kikwit, Democratic Republic of Congo (DRC), and in Gulu, Uganda in 2000-2001. However, the 2014 West African outbreak significantly exceeds all previous outbreaks in geographic range, number of patients affected, and in disruption of typical activities of civil society.

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

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

Arms:
arm 1: A/Current Standard of Care Alone: Optimized standard of care to include aggressive fluid resuscitation, hemodynamic support, and other interventions available in an optimized care setting arm 2: B/Current Standard of Care Plus ZMapp: ZMapp (Trademark) + Optimized standard of care to include aggressive fluid resuscitation, hemodynamic support, and other interventions available in an optimized care setting.

ZMapp 50mg/kg IV administered every third day for 3 infusions.

Interventions: intervention 1: B/Current Standard of Care Plus ZMapp intervention 2: A/Current Standard of Care Alone
Intervention descriptions: intervention 1: Triple monoclonal cocktail of antibodies against Zaire species of Ebola virus intervention 2: Optimized standard of care for Ebola virus infection

Protocol document:
Prot_SAP_ICF_000.pdf: 
 


 
This supplement contains the following items: 
1. Original protocol (version 1.0), summary of approved amendments, 
and the final protocol (version 6.0). 
2. Original statistical analysis plan (DSMB Charter) and the final 
statistical analysis plan. There were no formal amendments made to the 
original SAP. Rather, the Final SAP arose from a running series of 
discussions with FDA that culminated in the final plan that was DSMB- 
approved prior to unblinding of study data. 


 
A Multicenter Randomized Safety and Efficacy Study of Putative Investigational Therapeutics 
in the Treatment of Patients with Known Ebola Infection 
 
 
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: 301-496-8029; Email: rdavey@niaid.nih.gov 
 
Liberia Principal Investigator: Moses Massaquoi, M.D. 
Clinton Health Access Initiative 
Monrovia, Liberia 
Phone: 231-8863-83487Email: mmassaquoi@clintonhealthaccess.org 
 
Associate Investigators: 
John Beigel, MD, Leidos Biomedical Research, Inc, 301-451-9881, jbeigel@niaid.nih.gov 
Michael Proschan, PhD, DCR/NIAID/NIH, 301-451-5129, proscham@niaid.nih.gov 
Lori E. Dodd, PhD, DCR/NIAID/NIH, 240-669-5247, doddl@mail.nih.gov  
Bruce Ribner, Emory University Hospital, 404-686-8114, bribner@emory.edu 
Aneesh Mehta, Emory University Hospital, 404-686-8114, aneesh.mehta@emory.edu 
Colleen S. Kraft, Emory University Hospital, 404-712-8889, colleen.kraft@emory.edu 
Jay B. Varkey, Emory University Hospital, 404-686-8114, mailto:jay.varkey@emory.edu 
Philip Smith, Nebraska Medical Center, 402-559-8650, pwsmith@unmc.edu 
Angela L. Hewlett, Nebraska Medical Center, 402-559-4015, alhewlett@unmc.edu 
Christopher J Kratochvil, Nebraska Medical Center, 402-354-6868 ckratoch@unmc.edu 
Andre C. Kalil, Nebraska Medical Center, 402-559-4015, akalil@unmc.edu 
Timothy M. Uyeki, Centers for Disease Control and Prevention, 404-639-0277,tmu0@CDC.Gov 
Mark Kortepeter, Uniformed Services University, 301-319-0349, mkortepeter@usuhs.mil 
Timothy Burgess, Walter Reed National Military Medical Center, 301-467-9680, timothy.h.burgess.mil@mail.mil 
Scott Miller, Uniformed Services University, 301-816-8424, smiller@idcrp.org 
Research Contact: 
Holly Ann Baus, R.N., 301-443-5447, holly.baus@nih.gov 
Rose McConnell, R.N., 301-443-7106, rosemary.mcconnell@nih.gov 
 
Participating Sites: 
NIH Clinical Center 
Emory University Hospital 
University of Nebraska Medical Center  
Walter Reed National Military Medical Center 
Other sites TBD 
 
IND Sponsor: Office of Clinical Research Policy and Regulatory Operations (OCRPRO) 
 
Sponsor Medical Monitor: 
H. Preston Holley, M.D., F.A.C.P. 
Leidos Biomedical Research 
Phone (301) 228-4005 
email: Preston.Holley@fnlcr.nih.gov 
Version: 1.0 


 
Date: January 27, 2015 
Protocol Number: pending 
IND #: pending 


 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................4 
LIST OF TABLES ...........................................................................................................................6 
LIST OF FIGURES .........................................................................................................................7 
LIST OF ABBREVIATIONS ..........................................................................................................8 
PROTOCOL SUMMARY .............................................................................................................10 
PRÉCIS ..........................................................................................................................................13 
1 BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ................................14 
BACKGROUND.................................................................................................................................................................... 14 
1.1.1 
Filoviruses ............................................................................................................................................ 14 
1.1.2 
Therapy ................................................................................................................................................ 15 
RATIONALE FOR STUDY ................................................................................................................................................. 16 
2 STUDY OBJECTIVES ...........................................................................................................18 
PRIMARY OBJECTIVE ...................................................................................................................................................... 18 
SECONDARY OBJECTIVES .............................................................................................................................................. 18 
3 STUDY DESIGN. ...................................................................................................................19 
GENERAL ............................................................................................................................................................................. 19 
3.2 OVERVIEW OF STUDY DRUGS ..................................................................................................................................... 22 
3.3 CONSIDERATIONS IN CHOICE OF STUDY DRUGS ................................................................................................. 23 
4 STUDY POPULATION ..........................................................................................................24 
RESEARCH SUBJECT RECRUITMENT ......................................................................................................................... 24 
4.1.1 
Participation of Site Employees ........................................................................................................... 24 
INCLUSION CRITERIA ...................................................................................................................................................... 24 
EXCLUSION CRITERIA ..................................................................................................................................................... 24 
PREGNANT WOMEN ......................................................................................................................................................... 25 
4.4.1 
Inclusion of Children ............................................................................................................................ 25 
SUBJECT WITHDRAWAL ................................................................................................................................................. 25 
DISCONTINUATION OF SUBJECT BY INVESTIGATOR ........................................................................................... 25 
DISCONTINUATION OF STUDY ..................................................................................................................................... 26 
5 TREATMENT .........................................................................................................................26 
RANDOMIZATION AND BLINDING .............................................................................................................................. 26 
STUDY DRUGS ................................................................................................................................................................... 26 
6 STUDY PROCEDURES .........................................................................................................26 
PERSONNEL FOR STUDY PROCEDURES .................................................................................................................... 26 
SCHEDULE OF ASSESSMENTS ....................................................................................................................................... 26 
6.2.1  Screening and Informed Consent ............................................................................................................. 29 
6.2.3 
Medical History .................................................................................................................................... 29 
6.2.4 
Clinical Data ........................................................................................................................................ 29 
6.2.5 
Physical Exam ...................................................................................................................................... 29 
6.2.6 
Laboratory Testing ............................................................................................................................... 29 
DAY 0 .................................................................................................................................................... 31 
6.3.1 
Informed Consent ................................................................................................................................. 31 


 
6.3.1.1 
Baseline Evaluation ................................................................................................................................................ 31 
6.3.1.2 
Interval History and Exam ...................................................................................................................................... 31 
6.3.1.3 
Clinical Safety Laboratory Testing ........................................................................................................................ 31 
STUDY DAY 1 ....................................................................................................................................... 31 
6.4.1 
Baseline CRF completion ..................................................................................................................... 32 
6.4.2 
Reference Laboratory Testing .............................................................................................................. 32 
6.4.3 
Pharmacokinetic Sampling ................................................................................................................... 32 
STUDY DAYS 2+ ................................................................................................................................... 32 
6.5.1 
Interval History and Exam ................................................................................................................... 32 
6.5.2 
Clinical Safety Laboratory Testing ....................................................................................................... 32 
6.5.3 
Reference Laboratory Testing .............................................................................................................. 33 
6.5.4 
Vital Signs, Including SaO2 .................................................................................................................. 33 
7 STATISTICAL METHODS ....................................................................................................33 
BACKGROUND.................................................................................................................................................................... 33 
DESIGN ................................................................................................................................................................................. 33 
INTERIM MONITORING ................................................................................................................................................... 34 
ANALYSES ........................................................................................................................................................................... 41 
8 RISKS AND BENEFITS .........................................................................................................41 
POTENTIAL RISKS ............................................................................................................................................................. 41 
8.1.1 
Unknown Risks ..................................................................................................................................... 41 
8.1.2 
Risks of Phlebotomy ............................................................................................................................. 42 
8.1.3 
Risks to the Study Personnel and the Environment ............................................................................... 42 
POTENTIAL BENEFITS ..................................................................................................................................................... 42 
ALTERNATIVES .................................................................................................................................................................. 43 
9 RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, AND DATA ...........43 
INTENDED USE OF THE SAMPLES/SPECIMENS/DATA ......................................................................................... 43 
STORAGE OF SAMPLES/SPECIMENS/DATA ............................................................................................................. 43 
STORAGE OF GENETIC SAMPLES ................................................................................................................................ 43 
REPORTING LOSS OR DESTRUCTION OF SAMPLES/SPECIMENS/DATA ........................................................ 43 
10 REMUNERATION PLAN ......................................................................................................43 
11 ASSESSMENT OF SAFETY ..................................................................................................44 
DOCUMENTING, RECORDING, AND REPORTING ADVERSE EVENTS ............................................................. 44 
DEFINITIONS ....................................................................................................................................................................... 44 
INVESTIGATOR ASSESSMENT OF ADVERSE EVENTS .......................................................................................... 46 
11.3.1 Severity ................................................................................................................................................. 46 
11.3.2 Causality .............................................................................................................................................. 46 
INVESTIGATOR REPORTING RESPONSIBILITIES TO THE SPONSOR ................................................................ 47 
11.4.1 Adverse Events ..................................................................................................................................... 47 
11.4.2 Serious Adverse Events......................................................................................................................... 47 
11.4.3 Unanticipated Problems ....................................................................................................................... 48 
11.4.4 Pregnancy ............................................................................................................................................ 48 
REPORTING PROCEDURES TO THE IRB ............................................................................................... 48 
11.5.1 Expedited Reporting to the IRB ............................................................................................................ 48 
11.5.2 Waiver of Reporting Anticipated Protocol Deviations, Expected UPnonAEs and Deaths to the IRB..48 
11.5.3    Annual Reporting to the IRB ................................................................................................................ 48 
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ......................................................... 49 
SPONSOR’S REPORTING RESPONSIBILITIES ............................................................................................................ 49 
TREATMENT INTERRUPTION OR DISCONTINUATION .......................................................................................... 49 


 
HALTING DECISION ......................................................................................................................................................... 49 
11.9.1    Resumption of a Halted Study............................................................................................................... 50 
SAFETY OVERSIGHT ............................................................................................................................................. 50 
11.10.1 Investigator Safety Monitoring ............................................................................................................. 50 
11.10.2 Safety Review and Communications Plan (SRCP) ............................................................................... 51 
11.10.3 Sponsor Medical Monitor (SMM) ......................................................................................................... 51 
11.10.4 Data and Safety Monitoring Board (DSMB) ........................................................................................ 51 
12 CLINICAL MONITORING STRUCTURE ............................................................................51 
SITE MONITORING PLAN................................................................................................................................................ 51 
13 ETHICS/PROTECTION OF HUMAN SUBJECTS ...............................................................52 
INFORMED CONSENT PROCESS ................................................................................................................................... 52 
SUBJECT CONFIDENTIALITY ......................................................................................................................................... 52 
14 DATA MANAGEMENT AND MONITORING ....................................................................52 
DATA MANAGEMENT RESPONSIBILITIES ................................................................................................................ 52 
DATA CAPTURE METHODS:  REDCAP OR SIMILAR SYSTEM TO BE IDENTIFIED ....................................... 52 
TYPES OF DATA ................................................................................................................................................................. 53 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ......................................................... 53 
RECORD RETENTION ....................................................................................................................................................... 53 
SELECTED REFERENCES .........................................................................................................54 
STATISTICAL APPENDIX .........................................................................................................56 
SAMPLE INFORMED CONSENT FORM TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY ..........................................................................................................................................58 
APPENDIX A ................................................................................................................................65 
1. Physical, Chemical, and Pharmaceutical Properties and Formulation ....................................72 
1.1 PRODUCT DESCRIPTION ................................................................................................................................................. 72 
1.2 PRODUCT CHARACTERIZATION .................................................................................................................................. 73 
1.3 PRODUCT FORMULATION .............................................................................................................................................. 73 
1.4 STORAGE AND HANDLING ............................................................................................................................................ 73 
2. Effects in Humans ....................................................................................................................74 
2.1 PHARMACOKINETICS AND PRODUCT METABOLISM IN HUMANS .................................................................. 74 
2.2 SAFETY AND EFFICACY .................................................................................................................................................. 74 
Summary of Data and Guidance for the Investigator ....................................................................77 
2.3 POSSIBLE RISKS AND ADVERSE DRUG REACTIONS ............................................................................................ 77 
2.4 GUIDANCE FOR THE INVESTIGATOR ......................................................................................................................... 78 
2.4.1 
Guidance for infusions ......................................................................................................................... 79 
2.4.2 
Patient Monitoring and Assessment ..................................................................................................... 79 
 
 
LIST OF TABLES 
Table 1: Ebolavirus Outbreaks ......................................................................................................14 
Table 2: Schedule of Assessment ..................................................................................................27 
Table 3: Flexibility of Trial Design ...............................................................................................36 


 
Table 4: Probability of Crossing the Boundary for Different Mortality, Probabilities, and Sample 
Sizes in the 2 Arms ........................................................................................................................37 
Table 5: Average Final Sample Size per Arm using Stopping Criteria Defined Above ...............37 
Table 6: Approximate Power under Different per Arm Sample Sizes (n) when the Larger and 
Smaller Mortality Probabilities are pA and pB, Respectively .........................................................56 
Table 7: Sample Sizes required for 80% and 90% Power for Different Values of the Larger and 
Smaller Mortality Probabilities, pA and pB.....................................................................................57 
LIST OF FIGURES 
Figure 1: Example of Possible Clinical Trial Design Schematic for the Common Protocol – First 
Phase ..............................................................................................................................................21 
Figure 2: Interim Analysis after 10/Arm .......................................................................................38 
Figure 3: Interim Analysis after 15/Arm .......................................................................................39 
Figure 4: Interim Analysis after 20/Arm .......................................................................................39 


 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event/Adverse Experience 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations (US) 
CI 
Confidence Interval 
CRF 
Case Report Form 
CSO 
Clinical Safety Office 
DCR 
Division of Clinical Research 
DRC 
Democratic Republic of Congo 
DSMB 
Data and Safety Monitoring Board 
EBOV 
Ebola virus 
ECG 
electrocardiogram 
EVD 
Ebola hemorrhagic fever 
EUA 
Emergency Use Authorization 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practices 
HCW 
health care workers 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Institutional Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MCMs 
medical countermeasures 
NHP 
nonhuman primate 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
OCRPRO 
Office of Clinical Research Policy and Regulatory Operations 
OHRP 
Office for Human Research Protections 
oSOC 
optimized standard of care 
OTC 
over-the-counter 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
POC 
point-of-care 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SERF 
Safety Expedited Report Form 
SMM 
Sponsor Medical Monitor 
SOC 
standard-of-care 
SRCP 
Safety Review and Communications Plan 
SUSAR 
Serious Unexpected Suspected Adverse Reactions 
UP 
Unanticipated Problem 
UPnonAE 
Unanticipated Problem that is not an Adverse Event 
WBC 
White Blood Cell Count 


 
ZEBOV 
Zaire ebolavirus 


 
PROTOCOL SUMMARY 
 
Full Title: 
A Multicenter Randomized Safety and Efficacy Study of Putative 
Investigational Therapeutics in the Treatment of Patients with 
Known Ebola Infection 
Short Title: 
MCM RCT in EBOV 
Clinical Phase: 
1/2 
IND Sponsor: 
Office of Clinical Research Policy and Regulatory Operations 
(OCRPRO) 
Conducted by: 
Multicenter Trial 
Principal Investigator: 
Richard T. Davey, Jr., MD 
Sample Size: 
Accrual Ceiling: 
Study Population: 
Up to 100 per arm 
1000 
Patients with known Ebola infection 
Accrual Period: 
January 2015 – December 2016 
Study Design: 
Randomized clinical trial 
Study Duration: 
Start Date: January 2015 
End Date: December 2016 
Study Agents: 
ZMapptm, convalescent plasma, favipiravir, TKM-Ebola, others 
Primary Objective: 
• To establish the safety and efficacy of investigational 
therapeutics in patients with Ebola virus infection 
 
Secondary Objectives: 
• Uniform observational database on clinical and virologic 
parameters associated with severe Ebola virus infection 
• To evaluate the comparative effects of investigational 
therapeutics on clinical parameters of Ebola infection 
• Comparative effects of different investigational agents on 
immediate plasma viral load kinetics 
• 24-48 hour pharmacokinetics of investigational therapeutics 
when possible and appropriate 
• Comparative frequency of adverse events (AEs) and serious 
adverse events (SAEs) 
• Duration of hospital stay 
• Time to viral load clearance 
 
Primary Endpoint: 
• Mortality at Day 28 
Inclusion Criteria 
• Males or females with documented positive PCR for Ebola 
virus infection within 10 days of enrollment 
• Willingness of study participant to accept randomization to 
any assigned treatment arm 
• Access to optimized standard-of-care (oSOC) 


 
• All males and females of childbearing potential, must be 
willing to use effective methods of contraception, from time 
of enrollment through at least 90 days after viral clearance 
• Must agree not to enroll in another study of an 
investigational agent prior to completion of last required 
protocol visit 
• Patient or Surrogate must provide written informed consent 
 
 
 
Exclusion Criteria: 
• Any serious medical condition that, in the opinion of the site 
investigator, would place the patient at an unreasonably 
increased risk through participation in this study, including 
any past or concurrent conditions that would preclude 
randomization to one or more of the assigned treatment 
arms. 
• Prior treatment with any investigational antiviral drug 
therapy against Ebola infection or investigational anti-Ebola 
vaccine within 5 half-lives or 30 days, whichever is longer, 
prior to enrollment. 
• Patients who, in the judgment of the investigator, will be 
unlikely to comply with the requirements of this protocol 
 
Study Design 
Principles: 
A randomized, controlled adaptive trial, with frequent interim 
monitoring to facilitate the following: dropping of poorly performing 
arms, introduction of new candidate therapies and modification of 
current optimized standard-of-care (oSOC). Comparisons of safety 
and efficacy will be based on data from concurrently randomized 
participants. In its simplest iteration, the study can be viewed as a 
series of 2-arm comparisons whereby the superior treatment, if 
identified, from each pairwise comparison becomes the basis of the 
new supportive care backbone (hence the term “optimized SOC”, or 
oSOC, to describe this potentially evolving backbone) common to 
each future arm of the study and against which additional 
investigational interventions may then be added to the protocol, 
tested and compared: 
Arm A: optimized SOC alone 
Arm B: Investigational treatment X + optimized SOC 
 
• In the initial iteration and at protocol team discretion, the 
optimized SOC employed in Arm A is expected to consist of 
aggressive fluid replacement, hemodynamic support, 


 
electrolyte monitoring and replacement, and other measures of 
advanced medical support, to be compared to Arm B in which 
both investigational therapeutic agent X plus that same 
optimized SOC are featured. 
• If this pairwise comparison shows the superiority of Arm B 
over Arm A, then investigational treatment X featured in Arm 
B will be incorporated into the new oSOC common to each 
future arm of the study (assuming adequate drug supply exists 
to permit this). 
• Conversely, if a given pairwise comparison of Arm A versus 
Arm B fails to yield a clear statistical winner in terms of the 
primary endpoint, then subsequent pairwise comparisons will 
not incorporate the “failed” intervention featured in current 
Arm B into the new oSOC backbone. 
 
Study Synopsis: 
• Informed consent for research participation upon admission 
into the treatment center 
• Baseline determination of clinical status according to 
standardized CRF 
• Baseline collection of plasma for viral load by PCR to be 
processed by an appropriate laboratory facility 
• Centralized randomization assignment made 
• Provision of Arm A or Arm B intervention according to 
assigned treatment arm and the individual pharmacologic or 
logistical requirements of the treatment intervention 
• 24-48 hour pharmacokinetic measurements of assigned 
intervention where appropriate and possible 
• Daily assessments of clinical status according to standardized 
CRF and flowsheet 
• Serial collection of plasma for viral load determination by 
PCR for processing in an appropriate laboratory facility 
• Primary and secondary endpoint determinations 


 
PRÉCIS 
 
Ebolaviruses (EBOV) are members of the Filoviridae and are known primarily as the underlying 
cause of severe viral hemorrhagic fevers with disturbingly high case fatality rates. Between 
1994 and the present, there have been many EBOV outbreaks affecting mostly central Africa, 
with 2 large outbreaks in 1995 in Kikwit, Democratic Republic of Congo (DRC), and in Gulu, 
Uganda in 2000-2001. However, the 2014 West African outbreak significantly exceeds all 
previous outbreaks in geographic range, number of patients affected, and in disruption of 
typical activities of civil society. 
 
There is strong consensus that the most important element necessary to improve survival from 
Ebola infection is the provision of full hemodynamic support in the form of aggressive fluid 
replacement, ability to diagnose and correct severe metabolic derangements, and other 
standards of modern medical care available in resource-rich environments. However, against 
this background, a small series of investigational agents or interventions have also been 
proposed as putative antiviral strategies of potential utility in treating this infection. 
Unfortunately, phase 1/2 data supporting the safety and efficacy of these agents is generally 
lacking, and thus there should be equipoise as to which, if any, of these interventions should be 
utilized in the treatment of severe infection. 
 
In this multicenter randomized trial, we propose a flexible trial design with frequent interim 
monitoring to facilitate early elimination of poorly performing treatments as well as the 
introduction of new candidate therapies. The trial allows for a series of pairwise comparisons of 
novel interventions against a background of optimized medical care, with the goal of 
determining whether one or more of these interventions can improve the mortality over that 
achievable through optimized standard-of-care (oSOC) alone. The primary endpoint of this trial 
will be comparative mortality at Day 28, with a number of secondary endpoints that hopefully 
will generate generalizable knowledge about the relative safety and antiviral activity of these 
adjunctive interventions. 


 
1 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
Background 
1.1.1 Filoviruses 
Ebolaviruses (EBOV) are members of the Filoviridae and are known primarily as the underlying 
cause of severe viral hemorrhagic fevers with disturbingly high case fatality rates. Between 
1994 and the present, there have been many EBOV outbreaks (Table 1) affecting mostly central 
Africa, with 2 large outbreaks in 1995 in Kikwit, DRC, and in Gulu, Uganda in 2000-2001. The 
ongoing West African outbreak significantly exceeds all previous outbreaks in geographic range, 
number of patients affected, and in disruption of typical activities of civil society. 
Table 1: Ebolavirus Outbreaks 
 
Viral species 
Year 
Outbreak location 
# of human cases (% fatality) 
1976 
Yambuku, Zaire (DRC) 
318 (88%) 
Zaire ebolavirus 
1977 
Tandala, Zaire (DRC) 
1 (100%) 
1994 
Ogooue-Invindo province, 
Gabon 
51 (60%) 
1995 
Kikwit, Democratic Republic of 
Congo 
315 (79%) 
1996 
Mayibout, Gabon 
37 (57%) 
1996 
Booue, Gabon and 
Johannesburg, South Africa 
61 (74%) 
2001-02 
Ogooue-Invindo province, 
Republic of Congo (RC) 
124 (79%) 
2002-03 
Cuvette region, RC and Ogooue- 
Invindo province, Gabon 
143 (90%) 
2003 
Mboma and Mbandza, Republic 
of Congo 
35 (83%) 
2005 
Etoumbi and Mbomo, Republic 
of Congo 
12 (75%) 
2007 
Kasai Occidental province, 
Democratic Republic of Congo 
25 (not determined) 
2008/2009 
Democratic Republic of the 
Congo 
32 (47%) 
Sudan ebolavirus 
1976 
Nzara, Maridi, Tembura, Juba, 
Sudan 
284 (53%) 
1979 
Nzara, Yambio, Sudan 
34 (65%) 
2000-01 
Gulu, Masindi, Uganda 
425 (53%) 
2004 
Yambio, Sudan 
17 (41%) 
2011 
Uganda (Luwero District) 
1 (100%) 
Taï 
1994 
Tai forest, Ivory Coast 
1 (0%) 
ebolavirus 
1995 
Liberia, Liberia 
1 (0%) 
Reston ebolavirus 
1989 
Reston, VA, USA 
4 (0%) 
1992 
Siena, Italy 
0 
1996 
Alice, TX, USA 
0 
2008 
Philippines 
0 


 
 
Bundibugyo 
ebolavirus 
2007/2008 
Uganda 
131 (37%) 
 
1.1.2 Therapy 
To date the standard treatment of Ebola hemorrhagic fever (EVD) during the present 2014 
outbreak has been strictly supportive, involving largely oral fluid and electrolyte replenishment 
and pain reduction. 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 have neither been available nor tested in most patients. However, in the few centers 
where such measures were able to be employed, a substantial reduction in mortality has been 
reported. Thus, substantial planning efforts are currently geared towards identification, 
standardization, and deployment of the most successful standard-of-care (SOC) measures that 
potentially could be introduced into these previously resource-poor areas where the majority 
of patients have been treated. In addition to ongoing epidemiologic measures to limit the 
spread to uninfected populations, there is widespread consensus that improved SOC measures 
could represent the single most effective means of reducing the substantial mortality rates 
associated with the disease in the affected regions. 
 
In contrast, in the United States and other developed nations to which a small number of 
infected health care workers (HCW) have been medically evacuated, aggressive intravenous 
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 optimized standard of 
care (oSOC) there 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 October 8, 2014, investigational treatment data were available 
on a total of 13 HCWs or other individuals with documented Ebola infection who had been 
medically evacuated to special isolation units in the US or Europe. The reported distribution to 
date of MCMs in these individuals was as follows: 
 
 
2 have received no MCMs to date
 6 have received 1 MCM to date
 4 have received 2 MCMs to date
 1 has received 3 MCMs to date
 
The reported list of MCMs employed in the experimental treatment of these individuals 
includes convalescent plasma (4 patients), zMapp triple monoclonal antibody cocktail (4 
patients), Tekmira siRNA product (3 patients), favipiravir (4 patients), brincidofovir (2 patients), 
and zMaB monoclonal antibody cocktail (1 patient). In addition, to date 5 medically evacuated 
HCWs with serious needlestick exposures to Ebola virus, while in country, but no documented 
infection, have also received 1 putative MCM each: Tekmira siRNA in one case and the 
investigational VSVΔG-ZEBOV vaccine in the other four. It should be emphasized that in 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 humans 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 in 
rodent models, but either failed testing or were not thoroughly tested in the nonhuman 
primate (NHP) model, which is 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 current 
outbreak and, in fact, was also used in a limited number of patients during the Kikwit 1995 
ZEBOV outbreak. However, its earlier success remains a matter of dispute (1). Experimentally, 
passive immunization with horse serum resulted in protection of Hamadryl baboons (2), 
whereas it only delayed death in Cynomolgus macaques (3, 4). Certain monoclonal antibody 
treatments have also been successful in rodent models (5-7) but have failed in preliminary 
nonhuman primate studies (8), indicating possible evasion of antibody neutralization as an 
escape mechanism of the virus. Other, more recent monoclonal antibody cocktails may avoid 
this limitation. However, it remains fair to say, at least at this time, that the therapeutic role of 
convalescent plasma or monoclonal preparations as treatment adjuncts remain as 
unsubstantiated in this disease as do direct antiviral agents. 
Rationale for Study 
The current state of medical science with respect to the treatment of filovirus infections such as 
Ebola does not adequately address the role of therapeutic adjuncts beyond supportive care in the 
successful management of these infections. In many cases, our understanding of the role that 
these adjunctive therapies may play is greatly hampered by lack of an adequate phase 1 safety 
and toxicity database of the lead drug candidates, or by lack of data concerning even how the 
candidates in more advanced development may perform in this particular patient population. The 
tragic dimensions of the ongoing Ebola epidemic in West Africa afford little time to explore 
these issues according to a more conventional time frame of traditional drug development, and 
argue strongly for an accelerated exploration of the safety, toxicity, and potential preliminary 
efficacy of lead agents in a controlled research setting. 
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: 
• Even in highly-resourced medical environments such as those available in the US, 
Europe, or other developed regions, the past record of being able to generate important 
and generalizable knowledge concerning the role of experimental therapies for infectious 
diseases of public health importance when those agents have been made available under 
single-use emergency IND, Emergency Use Authorization (EUA), or similar mechanisms 
has been disappointing at best. A consolidated multicenter approach to study lead 
candidates according to a single research protocol offers a potential opportunity to 
improve upon this record. 
• Even if concentrated efforts to generate important comparative efficacy assessments 
between individual treatment interventions falls short, 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 receiving oSOC. 
• Optimized SOC must be the mainstay of therapy and remain the backbone to which 
experimental treatment modalities must be introduced and compared. 
• Depending upon site and resources, invariably differences in oSOC may occur that may 
obscure the potential additional contribution of experimental therapeutics. Therefore, 
every effort must be made to standardize the oSOC that exists as the backbone to this 
experimental treatment protocol. In situations where this may not be fully possible, i.e. in 
comparing in-country oSOC versus oSOC available in intensive care settings within 
developed nations, this difference must be taken into account when comparing outcome 
in different patient cohorts. 
• Questions of equity concerning the ethics of allowing potentially beneficial experimental 
treatments to be studied in places where fully optimized supportive care may be possible, 
and not in places where optimized care has not been introduced to date, are certainly 
reasonable, heartfelt, and compelling but, if taken to their logical extreme when involving 
drugs in extremely limited supply and of unknown safety, could prevent their scientific 
study altogether and result in no generalizable knowledge being generated about the 
value of these agents in any setting, an outcome that would disadvantage society as a 
whole. 
• A unique and presently unavoidable factor in establishing pairwise comparisons 
identified for this trial is the limited, intermittent, or absent drug supply that may exist for 
several of the lead candidates proposed for study. The current flexible treatment design is 
an attempt to overcome this unpredictable element. 
• As present knowledge of the potential toxicity of lead candidates in this patient 
population is as limited as knowledge of their potential therapeutic value, investigators 
should and must be able to maintain equipoise as to the introduction and role of 
individual agents in treating patients severely ill with Ebola infection. 
 
• A key ethical feature and justification for this approach, based upon the current and 
foreseeable circumstances, is that there is a significant degree of ‘acceptability of [trial 
drug] risk,’ in the face of unprecedented individual and community risk for morbidity and 
mortality. 
• The use of a common protocol is recommended for the following reasons: 
o This design can accommodate the study of more than 1 investigational therapy using 
a single shared control group. 
o As mentioned above, this design can accommodate staggered and intermittent 
availability of limited supplies of the anti-Ebola investigational drugs 


 
o This design can also provide a more equitable means of allocating scarce product 
through randomization (much like a lottery) while also allowing critically important 
data to be gathered on the safety and efficacy of these investigational products that 
will benefit patients (i.e., knowledge of whether an investigational product is 
actually helping, hurting, or of no consequence). 
o Having a randomized concurrent control group is essential to maximize the 
likelihood that the conclusions drawn from the trial are correct. 
o A single trial design allows for having a data safety monitoring board (DSMB) and 
stopping rules in place. The stopping rules should be reasonable, and if one of the 
products is found to be effective at an interim time point but there is not a sufficient 
supply of the product that has been found to be effective, it may still be ethical to 
continue the common protocol. When sufficient supplies of the product become 
available, that product might be incorporated into the revised oSOC, as discussed 
earlier. If there are insufficient supplies of a product, even if efficacy has been 
shown, one may be able to argue that providing the scarce supplies of drug through 
a clinical trial is more equitable than other potential approaches in addition to 
allowing continued comparative data generation to improve the understanding of its 
appropriate use. 
2 
STUDY OBJECTIVES 
Primary Objective 
• To establish the safety and efficacy of investigational therapeutics in patients with Ebola 
virus infection. 
Secondary Objectives 
• To create a uniform observational database on clinical and virologic parameters 
associated with severe Ebola virus infection 
• To evaluate the comparative effects of investigational therapeutics on clinical parameters 
of Ebola infection 
• To study the comparative effects of different investigational agents on immediate plasma 
viral load kinetics 
• To obtain 24-48 hour pharmacokinetics of investigational therapeutics when possible and 
appropriate* 
• To determine the comparative frequency of adverse events (AEs) and serious adverse 
events (SAEs) 
• To compare the duration of hospital stay 
• To compare the time to viral load clearance 
 
* 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 of infectious samples falling under Select Agent regulations, could limit 
these explorations outside the context of a high containment laboratory such as a BSL-4 facility. 
3 
STUDY DESIGN 
General 
Study size: up to 1000 patients 
Study duration: 24 months 
Study duration of individual subjects: 30 days following the primary endpoint (mortality at day 
28), or for a total of 58 days. 
Sex distribution: males and females 
Age range: unrestricted 
 
A randomized, controlled clinical trial of experimental Ebola virus disease therapies compared 
to current oSOC. Treatment efficacy evaluations are based on outcome comparisons between 
treatment arms from concurrently enrolled subjects. The study can be conceptualized as a 
series of 2-arm comparisons between different therapeutic interventions: oSOC versus an 
experimental therapy plus oSOC. It is intended that the oSOC will be updated to incorporate an 
experimental therapy when the latter’s efficacy has been demonstrated. While the updated 
oSOC should be the comparator for unproven therapies, this may not always be practical (e.g., 
when supply of the new drug is limited). Whether the updated oSOC is always added as 
optimized background therapy to existing unproven/experimental therapies will depend on 
practical considerations, including drug availability and the appropriateness of combining 
specific therapies. However, the intent is that the study will continue enrolling and employ the 
next selection of available medical countermeasure in the comparison if there is a temporary 
shortage of the present countermeasure being studied. 
 
Stage 1: the initial phase (see figure 1) 
Randomization to the following: 
 
Arm A: oSOC1** alone 
or 
Arm B: Investigational treatment X + oSOC1** 
 
*The subscript “1” indicates the first or current “optimized standard-of-care.” In the 
initial iteration and at protocol design team discretion, Arm A will be an oSOC alone arm 
to be compared to Arm B in which both an investigational therapeutic agent (i.e. Drug 
“X”) plus oSOC are combined. 
** In developed countries, oSOC is defined as the application of aggressive fluid 
resuscitation, hemodynamic and respiratory support, metabolic corrections, diagnostic 
evaluation, and other modalities of advanced critical care that are generally available in 
most academic centers capable of caring for critically ill patients. In areas where such 
advanced methods may not be fully available (i.e., in advanced medical care units to be 


 
built and supported in the affected countries of West Africa by the USG and other 
government entities), this definition should apply to the optimal standards of care 
possible in those settings. 
 
If and when a statistical difference is shown between the 2 arms supporting superiority of one 
intervention over the other, the superior (“winning”) intervention is then used as the basis of a 
modified oSOC in which incorporation of that intervention as an addition to the prior oSOC 
becomes the new basis of comparison. This is assuming that sufficient drug supply exists to 
permit the incorporation of that superior therapy into a new oSOC backbone and fuel 
additional comparisons. If that is not the case, then subsequent comparisons will have to revert 
back to the previous oSOC until such time as additional quantities of the superior therapy can 
be made available. If, however, incorporation into a new oSOC is possible, then that modified 
arm can then compared to new Arm C (i.e., consisting of a new therapeutic intervention not 
previously tested) so that the pairwise comparisons can continue until the list of favored 
treatment explorations is exhausted and/or until an optimal regimen appears clear. This can be 
summarized as follows: 
 
Stages 2-K: the post-initial phase with up to K additional therapies. 
Randomization to the following: 
Control arm: Updated current oSOC (oSOCk; where k=2,…, K to indicate the possible 
updated oSOCs) 
Experimental arm: Investigational therapy + best oSOC, where the best oSOC may be the 
most current oSOC or the previous oSOC, depending on drug availability, 
appropriateness of combination therapy, etc. as determined by the study team in 
concordance with the DSMB. 
 
Advisory stopping boundaries for efficacy (and futility) will be provided to the DSMB to guide 
decisions about when an experimental arm is deemed superior (or not worthy of further 
investigation). A description of these boundaries is provided in the statistics section (Section 7). 
Specifics about these boundaries will be provided in a DSMB statistical analysis plan. 
 
While for illustrative purposes, the strategy is described with sequential pairwise comparisons, 
in practice, it can be adapted for more than 2 pairwise comparisons. The study might be 
modified accordingly, if there is compelling scientific interest to study more than 2 different 
interventions simultaneously (“Drug Y” example in Figure 1). Success at being able to 
demonstrate statistical difference between comparator arms will of course depend upon being 
able to enroll sufficient numbers into each arm to power these comparisons. 


 
 Version 1.0 
 
 
 
Figure 1: Example of Possible Clinical Trial Design Schematic for the Common Protocol – First Phase 
 


 
 Version 1.0 
 
 
 
3.2 
Overview of Study Drugs 
At the present time (fall 2014) preclinical studies, and/or past use of interventions with 
anecdotal evidence, have identified at least 7 candidate therapeutic interventions that might be 
considered as prime candidates for further study in patients with known Ebola infection. With 
time it is possible that additional antiviral or immune-enhancing agents with preclinical 
supporting data may be identified and added to this list. Conversely, emerging toxicity data, 
failure to replicate previous supportive findings in additional preclinical animal model testing, 
or similarly negative factors could also lead to narrowing of this list over time. Further, if 
inclusion were to be expanded to patients with high-risk exposures but no documented 
infection, the list of putative MCMs could be broadened even further and would likely include 
putative vaccine candidates. However, confining this proposed RCT to just enrollees with 
documented infection, the likely lead candidates for consideration of study would include: 
• Convalescent or post-immunization plasma harvested from recent Ebola infection 
survivors: 
o In time it is possible that this category could potentially be expanded to include 
plasma donors who have participated in phase 1 anti-Ebola vaccine testing and whose 
plasma shows high neutralizing activity against the virus in animal or in vitro assays. 
• zMapp triple monoclonal antibody cocktail from Mapp Biopharmaceutical: 
o A combination of 3 different humanized monoclonal antibodies against the 
glycoprotein of Ebola 
• Tekmira siRNA (or “TKM-Ebola”) from Tekmira Pharmaceuticals Corp: 
o 
A combination of small interfering RNAs targeting 2 of the 7 proteins in Ebola: Zaire 
Ebola L polymerase and Zaire Ebola polymerase complex protein (VP35), formulated 
with Tekmira's lipid nanoparticle technology. 
• Favipiravir from Toyama Chemical Co., LTD: 
o A selective inhibitor of RNA-dependent RNA polymerase with activity against a 
wide variety of viruses. 
• Brincidofovir (CMX001) from Chimerix: 
o An oral nucleotide analog with reportedly a more favorable toxicity profile than 
cidofovir and activity against DNA viruses that also has been shown in vitro to have 
activity against Ebola virus. 
• BCX4433 from BioCryst 
o 
viral RNA-dependent RNA polymerase (RdRp) inhibitor 
• AVI-7537 from Sarepta 
o 
phosphorodiamidate morpholino oligomer 


 
 
 
 
 
 
 
3.3 Considerations in Choice of Study Drugs 
Several factors influencing choice and sequence of study drugs/interventions to be compared in 
this protocol must be considered: 
• Willingness of both the pharmaceutical sponsors and the FDA to allow each of these 
drugs to be studied according to this proposed trial design 
• Sufficient and dedicated supply of individual agents to allow them to be available for 
study over the projected timeline of the trial 
• Ongoing equipoise of the investigators that 
o No available individual agent has yet been demonstrated to be superior to oSOC 
o No available individual agent has yet been demonstrated to be superior to other 
agents 
• No compelling safety/toxicity concern has emerged with respect to individual agents to 
favor their removal from consideration as study interventions 
• The status of eIND access to these interventions during the projected timeline of this trial 
that may preclude, or circumvent, interest in enrollment of patients into this RCT. 
 
With these considerations in mind, the starting choice of interventions to be entered into and 
compared in this trial will be determined by a consensus of the site investigators performing 
this study at their individual treatment centers. The most recent deliberations of this group are 
reflected in Appendix A of this protocol. 
 
3.4 
Definitions for the Purpose of this Study 
Enrolled 
For the purpose of collecting data and samples, and reporting AEs, a subject will be 
considered enrolled beginning from when the informed consent form is signed until the 
subject is considered either “discontinued”, or “completed”. 
 
Discontinued 
Subjects are considered discontinued when they meet 1 or more of the following criteria: 
o Subject withdraws consent after being dosed and prior to the completion of Day 28 
(see section 4.5) 
o Subject is withdrawn after enrollment by investigator (see Section 4.6) including lost 
to follow-up 
 
Completed 
Subjects are considered completed when they 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 scheduled for that time 


 
 
 
4 
STUDY POPULATION 
Research Subject Recruitment 
Enrollees will be sought from amongst those HCWs and other individuals who are medically 
evacuated to the United States or other participating countries for additional medical care not 
available at the site of Ebola infection, whose infection was diagnosed in the United States or 
other participating countries following their return, or who may have acquired the infection as 
cases of secondary transmission. This trial will also be expanded to include medical treatment 
units in West Africa capable of providing an enhanced level of supportive care at the time that 
those facilities declare themselves capable of supporting clinical research endeavors of this type 
and complexity. At the very least this designation of being able to provide enhanced supportive 
care should include the provision of aggressive fluid resuscitation (preferably intravenously, but 
potentially orally through nasogastric tubes), hemodynamic monitoring, and point-of-care 
monitoring of fluid and electrolyte disturbances coupled with the ability to correct such 
abnormalities as they are detected. 
4.1.1 Participation of Site Employees 
Site employees who meet inclusion 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. 
• To protect the privacy and confidentiality of employee’s participation the employee 
participant must not work directly for the Principal Investigator (PI) or any of the 
associate investigators on this protocol. 
Inclusion Criteria 
• Males or females with documented positive PCR for Ebola virus infection within 10 days 
of enrollment 
• Willingness of study participant to accept randomization to any assigned treatment arm 
• Access to oSOC 
• All males and females of childbearing potential, must be willing to use highly effective 
[e.g. absolute abstinence from potentially reproductive sexual activity, hormonal, 
surgical or multiple barrier/combined] methods of contraception, from time of 
enrollment through at least 90 days after viral clearance 
• Must agree not to enroll in another study of an investigational agent prior to completion 
of last required protocol visit 
• Ability to provide informed consent personally, or by a legally-authorized [per applicable 
local laws and regulations] representative [LAR] if the patient is unable to do so. 
Exclusion Criteria 
• Any medical condition that, in the opinion of the site investigator, would place the 
patient at an unreasonably increased risk through participation in this study, including 
any past or concurrent conditions that would preclude randomization to one or more of 


 
 
 
the assigned treatment arms (e.g., severe nausea and vomiting precluding use of oral 
therapies). 
• Prior treatment with any investigational antiviral drug therapy against Ebola infection or 
investigational anti-Ebola vaccine within 5 half-lives or 30 days, whichever is longer, 
prior to enrollment. 
• Patients who, in the judgment of the investigator, will be unlikely to comply with the 
requirements of this protocol 
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 infection than from the study 
medications themselves, pregnant women will be permitted entry into the study. However, 
there may still be certain study medications (e.g., favipiravir) with known teratogenic potential 
to which pregnant women should not be assigned, and these considerations must be reviewed 
on a case-by-case basis with study investigators. If favipiravir happens to be the drug currently 
under study, pregnant women should not be enrolled in the trial during the period this 
particular drug is being tested. The risks from the study medications to nursing infants are also 
unknown at this time. Therefore, female subjects will be required to avoid breastfeeding during 
the study to minimize any potential risk. 
Whenever possible, every attempt will be made to track the pregnancy until delivery in order to 
determine the outcome of the study intervention on the fetus. 
4.4.1 Inclusion of Children 
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 study participation. 
Subject Withdrawal 
Subjects can terminate 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. Subjects who withdraw prior to receipt of their assigned 
experimental treatment intervention will be replaced and will not be counted against the 
cap/arm. 
 
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 be withdrawn 
from the study for any of the following reasons: 


 
 
 
• The investigator believes that continuation in the study would be detrimental to the 
subject. In general, subjects withdrawn for AEs will still be followed for safety follow-up 
if possible. 
• If in the investigator’s best judgment discontinuation is in the subject’s best interest. 
The reason for withdrawal from the study is to be recorded in the study record. If a non-serious 
AE is unresolved at the time of discontinuation, efforts should be made to follow up until the 
event resolves or stabilizes, the subject is lost to follow-up, or there is some other resolution of 
the event. The investigator is to make every attempt to follow all SAEs to resolution. 
Discontinuation of Study 
The National Institute of Allergy and Infectious Diseases (NIAID), each institution’s Institutional 
Review Board (IRB), or the Food and Drug Administration (FDA) may terminate this study at any 
time. Reasons for terminating the study may include, but are not limited to, the following: 
• The incidence or severity of an AE in this or other studies indicates a potential health 
hazard to subjects 
• Subject enrollment is unsatisfactory 
• Data recording is inaccurate or incomplete 
• Investigators do not adhere to the protocol or applicable regulatory guidelines in 
conducting the study 
5 
TREATMENT 
Randomization and Blinding 
This study follows an open-label randomization design. A randomization scheme will be 
generated by the Data Management Center prior to the initiation of the study. 
Study Drugs 
Every attempt will be made to pre-position the study drugs under active study at the 
participating sites’ pharmacies in advance of enrollments. Randomization of individual patients 
to a given study drug will only occur when there is sufficient quantity of that drug to complete a 
full treatment course for those individuals. 
6 
STUDY PROCEDURES 
Personnel for Study Procedures 
The physical examination (excluding vital signs) will be performed by a physician, nurse 
practitioner, or physician’s assistant, as allowable by state or local regulations. All other 
assessments may be performed by other members of the investigative team (as noted on the 
Delegation of Responsibilities form). 
Schedule of Assessments 
The day when the subject is enrolled and randomized to their assigned treatment arm is 
denoted as Study Day 0. The first day after enrollment/randomization is Study Day 1 and will 


 
 
 
generally be the day in which an investigational treatment intervention will be initiated (if part 
of the assigned treatment arm). Subsequent days will be numbered chronologically through 
Day 58 of study. 
 
Table 2: Schedule of Assessment 
 
 
 
 
 


 
 
Day 
0 
1 
2 
3 
4 
5 
6 
7 
10 
14 
21 
28 
58 
ELIGIBILITY 
informed consent 
medical history & physical 
enrollment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
RANDOMIZATION TO TREATMENT ARM 
baseline laboratory studies* 
pregnancy testing (if applicable) 
X 
X** 
X 
X** 
INITIATE ASSIGNED INTERVENTION 
baseline PCR 
X** 
X 
X** 
MONITORING 
Serial PCR 
Serial laboratory safety studies*                PK 
if feasible (baseline & serial samples)**** 
X 
X 
X 
X 
X 
X 
X 
x 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X*** 
X 
XX*** 
X*** 
X*** 
X 
STANDARDIZED CRF 
baseline 
X 
daily or specific day 
Adverse Events 
SPECIMENSTORAGE***** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X*** 
X*** 
* whenever possible, full panel of POC studies toinclude CBC with diff, PT/PTT/INR, D---Dimer, acute/hepatic/mineral chemistry panels, and U/A 
** indicatestestcanbedoneeitheron Day 0 orpre---drugon Day 1 
*** as clinically warranted 
**** where technically feasible according to appropriate safety precautions and Select Agent regulations 
***** serum, plasma, and PBMCs, where possible to do so under Select Agent storage regulations 


 
 
 
 
6.2.1 Screening and Informed Consent 
The investigator or a qualified and previously designated member of the study team will review 
informed consent with the subject. 
 
6.2.2 Demographics 
The following information should be recorded: 
• Age 
• Sex 
• Ethnicity 
• Race 
6.2.3 Medical History 
The following information should be recorded: 
• Medical history including any chronic medical conditions 
• Current use of prescription and over-the-counter (OTC) medications within the last 14 
days 
• History of allergies 
• Current participation in any recent research protocols 
• Reproductive history to include contraceptive experience, current practice, and 
willingness to adhere to protocol requirements 
6.2.4 Clinical Data 
• Vital signs 
6.2.5 Physical Exam 
A focused physical exam to ensure there are not medical conditions that would increase a 
subject’s risk for participation in this study 
6.2.6 Laboratory Testing 
When possible, the following tests will be performed and recorded as baseline determinations: 
• CBC with differential 
• Acute/hepatic/mineral chemistry panels as available via POC testing 
• PT/aPTT/INR 
• D-Dimer 
• Urinalysis (evaluating RBC, protein, and glucose only) if available as POC test 
Serum or urine pregnancy test (females of childbearing potential only) if available as POC test 
 
6.2.7 
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 (or told directly if 
found ineligible during screening evaluation), and the reason for ineligibility will be discussed. 
 
 
 
 
 
 
 
 
 


 
 
 
If desired by the subject, and if applicable for the reason for ineligibility, the results will be 
shared with their outside health care provider. 
Day 0 
6.3.1 Informed Consent 
For subjects evaluated for enrollment, the investigator/qualified designee will review the study 
specific informed consent with the subject. Subjects interested in participating will complete the 
study specific informed consent on or before Day 0. 
6.3.1.1 Baseline Evaluation 
Prior to study drug administration, a baseline evaluation will be performed as follows consisting 
of an interval history and exam plus clinical safety laboratory testing if more than 24 hours has 
elapsed since prior measurements. 
6.3.1.2 Interval History and Exam 
An interval medical history will be performed. This will include: 
• Any new medical conditions 
• Any baseline symptoms 
• Current prescription and OTC medications 
• Allergies 
• A brief physical exam to ensure there are not medical conditions that would increase a 
subject’s risk for study participation 
6.3.1.3 Clinical Safety Laboratory Testing 
The following clinical laboratory tests will be performed and documented either on study Day 0 
or on study Day 1 prior to administration of any investigational treatments: 
• CBC with differential (evaluating only the WBC, hemoglobin, hematocrit, and platelets) 
• Acute/hepatic/mineral chemistry panels as available via POC testing 
• PT/aPTT/INR 
• D-Dimer 
• PCR 
• Urinalysis (evaluating RBC, protein, and glucose only) if POC testing available 
• Serum or urine pregnancy test (females of childbearing potential only) if appropriate and 
POC testing available 
As these are performed for baseline assessment only the pregnancy test needs to be resulted 
prior to proceeding with initiation of an investigational treatment assignment. 
Study Day 1 
It is possible that Study Day 0 may be consumed by longitudinal determination of patient’s 
overall clinical status, implementation of oSOC provisions, assessment for study eligibility, and 
study randomization. Therefore, it is likely that actual implementation of an investigational 
study intervention (if part of the assigned treatment arm) will be deferred until study Day 1. 


 
 
 
6.4.1 Baseline CRF completion 
This will include: 
• Any past medical conditions or symptoms 
• Comprehensive assessment of current clinical status and oSOC interventions 
• Vital signs and physical examination 
• Baseline safety laboratory measurements 
• medications 
6.4.2 Reference Laboratory Testing 
The following reference laboratory tests will be collected and stored: 
• Blood for Ebola PCR 
o Consideration of other bodily fluid sampling as clinically appropriate 
6.4.3 Pharmacokinetic Sampling 
• 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: 
o Collection of baseline drug level prior to assigned treatment intervention 
o Initiation of serial PK blood draws whose frequency and duration (24-48 hours) will 
be guided by anticipated PK profile based upon preclinical data 
Study Days 2+ 
For those medical interventions where the drug is to be administered on a serial basis according 
to known PK, the sponsor’s recommended dose and schedule of administration will be followed 
and recorded on interval CRFs. 
6.5.1 Interval History and Exam 
Interval medical history and physical exam will be performed daily. This will include: 
• Any new medical conditions or symptoms 
• Current medications 
• Vital signs 
• Physical exam 
• Adverse events 
• Discharge date and clinical status, as appropriate 
6.5.2 Clinical Safety Laboratory Testing 
The following clinical laboratory tests will be performed and documented according to the 
study flowsheet: 
• CBC with differential (evaluating only the WBC, hemoglobin, hematocrit, and platelets) 
• Acute/hepatic/mineral chemistry panels as available via POC testing 
• Urinalysis (evaluating RBC, protein, and glucose only) if POC testing available 
• PT/aPTT/INR 


 
 
 
• D-Dimer 
• PCR 
6.5.3 Reference Laboratory Testing 
The following reference laboratory tests will be collected and stored: 
• Blood for Ebola PCR as per study flowsheet 
o Consideration of other bodily fluid sampling as clinically appropriate 
o Date of first PCR negative result 
6.5.4 Vital Signs, Including SaO2 
Vital signs assessments should include BP, HR, temperature, respiration rate, and pulse 
oximetry whenever possible. 
7 
STATISTICAL METHODS 
Background 
A statistically valid plan for conducting a randomized trial of limited and unproven treatment 
options for Ebola virus disease is not straightforward. Such a trial is unlike most others in 
several respects: 1) the mortality rate of the “control” arm, i.e., best supportive care arm, is not 
well known, nor are the factors associated with improved outcome, 2) the oSOC may  change 
as a result of accumulating results from the trial, 3) although the target number of patients is 
100/arm, the actual number may be much smaller because the supply of one or more 
treatments may be severely limited and intermittent, superiority of one arm over another 
might be established with lesser numbers, and/or the epidemic itself may resolve . However, 
rather than precluding a randomized controlled trial (RCT), these circumstances favor it, for an 
RCT is the most efficient and accurate means of evaluating the benefits of alternative therapies. 
Nonetheless, an unusual amount of flexibility in trial design is needed to seamlessly 
accommodate changing circumstances. Flexibility is critical for many reasons. For example, if 
evidence supports updating the existing oSOC (and dissemination of the new standard is 
feasible), this change should be implemented seamlessly. If however, the new standard 
requires a drug with a supply that is nearly depleted (and will remain so for some time), 
immediate changes to the oSOC may not be possible. Continuation of randomization to the 
treatment (with the nearly depleted supply) versus the initial standard may be the preferred 
strategy to allocate the limited supply. Plans for every potential scenario are not possible to 
specify a priori, which leaves such decision making to the domain of the study team in 
consultation with the DSMB. The present study design attempts to maximize the informational 
content of the limited data generated, given the above considerations. 
Design 
The trial will commence with randomization to oSOC (i.e., best supportive care) versus an 
experimental arm receiving oSOC plus treatment. Randomization will use permuted blocks 
with variable but small block sizes, and will be stratified by duration of clinical symptoms (0-5 
days versus >5 days) and site of treatment (western Africa versus the United States/Europe). 
The trial endpoint is mortality by 28 days. The high mortality rate of Ebola virus disease and the 


 
 
 
uncertainty associated with the oSOC efficacy, mandate aggressive interim monitoring, which is 
described in the next section. If more than 2 treatment strategies are evaluated, the design will 
follow the same stopping rules outlined below, but randomization will proceed with equal 
probability to each of the arms. Strict control of the type I error rate would require adjustment 
of boundaries for comparison of multiple arms. We recommend against such adjustments, 
given the exigent circumstances surrounding the Ebola epidemic. Intention-to-treat analyses 
will be employed. Each patient will undergo only a single randomization in the study. 
 
Interim Monitoring 
Methods of monitoring clinical trials generally require knowledge of the total amount of 
information at trial’s end. Boundaries are then constructed to guide decisions to control the 
probability of falsely declaring a treatment benefit at one or more interim analyses, including 
the final analysis. Such boundaries correspond to scenarios in which the level of evidence in 
support of treatment efficacy (or the lack thereof) exceeds some pre-determined threshold. 
Early boundaries are usually very difficult to cross, while boundaries at the end of the trial are 
similar to what they would be in the absence of monitoring. Our setting requires a somewhat 
different paradigm because although the target sample size is 100/arm, circumstances beyond 
our control may lead to a smaller number of patients. Moreover, we would like the flexibility of 
modifying the oSOC arm quite early if results show the superiority of an experimental agent 
plus oSOC, for example. We recommend monitoring beginning with 6 participants in an 
experimental arm and 6 in the best supportive care arm, and continuing after every additional 
patient per arm, if necessary, up to 20. After that, monitoring would be after every 20 patients 
per arm until the target number of 100/arm is reached or the trial ends for other reasons. Any 
decision to curtail for other reasons will be made by a group blinded to trial results. The 
boundary we recommend is motivated from a Bayesian perspective. Bayesians formulate their 
prior opinion about the size of the treatment effect through a `prior’ distribution, which is 
updated to a `posterior’ distribution after observing data.  We give details of the specification 
of the prior distribution and the construction of the boundary later. What are most important 
are the boundary itself and its statistical properties such as type I error rate (the probability of 
crossing the boundary inappropriately, i.e., when the 2 arms are equally effective) and power 
(the probability of crossing the boundary appropriately, i.e., when one arm is superior to the 
other). 
 
Table 3 illustrates the design’s flexibility by showing the boundaries assuming that factors 
beyond our control result in only 20 participants per arm by trial’s end instead of the planned 
100 per arm (stopping boundaries for 100 subjects per arm are included in Appendix B). For 
example, with 6 people evaluated in each arm, we declare superiority of one arm over the 
other only if all 6 die in one arm and none die in the other. On the other hand, with 10 people 
per arm, we cross the boundary if the numbers of deaths out of 10 in the 2 arms are as follows: 
1. 7 or more and 0, 
2. 8 or more and 1 
3. 9 or more and 2 


 
 
 
4. 10 and 3 
Notice that the boundaries at the end of the trial are more lenient than interim boundaries: 
interim boundaries use a probability level of 99.9%, whereas the final boundary uses a level of 
97.5%. This reinforces the need for a blinded group to make stopping recommendations for 
reasons other than safety or efficacy; otherwise, inflation of the type I error rate could result 
from lowering the boundary for the final analysis. Boundaries for a sample size of 100 per 
group will be generated following this same procedure and will be distributed to the DSMB. 
Type I Error Rate 
Table 4 shows the probability of crossing the boundary and declaring a treatment difference if 
we begin monitoring after 6 patients per arm and continue monitoring after each additional 
patient in both arms up to 20/arm, then every 20 per arm up to 100/arm. This probability of 
crossing the boundary depends on the true mortality probabilities in each arm, but the 
maximum value when the event probabilities in the 2 arms are equal is approximately 6% for a 
trial with 100 participants per arm. Even though the Bayesian methodology does not explicitly 
aim to control the type I error rate, that rate is controlled at close to the conventional level of 
0.05. The first 5 rows of numbers in Table 4 also show type I error rate if circumstances beyond 
our control result in a final sample size of 20, 40, 60, or 80 per arm. 
 
Power and Sample Size 
The last 6 rows of numbers in Table 4 show scenarios with event probabilities differing in the 2 
arms. With 100 per group, power is 88% to detect a difference if the true mortality 
probabilities in the 2 arms are 0.20 and 0.40, a 50% relative reduction. The selected sample 
size of 100/arm also gives reasonably high power (83%) to detect a difference if the true 
mortality probabilities are 0.30 and 0.50, a 40% relative reduction. 
 
Table 5 shows the average sample size, taking into account the possibility of stopping early, for 
the scenarios with a treatment effect. If the true mortality rates in arms A and B are 0.3 and 0.5, 
respectively, and a sample size of 100 is targeted, then the study will stop for efficacy, on 
average, with only 76 patients (per arm). 


 
 
 
 
 
Table 3: Flexibility of Trial Design 
The top row gives the number of patients per arm, and the boundaries in parentheses are the numbers of deaths in the 2 arms, with + indicating 
that number or greater (e.g., in the “8” column, 7+ means 7 or 8). 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
(6,0) 
(6+,0) 
(7+,0) 
(7+,0) 
(7+,0) 
(7+,0) 
(7+,0) 
(7+,0) 
(8+,0) 
(8+,0) 
(8+,0) 
(8+,0) 
(8+,0) 
(8+,0) 
(4+,0) 
(7,1) 
(8,1) 
(8+,1) 
(8+,1) 
(9+,1) 
(9+,1) 
(9+,1) 
(9+,1) 
(10+,1) 
(10+,1) 
(10+,1) 
(10+,1) 
(10+,1) 
(6+,1) 
(9,2) 
(9+,2) 
(10+,2) 
(10+,2) 
(10+,2) 
(11+,2) 
(11+,2) 
(11+,2) 
(11+,2) 
(11+,2) 
(12+,2) 
(8+,2) 
(10,3) 
(11+,3) 
(11+,3) 
(11+,3) 
(12+,3) 
(12+,3) 
(12+,3) 
(13+,3) 
(13+,3) 
(13+,3) 
(9+,3) 
(11,4) 
(12,4) 
(12+,4) 
(13+,4) 
(13+,4) 
(13+,4) 
(14+,4) 
(14+,4) 
(14+,4) 
(11+,4) 
(12,5) 
(13,5) 
(13+,5) 
(14+,5) 
(14+,5) 
(15+,5) 
(15+,5) 
(15+,5) 
(12+,5) 
(13,6) 
(14,6) 
(15,6) 
(15+,6) 
(15+,6) 
(16+,6) 
(16+,6) 
(13+,6) 
(15,7) 
(16,7) 
(16+,7) 
(16+,7) 
(17+,7) 
(14+,7) 
(16,8) 
(17,8) 
(17+,8) 
(18+,8) 
(15+,8) 
(17,9) 
(18,9) 
(18+,9) 
(16+,9) 
(18,10) 
(19,10) 
(17+,10) 
(19,11) 
(17+,11) 
(18+,12) 
(19+,13) 
(19+,14) 
(20,15) 
(20,16) 


 
 
Table 4: Probability of Crossing the Boundary for Different Mortality, Probabilities, and 
Sample Sizes in the 2 Arms 
 
Simulated Type I Error Rate* 
Mortality 
probability 
treatment 
A (PA) 
Mortality 
probability 
treatment 
B (PB) 
20 per 
group 
40 per 
group 
60 per 
group 
80 per 
group 
100 
per 
group 
0.1 
0.1 
0.038 
0.039 
0.042 
0.050 
0.048 
0.2 
0.2 
0.049 
0.052 
0.049 
0.049 
0.053 
0.3 
0.3 
0.046 
0.051 
0.052 
0.054 
0.055 
0.4 
0.4 
0.042 
0.057 
0.056 
0.054 
0.057 
0.5 
0.5 
0.041 
0.061 
0.061 
0.055 
0.063 
Simulated Power 
Mortality 
probability 
treatment 
A (PA) 
Mortality 
probability 
treatment 
B (PB) 
20 per 
group 
40 per 
group 
60 per 
group 
80 per 
group 
100 
per 
group 
0.1 
0.3 
0.36 
0.63 
0.80 
0.90 
0.96 
0.1 
0.4 
0.61 
0.90 
0.98 
1.00 
1.00 
0.1 
0.5 
0.82 
0.99 
1.00 
1.00 
1.00 
0.2 
0.4 
0.27 
0.50 
0.67 
0.80 
0.88 
0.2 
0.5 
0.50 
0.82 
0.94 
0.98 
1.00 
0.3 
0.5 
0.23 
0.46 
0.62 
0.74 
0.83 
*These type I error rates refer to comparisons of two arms and do not reflect the study-wise type I error rate. 
 
Table 5: Average Final Sample Size per Arm using Stopping Criteria Defined Above 
 
Mortality 
probability 
treatment 
A (PA) 
Mortality 
probability 
treatment 
B (PB) 
Targeted sample size (per arm) 
40 
60 
80 
100 
Average final sample size (per arm) 
0.1 
0.3 
39 
54 
67 
75 
0.1 
0.4 
35 
44 
48 
49 
0.1 
0.5 
29 
32 
32 
32 
0.2 
0.4 
38 
56 
70 
82 
0.2 
0.5 
35 
47 
53 
56 
0.3 
0.5 
38 
56 
71 
84 


 
 
 
The frequency of monitoring can be altered. For example, if patient heterogeneity is large, one 
may not conduct the first interim analysis until more patient outcome data has accrued (e.g., 10 
per arm). Regardless of the monitoring frequency, the data and safety monitoring board’s 
recommendation to stop or continue an ongoing trial will be based on consideration of multiple 
factors. The Bayesian perspective allows calculation of `credibility’ intervals (analogous to 
confidence intervals) for the difference in mortality probabilities between arms whether or not 
advisory boundaries are crossed. 
 
Comparison to Other Boundaries 
Even though the boundaries were motivated from a Bayesian perspective, they are actually 
quite similar to Haybittle-Peto boundaries using either Fisher’s exact test or Barnard’s test. 
Suppose circumstances beyond our control limit the total sample size to 20 participants per 
arm. A comparison of the 3 boundaries is shown, in Figures 2 and 3 for interim analyses after 
10 and 15 participants, and in Figure 4 at the final analysis after 20 participants per arm. The 
proposed boundary is quite similar to, but slightly less conservative than, Barnard’s test. 
Fisher’s exact test is slightly more conservative. 
Figure 2: Interim Analysis after 10/Arm 


 
 
 
 
 
Figure 3: Interim Analysis after 15/Arm 
 
Figure 4: Interim Analysis after 20/Arm 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Advisory Futility Boundaries 
Advisory boundaries for futility will be computed using the conditional probability of reaching a 
statistically significant result at the end of the trial with 100 per arm, given the results observed 
at an interim analysis (called conditional power). Serious consideration for stopping a 
treatment for futility will be given if the conditional power is less than 20% even assuming the 
relative treatment benefit for remaining patients is 50%. 
 
Technical Details of Boundary Construction 
Thoughtful specification of the prior distribution is crucial in Bayesian analysis. We want 
conclusions to depend primarily on data from the trial, not on prior opinion. This argues for a 
skeptical prior distribution that does not already assume that a treatment works. Let p denote 
the probability of survival in a given arm. Our prior distribution on p can be formulated by 
imagining having data on 2 people treated with a given agent, and observing that exactly 1 of 
the 2 survived. The probabilistic equivalent is to assume a beta prior distribution on p with 
parameters 1 and 1, equivalent to a uniform distribution on the interval (0,1). This is consistent 
with an overall survival probability of 0.50 for the current Ebola outbreak, but with wide 
variability reflecting substantial uncertainty about p. Moreover, a uniform distribution for p 
ensures very little influence of our prior opinion on conclusions. The observed data very quickly 
dominate in decision-making.  For instance, if 20 people are given the treatment and 12 of 
them survive, the posterior distribution for the survival probability is beta with parameters 13 
and 9. In other words, combining our prior opinion with the observed data equates to 
observing 13+9=22 people, 13 of whom survived. Our prior opinion constitutes only 2 of the 22 


 
people, and therefore has very little effect on the conclusions. Also, we use the same prior 
distribution in different arms. That way, our prior opinion does not favor any treatment over 
oSOC. If pA and pB denote the survival probabilities in arms A and B, respectively, we use 
independent beta posterior distributions in the 2 arms to calculate the probability that pA<pB, 
namely that the survival probability in arm B exceeds that in arm A. At any interim analysis 
preceding the final analysis, we declare arm B superior if this probability exceeds 99.9%. At the 
final analysis, we declare superiority of arm B if this probability exceeds 97.5%. 
Analyses 
Differences in mortality probabilities between an experimental arm and the best supportive 
care arm will be estimated using 95% Bayesian credibility intervals akin to confidence intervals. 
The treatment effect will be expressed in both an absolute and relative terms, and will be 
estimated in the overall group and in the pre-defined strata: duration of clinical symptoms (0-5 
days versus >5 days) at baseline and where the patient was treated (western Africa versus 
the United States/Europe). The posterior probability that the relative treatment benefit differs 
by strata will be calculated; if this probability exceeds 97.5% that will be taken as evidence of a 
differential treatment effect by strata. 
 
As noted earlier, Bayesian analysis with the non-informative prior distribution specified above is 
very similar to classical statistical analysis using Barnard’s test. To highlight this point, we will 
also present classical confidence intervals for the absolute and relative treatment benefit based 
on Barnard’s test. 
 
Some patients may receive MCMs other than the randomized treatment. This will be 
documented in the record, but it is extremely problematic statistically to try to account for the 
effect of supplementary treatment that may be administered in response to a patient’s failing 
health. A sensitivity analysis will be conducted by treating such patients as if they would have 
died by 28 days in the absence of the additional MCMs. 
 
Similar sensitivity analyses will be conducted for patients missing the primary endpoint of 28 
day mortality. 
8 
RISKS AND BENEFITS 
Potential Risks 
8.1.1 Unknown Risks 
The primary risks to participants are due to study interventions whose human safety profile is 
either absent or, in most cases, early and accumulating, due to ongoing animal and/or 
early/first in human trials. Generally these are either still in early phase 1 testing, have not yet 
entered phase 1 testing, or, for those interventions in more advanced development, have not 
yet been tested in a human population infected with Ebola virus. Thus, unlike conventional 
phase 2 trials in which a safety database has already been generated to guide the dosing and 
schedule of study drug administration, it is presently unknown what toxicities these agents 


 
could cause when used in this critically ill patient population or, for that matter, in any humans 
at all. 
 
It is anticipated that additional animal safety and toxicity studies will be in-progress at the time 
of trial initiation for some agents. Results will be made available to the study investigation 
team and pertinent regulatory bodies for review promptly, as they are available. In addition, in 
some cases phase 1 testing of lead candidates in normal human volunteers may commence 
during the same interval of time that this trial is conducted. Should it be concluded from any of 
these studies that there are additional significant risks to study subjects, participants will be 
informed and additional administration of study product may be suspended until review by the 
FDA as well as by each institution’s IRB. 
8.1.2 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. 
8.1.3 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 likely to be investigated 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 conceivable that one or more interventions may subsequently be 
shown to offer evidence of a greater reduction in morbidity and mortality than that 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 very early stage of 
testing. However, even if no experimental treatment intervention is shown 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 or to experimental therapies through other approved regulatory 
means. 
9 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, AND DATA 
Intended Use of the Samples/Specimens/Data 
Samples and data collected under this protocol will be used to determine the safety, 
immunogenicity, and antiviral effects of the treatment interventions. 
Storage of Samples/Specimens/Data 
Samples obtained in this study must adhere to CDC regulations governing 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 investigators (both at NIH and outside) may wish to study these samples 
and/or data. In that case, IRB approval must be sought prior to any sharing of samples. Any 
clinical information shared about the sample with or without patient identifiers would similarly 
require prior IRB approval. 
 
The research use of stored, unlinked or unidentified samples 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. 
 
Storage of Genetic Samples 
No samples are being stored for genetic testing on the subjects. 
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) will be reported 
to the institution’s IRB and to the protocol team. 
10 
REMUNERATION PLAN 


 
Subjects will not be compensated for the time and inconvenience of study participation, including 
for any outpatient assessments that may occur following hospital discharge. 
 
11 
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. 
Documenting, Recording, and Reporting Adverse Events 
At each contact with the subject, information regarding adverse events will be elicited by 
appropriate questioning and examinations and will be: 
• immediately documented in the subject’s medical record/source document, 
• recorded on the Adverse Event Case Report Form (AE CRF) or electronic database, and 
• reported as outlined below (e.g., IND Sponsor, IRB, FDA) 
Definitions 
Adverse Event (AE) 
An adverse event 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 (AR) 
An adverse event that is caused by an investigational agent (drug or biologic). 
 
Suspected Adverse Reaction (SAR) 
An adverse event for which there is a reasonable possibility that the investigational agent 
caused the adverse event. ‘Reasonable possibility’ means that there is evidence to suggest a 
causal relationship between the drug and the adverse event. A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which implies a high 
degree of certainty. 
 
Serious Adverse Event (SAE) 
A Serious Adverse Event is an AE that results in one or more of the following outcomes: 
• death 
• a life threatening (i.e., an immediate threat to life) event 
• 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 
• a medically important event* 


 
* Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but they 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 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 a Suspected Adverse Reaction that is both Serious and Unexpected. 
 
Unanticipated Problem (UP) 
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; and 
b. the characteristics of the subject population being studied; 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. (Per the IND Sponsor, 
an AE with a serious outcome will be considered increased risk.) 
 
Unanticipated Problem that is not an Adverse Event (UPnonAE) 
Unanticipated problem that is not an Adverse Event (UPnonAE): An unanticipated problem that 
does not fit the definition of an adverse event, but which may, in the opinion of the 
investigator, involve risk to the subject, affect others in the research study, or significantly 
impact the integrity of research data. Such events would be considered a non-serious UP. For 
example, we will report occurrences of breaches of confidentiality, accidental destruction of 
study records, or unaccounted-for study drug 
 
Protocol Deviation: 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 a Serious Adverse Event or 
compromises the safety, welfare or rights of subjects or others. 


 
Non-compliance: The failure to comply with applicable NIH HRPP policies, IRB requirements, or 
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. 
Investigator Assessment of Adverse Events 
If a diagnosis is clinically evident (or subsequently determined), the diagnosis rather than the 
individual signs and symptoms or lab abnormalities, will be recorded as the AE. 
 
The Investigator will evaluate all AEs with respect to Seriousness (criteria listed above), Severity 
(intensity or grade), and Causality (relationship to study agent and relationship to research) 
according to the following guidelines. 
11.3.1 Severity 
The Investigator will grade the severity of each AE according to the Division of Aids Table for 
Grading the Severity of Adult and Pediatric Adverse Events Version 1.0, December, 2004, 
(Clarification August 20) which can be found at: 
http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/documents/daidsaegradi 
ngtable.pdf 
 
 
11.3.2 Causality 
The likelihood that the event is related to the study agent will be assessed considering the 
factors listed under the following categories: 
Definitely Related 
• reasonable temporal relationship 
• follows a known response pattern 
• clear evidence to suggest a causal relationship 
• there is no alternative etiology 
Probably Related 
• reasonable temporal relationship 
• follows a suspected response pattern (based on similar agents) 
• no evidence of a more likely alternative etiology 


 
Possibly Related 
• reasonable temporal relationship 
• little evidence for a more likely alternative etiology 
Unlikely Related 
• does not have a reasonable temporal relationship 
OR 
• good evidence for a more likely alternative etiology 
Not Related 
• does not have a temporal relationship 
OR 
• definitely due to an alternative etiology 
Note: Other factors (e.g., dechallenge, rechallenge) should also be considered for 
each causality category when appropriate. Causality assessment is based on available 
information at the time of the assessment of the AE. The investigator may revise the 
causality assessment as additional information becomes available. 
Investigator Reporting Responsibilities to the Sponsor 
11.4.1 Adverse Events 
Line listings, frequency tables, and other summary AE data will be submitted to the IND Sponsor 
when needed for periodic safety assessments, review of IND annual reports, review of IND 
safety reports, and preparation of final study reports. 
11.4.2 Serious Adverse Events 
All SAEs (regardless of relationship and whether or not they are also UPs) must be reported on 
the Safety Expedited Report Form (SERF) and sent to the Sponsor Clinical Safety Office (CSO) by 
fax or e-mail attachment. Deaths and immediately life threatening SAEs must be reported to 
the CSO within 1 business day after the site becomes aware of the event. All other SAEs must 
be reported within 3 business days of site awareness. 
 
SPONSOR CLINICAL SAFETY OFFICE CONTACT INFORMATION: 
OCRPRO Clinical Safety Office 
5705 Industry Lane 
Frederick, MD 21704 
Phone 301-846-5301 
Fax 301-846-6224 
E-mail: rchspsafety@mail.nih.gov 


 
11.4.3 Unanticipated Problems 
Unanticipated Problems that are also adverse events must be reported to the CSO and sent by 
fax or e-mail attachment no later than 7 calendar days of site awareness of the event. UPs that 
are not AEs are not reported to the Sponsor CSO. 
 
Report all UPs that are also adverse events to the CSO on the NIH Problem Report Form. 
11.4.4 Pregnancy 
Pregnancy itself is not an AE. However, complications of pregnancies are AEs and may be SAEs. 
Pertinent obstetrical information for all pregnancies will be reported to the CSO via fax or email 
within 3 business days from site awareness of the pregnancy. 
 
Pregnancy outcome data (e.g., delivery outcome, spontaneous or elective termination of the 
pregnancy) will be reported to the CSO within 3 business days of the site’s awareness on a 
protocol-specified form. 
 
In the event of a pregnancy: 
• Withdraw from the study but continue in follow up for safety 
• Report to safety oversight committee and IRB 
• Advise research subject to notify the obstetrician of study agent exposure 
Reporting Procedures to the IRB 
11.5.1 Expedited Reporting to the IRB 
Serious and non-serious Unanticipated Problems, deaths, serious deviations, and serious or 
continuing non-compliance will be reported within 7 calendar days of investigator awareness. 
Serious Adverse Events that are possibly, probably, or definitely related to the research will be 
reported to the institution’s IRB within 7 calendar days of investigator’s awareness, regardless 
of expectedness. 
11.5.2 Waiver of Reporting Anticipated Protocol Deviations, Expected UPnonAEs and 
Deaths to the IRB 
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. Expected adverse events will not be 
reported to the IRB unless they occur at a rate greater than that known to occur in the general 
population. If the rate of these events exceeds the rate expected by the study team, the events 
will be classified and reported as though they are unanticipated problems. Deaths will be 
immediately reported as expedited SAEs. 
11.5.3 Annual Reporting to the IRB 
The following items will be reported to the IRB in summary at the time of Continuing Review: 
- 
Serious and non-serious unanticipated problems 
- 
Expected serious adverse events that are possibly, probably, or definitely related 
to the research 


 
- 
Serious adverse events that are not related to the research 
- 
All adverse events, except expected AEs and deaths granted a waiver of 
reporting. 
- 
Serious and Non-Serious Protocol deviations 
- 
Serious, continuing, and minor non-compliance 
- 
Any trends or events which in the opinion of the investigator should be reported 
Follow-Up of Adverse Events and Serious Adverse Events 
AEs that occur following enrollment of the subject (by signing the informed consent) are 
followed until the final outcome is known or until the end of the study follow-up period, Day 28. 
 
SAEs that have not resolved by the end of the follow-up period are followed until final outcome 
is known. 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. 
 
SAEs that occur after the study follow-up period, Day 28, that are reported to and are assessed 
by the Investigator to be possibly, probably, or definitely related must be reported to the CSO, 
as described above. 
Sponsor’s Reporting Responsibilities 
Serious and unexpected suspected adverse reactions (SUSARs) as defined in 21 CFR 312.32 and 
determined by the IND Sponsor will be reported to FDA 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 as defined in 21 CFR 312.33. 
Treatment Interruption or Discontinuation 
A subject’s study treatment may be discontinued at any time at the subject’s request or at the 
discretion of the Investigator or Sponsor. The following may be justifiable reasons for the 
Investigator to discontinue a subject from treatment: 
• The subject was erroneously included in the study (i.e., was found to not have met the 
eligibility criteria) 
• The subject experiences an AE that precludes further study participation 
• The subject is unable to comply with the requirements of the protocol 
• The subject participates in another investigational study without the prior written 
authorization of the Sponsor 
Halting Decision 
Halting the study requires immediate discontinuation of study agent administered for all 
subjects and suspension of enrollment until a decision is made whether or not to continue 


 
study agent administration. The Sponsor/Medical Monitor will be notified by the PI (or 
designee) within 24 hours if any subject develops any of the following: 
• An SAE, a Grade 4 AE or a Grade 4 laboratory event, for which no clear alternative 
explanation, other than study drug, exists. 
• Two or more of the same grade 3 AE that is related (possibly, probably, or definitely) to 
the study drug and which persists for >48 hours. 
 
Upon notification, the Sponsor/Medical Monitor must evaluate the clinical relevance of the 
reported AEs against the background of an underlying disease with a high case fatality rate and 
make a determination of whether or not to halt the study based upon this consideration from a 
safety perspective. The DSMB should be notified immediately of the Sponsor/Medical Monitor’s 
decision in this regard. If the decision is made to halt the study, the Site Investigator must inform 
the PI and the local IRB that a decision to put the study on hold has been made according to their 
requirements. The IND Sponsor will notify all sites that the study has been halted. 
 
The Sponsor/Medical Monitor can request additional information that might be needed (such as 
listing of graded adverse events) to evaluate the data. The Sponsor/Medical Monitor will 
ultimately make the decision to resume the study, ask for formal Data and Safety Monitoring 
Board (DSMB) review, or stop the study. 
 
If the trial is stopped due to unacceptably high AE or stopping criteria, the IRB will be notified. 
11.9.1 Resumption of a Halted Study 
The IND Sponsor, in collaboration with the PI and the DSMB will determine if it is safe to 
resume the study. The IND Sponsor will notify the Site Investigators of this decision. The 
conditions for resumption of the study will be defined in this notification. The Site Investigators 
will notify their local IRB(s) of the decision to resume the study. 
Safety Oversight 
11.10.1 Investigator Safety Monitoring 
The Investigator or designee may interrupt the administration of study drug to an individual 
subject, or enrollment into this study if indicated for unanticipated problems or AEs. In 
addition, the Investigators are responsible for: 
o Protecting the safety and welfare of subjects 
o Evaluating subject safety, including physician assessment of AEs for seriousness, 
severity, and causality 
o Notifying the sponsor of SAEs and immediately-reportable events 
o Providing detailed written reports, including confirmatory tests promptly following 
immediate initial reports 
o Informing the IRB/IEC of SAEs 
o Notifying the DSMB of SAEs 


 
11.10.2 Safety Review and Communications Plan (SRCP) 
A Safety Review and Communication Plan (SRCP) has been developed for the protocol. The 
SRCP is an internal communications document between the Principal Investigator and the IND 
Sponsor Clinical Safety Office (CSO), which delineates the safety oversight responsibilities of the 
PI, the CSO, and other stakeholders. The SRCP also includes the overall plan for conducting 
periodic safety surveillance assessments. 
11.10.3 Sponsor Medical Monitor (SMM) 
A Medical Monitor, representing the IND Sponsor, has been appointed for oversight of safety in 
this clinical study. The SMM will be responsible for performing safety assessments as outlined 
in a Safety Review and Communications Plan (SRCP). 
11.10.4 Data and Safety Monitoring Board (DSMB) 
The NIAID Intramural DSMB or a similarly constituted committee will review the study prior to 
initiation and no less frequently than twice a year thereafter. The Board may convene 
additional reviews as necessary. The Board will review the study data to evaluate the safety, 
efficacy, study progress, and conduct of the study. All serious adverse events, all unanticipated 
problems, and all IND Safety Reports will be reported by the PI to the DSMB at the same time 
they are submitted to the IRB or IND Sponsor. The PI will notify the Board at the time pausing or 
halting criteria are met and obtain a recommendation concerning continuation, modification, or 
termination of the study. The PI will submit the written DSMB summary reports with 
recommendations to the IRB. 
12 
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.” Monitors under contract to the NIAID/Office 
of Clinical Research Policy and Regulatory Operations (OCRPRO) will 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 will be: 1) to verify the existence of 
signed informed consent documents and documentation of the Informed Consent Form (ICF) 
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, physicians’ 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 will 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 will be available to discuss the study progress and monitoring visit. 


 
A specific protocol monitoring plan will be discussed with the PI and study staff prior to 
enrollment. The plan will outline the frequency of monitoring visits based on such factors as 
study enrollment, data collection status, and regulatory obligations. 
13 
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 
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. 
 
The participants will sign the informed consent document prior to any procedures being done 
specifically for the study. The participants may withdraw consent at any time throughout the 
course of the trial. 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. 
Subject Confidentiality 
All records will be kept confidential to the extent provided by federal, state and local law. 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, or the sponsor’s designee. 
14 
DATA MANAGEMENT AND MONITORING 
Data Management Responsibilities 
The 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 collected in the electronic data system, and must 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: RedCap or similar system to be identified 
Study data will be collected at the study site(s) as CRFs and maintained, preferably in an 
electronic data system. Manual CRFs will be used to collect data for sites without access to 


 
electronic data systems. This data will be completed on an ongoing basis during the study. Data 
entered into such systems shall be performed by authorized individuals. Corrections to 
electronic data systems will be tracked electronically (password protected or through an audit 
trail) with time, date, individual making the correction, and what was changed. 
Types of Data 
Source documents include, but are not 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. Data 
from the institutional Data System will be collected directly from subjects during study visits 
and telephone calls, or will be abstracted from subjects’ medical records. The subject’s medical 
record must record his/her participation in the clinical trial and, study treatment/vaccination 
(with doses and frequency) or other medical interventions or treatments administered, as well 
as any adverse reactions experienced during the trial. 
Record Retention 
The investigator is responsible for retaining all essential documents listed in the ICH Good 
Clinical Practice Guideline. All essential documentation for all study subjects are to be 
maintained by the investigators in a secure storage facility for a minimum of 3 years per NIAID 
policies. 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 law. 


 
SELECTED REFERENCES 
 
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humanitarian crisis. Lancet Infect Dis. 2014 Oct 1. pii: S1473-3099(14)70956-9. 
2. Kanapathipillai R. Ebola virus disease--current knowledge. N Engl J Med. 2014 Sep 
25;371(13):e18. 
3. Joffe S. Evaluating novel therapies during the Ebola epidemic. JAMA. 2014 Oct 
1;312(13):1299-300. 
4. Brady O. Scale up the supply of experimental Ebola drugs. Nature. 2014 Aug 
21;512(7514):233. 
5. Butler D. Ebola drug trials set to begin amid crisis. Nature. 2014 Sep 4;513(7516):13-4. 
6. Choi JH, Croyle MA. Emerging targets and novel approaches to Ebola virus prophylaxis 
and treatment. BioDrugs. 2013 Dec;27(6):565-83. 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 Oct 
2;514(7520):47-53. 
7. Florescu DF, Keck MA. Development of CMX001 (Brincidofovir) for the treatment of 
serious diseases or conditions caused by dsDNA viruses. Expert Rev Anti Infect Ther. 
2014 Oct;12(10):1171-8. 
8. Thi EP, Mire CE, Ursic-Bedoya R, Geisbert JB, Lee AC, Agans KN, Robbins M, Deer 
DJ, Fenton KA, MacLachlan I, Geisbert TW. Marburg virus infection in nonhuman 
primates: Therapeutic treatment by lipid-encapsulated siRNA. Sci Transl Med. 2014 Aug 
20;6(250):250ra116. 
9. Oestereich L, Lüdtke A, Wurr S, Rieger T, Muñoz-Fontela C, Günther S. Successful 
treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal 
model. Antiviral Res. 2014 May;105:17-21. 
10. Smith LM, Hensley LE, Geisbert TW, Johnson J, Stossel A, Honko A, Yen JY, Geisbert 
J, Paragas J, Fritz E, Olinger G, Young HA, Rubins KH, Karp CL. Interferon-β therapy 
prolongs survival in rhesus macaque models of Ebola and Marburg hemorrhagic fever. J 
Infect Dis. 2013 Jul 15;208(2):310-8. 
11. Mupapa K, Massamba M, Kibadi K, Kuvula K, Bwaka A, Kipasa M, et al. 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. 
12. 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. 
13. Jahrling PB, Geisbert TW, Geisbert JB, Swearengen JR, Bray M, Jaax NK, et al. 
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. 
14. Jahrling PB, Geisbert J, Swearengen JR, Jaax GP, Lewis T, Huggins JW, et al. Passive 
immunization of Ebola virus-infected cynomolgus monkeys with immunoglobulin from 
hyperimmune horses. Archives of virology Supplementum. 1996;11:135-40. 


 
15. 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. 
16. 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. doi: 
10.1016/j.vaccine.2006.09.076. 
17. Oswald WB, Geisbert TW, Davis KJ, Geisbert JB, Sullivan NJ, Jahrling PB, et al. 
Neutralizing antibody fails to impact the course of Ebola virus infection in monkeys. 
PLoS pathogens. 2007;3(1):e9. doi: 10.1371/journal.ppat.0030009. PubMed PMID: 
17238286; PubMed Central PMCID: PMC1779296. 
18. Upshur RE. Ebola Virus in West Africa: Waiting for the Owl of Minerva. J Bioeth Inq. 
2014 Oct 8. [Epub ahead of print] 


 
STATISTICAL APPENDIX 
 
Power Tables 
More extensive power tables: Table 6 shows the approximate power for a range of sample 
sizes and mortality probabilities in the 2 arms, while Table 7 shows the sample sizes required 
for approximately 80% and 90% power. 
 
Table 6: Approximate Power under Different per Arm Sample Sizes (n) when the Larger 
and Smaller Mortality Probabilities are pA and pB, Respectively 
Powers of 80% or higher are boldfaced. 
PA 
0.2 
0.3 
 
0.4 
 
0.5 
 
 
0.6 
 
 
 
0.7 
PB 
n=20 
n=30 
n=40 
n=50 
n=60 
n=70 
n=80 
n=90 
n=100 
0.1 
0.14 
0.16 
0.24 
0.27 
0.32 
0.38 
0.42 
0.47 
0.51 
0.1 
0.35 
0.49 
0.63 
0.72 
0.79 
0.86 
0.90 
0.93 
0.95 
0.2 
0.10 
0.14 
0.18 
0.21 
0.24 
0.27 
0.30 
0.34 
0.37 
0.1 
0.61 
0.79 
0.90 
0.95 
0.98 
0.99 
1 
1 
1 
0.2 
0.27 
0.39 
0.50 
0.60 
0.67 
0.74 
0.80 
0.84 
0.88 
0.3 
0.08 
0.12 
0.15 
0.18 
0.20 
0.23 
0.26 
0.29 
0.31 
0.1 
0.82 
0.95 
0.99 
1 
1 
1 
1 
1 
1 
0.2 
0.49 
0.69 
0.82 
0.89 
0.94 
0.97 
0.98 
0.99 
1 
0.3 
0.22 
0.35 
0.46 
0.55 
0.62 
0.67 
0.73 
0.79 
0.83 
0.4 
0.08 
0.12 
0.16 
0.18 
0.20 
0.22 
0.24 
0.26 
0.31 
0.1 
0.94 
0.99 
1 
1 
1 
1 
1 
1 
1 
0.2 
0.73 
0.90 
0.97 
0.99 
1 
1 
1 
1 
1 
0.3 
0.45 
0.66 
0.80 
0.88 
0.92 
0.95 
0.97 
0.98 
0.99 
0.4 
0.21 
0.35 
0.46 
0.54 
0.61 
0.67 
0.72 
0.75 
0.83 
0.5 
0.08 
0.12 
0.16 
0.18 
0.20 
0.22 
0.24 
0.26 
0.31 
0.1 
0.99 
1 
1 
1 
1 
1 
1 
1 
1 
0.2 
0.90 
0.99 
1 
1 
1 
1 
1 
1 
1 
0.3 
0.71 
0.90 
0.96 
0.99 
1 
1 
1 
1 
1 
0.4 
0.45 
0.66 
0.80 
0.88 
0.92 
0.95 
0.97 
0.98 
0.99 
0.5 
0.22 
0.35 
0.46 
0.55 
0.62 
0.67 
0.73 
0.79 
0.83 
0.6 
0.08 
0.12 
0.15 
0.18 
0.20 
0.23 
0.26 
0.29 
0.31 


 
 
Table 7: Sample Sizes required for 80% and 90% Power for Different Values of the Larger 
and Smaller Mortality Probabilities, pA and pB. 
 
pA 
pB 
n80 
n90 
0.2 
0.1 
198 
264 
0.3 
0.1 
61 
81 
0.2 
293 
392 
0.4 
0.1 
31 
40 
0.2 
81 
109 
0.3 
357 
476 
0.5 
0.1 
19 
26 
0.2 
39 
52 
0.3 
95 
126 
0.4 
392 
520 
0.6 
0.1 
13 
17 
0.2 
23 
30 
0.3 
41 
57 
0.4 
97 
128 
0.5 
392 
520 
0.7 
0.1 
10 
12 
0.2 
15 
20 
0.3 
22 
31 
0.4 
41 
57 
0.5 
95 
126 
0.6 
357 
477 


 
 
SAMPLE INFORMED CONSENT FORM TO PARTICIPATE IN A CLINICAL 
RESEARCH STUDY 
INTRODUCTION 
We invite you to take part in a research study at the [Institution Name]. 
First, we want you to know that: 
Taking part in this research is entirely voluntary. 
You may choose not to take part, or you may withdraw from the study at any time. In either case, 
you will not lose any benefits to which you are otherwise entitled. 
You may receive no benefit from taking part. The research may give us knowledge that may help 
people in the future. 
Second, some people have personal, religious, or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions). If you 
have such beliefs, please discuss them with your doctors or research team before you agree to the 
study. 
Now we will describe this research study. Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone on staff here, or with 
family, friends, or your personal physician or other health professional with whom you are able 
to communicate. 
PURPOSE OF THIS STUDY 
You have Ebola infection and have been referred to this medical facility for advanced level care. 
Advanced level care in this case refers to the use of modern medical methods that may be 
available in this treatment unit for restoring fluid losses, diagnosing and correcting metabolic 
imbalances, and treating other abnormalities in patients that are caused by the virus. Most 
physicians with experience in treating Ebola patients believe that by promptly and effectively 
reversing these fluid losses and providing other types of modern supportive care that the 
mortality caused by the infection can be greatly reduced. In this research protocol we are seeking 
to learn whether the addition of one or more experimental antiviral drugs or treatments in 
addition to this background of advanced level care can reduce the mortality from Ebola infection 
even further. If so, it is possible that the knowledge we gain from this study will help us improve 
the treatment of Ebola patients both here and elsewhere. 
Unfortunately, essentially all of the experimental drugs or treatments for Ebola infection that are 
currently available for testing are in very early stages of drug development and have not received 
prior in-depth study to determine their safety, toxicity in the human body, or even their 
effectiveness in suppressing the Ebola virus. Even those that have been tested in humans 
previously have been used mostly in patients with other types of infectious diseases but generally 
not as often in those with Ebola infection. Therefore, much of what we know about these 
treatments is quite limited and is based upon their study either in the test tube or in animal 
models of Ebola virus that may or may not truly mimic the course of human infection with 
Ebola. Because so little is known about these treatments to date, there is always the possibility 
that they may actually cause harm to humans and no benefit, especially when administered to ill 
patients. However, despite this concern, the scope of the current Ebola crisis in West Africa has 
forced us to accelerate the usual timeline by which we would normally study their safety and 


 
potential toxicity in humans prior even to fully testing whether they actually have any benefit in 
suppressing or reversing the often fatal course of Ebola virus infection. 
STUDY DESIGN 
You are eligible to be in this study because you have recently been diagnosed as having Ebola 
infection, usually by a laboratory test called the Polymerase Chain Reaction, or “PCR”, and have 
been hospitalized in an isolation unit for treatment of this infection. The PCR test shows that you 
have genetic material, such as RNA, from the virus circulating in your bloodstream that is 
indicative of active infection. Participants in this protocol can be from the general public as well 
as health care workers who were infected by the virus during the course of caring for Ebola 
patients. 
All eligible persons will undergo a medical evaluation to determine: 
• _When and where the infection likely occurred 
• _How you were likely infected (e.g., by skin contact, accidental needle stick, etc.) 
• _Your past and current medical condition and any medical care delivered thus far 
• _Any aspects of your past medical history that might be relevant to the standard medical care 
you are being given, or to the use of any proposed experimental treatment(s) that might be 
offered you. 
This evaluation will generally be done by the physician or medical team in charge of your overall 
care while in the hospital. After the initial evaluation, we will decide whether it is safe to enroll 
you on this study for possible experimental treatment in addition to the advanced level care you 
will automatically receive. However, the decision whether to actually accept enrollment on this 
experimental protocol is entirely your own, and if you decline enrollment you will still receive 
the same advanced level care that the hospital can provide. To enroll on this study you must be 
willing to sign an informed consent document that explains your rights and responsibilities as a 
potential research participant. 
Enrollment in this protocol is voluntary. If you decide to enroll on this study, you will be 
randomly assigned (that is, like the flip of a coin) to 1 of at least 2 different treatment groups, 
each of which will provide a different study intervention. It is very important to understand that, 
at this time, there is no scientific basis for either you or your physicians to choose one particular 
type of drug over another, nor is there even any reason at present to believe that adding an 
experimental drug to the backbone of advanced level care you will automatically receive will 
produce a better outcome than just that backbone alone. Indeed, the addition of that experimental 
drug could potentially harm, not improve, the course of your clinical recovery from Ebola. 
Hence, one of the treatment arms to which you may be randomly assigned may employ just that 
backbone itself, and it will then be compared experimentally to an arm that consists of that 
backbone plus an experimental antiviral drug. The choice, of which experimental antiviral drugs 
or treatments to study in this protocol and the order in which they are to be studied, was made by 
a panel of physicians with expertise in the care and management of patients with Ebola infection. 
By the type of comparison planned in this study, we hope to learn whether adding a given 
experimental drug does or does not improve upon the recovery rate that is possible when 
advanced level care measures are used alone. If it does, and especially if it does not cause any 


 
severe side effects when given in this manner, it is possible that that experimental drug may then 
be recommended to become part of the standard care that Ebola patients receive in the future. 
Conversely, if it does not, or if it causes severe side effects that complicate a patient’s care, then 
it may be less likely that a given antiviral drug will be recommended in the future for this 
particular purpose. 
Overall, the study teams hope to compare a small number of experimental antiviral drugs or 
treatments in the manner described above. At present, that none of these experimental drugs is 
currently approved by the United States Food and Drug Administration (FDA) for the treatment 
of Ebola. It is possible that some of these may be helpful to a patient’s recovery, some may 
potentially be harmful, and some may have no effect at all. By the end of the study we hope to 
learn whether adding one or more of the “helpful” drugs to the backbone of advanced level care 
will be an important improvement in our successful care of patients with Ebola infection. 
WHAT YOU SHOULD EXPECT 
If a mutual decision is made by you, your doctor, and the study team, you will be offered 
enrollment in the protocol. A member of the study team will speak in person with you. If you 
agree, you will be asked to sign this informed consent document. 
After enrollment, your protocol team will learn to which study treatment arm you have been 
assigned by chance. Baseline blood studies (e.g., a complete blood count, chemistry 
measurements, coagulation measurements, etc.) may be drawn to document your medical 
condition at the time of enrollment, and another PCR test may also be collected in order to learn 
what level of Ebola virus is circulating in your blood at the time of study entry. In some cases 
these will already be part of your standard medical care and may not increase the amount of 
blood drawn from you for this purpose. If your assigned arm involves the addition of an 
experimental antiviral drug or treatment, it is likely that this medication will already be available 
at your hospital to begin its administration within 24 hours of your enrollment. Depending upon 
the nature of the particular drug or treatment, this medication may be given to you by oral (by 
mouth) or intravenous (given by vein) means. Because different drugs remain in the bloodstream 
for different lengths of time, it is possible that a single dose of a particular drug or treatment may 
not be sufficient and that dosing may need to be repeated on subsequent days in order to keep the 
bloodstream levels of that medication in the desired range. 
Over the course of your hospitalization, frequent blood tests will be drawn in order to determine 
your overall medical condition, to determine if your assigned treatment is causing any side 
effects that may be reflected in the bloodstream (e.g., liver or kidney abnormalities, bone marrow 
effects, etc.), and also to monitor the level of Ebola virus circulating in your body. We may also 
collect samples of other body fluids (e.g., saliva, urine, stool, vaginal fluid, etc.) to learn if Ebola 
virus may be present in those fluids or secretions as well. If it is both safe and possible to process 
blood specimens for this purpose within your hospital’s laboratory, the level of study medication 
in your bloodstream may be monitored by drawing a series of timed blood tests over the first 24 
to 48 hours after that medication is given to you. 
The information we learn about your individual clinical course, the possible effect of your 
assigned treatment arm on the level of Ebola virus in your bloodstream, and the potential side 


 
effects of any experimental treatment you receive will, by itself, not be sufficient for us to 
conclude anything meaningful about how your assigned treatment did or did not affect your 
clinical recovery from Ebola infection. However, by combining your information with that of 
other enrolled patients receiving the same treatment, and comparing that information with similar 
data from patients assigned to a different treatment arm, we hope to be able to learn whether one 
treatment was better than the other in terms of possibly speeding the time to recovery, causing 
fewer side effects, and similar such conclusions. Alternatively, we may learn that no 
experimental treatment appears to improve greatly upon what is currently possible through 
providing advanced level care in a hospital setting where such care is available. In any case, for 
this study to be successful we will need a sufficient number of patients enrolled in each of the 
treatment arms in order to make these comparisons statistically meaningful, and at this time we 
cannot predict how many individuals will be available to join this study. Thus, there is always a 
risk that it will not be possible to draw firm conclusions from this study as currently planned. 
However, the study team feels strongly that this risk is greatly outweighed by the potential to add 
to our knowledge of how to care optimally for patients with Ebola infection. 
Follow-up 
Your participation in the protocol will continue for the duration of your hospitalization or, if you 
are discharged early, for a total of up to 58 days following enrollment. In addition, there may be 
interest in evaluating you for any long-term effects of the experimental treatment(s) you may 
have received. If so, you may be asked to return after hospital discharge for 1 or more outpatient 
visits on a voluntary basis. The potential need for these evaluations will be determined on a case- 
by-case basis by your treating physicians and the study team. Your participation in these 
evaluations is voluntary and may be discontinued at any time without affecting your potential 
eligibility for other care, including enrollment on other research protocols. 
Risks of Protocol Participation 
Your major risk of study participation generally includes the risks of any experimental drug or 
treatment to which you are assigned (see below). These will be discussed with you at the time of 
treatment. Also, any new significant findings that may emerge during the course of the study that 
may affect your willingness to participate will be provided to you. 
Also, blood draws may cause pain and bruising and, rarely, infection at the place where the 
blood is taken. Sometimes drawing blood causes people to feel lightheaded or even faint. 
Risks of Treatment Arm A 
Treatment Arm A will consist of providing advanced level care for your infection. This will 
include fluid replacement for gastrointestinal or other body losses of fluids caused by Ebola, 
monitoring of your blood pressure and other vital signs to measure your body’s response to the 
infection, frequent monitoring of electrolytes (e.g. sodium, potassium, and other minerals within 
your bloodstream whose proper levels are essential to health) to indicate when deficiencies in 
these electrolytes might be present and must be replaced, the use of oral or intravenous licensed 
medications [e.g. loperamide (or Lomotiltm) to treat diarrhea, or ondansetron (or Zofrantm) to 
treat nausea] to treat some of the known side effects of Ebola, and other standard measures of 
good medical care to help you fight Ebola and aid your recovery. In some hospitals even more 


 
advanced levels of care, such as providing mechanical ventilation to combat respiratory failure, 
or hemodialysis to combat kidney failure, might also be available and may also be used to help 
improve your chances of recovery. While none of these therapies is considered experimental, and 
while their value in treating Ebola has been shown by experience, like any medical procedure 
each does carry its own separate risk of potentially causing harm in a given individual. Your 
doctor will explain to you how each therapy will be used and what the potential risks of each 
procedure might be in your case. 
If you are assigned to Treatment Arm A it is important that you do not receive investigational 
medications for treating Ebola by other means outside of this clinical trial, as doing so will 
impair the ability to determine whether the treatments used in Arm A were responsible for your 
recovery from the infection. As mentioned previously, it is also possible that those experimental 
medications could cause harm to you rather than benefit. 
 
Risks of Treatment Arm B 
If you are randomly assigned to Treatment Arm B, you will receive the same level of advanced 
care described above for Treatment Arm A but will also receive an experimental medication in 
addition. The type of experimental medication you will receive will be described to you in a 
separate written document and will also be explained to you in person by your study team. The 
known facts about that medication, whether and how it has been used previously in humans, 
and the potential side effects will be included in the written description of the medication. You 
will be given ample opportunity to ask questions about the experimental medication prior to it 
being given to you. Depending upon which experimental medication is being studied, it may be 
given to you by mouth or intravenously through an IV line. It may also need to be given to you 
on a daily basis rather than as just a one-time dose. If given intravenously, it may take up to 
several hours to complete each infusion of medication through your IV line. 
Potential Benefits 
We do not know if you will receive any direct benefit for participating in this study. While it is 
possible that you may be assigned to receive an experimental treatment that is later shown to 
have antiviral activity against Ebola, this activity cannot be assumed to exist at this time. It is 
also possible that even if such activity exists, it may be compromised by side effects caused by 
the treatment that overall may outweigh the value of giving this particular therapy to patients in 
the future. However, what we learn from this study may allow us to better understand the disease 
process and potentially develop better ways of treating the infection. 
Alternative to Participation 
The alternative to enrollment in this protocol is to continue to receive advanced level care 
through your hospital as previously outlined. In some circumstances it may also be possible for 
your physicians to apply to the FDA and various drug manufacturers to receive access to 
experimental therapies through other regulatory mechanisms beyond the bounds of this research 
protocol. 


 
 
Stored Samples and Future Research 
It is likely that we will store blood and possibly tissue samples from you to permit the 
performance of additional testing in the future either for clinical or for research purposes related 
to Ebola infection. If for clinical purposes, these tests may also help guide your medical 
evaluation as new or improved tests become available. If for research purposes, these tests may 
help us to better understand Ebola and how it causes disease. However, there are federal 
regulations that govern the long-term storage of samples from patients infected with a known 
“Select Agent” pathogen such as Ebola virus. Such regulations may restrict the storage of such 
specimens after a certain number of days to only a small number of containment laboratories 
operating at what is termed Biosafety Level 4 containment. If access to such a facility for long- 
term storage of your samples is not possible, it may be necessary to destroy your samples 
according to approved disposal methods. 
Future Studies 
Other investigators may want to study your stored blood or tissue samples if it is safe to do so. 
One example might be scientists from the Centers for Disease Control and Prevention who guide 
clinicians in the care and management of patients with Ebola infection. If so, your study team 
may agree to send your samples to them, and may also share information such as your gender, 
age, health history, or ethnicity. In some cases, your hospital’s Institutional Review Board (IRB) 
will need to review other new research that uses your samples. Investigators will use your 
samples only for research and will not sell them. Future research that uses your samples may 
lead to new products, but you will not receive payment for these products. 
Confidentiality 
The data collected from your participation in the protocol may be published, but your identity 
will remain strictly confidential. 
Compensation 
There will be no financial compensation offered for your participation in this protocol. 
Conflicts of Interest 
The policy of the NIH is to evaluate investigators for any conflicts of interest. Research 
participants may review the system for assessing conflicts of interest by checking the web 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. 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law. This web site will not include information that can identify you. At most the Web 
site will include a summary of the results. You can search this Web at any time 


 
Signature of Adult Patient/Legal Representative Date 
Print Name 
Signature of Investigator Date 
Print Name 
Signature of Witness Date 
Print Name 
 
 
 
 
 
 
Consent Document. Please keep a copy of this document in case you want to read it again. 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
I have read the explanation about this study and have been given the opportunity to discuss it 
and to ask questions. I hereby consent to take part in this study. 


 
APPENDIX A 
 
 


 
 
 


 
 
 


 
APPENDIX B 
 


 
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Patient Information Sheet: ZMapptm Triple Monoclonal Cocktail 
 
 
Sponsor's Name: LeafBio 
Investigational Product Name: ZMappTM 
Investigational Product Description: Three chimeric human/murine monoclonal 
antibodies (13C6-FR1, c2G4 and c4G7; 
IgG1 , kappa isotype) against the Ebola 
(Zaire) surface glycoprotein. 
 
Why ZMapp? 
The first experimental treatment to be studied in the protocol will be the use of two or 
three separate intravenous (given by vein) infusions of ZMapptm, an investigational product 
called a “triple monoclonal antibody cocktail” that consists of antibodies raised against a 
surface protein of the Ebola virus. Antibodies are natural infection-fighting proteins produced 
by the body that bind to the surfaces of viruses and prevent them from infecting cells. ZMapptm 
is called a “cocktail” because it contains more than one type of antibody (in this case, three) 
against Ebola and they work together to inhibit the virus. In the case of ZMapptm , the 
antibodies are produced in, and harvested from, plants genetically altered to produce large 
quantities of these three different antibodies against Ebola. 
In monkey studies this triple cocktail has been shown capable of rescuing infected 
animals from death when the product was given as late as five days after infection with what 
would otherwise have been a lethal dose of Ebola virus in those monkeys. In addition, there is 
now some very limited (“anecdotal”) experience with use of this monoclonal cocktail in at least 
nine different patients with Ebola who received this drug on a “compassionate use” basis in 
2014. Of those first nine patients, some of whom also received other experimental treatments 
plus ZMapp, six survived and three died. However, it is very important to note that we have no 
way of knowing whether ZMapp was actually responsible for the survival of those six prior 
patients. 
 
How is ZMapp given? 
ZMapptm is not available in pill form and must be given by slow intravenous infusion 
over several hours on two or three separate occasions three days apart. The rate of each 
infusion can be increased slowly over time if the drug continues to be well tolerated, but each 
infusion may last up to 12 hours in order to give the drug safely and minimize the chances of 
developing any severe side effects. 
 
What is known about ZMapp in humans? 
These first few patients with Ebola who have received ZMapptm to date have generally 
tolerated the medication without significant side effects. When side effects have occurred, their 
severity has generally been lessened by slowing down, or temporarily stopping, the rate in which 


 
 
the drug has been given by vein. Some of the side effects that have been reported include: 
skin flushing (turning red), fast heart rate, chills, a rise or fall in blood pressure, itchiness, 
edema, fever, chest pain, shortness of breath, brief seizures, and skin rash. However, in 
some cases it could not always be determined whether ZMapptm caused these side effects or 
whether they were due to Ebola. Regardless, this experience is far too limited to know whether 
the drug will continue to be safe when given to larger numbers of patients and, in particular, 
whether either new short term or longer term side effects may be seen as the numbers of patients 
who receive this experimental therapy increases over time. There is always the risk that the drug 
may not cause benefit and, in fact, may cause harm that outweighs any potential favorable effect 
of the drug upon the virus itself. In particular, ZMapptm is a drug that consists of antibody 
proteins that are made in plants. Whenever a human receives a drug consisting of protein(s), 
especially proteins not produced in humans, there is always the chance that they could have a 
severe allergic reaction (called “anaphylaxis” ) to the protein. Anaphyaxis can cause a rapid drop 
in blood pressure, fast heart rate, difficulty breathing, and other serious side effects that, if 
untreated, can result in death. It cannot always be predicted in advance who might develop this 
type of severe reaction. 
What will happen to me while receiving ZMapptm ? 
 
If you are assigned to the arm of the study that includes receiving ZMapptm, you will 
have baseline blood tests drawn in order to measure the current level of Ebola virus in your 
bloodstream and to monitor your kidney function, liver function, bone marrow function, and 
other safety measures. Vital signs will also be checked and then repeated frequently while you 
are receiving the medication intravenously. An electrocardiogram (EKG) will be performed to 
monitor your heart. If necessary to prevent or control side effects, you may be given 
acetaminophen and/or an antihistamine by mouth either prior to, or during, the ZMapptm 
infusion. If not already in place, you will have an IV (intravenous line) inserted into an arm vein 
or other vein to allow your doctors to give the ZMapptm medication. 
The ZMapptm infusion will be started at a slow rate and then increased if you are not 
having any significant side effects. If side effects do develop, your doctors may need to slow the 
infusion rate, temporarily discontinue it until you recover, or administer other medications to 
reduce the severity of the side effects. For example, if you develop fever your doctors may 
decide to treat you with acetaminophen to reduce the height of the fever. However, even when 
given at the highest rate the entire infusion may take up to 12 hours to complete. At the end of 
each infusion you will continue to be monitored for any side effects that may develop as a 
result of the infusion. 
At the present time we are planning to administer only two separate infusions of 
ZMapptm to each individual rather than the three infusions that have often been givenin the 
past. This is because the latest data from monkey studies suggests that just two infusions may 
be as effective as three in fighting Ebola in treated animals. 
After you receive your treatment course of ZMapptm, your doctors will continue to 
monitor the level of Ebola in your bloodstream in order to try to learn whether the ZMapptm 
infusions had any effect in lowering that level. Throughout your participation in this study they 
will continue to provide you with all of the other standard medical measures that have been 
proven to be effective in helping people recover from Ebola. 


 
 


 
 
 
 
 
 
A Multicenter Randomized Safety and Efficacy Study of Putative 
Investigational Therapeutics in the Treatment of Patients with 
Known Ebola Infection 
 
 
Short Title: 
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: 
15-I-0083 
Protocol IND #: 
125530 
ZMappTM IND#: 
122451 
ClincalTrials.gov Number: 
NCT02363322 
 
 
 
Date: 
22 October 2015 
 
 
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. 
Version: 
6.0 


 
 
Key Roles: 
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 
Liberia Principal Investigator: 
Moses Massaquoi, MD, MPH 
Clinton Health Access Initiative 
Monrovia, Liberia 
Phone: +231-8863-83487 
Email: mmassaquoi@clintonhealthaccess.org 
Sierra Leone Principal Investigator: Colonel Professor Foday Sahr MD 
Commanding Officer, Joint Medical Unit 
Freetown, Sierra Leone 
Phone: +232-764-80-288 
Email: fsahr@yahoo.com 
Guinea Principal Investigator: 
Denis Malvy, MD 
Professuer de Universités-Médecins des hôpitaux chez 
CHU Bordeaux 
INSERM 
Email: denis.malvy@chu-bordeaux.fr 
 
Medical Monitor: 
Alan R. Lifson, MD, MPH 
University of Minnesota 
Division of Epidemiology and Community Health 
1300 S. Second Street, Suite 300 
Minneapolis MN 55454-1015 
United States 
Telephone: 1.612.626.9697 
FAX: 1.612.624.0315 
Email: lifso001@umn.edu 
Data Coordinating Center: 
University of Minnesota 


 
 
TABLE OF CONTENTS 
LIST OF TABLES .........................................................................................................................88 
LIST OF ABBREVIATIONS........................................................................................................89 
PROTOCOL SUMMARY .............................................................................................................91 
PRÉCIS ..........................................................................................................................................94 
1 BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ................................95 
BACKGROUND ................................................................................................................................................................... 95 
Filoviruses ............................................................................................................................................. 95 
Therapy ................................................................................................................................................. 96 
RATIONALE FOR STUDY ................................................................................................................................................. 97 
2 STUDY OBJECTIVES ...........................................................................................................99 
PRIMARY OBJECTIVE ...................................................................................................................................................... 99 
SECONDARY OBJECTIVES .............................................................................................................................................. 99 
3 STUDY DESIGN ..................................................................................................................100 
GENERAL ........................................................................................................................................................................... 100 
STUDY ENDPOINTS......................................................................................................................................................... 103 
Primary Endpoint ................................................................................................................................ 103 
Secondary Endpoints ........................................................................................................................... 103 
OVERVIEW OF STUDY DRUGS ................................................................................................................................... 104 
CONSIDERATIONS IN CHOICE OF STUDY DRUGS ............................................................................................... 105 
DEFINITIONS FOR THE PURPOSE OF THIS STUDY ............................................................................................... 105 
4 STUDY POPULATION ........................................................................................................106 
RESEARCH SUBJECT RECRUITMENT ....................................................................................................................... 106 
Participation of Site Employees .......................................................................................................... 106 
INCLUSION CRITERIA .................................................................................................................................................... 106 
EXCLUSION CRITERIA ................................................................................................................................................... 106 
VULNERABLE POPULATIONS ..................................................................................................................................... 107 
Pregnant Women ................................................................................................................................. 107 
Inclusion of Children ........................................................................................................................... 107 
SUBJECT WITHDRAWAL ............................................................................................................................................... 107 
DISCONTINUATION OF SUBJECT BY INVESTIGATOR ......................................................................................... 107 
DISCONTINUATION OF STUDY ................................................................................................................................... 108 
5 TREATMENT .......................................................................................................................108 
RANDOMIZATION AND BLINDING ............................................................................................................................ 108 
STUDY DRUGS ................................................................................................................................................................. 108 
6 STUDY PROCEDURES .......................................................................................................108 
PERSONNEL FOR STUDY PROCEDURES .................................................................................................................. 108 
SITE-SPECIFIC CONSIDERATIONS ............................................................................................................................. 108 
SCHEDULE OF EVALUATIONS .................................................................................................................................... 109 
6.2.1  Screening and Informed Consent ........................................................................................................... 111 
6.2.3 
Medical History ................................................................................................................................... 111 
6.2.4 
Clinical Data ....................................................................................................................................... 111 
DAY 0 .................................................................................................................................................. 111 


 
Baseline Evaluation ............................................................................................................................. 111 
Baseline Laboratory Testing ............................................................................................................... 112 
6.4.2.1 
Minimum Baseline Requirements ....................................................................................................................... 112 
6.4.2.2 
Optimal Baseline Laboratories............................................................................................................................. 112 
Randomization ..................................................................................................................................... 112 
Study Drug Administration Timing...................................................................................................... 113 
FOLLOW UP STUDY DAYS ........................................................................................................................................... 113 
Follow-up Daily Assessment and Optimized Supportive Care ............................................................ 113 
Pharmacokinetic Sampling .................................................................................................................. 113 
Clinical Safety Laboratory Testing...................................................................................................... 113 
6.5.3.1 
Minimum Requirements ....................................................................................................................................... 113 
6.5.3.2 
Optimal Daily Laboratory Monitoring ................................................................................................................ 113 
Special Follow-up Assessments ........................................................................................................... 114 
6.5.4.1 
Day of Discharge .................................................................................................................................................. 114 
6.5.4.2 
Day 28 ................................................................................................................................................................... 114 
6.5.4.3 
Pregnancy .............................................................................................................................................................. 114 
6.5.4.3 
Extended Follow-up .................................................................................................... 114 
7 STATISTICAL METHODS ..................................................................................................114 
BACKGROUND ................................................................................................................................................................. 114 
DESIGN ............................................................................................................................................................................... 115 
INTERIM MONITORING ................................................................................................................................................. 115 
ANALYSES ......................................................................................................................................................................... 123 
8 RISKS AND BENEFITS .......................................................................................................124 
POTENTIAL RISKS ........................................................................................................................................................... 124 
Unknown Risks .................................................................................................................................... 124 
Risks of Phlebotomy ............................................................................................................................ 124 
Risks to the Study Personnel and the Environment ............................................................................. 124 
POTENTIAL BENEFITS ................................................................................................................................................... 124 
ALTERNATIVES ................................................................................................................................................................ 125 
9 RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, AND DATA .........125 
INTENDED USE OF THE SAMPLES/SPECIMENS/DATA ....................................................................................... 125 
STORAGE OF SAMPLES/SPECIMENS/DATA ........................................................................................................... 125 
STORAGE OF GENETIC SAMPLES .............................................................................................................................. 126 
REPORTING LOSS OR DESTRUCTION OF SAMPLES/SPECIMENS/DATA ...................................................... 126 
10 REMUNERATION PLAN ....................................................................................................126 
11 ASSESSMENT OF SAFETY ................................................................................................126 
DOCUMENTING, RECORDING, AND REPORTING ADVERSE EVENTS ........................................................... 126 
DEFINITIONS ..................................................................................................................................................................... 126 
ASSESSMENT OF SAFETY ............................................................................................................................................. 127 
INVESTIGATOR ASSESSMENT OF SERIOUS ADVERSE EVENTS ...................................................................... 128 
Causality ............................................................................................................................................ 128 
INVESTIGATOR REPORTING RESPONSIBILITIES TO THE SPONSOR............................................................... 128 
Serious Adverse Events ...................................................................................................................... 128 
Unanticipated Problems ..................................................................................................................... 128 
Pregnancy .......................................................................................................................................... 129 
REPORTING PROCEDURES TO THE IRB ............................................................................................. 129 
Expedited Reporting to the IRB .......................................................................................................... 129 
Annual Reporting to the IRB .............................................................................................................. 129 
FOLLOW-UP OF SERIOUS ADVERSE EVENTS ....................................................................................................... 129 


 
SPONSOR’S REPORTING RESPONSIBILITIES .......................................................................................................... 129 
SAFETY OVERSIGHT ...................................................................................................................................................... 130 
Investigator Safety Monitoring ........................................................................................................... 130 
Sponsor Medical Monitor (SMM) ...................................................................................................... 130 
Data and Safety Monitoring Board (DSMB) ...................................................................................... 130 
12 CLINICAL MONITORING STRUCTURE ..........................................................................130 
SITE MONITORING PLAN ............................................................................................................................................. 130 
13 ETHICS/PROTECTION OF HUMAN SUBJECTS .............................................................131 
INFORMED CONSENT PROCESS ................................................................................................................................. 131 
SUBJECT CONFIDENTIALITY ....................................................................................................................................... 131 
14 DATA MANAGEMENT AND MONITORING ..................................................................132 
DATA MANAGEMENT RESPONSIBILITIES .............................................................................................................. 132 
DATA CAPTURE METHODS ......................................................................................................................................... 132 
TYPES OF DATA ............................................................................................................................................................... 132 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ....................................................... 132 
RECORD RETENTION ..................................................................................................................................................... 132 
SELECTED REFERENCES .......................................................................................................134 
STATISTICAL APPENDIX .......................................................................................................136 
APPENDIX A: Historical Background on Protocol Development .............................................139 
APPENDIX B: Adaptive Trial Design Stopping Boundaries .....................................................144 
 
LIST OF TABLES 
Table 1: Ebola Virus Outbreaks ....................................................................................................95 
Table 2: Schedule of Evaluations ................................................................................................110 
Table 3: Flexibility of Trial Design .............................................................................................118 
Table 4: Probability of Crossing the Boundary for Different Mortality, Probabilities, and Sample 
Sizes in the 2 Arms ......................................................................................................................119 
Table 5: Average Final Sample Size per Arm using Stopping Criteria Defined Above .............119 
Table 6: Approximate Power under Different per Arm Sample Sizes (n) when the Larger and 
Smaller Mortality Probabilities are pA and pB, Respectively .......................................................136 
Table 7: Sample Sizes required for 80% and 90% Power for Different Values of the Larger and 
Smaller Mortality Probabilities, pA and pB ..................................................................................137 
 
LIST OF FIGURES 
Figure 1: Example of Possible Clinical Trial Design Schematic for the Common Protocol – First 
Phase ............................................................................................................................................103 
Figure 2: Interim Analysis after 10/Arm .....................................................................................120 
Figure 3: Interim Analysis after 15/Arm .....................................................................................121 
Figure 4: Interim Analysis after 20/Arm .....................................................................................121 


 
 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event/Adverse Experience 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations (US) 
CI 
Confidence Interval 
CRF 
Case Report Form 
CSO 
Clinical Safety Office 
DCR 
Division of Clinical Research 
DRC 
Democratic Republic of Congo 
DSMB 
Data and Safety Monitoring Board 
EBOV 
Ebola virus 
ECG 
electrocardiogram 
EVD 
Ebola hemorrhagic fever 
ETU 
Ebola treatment unit 
EUA 
Emergency Use Authorization 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practices 
HCW 
health care workers 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Institutional Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MCMs 
medical countermeasures 
NHP 
nonhuman primate 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
OCRPRO 
Office of Clinical Research Policy and Regulatory Operations 
OHRP 
Office for Human Research Protections 
oSOC 
optimized standard-of-care 
OTC 
over-the-counter 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
POC 
point-of-care 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SERF 
Safety Expedited Report Form 
SMM 
Sponsor Medical Monitor 
SOC 
standard-of-care 
SRCP 
Safety Review and Communications Plan 
SUSAR 
Serious Unexpected Suspected Adverse Reactions 
UP 
Unanticipated Problem 
WBC 
White Blood Cell Count 


 
 
ZEBOV 
Zaire Ebola virus 


 
 
PROTOCOL SUMMARY 
 
Full Title: 
A Multicenter Randomized Safety and Efficacy Study of Putative 
Investigational Therapeutics in the Treatment of Patients with 
Known Ebola Infection 
Short Title: 
MCM RCT in EBOV 
Clinical Phase: 
1/2 
IND Sponsor: 
Office of Clinical Research Policy and Regulatory Operations 
(OCRPRO) 
Conducted by: 
Multicenter Trial 
Principal Investigator: 
Richard T. Davey, Jr., MD 
Sample Size: 
Accrual Ceiling: 
Study Population: 
Up to 100 per arm 
1000 
Patients with known Ebola infection 
Accrual Period: 
February 2015 – December 2016 
Study Design: 
Randomized clinical trial 
Study Duration: 
Start Date: February 2015 
End Date: December 2017 
Study Agents: 
ZMapptm, convalescent plasma, favipiravir, TKM-Ebola, others 
Primary Objective: 
• To establish the safety and efficacy of investigational 
therapeutics in patients with Ebola virus infection 
 
Secondary Objectives: 
• Uniform observational database on clinical and virologic 
parameters associated with severe Ebola virus infection 
• To evaluate the comparative effects of investigational 
therapeutics on clinical parameters of Ebola infection 
• Comparative effects of different investigational agents on 
immediate plasma viral load kinetics 
• 24-48 hour pharmacokinetics of investigational therapeutics 
when possible and appropriate 
• Comparative frequency of serious adverse events (SAEs) 
• Duration of hospital stay 
• Time to viral load clearance 
• Late onset of any clinical symptoms possibly consistent with 
delayed virologic relapse 
 
Primary Endpoint: 
• Mortality at Day 28 
Inclusion Criteria 
• Males or females with documented positive PCR for Ebola 
virus infection within 10 days of enrollment 
• Willingness of study participant to accept randomization to 
any assigned treatment arm 
• Access to oSOC 


 
 
• All males and females of childbearing potential, must be 
willing to use highly effective methods of contraception, 
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 58 of study 
• Ability to provide informed consent personally, or by a 
legally-authorized representative if the patient is unable to 
do so. 
Exclusion Criteria: 
• Any medical condition that, in the opinion of the site 
investigator, would place the patient at an unreasonably 
increased risk through participation in this study, including 
any past or concurrent conditions that would preclude 
randomization to one or more of the assigned treatment 
arms. 
• Prior treatment with any investigational antiviral drug 
therapy against Ebola infection, other than experimental 
vaccines, within 5 half-lives or 30 days, whichever is longer, 
prior to enrollment 
 
Study Design 
Principles: 
A randomized, controlled adaptive trial, with frequent interim 
monitoring to facilitate the following: dropping of poorly performing 
arms, introduction of new candidate therapies and modification of 
current optimized standard-of-care (oSOC). Comparisons of safety 
and efficacy will be based on data from concurrently randomized 
participants. In its simplest iteration, the study can be viewed as a 
series of 2-arm comparisons whereby the superior treatment, if 
identified, from each pairwise comparison becomes the basis of the 
new supportive care backbone (hence the term “optimized SOC”, or 
oSOC, to describe this potentially evolving backbone) common to 
each future arm of the study and against which additional 
investigational interventions may then be added to the protocol, 
tested and compared: 
Arm A: optimized SOC alone 
Arm B: Investigational treatment X + optimized SOC 
 
• In the initial iteration and at protocol team discretion, the 
optimized SOC employed in Arm A is expected to consist of 
aggressive fluid replacement and electrolyte monitoring and 
replacement to be compared to Arm B in which both 
investigational therapeutic agent X plus that same optimized 
SOC are featured. 


 
 
• If this pairwise comparison shows the superiority of Arm B 
over Arm A, then investigational treatment X featured in Arm 
B will be incorporated into the new oSOC common to each 
future arm of the study (assuming adequate drug supply exists 
to permit this). 
• Conversely, if a given pairwise comparison of Arm A versus 
Arm B fails to yield a clear statistical winner in terms of the 
primary endpoint, then subsequent pairwise comparisons will 
not incorporate the “failed” intervention featured in current 
Arm B into the new oSOC backbone. 
 
Study Synopsis: 
• Informed consent for research participation upon admission 
into the treatment center 
• Baseline determination of clinical status according to 
standardized CRF 
• Baseline collection of plasma for Ebola viral load by PCR to be 
processed by an appropriate laboratory facility 
• Centralized randomization assignment made 
• Provision of Arm A or Arm B intervention according to 
assigned treatment arm and the individual pharmacologic or 
logistical requirements of the treatment intervention 
• 24-48 hour pharmacokinetic measurements of assigned 
intervention where appropriate and possible 
• Daily assessments of clinical status according to standardized 
CRF and flow sheet 
• Serial collection of plasma for viral load determination by 
PCR for processing in an appropriate laboratory facility, as 
possible. 
• Long term follow-up, when feasible, for any late onset clinical 
history or symptoms possibly consistent with delayed 
virologic relapse. 


 
 
PRÉCIS 
 
Ebola viruses (EBOV) are members of the Filoviridae and are known primarily as the underlying 
cause of severe viral hemorrhagic fevers with disturbingly high case fatality rates. Between 
1994 and the present, there have been many EBOV outbreaks affecting mostly central Africa, 
with 2 large outbreaks in 1995 in Kikwit, Democratic Republic of Congo (DRC), and in Gulu, 
Uganda in 2000-2001. However, the 2014 West African outbreak significantly exceeds all 
previous outbreaks in geographic range, number of patients affected, and in disruption of 
typical activities of civil society. 
 
There is strong consensus that the most important element necessary to improve survival from 
Ebola infection is the provision of full hemodynamic support in the form of aggressive fluid 
replacement, ability to diagnose and correct severe metabolic derangements, and other 
standards of modern medical care available in resource-rich environments. However, against 
this background, a small series of investigational agents or interventions have also been 
proposed as putative antiviral strategies of potential utility in treating this infection. 
Unfortunately, phase 1/2 data supporting the safety and efficacy of these agents is generally 
lacking, and thus there should be equipoise as to which, if any, of these interventions should be 
utilized in the treatment of severe infection. 
 
In this multicenter randomized trial, we propose a flexible trial design with frequent interim 
monitoring to facilitate early elimination of poorly performing treatments as well as the 
introduction of new candidate therapies. The trial allows for a series of pairwise comparisons of 
novel interventions against a background of optimized medical care, with the goal of 
determining whether one or more of these interventions can improve the mortality over that 
achievable through optimized standard-of-care (oSOC) alone. The primary endpoint of this trial 
will be comparative mortality at Day 28, with a number of secondary endpoints that hopefully 
will generate generalizable knowledge about the relative safety and antiviral activity of these 
adjunctive interventions. 


 
 
16 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
Background 
16.1.1 Filoviruses 
Ebola viruses (EBOV) are members of the Filoviridae and are known primarily as the underlying 
cause of severe viral hemorrhagic fevers with disturbingly high case fatality rates. Between 
1994 and the present, there have been many EBOV outbreaks (Table 8) affecting mostly central 
Africa, with 2 large outbreaks in 1995 in Kikwit, DRC, and in Gulu, Uganda in 2000-2001. The 
ongoing West African outbreak significantly exceeds all previous outbreaks in geographic range, 
number of patients affected, and in disruption of typical activities of civil society. 
Table 8: Ebola Virus Outbreaks 
 
Viral species 
Year 
Outbreak location 
# of human cases (% fatality) 
1976 
Yambuku, Zaire (DRC) 
318 (88%) 
Zaire Ebola virus 
1977 
Tandala, Zaire (DRC) 
1 (100%) 
1994 
Ogooue-Invindo province, 
Gabon 
51 (60%) 
1995 
Kikwit, Democratic Republic of 
Congo 
315 (79%) 
1996 
Mayibout, Gabon 
37 (57%) 
1996 
Booue, Gabon and 
Johannesburg, South Africa 
61 (74%) 
2001-02 
Ogooue-Invindo province, 
Republic of Congo (RC) 
124 (79%) 
2002-03 
Cuvette region, RC and Ogooue- 
Invindo province, Gabon 
143 (90%) 
2003 
Mboma and Mbandza, Republic 
of Congo 
35 (83%) 
2005 
Etoumbi and Mbomo, Republic 
of Congo 
12 (75%) 
2007 
Kasai Occidental province, 
Democratic Republic of Congo 
25 (not determined) 
2008/2009 
Democratic Republic of the 
Congo 
32 (47%) 
Sudan Ebola virus 
1976 
Nzara, Maridi, Tembura, Juba, 
Sudan 
284 (53%) 
1979 
Nzara, Yambio, Sudan 
34 (65%) 
2000-01 
Gulu, Masindi, Uganda 
425 (53%) 
2004 
Yambio, Sudan 
17 (41%) 
2011 
Uganda (Luwero District) 
1 (100%) 
Taï 
1994 
Tai forest, Ivory Coast 
1 (0%) 
Ebola Virus 
1995 
Liberia, Liberia 
1 (0%) 
Reston Ebola virus 
1989 
Reston, VA, USA 
4 (0%) 
1992 
Siena, Italy 
0 
1996 
Alice, TX, USA 
0 
2008 
Philippines 
0 


 
 
 
Bundibugyo 
Ebola virus 
2007/2008 
Uganda 
131 (37%) 
 
16.1.2 Therapy 
To date the standard treatment of Ebola hemorrhagic fever (EVD) during the present 2014 
outbreak has been strictly supportive, involving largely oral fluid and electrolyte replenishment 
and pain reduction. 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 have neither been available nor tested in most patients. However, in the few centers 
where such measures were able to be employed, a substantial reduction in mortality has been 
reported. Thus, substantial planning efforts are currently geared towards identification, 
standardization, and deployment of the most successful standard-of-care (SOC) measures that 
potentially could be introduced into these previously resource-poor areas where the majority 
of patients have been treated. In addition to ongoing epidemiologic measures to limit the 
spread to uninfected populations, there is widespread consensus that improved SOC measures 
could represent the single most effective means of reducing the substantial mortality rates 
associated with the disease in the affected regions. 
 
In contrast, in the United States and other developed nations to which a small number of 
infected health care workers (HCW) have been medically evacuated, aggressive intravenous 
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 optimized standard of 
care (oSOC) there 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 late fall, 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. The reported distribution of 
investigational agents in these individuals was as follows: 
 
ZMapp or MIL77 
  ZMab 
 
TKM-Ebola 
  Favipiravir 
 
Brincidofovir 
  FX06 
 
Convalescent plasma 
  Convalescent whole blood 
 
Amiodarone 
Melanocortine 


 
 
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 extremely difficult to discern. In addition, to date 
6 medically evacuated HCWs brought back to the United States following a serious 
percutaneous exposure to Ebola virus while in country, but without documented infection at 
the time of transfer, also received 1 putative MCM each: Tekmira siRNA in one case and the 
investigational VSVΔG-ZEBOV vaccine in the remaining five. It should be emphasized that in 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 humans 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 
in rodent models, but either failed testing or were not thoroughly tested in the nonhuman 
primate (NHP) model, which is 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 current 
outbreak and, in fact, was also used in a limited number of patients during the Kikwit 1995 
ZEBOV outbreak. However, its earlier success remains a matter of dispute (1). Experimentally, 
passive immunization with horse serum resulted in protection of Hamadryl baboons (2), 
whereas it only delayed death in Cynomolgus macaques (3, 4). Certain monoclonal antibody 
treatments have also been successful in rodent models (5-7) but have failed in preliminary 
nonhuman primate studies (8), indicating possible evasion of antibody neutralization as an 
escape mechanism of the virus. Other, more recent monoclonal antibody cocktails may avoid 
this limitation. However, it remains fair to say, at least at this time, that the therapeutic role of 
convalescent plasma or monoclonal preparations as treatment adjuncts remain as 
unsubstantiated in this disease as do direct antiviral agents. 
Rationale for Study 
The current state of medical science with respect to the treatment of filovirus infections such as 
Ebola does not adequately address the role of therapeutic adjuncts beyond supportive care in the 
successful management of these infections. In many cases, our understanding of the role that 
these adjunctive therapies may play is greatly hampered by lack of an adequate phase 1 safety 
and toxicity database of the lead drug candidates, or by lack of data concerning even how the 
candidates in more advanced development may perform in this particular patient population. The 
tragic dimensions of the ongoing Ebola epidemic in West Africa afford little time to explore 
these issues according to a more conventional time frame of traditional drug development, and 
argue strongly for an accelerated exploration of the safety, toxicity, and potential preliminary 
efficacy of lead agents in a controlled research setting. 
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: 
• Even in highly-resourced medical environments such as those available in the US, 
Europe, or other developed regions, the past record of being able to generate important 


 
 
and generalizable knowledge concerning the role of experimental therapies for infectious 
diseases of public health importance when those agents have been made available under 
single-use emergency IND, Emergency Use Authorization (EUA), or similar mechanisms 
has been disappointing at best. A consolidated multicenter approach to study lead 
candidates according to a single research protocol offers a potential opportunity to 
improve upon this record. 
• Even if concentrated efforts to generate important comparative efficacy assessments 
between individual treatment interventions falls short, 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 receiving oSOC. 
• Optimized SOC must be the mainstay of therapy and remain the backbone to which 
experimental treatment modalities must be introduced and compared. 
• Depending upon site and resources, invariably differences in oSOC may occur that may 
obscure the potential additional contribution of experimental therapeutics. Therefore, 
every effort must be made to standardize the oSOC that exists as the backbone to this 
experimental treatment protocol. In situations where this may not be fully possible, i.e. in 
comparing in-country oSOC versus oSOC available in intensive care settings within 
developed nations, this difference must be taken into account when comparing outcome 
in different patient cohorts. 
• Questions of equity concerning the ethics of allowing potentially beneficial experimental 
treatments to be studied in places where fully optimized supportive care may be possible, 
and not in places where optimized care has not been introduced to date, are certainly 
reasonable, heartfelt, and compelling but, if taken to their logical extreme when involving 
drugs in extremely limited supply and of unknown safety, could prevent their scientific 
study altogether and result in no generalizable knowledge being generated about the 
value of these agents in any setting, an outcome that would disadvantage society as a 
whole. 
• A unique and presently unavoidable factor in establishing pairwise comparisons 
identified for this trial is the limited, intermittent, or absent drug supply that may exist for 
several of the lead candidates proposed for study. The current flexible treatment design is 
an attempt to overcome this unpredictable element. 
• As present knowledge of the potential toxicity of lead candidates in this patient 
population is as limited as knowledge of their potential therapeutic value, investigators 
should and must be able to maintain equipoise as to the introduction and role of 
individual agents in treating patients severely ill with Ebola infection. 
 
• A key ethical feature and justification for this approach, based upon the current and 
foreseeable circumstances, is that there is a significant degree of ‘acceptability of [trial 


 
 
drug] risk,’ in the face of unprecedented individual and community risk for morbidity and 
mortality. 
• The use of a common protocol is recommended for the following reasons: 
o This design can accommodate the study of more than 1 investigational therapy using 
a single shared control group. 
o As mentioned above, this design can accommodate staggered and intermittent 
availability of limited supplies of the anti-Ebola investigational drugs. 
o This design can also provide a more equitable means of allocating scarce product 
through randomization (much like a lottery) while also allowing critically important 
data to be gathered on the safety and efficacy of these investigational products that 
will benefit patients (i.e., knowledge of whether an investigational product is 
actually helping, hurting, or of no consequence). 
o Having a randomized concurrent control group is essential to maximize the 
likelihood that the conclusions drawn from the trial are correct. Site-specific case 
fatality rates (CFR) have varied substantially both between different treatment 
centers as well as even chronologically within the same centers over the course of 
the present epidemic, making the use of historical controls fixed in time or place 
fraught with significant hazard. 
o A single trial design allows for having a data safety monitoring board (DSMB) and 
stopping rules in place. The stopping rules should be reasonable, and if one of the 
products is found to be effective at an interim time point but there is not a sufficient 
supply of the product that has been found to be effective, it may still be ethical to 
continue the common protocol. When sufficient supplies of the product become 
available, that product might be incorporated into the revised oSOC, as discussed 
earlier. If there are insufficient supplies of a product, even if efficacy has been 
shown, one may be able to argue that providing the scarce supplies of drug through 
a clinical trial is more equitable than other potential approaches in addition to 
allowing continued comparative data generation to improve the understanding of its 
appropriate use. 
17 
STUDY OBJECTIVES 
Primary Objective 
• To establish the safety and efficacy of investigational therapeutics in patients with Ebola 
virus infection. 
Secondary Objectives 
• To create a uniform observational database on clinical and virologic parameters 
associated with severe Ebola virus infection 


 
 
• To evaluate the comparative effects of investigational therapeutics on clinical parameters 
of Ebola infection 
• To study the comparative effects of different investigational agents on immediate plasma 
viral load kinetics 
• To obtain 24-48 hour pharmacokinetics of investigational therapeutics when possible and 
appropriate* 
• To determine the comparative frequency of serious adverse events (SAEs) 
• To describe infusion related adverse reactions 
• To compare the duration of hospital stay 
• To compare the time to viral load clearance 
• Long term follow-up for any late onset clinical history or symptoms possibly consistent 
with delayed virologic relapse. 
 
* 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 and transport 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. 
18 
STUDY DESIGN 
General 
Study size: up to 1000 patients 
Study duration: 24 months 
Study duration of individual subjects: Initially for 30 days following the primary endpoint 
(mortality at Day 28), or for a total of 58 days. Interested subjects will also be offered the 
opportunity, where and whenever feasible, to participate in long term follow-up (up to 1 year or 
more depending upon need) past Day 58 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 CNS or the male testes). 
Sex distribution: males and females 
Age range: unrestricted 
 
A randomized, controlled clinical trial of experimental Ebola virus disease therapies compared 
to current oSOC. Treatment efficacy evaluations are based on outcome comparisons between 
treatment arms from concurrently enrolled subjects. The study can be conceptualized as a 
series of 2-arm comparisons between different therapeutic interventions: oSOC versus an 
experimental therapy plus oSOC. It is intended that the oSOC will be updated to incorporate an 
experimental therapy when the latter’s efficacy has been demonstrated. While the updated 
oSOC should be the comparator for unproven therapies, this may not always be practical (e.g., 
when supply of the new drug is limited). Whether the updated oSOC is always added as 
optimized background therapy to existing unproven/experimental therapies will depend on 


 
 
practical considerations, including drug availability and the appropriateness of combining 
specific therapies. However, the intent is that the study will continue enrolling and employ the 
next selection of available medical countermeasure in the comparison if there is a temporary 
shortage of the present countermeasure being studied. 
 
Stage 1: the initial phase (see Figure 5) 
Randomization to the following: 
 
Arm A: oSOC1** alone 
or 
Arm B: Investigational treatment X + oSOC1** 
 
*The subscript “1” indicates the first or current “optimized standard-of-care.” In the 
initial iteration and at protocol design team discretion, Arm A will be an oSOC alone arm 
to be compared to Arm B in which both an investigational therapeutic agent (i.e. Drug 
“X”) plus oSOC are combined. 
 
** In developed countries, oSOC is defined as the application of aggressive fluid 
resuscitation, hemodynamic and respiratory support, metabolic corrections, diagnostic 
evaluation, and other modalities of advanced critical care that are generally available in 
most academic centers capable of caring for critically ill patients. In areas where such 
advanced methods may not be fully available (i.e., in advanced medical care units to be 
built and supported in the affected countries of West Africa by the USG and other 
government entities), this definition should apply to the optimal standards of care 
possible in those settings. 
 
If and when a statistical difference is shown between the 2 arms supporting superiority of one 
intervention over the other, the superior (“winning”) intervention is then used as the basis of a 
modified oSOC in which incorporation of that intervention as an addition to the prior oSOC 
becomes the new basis of comparison. This is assuming that sufficient drug supply exists to 
permit the incorporation of that superior therapy into a new oSOC backbone and fuel 
additional comparisons. If that is not the case, then subsequent comparisons will have to revert 
back to the previous oSOC until such time as additional quantities of the superior therapy can 
be made available. If, however, incorporation into a new oSOC is possible, then that modified 
arm can then compared to new Arm C (i.e., consisting of a new therapeutic intervention not 
previously tested) so that the pairwise comparisons can continue until the list of favored 
treatment explorations is exhausted and/or until an optimal regimen appears clear. This can be 
summarized as follows: 


 
 
Stages 2-K: the post-initial phase with up to K additional therapies. 
Randomization to the following: 
Control arm: Updated current oSOC (oSOCk; where k=2,…, K to indicate the possible 
updated oSOCs) 
Experimental arm: Investigational therapy + best oSOC, where the best oSOC may be the 
most current oSOC or the previous oSOC, depending on drug availability, 
appropriateness of combination therapy, etc. as determined by the study team in 
concordance with the DSMB. 
 
Advisory stopping boundaries for efficacy (and futility) will be provided to the DSMB to guide 
decisions about when an experimental arm is deemed superior (or not worthy of further 
investigation). A description of these boundaries is provided in the statistics section (Section 
22). Specifics about these boundaries will be provided in a DSMB statistical analysis plan. 
 
While for illustrative purposes, the strategy is described with sequential pairwise comparisons, 
in practice, it can be adapted for more than 2 pairwise comparisons. The study might be 
modified accordingly, if there is compelling scientific interest to study more than 2 different 
interventions simultaneously (“Drug Y” example in Figure 5). Success at being able to 
demonstrate statistical difference between comparator arms will of course depend upon being 
able to enroll sufficient numbers into each arm to power these comparisons. 


 
 
Figure 5: Example of Possible Clinical Trial Design Schematic for the Common Protocol – 
First Phase 
 
 
Study Endpoints 
 
Study endpoints will be evaluated by comparing randomized groups. 
18.2.1 Primary Endpoint 
 
• 
28-day survival 
18.2.2 Secondary Endpoints 
• 
58 day survival time 
• 
Change in Ebola virus threshold cycle within first 72 hours after randomization 
• 
Rate of Ebola viral clearance, quantified as change in threshold cycle per day 
• 
Time from randomization to first negative Ebola PCR 
• 
Cumulative incidence of serious adverse events (SAEs) 
• 
Cumulative incidence of adverse events (AEs) as assessed by laboratory monitoring 
• 
Incidence of infusion related adverse reactions 
• 
Frequency of clinically significant study agent administration or infusion reactions 
• 
Duration from time of symptom onset to discharge from treatment unit or hospital 
• 
Cumulative incidence of progression to severe disease (hemorrhage, multi-organ 
failure, seizures) 
• 
Cumulative incidence from the time of randomization to resolution of 
gastrointestinal symptoms (vomiting and diarrhea). 


 
 
• 
Cumulative incidence from time of randomization to resolution/progression of 
individual clinical symptoms 
• 
Maximal serum creatinine in first 14 days 
• 
Pharmacokinetics of investigational therapeutics 
• 
Long term follow-up, when feasible, for any late onset clinical history or symptoms 
possibly consistent with delayed virologic relapse. 
 
 
 
Overview of Study Drugs 
By the fall of 2014 preclinical studies, and/or past use of interventions with anecdotal evidence, 
had identified a number of lead candidate therapeutic interventions that might be considered 
as prime candidates for further study in patients with known Ebola infection. With time it was 
thought possible that additional antiviral or immune-enhancing agents with preclinical 
supporting data may be identified and added to this list. Conversely, emerging toxicity data, 
failure to replicate previous supportive findings in additional preclinical animal model testing, 
emerging data from other recent therapeutic trials in West Africa, or similarly negative factors 
conceivably could also lead to narrowing of this list over time. Further, if inclusion were to be 
expanded to patients with high-risk exposures but no documented infection, the list of putative 
MCMs could be broadened even further and would likely include putative vaccine candidates. 
However, confining this proposed RCT to just enrollees with documented infection, the likely 
lead candidates initially identified for consideration of study included: 
• Convalescent or post-immunization plasma harvested from recent Ebola infection 
survivors: 
o In time it is possible that this category could potentially be expanded to include 
plasma donors who have participated in phase 1 anti-Ebola vaccine testing and 
whose plasma shows high neutralizing activity against the virus in animal or in 
vitro assays. 
• ZMappTM triple monoclonal antibody cocktail from Mapp Biopharmaceutical: 
o A combination of 3 different humanized monoclonal antibodies against the Ebola 
glycoprotein. 
• Tekmira siRNA (or “TKM-Ebola”) from Tekmira Pharmaceuticals Corp: 
o A combination of small interfering RNAs targeting 2 of the 7 proteins in Ebola: 
Zaire Ebola L polymerase and Zaire Ebola polymerase complex protein (VP35), 
formulated with Tekmira's lipid nanoparticle technology. Targeting of the initial 
product was subsequently optimized against the prevalent Guinea strain of the 
2014 virus. 
• Favipiravir from Toyama Chemical Co., LTD: 
o A selective inhibitor of RNA-dependent RNA polymerase with activity against a 
wide variety of viruses. 
• BCX4433 from BioCryst 
o viral RNA-dependent RNA polymerase (RdRp) inhibitor 
• AVI-7537 from Sarepta 
o phosphorodiamidate morpholino oligomer 


 
 
This list was not intended to be exhaustive, and future inclusion of other drug 
candidates (e.g. different monoclonal antibody cocktails targeted at epitopes identical 
to those in ZMappTM) was not prohibited by these examples. 
Considerations in Choice of Study Drugs 
Several factors influencing choice and sequence of study drugs/interventions to be compared in 
this protocol must be considered: 
• Willingness of both the pharmaceutical sponsors and the FDA to allow each of these 
drugs to be studied according to this proposed trial design 
• Sufficient and dedicated supply of individual agents to allow them to be available for 
study over the projected timeline of the trial 
• Ongoing equipoise of the investigators that 
o No available individual agent has yet been demonstrated to be superior to oSOC 
o No available individual agent has yet been demonstrated to be superior to other 
agents 
• No compelling safety/toxicity concern has emerged with respect to individual agents to 
favor their removal from consideration as study interventions 
• The status of eIND access to these interventions during the projected timeline of this trial 
that may preclude, or circumvent, interest in enrollment of patients into this RCT. 
 
With these considerations in mind, the starting choice of interventions to be entered into and 
compared in this trial was determined by a consensus of the site investigators performing this 
study at their individual treatment centers. The most recent deliberations of this group are 
reflected in Appendix A of this protocol. 
Definitions for the Purpose of this Study 
Enrolled 
For the purpose of collecting data and samples, and reporting SAEs, a subject will be 
considered enrolled beginning from when the informed consent form is signed until the 
subject is considered either “discontinued”, or “completed”. 
 
Discontinued 
Subjects are considered discontinued when they meet 1 or more of the following criteria: 
o Subject withdraws consent after being dosed and prior to the completion of Day 28 
(see Section 19.5) 
o Subject is withdrawn after enrollment by investigator (see Section 19.6) including 
lost to follow-up 
 
Completed 
Subjects are considered completed for the main study endpoint when they 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 scheduled for that time. Patients willing to undergo 
extended follow-up for one year or more (i.e. to determine the incidence of any late onset 
history or symptoms potentially c/w virologic relapse) will still be considered as having 


 
 
completed the study if a) they decline this extended follow-up, or 2) choose to discontinue 
extended follow-up prior to reaching one year past Day 58. 
19 
STUDY POPULATION 
Research Subject Recruitment 
Persons with confirmed Ebola virus infection at participating health centers may participate in 
the trial so long as the site can provide enhanced supportive care including the provision of fluid 
resuscitation (preferably intravenously, but potentially orally through nasogastric tubes), 
hemodynamic monitoring, and laboratory monitoring of fluid and electrolyte disturbances 
coupled with the ability to correct such abnormalities as they are detected. 
19.1.1 Participation of Site Employees 
Site employees who meet inclusion 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. 
Inclusion Criteria 
• Males or females with documented positive PCR for Ebola virus infection within 10 days 
of enrollment 
• Willingness of study participant to accept randomization to any assigned treatment arm 
• Access to oSOC 
• All males and females of childbearing potential, must be willing to use highly effective 
methods of contraception [e.g. absolute abstinence from potentially reproductive 
sexual activity, hormonal, surgical or multiple barrier/combined], from time of 
enrollment for the duration of study participation. 
• Must agree not to enroll in another study of an investigational agent prior to completion 
of last required protocol visit (Day 58) 
• Ability to provide informed consent personally, or by a legally-authorized [per applicable 
local laws and regulations] representative [LAR] if the patient is unable to do so. 
Exclusion Criteria 
• Any medical condition that, in the opinion of the site investigator, would place the 
patient at an unreasonably increased risk through participation in this study, including 
any past or concurrent conditions that would preclude randomization to one or more of 
the assigned treatment arms. 
• Prior treatment with any investigational antiviral drug therapy against Ebola infection, 
other than experimental vaccines, within 5 half-lives or 30 days, whichever is longer, 
prior to enrollment. 


 
 
Vulnerable Populations 
19.4.1 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 infection than 
from the study medications themselves, pregnant women will be permitted entry into 
the study. However, there may still be certain study medications (e.g., favipiravir) with 
known teratogenic potential to which pregnant women should not be assigned, and 
these considerations must be reviewed on a case-by-case basis with study investigators. 
For example, if favipiravir happens to be the drug currently under study, pregnant 
women should not be enrolled in the trial during the period this particular drug is being 
tested. 
 
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 Ebola Treatment Unit (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. 
19.4.2 Inclusion of Children 
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 study participation. 
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. 
 
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 be 
withdrawn from the study for any of the following reasons: 
• The investigator believes that continuation in the study would be detrimental to the 
subject. In general, subjects withdrawn for AEs will still be followed for safety follow-up, 
if possible, as well as for ascertainment of the Day 28 mortality endpoint. If in the 
investigator’s best judgment discontinuation is in the subject’s best interest. 


 
 
The reason for withdrawal from the study is to 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. 
Discontinuation of Study 
The National Institute of Allergy and Infectious Diseases (NIAID), each institution’s 
Institutional Review Board (IRB), or the Food and Drug Administration (FDA) may terminate 
this study at any time. 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 
• Investigators do not adhere to the protocol or applicable regulatory guidelines in 
conducting the study 
20 
TREATMENT 
Randomization and Blinding 
This study follows an open-label randomization design. A randomization scheme will be 
generated by the Data Management Center prior to the initiation of the study. 
Study Drugs 
Every attempt will be made to pre-position the study drugs under active study at the 
participating sites’ pharmacies in advance of enrollments. Randomization of individual 
patients to a given study drug will only occur when there is sufficient quantity of that 
drug to complete a full treatment course for those individuals. 
21 
STUDY PROCEDURES 
Personnel for Study Procedures 
Assessments and study procedures may be performed by members of the investigative 
team and clinical team as noted on the Delegation of Responsibilities log. 
 
The study will be conducted in accordance with the protocol, GCP, and all applicable US 
and West African regulations. 
Site-Specific Considerations 
The reality of the 2014-15 outbreak of Ebola infection is that patient care has been, and 
will likely continue to be, provided in a wide variety of different clinical settings, some of 
which have been fortunate to be comparatively resource-rich and others of which have 
faced significant resource challenges. Accordingly, the capability of individual sites to 
conduct the full spectrum of clinical research components outlined in this protocol will 
almost certainly vary widely depending upon such factors as staffing, available 


 
 
equipment, and current operational, clinical, and safety practices. With this 
consideration in mind, as long as sites can fulfill the minimal standards of oSOC as 
outlined in Section 3.1 and obtain the necessary information to inform the primary 
endpoint, it is appropriate that 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. The inability of a site to collect the full optimal 
frequency of assessments as outlined below due to unavoidable resource limitations will 
not constitute a protocol deviation. 
Schedule of Evaluations 
The day when the subject is enrolled and randomized to their assigned treatment arm is 
denoted as Study Day 0. The first day after randomization is Study Day 1. 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 past Day 58 to 
determine the incidence of potential virologic relapse will either be seen in person or 
contacted via phone on a periodic basis; all study days past Day 58 will be considered 
Extended Follow-Up assessments. If necessary, and with the patient’s verbal consent at 
the time they agree to extended follow-up, 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 a late onset virologic 
relapse syndrome. The expected frequency of such periodic assessments will be every 1- 
3 months up to one full year past Day 58, subject to the patients’ wishes and the 
logistics and feasibility of contacting individual participants on a serial basis. 


 
 
Table 9: Schedule of Evaluations 
Evaluation / Procedure 
Day +/- Window 
Screen 
Baseline 
Follow Up 
−1 to 0 
0 
1 
2 
3 
4 
5 
6 
7 
8+ while 
hospitalized 
28- 
35 
58 
±7 
Ext. F/U 
(Q 1-3 mo.) 
ELIGIBILTY/RANDOMIZATION 
Informed consent 
X 
Demographics 
X 
Ebola PCR 
-10 to 0 
Randomize subject 
X 
STUDY DRUG ADMINISTRATION 
ZMappTM (if randomized to receive ZMappTM) 
X (Day 0 if possible) 
+ 3 days from 
1
st dose 
+ 3 days from 
2
nd dose 
Investigational agents #2 
Other investigational agents per the adaptive trial design, refer to most 
recent SOP 
MINIMUM STUDY PROCEDURES (only obtained while in treatment unit) 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record of Optimized Supportive Care 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of current symptoms/conditions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ebola PCR with ct 
X 
X 
X 
Every 2-3 days until 
1 negative 
Creatinine, Potassium 
X 
X 
X 
X 
OPTIMAL 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 PCR with ct 
X 
X 
X 
X 
X 
X 
X 
X 
until 2 negative 
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 
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 
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 
Stored plasma, serum specimens 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
 
6.2.1 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 and time when signed. The informed consent process will 
occur on or before Day 0. 
 
6.2.2 Demographics 
The following information should be recorded from the participant or surrogate: 
• Age 
• Sex 
• Ethnicity 
• Race 
• Country of Birth 
6.2.3 Medical History 
The following information should be recorded: 
• Focused Medical history regarding EVD, including all prior PCR results 
• Current Symptoms 
• Current participation in any recent research protocols 
6.2.4 Clinical Data 
• Vital signs (temperature, heart rate, respiratory rate, blood pressure) with 
oxygen saturation as possible 
• Weight (actual or estimated) 
 
6.2.7 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 (or told directly if found ineligible during screening evaluation), and the 
reason for ineligibility will be discussed. If desired by the subject, and if applicable 
for the reason for ineligibility, the results will be shared with their outside health 
care provider. 
 
Day 0 
21.4.1 Baseline Evaluation 
Within 24 hours prior to randomization, a baseline clinical evaluation will be performed 
with documentation of current symptoms and clinical conditions including vital signs. 


 
The list of symptoms and signs to assess includes: fever, sore throat, cough, fatigue, 
weakness, dizziness, confusion, hearing loss, headache, myalgia, arthralgia, loss of 
appetite, vomiting, diarrhea, symptoms, abdominal pain, trouble urinating, chest pain, 
breathing difficulties, shortness of breath, hiccups, rash, edema, conjunctivitis, oral 
ulcers/thrush, hemorrhage, multi-organ failure, convulsions. 
21.4.2 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). 
21.4.2.1 Minimum Baseline Requirements: 
• Creatinine 
• Potassium 
• Ebola PCR with threshold cycle (ct) 
▪ 
Although any positive Ebola PCR collected up to 10 days prior to 
informed consent provides eligibility, a baseline specimen should 
be collected on Day 0 if the prior specimen was collected >24 hours, 
as the viral load may have substantially changed. 
21.4.2.2 Optimal Baseline Laboratories 
• CBC with differential 
• Acute/hepatic/mineral chemistry panels as available via POC testing, 
defined as: 
• Metabolic Panel = Na, K, Cl, HCO3, blood urea nitrogen, 
creatinine, glucose, Ca, Mg 
• Hepatic Panel = AST/SGOT, ALT/SGPT, Alkaline phosphatase, t- 
Bilirubin, 
• Lactate 
• Albumin 
• ionized Calcium 
• Ebola PCR with threshold cycle (ct) and/or quantitative copies/mL 
• PT/aPTT/INR 
• D-Dimer 
• Urinalysis (evaluating RBC, protein, and glucose) if available as POC test 
• Serum or urine pregnancy test (females of childbearing potential only) if 
available as POC 
• Specimen storage 
21.4.3 Randomization 
Randomization occurs on Day 0 with the site communicating with the regional 
operations center for the randomization. 


 
21.4.4 Study Drug Administration Timing 
It is possible that Study Day 0 may be consumed by longitudinal determination of a 
patient’s overall clinical status, implementation of oSOC provisions, assessment for 
study eligibility, and study randomization. Therefore, it is possible that actual 
administration of an investigational study intervention (if part of the assigned treatment 
arm) may be deferred until Study Day 1. Refer to the Pharmacy SOP for specific 
administration details. 
Follow Up Study Days 
The plan for study drug administration, clinical assessments, and lab monitoring are outlined in 
the Schedule of Evaluations. Details are below on assessments are as follows: 
21.5.1 Follow-up Daily Assessment and Optimized Supportive Care 
This will include documentation of: 
• Current Symptoms or conditions 
• Vital signs 
• Optimized Supportive Care received 
• Study agent administration, as applicable 
• Laboratory (as performed) 
• Urinalysis (as performed, optional) 
• Imaging and Resuscitation (as performed, optional) 
• Any Serious Adverse Events 
• Discharge / Outcome information, as appropriate 
21.5.2 Pharmacokinetic Sampling 
• 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: 
o Collection of baseline drug level prior to assigned treatment intervention 
o Initiation of serial PK blood draws whose frequency and duration (24-48 hours) will 
be guided by anticipated PK profile based upon preclinical data 
21.5.3 Clinical Safety Laboratory Testing 
21.5.3.1 Minimum Requirements: 
• Creatinine 
• Potassium 
• Ebola PCR with threshold cycle (ct) 
For the frequency of required minimum lab testing, refer to the Schedule of 
Evaluations in Section 6.2 
21.5.3.2 Optimal Daily Laboratory Monitoring 
Refer to Schedule of Evaluations (Table 9) in Section 21.2. Testing should be 
performed during hospitalization and thereafter additionally as clinically indicated: 


 
• CBC with differential 
• Chemistry panels as available via POC testing, as defined in Section 6.3.2 
• Ebola PCR with threshold cycle (ct) 
▪ 
After two negative Ebola PCRs, testing may be discontinued. 
▪ 
Consideration of other bodily fluid sampling as clinically appropriate 
▪ 
Date of first PCR negative result 
• PT / aPTT / INR 
• D-Dimer 
• Urinalysis, if available as POC test 
• Specimen Storage 
 
21.5.4 Special Follow-up Assessments 
21.5.4.1 Day of Discharge 
Additional information will be obtained on the day of discharge regarding the criteria for 
discharge and negative Ebola PCR testing prior to discharge. 
21.5.4.2 Day 28 
As the primary endpoint is 28-day mortality, the Day 28 visit is essential for data needed for this 
endpoint. All efforts should be made to ensure timely completion of this study visit. 
21.5.4.3 Pregnancy 
Any pregnant women enrolled into this study will be followed through term and for 6 months 
after delivery as able and with the consent of the subject. 
 
21.5.4.4 Extended Follow-Up 
Patients will be contacted either in person or by telephone to answer questions according to a 
special CRF dedicated to eliciting a history of signs or symptoms potentially c/w late onset of a 
virologic relapse, with particular focus on neurologic symptoms that may represent re- 
emergence of virus from a CNS source. 
22 
STATISTICAL METHODS 
Background 
A statistically valid plan for conducting a randomized trial of limited and unproven treatment 
options for Ebola virus disease is not straightforward. Such a trial is unlike most others in 
several respects: 1) the mortality rate of the “control” arm, i.e., best supportive care arm, is not 
well known, nor are the factors associated with improved outcome, 2) the oSOC may  change 
as a result of accumulating results from the trial, 3) although the target number of patients is 
100/arm, the actual number may be much smaller because the supply of one or more 
treatments may be severely limited and intermittent, superiority of one arm over another 
might be established with lesser numbers, and/or the epidemic itself may resolve . However, 
rather than precluding a randomized controlled trial (RCT), these circumstances favor it, for an 


 
RCT is the most efficient and accurate means of evaluating the benefits of alternative therapies. 
Nonetheless, an unusual amount of flexibility in trial design is needed to seamlessly 
accommodate changing circumstances. Flexibility is critical for many reasons. For example, if 
evidence supports updating the existing oSOC (and dissemination of the new standard is 
feasible), this change should be implemented seamlessly. If however, the new standard 
requires a drug with a supply that is nearly depleted (and will remain so for some time), 
immediate changes to the oSOC may not be possible. Continuation of randomization to the 
treatment (with the nearly depleted supply) versus the initial standard may be the preferred 
strategy to allocate the limited supply. Plans for every potential scenario are not possible to 
specify a priori, which leaves such decision making to the domain of the study team in 
consultation with the DSMB. The present study design attempts to maximize the informational 
content of the limited data generated, given the above considerations. 
Design 
The trial will commence with randomization to oSOC (i.e., best supportive care) versus an 
experimental arm receiving oSOC plus treatment. Randomization will use permuted blocks with 
variable but small block sizes, and will be stratified by baseline Threshold cycle (CT) value on 
PCR (≤22 versus > 22) and site of treatment (western Africa versus the United States/Europe). 
The PCR resulted nearest the time of randomization should be used for the stratification. 
 
The trial primary endpoint is mortality by 28 days. The high mortality rate of Ebola virus disease 
and the uncertainty associated with the oSOC efficacy, mandate aggressive interim monitoring, 
which is described in the next section. If more than 2 treatment strategies are evaluated, the 
design will follow the same stopping rules outlined below, but randomization will proceed with 
equal probability to each of the arms. Strict control of the type I error rate would require 
adjustment of boundaries for comparison of multiple arms. We recommend against such 
adjustments, given the exigent circumstances surrounding the Ebola epidemic. Intention-to- 
treat analyses will be employed. Each patient will undergo only a single randomization in the 
study. 
 
Interim Monitoring 
Methods of monitoring clinical trials generally require knowledge of the total amount of 
information at trial’s end. Boundaries are then constructed to guide decisions to control the 
probability of falsely declaring a treatment benefit at one or more interim analyses, including 
the final analysis. Such boundaries correspond to scenarios in which the level of evidence in 
support of treatment efficacy (or the lack thereof) exceeds some pre-determined threshold. 
Early boundaries are usually very difficult to cross, while boundaries at the end of the trial are 
similar to what they would be in the absence of monitoring. Our setting requires a somewhat 
different paradigm because although the target sample size is 100/arm, circumstances beyond 
our control may lead to a smaller number of patients. Moreover, we would like the flexibility of 
modifying the oSOC arm quite early if results show the superiority of an experimental agent 
plus oSOC, for example. We recommend monitoring beginning with 6 participants in an 
experimental arm and 6 in the best supportive care arm, and continuing after every additional 


 
patient per arm, if necessary, up to 20. After that, monitoring would be after every 20 patients 
per arm until the target number of 100/arm is reached or the trial ends for other reasons. Any 
decision to curtail for other reasons will be made by a group blinded to trial results. The 
boundary we recommend is motivated from a Bayesian perspective. Bayesians formulate their 
prior opinion about the size of the treatment effect through a `prior’ distribution, which is 
updated to a `posterior’ distribution after observing data. We give details of the specification 
of the prior distribution and the construction of the boundary later. What are most important 
are the boundary itself and its statistical properties such as type I error rate (the probability of 
crossing the boundary inappropriately, i.e., when the 2 arms are equally effective) and power 
(the probability of crossing the boundary appropriately, i.e., when one arm is superior to the 
other). 
 
Table 10 illustrates the design’s flexibility by showing the boundaries assuming that factors 
beyond our control result in only 20 participants per arm by trial’s end instead of the planned 
100 per arm (stopping boundaries for 100 subjects per arm are included in Appendix B). For 
example, with 6 people evaluated in each arm, we declare superiority of one arm over the 
other only if all 6 die in one arm and none die in the other. On the other hand, with 10 people 
per arm, we cross the boundary if the numbers of deaths out of 10 in the 2 arms are as follows: 
5. 7 or more and 0, 
6. 8 or more and 1 
7. 9 or more and 2 
8. 10 and 3 
Notice that the boundaries at the end of the trial are more lenient than interim boundaries: 
interim boundaries use a probability level of 99.9%, whereas the final boundary uses a level of 
97.5%. This reinforces the need for a blinded group to make stopping recommendations for 
reasons other than safety or efficacy; otherwise, inflation of the type I error rate could result 
from lowering the boundary for the final analysis. Boundaries for a sample size of 100 per 
group will be generated following this same procedure and will be distributed to the DSMB. 
Type I Error Rate 
Table 11 shows the probability of crossing the boundary and declaring a treatment difference if 
we begin monitoring after 6 patients per arm and continue monitoring after each additional 
patient in both arms up to 20/arm, then every 20 per arm up to 100/arm. This probability of 
crossing the boundary depends on the true mortality probabilities in each arm, but the 
maximum value when the event probabilities in the 2 arms are equal is approximately 6% for a 
trial with 100 participants per arm. Even though the Bayesian methodology does not explicitly 
aim to control the type I error rate, that rate is controlled at close to the conventional level of 
0.05. The first 5 rows of numbers in Table 11 also show type I error rate if circumstances 
beyond our control result in a final sample size of 20, 40, 60, or 80 per arm. 
Power and Sample Size 
The last 6 rows of numbers in Table 11 show scenarios with event probabilities differing in the 2 
arms.  With 100 per group, power is 88% to detect a difference if the true mortality 
probabilities in the 2 arms are 0.20 and 0.40, a 50% relative reduction. The selected sample 


 
size of 100/arm also gives reasonably high power (83%) to detect a difference if the true 
mortality probabilities are 0.30 and 0.50, a 40% relative reduction. 
 
Table 12shows the average sample size, taking into account the possibility of stopping early, for 
the scenarios with a treatment effect. If the true mortality rates in arms A and B are 0.3 and 0.5, 
respectively, and a sample size of 100 is targeted, then the study will stop for efficacy, on 
average, with only 76 patients (per arm). 


 
 
 
 
 
Table 10: Flexibility of Trial Design 
The top row gives the number of patients per arm, and the boundaries in parentheses are the numbers of deaths in the 2 arms, with + indicating 
that number or greater (e.g., in the “8” column, 7+ means 7 or 8). 
 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
(6,0) 
(6+,0) 
(7+,0) 
(7+,0) 
(7+,0) 
(7+,0) 
(7+,0) 
(7+,0) 
(8+,0) 
(8+,0) 
(8+,0) 
(8+,0) 
(8+,0) 
(8+,0) 
(4+,0) 
(7,1) 
(8,1) 
(8+,1) 
(8+,1) 
(9+,1) 
(9+,1) 
(9+,1) 
(9+,1) 
(10+,1) 
(10+,1) 
(10+,1) 
(10+,1) 
(10+,1) 
(6+,1) 
(9,2) 
(9+,2) 
(10+,2) 
(10+,2) 
(10+,2) 
(11+,2) 
(11+,2) 
(11+,2) 
(11+,2) 
(11+,2) 
(12+,2) 
(8+,2) 
(10,3) 
(11+,3) 
(11+,3) 
(11+,3) 
(12+,3) 
(12+,3) 
(12+,3) 
(13+,3) 
(13+,3) 
(13+,3) 
(9+,3) 
(11,4) 
(12,4) 
(12+,4) 
(13+,4) 
(13+,4) 
(13+,4) 
(14+,4) 
(14+,4) 
(14+,4) 
(11+,4) 
(12,5) 
(13,5) 
(13+,5) 
(14+,5) 
(14+,5) 
(15+,5) 
(15+,5) 
(15+,5) 
(12+,5) 
(13,6) 
(14,6) 
(15,6) 
(15+,6) 
(15+,6) 
(16+,6) 
(16+,6) 
(13+,6) 
(15,7) 
(16,7) 
(16+,7) 
(16+,7) 
(17+,7) 
(14+,7) 
(16,8) 
(17,8) 
(17+,8) 
(18+,8) 
(15+,8) 
(17,9) 
(18,9) 
(18+,9) 
(16+,9) 
(18,10) 
(19,10) 
(17+,10) 
(19,11) 
(17+,11) 
(18+,12) 
(19+,13) 
(19+,14) 
(20,15) 
(20,16) 


 
 
Table 11: Probability of Crossing the Boundary for Different Mortality, Probabilities, and 
Sample Sizes in the 2 Arms 
 
Simulated Type I Error Rate* 
Mortality 
probability 
treatment 
A (PA) 
Mortality 
probability 
treatment 
B (PB) 
20 per 
group 
40 per 
group 
60 per 
group 
80 per 
group 
100 
per 
group 
0.1 
0.1 
0.038 
0.039 
0.042 
0.050 
0.048 
0.2 
0.2 
0.049 
0.052 
0.049 
0.049 
0.053 
0.3 
0.3 
0.046 
0.051 
0.052 
0.054 
0.055 
0.4 
0.4 
0.042 
0.057 
0.056 
0.054 
0.057 
0.5 
0.5 
0.041 
0.061 
0.061 
0.055 
0.063 
Simulated Power 
Mortality 
probability 
treatment 
A (PA) 
Mortality 
probability 
treatment 
B (PB) 
20 per 
group 
40 per 
group 
60 per 
group 
80 per 
group 
100 
per 
group 
0.1 
0.3 
0.36 
0.63 
0.80 
0.90 
0.96 
0.1 
0.4 
0.61 
0.90 
0.98 
1.00 
1.00 
0.1 
0.5 
0.82 
0.99 
1.00 
1.00 
1.00 
0.2 
0.4 
0.27 
0.50 
0.67 
0.80 
0.88 
0.2 
0.5 
0.50 
0.82 
0.94 
0.98 
1.00 
0.3 
0.5 
0.23 
0.46 
0.62 
0.74 
0.83 
*These type I error rates refer to comparisons of two arms and do not reflect the study-wise type I error rate. 
 
Table 12: Average Final Sample Size per Arm using Stopping Criteria Defined Above 
 
Mortality 
probability 
treatment 
A (PA) 
Mortality 
probability 
treatment 
B (PB) 
Targeted sample size (per arm) 
40 
60 
80 
100 
Average final sample size (per arm) 
0.1 
0.3 
39 
54 
67 
75 
0.1 
0.4 
35 
44 
48 
49 
0.1 
0.5 
29 
32 
32 
32 
0.2 
0.4 
38 
56 
70 
82 
0.2 
0.5 
35 
47 
53 
56 
0.3 
0.5 
38 
56 
71 
84 


 
 
 
 
The frequency of monitoring can be altered. For example, if patient heterogeneity is large, one 
may not conduct the first interim analysis until more patient outcome data has accrued (e.g., 10 
per arm). Regardless of the monitoring frequency, the data and safety monitoring board’s 
recommendation to stop or continue an ongoing trial will be based on consideration of multiple 
factors. The Bayesian perspective allows calculation of `credibility’ intervals (analogous to 
confidence intervals) for the difference in mortality probabilities between arms whether or not 
advisory boundaries are crossed. 
 
Comparison to Other Boundaries 
Even though the boundaries were motivated from a Bayesian perspective, they are actually 
quite similar to Haybittle-Peto boundaries using either Fisher’s exact test or Barnard’s test. 
Suppose circumstances beyond our control limit the total sample size to 20 participants per 
arm. A comparison of the 3 boundaries is shown, in Figure 6 and Figure 7 for interim analyses 
after 10 and 15 participants, and in Figure 8 at the final analysis after 20 participants per arm. 
The proposed boundary is quite similar to, but slightly less conservative than, Barnard’s test. 
Fisher’s exact test is slightly more conservative. 
 
Figure 6: Interim Analysis after 10/Arm 
 
 


 
 
 
 
 
 
Figure 7: Interim Analysis after 15/Arm 
 
 
 
 
Figure 8: Interim Analysis after 20/Arm 


 
 
 
 
 
 
 
 
Advisory Futility Boundaries 
Advisory boundaries for futility will be computed using the conditional probability of reaching a 
statistically significant result at the end of the trial with 100 per arm, given the results observed 
at an interim analysis (called conditional power). Serious consideration for stopping a 
treatment for futility will be given if the conditional power is less than 20% even assuming the 
relative treatment benefit for remaining patients is 50%. 
 
Technical Details of Boundary Construction 
Thoughtful specification of the prior distribution is crucial in Bayesian analysis. We want 
conclusions to depend primarily on data from the trial, not on prior opinion. This argues for a 
skeptical prior distribution that does not already assume that a treatment works. Let p denote 
the probability of survival in a given arm. Our prior distribution on p can be formulated by 
imagining having data on 2 people treated with a given agent, and observing that exactly 1 of 
the 2 survived. The probabilistic equivalent is to assume a beta prior distribution on p with 
parameters 1 and 1, equivalent to a uniform distribution on the interval (0,1). This is consistent 
with an overall survival probability of 0.50 for the current Ebola outbreak, but with wide 
variability reflecting substantial uncertainty about p. Moreover, a uniform distribution for p 
ensures very little influence of our prior opinion on conclusions. The observed data very quickly 
dominate in decision-making.  For instance, if 20 people are given the treatment and 12 of 
them survive, the posterior distribution for the survival probability is beta with parameters 13 
and 9. In other words, combining our prior opinion with the observed data equates to 
observing 13+9=22 people, 13 of whom survived. Our prior opinion constitutes only 2 of the 22 


 
people, and therefore has very little effect on the conclusions. Also, we use the same prior 
distribution in different arms. That way, our prior opinion does not favor any treatment over 
oSOC. If pA and pB denote the survival probabilities in arms A and B, respectively, we use 
independent beta posterior distributions in the 2 arms to calculate the probability that pA<pB, 
namely that the survival probability in arm B exceeds that in arm A. At any interim analysis 
preceding the final analysis, we declare arm B superior if this probability exceeds 99.9%. At the 
final analysis, we declare superiority of arm B if this probability exceeds 97.5%. 
Analyses 
Differences in mortality probabilities between an experimental arm and the best supportive 
care arm will be estimated using 95% Bayesian credibility intervals akin to confidence intervals. 
The treatment effect will be expressed in both an absolute and relative terms, and will be 
estimated in the overall group and in the pre-defined strata: baseline threshold cycle (CT) value 
on PCR (≤22 versus > 22) and where the patient was treated (western Africa versus the United 
States/Europe). The posterior probability that the relative treatment benefit differs by strata 
will be calculated; if this probability exceeds 97.5% that will be taken as evidence of a 
differential treatment effect by strata. 
 
As noted earlier, Bayesian analysis with the non-informative prior distribution specified above is 
very similar to classical statistical analysis using Barnard’s test. To highlight this point, we will 
also present classical confidence intervals for the absolute and relative treatment benefit based 
on Barnard’s test. 
 
Some patients may receive MCMs other than the randomized treatment. This will be 
documented in the record, but it is extremely problematic statistically to try to account for the 
effect of supplementary treatment that may be administered in response to a patient’s failing 
health. A sensitivity analysis will be conducted by treating such patients as if they would have 
died by 28 days in the absence of the additional MCMs. 
 
Similar sensitivity analyses will be conducted for patients missing the primary endpoint of 28 
day mortality. 
 
The analyses of the symptom histories obtained in extended follow-up of patient are intended 
to be observational and descriptive in nature, will apply to patients in all treatment arms, and 
are designed to provide some additional information as to whether there is a detectable 
increase in delayed virologic relapse in trial participants over a period of one year or more 
following recovery and initial clearance of virus from the plasma. 


 
23 
RISKS AND BENEFITS 
Potential Risks 
23.1.1 Unknown Risks 
The primary risks to participants are due to study interventions whose human safety profile is 
either absent or, in most cases, early and accumulating, due to ongoing animal and/or 
early/first in human trials. Generally these are either still in early phase 1 testing, have not yet 
entered phase 1 testing, or, for those interventions in more advanced development, have not 
yet been tested in a human population infected with Ebola virus. Thus, unlike conventional 
phase 2 trials in which a safety database has already been generated to guide the dosing and 
schedule of study drug administration, it is presently unknown what toxicities these agents 
could cause when used in this critically ill patient population or, for that matter, in any humans 
at all. 
 
It is anticipated that additional animal safety and toxicity studies will be in-progress at the time 
of trial initiation for some agents. Results will be made available to the study investigation 
team and pertinent regulatory bodies for review promptly, as they are available. In addition, in 
some cases phase 1 testing of lead candidates in normal human volunteers may commence 
during the same interval of time that this trial is conducted. Should it be concluded from any of 
these studies that there are additional significant risks to study subjects, participants will be 
informed and additional administration of study product may be suspended until review by the 
FDA as well as by each institution’s IRB. 
23.1.2 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. 
23.1.3 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 likely to be investigated 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 conceivable that one or more interventions may subsequently be 
shown to offer evidence of a greater reduction in morbidity and mortality than that 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 very early stage of 
testing. However, even if no experimental treatment intervention is shown 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 or to experimental therapies through other approved regulatory 
means. 
24 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, AND DATA 
Intended Use of the Samples/Specimens/Data 
Samples and data collected under this protocol will be used to determine the 
interventional agent safety, anti-viral effects, development of anti-drug antibodies, 
effects on immune response, and pharmacokinetics. Viral specific items of interest 
include: diagnostics and viral pathogenesis. 
Storage of Samples/Specimens/Data 
Samples obtained in this study must adhere to national regulations for long term 
storage. For U.S. sites, CDC regulations governing 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 at NIH and outside) may wish to 
study these samples and/or data. In that case, IRB approval must be sought prior to any 
sharing of samples. Any clinical information shared about the sample with or without 
patient identifiers would similarly require prior IRB approval. 
 
The research use of stored, unlinked or unidentified samples 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. 
Storage of Genetic Samples 
No samples are being stored for genetic testing on the subjects. 
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) 
will be reported to the institution’s IRB and to the protocol team. 
 
25 
REMUNERATION PLAN 
 
Subjects will not be compensated for the time and inconvenience of study participation, 
including for any outpatient assessments that may occur following hospital discharge. 
 
26 
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. 
Documenting, Recording, and Reporting Adverse Events 
At each contact with the subject, information regarding serious adverse events will be 
elicited by appropriate questioning and will be: 
• documented in the subject’s medical record/source document, 
• recorded on the Serious Adverse Event Case Report Form (SAE CRF), and 
• reported to relevant regulatory authorities by the principal investigator or 
designee as outlined below 
Definitions 
Adverse Event (AE) 
An adverse event 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. 
 
Serious Adverse Event (SAE) 
A Serious Adverse Event is an AE that results in one or more of the following outcomes: 
• 
death 
• 
a life threatening (i.e., an immediate threat to life) event 


 
• 
prolongation of the existing hospitalization (or re-hospitalization) 
• 
a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• 
a congenital anomaly/birth defect 
• 
a medically important event* 
 
* Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may 
not be immediately life threatening or result in death or hospitalization but they may 
jeopardize the subject or may require intervention to prevent one of the other 
outcomes listed above. 
 
Protocol Deviation: 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 
4. Those that occur because a member of the research team deviates from the 
protocol. 
5. Those that are identified before they occur, but cannot be prevented. 
6. Those that are discovered after they occur 
 
Serious Protocol Deviation: A deviation that meets the definition of a Serious Adverse 
Event or compromises the safety, welfare or rights of subjects or others. 
 
Non-compliance: The failure to comply with applicable NIH HRPP policies, IRB 
requirements, or regulatory requirements for the protection of human subjects. Non- 
compliance is further characterized as 
4. 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 
5. Continuing: Non-compliance that is recurring 
6. Minor: Non-compliance that, is neither serious nor continuing. 
Assessment of Safety 
Safety data in this study will be limited to the collection of targeted symptoms (daily, 
while hospitalized or in an ETU) and SAEs. Until participants are discharged from the 
hospital or ETU, items on the targeted list do not additionally need to be reported as SAEs. 
 
The Data Coordinating Center will grade the severity of laboratory values according to the 
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
Version 2.0, 2014. 


 
 
 
Investigator Assessment of Serious Adverse Events 
Due to severity of critical illness in Ebola disease and expected clinical progression, for 
clinical events, investigators will capture only SAEs and a targeted list of current 
symptoms and conditions. The Investigator will evaluate all SAEs with respect to 
Seriousness and Causality (relationship to study agent and relationship to research) as 
defined below. 
26.4.1 Causality 
The likelihood that the SAE is related to the study agent will be assessed by the 
investigator considering by 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 
Investigator Reporting Responsibilities to the Sponsor 
 
26.5.1 Serious Adverse Events 
All SAEs must be reported on the Serious Adverse Event case report form (SAE CRF). 
Deaths and immediately life threatening SAEs must be reported within 1 business day 
after the site becomes aware of the event to the Data Coordinating Center. All other 
SAEs must be reported within 3 business days of site awareness. All deaths must be 
reported as SAEs. 
 
The medical monitor, in consultation with the site investigator, will determine the 
expectedness of all SAEs. 
26.5.2 Unanticipated Problems 
An Unanticipated Problem is any event, incident, experience, or outcome that is 
4. unexpected in terms of nature, severity, or frequency in relation to 
c. the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study 
documents; 
d. the characteristics of the subject population being studied (persons with life 
threatening EEbola infection); and 


 
5. possibly, probably, or definitely related to participation in the research; and 
6. places subjects or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized. 
 
Unanticipated Problems must be reported to the Data Coordinating Center at the 
University of Minnesota, and local IRB 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 sent by e- 
mail no later than 7 calendar days of site awareness of the event. 
 
Report all Unanticipated Problems that are also SAEs on the SAE CRF. 
26.5.3 Pregnancy 
Pregnancy itself is not an AE. However, complications of pregnancies are AEs and may 
be SAEs. Report any complications that are SAEs on the SAE CRF within the above 
timelines. 
 
Pregnancy outcome data (e.g., delivery outcome, spontaneous or elective termination 
of the pregnancy) will be on a protocol-specified form. Pregnant participants should be 
advised to notify their obstetrical care provider of study agent exposure, if applicable. 
Reporting Procedures to the IRB 
26.6.1 Expedited Reporting to the IRB 
SAEs, Serious and non-serious Unanticipated Problems, and deaths will be reported per 
institutional requirements. Please refer to the Manual of Operations, Reporting SOP 
about site specific requirements. 
26.6.2 Annual Reporting to the IRB 
Annual reporting will occur in accordance with institutional requirements. 
Follow-Up of Serious Adverse Events 
SAEs that have not resolved by the end of the initial follow-up period are followed until 
final outcome is known. This includes pregnancy. 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. 
Safety Oversight 
26.9.1 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: 
o Protecting the safety and welfare of subjects 
o Evaluating subject safety 
o Notifying the sponsor of SAEs and immediately-reportable events 
o Informing the IRB/IEC of SAEs, as per institutional requirements 
26.9.2 Sponsor Medical Monitor (SMM) 
A Medical Monitor, representing the IND Sponsor, has been appointed for oversight of 
safety in this clinical study. 
26.9.3 Data and Safety Monitoring Board (DSMB) 
An independent DSMB 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 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 PI will submit the written 
DSMB summary open reports with the DSMB recommendations to the IRB. 
• 
The DSMB will monitor safety closely throughout the trial and may pause 
enrollment in the event of 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 continuing the study as planned, 
modifying the study, or terminating the study. 
27 
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.” Monitors under 
contract to the NIAID/Office of Clinical Research Policy and Regulatory Operations 
(OCRPRO) will 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 will be: 1) to verify the existence of signed informed consent 


 
documents and documentation of the Informed Consent Form (ICF) 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 will 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 will be available to discuss the study 
progress and monitoring visit. 
 
28 
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 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. 
 
The participants will sign the informed consent document prior to any procedures being 
done specifically for the study. The participants may withdraw consent at any time 
throughout the course of the trial. 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, a photograph or scanned 
image of the informed consent signature page will be stored. No paper copy will be 
retained. 
Subject Confidentiality 
All records will be kept confidential to the extent provided by federal, state and local 
law. 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, or the 
sponsor’s designee. 
29 
DATA MANAGEMENT AND MONITORING 
Data Management Responsibilities 
The 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 collected in the electronic data system, and 
must 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 will be collected at the study site(s) as paper CRFs with transmission to the 
Data Coordinating Center. Data Coordinating Center personnel shall enter data into the 
electronic database. Corrections to electronic data systems will be tracked electronically 
(password protected or through an audit trail) with time, date, individual making the 
correction, and what was changed. 
Types of Data 
Source documents include, but are not 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 source documents 
created at the bedside and in the ‘hotzone’ will be incinerated and not be retained. 
Where possible, photographs or digital scans will be obtained. 
Record Retention 
The investigator is responsible for retaining all essential documents listed in the ICH Good 
Clinical Practice Guideline. All essential documentation for all study subjects are to be 
maintained by the investigators in a secure storage facility for a minimum of 3 years per NIAID 
policies. 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 law. 


 
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Marburg hemorrhagic fever. J Infect Dis. 2013; 208(2):310-8. 
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of Ebola hemorrhagic fever with blood transfusions from convalescent patients. 
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2014 Oct 8. [Epub ahead of print] 


 
STATISTICAL APPENDIX 
 
Power Tables 
More extensive power tables: Table 13 shows the approximate power for a range of sample 
sizes and mortality probabilities in the 2 arms, while Table 14 shows the sample sizes required 
for approximately 80% and 90% power. 
 
Table 13: Approximate Power under Different per Arm Sample Sizes (n) when the Larger 
and Smaller Mortality Probabilities are pA and pB, Respectively 
Powers of 80% or higher are boldfaced. 
PA 
0.2 
0.3 
 
0.4 
 
0.5 
 
 
0.6 
 
 
 
0.7 
PB 
n=20 
n=30 
n=40 
n=50 
n=60 
n=70 
n=80 
n=90 
n=100 
0.1 
0.14 
0.16 
0.24 
0.27 
0.32 
0.38 
0.42 
0.47 
0.51 
0.1 
0.35 
0.49 
0.63 
0.72 
0.79 
0.86 
0.90 
0.93 
0.95 
0.2 
0.10 
0.14 
0.18 
0.21 
0.24 
0.27 
0.30 
0.34 
0.37 
0.1 
0.61 
0.79 
0.90 
0.95 
0.98 
0.99 
1 
1 
1 
0.2 
0.27 
0.39 
0.50 
0.60 
0.67 
0.74 
0.80 
0.84 
0.88 
0.3 
0.08 
0.12 
0.15 
0.18 
0.20 
0.23 
0.26 
0.29 
0.31 
0.1 
0.82 
0.95 
0.99 
1 
1 
1 
1 
1 
1 
0.2 
0.49 
0.69 
0.82 
0.89 
0.94 
0.97 
0.98 
0.99 
1 
0.3 
0.22 
0.35 
0.46 
0.55 
0.62 
0.67 
0.73 
0.79 
0.83 
0.4 
0.08 
0.12 
0.16 
0.18 
0.20 
0.22 
0.24 
0.26 
0.31 
0.1 
0.94 
0.99 
1 
1 
1 
1 
1 
1 
1 
0.2 
0.73 
0.90 
0.97 
0.99 
1 
1 
1 
1 
1 
0.3 
0.45 
0.66 
0.80 
0.88 
0.92 
0.95 
0.97 
0.98 
0.99 
0.4 
0.21 
0.35 
0.46 
0.54 
0.61 
0.67 
0.72 
0.75 
0.83 
0.5 
0.08 
0.12 
0.16 
0.18 
0.20 
0.22 
0.24 
0.26 
0.31 
0.1 
0.99 
1 
1 
1 
1 
1 
1 
1 
1 
0.2 
0.90 
0.99 
1 
1 
1 
1 
1 
1 
1 
0.3 
0.71 
0.90 
0.96 
0.99 
1 
1 
1 
1 
1 
0.4 
0.45 
0.66 
0.80 
0.88 
0.92 
0.95 
0.97 
0.98 
0.99 
0.5 
0.22 
0.35 
0.46 
0.55 
0.62 
0.67 
0.73 
0.79 
0.83 
0.6 
0.08 
0.12 
0.15 
0.18 
0.20 
0.23 
0.26 
0.29 
0.31 


 
 
Table 14: Sample Sizes required for 80% and 90% Power for Different Values of the 
Larger and Smaller Mortality Probabilities, pA and pB. 
 
pA 
pB 
n80 
n90 
0.2 
0.1 
198 
264 
0.3 
0.1 
61 
81 
0.2 
293 
392 
0.4 
0.1 
31 
40 
0.2 
81 
109 
0.3 
357 
476 
0.5 
0.1 
19 
26 
0.2 
39 
52 
0.3 
95 
126 
0.4 
392 
520 
0.6 
0.1 
13 
17 
0.2 
23 
30 
0.3 
41 
57 
0.4 
97 
128 
0.5 
392 
520 
0.7 
0.1 
10 
12 
0.2 
15 
20 
0.3 
22 
31 
0.4 
41 
57 
0.5 
95 
126 
0.6 
357 
477 


 
 


 
 
 
 
 
 
APPENDIX A: 


 
 
 
 
 
product to product, 


 
 
 
 
 
 


 
 
 


 
 
 
 
 
 


 
PPENDIX B:
 
A 
 
 
 
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SUMMARY of AMENDMENTS TO PROTOCOL 
 
Amendment Label 
IRB Approval Date 
Amendment Summary 
A 
3/9/15 
addition of the Liberian 
Principal Investigator and 
study sites. Updated 
information has been 
included regarding ZMAPP 
product and infusion details 
(three infusion set three days 
apart). An update of the 
ongoing conversations of 
Investigators from all sites 
has been added to Appendix 
A. 
B 
4/6/15 
Clarification of the site- 
specific considerations have 
been added to the protocol 
(section 6.15) based on the 
resources available. Further 
information from Liberian 
Ebola Treatment Units has 
preliminarily identified a 
correlation between baseline 
Cycle Threshold (CT) value on 
Ebola PCR and patient 
outcomes. This has 
prompted the Study Team to 
change the stratification for 
the randomization 
procedures of this study 
C 
4/20/15 
The main purposes of the 
amendment are to 
acknowledge that the ability 
of individual sites to perform 
full spectrum of clinical 
research components 
outlined in prior versions 
protocol varied widely 
depending upon such factors 
as staffing, available 
equipment, and current 
operational, clinical, and 
safety practices. Therefore 
this version of the protocol 


 
 
 
attempts to define the 
minimal standards for 
assessment of efficacy and 
safety as well as allow full 
detailed assessments to 
obtain full longitudinal data 
collection when sites are 
able. 
D 
7/13/15 
An updated Investigator’s 
Brochure and an updated 
version of the ZMAPP Patient 
Information Sheet was added 
which will be given to 
participants at the time of 
consent. 
E 
11/23/15 
Added long-term follow-up. 
The DSMB strongly 
recommended long-term 
follow-up of enrolled 
subjects be considered 
(within reasonable limits of 
access and feasibility) given 
reports of the recurrence of 
Ebola virus disease in some 
patients. Interested subjects 
will be offered the 
opportunity, where and 
whenever feasible, to 
participate in long term 
follow-up (up to 1 year or 
more depending upon need) 
past Day 58 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. 


 
 
 
Data Analysis Plan for MCM RCT 
1 
STUDY OVERVIEW .......................................................................................................... 2 
2 
SUMMARY OF REPORTS ................................................................................................ 3 
3 
OPEN REPORT TO THE DSMB ....................................................................................... 4 
3.1 
ACCRUAL .................................................................................................................................................................. 4 
3.2 
ELIGIBILITY VIOLATIONS .................................................................................................................................... 4 
3.3 
BASELINE CHARACTERISTICS ........................................................................................................................... 4 
3.4 
DATA COMPLETENESS ......................................................................................................................................... 5 
4 
CLOSED REPORT TO THE DSMB .................................................................................. 5 
4.1 
BASELINE CHARACTERISTICS ........................................................................................................................... 5 
4.2 
DATA COMPLETENESS ......................................................................................................................................... 6 
4.3 
PRIMARY OUTCOME .............................................................................................................................................. 6 
4.3.1 
Primary analysis at study completion ................................................................................. 6 
4.3.2 
Additional analyses ............................................................................................................. 8 
4.4 
SECONDARY OUTCOMES ..................................................................................................................................... 8 
4.4.1 
Overall Survival .................................................................................................................. 8 
4.4.2 
Time-to-viral load clearance .............................................................................................. 8 
4.4.3 
Daily Outcomes .................................................................................................................. 9 
4.5 
SAFETY OUTCOMES ............................................................................................................................................... 9 
4.5.1 
SAEs.................................................................................................................................... 9 
4.5.2 
Safety listings .................................................................................................................... 10 
4.5.3 
Pregnancies ...................................................................................................................... 10 
4.5.4 
Infusion Reactions ............................................................................................................ 10 
4.5.5 
Infusion Interruptions ....................................................................................................... 10 
4.5.6 
Unanticipated problems ................................................................................................... 10 
5 
DAILY STUDY PROGRESS REPORTS ON THE WEB ................................................ 10 
6 
SAE REPORTS TO LEAFBIO ............................................................................................. 10 
7 
SHELLS FOR TABLES AND FIGURES......................................................................... 10 


 
 
 
31 1 STUDY OVERVIEW 
The study protocol serves as the master protocol for the evaluation of multiple 
candidate countermeasures for the treatment of Ebola virus disease (EVD). The initial 
phase of the trial will focus on the evaluation of ZMapp and the order of additional 
treatments to be evaluated is still to be determined. 
 
Participants in the initial phase will be randomized in a 1:1 allocation ratio to optimized 
standard of care (oSOC) or oSOC plus ZMapp. A maximum of 200 subjects will be 
randomized (100 per treatment arm) but frequent interim monitoring will be used to 
allow termination of the trial if a definitive result is achieved early in the trial. 
 
The primary objective of this trial is to establish the safety and efficacy of investigational 
therapeutics in patients with Ebola virus infection. The primary endpoint for this trial is 
28-day survival. Other key efficacy endpoints include: overall survival and time-to-viral 
load clearance. Safety endpoints 


 
 
 
 
32 2 SUMMARY OF REPORTS 
Table A3.1. Type of reports and their distribution 
 
Reports 
Prepared 
by* 
Distribution 
Frequency† 
Distributed to 
Protocol co-chairs, 
blinded biostatisticians 
DSMB 
LeafBio 
Open Report to the DSMB 
S 
Electronic ‡ 
M 
X 
X 
X 
Closed Report to the DSMB 
S 
Electronic ‡ 
M 
X 
Study Progress Reports 
S, DM 
Web site 
Updated daily 
X 
X 
SAE Reports 
By trt group 
S 
DSMB report 
M 
X 
Pooled ** 
S 
Email 
Upon request 
X 
SAEs related to treatment 
S, SO 
Electronic 
Event-driven 
X 
X 
Safety Reports 
S, SO 
Electronic 
Event-driven 
X 
X 
X 
* Prepared by: 
DM = data manager, S = Independent biostatisticians, 
SO = Safety office at the Statistical and Data Management Center (SDSMB), blinded to study arm 
† Frequency: M = Prior to each DSMB meeting 
‡ Reports to the DSMB will be available for download from a secure server; upon request, DSMB members will also receive a hard copy. The open report will 
be posted on the study web site after the DSMB meeting. 
** Reports are blinded to study arm assignment. All information will also be provided to the DSMB as part of the closed reports, by treatment group. 
Abbreviations: 
SAE = serious adverse event 


 
3 
OPEN REPORT TO THE DSMB 
The open report to the DSMB includes reports on accrual, eligibility violations, baseline 
characteristics, and data completeness as described below. The data are presented 
pooled across study groups. Open reports will be produced by the independent 
biostatisticians, under direction of the protocol principal investigators and blinded 
statisticians. 
 
The open reports will be distributed as indicated in table A3.1, and posted to the study 
web site after each DSMB review together with the DSMB summary recommendations. 
 
3.1 
Accrual 
The following reports will be provided: 
 
• Enrollment, by calendar time, geographic location (United States vs. West 
Africa) and treatment site. 
 
3.2 
Eligibility violations 
Number (N) and percent (%) of participants who were enrolled in violation of 
inclusion/exclusion criteria will be reported for each inclusion/exclusion criterion 
separately and total. Reports will be overall, geographic location (United States vs. 
West Africa) and by treatment site. 
 
3.3 
Baseline Characteristics 
The following baseline data will be summarized, overall, by geographic location (United 
States vs. West Africa) and by treatment site: 
• Demographics: Age, sex, race, country of birth, work involving contact with a 
person with Ebola or decedents (N and %), and role (e.g., doctor, nurse, 
ambulance driver, laboratory) and enrollment in any other studies related to 
Ebola 
• Clinical Information: Results of pregnancy test, weight, height, blood 
pressure, pulse, body temperature, respiratory rate and oxygen saturation 
• Illness Information: days since onset of symptoms, cycle threshold (actual 
value and dichotomized as CT > 22 vs. CT ≤ 22), country where EVD diagnosis 
was confirmed 
• Symptoms: Fever, sore throat, cough, etc. 
• Chemistries: creatinine and potassium are required, all other chemistries are 
optional. Optional data will be summarized for subjects where data is 
available. 
• Hematology and Coagulation: optional data summarized as provided. 
• Urinalysis: optional data, summarized for subjects where data is available. 
• Imaging and Resuscitation: optional data, summarized for subjects where 


 
data is available. 
Summaries for continuous-valued outcome will include N and mean, SD or median, 
IQR. Summaries for categorical outcomes will include N and %. 
 
 
 
 


 
3.4 
Data Completeness 
The following reports will be provided, overall, by geographic location (United States 
vs. West Africa) and by treatment site: 
• Withdrawal of consent (N and %) 
• Required forms: 
o Number (and % of expected) of completed baseline forms 
o Number (and % of expected) for each item on the baseline form 
o Number (and % of expected) of daily follow-up forms (overall and by 
study day) 
o Number (and % of expected) for each item on the daily follow-up 
form (overall and by study day) 
o Number (and % of expected) of current symptom forms (overall and 
by study day) 
o Number (and % of expected) for each item on the daily follow-up 
form (overall and by study day) 
o Number (and % of expected) of daily chemistries forms 
o Number (and % of expected) for each item on the daily 
chemistries form (overall and by study day) 
o Number (and % of expected) of ZMapp forms (overall and by study day) 
o Number (and % of expected) of completed day 28 forms received, 
according to the following categories: completed, still in follow-up 
period, withdrawn and lost to follow-up 
o Number (and % of expected) of completed day 58 forms received, 
according to the following categories: completed, still in follow-up 
period, withdrawn and lost to follow-up 
o Number (and % of expected) of discharge forms 
o Number (and % of expected) of death forms 
• Optional forms: 
o Number (and % of maximum possible) of completed daily hematology 
forms 
o Number (and % of maximum possible) of daily urinalysis forms 
o Number (and % of maximum possible) of daily resuscitation forms 
4 
CLOSED REPORT TO THE DSMB 
Closed reports are by treatment group, unless otherwise noted. Treatment groups will be 
labeled by letters. A sealed envelope to break the blind of the treatment groups will be 
provided with the report to the DSMB Chair. 
 
4.1 
Baseline Characteristics 
Baseline characteristics provided in the open report will be summarized by treatment 
group in the closed report section. Summaries for continuous-valued outcomes by 
treatment group will include N and mean, SD or median, IQR. Summaries for 
categorical outcomes will include N and %. 


 
P-values for comparisons of baseline characteristics between treatment groups will not 
be provided. 


 
 
4.2 
Data Completeness 
Data completeness reports in the open report section (see 3.4) will be provided by 
treatment group in the closed section. The proportion of patients for which the day 28 
form is available from among those who have completed the 28-day follow period will 
be compared between treatment groups using Fisher’s exact’s test. 
 
4.3 
Patient Profiles 
A one page patient profile will be provided for each patient in the trial. This will provide a 
basic summary of their current status in the trial (i.e. treatment group, current study 
day, if they have been discharged, etc.). In addition, for each day, we will provide the 
CT value, vital signs, required chemistries (creatinine and potassium), days which 
infusions occurred and any SAEs. 
4.4 
Primary Outcome 
The primary endpoint for this trial is 28-day mortality. All comparisons between 
treatment groups will follow the intent-to-treat principle, unless otherwise noted. 
 
4.4.1 Primary analysis at study completion 
 
Inference relating to the primary endpoint will quantify the probability that the 28-day 
mortality rate is lower (or higher) under ZMapp relative to oSOC using the Bayesian 
paradigm. A uniform(0,1) prior will be used for the 28-day mortality rate in both groups. 
The following summaries will be presented: 
 
1. Basic summaries of 28-day survival (N and %) for each group, broken down 
into the following categories: dead, alive and still in follow-up period. 
2. Point estimate (all point estimates derived from Bayesian inference will use the 
posterior mean) and 95% credible interval (all credible intervals derived from 
Bayesian inference will use quantiles of the posterior distribution; i.e. 2.5th and 
97.5th percentile) for the absolute difference in 28-day mortality rate between 
the two treatment arms. 
3. Point estimate and 95% credible interval for the relative risk of 28-day mortality 
between the two treatment arms. 
4. The posterior probability that arm A is superior to arm B, given the observed data. 
5. Graphical displays of the updated posterior distribution for the absolute 
difference and relative risk, given the observed data. 
The difference in 28-day mortality will be considered statistically significant if the 
posterior probability that the 28-day mortality rate in arm A is greater than the 28-day 
mortality rate in arm B is greater than 0.975 or vice versa. 
 
Additional details about the computation of the posterior probabilities required for 
inference can be found in the following two documents: “Thumbnail sketch of Ebola 


 
Treatment Trial Monitoring, with Examples” and “Monitoring a Trial of MCMs for Ebola 
Virus Disease.” 


 
4.4.1.1 INTERIM MONITORING AND ANALYSES 
 
Interim analyses will first occur after the primary outcome is available for 12 subjects. 
Thereafter, interim analyses will be completed every 2 subjects until outcomes are 
available for 40 subjects, at which points interim analyses will occur after every 40 
subjects. Ideally, the treatment groups would be balanced at the interim analyses (i.e. 
6/group, 7/group, etc.) but, in practice, slight imbalances are expected at any point 
during the trial and this will have minimal impact on the operating characteristics of the 
proposed interim monitoring procedure. 
 
The following summaries will be presented at all interim analyses: 
 
1. Basic summaries of 28-day survival (N and %) for each group, broken down 
into the following categories: dead, alive and still in follow-up period. 
2. Point estimate and 99.8% credible interval for the absolute difference in 28-day 
mortality rate between the two treatment arms. 
3. Point estimate and 99.8% credible interval for the relative risk of 28-day 
mortality between the two treatment arms. 
4. The posterior probability that arm A is superior to arm B, given the observed data. 
5. Graphical displays of the updated posterior distribution for the absolute 
difference and relative risk, given the observed data. 
The difference in 28-day mortality will be considered statistically significant at the interim 
analyses if the posterior probability that the 28-day mortality rate in arm A is greater than 
the 28- day mortality rate in arm B is greater than 0.998 or vice versa. 
 
Conditional power will be included in DSMB reports after outcomes are available for 40 
subjects. The conditional probability will be computed as the probability of a significant 
result at the end of the trial, as defined in Section 4.3.1, given the current data. 
 
A detailed description of the interim monitoring for this trial, including the rationale and 
operating characteristics, can be found in a separate document entitled, “Monitoring a 
Trial of MCMs for Ebola Virus Disease.” 
 
4.4.1.2 PARTIALLY OBSERVED OBSERVATIONS 
The analysis described above only utilizes subjects for which the primary endpoint has 
been fully observed (i.e. death or 28-day survival). At the interim analyses, there will be 
subjects that have been enrolled and randomized but have yet to complete the 28-day 
follow-up period. In this case, we will complete a sensitivity analysis to determine how 
the results of the analysis presented in Section 4.3.1.1 would change depending on the 
outcomes for these subjects. Specifically, we will present the summaries described in 
Section 4.3.1.1 assuming that all remaining subjects in group A will survive, while all 
subjects in group B will die and assuming that all remaining subjects in group B will 
survive, while all subjects in group A. This will provide a “worst-case-scenario” for how 


 
much the results of our primary analysis could change based on the outcomes of the 
partially observed subjects. 


 
4.4.1.3 EARLY TERMINATION FOR EXTERNAL REASONS 
There are several scenarios where the trial may terminate early for external reasons 
(end of the epidemic, inadequate drug supply, etc.). This situation is discussed in more 
detail in guidance document provided to the DSMB. In the event that the trial is 
terminated for external reasons, we will summarize the difference in 28-day mortality 
rate by group as described in Section 4.3.1 and the difference between groups will be 
declared statistically significant if the posterior probability that the 28-day mortality rate 
in arm A is greater than the 28-day mortality rate in arm B is greater than 0.975 or vice 
versa. 
 
4.4.2 Additional analyses 
4.4.2.1 STRATIFIED ANALYSIS 
In addition to the above grouped summaries, we will also complete a stratified analysis 
by the location of treatment (West Africa vs. U.S.) and CT value (> 22 vs. ≤ 22). Stratified 
analyses will be completed separately for the two stratification factors and will be 
completed once data are available for the two stratum. Analyses will be completed 
assuming the Bayesian paradigm with uniform(1,1) prior distributions for the 28-day 
mortality rate in each stratum. The following summaries of the stratified analyses will be 
reported: 
 
1. Basic summaries of 28-day survival (N and %) for each group within a stratum, 
broken down into the following categories: dead, alive and still in follow-up 
period. 
2. Point estimate and 99.8% credible interval for the relative risk of 28-day 
mortality between the two treatment arms for each stratum. 
3. The posterior probability that the relative risk in stratum 1 is greater than the 
relative risk in stratum 2. The relative risks will be considered significantly 
different if the posterior probability is greater than 0.975 or less than 0.025. 
 
4.5 
Secondary Outcomes 
4.5.1 Overall Survival 
Overall survival, defined as the time from randomization to death, will be summarized 
by Kaplan-Meier curves for the two treatment groups for the overall study population 
and stratified by location (West Africa vs. U.S.) and CT value (> 22 vs. ≤ 22). Overall 
survival will be compared between treatment groups using the Cox proportional 
hazards regression model stratified by location and CT value. 
 
In addition, we will also provide basic summaries of survival at discharge and 58-day 
survival (N and %) for each group, broken down into the following categories: dead, alive 
and still in follow- up period. 
 
4.5.2 Time-to-viral load clearance 


 
Time-to-viral load clearance will be summarized by treatment group as follows: mean 
(SD) for subjects with an observed time-to-viral load clearance, N (%) of patients that 
died before clearance and N (%) of patients that remain unresolved (i.e. patients that 
are still being followed). Time-to-viral load clearance will be compared between groups 
using both the 


 
Wilcoxon and chop-lump test. In both cases, we will order subjects first by time-to-viral 
load clearance (shortest to longest), followed by subjects that died before clearance 
(longest to shortest). This treats any death as a worse outcome that than the longest 
time-to-viral load clearance and will allow us to include all data in a single hypothesis 
test. 
 
4.5.3 Change in CT value within first 72 hours after randomization 
 
The change in CT value within the first 72 hours will be summarized by treatment 
group by the mean (SD) and compared using the two-sample t-test. The number and 
percent of patients that died within 72 hours will also be reported. 
 
4.5.4 Daily Outcomes 
 
The following will be summarized by treatment group as described: 
• Vital Signs: blood pressure, pulse, body temperature, respiratory rate, oxygen 
saturation – summarized daily by treatment group 
• Summary of optimized supportive care provided: electrolytes and intravenous 
fluids, other treatments (ventilation, ECMO, supplemental oxygen, etc.) – 
summarized daily by treatment group 
• Current symptoms – summarized daily by treatment group 
• Chemistries: creatinine and potassium are required and will be summarized for 
each 3- day window (i.e. days 1- 3, days 4 – 6, etc.) by treatment groups, all 
other chemistries are optional and will be summarized as available 
• PCR: summarized for each 3-day window (i.e. days 1- 3, days 4 – 6, etc.) by 
treatment groups 
• Hematology and coagulation: optional data – summarized as available 
• Urinalysis: optional data – summarized as available 
• Imaging and resuscitation: optional data – summarized as available 
Summaries for continuous-valued outcomes by treatment group will include N and 
mean, SD or median, IQR. Summaries for categorical outcomes will include N and %. 
4.6 
Safety outcomes 
4.6.1 SAEs 
SAEs will be summarized and compared between treatment groups as follows: 
• Number and percent of patients experiencing SAEs by treatment group. Test of 
statistical significance will use Fisher’s exact test. 
• Counts of SAEs by treatment group. The rate of SAEs will be formally compared 
using a zero-inflated negative binomial model. 
• Kaplan-Meier cumulative event curves by treatment group; p-values will be 
provided for comparing the active treatment groups to placebo using the log- 
rank test 


 
• For SAEs that are assessed as related to study drug, counts by treatment 
groups and p- value from zero-inflated negative binomial model. 


 
 
4.6.2 Safety listings 
Line listings by treatment group will be provided for SAEs and “unanticipated 
problems”. Listings will include the SID, treatment group label, diagnosis, 
relatedness to treatment, date of onset, time from treatment to onset, event status 
(recovered/resolved, recovering/resolving, not recovered/not resolved, 
recovered/resolved with sequelae, death), date of resolution or death, and EVD 
status. 
 
4.6.3 Pregnancies 
The number of pregnancies reported during the 58-day follow-up period after 
randomization, and the outcomes of these pregnancies, will be summarized by 
treatment group. 
 
4.6.4 Infusion Reactions 
The number and percent of patients experiencing infusion reactions will be 
summarized for patients randomized to ZMapp. 95% CIs for the rate of infusion 
reactions will also be provided. Infusion reactions will also be broken down by the 
specific infusion reactions reported on the ZMapp infusion form and summarized by 
the number and percent experiencing each infusion reaction. 
 
4.6.5 Infusion Interruptions 
The number and percent of patients for which infusion interruptions occurred will be 
summarized for patients randomized to ZMapp. 95% CIs for the rate of infusion 
interruptions will also be provided. 
 
4.6.6 Unanticipated problems 
Incidence of “unanticipated problems” will be tabulated for each of the treatment 
groups. Reports will have similar format as the summary reports for SAEs. 
 
5 
DAILY STUDY PROGRESS REPORTS ON THE WEB 
Progress reports include reports on accrual, baseline characteristics, and data 
completeness. These data summaries are pooled across study groups. The reports 
are similar to those described in the open report section. 
 
These reports will be available on the study web site (controlled access), updated 
daily. Additional reports may be provided to study leadership on request. 
 
6 
SAE REPORTS TO LEAFBIO 
Listings for SAEs that are assessed as related to the studied treatment will be 
provided to LeafBio. Reports will be as described in the protocol. 


 
 
7 
SHELLS FOR TABLES AND FIGURES 
Shells for key tables and figures are provided in this section. For example, a shell 
for Kaplan- Meier curves for the primary endpoint is shown; similar Kaplan-Meier 
curves will also be provided for several secondary endpoints, as described earlier. 


 
Final Data Analysis Plan for PREVAIL II 
Ebola Virus Disease Medical Countermeasures (EVD MCM) Trial 
January 20, 2016 
Table of Contents 
1 Introduction ..................................................................................................................... 19 
2 Study Overview ............................................................................................................... 19 
3 PLANNED Analyses ....................................................................................................... 20 
3.2 SUBJECT ACCRUAL .......................................................................................................................................................... 20 
3.3 ELIGIBILITY VIOLATIONS .............................................................................................................................................. 20 
3.4 BASELINE CHARACTERISTICS...................................................................................................................................... 21 
3.5 DATA COMPLETENESS .................................................................................................................................................... 21 
3.6 OPTIMIZED SUPPORTIVE CARE DESCRIPTIONS ..................................................................................................... 22 
3.7 ZMAPP INFUSION SUMMARIES .................................................................................................................................... 22 
3.8 PRIMARY OUTCOME ........................................................................................................................................................ 23 
3.9 SECONDARY OUTCOMES ............................................................................................................................................... 26 
3.9.1 OTHER SECONDARY OUTCOMES ................................................................................................................................ 29 
3.9.2 SAFETY-RELATED OUTCOMES .................................................................................................................................... 13 
3.9.3 PREGNANCIES .................................................................................................................................................................... 14 
3.9.4 LATE CLINICAL SYMPTOMS ......................................................................................................................................... 14 


 
 
 
1 
Introduction 
This document describes the content proposed for the primary statistical analysis of PREVAIL II, 
the randomized controlled trial of ZMapp in acute Ebola virus disease (EVD). The focus is on 
analyses that address the major randomized comparisons for key safety, tolerability and 
efficacy outcome measures, including those needed to address the study’s primary objective as 
well as the main secondary objectives. This analysis plan therefore includes the key analyses 
for presentation or publication of the primary conclusions of the study. 
2 
Study Overview 
The study protocol is a master protocol for the evaluation of multiple candidate countermeasures for 
the treatment of EVD. Given the waning epidemic, the initial (and, to date, only) phase of the trial was 
focused only on the evaluation of ZMapp, although the study was designed to provide flexibility to 
introduce additional treatments under certain situations that are described in the protocol. The Primary 
Objective of this study was to establish the safety and efficacy of ZMapp in patients diagnosed with 
Ebola virus infection. 
 
Patients were randomized in the United States, Liberia, Sierra Leone, and Guinea in a 1:1 allocation ratio 
to optimized standard of care (oSOC) versus oSOC plus ZMapp. A maximum of 200 subjects were to be 
randomized (100 per treatment arm) in this trial. The primary endpoint for the trial is survival as 
assessed at Day 28. 
 
Following the first randomized patient on March 13, 2015, the Data and Safety Monitoring 
Board (DSMB) reviewed interim data on 7 occasions. Following each review, the DSMB 
indicated that they had no safety concerns and recommended the study continue. 
In anticipation of study closure due to the absence of EVD, pooled (both treatment groups 
combined and blinded) outcome data were provided to the U.S. study team by the unblinded 
statisticians, Dr. Joe Koopmeiners and Ms. Jacquie Nordwall, on November 25, 2015. These 
data were used to update the data analysis plan that was prepared prior to the beginning of the 
trial. The pooled data were updated on December 31, 2015 following submission of 28 day 
follow-up data for the last person randomized on November 21, 2015. 
On January 8, 2016, a provisional draft of the updated data analysis plan was shared with the 
Food and Drug Administration, Mapp Biopharmaceutical, INSERM, and other participating site 
investigators. The final data analysis plan detailed in the present document considers the 
comments that were received concerning that January 8th proposal. The document retains 
some of the information from the original analysis plan concerning the format and content of 
open and closed DSMB reports. 
As of January 14, 2016, 42 days after the last case of EVD in Liberia was discharged, all three 
countries in West Africa had been declared Ebola-free. Accordingly, the study was planned for 
closure to new accrual as of that date. Subsequent to that determination there has been a 
potential resurgence of EVD reported in Sierra Leone; the scope and duration of that recent 
outbreak, as well as whether any potential new cases may be referred for enrollment, are 
unclear at this time. If additional enrollments do occur, this will delay the timeline for 
implementing the final study analysis as summarized in this document. As of the original 


 
planned date of closure on 1-14-2016 there have been a total of 72 patients randomized on the 
protocol. 
 
3 
PLANNED Analyses 
Unless otherwise stated, all tables, figures, and listings will show results by randomized arms. 
For tables with categorical variables, the number (%) will be presented. For tables with 
continuous variables, the mean, standard deviation, median, 25th and 75th percentiles, min 
and max will be presented. The number with missing values will also be shown. In calculation 
of percentages, subjects with missing data will not be included in the denominator. Data 
presented as listings or figures will be specifically noted. 
 
3.1 
Analysis Populations 
 
The primary population includes all randomized patients, with the exception of one individual 
who fled from the ETU on the first day. This is the only subject for whom there is missing 
primary outcome data. (Sensitivity analyses will also be performed including this individual in 
his/her assigned group, as described below). 
The primary analyses will be performed on all subjects regardless of baseline covariates. The 
study stratified randomization based on cycle threshold (CT > 22 vs. CT ≤ 22) and geographic 
location, and analyses will be presented accordingly. In addition, some analyses will specify age 
subgroups defined as: adults ≥ 18 years vs. children aged <18 years. 
 
3.2 
Subject Accrual 
The following information about accrual will be summarized: 
• Number randomized: overall and by month/year. Dates of first and last randomizations. 
• Number randomized by geographic location (United States, Liberia, Sierra Leone, 
Guinea), country, and site 
• Number randomized by cycle threshold (CT ≤ 22 versus > 22) 
• Number randomized by children versus adults 
 
 
3.3 
Eligibility violations 
Number (N) and percent (%) of any participants who were enrolled in violation of 
inclusion/exclusion criteria will be reported for each inclusion/exclusion criterion separately 
and total. Reports will be overall, by geographic location (United States vs. West Africa) and by 
treatment site. 
Listing: Description of violations of eligibility criteria among randomized subjects. 


 
3.4 
Baseline Characteristics 
The following baseline data will be summarized overall and by treatment assignment, 
geographic location (United States, Liberia, Sierra Leone and Guinea) and treatment center: 
• Demographics: Age, sex, race, country of birth, work involving contact with a person 
with Ebola or decedents (N and %), and role (e.g., doctor, nurse, ambulance driver, 
laboratory) and enrollment in any other studies related to Ebola 
• Clinical information: Results of pregnancy test, weight, height, blood pressure, pulse, 
body temperature, respiratory rate and oxygen saturation 
• Illness information: days since onset of symptoms, cycle threshold (actual value and 
dichotomized as CT > 22 vs. CT ≤ 22), country where EVD diagnosis was confirmed 
• Symptoms: Fever, sore throat, cough, etc. 
• Chemistries: measurement of serum creatinine and potassium were required, all other 
chemistries were considered optional. Optional data will be summarized for subjects 
where data is available. 
• Hematology and Coagulation: optional data summarized as provided. 
• Urinalysis: optional data, summarized for subjects where data is available. 
• Imaging and Resuscitation: optional data, summarized for subjects where data is 
available. 
 
3.5 
Data Completeness 
The following reports will be provided overall and by treatment assignment, geographic 
location and treatment center: 
• Withdrawal of consent (N and %) 
• Required forms: 
o Number (and % of expected) of completed baseline forms 
o Number (and % of expected) for each item on the baseline form 
o Number (and % of expected) of daily follow-up forms (overall and by study 
day) 
o Number (and % of expected) for each item on the daily follow-up form 
(overall and by study day) 
o Number (and % of expected) of current symptom forms (overall and by 
study day) 
o Number (and % of expected) for each item on the daily follow-up form 
(overall and by study day) 
o Number (and % of expected) of daily chemistries forms 
o Number (and % of expected) for each item on the daily chemistries form 
(overall and by study day) 
o Number (and % of expected) of ZMapp forms (overall and by study day) 
o Number (and % of expected) of completed day 28 forms received, according 
to the following categories: completed, still in follow-up period, withdrawn 
and lost to follow-up 


 
o Number (and % of expected) of completed day 58 forms received, according 
to the following categories: completed, still in follow-up period, withdrawn 
and lost to follow-up 
o Number (and % of expected) of discharge forms 
o Number (and % of expected) of death forms 
• Optional forms: 
o Number (and % of maximum possible) of completed daily hematology forms 
o Number (and % of maximum possible) of daily urinalysis forms 
o Number (and % of maximum possible) of daily resuscitation forms 
 
3.6 
Optimized Supportive Care Descriptions 
• Optimized supportive care provided by study day: 
o Intravenous fluids as total volume (continuous variable) and % receiving fluids 
o Intravenous fluids will also be presented by combining all fluids (normal saline 
and lactated ringers, etc) and presenting in ml/kg to adjust for differences in age 
and body mass. 
o Other treatments (electrolytes, ventilation, ECMO, supplemental oxygen, 
medications etc.) as % 
• The number of days with supportive care infusions until discharge/death will be 
summarized. 
• Also, for 3-day windows: 1-3, days, 4-6 days, etc. supportive care infusions will be 
summarized. 
• Data will be analyzed both by geographic region and, where applicable, by incorporation 
of Favipiravir as oSOC. 
 
3.7 
ZMapp Infusion Summaries 
Note: for patients assigned to the ZMapp group, ZMapp was to be started immediately 
following randomization. The 2nd dose was to be given 3 days after the 1st dose; the 3rd dose 
was to be given 3 days after the 2nd dose. 
• The distribution of the number of infusions per patient (0, 1, 2, 3) 
• Time elapsed between randomization and first dose 
• Study day of infusion of each dose will be summarized 
• Duration (minutes and mean) by study day 
o additional separate tables for adults and children 
• Volume received (mean and ml/kg) by study day. 
• Percent receiving prepared volumes of 95% or greater. 
• Calculated dose (mg/kg) of ZMapp Dose actually administered 
• Number and percent of patients experiencing infusion reactions 
o Total N (%) 
o N (%) categorized by the specific infusion reactions reported 
o N (%) which required intervention 
▪ 
N% by intervention taken 
• Number and percent of patients experiencing infusion interruptions 


 
o Total N (%) 
• Pre-treatments administered before infusions to ameliorate reactions 
• Other problems with the infusion noted on the case report form. 
• Listing of other problems related to infusion 
• Listing of subjects assigned to ZMapp who did not receive all doses before death: subject 
ID, site, days from randomization to first dose, days from first ZMapp to death, total 
doses given 
 
 
3.8 
Primary Outcome 
The primary outcome is death within 28 days from randomization, and the primary population 
includes all randomized patients, with the exception of one individual who fled from the ETU on 
the first day and for whom no other primary data were subsequently captured. 
Note: as a sensitivity analysis to assess the impact of the single subject with unknown vital 
status following randomization, the primary analysis described below will be performed 
assuming the subject was alive at 28 days and repeated assuming the subject was dead at 28 
days. 
Primary analysis 
Inference relating to the primary endpoint will quantify the probability that the 28-day 
mortality rate is lower (or higher) under ZMapp relative to oSOC using the Bayesian paradigm 
as follows: 
A. The prior distribution of 28-day mortality probabilities, p0 and p1, in the oSOC and 
ZMapp arms is that of independent uniforms on [0,1]. 
B. The posterior distributions of p0 and p1 after observing x0 and x1 deaths among n0 and n1 
people in the two arms is that of independent betas with respective parameters (x0+1, n0- 
x0+1) and (x1+1, n1-x1+1). 
C. The posterior probability that p1<p0 will be computed: if this probability is 0.975 or 
greater, ZMapp will be declared superior to oSOC, whereas if the probability is 0.025 or 
less, ZMapp will be declared inferior to oSOC. 
D. Treatment effect estimates and 95% credible intervals will be computed for both the 
relative risk p1/p0 and absolute risk difference p1-p0. The medians of the posterior 
distributions of p1/p0 and p1-p0 are used to estimate these quantities. 95% credible 
intervals are computed as follows. 
a. For p1/p0, compute lower and upper limits (L and U, respectively) satisfying 
P(p1/p0<L given x0,x1)=0.025 and P(p1/p0>U given x0,x1)=0.025. 
b. For p1-p0, compute lower and upper limits (L and U, respectively) satisfying P(p1- 
p0<L given x0,x1)=0.025 and P(p1-p0>U given x0,x1)=0.025. 
 
Additional Supportive Analyses Using Primary Outcome: 
Alternative test statistics: 
The following alternative test statistics will be performed on the primary outcome as secondary 
analyses. 


 
• Barnard’s unconditional test will be performed using a one-tailed test of p1=p0 versus 
p1<p0. 
A. The first alpha level used is 0.025 (one-sided). As with the Bayesian analysis, the 
overall type 1 error rate including monitoring may exceed 0.025. 
B. The second alpha level is adjusted using the Haybittle-Peto monitoring procedure: 
α=0.025-(0.001)k, where k is the number of interim looks at the data. 
A confidence interval will be computed for the absolute risk difference using Barnard 
test methodology and confidence level 1-2α. This will be done for each of the two alpha 
levels specified above. 
• The same approach specified above for Barnard’s test, including the two separate alpha 
levels, will also be performed for Fisher’s exact test. A confidence interval for the odds 
ratio will be computed using the non-central hypergeometric distribution. 
• An analysis of time to death will be performed using a log-rank test. In addition, a 
stratified log-rank test will be performed with 4 strata defined by location and cycle 
threshold. (See description of stratification variables below). This will be done for each 
of the two alpha levels specified above. Tests of treatment by subgroup interaction will 
be performed. 
Stratification and subgroup analyses 
▪ 
Additional analyses will be performed within two strata defined by cycle threshold: ≤22 
versus >22 for all subjects. To assess whether there is a treatment by cycle threshold 
interaction, we will compute the posterior probability that the treatment effect (absolute 
or relative) differs by cycle threshold. 
▪ 
Analysis combining the United States, Liberia, and Sierra Leone as one location stratum, 
while Guinea constitutes the other location stratum. (The standard of care in Guinea 
typically included favipiravir, which was not the case in the other countries). Note that 
the protocol initially specified stratified randomization for the USA. However, only one 
patient in the USA was randomized, which is why the location strata have been changed 
to USA/Liberia/Sierra Leone vs Guinea. To assess whether there is a treatment by 
location interaction, we will compute the posterior probability that the treatment effect 
(absolute or relative) differs by location. An additional sensitivity analysis will exclude 
the lone patient treated in the United States. The treatment effect within the United States 
cannot be estimated with only one patient, and the differential oSOC in the United States 
versus West Africa could make interpretation of results more difficult. For example, if 
the patient was assigned to oSOC and survived, that may simply reflect better oSOC in 
the United States. 
▪ 
A stratified analysis of odds ratios by the 4 strata defined by location (USA/Liberia/Siera Leone 
versus Guinea) and cycle threshold (≤22 versus >22) will also be performed using the 
Mantel-Haenszel test and estimator. The corresponding alpha levels are as specified 
above. Separate tests of whether the treatment effect differs by location and by cycle 
threshold will be conducted. 
▪ 
Subgroup analysis will repeat the above analyses (main analysis, then divided by CT and 
geographic area) for adults and children 


 
▪ 
All other subgroup analyses (e.g. age, duration of symptoms, baseline risk score [see 
description below]) will follow the strategies above 
▪ 
A baseline risk stratification analysis using a risk score for mortality. This analysis is 
motivated by the following hypothesis: some individuals will enroll who are at a stage of 
disease where a fatal outcome can no longer be prevented. However, exclusion of 
patients in each treatment group who die shortly after randomization would be biased 
because deaths could be due to the toxicity of ZMapp. A modified intention to treat 
analysis in which patients who did not receive at least one dose of ZMapp were excluded 
would also be problematic because early deaths would only be excluded from one of the 
treatment groups. To address this hypothesis we will carry out subgroup analyses that are 
protected by randomization based on the risk (or propensity) of death at the time of 
randomization. With this approach, baseline predictors of death in the first 3 days 
following randomization and in the first 8 days following randomization (all deaths 
occurred within 8 days) will be determined using separate logistic models. With the 
estimated parameters from the logistic models, the probability of 3- and 8-day mortality 
will be determined for each patient. This probability or “risk score” for each person will 
be used to stratify/subgroup patients according to high/medium/low risk of death 
(approximate tertiles) and within each subgroup the two treatment groups will be 
compared. The primary goal is to determine whether the treatment effect differs by risk 
of early death. Development of the risk score will be conducted using the pooled (i.e. 
blinded) data. This will ensure validity of a permutation test, include a larger number of 
events, and allow a more thorough search for relevant baseline predictors. 
 
The following baseline predictors will be considered: age, gender, geographic location, 
CT value, duration of symptoms at enrollment, and type of symptoms (e.g.: systemic 
symptoms [fever, myalgias, arthalgias], fluid loss [diarrhea, vomiting, blood loss], 
respiratory compromise [SOB, hypoxia, elevated respiratory rate >24, supplemental 
oxygen requirement], hemodynamic instability [systolic BP <90, pulse >100, pressor 
support requirement], renal compromise [anuria, serum creatinine > 2x ULN], and CNS 
compromise [confusion, seizures, coma]. We hypothesize based on these analyses that 
benefits of ZMapp on mortality (compared to oSOC) will be greater among patients with 
a medium to low risk of early (1st 3 days) death, relative to those for whom it is high. 
Since there may be some patients who enter the trial with a very low risk of death (e.g., 
no matter the intervention, they were likely to survive), we also hypothesize that the 
benefits of ZMapp on mortality (compared to oSOC) will be greater among patients 
whose risk of death within 8 days is medium or high compared to those from whom it is 
low. 
▪ 
Figures: 
o Forest plots of above mortality rates according to the following subgroups: 
▪ 
CT≤22/>22 
▪ 
Geographic area 
▪ 
Adults vs children 
▪ 
Sex 
▪ 
Duration of time from onset of symptoms to randomization 
▪ 
Baseline risk stratification score (as defined above) 
o 
Kaplan-Meier plots will be made for the following: 


 
▪ 
Treatment group 
▪ 
Treatment group and adults and children 
▪ 
Treatment group and CT ≤22 versus >22 for all subjects 
▪ 
Treatment group and duration of time from onset of symptoms to 
randomization 
 
 
3.9 
Secondary Outcomes 
Major secondary outcomes: 
This section prioritizes the secondary analyses. The study has limited power—the end of the 
epidemic means the study will close prior to accruing its targeted sample size. As a result, 
prioritization of secondary endpoints is needed. We also feel it is important to carefully 
consider the strengths and limitations of the secondary outcomes prior to unblinding. It is 
recognized that the secondary endpoint analyses described below will be difficult to interpret if 
the primary analysis does not demonstrate that ZMapp significantly reduces mortality 
compared to oSOC alone. 
Two endpoints are under consideration: time-to-viral clearance (clearance is defined as the first 
negative PCR result) and time-to-discharge. One could give different arguments for which is a 
better choice. Time to discharge undoubtedly encompasses several aspects simultaneously: 
clearance of virus, amelioration of symptoms, etc. However, there is the possibility of a 
treatment-associated bias in this outcome. For example, if some patients who were given 
ZMapp were discharged later to make sure there were no drug-related safety issues, then 
ZMapp may appear less favorable using this endpoint. Also, we have heard reports that 
patients were kept in a treatment unit after recovery for a variety of reasons, including waiting 
for discharge kits containing food supplies and other household items or the presence of a 
relative undergoing treatment for Ebola at the same unit. These issues make time-to-discharge 
a less precise indication of how a patient feels or functions. 
Time-to-viral clearance is a more objective outcome, but it is also not free of problems. 
Specifically, it is unclear whether this assay was adequately standardized across sites in this 
study, leading to concerns about measurement variability. Further, samples were taken on half 
or fewer of participants on many of the days. Nonetheless, failure to measure PCR is likely to 
have occurred equally in the two arms and the time interval between a positive and negative 
PCR was within 3 days for 39 of 50 patients (78%) and within 5 days for 47/50 (94%) of patients 
. Therefore, it is felt that time to viral clearance should be the more important secondary 
outcome, although both outcomes will be analyzed. Note that, for either outcome, death must 
be taken into account. 
1. Viral clearance/death 
Unless otherwise stated, viral clearance is defined by the occurrence of a negative PCR. 
A. The first analysis of viral clearance/death is a rank test in which patients who die within 
28 days receive worse ranks than survivors, with earlier deaths given worse ranks than 
later deaths. Among 28-day survivors, patients with longer times to viral clearance will 
be given worse ranks. Average ranks will be used in the case of ties. A permutation test 
will be used to determine a p-value for this test. 


 
 
An additional analysis will use the van Elteren stratified Wilcoxon test on the four strata defined 
by location (USA/Liberia/Sierra Leone versus Guinea) and cycle threshold (≤22 versus >22). An 
interaction test will be conducted to determine whether the treatment effect differs by each of 
these subgroups, and subgroups defined by age, gender, and duration from onset of symptoms 
to randomization. Subgroup results will be presented using a forest plot. [Ref: Van Elteren, 
P.H. (1960). On the combination of independent two-sample tests of Wilcoxon. Bulletin of the 
International Statistical Institute 37, 351-361.] 
 
B. The second analysis of viral clearance/death is based on Fisher’s exact test with outcome 
being death or time to viral clearance exceeding 10 days (i.e., 11 or more days). The 
rationale for this secondary analysis is as follows. It may be that ZMapp prevents very 
long times to viral clearance, but has no effect on intermediate times. If we knew the right 
threshold constituting a “long time to viral clearance,” we would select that number. To 
determine the appropriate threshold, we examined data blinded to treatment assignment. 
If we select a threshold that is too small, then exceeding the threshold may not represent a 
bad outcome. On the other hand, if the threshold is too large, the number of people 
exceeding it may be very small. In that case, the test of whether the proportion of people 
dead or with large time to viral clearance differs by treatment arm will be nearly the same 
as the test of whether the proportion of people dead differs by treatment arm. Therefore, 
the key is to choose a threshold that is among the higher times, but not so high that very 
few people exceed it. Figure 1 (below) shows the plot of days to viral clearance. 
Approximately one quarter (13/49=26.5%) of the observations are longer than 10 days. 
This threshold seems to balance the above concerns. Therefore, the second analysis of 
viral clearance/death will use Fisher’s exact test on outcome: death within 28 days or 
time to viral clearance exceeding 10 days (i.e., 11 or more days). Note that Fisher’s exact 
test is a permutation test, and permutation tests remain valid even if the threshold is 
determined after examining blinded data. 
An additional analysis will use the Mantel-Haenszel estimator and test to stratify by the 4 
strata defined by location (USA/Liberia/Sierra Leone versus Guinea) and cycle threshold 
(≤22 versus >22). An interaction test will be conducted to determine whether the 
treatment effect differs by each of these subgroups, and subgroups defined by age, 
gender, and duration from onset of symptoms to randomization. Subgroup results will be 
presented using a forest plot. 
2. Discharge/Death 
A. The first analysis of discharge/death will be the same rank-based method as for viral 
clearance/death, but substituting “discharge” for “viral clearance.” An unstratified and 
stratified test (van Elteren test) will be performed, where the four strata are defined by location 
(USA/Liberia/Sierra Leone versus Guinea) and cycle threshold (≤22 versus >22). 
B. The second analysis of discharge/death uses Fisher’s exact test with outcome being death or 
time to discharge exceeding 16 days (i.e., 17 or more days). The rational for this threshold is as 
follows. Figure 2 (below) is a blinded display of times to discharge. A threshold of greater than 


 
16 days again separates approximately the highest 25% of times (13/49=26.5%). This threshold 
is also a reasonable choice to minimize overlap between this analysis and that of time to viral 
clearance. Figure 3 (below) shows the threshold lines (plotted at 10.5 for time to viral clearance 
and 16.5 for time to discharge). Although there is substantial overlap, represented by the 
upper right region, there are also 5 people meeting the >10 days to viral clearance, but not the 
>16 days to discharge. Likewise, there are 5 people meeting the >16 days to discharge, but not 
the >10 days to viral clearance. 
As with the corresponding analysis of time to viral clearance, a stratified analysis will also be 
performed using the Mantel-Haenszel estimator and test on the four strata defined by location 
(USA/Liberia/Sierra Leone versus Guinea) and cycle threshold (≤22 versus >22). An interaction 
test will be conducted to determine whether the treatment effect differs by each of these 
subgroups, and subgroups defined by age, gender, and duration from onset of symptoms to 
randomization. Subgroup results will be presented using a forest plot. 
 
Figure 1. Distribution of days to viral clearance for all subjects who cleared Ebola virus 


 
 
 
 
 
 
 
Figure 2. Distribution of days to discharge for all discharged subjects 
 
 
 
 
 
Figure 3. Scatter plot of days to discharge versus days to viral clearance for all surviving 
subjects 
 
 
 
3.9.1 
Other Secondary Outcomes 
In addition to those parameters described in Section 3.6 above, the following will be 
summarized by treatment group as described: 
• Vital Signs: blood pressure, pulse, body temperature, respiratory rate, oxygen saturation – 
summarized daily by treatment group 


 
• Current symptoms – 
Two analyses will be performed to compare the number of symptoms across groups: 
1. The first analysis of symptoms will compute the average number of symptoms per day 
during the first 28 days for each patient as well as the average number of days with 
symptoms. Days with no information on symptoms, including days following the death 
or discharge of a patient, will be excluded. The groups will be compared using the 
Wilcoxon rank-sum test. An additional analysis will be conducted using the van Elteren 
stratified Wilcoxon test on the four strata defined by location (USA/Liberia/Sierra Leone 
versus Guinea) and cycle threshold (≤22 versus >22). 
2. The second analysis of symptoms will be identical to the above analysis, but only during 
the first 3 days. The rationale is that analyses over the entire 28-day period may be 
difficult to interpret because some patients will be discharged and others may die. 
Furthermore, the proportion discharged and proportion dying may differ by arm. 
Restricting attention to the first 3 days will focus the analysis on the initial stage which is 
free from discharges and some of the deaths. 
o Percent with any symptom 
o Daily summary of number of reported symptoms 
o Summarized for 7 day intervals by treatment group 
o Symptoms at day 28 and day 58 are also summarized. 
• Chemistries: measurement of serum creatinine and potassium were required and will be 
summarized for each 3-day window (i.e. days 1- 3, days 4 – 6, etc.) by treatment groups, 
all other chemistries were considered optional and will be summarized as available 
o Additional subgroup analysis will repeat the above for adults and children 
• PCR: blood (note- any CT 40.0 or greater will be treated as negative) 
o summarized for each 3-day window (i.e. days 1- 3, days 4 – 6, etc.) 
▪ 
if more than one PCR is available in a 3 day period for a given subject, the 
mean result will be used. 
o summarized as change from baseline for each 3-day window 
o Both of the above will be presented as quantitative (continuous) and qualitative 
o Improvement or worsening of the CT value within the first 72 hours 
o Figure: Kaplan-Meier plot of time to negative Ebola PCR 
▪ 
Kaplan-Meier plot repeated for adults and children 
o Individual PCR curves will be presented 
• PCR – urine (as available) 
o summarized for each 3-day window (i.e. days 1- 3, days 4 – 6, etc.) by treatment 
groups 
o presented as % positive 
▪ 
additional separate tables for adults and children 
• Hematology, chemistries, and coagulation: optional data – summarized as available 
o summarized for each 3-day window (i.e. days 1- 3, days 4 – 6, etc.) 
o summarized as change from baseline for each 3-day window 
o additional separate tables for adults and children 


 
 
 
32.1.1 
• Urinalysis: optional data – summarized as available 
• Imaging and resuscitation: optional data – summarized as available 
 
 
3.9.2 
Safety-Related Outcomes 
 
• SAEs will be summarized and compared between treatment groups as follows: 
o Number and percent of patients experiencing SAEs by treatment group. Test of 
statistical significance will use Fisher’s exact test. 
o For SAEs that are assessed as related to study drug, counts by treatment groups 
and p-value from zero-inflated negative binomial model. 
• Safety line listings by treatment group will be provided for SAEs and “unanticipated 
problems”. Listings will include treatment group label, diagnosis, relatedness to 
treatment, date of onset, time from treatment to onset, event status (recovered/resolved, 
recovering/resolving, not recovered/not resolved, recovered/resolved with sequelae, 
death), date of resolution or death, and EVD status. 
• Unanticipated problems 
Incidence of “unanticipated problems” will be tabulated for each of the treatment groups. 
Reports will have similar format as the summary reports for SAEs. 
 
3.9.3 Pregnancies 
- a listing of subjects pregnant at enrollment 
- listing of pregnancies that occurred on study (from randomization to day 58) 
 
 
3.9.4 Late Clinical Symptoms: 
Subjects will be followed for 1 year to evaluate for late symptoms and/or complications. 
This analysis will be performed at a separate time from the above stated analyses since it 
must await completion of the one-year follow-up data. 
▪ 
Number (and % of expected) of subjects with follow up data between day 56 and 365 
(i.e. had any follow up visit) 
o Total, and by country 
▪ 
Number (and % of expected) of subjects with follow up data at Day 365 (i.e. had 1 
year follow-up) 
o Total, and by country 
▪ 
Number (%) with symptoms at 3 month, 6 months, and 1 year 
o Table of symptoms present 
▪ 
Number (%) with complications 
▪ 
Listings of complications (if any) 
▪ 
Pregnancies 


 
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