Conditions: RSV Infection
Keywords: challenge study RSV antiviral RSV-A Memphis 37b
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 179
Healthy volunteers: yes

Brief summary:
A randomised, Phase 2a, double-blind, placebo-controlled study to evaluate the safety, pharmacokinetics and antiviral activity of multiple doses of orally administered EDP-938 in healthy subjects infected with RSV-A Memphis 37b. This study is designed to compare the antiviral effect of EDP-938 compared to a placebo control in the respiratory syncytial virus challenge model.

Detailed description:

Arms:
arm 1: Subjects will take EDP-938 Dose 1 oral suspension for 5 days arm 2: Subjects will take EDP-938 Dose 2 oral suspension for 5 days arm 3: Subjects will take matching placebo oral suspension for 5 days arm 4: Subjects will take EDP-938 Dose 3 oral suspension for 5 days arm 5: Subjects will take EDP-938 Dose 4 oral suspension for 5 days arm 6: Subjects will take matching placebo oral suspension for 5 days

Interventions: intervention 1: EDP-938 Dose 1 intervention 2: EDP-938 Dose 2 intervention 3: Placebo intervention 4: EDP-938 Dose 3 intervention 5: EDP-938 Dose 4 intervention 6: Placebo
Intervention descriptions: intervention 1: Oral suspension for 5 days intervention 2: Oral suspension for 5 days intervention 3: Oral suspension for 5 days intervention 4: Oral suspension for 5 days intervention 5: Oral suspension for 5 days intervention 6: Oral suspension for 5 days

Protocol document:
Prot_000.pdf: 
Protocol Number:  EDP 938-101 
 
Official Title:  Randomised, Phase 2a, Double-Blind, Placebo-Controlled Study to 
Evaluate the Safety, Pharmacokinetics and Antiviral Activity of 
Multiple Doses of Orally Administered EDP-938 Against Respiratory 
Syncytial Virus Infection in the Virus Challenge Model 
 
NCT Number: NCT03691623 
 
Document Date:  07 NOV 2019 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
 
Sponsor’s study number: EDP 938-101 
hVIVO Protocol No: ENA-CS-001 
A Randomised, Phase 2a, Double-Blind, Placebo-Controlled study to Evaluate the Safety, 
Pharmacokinetics and Antiviral Activity of Multiple Doses of Orally Administered EDP-938 
Against Respiratory Syncytial Virus Infection in the Virus Challenge Model. 
 
 
Short title:  
 
Safety, Pharmacokinetics and Antiviral Activity of Orally 
Administered EDP-938 Against RSV 
Version: 
Amendment 4.0 (version 5.0) Date 07NOV2019 
Sponsor: 
 
ENANTA Pharmaceuticals, Inc 
 
500 Arsenal Street 
Watertown, MA 02472 
United States of America (USA). 
Principal Investigator: 
 
  
hVIVO Services Limited (hVIVO), 
Queen Mary BioEnterprises Innovation Centre, 42 New 
Road, 
London E1 2AX, United Kingdom (UK).  
Study carried out at the facilities 
of: 
 
 
hVIVO Services Limited, 
Queen Mary BioEnterprises Innovation Centre, 42 New 
Road,  
London. E1 2AX. United Kingdom. 
 
EUDRACT Number:  
2018-001878-21 
 
Are any sub-studies in progress at the trial sites?  
 
Yes 
 
☐ 
 
No 
 
☒ 
 
 
 
 
 
 
 
 
 
 
 
 




Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019  
  
 
 
CONFIDENTIAL 
Page 3 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
afternoon of Day 5 post viral 
challenge. 
Appendix 7 footnote added to 
clarify the 72h PK plasma 
sample collection post last 
dose for Part 1. 
Clarification of rescreening 
process 
Section 
9.3.1 
clarified 
rescreening 
process 
for 
subjects who  are found 
ineligible based on review of 
eligibility criteria. 
Amendment 3.0 
(v4.0) 
11JUL2019 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of the 
treatment groups for Part 2 
Section 
9.1 
updated 
to 
include a confirmation of the 
treatment groups for Part 2 
following the emerging data 
from Part 1. Due to the 
combination 
in 
dosing 
schedule (i.e OD and BD) all 
subjects will be treated Twice 
daily (similar to part 1) in 
order to maintain the blind 
between treatment groups. 
The duration of dosing for 
Part 2 clarified as a 5 days 
dosing regimen. 
The 
number 
of subjects 
enrolled in each of the 
treatment groups for Part 2 
confirmed as n=21 subjects 
per treatment group. 
Clarification of the 
randomisation ratio for Part 
2 
Section 10.1: randomisation 
ratio for Part 2 clarified as a 
1:1:1 ratio. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019  
  
 
 
CONFIDENTIAL 
Page 4 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 
 
Clarification of the PK 
blood sampling schedule 
for Part 2 
Appendix 
7: 
PK 
blood 
sampling schedule for Part 2 
clarified. 
Clarification of adverse 
events reporting for 15% 
drop in spirometry value  
Section 15 Adverse Events 
and Toxicity Management 
clarified for the reporting of 
adverse events related to a 
15% 
drop 
in 
spirometry 
value. 
Amendment 4.0 
(v5.0) 
07NOV2019 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 






Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019  
  
 
 
CONFIDENTIAL 
Page 7 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
TABLE OF CONTENTS 
1 
STUDY PERSONNEL CONTACT LIST ............................................................ 13 
2 
PROTOCOL SYNOPSIS .................................................................................. 15 
3 
GLOSSARY OF ABBREVIATIONS ................................................................. 25 
4 
DEFINITIONS ................................................................................................... 28 
4.1 
General ............................................................................................................................. 28 
4.2 
Study definitions of infection and illness ........................................................................... 29 
5 
BACKGROUND AND INTRODUCTION ........................................................... 31 
5.1 
Information about Respiratory Syncytial Virus (RSV) ....................................................... 31 
5.2 
Information about EDP-938 .............................................................................................. 31 
 
Product description .............................................................................................. 31 
 
Non-clinical studies .............................................................................................. 32 
5.2.2.1 Non-Clinical Pharmacology Studies ....................................................... 32 
5.2.2.2 Non-Clinical Pharmacokinetics ............................................................... 32 
5.2.2.3 Non-Clinical Toxicology in Animal Summary .......................................... 33 
 
Clinical studies ..................................................................................................... 34 
5.2.3.1 Effects in Humans ................................................................................... 34 
5.3 
Rationale for the study ...................................................................................................... 34 
 
Study design ........................................................................................................ 35 
 
EDP-938 dose regimen ....................................................................................... 35 
5.4 
Potential risks and benefits to participants ....................................................................... 36 
 
Virus ..................................................................................................................... 36 
5.4.1.1 Vulnerable populations ........................................................................... 37 
 
EDP-938 .............................................................................................................. 37 
 
Study procedures ................................................................................................. 37 
6 
STUDY OBJECTIVES and ENDPOINTS ......................................................... 39 
6.1 
Primary Objective ............................................................................................................. 39 
 
Primary Endpoint ................................................................................................. 39 
6.2 
Secondary Objectives ....................................................................................................... 39 
 
Secondary Endpoints ........................................................................................... 39 
6.2.1.1 Efficacy.................................................................................................... 39 
6.2.1.2 Safety ...................................................................................................... 40 
6.2.1.3 Pharmacokinetics .................................................................................... 40 
6.3 
Exploratory Objectives ...................................................................................................... 40 
 
Exploratory Endpoints .......................................................................................... 41 
7 
STUDY POPULATION ..................................................................................... 42 
7.1 
Study Population............................................................................................................... 42 
7.2 
Number of subjects ........................................................................................................... 42 
7.3 
Inclusion criteria ................................................................................................................ 42 
7.4 
Exclusion criteria............................................................................................................... 45 
7.5 
Discontinuation of a subject’s participation ...................................................................... 48 
 
Subject withdrawal ............................................................................................... 48 
 
Subject discontinuation ........................................................................................ 49 
 
Replacements ...................................................................................................... 49 
 
Pregnancy ............................................................................................................ 49 
 
Arrangements for additional care if required ....................................................... 49 
7.6 
Reserve subjects .............................................................................................................. 50 
7.7 
Subject numbering ............................................................................................................ 50 
8 
PROCEDURES FOR MONITORING SUBJECT COMPLIANCE WITH 
TREATMENT AND RESTRICTIONS .................................................................................. 51 
8.1 
Concomitant therapies ...................................................................................................... 51 
 
Prohibited Medications: ....................................................................................... 52 
 
Permitted medications ......................................................................................... 53 
8.2 
Strenuous Exercise .......................................................................................................... 53 
8.3 
Alcohol, drugs of abuse and tobacco ............................................................................... 53 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019  
  
 
 
CONFIDENTIAL 
Page 8 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
8.4 
Restrictions related to study assessments ....................................................................... 53 
 
Spirometry............................................................................................................ 53 
9 
STUDY DESIGN ............................................................................................... 54 
9.1 
Summary .......................................................................................................................... 54 
 
Part 2 Progression and Additional Evaluation Guidelines ................................... 56 
9.2 
Screening Visit .................................................................................................................. 58 
 
Informed consent procedure ................................................................................ 58 
 
Screening Procedure ........................................................................................... 59 
9.3 
Quarantine Phase ............................................................................................................. 59 
 
Admission ............................................................................................................ 60 
 
Viral Challenge .................................................................................................... 60 
 
Discharge ............................................................................................................. 60 
9.4 
Follow-up phase ............................................................................................................... 61 
 
Study Day 13 to Day 18 ....................................................................................... 61 
 
Day 28 (±3 days) Follow-up Visit ......................................................................... 61 
9.5 
Duration of Subject Participation ...................................................................................... 62 
9.6 
Lost to follow-up................................................................................................................ 62 
9.7 
End of trial ......................................................................................................................... 62 
9.8 
Clinical Trial Summary Report .......................................................................................... 62 
10 
RANDOMISATION AND BLINDING ................................................................ 71 
10.1 
Randomisation .................................................................................................................. 71 
 Replacements ...................................................................................................... 72 
10.2 
Blinding ............................................................................................................................. 72 
10.3 
Unblinding ......................................................................................................................... 72 
11 
CHALLENGE VIRUS ........................................................................................ 74 
11.1 
Production ......................................................................................................................... 74 
11.2 
Supply and accountability ................................................................................................. 74 
11.3 
Preparation and administration ......................................................................................... 74 
11.4 
Disposal ............................................................................................................................ 75 
12 
INVESTIGATIONAL MEDICINAL PRODUCT .................................................. 76 
12.1 
Description ........................................................................................................................ 76 
12.2 
Dispensing and accountability .......................................................................................... 78 
12.3 
Packing and labelling ........................................................................................................ 78 
12.4 
Storage ............................................................................................................................. 79 
12.5 
Administration ................................................................................................................... 79 
 Fasting Schedule ................................................................................................. 80 
12.6 
Compliance ....................................................................................................................... 80 
12.7 
Overdose .......................................................................................................................... 80 
12.8 
Disposal ............................................................................................................................ 81 
13 
ASSESSMENTS AND PROCEDURES ............................................................ 82 
13.1 
Medical and medication history ........................................................................................ 82 
13.2 
Demographics ................................................................................................................... 82 
13.3 
Height, weight, and body mass index ............................................................................... 82 
13.4 
Complete physical examination ........................................................................................ 82 
13.5 
Directed physical examination .......................................................................................... 83 
13.6 
Vital signs ......................................................................................................................... 83 
13.7 
Tympanic Temperature .................................................................................................... 84 
13.8 
ECG .................................................................................................................................. 85 
13.9 
Spirometry ........................................................................................................................ 85 
13.10 hVIVO Symptom Diary Cards ........................................................................................... 86 
13.11 Nasal discharge collection from paper tissues ................................................................. 86 
13.12 Routine blood analysis ..................................................................................................... 87 
13.13 Challenge Virus serology .................................................................................................. 87 
13.14 Nasal samples .................................................................................................................. 87 
 Nasopharyngeal swab ......................................................................................... 87 
13.14.1.1 
Respiratory Pathogen Screen .......................................................... 88 
13.14.1.2 
Rapid Viral Screen ............................................................................ 88 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019  
  
 
 
CONFIDENTIAL 
Page 9 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 Nasal wash .......................................................................................................... 88 
13.15 Breath alcohol ................................................................................................................... 88 
13.16 Adverse events and concomitant medications ................................................................. 88 
14 
LABORATORY ASSESSMENTS ..................................................................... 90 
14.1 
Blood volume .................................................................................................................... 90 
14.2 
Safety Blood Samples and Assessments ......................................................................... 90 
 Biochemistry ........................................................................................................ 91 
 Thyroid function test ............................................................................................ 91 
 Haematology ........................................................................................................ 91 
 Cardiac enzymes ................................................................................................. 92 
 Coagulation .......................................................................................................... 92 
 Human Immunodeficiency Virus and Hepatitis A, B, and C ................................ 92 
 Serum follicle stimulating hormone ...................................................................... 92 
 Serum pregnancy test .......................................................................................... 92 
14.3 
Urine Samples and Assessments..................................................................................... 92 
 Urinalysis ............................................................................................................. 92 
 Drugs of abuse and cotinine ................................................................................ 93 
 Pregnancy ............................................................................................................ 93 
14.4 
Virology Assessments ...................................................................................................... 93 
 Serum RSV neutralising antibody ........................................................................ 93 
 Respiratory Pathogen Screen ............................................................................. 93 
 Rapid Viral Screen ............................................................................................... 94 
 Viral load .............................................................................................................. 94 
14.4.4.1 
Quantitative Reverse Transcription Polymerase Chain Reaction (RT-
qPCR) ..................................................................................................... 94 
14.4.4.2 
Cell Based Infectivity Assay ............................................................... 94 
 Viral shedding for dosing ..................................................................................... 94 
14.4.5.1 
Qualitative Integrated Cycler Polymerase Chain Reaction (qicPCR) . 94 
 Replicative Strand PCR ....................................................................................... 94 
 Viral resistance .................................................................................................... 94 
14.5 
PK Assessments............................................................................................................... 95 
 Blood Plasma Samples ........................................................................................ 95 
 Nasal Wash samples ........................................................................................... 95 
15 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ..................................... 96 
15.1 
Definitions ......................................................................................................................... 96 
 Adverse Event ..................................................................................................... 96 
 Adverse Drug Reaction ........................................................................................ 96 
 Unexpected Adverse (Drug) Reaction ................................................................. 97 
 Serious Adverse Event ........................................................................................ 97 
 Suspected Unexpected Serious Adverse Reaction ............................................. 98 
15.2 
Recording and reporting ................................................................................................... 98 
15.3 
Assessment ...................................................................................................................... 99 
 Description ........................................................................................................... 99 
 Onset and end ..................................................................................................... 99 
 Seriousness ......................................................................................................... 99 
 Intensity and severity ........................................................................................... 99 
 Adverse Events critical to the safety evaluation .................................................. 99 
 Challenge Virus symptoms ................................................................................ 100 
 Physical Examination ......................................................................................... 100 
 Directed Physical Examination .......................................................................... 100 
 Vital signs........................................................................................................... 100 
 Temperature ...................................................................................................... 100 
 Spirometry.......................................................................................................... 100 
 Laboratory values .............................................................................................. 101 
15.3.12.1 
C-reactive protein ........................................................................... 101 
15.4 
Classification of Adverse Events .................................................................................... 101 
 Severity .............................................................................................................. 101 
 Frequency .......................................................................................................... 102 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019  
  
 
 
CONFIDENTIAL 
Page 10 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 Relationship ....................................................................................................... 102 
 Action taken ....................................................................................................... 103 
 Outcome ............................................................................................................ 103 
 Follow-up ........................................................................................................... 104 
15.5 
Serious Adverse Event reporting .................................................................................... 104 
 Reporting of SUSARs ........................................................................................ 106 
 Adverse Drug Reactions to non-IMPs ............................................................... 106 
 Post-study AEs and SAEs ................................................................................. 106 
 Pregnancy .......................................................................................................... 107 
16 
STATISTICAL METHODS AND PLANNED ANALYSES ............................... 108 
16.1 
Study analysis sets ......................................................................................................... 108 
 Subgroup analysis ............................................................................................. 109 
16.2 
Sample size .................................................................................................................... 109 
16.3 
Interim Analysis .............................................................................................................. 109 
16.4 
Statistical Analysis Plan .................................................................................................. 109 
 Clinical Study Report ......................................................................................... 110 
 Subject accountability ........................................................................................ 110 
 Protocol deviations ............................................................................................ 110 
 Demographic and baseline characteristics ........................................................ 110 
16.5 
Primary efficacy analysis ................................................................................................ 110 
16.6 
Secondary efficacy analysis ........................................................................................... 110 
 Safety analysis ................................................................................................... 111 
 Pharmacokinetic analysis .................................................................................. 111 
16.7 
Exploratory analysis ....................................................................................................... 112 
17 
STUDY FILES AND CLINICAL SOURCE DOCUMENTATION ...................... 113 
17.1 
Investigator’s Study File ................................................................................................. 113 
17.2 
Clinical source documentation ........................................................................................ 113 
17.3 
Data Capture .................................................................................................................. 113 
17.4 
Data quality assurance and quality control ..................................................................... 113 
17.5 
Data coding ..................................................................................................................... 114 
17.6 
Database lock ................................................................................................................. 114 
17.7 
Data protection ............................................................................................................... 114 
18 
STUDY MANAGEMENT AND ETHICAL RESPONSIBILITIES ...................... 115 
18.1 
Regulatory and Ethics Opinions and Good Clinical Practice ......................................... 115 
18.2 
Quality Assurance........................................................................................................... 115 
18.3 
Quality Control ................................................................................................................ 115 
18.4 
Deviations from the Protocol .......................................................................................... 115 
 Protocol Waivers ................................................................................................ 115 
 Protocol Deviations ............................................................................................ 115 
 Serious breach of the protocol or GCP .............................................................. 115 
 Protocol amendments ........................................................................................ 116 
 Urgent Safety Measures .................................................................................... 117 
18.4.5.1 
Pandemic .......................................................................................... 117 
18.5 
Discontinuation of the study ........................................................................................... 117 
 Stopping Criteria ................................................................................................ 118 
18.6 
Study records retention and direct access to source documents ................................... 119 
 Archiving ............................................................................................................ 120 
18.7 
Sponsor responsibilities .................................................................................................. 120 
 General .............................................................................................................. 120 
 No-fault compensation and indemnity ............................................................... 120 
 Monitoring .......................................................................................................... 120 
 Audits and inspections ....................................................................................... 121 
 Reports to the REC and MHRA ......................................................................... 121 
18.8 
Investigator responsibilities ............................................................................................ 121 
 Ethical considerations ........................................................................................ 121 
 Laboratory certification and normal values ........................................................ 122 
 Delegation of Investigator responsibilities ......................................................... 122 
 Informed Consent Process ................................................................................ 122 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019  
  
 
 
CONFIDENTIAL 
Page 11 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 Information for General Practitioners ................................................................. 123 
 Compensation and Expenses ............................................................................ 123 
 Liability and insurance ....................................................................................... 123 
 Investigator’s Protocol Agreement ..................................................................... 123 
 Quality assurance .............................................................................................. 124 
18.9 
Study termination ............................................................................................................ 124 
18.10 GCP Compliance ............................................................................................................ 124 
19 
DISCLOSURE OF DATA................................................................................ 125 
19.1 
Subject confidentiality ..................................................................................................... 125 
19.2 
Sponsor confidentiality ................................................................................................... 125 
19.3 
Publication ...................................................................................................................... 125 
20 
REFERENCES AND BIBLIOGRAPHY ........................................................... 127 
21 
APPENDICES ................................................................................................ 132 
 
 
 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019  
  
 
 
CONFIDENTIAL 
Page 12 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
LIST OF APPENDICES 
Appendix 1: Patient Health Questionnaire (PHQ-9)40 ................................................................. 133 
Appendix 2: Generalised Anxiety Disorder Questionnaire (GAD-7)41 ........................................ 134 
Appendix 3: Normal ranges ........................................................................................................ 135 
Appendix 4: hVIVO Symptom Diary Card ................................................................................... 136 
Appendix 5: AE and Toxicity Grading Scales ............................................................................. 137 
Appendix 6: Assessment of Baseline by Investigator for Clinical Conduct ................................ 138 
Appendix 7: PK Blood Sampling Schedule ................................................................................. 140 
 
LIST OF TABLES  
Table 9-1: Time and events schedule ........................................................................................... 63 
Table 12-1: Physicochemical properties of EDP-938 Drug Substance ........................................ 76 
Table 12-2: Physical description of the Oral 
 ............................................................. 76 
Table 15-1: Classification of adverse event severity .................................................................. 102 
Table 15-2: Classification of Adverse Event relationship ........................................................... 102 
Table 15-3: Classification of adverse event outcome ................................................................. 103 
Table 15-4: Contact details for reporting all SAEs ...................................................................... 105 
Table 18-1: Study stopping criteria ............................................................................................. 118 
 
LIST OF FIGURES 
Figure 9-1: Study design ............................................................................................................... 57 
  




Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019  
  
 
 
CONFIDENTIAL 
Page 14 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
OTHER PARTIES 
The Sponsor Trial Master File (TMF) / hVIVO TMF contains 
details of third party contractors, sub-investigators, 
laboratories, clinical monitors, data management suppliers, 
statisticians and all other service providers. 
 
 


































Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
  
CONFIDENTIAL 
Page 31 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
5 
BACKGROUND AND INTRODUCTION  
5.1 
Information about Respiratory Syncytial Virus (RSV)   
RSV Virus Challenge strain Memphis-37b strain has been utilised in over 900 healthy subjects 
in at least 17 clinical studies. RSV inoculation of healthy subjects was shown to infect 
approximately 65 - 85% of placebo subjects and produced mild to moderate upper respiratory 
tract illness24. 
 
Additionally, another sub-batch of live RSV (Memphis 37c) has been used as a challenge 
agent and was shown to be safe in over 77 healthy young adults across three studies. RSV 
infection was not associated with any serious adverse side effects7-9. 
 
The study virus, like many viruses, can cause more substantial health issues such as 
myocarditis (inflammation or damage to the heart muscle). However, the chance of this 
resulting in serious or permanent changes is rare, as most cases are minor and resolve without 
any lasting changes. In our virus challenge studies, uncommonly blood tests have shown a 
change suggestive of myocarditis, although in these few subjects the blood tests returned to 
normal without treatment and were not associated with specific symptoms or ECG changes. 
 
Human RSV is an enveloped, single-stranded ribonucleic acid (ssRNA) virus, which infects all 
human age groups, but causes the most severe disease burden in the paediatric population. 
RSV infects over half of all infants within their first year of life10, and is the single most common 
cause of hospitalisation of infants11, 12, representing more than 126,000 childhood 
hospitalisations per year in the United States (US) and a similar number in the European Union 
(EU)13. Furthermore, the development of childhood asthma and other post-acute sequelae is 
also known to occur after severe childhood RSV infections14-16.  
Childhood infection is not associated with life-long immunity to RSV and infections in 
adulthood occur periodically with an acute, mild rhinitis10, 14, 17. In susceptible adult populations 
(e.g., the elderly, those with co-existing heart or lung disease, individuals receiving 
chemotherapy or who are immuno-compromised), RSV can produce more severe and 
potentially life-threatening lower respiratory tract infections18-22.  
No vaccine to treat or prevent RSV mediated disease is available. The only approved antiviral 
therapy for RSV, ribavirin, is rarely used in the US or European paediatric population due to 
its unfavourable toxicity, its poor antiviral effect, and its controversial and limited efficacy23-25. 
Existing prevention strategies rely on monoclonal antibodies which are only partially effective 
and which are administered to only a small fraction of the at-risk population26. Thus, an 
effective therapy for RSV infection represents a major unmet medical need. 
5.2 
Information about EDP-938 
 
Product description 
The study drug is EDP-938, is a novel, orally administered, non-fusion replication inhibitor of 
RSV that is being developed as a potential treatment for RSV infection.  
 
EDP-938 is a small molecule, with a molecular formula C27H22F3N7O3. The drug product is  
 
 
 
  
 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
  
CONFIDENTIAL 
Page 32 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 
Non-clinical studies 
5.2.2.1 Non-Clinical Pharmacology Studies 
The principal findings from the non-clinical pharmacology studies are summarised below: 
• 
EDP-938 is a novel non-fusion replication inhibitor of RSV with in vitro resistance 
studies suggesting that the compound targets RSV nucleoprotein (N) 48-49. 
 
• 
It is specific for RSV with no cross-activity against two unrelated viruses, HBV and 
HCV, and the antiviral effect is not due to cytotoxicity. 
 
• 
In vitro resistance study revealed that mutations selected with EDP-938 are mainly 
located in the P-binding pocket of RSV N protein, which is consistent with previous 
reports with other inhibitors of the same class48. 
 
• 
RSV N protein is an essential component of viral RNA-dependent RNA polymerase 
(RdRp), which is responsible for viral replication and transcription. In vitro time-of-
addition study confirms that EDP-938 works at a post-entry, replication step of RSV. 
 
• 
 
 
 
 
 
• 
Taken together, these data suggest that the anti-RSV effect of EDP-938 is likely 
mediated through viral N protein, although the exact mechanism of action remains to 
be further elucidated. 
 
5.2.2.2 Non-Clinical Pharmacokinetics  
The PK properties of EDP-938 were investigated in non-clinical studies conducted 
 
 The PK of EDP-938 
following single intravenous (IV) and oral (PO) doses were determined in each of these animal 
species. In addition, multiple-dose oral pharmacokinetic studies were conducted as 
components 
 Good Laboratory Practice (GLP) toxicology studies in mice and 
monkeys. The mouse and the monkey comprised the primary species used to evaluate the 
safety of the compound. 
• 
 
 
 
 
 
 
• 
 
 
 
 
 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
  
CONFIDENTIAL 
Page 33 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.2.2.3 Non-Clinical Toxicology in Animal Summary 
Key findings from these studies are summarised below: 
 
• 
Oral EDP-938 treatment in single and repeat dose general toxicity studies at up to 
 of once-daily dosing across species was well-tolerated.  
 
• 
 
 
 
 
 
 
 
• 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
It was concluded that the toxicology studies support progression into clinical trials in healthy 
subjects. 
 
 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
  
CONFIDENTIAL 
Page 34 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 
Clinical studies 
5.2.3.1 Effects in Humans 
EDP- 938 is being evaluated in an ongoing Phase 1, randomized, double-blind, placebo-
controlled, first-in-human (FIH) study in which the safety, tolerability, and PK is being assessed 
in healthy adult subjects. The Phase 1 study included a SAD phase enrolling a total of 6 dose 
cohorts of which, one was a two-part Food Effect (FE) cohort, and a MAD phase enrolling 5 
dose cohorts.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In summary: 
• 
 
 
 
 
 
 
These results support further clinical evaluation of EDP-938 in patients with RSV. 
For a detailed description of available clinical data, please refer to the EDP-938 IB addendum. 
5.3 
Rationale for the study 
EDP-938 is an investigational drug substance being developed for the treatment of RSV 
infection.  
 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
  
CONFIDENTIAL 
Page 35 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
EDP-938 is a novel non-fusion replication inhibitor of RSV, and it is against all RSV A and B 
laboratory strains and clinical isolates tested in vitro. In the primary human bronchial epithelial 
cells, EDP-938 had an EC50 of 21nM, 23nM and 64nM, against RSV-A Long, M37 and RSV-
B Washington strains, respectively. EDP-938 appears to inhibit RSV replication by modulating 
viral nucleoprotein (N), based on in vitro resistance studies, although the exact mechanism of 
action is under further investigation. EDP-938 has demonstrated in vivo efficacy in the RSV 
infected African Green Monkey model.  
The rationale for taking EDP-938 into further development is the expectation that this 
compound could be effective for the treatment of RSV, to address the unmet medical need for 
more effective antiviral therapies for RSV. 
 
Study design 
The study will be conducted by hVIVO Services Limited, which has extensive experience with 
viral challenge studies. Numerous studies have been performed using experimental RSV-A 
Memphis 37b infection in human subjects. To date, in hVIVO’s studies, more than 900 subjects 
have been successfully and safely inoculated with RSV-A Memphis 37b. These studies42-47 
demonstrated that adults could be infected by nasal inoculation. This strain has been shown 
to cause symptoms and virus shedding that closely match natural infection. 
Administration of study drug and challenge with RSV-A Memphis 37b will take place in 
hVIVO’s specialised Unit. Standard study procedures (including collection of blood, urine, and 
nasopharyngeal secretions for assessment of safety and efficacy) have been employed in 
previous studies conducted by hVIVO. 
 
EDP-938 dose regimen 
Doses selected for Part 1 of the Study are: 
▪ 
600mg OD every 24 hours (+/- 1hr) for 5 days  
▪ 
A single Loading Dose (LD) of 500mg followed by a 300mg dose every 12 hours (+/-
1hr) for 5 days.  
These doses are expected to provide exposures in the anticipated therapeutic range.  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
  
CONFIDENTIAL 
Page 36 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
Based on in vitro testing, an EC90 value for EDP-938 of 20 ng/ml was determined in human 
bronchial epithelial cells (HBEC). The EDP-938 doses selected for Part 1 (600mg OD or a 
single LD of 500mg followed by 300mg dose every 12 hours) are expected to result in mean 
Ctrough concentrations at steady state of approximately 600ng/ml. These values are expected 
to provide mean exposures of approximately 30x compared to the EC90 in HBEC (based on 
total EDP-938 concentrations). As EDP-938 is 95% plasma protein bound, the corresponding 
multiple corrected for plasma protein binding is approximately 1.5x for both dosing regimens.  
Doses and regimens for Part 2 of the Study will be determined based on emerging PK, 
virology, clinical symptom score and safety data from Part 1. However, the maximum individual 
dose in any treatment regimen will not exceed a loading dose followed by maintenance doses 
which are projected to deliver mean IMP exposure of 28745 ng.hr/mL (AUC).  
5.4 
Potential risks and benefits to participants 
There are no expected benefits to study participants, although subjects may develop some 
immunity to RSV-A Memphis 37b and benefit from a general health check at screening.  
The known risks to participants are detailed below. However, there may also be risks that are 
unforeseen and not anticipated (e.g., unknown allergies). Every effort will be made to monitor 
the health of the subjects to ensure that such risks are minimised. Trained medical personnel 
and facilities will be available to provide medical emergency care. 
 
Virus  
Subjects have approximately 65% to 85% chance of becoming infected with RSV following 
the administration of the virus6. Typical RSV illness is characterised by an abrupt onset of 
rhinitis, nasal stuffiness, fever, malaise, myalgia (muscle aches), and sore throat. In healthy 
adults, the illness usually resolves without any treatment, with relief of symptoms occurring 
naturally within 7 to 10 days. Qualified doctors and nurses in the Quarantine Unit will manage 
any symptoms. 
 
The study virus, like many viruses, can cause more substantial health issues such as 
myocarditis (inflammation or damage to the heart muscle). However, the chance of this 
resulting in serious or permanent changes is rare, as most cases are minor and resolve without 
any lasting changes. In hVIVO’s virus challenge studies, uncommonly blood tests have shown 
a change suggestive of myocarditis, although in these few subjects the blood tests returned 
to normal without treatment and were not associated with specific symptoms or ECG changes. 
Severe complications of naturally occurring RSV infection tend to occur almost exclusively in 
infants, the elderly, and persons of any age with chronic co-morbidities and significant immune 
compromise.  
 
It is unlikely for the subjects to transmit RSV to their close contacts. After infection with RSV, 
the virus will be present in the subjects’ noses for several days; although it is not expected 
that infectious RSV will be present in the respiratory tract at the time of discharge from the 
isolation facility (quarantine). This is because the usual duration of time that RSV infection 
remains in adults is several days shorter than the time subjects spend in the isolation facility 
(quarantine). A nasal swab sample will also be tested for RSV prior to discharge using a 
qualitative RSV Rapid Viral Antigen Test (RVAT) to determine subjects’ suitability for 
departure. If a subject is still positive for RSV (using RVAT) on Day 12, he/she may be asked 
to remain in quarantine. A further test will be carried out on Day 12 evening, if negative the 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
  
CONFIDENTIAL 
Page 37 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
subject can be discharged. If the test is still positive on Day 12 or 13 and following review by 
the Investigator, the subject may be asked to remain in quarantine for further observation.  
If symptoms are present, but no virus is detected (negative RVAT), discharge will be at the 
investigator’s discretion. If appropriate, subjects may reside in quarantine for extra days if 
required. 
 
5.4.1.1 Vulnerable populations  
To reduce the risk of passing the Challenge Virus to others, subjects will be asked to avoid 
contact (have close contact or share the same apartment or house) with vulnerable people for 
2 weeks after they leave quarantine. For the purposes of this protocol, a vulnerable individual 
includes but not limited to the following:   
• 
Persons ≥65 years of age. 
• 
Children ≤2 years of age. 
• 
Residents of nursing homes. 
• 
Persons of any age with significant chronic medical conditions such as:  
o Chronic pulmonary disease (e.g., severe asthma, COPD).  
o Chronic cardiovascular disease (e.g., cardiomyopathy, congestive heart failure, 
cardiac surgery, ischemic heart disease, known anatomic defects). 
o Contacts that required medical follow-up or hospitalization during the past 5 years 
because of chronic metabolic disease (e.g., insulin dependent diabetes mellitus, 
renal dysfunction, hemoglobinopathies). 
o Immunosuppression or cancer.  
o Neurological and neurodevelopmental conditions (e.g., cerebral palsy, epilepsy, 
stroke, seizures).  
• 
Individuals who are receiving long-term aspirin therapy. 
• 
Women who are pregnant or who are trying to become pregnant. 
 
 
EDP-938 
Based on pre-clinical data and final unblinded data for the SAD part and preliminary blinded 
data for the MAD part of the ongoing FIH Study EDP- 938-001, EDP-938 is expected to be 
safe and well tolerated in subjects inoculated with RSV.  
 
 
  
 
Study procedures 
Some of the study procedures may cause discomfort to the subject, however these normally 
resolve without further problems. The discomforts due to study procedures are described in 
the Volunteer Information Sheet (VIS). 
The blood tests performed to address the health of the subjects at screening and during the 
study may indicate that a subject has an infection that he/she was not previously aware of 
(such as HIV or hepatitis) or an unexpected illness. The hVIVO doctor will provide the subject’s 
general practitioner (GP), or doctor with a referral letter if the subject agrees. There may also 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
 
Page 38 of 144 
CONFIDENTIAL  
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
be circumstances in which disclosing information without consent is justified in the public 
interest for important public benefits as required by local regulations. 
Should any new information relevant to the subjects’ participation in the study and their safety 
become available, a member of the hVIVO medical staff will notify subjects in a timely manner. 
If appropriate, subjects will be asked to reconfirm their consent to their participation in the 
study. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
 
Page 39 of 144 
CONFIDENTIAL  
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
6 
STUDY OBJECTIVES AND ENDPOINTS 
6.1 
Primary Objective 
To evaluate the antiviral activity of EDP-938 compared to placebo in healthy adult subjects 
inoculated with RSV-A Memphis 37b. 
 
Primary Endpoint 
The area under the curve (AUC) for RSV viral load measured in nasal washes by quantitative 
reverse transcription polymerase chain reaction (RT-qPCR), in subjects inoculated with RSV-
A Memphis 37b. 
6.2 
Secondary Objectives 
• 
To evaluate EDP-938 compared to placebo in healthy adult subjects inoculated with 
RSV-A Memphis 37b in terms of: 
 
o Clinical symptoms 
o Viral load 
o Safety and Tolerability 
 
• 
To characterise the PK profile of multiple doses of EDP-938 and metabolites in healthy 
adult subjects inoculated with RSV-A Memphis 37b. 
 
• 
To characterise the relationship between Plasma PK of EDP-938 and viral load AUC 
(RT-PCR) and total symptom score AUC  
 
 
Secondary Endpoints 
Secondary endpoints relating to efficacy include, but not limited to: 
6.2.1.1 Efficacy 
• 
Clinical Symptoms: 
o Effect of EDP-938 compared to placebo on RSV symptoms (using the 10- item diary 
card), with endpoints including: 
 
▪ 
AUC of total symptom score 
▪ 
Peak total symptom score over the duration of quarantine 
▪ 
Total symptom score  
▪ 
Time to peak symptom score after IMP dosing.  
▪ 
Time to resolution from peak symptom. 
 
o Total weight of nasal mucus produced (via weighed paper tissues).  
• 
Viral Load: 
o Additional viral load endpoints calculated separately using data from RT-qPCR of 
nasal wash comparing placebo and EDP-938 treated including: 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
 
Page 40 of 144 
CONFIDENTIAL  
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
▪ 
Peak viral load 
▪ 
Time to peak viral load 
▪ 
Time to resolution from peak 
▪ 
Time to cessation of virus quantifiable post first dosing 
 
6.2.1.2 Safety 
Secondary endpoints relating to safety include, but are not limited to: 
• 
AEs 
• 
Physical Examinations 
• 
Vital signs 
• 
12-lead ECGs 
• 
Spirometry 
• 
Clinical laboratory results (including biochemistry, haematology, coagulation (if 
required), cardiac enzymes and urine analysis 
 
6.2.1.3 Pharmacokinetics 
Secondary endpoints related to PK include, but are not limited to: 
• 
Plasma PK parameters of EDP-938 (and metabolites) following repeat dose 
administration in healthy adult subjects inoculated with RSV-A Memphis 37b: Cmax, 
Tmax, t1/2, CL/F, λz, Vd/F, C12, C24, AUClast, AUC0-tau, or AUC0-inf (as applicable). 
• 
Plasma PK (AUC) correlations with viral load AUC (e.g. RT-PCR) and TSS AUC 
 
6.3 
Exploratory Objectives 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
 
Page 41 of 144 
CONFIDENTIAL  
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 
Exploratory Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
















Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
 
Page 49 of 144 
CONFIDENTIAL  
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
Subjects will be counselled that early withdrawal from the viral challenge phase of the study 
is strongly discouraged, as it may pose a risk both to the subject and his/her contacts. In the 
event of a subject insisting on early withdrawal during the challenge isolation period, the 
subject will be encouraged to stay and would be advised of the potential risks of carrying RSV-
A Memphis 37b infection into the community, and to vulnerable groups (5.4.1.1) in particular.  
 
 
Subject discontinuation 
A subject's participation may be stopped (early discontinuation) for any of the following 
reasons: 
• 
Non-compliance with the study requirements and restrictions. 
• 
Clinically significant abnormal laboratory findings, which in the opinion of the 
Investigator(s) and/or Sponsor, precludes further participation in the study. 
• 
Development of inter-current illness which, in the opinion of the Investigator would 
compromise the health of the subject or the study objectives. 
• 
The Investigator’s decision that withdrawal from further participation would be in the 
subject’s best interest.  
• 
Termination of the study at the discretion of the Investigator(s) or Sponsor for safety, 
behavioural, or administrative reasons. 
• 
The wish of the subject. 
Subjects who are withdrawn from the study, will be requested to attend an Early Withdrawal 
Visit, with assessments as detailed in Table 9-1. 
 
Replacements 
Subjects that have been inoculated but not dosed will be replaced. 
Subjects who have been dosed with IMP (i.e. subject has received at least one IMP dose) and 
end participation early will not be replaced. 
 
Pregnancy 
In the event of a subject discontinuing the study prematurely due to pregnancy, or if pregnancy 
in a study subject’s partner becomes known, please refer to section 15 for pregnancy reporting 
requirements.  
 
Arrangements for additional care if required 
Subjects who still have significant worsening of their clinical signs compared to baseline may 
be required to stay in quarantine for additional observation and medical management longer 
than the scheduled Day 12 discharge date. Assessments will be conducted as clinically 
indicated by the Investigator. Such subjects upon discharge may be asked to return for a follow 
-up visit whether that be at the scheduled day 28 or an unscheduled visit.  


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV : 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
 
 
 
 
CONFIDENTIAL 
Page 50 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
7.6 
Reserve subjects 
Reserve subjects may remain available to replace any subjects who become ineligible for the 
study between the day of admission to quarantine and the final assessment of eligibility prior 
to Viral Challenge.  
Reserve subjects who are not needed for a particular quarantine group may be discharged 
from the planned quarantine before or on the day of Viral Challenge (Day 0) at the latest. 
A reserve subject who was not enrolled into a quarantine group may be enrolled into a later 
quarantine group within 56 days of screening with no re-screening required if the Day - 2 (or 
Day -1) clinical assessments meet the eligibility criteria, and provided sero-susceptibility 
results are within the 90 days (inclusive) window from the planned inoculation date (Day 0).  
7.7 
Subject numbering 
hVIVO assigns a unique subject number to each subject in the hVIVO subject database. This 
subject number will be used to identify a subject up to the point of randomisation (Section 
10.1), on source documents, on all study correspondence and in the study database. 
A separate randomisation number will be allocated to the subjects at randomisation and will 
be used for allocation of IMP. 
For subjects who subsequently do not enter the study, a reason will be documented in the 
source documentation and the subject’s medical notes.  
For subjects who are subsequently enrolled into the study, the Investigator will maintain an 
enrolment log, listing the identifiers for each subject alongside the subject number assigned 
and the date enrolled. A copy of the log will be filed in the hVIVO TMF at the study site. 
 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV : 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
 
 
 
 
CONFIDENTIAL 
Page 51 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
8 
PROCEDURES FOR MONITORING SUBJECT COMPLIANCE WITH 
TREATMENT AND RESTRICTIONS 
8.1 
Concomitant therapies 
All medications taken from the time the subject consents to participation in the study will be 
recorded. Concomitant medications taken during the quarantine stage will be stored, 
prescribed and administered in line with their label-specific requirements and full 
accountability will be maintained. Any medications taken and changes in medications during 
the study up to final study contact Day 28 (±3 days) will be recorded in the source data. 
• 
All medications must be stopped prior to the planned date of dosing with IMP/viral 
challenge (whichever occurs first) unless in the opinion of the Investigator and/or 
Sponsor’s Medical Monitor, the medication will not interfere with the study procedures 
or compromise subject safety. Specifically, the following are excluded: 
 
• 
Herbal supplements within 7 days prior to the planned date of Viral Challenge. 
 
• 
Chronically used medications, vitamins or dietary supplements, including any 
medication known to be an inducer or inhibitor of CYP450 enzymes, within 21 days 
prior to the planned date of viral challenge. 
 
• 
Over-the-counter (OTC) medications (e.g., paracetamol or ibuprofen) where the dose 
taken over the preceding 7 days prior to the planned date of viral challenge has 
exceeded the maximum permissible 24-hour dose (e.g., ≥4 g paracetamol over the 
preceding week). 
 
During the quarantine, the Investigator may permit a limited amount of paracetamol (no more 
than 4 g per day i.e. maximum daily dose) or topical medication, as clinically required for the 
treatment of headache or any other pain. Other medication to treat AEs may be prescribed if 
required.  
Use of all concomitant medications will be recorded in the subject’s source notes, including all 
details/parameters that are required by the clinical database. This will include all prescription 
drugs, herbal preparations, and OTC medications.  
Any concomitant medication required for the subject’s welfare may be given by the 
Investigator. However, it is the responsibility of the Investigator to ensure that details regarding 
the medication and the reason for its use are recorded appropriately in the source notes to 
permit their transfer to the clinical database. 
 
 
 
 
 






Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
 
Page 54 of 144 
CONFIDENTIAL  
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
9 
STUDY DESIGN 
9.1 
Summary 
This is a randomised, Phase 2a, double-blind, placebo-controlled study in healthy subjects 
challenged with RSV-A Memphis 37b.  
The study is divided into 2 parts: 
• 
In Part 1:  
• 
5 consecutive days of dosing in three treatment groups, dosing BD to maintain the blind. 
Active doses administered OD (every 24 hours (±1 hour) interval) or as a single loading 
dose followed by BD (every 12 hours (±1 hour) interval) for a total 10 doses respectively 
of either: 
o Group 1: Placebo (n=38); subjects in this group will receive placebo dose BD 
(every 12 hours (±1 hour) interval) for a total of 10 doses. 
o Group 2: EDP-938 oral 
 loading dose group (n=38): subjects in this 
group will receive 500mg first dose, and at 12 hours (±1 hour) interval receive 
300mg second dose, then 300mg doses BD for a total of 10 doses. 
o Group 3: EDP-938 oral 
 600mg dose group (n=38): subjects in this 
group will receive a daily 600mg dose followed by a placebo dose at 12 hours 
(±1 hour) interval for a total of 10 doses.  
 
• 
IMP dosing to start on confirmation of positive result by qualitative integrated cycler 
polymerase chain reaction (qicPCR) on nasal wash. Nasal wash for qicPCR will be 
performed BD on Study Days 2-5 (Study Day 5 morning only), or until a positive result 
is achieved, whichever is sooner.  
 
• 
Earliest start of IMP dose will be in the evening on Study Day 2 post viral challenge (IMP 
will be initiated 12 ± 1-hour post nasal wash confirmation of a positive qicPCR result). 
 
OR 
 
• 
Dosing will start in the evening of Study Day 5 if no positive result is obtained by qicPCR.  
• 
In Part 2:  
• 
Up to a maximum of 84 subjects in total for Part 2 will be enrolled following an 
analysis of Part 1. Up to 63 subjects will complete dosing with EDP-938 and up to 
21 subjects will complete dosing with placebo.  
• 
The dose(s) of EDP-938 selected will be projected to deliver an efficacious 
exposure and will be based on emerging PK, PK/PD modelling, virology, clinical 
symptom score and safety data. 
 
 
 
• 
In Part 2, 63 subjects will be randomised equally into 1 of 3 treatment groups as 
below. Additional treatment groups may be evaluated, however, the maximum 
number of subjects enrolled in Part 2 will be 84. 
o Group 1 (n=21): Placebo dosed BD for 5 days, with dosing at 12 hours (± 1 
hour) interval   
o Group 2 (n=21): A single Loading Dose of 400mg (Dose 1), followed by 
200mg second dose at 12 hours (± 1-hour interval), then 200mg doses  BD, 
and with dosing for 5 days, 




Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
 
Page 56 of 144 
CONFIDENTIAL  
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
Follow-up phase 
 
Part 1:  
 
Follow-up Visit 
 
• 
 Study Day 28 [± 3 days] and study termination 
 
 
Part 2: 
 
Follow-up Visit 
• 
Study Day 13, where applicable (only subjects 
who started IMP dosing on the evening of Study 
Day 5 (up to Day 8 evening) will return for a PK 
sample on Study Day 13) 
• 
Study Day 14, where applicable (only subjects 
who started IMP dosing on the evening of Study 
Day 5 (up to Day 8 evening) will return for a PK 
sample on Study Day 14) 
• 
Study Day 15, where applicable (only subjects 
who started IMP dosing on the evening of Study 
Day 5 (up to Day 8 evening) will return for a PK 
sample on Study Day 15) 
• 
Study Day 28 [± 3 days] and study termination 
The overall study design is depicted in Figure 9-1. 
 
 
Part 2 Progression and Additional Evaluation Guidelines 
Part 2 will commence no earlier than after an evaluation by the Sponsor and Investigator of 
the virology, clinical symptom score, PK, and safety data from Part 1.   
 
Prior to Part 2, the Sponsor will review the emerging data to confirm dose(s) (up to 600mg 
dose) and dose frequencies (OD or BD) to be evaluated in Part 2. Higher doses may be 
evaluated in the event that there is the potential for additional antiviral responses; 
 
 
 and an acceptable safety profile is observed. Lower doses may be evaluated 
in the event that a degree of viral suppression is observed. A longer duration of dosing (up to 
7 days maximum) may be evaluated if there is evidence of incomplete viral suppression or 
viral rebound after completion of therapy, and an acceptable safety profile is observed. See 
section 18.5.1 for stopping criteria.    
 
 
 
 
The maximum duration of treatment in parts 1 & 2 will not exceed 5 days and 7 days 
respectively. 




Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 58 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
The timing of study procedures relative to each phase is shown in Section 9. The procedures and 
assessments which will be undertaken to evaluate safety and efficacy are described in Section 
13: Assessments and Procedures. 
Subjects will: 
• 
Attend Screening Visit from -56 to Day -3 prior to challenge  
• 
Be admitted to the Quarantine Unit on Day -2/-1 
• 
Be inoculated with Challenge Virus on Day 0 
• 
Be discharged from the Quarantine Unit on Day 12 (if necessary, subjects may reside in 
quarantine for a further night or longer before discharge) 
• 
Return to the clinic on Study Day 13, 14, 15, 16, 17 and 18, as applicable (subjects who 
start IMP dosing in the evening of study Day 5 (up to Day 8 evening) will return for a PK 
sample. 
• 
Return to the clinic for a Follow-up Visit(s) on Day 28 (± 3 days) (all subjects). 
The duration of a subject’s participation from Screening Visit to the scheduled Follow-up Visit(s) 
on Day 28 (± 3 days) will be approximately 3 months.  
The total duration of the clinical phase of the study, from the start of subject screening to the last 
subject’s last visit (LSLV) is expected to be approximately 18 months.  
9.2 
Screening Visit 
Subjects who are sero-suitable for the challenge virus (screened through the hVIVO generic 
screening process) will be invited to attend a Screening Visit within 56 days to 3 days prior to viral 
challenge.  
 
Historical generic screening data collected through the hVIVO generic screening process within 
56 days to 3 days prior to inoculation (90 days for viral serology) may be transferred to the study 
after the study specific consent form has been signed by the trial participant. Historical pre-
screening data obtained prior to this window can be re-assessed any time within 56 days to 3 
days prior to viral challenge.  
 
 
Informed consent procedure 
The Investigator will obtain a signed ICF from each subject before any study specific procedures 
are performed.  
When historical screening data collected through the hVIVO generic screening process is used 
for screening, the study specific ICF will be obtained at quarantine admission (Day -2/-1) from 
each subject before any study specific procedures are performed.  
Potential subjects will typically be sent a copy of the ICF when their Screening Visit/Quarantine 
admission visit (as applicable) is arranged and at least 24 hours prior to the visit, and will be 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 59 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
encouraged to read it prior to their appointment. Upon arrival at the Screening Visit/Quarantine 
admission visit (as applicable), the ICF is discussed by the Investigator, and they will be given the 
opportunity to ask any questions, and may take the information sheet away to consider their 
participation. 
All subjects will be required to have a good understanding of English and the Investigator will be 
responsible for ensuring that the subject understands the information contained in the ICF. Once 
the Investigator has confirmed that the subject has understood the study, including the benefits 
and risks of participation, the subject and the Investigator can sign and date the ICF.  
The ICF must be signed and dated by the subject and countersigned by the Investigator (whoever 
conducted the consent discussion). A copy of the ICF will be given to the subject, and the original 
will be held in the hVIVO TMF. 
Subjects will be assured that they can withdraw from the study at any time and for any reason 
without prejudice to their future medical care, and that they will be informed in a timely manner if 
new information becomes available that may affect their willingness to continue their participation 
in the study. This information will be included within in the ICF.  
If the ICF is amended during the study, the PI/Investigator will follow all applicable regulatory 
requirements pertaining to approval of the amendment by the research ethics committee (REC). 
The site(s) must use the amended ICF for all new subjects and if required, the consent process 
will be repeated with the amended ICF for on-going subjects. 
 
Screening Procedure 
Screening assessments will be performed as detailed in Table 9-1 and may be repeated as 
necessary on admission to the hVIVO Quarantine Unit.  
Results of tests or examinations performed under other ethically approved hVIVO protocols within 
56 days to 3 days prior to viral challenge (90 days for viral serology) may be used to determine 
eligibility. Historical pre-screening data obtained prior to this window can be re-assessed any time 
within 56 days to 3 days prior to viral challenge. Serosuitability to the Challenge Virus may be 
reconfirmed at the PI/Investigator’s discretion any time between the Screening Visit and the day 
of Viral Challenge. The subject will be excluded from the study if the results demonstrate that the 
subject is no longer serosuitable to the Challenge Virus. The specific virus neutralisation antibody 
titre used to determine subjects’ serosuitability and the associated assay will be detailed in the 
Analytical Plan (AP).  
9.3 
 Quarantine Phase 
Subjects will be monitored closely throughout their stay in the Quarantine Unit; standard 
procedures will be performed as detailed in Table 9-1.  


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 60 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 
Admission 
On Day -2 or Day -1, 2 or 1 days prior to the day of challenge, the subject will attend the 
Quarantine Unit; eligibility will be reviewed and a nasopharyngeal swab will be taken for 
respiratory pathogen screen (Section 13.14.1.1). Various study assessments and tests as 
detailed in Table 9-1 will be performed during this admission visit.  
When historical screening data collected through the hVIVO generic screening process is used 
for screening, the study specific ICF will be obtained at quarantine admission (Day -2/-1) from 
each subject before any study specific procedures are performed.  
If a subject is found to be ineligible based on review of the eligibility criteria, the subject will not 
proceed in that quarantine group. The Investigator/Study Physician will decide whether the 
subject should be permanently excluded from the study  or invited back  for repeat of assessments 
(i.e. repeat clinical laboratory test, if the initial screening assessments are still within the -56 to -3 
window) or rescreening for a later quarantine, as appropriate . 
Eligible subjects may be invited to attend quarantine as reserves for each group. If a subject no 
longer complies with the study eligibility criteria, the subject will be discharged and may be 
replaced with a reserve subject. 
Subjects may be admitted to the Quarantine Unit on Day -1 at the Investigator’s discretion. 
Any assessments planned for Day -2 may be performed or repeated on Day -1.  
During the Quarantine and Challenge phase, assessments and procedures will be performed as 
detailed in Table 9-1: Time and events schedule. 
Viral Challenge is described in Section 11. EDP-938 dosing is described in Section 12.5. 
 
Viral Challenge 
If the subject remains eligible for the study, he/she will be inoculated with challenge virus on Day 
0. 
 
Discharge 
On Day 12, subjects will be discharged from the Quarantine Unit if the nasopharyngeal swab 
sample, confirmed by rapid viral antigen test (RVAT), is negative for Challenge Virus. If a subject 
is still positive for RSV (using RVAT) on Day 12, he/she may be asked to remain in quarantine. A 
further test will be carried out on Day 12 evening, if negative the subject can be discharged. If the 
test is still positive on Day 12 or 13 and following review by the Investigator, the subject may be 
asked to remain in quarantine for further observation. If symptoms are present, but no virus is 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 61 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
detected (negative RVAT), discharge will be at the investigator’s discretion. If appropriate, 
subjects may reside in quarantine for extra days if required. 
Subjects may be discharged based on the subject’s clinical condition and the PI/Investigator’s 
assessment. If subjects are required to remain in quarantine longer than the scheduled day/time, 
all assessments will be at the discretion of the PI/Investigator. AEs and concomitant medications 
will be monitored.  
Various study assessments and tests will be performed during this discharge day as detailed in 
Table 9-1. 
 
9.4 
Follow-up phase 
The follow-up phase will commence once a subject has been discharged from the Quarantine 
Unit.  
 
Further Follow-up Visits before Day 28 may be scheduled at the discretion of the PI/Investigator, 
if the subject has been symptomatic or require additional follow-up since discharge from the 
Quarantine Unit.  
 
 
 Study Day 13 to Day 18 
Subjects who started IMP dosing on the evening of Study Day 5 (up to Day 8 evening) post Viral 
Challenge for up to 7 days dosing regimen in Part 2 will return for PK sampling on Study Day 13, 
14, and 15, 16, 17 and 18 (as applicable) in order to obtain the PK sample(s) associated with the 
final dose of IMP, for the pre-dose, 0.5-hour,1-hour, 2-hour, 3-hour, 4-hour, 5-hour, 6-hour, 8-
hour, 10-hour, 12-hour, 15-hour, 24-hour, 30-hour, 36-hour, 48-hour, 60-hour, and 72-hour post 
final dose time points as applicable. 
Other assessments performed at this Follow-up Visit (s) could include ECG, AE and ConMed 
review (in addition to the PK blood draw). 
 
Day 28 (±3 days) Follow-up Visit  
Subjects will return to the hVIVO clinic for 1 scheduled Follow-up Visit; at 28 days post-Viral 
Challenge (±3 days). Assessments will be performed as detailed in Table 9-1: Time and events 
schedule. For subjects lost to follow up, refer to Section 9.6. 
 
Any AEs that are unresolved at the final Follow-up Visit may necessitate further unscheduled 
visits until the AE has resolved or the subject is deemed fit by the Investigator. Subjects may be 
discharged for GP follow-up if appropriate. 
 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 62 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
9.5 
Duration of Subject Participation 
The maximum duration of a subject’s participation from screening to the last scheduled Follow-
up Visit is expected to be approximately 3 months.  
9.6 
Lost to follow-up 
In the event that a subject does not return or cannot be contacted for the final Follow-up Visit at 
Day 28 (±3 days) post-Viral Challenge, the Investigator will make every reasonable effort to 
contact the subject to review all AEs. In the event that a subject drops out of the study at any time, 
the reason for discontinuation, if known, must be fully documented in the source data. The site 
personnel will document the AEs and any other assessments and will make every effort to 
complete all required end of study assessments. 
9.7 
End of trial  
The end of the trial is defined as the last subject’s last scheduled visit (LSLV) at Day 28 (±3 days). 
If a safety visit is required after the last scheduled visit, this will be at the PI/Investigator’s 
discretion as a duty of care, e.g., repeat spirometry or laboratory tests. These discretionary 
Follow-up Visits will not be considered part of the trial data unless they represent follow-up and 
closure on an AE or SAE identified during the trial period.  
AEs that are unresolved at the Day 28 (±3 days) post-challenge Follow-up Visit may necessitate 
further Follow-up Visits if required. 
9.8 
Clinical Trial Summary Report 
It is the Sponsor’s (or Sponsor delegate) responsibility to send the Clinical Trial Summary Report 
to the REC and Medicines and Healthcare Regulatory Agency (MHRA) (if required) within 1 year 
of the end of the trial. In addition, the Sponsor or Sponsor delegate is responsible for entering 
appropriate data into the EudraCT results database within 1 year of the end of the trial. 










Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 67 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 
X 
Once 
BD 
Twice Daily, 12 hours between assessments (± 1 hour). 
TDS 
Three Times Daily, at the same time each day (± 1 hour). 
T 
To determine tolerance of the procedure only (sample will not be tested). 
+ 
Only the applicable Inclusion/Exclusion criteria will be reviewed at each time point. 
a 
Subjects will be assigned a randomisation number once the decision to dose is confirmed (i.e. RSV RNA positive confirmed by 
qicPCR). 
b 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
c 
Height will be taken at Screening only.  


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 68 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
d 
Distribution of paper issues and bags will start on Day -1, with the first collection on Day 0. Thereafter distribution 
and collection of tissues will occur at 08:00 (± 1 hour). Tissues will be handed out daily and collection will occur until discharge 
from quarantine. 
e 
Spirometry will be performed at the same time each day during quarantine (± 1 hour). 
f 
A serum follicle stimulating hormone (FSH) test will be performed in all post-menopausal women 
g 
Blood serum pregnancy test (ß-HCG) will be performed in all female subjects 
h 
Blood will be drawn under non-fasted conditions.  
Repeat bloods may be drawn under fasted conditions if a lipid profile (cholesterol and triglyceride) or glucose is required (at PI 
discretion).  
i 
Virus serology (RSV neutralisation antibody assay) will be performed within 90 days of inoculation to determine eligibility, on 
entry to Quarantine, and at Day 28 Follow-up Visit 
j 
Nasopharyngeal swab for respiratory virus screen to assess for the presence of other respiratory viruses. 
k 
Nasal wash virology/ Pharmacokinetics samples will be collected at the same time each day during quarantine (± 1 hour) and 
used for RT-qPCR, and may be used for other secondary or exploratory assessments 
 
  
Samples collected between Days 2 and 5 (Study Day 5 Morning) will also be used for qicPCR until a positive result is received 
(to support dosing decisions). 
l 
Plasma Pharmacokinetics: plasma samples for IMP assay will be collected as outlined in Appendix 7 (PK Blood Sampling 
Schedule): 
 
The allowable time windows for the sampling are as follows: 
 
▪ 
± 5 minutes from the scheduled time for time points ≤ 1 hour from dosing; 
 
▪ 
± 15 minutes from the scheduled time for time points > 1 hour from dosing, with NOTE below: 
o 
24 hours timepoint: +/- 1 hour window 
o 
30 hours timepoint: +/- 1 hour window 
o 
36 hours timepoint: +/- 1 hour window 
o 
48 hours timepoint: +/- 2 hours window 
o 
60 hours timepoint: +/- 2 hours window 
o 
72 hours timepoint: +/- 2 hours window 
 
▪ 
There is no time window requirement for the pre-dose sample. The pre-dose sample must be taken prior to dose. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 69 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 
For Part 1 subjects who start dosing on the afternoon of Day 5 post viral challenge (PM starters), the 72-hour timepoint after 
Dose 10 would occur on Day 13. Thus, for a subset of subjects, this timepoint could be after discharge. The guidance for the 72-
hour PK sample collection is as follow:  
 
▪ 
For PM starters who start dosing on Day 5 post viral challenge and meet discharge criteria on Day 12, the 72-hour 
timepoint sample can be omitted. 
▪ 
For PM starters who start dosing on Day 5 post viral challenge and do not meet discharge criteria on Day 12 and are 
therefore still in the quarantine unit for the 72-hour PK timepoint, this sample should be collected. 
▪ 
The same guidance for 72-hour PK sample collection will apply to Part 2 when the PK Blood sampling for 5 days TWICE 
a day dosing for Part 1 will be used for Part 2. 
m 
Can be performed on Study Day -2 or Study Day -1. 
n 
Historical pre-screening data collected through the hVIVO generic screening process within 56 days (90 days for viral serology) 
to 3 days prior to quarantine admission may be used for screening procedures and to determine eligibility without the need to 
repeat the assessment. Historical pre-screening data obtained prior to this window can be re-assessed any time from 56 days to 
3 days prior to viral inoculation. 
o 
 
 
 
 
 
p 
When historical pre-screening data collected through the hVIVO generic screening process within 56 days to 3 days prior to 
inoculation (90 days for viral serology) is used for screening procedures, the study specific ICF will be obtained at quarantine 
admission (Day -2/-1) from each subject before any study specific procedures are performed. 
q 
Only Subjects who started IMP dosing on the evening of Study Day 5 (up to Day 8 evening) post Viral Challenge for up to 7 days 
dosing regimen (Part 2) will return for PK sampling on Study Day 13, 14,  15, 16, 17 and 18 (as applicable) in order to obtain the 
PK sample(s) associated with the final dose of IMP, for the pre-dose, 0.5-hour, 1-hour, 2-hour, 3-hour, 4-hour, 5-hour, 6-hour, 8-
hour, 10-hour, 12-hour, 15-hour, 24-hour, 30-hour, 36-hour, 48-hour, 60-hour, and 72-hour post final dose time points as 
applicable. 
r 
ECGs will also be recorded:  
 
▪ 
First IMP dose (Dose 1): pre-dose, 4 and 8 hours after the initial dose  
▪ 
Dose 2 to Dose 6: pre-dose  


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 70 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
▪ 
Last IMP dose: 24 and 48 hours post last dose  
 
All pre-dose ECGs can be obtained up to 2 hours prior to dosing.  Post dose ECGs will be obtained ± 30 minutes of the target 
time.  
Notes: 
Parenthesis indicates the assessment may be optional, or at the PI/Investigator's discretion, or as required relative to the start of 
IMP dosing. 
For all subjects TDS assessments will commence on Day 0, the first assessment will be pre-virus challenge. 
The PI/Investigator may perform additional safety assessments as required. 
Where any nasal sampling time points occur together, the order of sampling will typically be (1) Nasopharyngeal swab followed 
by (2) Nasal wash. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 71 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
10 
RANDOMISATION AND BLINDING 
10.1 
Randomisation 
The randomisation schedule will be generated at the beginning of the study on the assumption 
that subjects will be randomised as below: 
 
▪ 
In the first part of the study, subjects will be randomised to receive one of two doses 
of EDP-938 or placebo according to 1:1:1.  
 
▪ 
Following an analysis and emerging data from Part 1, Part 2 of the study will 
commence in which up to 84 subjects will be assigned to 1 of up to 3 treatment groups 
of up to 28 subjects each randomised in a 1:1:1 ratio. Up to a maximum of 84 subjects 
in total will be enrolled in Part 2.  
 
Subjects will be assigned a randomisation number prior to administration of the IMP.  
 
In Part 1 and Part 2 of the study, dosing will be triggered once the decision to dose is 
established based on confirmation of RSV infection by qicPCR between Study Day 2 and 
Study Day 5 (Day 5 morning only). If infection is not confirmed by positive qicPCR by Study 
Day 5 morning, subjects will be randomised on Study Day 5 and will commence IMP dosing 
in the evening of Study Day 5..    
 
Randomisation numbers will be assigned sequentially in ascending order; and once assigned, 
that randomisation number shall not be reassigned. The study site will keep a log of the 
randomisation number assigned to each subject. 
The Randomisation schedule and assigned randomisation number in Part 1 of the study will 
determine whether a subject is randomised into one of three treatment groups to receive  EDP-
938 at 600mg OD or 500mg LD followed by 300 mg BD or placebo. The Randomisation 
schedule and assigned randomisation number in Part 2 of the study will determine whether a 
subject receives either EDP-938 at 400mg LD followed by 200mg BD or 600mg LD followed 
by 300mg OD, or placebo.  
For the purposes of statistical analysis, placebo subjects from Part 1 will be analysed as a 
single placebo treatment group, as will placebo subjects from Part 2 based on the assumptions 
that the placebo substance is expected to be completely inert and have no antiviral properties 
and subsequently no effect on the efficacy endpoints and their analyses. 
 
A designated unblinded statistician, separate from the conduct or analysis of the study, will be 
responsible for the computer-generated randomisation schedule. Sealed copies of the 
randomisation code will be stored in a secure location.  
Randomisation numbers will follow a 5-digit format e.g., Part 1 will start with 10001, 10002, 
etc, and Part 2 will start with 20001, 20002, etc. A copy of the randomisation code list will be 
sent to the unblinded pharmacist/ designee preparing the IMP, so that EDP-938/placebo can 
be prepared for each subject as appropriate. 
Following database lock, on receipt of authorisation from the Sponsor, a copy of the 
randomisation code list will be provided to the Study Statistician to conduct study unblinding 
prior to analysis. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 72 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 
Replacements 
Subjects that have been inoculated but not dosed will be replaced. Subjects who are 
withdrawn before they have received all doses of IMP (i.e. subject has received at least one 
IMP dose) will not be replaced (refer to Section 7.5.3).   
If any of the quarantine groups has less than the planned number of subjects, additional 
subjects may be recruited into later quarantines, or additional quarantines may be conducted 
in order to maintain the power of the study. 
10.2 
Blinding 
The PI/Investigator will be provided with a tamper evident sealed envelope containing details 
of the treatment for each subject. All opened and unopened envelopes will be collected or 
destroyed after the end of the study, as agreed with the Sponsor. 
Due to the differing treatment regimens being tested, all subjects will be treated BD in order 
to maintain the blind between treatment groups. Subjects in the active OD dosing group will 
have their regimen supplemented by the administration of a placebo matched to EDP-938 in 
order to mimic the BD dosing group, and subjects randomised to the placebo arm will receive 
placebo matched to EDP-938 twice a day. 
 
Each subject is accommodated in their own individual room within the quarantine without direct 
contact with any other subject. In this way subjects assigned to different treatment groups will 
have no awareness of differences in their treatment or treatment administered. 
With the exception of the IMP manufacturer’s unblinded  pharmacist/designee, the statistician 
preparing the randomisation code list, the unblinded Clinical Research Associate (CRA) and 
the Quality Assurance (QA) auditors where necessary, the Investigator and all other clinical 
and non-clinical staff, (including the Study Statistician, data management staff), and the 
subjects will remain blinded to the treatment allocation until after the database has been locked 
and approval for study unblinding has been given. The confidentiality of the randomisation 
code lists and study blinding will be maintained. 
10.3 
Unblinding 
An independent Statistician at 
 Biometrics 
 will prepare the randomisation 
schedule, and the IMP Manufacturer’s pharmacist/designee at Hammersmith Medicines 
Research (HMR) will prepare the subject level IMP doses in line with the randomisation 
schedule.  
Individual emergency code break envelopes will be provided to hVIVO should it be necessary 
to break the blind for a subject. The Investigator will ensure there is an appropriate procedure 
in place to allow access to the code break envelopes in case of an emergency arising during 
the quarantine period, as per hVIVO's standard operating procedures (SOPs). An emergency 
means that the relevant medical decision on the further care of a subject is dependent on the 
actual identity of the study treatment that the subject has received. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV  
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 73 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
The emergency code break envelopes will contain information stating either ‘This subject was 
on active drug (and dosage)’ or ‘This subject was on placebo’. Any premature code-breaking 
will be explained and justified by the Investigator and hVIVO, and the Sponsor must be 
promptly informed. If possible, the Sponsor should be consulted before the code is broken, 
but this will only occur if the safety of the subject will not be compromised.  
When the code break envelope is opened, the Investigator must note the date, time, reason 
for unblinding and the details of the investigator and or designated site staff that broke the 
blind and record this information according to hVIVO SOPs. The Investigator must also 
immediately notify the Sponsor’s Medical Monitor (SMM) that the code has been broken. 
Even if the code is broken, blood samples for safety, efficacy, PK and other parameters 
assessments will continue to be drawn for the remainder of the planned study period following 
the last dose if doing so will not compromise subject welfare. 
The IMP must be discontinued after unblinding, but the subject will be followed up until 
resolution of any AEs. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 74 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
11 
CHALLENGE VIRUS  
The Challenge Virus is RSV-A Memphis 37b. The Challenge Virus inoculum titre (~4 Log10 
PFU) used will be one that has supporting evidence of safety. 
11.1 
Production 
The Challenge Virus strain RSV-A Memphis 37b was isolated from an infant who developed 
respiratory symptoms without fever. A nasal aspirate taken from the infant tested positive for 
RSV by antigen detection assays. The RSV was isolated from the infant’s nasal aspirate and 
plaque purified to obtain a “single” virus entity. The selected plaque, B, was used in the 
manufacture of the Challenge Virus stock at Meridian Life Science®, Inc. USA, according to 
GMP. The Challenge Virus has undergone quality testing performed during manufacture 
(identity, appearance, sterility, infectivity, and contaminants) according to pre-determined 
specifications. The Challenge Virus is stored in a secure -80 °C freezer (normal temperature 
range -60 °C to -90 °C). 
This virus has been used in previous hVIVO Virus Challenge studies and is expected to (as it 
has in the past) produce cold-like symptoms, such as cough, nasal congestion or low-grade 
fever 6,46  
11.2 
Supply and accountability 
hVIVO is obliged to establish a system for control of Challenge Virus in accordance with hVIVO 
SOPs and as detailed in the AP or a separate Note to File (NTF). 
The Investigator will maintain accurate records of receipt and condition of all Challenge Virus 
inoculum stock used for challenge in accordance with hVIVO SOPs, including details and 
dates of the quantities dispensed and used in the study. Any departures from the protocol-
dispensing regimen will be fully documented. 
Accountability records must be maintained as per the hVIVO SOPs. All Challenge Virus 
storage and accountability records will be available for verification by auditors. 
11.3 
Preparation and administration 
Challenge Virus inoculum will be prepared according to the hVIVO AP and administered in 
accordance with hVIVO's SOPs. Each subject will be allocated a unique vial containing the 
Challenge Virus and will receive the inoculum intranasally.  
The time from the Challenge Virus inoculum thawing to inoculation should be no longer than 
2 hours. All administrations will be made by a member of the clinical team and witnessed by 
a second member of the team. The exact time of inoculation will be recorded in the 
administration log and the subject’s source notes. Accurate records will be kept of when and 
how much study inoculum is prepared and used. The oversight process will be signed off prior 
to administration of the Viral Challenge. Any non-compliance or problems with the inoculation 
will be recorded in the subject’s source notes and reported to the PI/Investigator. 
Following inoculation, subjects will be closely observed specifically for potential allergic 
reactions within 30 minutes, and for the following 24 hours. Post inoculation subjects will lie 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV  
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 75 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
flat for 10 minutes then sit up with nose pegs on for 20 minutes. Subjects will continue to be 
monitored throughout the clinical phase of the study. 
11.4 
Disposal  
Disposal of used and unused Challenge Virus inoculum vials will be in accordance with 
hVIVO’s SOPs. 
 
 
 






Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV  
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 78 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
12.2 
Dispensing and accountability 
hVIVO will receive individual doses of subject-specific IMP (oral 
 following 
Qualified Person (QP) certification by HMR QP. All IMP supplies will be used only for this 
protocol and for no other purpose.  
Once received at hVIVO, hVIVO will perform stock level accountability and the IMP will be 
stored as per section 12.4. IMP accountability will be controlled by hVIVO and monitored by 
the Study Monitor throughout the study and at study close-out.  
IMP will be dispensed as per hVIVO standard processes and the requirements detailed in the 
Pharmacy manual. 
The Sponsor will provide the IMP and retain responsibility for maintenance of the associated 
essential documents in the Sponsor’s TMF.  
The Investigator will ensure that all supplies are received by a responsible person, all 
deliveries and returns are documented and signed for, and the condition of the IMP is 
monitored. Accurate records will be kept of when and how much IMP is dispensed and used 
in the study. Any reasons for departure from the protocol dispensing regimen will also be 
recorded. 
Accountability records will be available for verification by the Study Monitor at each monitoring 
visit. At the completion of the study, there will be a final reconciliation of all IMP. 
12.3 
Packing and labelling 
The preparation of oral 
 and labelling of the IMP will be performed by the HMR 
Pharmacy in compliance with GMP regulations , in accordance with Annex 13 of EudraLex 
volume 4 and the current version of the ‘Rules and Guidance for Pharmaceutical 
Manufacturers and Distributors’50,52. Blinding of subject specific doses will be performed by the 
HMR Pharmacy. 
A release document signed by the HMR QP will be kept in the hVIVO TMF to document 
labelling and dispensing of the IMP to hVIVO. All documents required to perform GMP 
activities will be supplied as per the Technical Agreement between HMR and Sponsor.  
 
  
IMP will be labelled in accordance with the pre-prepared randomisation list. The statistician at 
 will prepare the randomisation schedule and HMR Pharmacy will prepare the subject 
level bottles in line with the randomisation schedule.  Package labelling will comply with the 
requirements of Annex 13 of EudraLex volume 4, and will include at least the following 
information: 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV  
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 79 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 
• 
Sponsor’s name 
• 
Pharmaceutical dosage form, route of administration, quantity of dosage units  
• 
Batch and/ or code number to identify the contents and packaging operation 
• 
Trial subject randomisation number 
• 
Directions for use 
• 
‘For clinical trial use only’ 
• 
Name of the Investigator  
• 
Trial reference code allowing identification of the trial site 
• 
Storage conditions 
• 
Period of use (use-by date, expiry date or re-test date as applicable), in month/year) 
• 
‘Keep out of reach of children’. 
Labelling and packing of study medication will be in accordance with current regulatory 
standards and sample label(s) will be submitted to the MHRA according to submission 
requirements.3, 51-53 
12.4 
Storage 
 
 
  
12.5 
Administration 
• 
In Part 1:  
 
• 
5 consecutive days of dosing in three treatment groups: 
o Group 1: Placebo (n=38); subjects in this group will receive placebo dose 
BD every 12 hours (±1 hour) interval for a total of 10 doses. 
o Group 2: EDP-938 oral 
 loading dose group (n=38): subjects in 
this group will receive 500mg first dose, and at 12 hours (±1 hour) interval 
receive 300mg second dose, then 300mg doses BD for a total of 10 doses. 
o Group 3: EDP-938 oral 
 600mg dose group (n=38): subjects in 
this group will receive a daily 600mg dose followed by a placebo dose at 12 
hours (±1 hour) interval for a total of 10 doses.   
 
• 
IMP dosing to start on confirmation of positive result by qualitative integrated cycler 
polymerase chain reaction (qicPCR) on nasal wash. Nasal wash for qicPCR will 
be performed BD on Study Days 2-5 (Study Day 5 morning only), or until a positive 
result is achieved, whichever is sooner.  
IMP dosing will be initiated 12 hours (± 1hour) post nasal wash confirmation of a 
positive qicPCR result.  
• 
In Part 2:  
• 
The planned treatment groups in Part 2 are as follows: 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 80 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
o Placebo dosed BD (every 12 hours (± 1 hour) interval), and with dosing for 
5 days,   
o A single Loading dose of 400mg  (Dose 1), followed by 200mg second dose 
at 12 hours (± 1-hour interval), then 200mg doses BD. and with dosing for 5 
days 
o A single Loading Dose of 600mg (Dose 1), followed by a 300mg dose OD 
(every 24 hours (±1 hour) interval), and with dosing for 5 days. 
 
• 
In order to maintain the study blind, subjects in the active OD dosing group will 
have their regimen supplemented by the administration of  placebo matched to 
EDP-938 in order to mimic the BD dosing group. 
 
 
 
 
 
 
All subjects will be dosed orally, in the seated position, and under the direct supervision of the 
Investigator (or delegate), and in accordance with the randomisation schedule.   
 
Fasting Schedule 
Blood will be drawn under non-fasted conditions. Repeat bloods may be drawn under fasted 
conditions if a lipid profile (cholesterol and triglyceride) or glucose is required (at PI 
discretion).  
 
12.6 
Compliance 
IMP will be administered by trained clinical site staff responsible for adequate and accurate 
IMP administration, accounting and management. Dosing will take place in the quarantine unit 
and will be monitored by hVIVO quarantine staff to ensure compliance.  
The exact times of IMP dosing will be recorded in the relevant dispensing/ administration logs 
and subject’s source notes. Any non-compliance or problems with the administration of the 
IMP will be recorded in the subject’s source notes and reported to the Sponsor if appropriate. 
12.7 
Overdose 
In the event of an IMP overdose the Sponsor is responsible for notifying the MHRA and REC 
of the potential serious breach (see Section 18.4.3) within 7 days of becoming aware of it. The 
SME/Sponsor will be contacted within 24 hours or before the next scheduled dose time (see 
the Pharmacy Manual for further procedural details). General supportive measures will be 
taken to manage any AEs associated with overdose and subjects will be clinically followed up 
until the AE has resolved (see section 15).  


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 81 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
12.8 
Disposal 
Unless specifically instructed by Sponsor, the Investigator will not destroy any partly used or 
unused IMP supply. 
On written authorisation from the Sponsor, the Investigator will send unused and partly used 
IMP supplies and any empty containers for destruction to the address provided at the time of 
authorisation.  
Alternatively, the destruction of unused and partly used drug supplies and any empty 
containers may be facilitated by the Investigator using a partner service, according to local 
procedures, and a destruction certificate will be provided. Destruction of any material must be 
witnessed and documented in writing.  
 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 82 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
13 
ASSESSMENTS AND PROCEDURES 
All procedures will be performed according to applicable hVIVO SOPs. 
The Investigator may perform additional safety procedures in order to evaluate or manage 
clinical illness and AEs. 
The following assessments and procedures will be performed as detailed in Table 9-1: Time 
and events schedule 
Results will be recorded in the source documents. 
Where applicable, unless otherwise stated:  
• 
Normal ranges described in Appendix 3, and local laboratory reference ranges will be 
filed in the hVIVO TMF.  
During the clinical conduct of the study, the Investigator will use Appendix 6 for clinical 
assessment of change from baseline. 
 
13.1 
Medical and medication history 
Personal medical and medication histories and family histories will be recorded, including, but 
not limited to, detailed histories on allergies (e.g. rhinitis, dermatitis, food, aspirin/non-steroidal 
anti-inflammatory drugs (NSAIDs) and asthma. 
Patient Health Questionnaire (PHQ-9) and Generalised Anxiety Disorder Questionnaire 
(GAD-7), may be administered at screening and/or admission at the Investigator’s discretion. 
 
13.2 
Demographics 
Demographic data will be recorded at the Screening Visit. 
13.3 
Height, weight, and body mass index 
Height and weight measurements will be recorded in compliance with hVIVO’s standard 
procedures. 
BMI will be calculated as: BMI (kg/m2) =  
Weight (kg) 
 
 
 
 
 
 
 
 
 
 
Height (m)2 
13.4 
Complete physical examination 
A complete physical examination will include but not limited to an evaluation of the following 
body systems: 
• 
General appearance 
• 
Skin 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 83 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
• 
Eyes 
• 
Ears 
• 
Nose 
• 
Throat 
• 
Heart 
• 
Lungs 
• 
Abdomen 
• 
Peripheral pulses 
• 
Lymph nodes 
• 
Neurological/ nervous system 
• 
Musculoskeletal 
• 
Head, neck, and thyroid. 
13.5 
Directed physical examination 
Directed physical examinations will be conducted as deemed appropriate by the Investigator 
and will include examination of the: 
• 
Ear 
• 
Nose 
• 
Throat 
• 
Chest (via stethoscope). 
Assessment and grading of any URT (nasal discharge, otitis, pharyngitis, sinus tenderness) 
and LRT symptoms (abnormal breath sounds externally [e.g. stridor] and on chest auscultation 
[wheezing or rhonchi, crepitations] will be performed. Physician-reported assessments of viral 
challenge related illness will be graded in accordance with their intensity and documented in 
the source data. 
Following viral challenge, URT and LRT symptoms (as described above) will be expected and 
presumed to represent virus infection consequent to viral challenge, and will not be additionally 
captured as AEs unless they meet the definition of an AE, and are deemed to be clinically 
significant (in the opinion of the Investigator) to be classed as AEs. 
Following viral challenge all unexpected (in the opinion of the Investigator) directed physical 
examination findings will be captured as AEs, along with all other occurrences that meet the 
criteria for an AE (see section 15). 
13.6 
Vital signs 
Study specific normal ranges are provided in Appendix 3. 
Vital signs assessments will be recorded as follows: 
• 
Heart rate (HR) will be recorded in beats per minute (bpm). 
• 
Respiratory rate (RR): respirations will be counted and recorded as breaths per minute. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 84 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
• 
BP: systolic BP and diastolic BP will be measured in millimetres of mercury (mmHg); 
measurements will be made supine. Where possible, the same arm will be used for all 
measurements. 
• 
Peripheral arterial oxygen saturation (SpO2%) will be assessed using pulse oximetry. 
In the event of a subject having an unexpected abnormal or out of normal range result, the 
assessment may be repeated after at least 2 minutes to exclude a technical fault and confirm 
the original reading. The assessment may then be repeated at the PI/Investigator’s discretion 
and in accordance with hVIVO’s SOPs. 
If a result is out of the normal range and meets the criteria for an AE, the severity of the AE 
will be guided by the CTCAE (referenced in Appendix 5). 
Deterioration in a vital sign (compared to baseline) should only be reported as an AE if the 
deterioration fulfils the criteria for an AE. If deterioration in a vital sign is associated with clinical 
signs and symptoms, the sign or symptom will be reported as an AE and the associated vital 
sign will be considered as additional information. 
13.7 
Tympanic Temperature 
The study specific normal range for tympanic temperature is detailed in Appendix 3. The 
severity of out of normal range values will be assigned using the CTCAE (Appendix 5) as a 
guide. 
Temperature is related to definitions of illness (Section 4.2) and to symptomatic and specific 
therapy criteria; therefore temperatures ≥ 37.9 ºC must be confirmed by a repeat measurement 
not less than 20 minutes and not more than 60 minutes after the first reading. 
The first temperature measurement will be used if it is confirmed by the second reading; both 
readings will be recorded in the source document. 
Temperature may be more frequently monitored in quarantine if appropriate. 
Following viral challenge, pyrexia will be expected and presumed to represent virus infection 
consequent to viral challenge, and will not be additionally captured as an AE unless it meets 
the definition of an AE, and is deemed to be clinically significant (in the opinion of the 
Investigator) to be classed as an AE. 
Following viral challenge all unexpected (in the opinion of the Investigator) pyrexia will be 
captured as an AE, along with all other occurrences that meet the criteria for an AE. 
Febrile illness (FI) is defined as (see section 4.2): 
Febrile Illness 
Any occurrence of temperature ≥ 37.9 oC (confirmed by a repeat 
measurement as ≥ 37.9 oC within 20 to 60 minutes),  
 
Or 
 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 85 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
Temperature change (post inoculation) of ≥ 2 standard deviations 
(SD) greater than a baseline measure (from all scheduled 
temperatures taken by any method on Days -2, -1, and Pre-
challenge on Day 0). 
 
13.8 
ECG 
Study specific normal ranges are provided in Appendix 3. 
Twelve-lead ECGs will be obtained to evaluate the electrical activity of the heart. ECGs will 
be read on site by an appropriately qualified Investigator. Wherever possible the same 
Investigator will review subsequent ECGs from the same subject for the assessment of any 
change from baseline. 
ECGs will be obtained at Screening, at Quarantine Admission (Day -2 or -1), Day 4, Day 7, 
Day 11 and at Follow-up Visit Day 28. ECGs will also be obtained pre first IMP dose, at 4 
hours post and 8 hours post first IMP dose, then pre-dose for all subsequent doses for the 
next 2 days (ie, up to Dose 6), at 24 hours and 48 hours post last IMP dose. ECGs may be 
repeated at the discretion of the PI/Investigator.  
All pre-dose ECGs can be obtained up to 2 hours prior to dosing. Post dose ECGs will be 
obtained ± 30 minutes of the target time.  
Any changes from screening during the study will be assessed for their clinical significance. 
Clinically significant changes will be reported as AEs (Section 15). The PI/Investigator will 
assess non-clinically significant changes to determine whether they should be recorded as 
described in Section 15.2. 
13.9 
Spirometry 
Spirometry will be performed according to hVIVO’s SOPs. Height at screening will be used as 
the baseline measurement for all spirometry assessments. 
Spirometry should meet the American Thoracic Society (ATS) / European Respiratory Society 
(ERS) guidelines criteria (as per ATS/ERS guidelines for standardisation of spirometry). For 
FEV1, the highest value from 3 technically satisfactory attempts will be considered. The chosen 
value should not exceed the next one by more than 150 mL or 5%. If the difference is larger, 
up to 8 measurements will be made if appropriate. 
Predicted values will be calculated according to the formula of the European Community for 
Coal and Steel (ECCS).   
Spirometry may be repeated at any time in the event of respiratory signs or symptoms 
(repeated coughing, bradypnea, tachypnoea, râles and rhonchi) or respiratory difficulties. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 86 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
13.10 
hVIVO Symptom Diary Cards 
Subjects will report and assess the severity of any challenge virus related signs and symptoms 
using the hVIVO Symptom Diary Card. This information will be collected using a paper source 
document.  
Following viral challenge all unexpected (in the opinion of the Investigator) post viral challenge 
symptoms will be captured as AEs, along with all other occurrences that meet the criteria for 
an AE. 
Previous studies with RSV-A Memphis 37b have used a 10-item symptom questionnaire. The 
10-item diary card total symptom score will be used for the secondary endpoint analysis
 
 
   
The following symptoms in the 10-item symptoms questionnaire will be graded on a scale of 
0-3, where Grade 0 is absence, Grade 1 is just noticeable, Grade 2 is bothersome but does 
not prevent participation in activities, and Grade 3 is bothersome and interferes with activities.  
• 
Runny nose 
• 
Stuffy nose 
• 
Sneezing 
• 
Sore throat 
• 
Earache 
• 
Malaise (Tiredness) 
• 
Cough 
• 
Shortness of breath 
• 
Headache 
• 
Muscle/ joint ache/ stiffness 
 
 
  
 
 
The Investigator will assess and review challenge virus related symptoms that are recorded 
on the Quarantine Subject Symptom Dairy Card following each scheduled completion.  
13.11 
Nasal discharge collection from paper tissues 
Each subject will be given pre-weighed packets of paper tissues. Subjects will be asked to 
place single tissues used for nose blowing or sneezing into a specified bag (for that subject 
only). 
A daily 24-hour collection will take place throughout the quarantine period. Distribution of 
paper tissues and bags will start on Day -1, with the first collection on Day 0. Thereafter 
distribution and collection of tissues will occur at 08:00h (± 1 hour). Tissues will be handed out 
daily and collection will occur until the discharge from quarantine. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 87 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
In the event of a subject staying in quarantine beyond the planned day of discharge, the 24-
hour distribution and collection of tissues and bags will continue until the subject is finally 
discharged from quarantine. 
24-hour paper tissue collections will be analysed to determine the following over the 
quarantine period: 
• 
24-hour nasal discharge weight (mucous). 
The number of paper tissue used for nasal discharge over 24-hour period will also be 
collected. 
13.12 
Routine blood analysis 
Section 14.2 describes the routine blood tests that will be performed including, but not limited 
to, haematology, biochemistry and cardiac enzymes. Additional safety assessments (e.g. 
coagulation) will be conducted at the discretion of the PI/Investigator, as required. 
13.13 
Challenge Virus serology 
A subject must be sero-suitable to take part in the study; i.e. he/she must have no or low pre-
existing serum levels of antibodies specific to the Challenge Virus strain. This antibody titre 
cut-off for serosuitability will be described in the AP / AP NTF. 
Serum levels of pre-existing RSV-A Memphis 37b specific antibodies to the Challenge Virus 
will be determined using a RSV neutralization antibody assay.  
13.14 
Nasal samples  
The following nasal sampling procedures will be performed during the study: 
• 
Nasopharyngeal swab 
• 
Nasal wash 
Where any nasal sampling timepoints occur together the order of sampling will typically be (1) 
Nasopharyngeal swab, followed by (2) Nasal wash 
 Nasopharyngeal swab 
Nasopharyngeal swab samples will be collected for the following assessments:  
• 
Respiratory Pathogen Screen 
• 
Rapid Viral Screen  
Tolerance of the procedure will be determined at the Screening Visit. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 88 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
13.14.1.1 
Respiratory Pathogen Screen 
On entry to quarantine, a nasopharyngeal swab will be collected and tested to detect the 
presence of a set of respiratory pathogens that could potentially contraindicate a subject’s 
participation in the study. Nasopharyngeal swabs will be tested using a direct fluorescent 
antibody assay (DFA). Any additional screening tests will be conducted at the discretion of the 
PI/Investigator. 
Tolerance of the procedure will be determined at the Screening Visit. 
13.14.1.2 
Rapid Viral Screen  
A rapid viral screen e.g. Rapid Viral Antigen Test (RVAT) will be used to determine the 
presence of RSV in a nasopharyngeal swab sample prior to discharge from the Quarantine 
Unit on Day 12. Additional screening tests may be conducted at the discretion of the 
PI/Investigator.  
 Nasal wash 
Nasal wash samples will be collected to evaluate: 
• 
Viral shedding (as described in section 14.4) 
o qicPCR 
o RT-qPCR 
o Cell based infectivity assay (e.g. plaque assay) 
o Replicative Strand PCR 
o Viral resistance monitoring 
 
• 
PK testing (as described in section 14.4) 
o Potential measurement of EDP-938 and metabolite levels 
Tolerance of the procedure will be determined at the Screening Visit. 
13.15 
Breath alcohol 
Breath alcohol samples will be obtained to determine compliance with the study alcohol 
restrictions. Alcohol and drugs of abuse testing will be conducted during the study and must 
be negative at all times. Additional samples may be taken at PI’s discretion if positive. Results 
will be recorded in the source documents.  
13.16 
Adverse events and concomitant medications 
The PI/Investigator is responsible for the detection and documentation of events meeting the 
criteria for AEs or SAEs (Section 15) from the time of completion of written informed consent 
until completion of the final Follow-up Visit. 
Throughout the study, from screening to the final Follow-up Visit, subjects will be asked to 
report any unusual, undesirable, or unwanted symptoms, worsening of existing conditions or 
changes in their health and wellbeing. Subjects will be asked to report any problems and a 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 89 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
delegated physician will periodically enquire about the occurrence of AEs and need for 
concomitant medications. 
During quarantine, subjects will be asked about AEs using open-ended questions, for 
example: 
• 
how are you feeling? 
• 
have you had any medical problems since your last visit/assessment? 
• 
have you taken any new medicines, other than those given to you in this study, since 
your last visit/assessment? 
AEs  will be assessed and recorded as described in Section 15.  
Concomitant medications (prescription and OTC drugs and supplements that a study subject 
has taken alongside the study intervention) will be recorded. 
 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 90 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
14 
LABORATORY ASSESSMENTS 
14.1 
Blood volume 
A maximum volume of 470 mL of blood may be taken from each subject from Screening Visit 
through to the final study contact. If additional samples are required in excess of this amount, 
e.g., to monitor abnormalities, these will be collected at the discretion of the Investigator. 
14.2 
Safety Blood Samples and Assessments 
During the study, safety samples will be collected as detailed below. The hVIVO designated 
laboratory will be responsible for analysing clinical blood safety samples at scheduled times 
during the study. Further details on the hVIVO designated laboratory processes for shipment, 
processing, results and reporting are documented in the Safety Blood “Scope of Work” 
document. Baseline assessments will be defined in the Statistical Analysis Pan (SAP). 
Laboratory results will be reviewed by a study physician. The Investigator may request the 
collection of additional samples if required for safety monitoring. 
Deterioration in a laboratory value (compared to baseline) should only be reported as an AE 
if the deterioration fulfils the criteria for an AE (see section 15). If deterioration in a laboratory 
result is associated with clinical signs and symptoms, the sign or symptom will be reported as 
an AE and the associated laboratory result will be considered as additional information. 
Baseline laboratory values that are out of range of normal values but within CTCAE Grade 1, 
with no accompanying relevant clinical signs and symptoms will not be deemed to be AEs. 
All clinically significant laboratory abnormalities deemed to be AEs or SAEs will be 
documented in the source documents. 
The severity of the laboratory abnormalities will be determined based on the grading scales in 
Appendix 5.  Grade 3 laboratory abnormalities must be reported to the PI, who will determine 
whether further reporting is required. 
Relationship to the challenge virus will be assessed. Challenge virus associated laboratory 
abnormalities may be recorded as AEs.  
The PI/Investigator will monitor all clinically significant abnormal laboratory results or 
assessments until they return to normal or baseline values (i.e. resolve), stabilise, or are no 
longer clinically significant. Where appropriate, (e.g., after a period of monitoring of an 
abnormal result), clinically significant abnormalities should be reassessed by the PI/ 
Investigator to determine whether an AE has changed.  
Clinically important abnormalities persisting at the end of the study will be monitored at the 
discretion of the Investigator until they are resolved or are clinically stable.  
As a minimum the following analytes will be measured, others may be included as required. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 91 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 
Biochemistry 
• 
Sodium 
• 
Potassium 
• 
Glucose (random) 
• 
Albumin 
• 
Chloride 
• 
Bicarbonate 
• 
Calcium 
• 
Uric acid 
• 
Total protein 
• 
Creatinine 
• 
Total, direct, and indirect bilirubin 
• 
Inorganic phosphate 
• 
Blood urea nitrogen 
• 
C-reactive protein (CRP) 
• 
Gamma glutamyl transferase 
• 
Alkaline phosphatase (ALP) 
• 
Alanine transaminase 
• 
Lactate dehydrogenase 
• 
Aspartate transaminase (AST) 
• 
Urea. 
 
Thyroid function test 
• 
Thyroid Stimulating Hormone (TSH) 
• 
Thyroxine 
 
 
Haematology 
• 
Platelet Count. 
• 
White blood cell (WBC) count (absolute) 
• 
WBC differential: 
• 
Neutrophils 
• 
Lymphocyte 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
• 
Red blood cell (RBC) count  
• 
Reticulocyte count (% and absolute)  
• 
Haemoglobin 
• 
Haematocrit 
• 
Mean corpuscular volume (MCV) 
• 
Mean corpuscular haemoglobin (MCH) 
• 
MCH concentration (MCHC). 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 92 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 
Cardiac enzymes 
• 
Creatine kinase (CK) 
• 
CK-MB 
• 
Troponin T 
 
Coagulation 
• 
Prothrombin time (PT) 
• 
Activated Partial Thromboplastin Time (APTT) 
 
Human Immunodeficiency Virus and Hepatitis A, B, and C  
Serum will be tested to detect the presence of the following: 
• 
HIV-1 and HIV-2 antibodies. 
• 
Hepatitis A antibodies (HepA IgM). 
• 
Hepatitis B surface antigen (HBsAg). 
• 
Hepatitis C antibodies (HCAb). 
 
Serum follicle stimulating hormone 
Serum samples will be tested for serum follicle stimulating hormone (FSH) in post-menopausal 
women only. 
 
Serum pregnancy test 
All female subjects will have a serum sample tested for β-human chorionic gonadotrophin (β-
hCG) on admission to quarantine. 
14.3 
Urine Samples and Assessments 
 
Urinalysis 
Clinical urine safety analysis will be undertaken using commercially available urine test strips 
that provide an instant result that will be documented in the source data. 
Urinalysis will be performed to evaluate the following parameters:  
• 
Colour 
• 
Specific gravity 
• 
Appearance 
• 
pH. 
and to detect the presence of:  
• 
Blood 
• 
Glucose 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 93 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
• 
Leukocytes 
• 
Ketones 
• 
Nitrite 
• 
Protein 
• 
Urobilinogen 
• 
Bilirubin. 
If the dipstick yields abnormal results, a urine sample may be sent for microscopy, culture and 
sensitivity (MCS), at the Investigator’s discretion. MCS will include but is not limited to RBC, 
WBC, epithelial cells, crystals, casts, and bacteria. 
Urine safety analysis values will be evaluated by the Investigator for clinical relevance. Those 
deemed to be clinically significant will be reported as AEs (Section 15.1.1 and 15.2). 
 
Drugs of abuse and cotinine 
Urinalysis will be performed for drugs of abuse and cotinine using commercially available kits 
that provide an instant result, which will be documented in the source data. 
Drugs of abuse screen will include (but is not limited to) amphetamines, barbiturates, cocaine, 
opiates, cannabinoids and benzodiazepines. 
 
Pregnancy  
Urine pregnancy tests will be performed at the times detailed in Table 9-1. 
The Investigator may request additional safety assessments and/or unscheduled pregnancy 
tests in order to evaluate or manage clinical illness. 
14.4 
Virology Assessments 
Samples will be collected as detailed in Table 9-1: Time and events schedule. Details of how 
the samples will be processed, stored and where relevant, how the analysis will be conducted 
will be documented in the AP. 
 
 
Serum RSV neutralising antibody 
A RSV neutralising antibody assay will be used to measure levels of pre-existing specific 
antibodies to the Challenge Virus strain in serum collected at Screening to determine subject 
serosuitability. The same assay will be used to measure antibody titres in serum samples 
collected on admission to quarantine and at Day 28 Follow-up Visit.  
 
 
Respiratory Pathogen Screen 
At the times outlined in Table 9-1: Time and events schedule, a respiratory pathogen screen 
will be performed on a nasopharyngeal swab sample to detect the presence of a number of 
respiratory viruses that could potentially contraindicate a subject’s participation in the study. 
Nasopharyngeal swabs will be tested using a direct fluorescent antibody assay (DFA).  


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 94 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 
 
Rapid Viral Screen 
A rapid viral screen e.g. Rapid Viral Antigen Test (RVAT) will be used to determine the 
presence of RSV in a nasopharyngeal swab sample prior to discharge from the Quarantine 
Unit.  Additional screening tests may be conducted at the discretion of the PI/Investigator.  
 
Viral load 
RSV viral load will be measured in nasal washes by RT-qPCR and Cell based infectivity assay 
(e.g. plaque assay).  
 
RT-qPCR and Cell based infectivity assay (e.g. plaque assay) will also be used to determine 
viral dynamics (e.g. duration, peak, time to peak). 
14.4.4.1 Quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR) 
A Quantitative Reverse transcription polymerase chain reaction (RT-qPCR) assay will be used 
to quantify RSV-A Memphis 37b in nasal wash samples.  
14.4.4.2 Cell Based Infectivity Assay 
A cell based infectivity assay (e.g. Plaque assay) will be used to quantify infectious RSV-A 
Memphis 37b in nasal wash samples.  
 
 
Viral shedding for dosing 
Viral shedding will be confirmed by positive qualitative qicPCR assay of nasal wash.  
 
14.4.5.1 Qualitative Integrated Cycler Polymerase Chain Reaction (qicPCR)  
A qualitative integrative cycler PCR (qicPCR) assay will be used to demonstrate virus 
shedding in nasal wash samples to indicate Challenge Virus infection. The qicPCR assay will 
be used to support dosing decisions.  
 
 
Replicative Strand PCR 
A replicative strand PCR may be used to evaluate viral replication in cells isolated from nasal 
wash samples.  
 
 
Viral resistance 
Nasal wash samples may be analysed for potential viral resistance monitoring assessment.  
Resistance monitoring assessment if performed, will be conducted by population and /or deep 
sequencing of the RSV gene to monitor for treatment emergent resistance mutations.  


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 95 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
14.5 
PK Assessments 
 
Blood Plasma Samples 
Blood (plasma) samples for the evaluation of PK parameters of EDP-938 will be collected as 
outlined in Appendix 7 (PK Blood Sampling Schedule). 
Blood samples will be transported, processed and stored in accordance with the AP, and 
analysed using a bioanalytical assay. 
 
Nasal Wash samples 
Nasal wash for the evaluation of PK parameters of EDP-938 will be collected in accordance 
with Table 9-1 and processed and sent to the Sponsor’ PK vendor according to the AP.  
  


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 96 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
15 
ADVERSE EVENTS AND TOXICITY MANAGEMENT 
The PI/Investigator is responsible for ensuring that all AEs, SAEs and pregnancies are 
identified, evaluated, recorded and reported in a timely manner as per Regulatory 
requirements and hVIVO’s SOPs, and also for ensuring that the medical management 
(including 
follow 
up) 
of 
AEs, 
SAEs 
and, 
where 
appropriate, 
pregnancy 
symptoms/complications is provided by competent Investigator Site staff. 
15.1 
Definitions  
 
Adverse Event 
An AE is defined as any untoward medical occurrence in subjects. An AE can therefore be 
any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of an investigational medicinal product, whether 
or not considered related to the investigational medicinal product, or for the purposes of 
Human Viral Challenge studies, the Challenge Virus. 
An AE includes: 
• 
Exacerbation of a pre-existing illness. 
• 
Increase in frequency or severity of a pre-existing episodic condition. 
• 
A condition detected or diagnosed after IMP or inoculum administration even though it 
may have been present prior to the start of the study. 
• 
A complication that occurs during a hospitalisation. 
• 
A clinically significant change in laboratory parameter. 
An AE does not include: 
• 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion); the condition that leads to the procedure is an AE. 
• 
Pre-existing disease or conditions present or detected prior to start of IMP or Challenge 
Virus inoculation administration that does not worsen (including screening findings 
such as abnormal laboratory results). 
• 
Hospitalisation for elective surgery, social and/or convenience admissions provided 
they are arranged before the start of IMP administration. 
• 
Over-administration of either the challenge virus, IMP or concomitant medication 
without any signs or symptoms. 
• 
An uncomplicated pregnancy or an induced elective abortion to terminate a pregnancy 
without medical reason. 
• 
Typical/normal viral symptoms on symptom diary cards (see Section 15.3.6). 
 
Adverse Drug Reaction 
An adverse drug reaction (ADR) is any untoward and unintended response in a subject to an 
IMP which is related to any dose administered to that subject. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 97 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
‘Response’ in this context means that a causal relationship between a medicinal product and 
an AEis at least a reasonable possibility32. 
All AEs judged by either the reporting investigator or the Sponsor as having a reasonable 
causal relationship to a medicinal product qualify as ADRs. The expression ‘reasonable causal 
relationship’ means to convey in general that there is evidence or argument to suggest a 
causal relationship. 
 
Unexpected Adverse (Drug) Reaction 
An “Unexpected Adverse (Drug) Reaction” means an adverse reaction, the nature and severity 
of which is not consistent with the information about the medicinal product in question set out: 
(a) In the case of a product with a marketing authorisation, in the Summary of Product 
Characteristics for that product, 
(b) In the case of any other investigational medicinal product, in the Investigator’s Brochure 
relating to the trial in question’4. 
 
Serious Adverse Event 
A SAE is any adverse event that - 
(a) results in death, 
(b) is life-threatening, 
(c) requires hospitalisation or prolongation of existing hospitalisation, 
(d) results in persistent or significant disability or incapacity, or 
(e) consists of a congenital anomaly or birth defect;4  
(f) is an important medical event. 
The above characteristics/consequences have to be considered at the time of the event, for 
example: 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the subject 
was at risk of death at the time of event; it does not refer to an event which, hypothetically, 
might have caused death if it were more severe2. 
‘Important medical events’ - some medical events may jeopardise the subject or may require 
an intervention to prevent one of the above characteristics/consequences. Such events should 
also be considered as ‘serious’ in accordance with the above definition.  
Medical judgement should be exercised in deciding whether an adverse event/reaction is 
serious. Important adverse events/reactions that are not immediately life threatening or do not 
result in death or hospitalisation, but may jeopardise the subject or may require intervention 
to prevent one of the other outcomes listed in the definition above occurring, should also be 
considered serious. Details of the SAE must be provided. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 98 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 
 Suspected Unexpected Serious Adverse Reaction  
A suspected unexpected serious adverse reaction (SUSAR) is ‘a serious adverse reaction, 
the nature and severity* of which is not consistent with the information about the medicinal 
product in question, as defined in the Investigator’s Brochure relating to the trial in question. 
Medical events will be assessed for expectedness by the PI/Investigator against the Summary 
of Data and Guidance for the Investigator section of the IB, and any available IB addendum. 
Any changes to the referenced safety information will be deemed as a change to the 
risk/benefit profile and will require a substantial amendment to be submitted to the MHRA. 
This amendment must be approved before the changes are implemented in the study. 
*The term ‘severity’ is used here to describe the intensity of a specific event. This is not the 
same as ‘serious’ which is based on subject/event outcome or action criteria. 
15.2 
Recording and reporting 
All AEs and SAEs will be collected from the time of written informed consent until study 
completion/final study contact or until the resolution of the AE. AEs will be fully recorded in the 
source documents as they are reported, whether spontaneously volunteered by a subject or 
in response to questioning about wellbeing at each face to face study visit and during 
telephone calls. Enquiries about AEs should cover the period between the previous and 
current visit. 
The following are examples of open ended, non-leading questions that may be used to obtain 
this information:  
• 
How are you feeling? 
• 
Have you had any medical problems since your last visit/assessment?  
• 
Have you taken any new medicines, other than those given to you in this study, 
since your last visit/assessment? 
Following the reporting of AEs and concomitant medication, the Investigator should assess 
the subject’s eligibility to continue in the study.  
The Investigator will record all relevant information regarding an AE/SAE in the source 
documents and evaluate AEs using the following guidelines:  
• 
Description of events (if the event consists of a cluster of signs and symptoms, a 
diagnosis should be recorded) 
• 
Seriousness 
• 
Severity (or grade) 
• 
Onset date and time 
• 
Frequency 
• 
Date and time of resolution (or ‘continuing’ if unresolved) 
• 
Action taken  
• 
Concomitant medication 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 99 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
• 
Clinical outcome 
• 
Relationship or causality (IMP/Challenge Virus/ study procedures/ concomitant 
medication/other). 
Any clinically significant abnormal laboratory result, vital sign or other measure will be followed 
until it returns to normal or baseline values, stabilises, or is judged by the Investigator to be 
no longer clinically significant.  
If an AE is not resolved at the end of the study, the AE should be followed until it has resolved 
or (in the case of pregnancy) the pregnancy has been terminated (including spontaneous 
abortion), resulted in a birth, or a decision has been made by the Sponsor that no further 
follow-up is required. 
Even if the AE or SAE is assessed by the Investigator as not reasonably attributable to the 
challenge virus, its occurrence must be fully documented in the source notes.  
15.3 
Assessment  
 
Description 
If the event consists of a cluster of signs and symptoms, where possible, a diagnosis should 
be recorded (e.g. gastroenteritis) rather than each sign and symptom.  
 
Onset and end 
The dates and times of the onset and end of the event should be recorded.  
 
Seriousness 
The PI/Investigator must record whether the AE meets the definition of serious. If the event is 
serious (Section 15.5), the PI/Investigator must complete an SAE report form.  
 
Intensity and severity  
Severity is a measure of intensity (whereas seriousness is defined by the criteria provided in 
Section 15.4.). 
CTCAE (Appendix 5) will be used as a reference to standardise the severity and grading of 
AEs and anatomical/ pathophysiological terms, and when collecting, reporting and clarifying 
database queries of AEs and SAEs.  
The severity of an AE that does not appear in Appendix 5 should be determined according to 
the definitions in Tables 15.1. 
 
Adverse Events critical to the safety evaluation 
For AEs deemed critical to the safety evaluation, and therefore to be reported to the 
Sponsor, refer to Section 15.1.5. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 100 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 
Challenge Virus symptoms  
The Investigator will assess and review Challenge Virus related symptoms recorded in 
subjects’ hVIVO Symptom Diary Cards. Symptoms greater than Grade 0 will be expected and 
presumed to represent virus infection consequent to Viral Challenge, and will not be 
additionally captured as AEs unless they meet the definition of an AE, and are deemed to be 
clinically significant (in the opinion of the Investigator) to be classed as AEs.  
Following Viral Challenge all unexpected (in the opinion of the Investigator) symptoms post 
inoculation will be captured as AEs, along with all other occurrences that meet the criteria for 
an AE. 
 
Physical Examination 
Any clinically significant change in complete physical examination findings during the study 
will be documented as an AE. 
 
Directed Physical Examination 
Following Viral Challenge, upper and lower respiratory symptoms (nasal discharge, otitis, 
pharyngitis, sinus tenderness, wheeze and crepitation) may be seen and presumed to 
represent virus infection consequent to Viral Challenge, and will not be additionally captured 
as AEs unless they meet the definition of an AE, and are deemed to be clinically significant 
(in the opinion of the Investigator) to be classed as AEs. 
 
Vital signs 
Deterioration in a vital sign (compared to baseline) should only be reported as an AE if the 
deterioration fulfils the criteria for an AE. If deterioration in a vital sign is associated with clinical 
signs and symptoms, the sign or symptom will be reported as an AE and the associated vital 
sign will be considered as additional information. 
 Temperature 
Following Viral Challenge, pyrexia will be expected and presumed to represent virus infection 
consequent to Viral Challenge, and will not be additionally captured as an AE unless it meets 
the definition of an AE, and is deemed to be clinically significant (in the opinion of the 
Investigator) to be classed as an AE.  
Following Viral Challenge all unexpected (in the opinion of the Investigator) pyrexia post 
inoculation will be captured as an AE, along with all other occurrences that meet the criteria 
for an AE. 
 Spirometry 
A 15% drop in a spirometry value (compared to baseline), confirmed by a repeat on the same 
day, will be a Grade 1 (mild) AE. The PI/Investigator will use his/her clinical judgement to 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 101 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
assign severity grades above Grade 1, based on evaluation of clinical signs and symptoms. If 
the repeated value has returned to normal an AE will not be raised. 
 Laboratory values 
Deterioration in a laboratory value (compared to baseline) should only be reported as an AE 
if the deterioration fulfils the criteria for an AE. If deterioration in a laboratory result is 
associated with clinical signs and symptoms, the sign or symptom will be reported as an AE 
and the associated laboratory result will be considered as additional information. 
The Investigator and/or SME will judge whether abnormal laboratory values are clinically 
significant or not clinically significant, and record this in the source document. This entry 
should be signed and dated by the relevant Investigator. Laboratory abnormalities detected at 
screening will be considered as part of the medical history and will not be reported as AEs. 
Challenge Virus associated laboratory abnormalities (e.g.: elevated ALT, AST or GGT; 
decreased neutrophils) may be recorded as AEs (at the discretion of the PI/Investigator).   
15.3.12.1 
C-reactive protein 
Any value above 5 mg/L but less than 60 mg/L will be a Grade 1 (mild) AE (unless deemed 
non-clinically significant by the PI/Investigator). The PI/Investigator will use his/her clinical 
judgement to assign severity grades above Grade 1, based on evaluation of clinical signs and 
symptoms.  
15.4 
Classification of Adverse Events 
 
Severity  
The term ’severe’ is often used to describe the intensity (severity) of a specific event. This is 
not the same as ‘serious’ which is based on subject/event outcome or action criteria. 
The CTCAE (see Appendix 5) will be used to standardise the severity and grading of AEs and 
anatomical/ pathophysiological terms. 
The Investigator will use the CTCAE as a reference when collecting, reporting and clarifying 
database queries of AEs, SAEs and ADRs.  
The severity of an AE that does not appear in the CTCAE should be determined according to 
the definitions in Table 15-1. 










Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 106 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 
Reporting of SUSARs  
The Sponsor is responsible for assessing SUSARs, unblinding potential SUSARs, and 
reporting SUSARs to the MHRA and REC.  
The Sponsor shall ensure that all relevant information about a SUSAR that occurs during the 
course of a clinical trial in the UK and is fatal or life threatening, is reported as soon as possible 
to the MHRA and the REC. This needs to be done within 7 calendar days after the Sponsor 
became aware of the event. Any additional relevant information should be sent within 8 
calendar days of the first report being sent. 
The Sponsor shall ensure that a SUSAR which is not fatal or life-threatening is reported as 
soon as possible and in any event within 15 calendar days after the Sponsor became aware 
of the event. 
In accordance with ICH GCP guidelines, the Sponsor will also inform the Investigator of 
findings that could affect adversely the safety of subjects and/or impact the conduct of the 
trial. 
 
Annual safety reporting to the national Competent Authority (MHRA) and the Ethics 
Committee will be in agreement with ICH guideline E2F “Note for guidance on Development 
Safety Update Reports (DSUR)”. 
 
In addition, any other safety issue which may alter the current benefit–risk assessment of the 
IMP will be reported by the Sponsor (or delegate) on an expedited basis to Competent 
Authorities, Ethics Committees and the Investigator. 
 
The detailed procedure of the SAE/SUSAR reporting will be described in a 
Pharmacovigilance Management Plan that will be finalised before the start of the study to 
exactly define the different tasks of the Investigator, Enanta (the Sponsor) and 
 
 (acting on behalf of Enanta). 
 
Adverse Drug Reactions to non-IMPs 
Any AEs and SAEs which are related to/caused by a concomitant medication or Challenge 
Agent, should not be classed as ADRs, SARs, or SUSARs (ADRs, SARs, SUSARs relate only 
to IMP by definition). However, an SAE caused by a non-IMP would need to be reported to 
the MHRA/REC for the appropriate action to be taken. 
 
Post-study AEs and SAEs  
All SAEs that occur during and up to the Follow-up Visit after the last dose of IMP must be 
reported by the Investigator to the Sponsor’s Pharmacovigilance provider, 
 
 Sciences as soon as possible, in accordance with Regulatory requirements and 
hVIVO’s SOPs, and at the latest within 24 hours of becoming aware of the event.  
SAEs occurring after the subject has completed the clinical trial, and for which a reasonable 
possibility of a causal relationship to IMP is assessed by the Investigator, should be reported 
by the Investigator to the Sponsor regardless of the time that has elapsed (post-trial events). 
 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 107 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 
Pregnancy 
If a female subject or partner of a male subject becomes pregnant within 90 days after the last 
dose of IMP, this must be reported by the Investigator to the Sponsor’s Pharmacovigilance 
provider, 
 and Study Monitor/SME by telephone as soon as 
possible, in accordance with hVIVO’s SOPs, and at the latest within 24 hours of becoming 
aware of the event.  
Following the telephone notification, the Investigator must fully and accurately complete the 
appropriate pregnancy reporting form, which must be e-mailed to the SME and the Study 
Monitor at the latest within 24 hours of becoming aware of the pregnancy.  
Subjects will be advised to contact their GP, as appropriate.  
Consent for follow-up of the pregnancy and pregnancy outcome will be sought from the 
pregnant study subject or the pregnant partner of the male study subject as applicable. 
Consent for follow-up will be documented in accordance with hVIVO SOPs.   
Provided that the appropriate consent is in place, information related to the pregnancy will be 
collected as per hVIVO’s SOPs and the Sponsor’s requirements. The completed Pregnancy 
Reporting Form(s) will be sent to the Sponsor’s Pharmacovigilance provider, 
 
 for review and assessment, and subsequent reporting as required. 
• 
A complete evaluation will be documented in the source data to permit transfer to the 
clinical database.  
• 
The emergency code break envelopes will be requested (Section 10.3) to break the 
blind for the appropriate study subject to ensure that further care can be based on the 
actual identity of the study treatment that the subject received. 
• 
hVIVO will maintain contact with the subject for a protracted period of time, but certainly 
until after the birth, in order to assess for outcomes that may be reportable as related 
AEs, and for reporting to the Sponsor as appropriate.  
• 
hVIVO in consultation with the subject will keep the subject’s GP informed.  
• 
All cases of foetal drug exposure via the parent as a study subject will be reported to 
the Sponsor and the REC.  
• 
Pregnant females will be referred to their GP or to a specialist, as appropriate 
Pregnancy of a study subject or subject’s partner during or within 3 months of the date of 
Challenge is not a SAE, but must still be reported to the Sponsor. However, complications of 
pregnancy and abnormal outcomes of pregnancy are AEs, and may meet the criteria for an 
SAE, therefore pregnancies occurring during the study must be followed up until the outcome 
of the pregnancy is known (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality). Please refer to Section 15.5 for details on the SAE reporting 
procedure. The Investigator will recommend that male subjects whose partners become 
pregnant from Quarantine discharge through to the Day 28 Follow-up Visit should contact their 
GP or a specialist as appropriate. Consent for follow-up will be requested from both partners 
and a complete evaluation will be documented in the source 
data.  
Subjects who are lost to follow-up will be managed as described in Section 9.6. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 108 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
16 
STATISTICAL METHODS AND PLANNED ANALYSES 
 will perform the statistical analysis for the study. Full details of the planned statistical 
analysis (including the Part 1 analysis) will be presented in the Statistical Analysis Plan (SAP). 
Any deviations from the SAP will be documented in the Clinical Study Report (CSR). 
Part 1 data analysis will be reported after completion of Part 1, and based on these results, 
Part 2 of the study will commence. Data Presentations will be the same in both parts of the 
study, unless otherwise stated. Part 2 placebo subjects will be pooled across the Part 2 
treatment cohorts unless there is a clear difference seen in the data of these subjects, in which 
they will be analysed only against the active treatment group in their treatment cohort. 
16.1 
Study analysis sets 
The following analysis sets are defined for this study: 
• 
The Intent to Treat (ITT) Analysis Set is defined as all randomised subjects receiving 
Challenge Virus and at least one dose of IMP. The ITT analysis set will be considered 
a secondary analysis population for efficacy endpoints. 
• 
The Intent to Treat Infected (ITT-I) Analysis Set is defined as all randomised subjects 
receiving Challenge Virus and at least one dose of IMP, and meeting the criterion for 
laboratory confirmed RSV infection as per the definition of laboratory confirmed 
infection for this protocol (see Section 4.2). The ITT-I set will be considered the primary 
analysis population for efficacy endpoints.   
• 
The Intent to Treat Infected (ITT-A) Analysis Population is defined as all randomised 
subjects receiving Challenge Virus and at least one dose of IMP, and meeting the 
criterion for laboratory confirmed RSV infection (as per the definition of laboratory 
confirmed infection for this protocol (see Section 4.2) using only assessments prior to 
taking IMP.  
• 
The Intent to Treat Infected (ITT-B) Analysis Population is defined as all randomised 
subjects not already in the ITT-A Analysis Population, receiving Challenge Virus and 
at least one dose of IMP, and meeting the criterion for laboratory confirmed RSV 
infection (as per the definition of laboratory confirmed infection for this protocol (see 
Section 4.2) using only assessments after IMP.  
• 
The Per Protocol (PP) Analysis Set is defined as all ITT-I Analysis Set subjects who 
have no major protocol deviations, and who complete the quarantine period up to the 
final day of quarantine (Study Day 12), and receive all doses of IMP. The PP Analysis 
Set will be considered a secondary analysis population for efficacy endpoints.  
• 
The Safety Analysis Set is defined as all subjects receiving challenge virus, regardless 
of whether they have received IMP or not. 
• 
The PK Analysis set is defined as all ITT subjects with at least one post-dose PK result. 
The primary analysis will be on the ITT-I Analysis Set. Analysis of the ITT-A, ITT-B and PP 
Analysis Sets will be secondary. The safety evaluation will be performed on the Safety 
Analysis Set. 
Membership of subjects in each analysis set will be determined at a planned blinded data 
review meeting (BDRM), prior to the any analysis and database lock. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 109 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 
Subgroup analysis 
A ‘Laboratory confirmed infected’ subgroup will be identified and certain pre-specified 
analyses (to be documented in the SAP) will also be performed by using the ITT-I, ITT-A, and 
ITT-B analysis sets. 
16.2 
Sample size 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
The results of Part 1 may be used to inform a sample size reassessment for Part 2 prior to the 
start of Part 2 enrolment.  
16.3 
Interim Analysis 
No formal interim analysis will be performed. However, an analysis of Part 1 data will be 
performed prior to starting Part 2 of the study.  
16.4 
Statistical Analysis Plan 
Data will be analysed and reported using SAS® version 9.4 or later.  
Primary and secondary efficacy endpoints will be analysed descriptively. Continuous variables 
will be summarised using number of observations, mean (and/or geometric mean, where 
applicable), standard deviation, standard error, median, lower quartile, upper quartile, 
minimum and maximum values. Categorical variables will be summarised using proportions 
(counts and percentages). Statistical analyses will be performed using appropriate two-sided 
hypothesis tests at the 5% significance level. Normally distributed continuous variables will be 
presented as mean, difference in means and a 95% confidence interval (CI).  The t-test will 
be used to compare means between groups (and/or an appropriate alternative test, if the t-
test assumptions are not satisfied). Methods for checking statistical model assumptions will 
be described in the SAP.  
 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 110 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
For endpoints that are not normally distributed (such as total symptom scores), the Wilcoxon 
Rank-Sum test will be used. No adjustment for multiple comparisons are planned, as this is 
an early stage study.  
 
The detailed SAP will be developed by 
 and approved by the Sponsor prior to any 
lock of the study database. The SAP will give a more detailed description of the report 
presentations to be produced for Parts 1 and 2 of the study, respectively, expanding on the 
protocol specified analysis. Any deviation(s) from the original statistical plan should be 
described and justified in an amendment to the protocol and/or SAP as appropriate and 
referenced also in the final clinical study report (CSR). The SAP will describe and account for 
the occurrence of and extent of missing data, and its possible impact on the study analysis. 
All baseline assessments will be described in the SAP.  
 
  
 
Clinical Study Report 
The CSR for the study will be written as set out in the roles and responsibilities.  
 
Subject accountability 
The number of subjects receiving Challenge Virus, receiving EDP-938 or Placebo, 
withdrawing from (also split by reason for withdrawal), and completing the study, and the 
numbers in each analysis set, will be summarised. 
 
Protocol deviations 
Subject data will be reviewed for major protocol deviations prior to database lock at a planned 
BDRM, and decisions will be documented within the meeting minutes. At this meeting, 
subjects will be reviewed for their inclusion/exclusion from the analysis sets. 
 
Demographic and baseline characteristics 
Descriptive statistics of demographics (age, sex, height, weight, BMI, and ethnicity) will be 
presented by treatment group and across all subjects. Medical history information will be listed. 
Other baseline characteristics will be defined in the SAP.  
16.5 
Primary efficacy analysis 
The AUC for RSV-A Memphis 37b viral load measured in nasal washes by RT-qPCR will be 
summarised and each active treatment group compared to placebo via a t-test or Wilcoxon 
Rank-Sum test as appropriate. The primary efficacy analysis will be supported by sensitivity 
analyses and these will be specified in the SAP.  
16.6 
Secondary efficacy analysis  
The following secondary endpoints will be presented by treatment group: 
Clinical Symptoms: 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 111 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
o Effect of EDP-938 compared to placebo on RSV symptoms (using the 10- item diary 
card), with endpoints including: 
o AUC of total symptom score 
o Peak total symptom score over the duration of quarantine 
o Total symptom score  
o Time to peak symptom score after IMP dosing.  
o Time to resolution from peak symptom. 
o Total weight of nasal mucus produced (via weighed paper tissues).  
Viral Load: 
o Additional viral load endpoints calculated separately using data from RT-qPCR of nasal 
wash comparing placebo and EDP-938 treated including: 
▪ 
Peak viral load 
▪ 
Time to peak viral load 
▪ 
Time to resolution from peak 
▪ 
Time to cessation of virus quantifiable post first dosing 
 
Safety analysis 
The following safety endpoints will be presented by treatment group: 
• 
AEs 
• 
Physical Examinations 
• 
Vital signs 
• 
12-lead ECGs 
• 
Spirometry 
• 
Clinical laboratory results (including biochemistry, haematology, coagulation (if 
required), cardiac enzymes and urine analysis) 
 
Pharmacokinetic analysis 
The following pharmacokinetic endpoints will be presented by treatment group: 
• 
Plasma PK parameters of EDP938 (and metabolites) following repeat dose 
administration in healthy adult subjects inoculated with RSV-A Memphis 37b: Cmax, 
Tmax, t1/2, CL/F, λz, Vd/F, C12, C24, AUClast, AUC0-tau, or AUC0-inf 
Plasma PK (AUC) correlations with viral load AUC (e.g. RT-PCR) and TSS AUC  
PK parameters will be calculated using non-compartmental methods. Parameters will be 
summarised descriptively. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 112 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
16.7 
Exploratory analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 114 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
The assigned study monitor will review the study data for accuracy and completeness during 
on-site monitoring visits. Any discrepancies will be resolved with the PI or designee as 
appropriate. After upload of the data into the study database, data will be verified for accuracy 
and consistency with the data sources. 
17.5 
Data coding 
AEs and medical histories will be coded using the most current version of Medical Dictionary 
for Regulatory Activities (MedDRA). 
 
Concomitant medications will be coded using the most current version of the World Health 
Organization (WHO) Drug Dictionary Enhanced version.  
At the time of coding, the latest version will be used for coding and the version number will be 
documented in the DMP.  
17.6 
Database lock 
The 
 database will undergo validation prior to database lock.  
Following 
 locking of the database the final database will be transferred to the Study 
Statistician for statistical analysis and reporting. 
17.7 
Data protection 
The study site will comply with the General Data Protection Regulation (EU) 2016/67953 and 
the UK Data Protection Act 2018. hVIVO has in place Data Processing Agreements (which 
comply with the above laws) with all vendors and partners where personal data will be 
transferred outside the EU, to bridge the differences in the privacy approaches for data 
protection law in other countries (e.g. the US).


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV  
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
 
 
CONFIDENTIAL 
Page 115 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
18 
STUDY MANAGEMENT AND ETHICAL RESPONSIBILITIES 
The study will be sponsored by ENANTA Pharmaceuticals Inc. and managed by hVIVO 
Services Limited. 
18.1 
Regulatory and Ethics Opinions and Good Clinical Practice 
This study will be conducted in accordance with the Ethical Principles for Medical Research 
Involving Human Subjects outlined in the Declaration of Helsinki 19961, the principles of ICH 
GCP2, current regulatory requirements as detailed in the Medicines for Human Use (Clinical 
Trials) Regulations (SI 2004/1031)4 and all subsequent amendments, the UK Data Protection 
Act 20185, any other applicable laws and guidance, and any Sponsor requirements.  
 All ethical and legal requirements will be met before the first subject is enrolled in the study.  
18.2 
Quality Assurance 
A quality assurance (QA) programme is in place to provide assurance that the trial/study is 
performed and data are generated, documented and reported in compliance with applicable 
regulatory requirements. The QA audit programme includes audits of systems, processes, 
facilities and documents. 
18.3 
Quality Control 
QC activities are performed throughout hVIVO to verify compliance and accuracy of all 
trial/study related activities. These are described in hVIVO SOPs and documented in the 
records. 
18.4 
Deviations from the Protocol 
 
Protocol Waivers 
Protocol waivers are never acceptable as per all EU competent authorities’ guidance 
(including the MHRA). It is not acceptable to include any subject by protocol waiver – i.e., 
included despite not meeting all inclusion criteria or fulfilling at least one exclusion criteria.  
 
Protocol Deviations  
A protocol deviation log will be used to document any unplanned or unintended departures 
from the study protocol. Protocol deviations should be recorded as soon as possible after they 
occur, and if major, reported to the Sponsor immediately by the PI/Investigator. 
The PI or delegate will maintain a log of protocol deviations on the study.  
 
Serious breach of the protocol or GCP 
Regulation 29A of the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 
2004/1031)4, as amended by SI 2006/192838, contains a requirement for the notification of 
‘serious breaches’ of GCP or the trial protocol: 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 116 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
‘29A.  
(1) The sponsor of a clinical trial shall notify the licensing authority in writing of any serious 
breach of: 
(a) the conditions and principles of GCP in connection with that trial; or 
(b) the protocol relating to that trial, as amended from time to time in accordance with 
regulations 22 to 25,  
within 7 days of becoming aware of that breach. 
 
(2) For the purposes of this regulation, a ‘serious breach’ is a breach which is likely to 
effect to a significant degree: 
(a) the safety or physical or mental integrity of the subjects of the trial; or 
(b) the scientific value of the trial’. 
Any serious breach of the conditions and principles of GCP or the study protocol in connection 
with the study will be reported to the Sponsor and the REC.   
The Sponsor will be responsible for notifying the MHRA within 7 days of becoming aware of 
any potential serious breach. 
Any potential serious breach of the conditions and principles of GCP in connection with the 
study will be escalated within hVIVO as soon as an individual becomes aware of the potential 
breach. Rapid escalation will permit the urgent notification to the Sponsor and allow sufficient 
time for hVIVO to fulfil the reporting timelines for the potential breach, as specified in UK 
Regulation 29A4, should reporting be necessary.  
 
Protocol amendments 
Neither the PI nor the Sponsor will alter the study protocol without obtaining the written 
agreement of the other. For all amendments, an evaluation will be made by the PI and the 
Sponsor as to whether the amendment is ‘substantial’ or ‘non-substantial’.  
Non-substantial amendments include for example, minor administrative or typographical 
changes to the protocol. 
Amendments are ‘substantial’ where they are likely to have a significant impact on subject risk 
or the clinical trial objectives, specifically the: 
• 
Safety or physical or mental integrity of the subjects 
• 
Scientific value of the trial 
• 
Conduct or management of the trial 
• 
Quality or safety of the IMP used in the trial. 
Substantial amendments must be reviewed and approved by the MHRA and/or REC prior to 
their implementation unless subject safety would be otherwise compromised (i.e., Urgent 
Safety Measures [USMs]). It is the responsibility of the Sponsor to decide whether an 
amendment is substantial or not, and therefore whether a substantial amendment requires 
MHRA authorisation, or an ethical opinion, or both. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 117 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
When a protocol amendment substantially alters the clinical trial design or the potential risks 
or burden to subjects, the VIS/ICF will also be amended and approved by the REC, and all 
active subjects will be asked to reconfirm their continued willingness to participate in the trial. 
A log of all protocol amendments, together with their designation as substantial or non-
substantial, will be maintained to support clinical study reporting.  
 
Urgent Safety Measures 
The Sponsor and the Investigator may take appropriate ‘urgent safety measures’ to protect 
clinical trial subjects from any immediate hazard to their health and safety.  
USM should be taken immediately. There is no need to wait for MHRA approval before 
implementing USM. 
The Sponsor should telephone the Clinical Trial Unit at the MHRA and discuss the issue with 
a safety scientist immediately. Should further clarification be required the Sponsor will be 
contacted by a medical assessor. 
The Sponsor must notify the MHRA and the REC in writing, of the measures taken and the 
reason for the measures within 3 days. This notification should include a covering letter 
detailing the measures taken, the reason for them, an Annex II substantial amendment form 
and any supporting documentation. 
If the PI (and not the Sponsor) has instigated the USM, the Sponsor should be notified 
immediately so that they can assess and report the USM within the timelines required.  
18.4.5.1 Pandemic 
For any period during which a disease is pandemic and a serious risk to human health or 
potentially a serious risk to human health, notice of USMs taken in order to protect the subjects 
of a clinical trial against any immediate hazard to their health or safety and the circumstances 
giving rise to those measures, may be given ‘as soon as possible’ to the MHRA and the REC.  
Written notification to the MHRA and the REC should be provided within 3 days in the form of 
a substantial amendment and should describe the event, the measures taken and justification 
for the measures taken. 
18.5 
Discontinuation of the study 
The Sponsor reserves the right to temporarily suspend or discontinue the study for any reason 
at any time. In addition, the study may be stopped at any time if, in the opinion of the PI or 
SME, the safety data suggest that the medical safety of subjects is being compromised. 
If the study is suspended or terminated for safety reason(s), the Sponsor will promptly inform 
the PI, and will also inform the regulatory authorities of the suspension or termination of the 
study and the reason(s) for the action.  






Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 120 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 
Archiving 
Paper and electronic records generated by hVIVO during the study will be archived as agreed 
in the CTA and in accordance with the applicable regulations and Sponsor requirements.  
18.7 
Sponsor responsibilities 
 
General 
The Sponsor agrees to adhere to the study protocol, and to comply with the principles of ICH 
GCP2, the Declaration of Helsinki 20131, the current regulatory requirements, as detailed in 
the Medicines for Human Use (Clinical Trials) Regulations (SI 2004/1031)4, and all subsequent 
amendments, the UK Data Protection Act 20185 and any other applicable regional and local 
regulations.  
The Sponsor has a legal responsibility to obtain MHRA approval to perform the study and to 
report the results of the study in full to the MHRA. A copy of the MHRA approval will be 
provided to the PI/Investigator before the start of the study. 
 
No-fault compensation and indemnity 
The Sponsor will comply with the Association of the British Pharmaceutical Industry (ABPI)39 
Clinical Trial Compensation Guidelines. The Sponsor will compensate subjects injured as a 
result of participation in the study, in accordance with the ABPI guidelines, for any harm or ill 
health incurred. The Sponsor has insurance to cover study-related injuries. 
The Sponsor will indemnify the PI (as detailed in a separate document). The indemnity will 
only apply where all study procedures have been carried out according to this protocol.  
hVIVO confirms that it holds a corporate medical professional liability insurance policy which 
insures hVIVO against any liability incurred as a result of the malpractice or negligence of any 
of its medical staff (including the PI), while acting within the scope of their role; and that this 
insurance policy satisfies any local insurance requirements. 
 
Monitoring  
The Study Monitor will contact the site prior to the start of the study to discuss the protocol 
and data collection procedures with site personnel. In accordance with applicable regulations, 
ICH GCP, and the procedures of the Sponsor, the Study Monitor will also periodically contact 
the site and conduct on-site visits. The Study Monitor will ensure that all monitoring visits are 
conducted according to protocol and regulatory requirements. 
During contacts with the study site, the Study Monitor’s activities will include: 
• 
Checking and assessing the progress of the study 
• 
Reviewing study data collected to date for completeness and accuracy 
• 
Checking the supply, storage, accountability, disposition and records pertaining to IMP 
• 
Conducting source data verification 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 121 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
• 
Identifying any issues and addressing resolutions. 
These activities will be done in order to verify that the: 
• 
Data are authentic, accurate, and complete 
• 
Study documentation is maintained properly 
• 
AEs are reported accurately 
• 
Safety and rights of the subjects are being protected 
• 
Study is conducted in accordance with the currently approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements. 
The PI/Investigator will allow the Study Monitor direct access to all relevant documents and 
records, and allocate his/her time and the time of his/her staff to the Study Monitor to discuss 
findings and any relevant issues. 
At study closure, the Study Monitors will conduct all activities as indicated in Section 18.9.  
 
Audits and inspections 
At its discretion, the Sponsor may conduct a QA audit of this study. The Sponsor’s auditing 
procedures will be followed in order to comply with GCP guidelines and ensure acceptability 
of the study data for registration purposes. If such an audit occurs, the PI/Investigator will give 
the auditor direct access to all relevant documents, and will allocate his/her time and the time 
of his/her staff to the auditor as may be required to discuss findings and any relevant issues.  
In addition, regulatory agencies (e.g., MHRA) may conduct an inspection of the study. If such 
an inspection occurs, the PI/Investigator will allow the inspector direct access to all source 
documents and other study documentation for source data check and/or on-site audit 
inspection. The PI must allocate his/her time and the time of his/her staff to the inspector(s) to 
discuss findings of any relevant issues. 
 
Reports to the REC and MHRA 
The Sponsor will submit an Annual Safety Report (ASR) and an Annual Progress Report to 
the REC once a year throughout the clinical trial or on request. The Sponsor will submit a 
Development Safety Update Report (DSUR) to the MHRA, the DSUR will take into account all 
new available safety information received during the reporting period. 
18.8 
Investigator responsibilities 
 
Ethical considerations 
In accordance with hVIVO SOPs, hVIVO will submit study related documents to the REC for 
review and approval including but not limited to the protocol, VIS/ICF, IB and any 
advertisements. Written approval of these documents must be received from the REC before 
the first subject is enrolled into the study.   


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 122 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
The PI/Investigator will notify the REC of any protocol amendments as described in Section 
18.4.4. Written approval must be obtained from the REC for all substantial amendments to the 
protocol, prior to their implementation, except when necessary to eliminate apparent 
immediate hazard to the subject (Section 18.4.5).  
The PI/Investigator should also obtain a written statement of the composition of the REC. 
Appropriate reports on the progress of the study will be made to the REC and the Sponsor by 
the PI/Investigator in accordance with local regulatory practices and in agreement with the 
Sponsor. 
IMP can only be supplied to the PI/Investigator after documentation of all ethical and legal 
requirements for starting the study has been received by the Sponsor. 
The REC and MHRA will be informed about the end of the trial within the required timelines: 
▪ 
In the event of early termination this is 15 days from trial completion and the reason 
for termination is required. 
▪ 
In the case of routine termination, this is 90 days from the protocol-defined end of trial. 
 
Laboratory certification and normal values 
The PI/Investigator will provide the Sponsor with the name and location of the clinical 
laboratory(ies) used for laboratory tests, plus a copy of the certification for all laboratory tests 
included in the protocol, certification number(s), date(s) of certification, and a list(s) of the 
normal values for all laboratory tests required by the protocol. These documents must be 
available prior to any subject being treated in the study. Updated versions of these documents 
must be provided to Sponsor as appropriate. 
 
Delegation of Investigator responsibilities 
The PI should ensure that all persons assisting with the study are adequately informed and 
trained about the protocol, any amendments to the protocol, their study-related duties and 
functions, and the study medication. The PI should maintain a list of Investigators and other 
appropriately qualified persons to whom he/she has delegated significant study-related duties. 
 
Informed Consent Process 
A properly executed, written, ICF, in compliance with the Declaration of Helsinki, ICH GCP, 
and other applicable regulations will be obtained from participants who are willing to 
participate. 
Potential subjects will be sent copies of the VIS and ICF at least 24 hours prior to their 
Screening Visit/Quarantine admission visit (as applicable) and will be encouraged to read 
them prior to their appointment. Upon arrival at the Screening Visit/Quarantine admission visit 
(as applicable), the VIS and ICF are explained and discussed in detail by an investigator and 
the subjects are given the opportunity to ask any questions, and can also take the information 
sheet away to consider their participation. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 123 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
All subjects are required to have a good understanding of English and it is the PI’s (or 
designated individual/delegate) responsibility to ensure that the subject understands the 
information contained in the VIS and ICF. Once the PI (or designated individual/delegate) has 
confirmed that the subject has understood the study, including the benefits and risks of 
participation, the subject and the PI (or designated individual/delegate) must sign and date the 
ICF. 
The ICF must be signed and dated by the subject and countersigned by the PI or designated 
individual (whoever conducted the consent discussion). All subjects will receive a copy of the 
signed consent form, and VIS. The VIS and ICF will be copied and filed within the subject 
notes; the original will be held in the hVIVO TMF. 
The subjects will be assured that they can withdraw from the study at any time and for any 
reason without prejudice to their future medical care, and that they will be informed in a timely 
manner if new information becomes available that may affect their willingness to continue 
participation in the study. The communication of this information must be documented. 
If the ICF is amended during the study, the PI/Investigator must follow all applicable regulatory 
requirements pertaining to approval of the amended ICF by the REC. The site must use the 
amended ICF for all new subjects and repeat the consent process with the amended ICF for 
any on-going subjects, if required. 
 
Information for General Practitioners 
Subjects will be required to consent to their GPs being contacted by the hVIVO team. 
Confirmation of the subject's medical history will be requested from the subject’s GP in order 
for the PI/Investigator to judge the subject’s suitability for the study.  
 
Compensation and Expenses 
The Sponsor will reimburse subjects for their inconvenience and out-of-pocket expenses, 
including travelling costs. All proposed payments to subjects will be approved by the REC prior 
to the start of the study and the amount of payment will be specified in the VIS. 
 
Liability and insurance 
Liability and insurance provisions for this study are specified in the CTA. 
 
Investigator’s Protocol Agreement 
The Investigator's Protocol Agreement at the front of this document must be signed by the PI. 
The original or a copy must be kept on file by the Sponsor and the PI/Investigator must retain 
the original or a copy. The completed Protocol Agreement signifies review and acceptance of 
the protocol by the PI prior to initiation of the study. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 124 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 
Quality assurance 
hVIVO must implement and maintain QA and QC systems which may involve auditing the 
study.  
Any contracted individual or group working on the study must implement QC and/or QA 
systems in their work on the study. 
18.9 
Study termination 
Upon completion of the study, the following activities, when applicable, must be conducted by 
the Study Monitor in conjunction with the PI/Investigator, as appropriate: 
• 
Review of site study records for completeness and accuracy 
• 
Return of all study data to the Sponsor (excluding source data) 
• 
Data clarifications and/or resolutions 
• 
Accounting, reconciliation, and final disposition of used and unused study medication 
(EDP-938 or placebo).  
In addition, the Sponsor reserves the right to temporarily suspend or prematurely terminate 
this study for any reason (see Section 18.518.5). 
18.10 
GCP Compliance 
The Investigator must undertake to perform the study in accordance with ICH GCP Guidelines, 
EU Directive 2001/20/EC, and the applicable regulatory requirements. 
 
It is the Investigator’s responsibility to ensure that adequate time and appropriate resources 
are available at the study site prior to commitment to participate in this study. The Investigator 
should also be able to estimate or demonstrate a potential for recruiting the required number 
of suitable subjects within the agreed recruitment period. 
 
Agreement with the final CSR will be documented by the dated signature of the PI, in 
compliance with Directive 75/318/EC, Directive 2001/83/EC, and ICH E3. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 125 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
19 
DISCLOSURE OF DATA 
19.1 
Subject confidentiality 
In line with EU Directive 95/46/EEC37, as transposed into the UK Data Protection Act 20185, 
the PI and hVIVO have a legal obligation to protect at all times the confidentiality of subject 
personal data from the point of capture, through processing, dissemination in line with consent 
from the subject and to its final disposition. 
The PI/Investigator shall provide assurance to subjects that their confidentiality will be 
maintained during all audits and inspections of the study site and in any documentation by 
third parties.  
hVIVO investigators, study nurses and other hVIVO personnel will record information about 
the subjects in a computerised database and in an hVIVO medical record. If the subject 
consents to participate in this study, any of their medical records may be reviewed by hVIVO 
staff and auditors for the purposes of checking that the study is being carried out correctly.  
Subjects’ medical records may also be reviewed by representatives from the REC, 
government agencies and the MHRA; all have the same legal obligation in respect of 
confidentiality. Subjects will be assigned a unique number prior to enrolment into the study 
(Section 7.7). Subjects’ names will not be supplied to the Sponsor. 
Any samples taken for analysis during the study will be labelled using the subject number. 
Some laboratories in the UK may require up to two or three identifiers for the accurate tracking 
and processing of samples, such as subject number, and date of birth. Under no 
circumstances will a laboratory involved in the analysis of samples in this study be given 
information regarding the identity of subjects, such as their full name. 
19.2 
Sponsor confidentiality 
As detailed in the CTA, information concerning the IMP and any information such as clinical 
indications for the IMP, its formula, methods of manufacture and other scientific data relating 
to it, that have been provided by the Sponsor and are unpublished, are confidential and must 
remain the sole property of the Sponsor. The PI/Investigator will agree to use the information 
only for the purposes of carrying out this study and for no other purpose, unless prior written 
permission from the Sponsor is obtained.  
19.3 
Publication 
 
 
 
 
 
 
 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 126 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 127 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
20 
REFERENCES AND BIBLIOGRAPHY 
1. 
World Medical Association Declaration of Helsinki; Brazil, 2013. Available from: 
http://www.wma.net/en/30publications/10policies/b3/index.html. 
2. 
ICH Harmonised Tripartite Guideline for Good Clinical Practice E6 (R2), (2016). 
3. 
Commission Directive 2003/94/EC of 8 October 2003, laying down the principles and 
guidelines of good manufacturing practice in respect of medicinal products for human 
use and investigational medicinal products for human use, (2003). 
4. 
The Medicines for Human Use (Clinical Trials) Regulations, (2004: SI No. 1031). 
5. 
Legislation.gov.uk. UK Data Protection Act 2018. Available from: 
http://www.legislation.gov.uk/ukpga/2018/12/contents/enacted 
6. 
DeVincenzo JP, Wilkinson T, Vaishnaw A, Cehelsky J, Meyers R, Nochur S, et al. Viral 
load drives disease in humans experimentally infected with respiratory syncytial virus. 
Am J Respir Crit Care Med. 2010;182(10):1305-14. 
7. 
Hall CB, Douglas RG, Jr., Schnabel KC, Geiman JM. Infectivity of respiratory syncytial 
virus by various routes of inoculation. Infect Immun. 1981;33(3):779-83. 
8. 
Hall CB, Walsh EE, Hruska JF, Betts RF, Hall WJ. Ribavirin treatment of experimental 
respiratory syncytial viral infection. A controlled double-blind study in young adults. 
JAMA. 1983;249(19):2666-70. 
9. 
Lee FE, Walsh EE, Falsey AR, Betts RF, Treanor JJ. Experimental infection of 
humans with A2 respiratory syncytial virus. Antiviral Res. 2004;63(3):191-6. 
10. 
Glezen WP, Taber LH, Frank AL, Kasel JA. Risk of primary infection and reinfection 
with respiratory syncytial virus. American Journal Disabled Children. 1986;140(6):543-
6. 
11. 
Glezen P, Denny FW. Epidemiology of acute lower respiratory disease in children. 
New England Journal of Medicine. 1973;288(10):498-505. 
12. 
Fisher RG, Gruber WC, Edwards KM, Reed GW, Tollefson SJ, Thompson JM, et al. 
Twenty years of outpatient respiratory syncytial virus infection: a framework for vaccine 
efficacy trials. Pediatrics. 1997;99(2):E7. 
13. 
hay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis-
associated hospitalizations among US children, 1980-1996. Journal of the American 
Medical Association. 1999;282(15):1440-6. 
14. 
Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B. Respiratory syncytial virus 
bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J 
Respir Crit Care Med. 2000;161(5):1501-7. 
 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 128 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
15. 
Sigurs N, Gustafsson PM, Bjarnason R, Lundberg F, Schmidt S, Sigurbergsson F, et 
al. Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at 
age 13. Am J Respir Crit Care Med. 2005;171(2):137-41. 
16. 
Collins P MK, Chanock R. Respiratory Syncytial Virus. In: Fields B KD, Howley P, 
editor. Fields Virology. 1. Third ed. Philadelphia: Lippincott-Raven Publishers; 1996. p. 
1313-50. 
17. 
Hall CB, Walsh EE, Long CE, Schnabel KC. Immunity to and frequency of reinfection 
with respiratory syncytial virus. Journal of Infectious Diseases. 1991;163(4):693-8. 
18. 
Glezen WP, Greenberg SB, Atmar RL, Piedra PA, Couch RB. Impact of respiratory 
virus infections on persons with chronic underlying conditions. Journal of the American 
Medical Association. 2000;283(4):499-505. 
19. 
Couch RB, Englund JA, Whimbey E. Respiratory viral infections in immunocompetent 
and immunocompromised persons. American Journal of Medicine. 1997;102(3A):2-9; 
discussion 25-6. 
20. 
De Vincenzo JP LD, Soiffer RJ, Siber GR. Immunotherapy of respiratory syncytial virus 
pneumonia following bone marrow transplantation. Divisions of Infectious Diseases, 
Dana Farber Cancer Institute, Boston, MA, USA, 1996. 
21. 
Falsey AR, Walsh EE. Respiratory syncytial virus infection in adults. Clinical 
Microbiology Reviews. 2000;13(3):371-84. 
22. 
Falsey AR. Respiratory syncytial virus infection in older persons. Vaccine. 
1998;16(18):1775-8. 
23. 
Kimpen JL, Schaad UB. Treatment of respiratory syncytial virus bronchiolitis: 1995 poll 
of members of the European Society for Paediatric Infectious Diseases. Pediatr Infect 
Dis J. 1997;16(5):479-81. 
24. 
Respiratory syncytial virus activity--United States. 2004 Dec 17. 
25. 
De Vincenzo JP. Therapy of respiratory syncytial virus infection. Pediatr Infect Dis J. 
2000;19(8):786-90. 
26. 
Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces 
hospitalization from respiratory syncytial virus infection in high-risk infants. The IMpact-
RSV Study Group. Pediatrics. 1998;102(3 Pt 1):531-7. 
27. 
MHRA. Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2014 - 
the 'Orange Guide' 2016. Available from: 
http://www.mhra.gov.uk/Publications/Regulatoryguidance/Medicines/CON2030291. 
28. 
Directive 2001/83/EC of the European Parliament and of the Council of 6 November 
2001 on the Community code relating to medicinal products for human use, (2001). 
29. 
EudraLex Volume 4 GMP Annex 13, Manufacture of Investigational Medicinal 
Products, 31 January. 2010. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 129 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
30. 
Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 
amending Directive 2001/83/EC on the Community code relating to medicinal products 
for human use, (2004). 
31. 
Miller MR HJ, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van 
der Grinten CPM, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, 
Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J. Series ‘‘ATS/ERS Task 
Force: Standardisation of Lung Function Testing’’ ‘Standardisation of Spirometry’ 
EurRespir J. 2005;26(2):319–38. 
32. 
Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 
April 2014 on Clinical Trials on Medicinal Products for Human Use, and Repealing 
Directive 2001/20/Ec (Text With EEA Relevance) (2014). 
33. 
Communication from the Commission - Detailed guidance on the collection, verification 
and presentation of adverse event/reaction reports arising from clinical trials on 
medicinal products for human use (‘CT-3’) 2011/C 172/01 (2011). 
34. 
Clinical safety data management: definitions and standards for expedited reporting, 
(1994). 
35. 
Good Clinical Practice Guide. MHRA, editor: TSO; 2014. 
36. 
Administration UFaD. CFR - Code of Federal Regulations Title 21 2013. Available 
from: 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=11
&showFR=1. 
37. 
Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 
on the protection of individuals with regard to the processing of personal data and on 
the free movement of such data  (1995). 
38. 
The Medicines for Human Use (Clinical Trials) Amendment Regulations, (2006: SI No. 
1928). 
39. 
ABPI. Clinical trial compensation guidelines 2013. Available from: 
http://www.abpi.org.uk/our-work/library/guidelines/Pages/ct-compensation.aspx. 
40. 
Spitzer RL WJ, Kroenke K, et al Patient Health Questionnaire-9 (PHQ-9) 2014. 
Available from: http://www.phqscreeners.com/pdfs/02 PHQ-9/English.pdf. 
41. 
Spitzer RL WJ, Kroenke K, et al Generalised Anxiety Disorder Assessment (GAD-7) 
2014. Available from: http://www.phqscreeners.com/pdfs/03 GAD-7/English.pdf. 
 
42. 
Bagga B, Cehelsky JE, Vaishnaw A, Wilkinson T, Meyers R, Harrison LM, Roddam 
PL, Walsh EE, DeVincenzo JP. Effect of Preexisting Serum and Mucosal Antibody on 
Experimental Respiratory Syncytial Virus (RSV) Challenge and Infection of Adults. J 
Infect Dis. 2015 Dec 1; 212(11):1719-25. doi: 10.1093/infdis/jiv281. Epub 2015 
May14. PubMed PMID: 25977264. 
 
43. DeVincenzo JP, McClure MW, Symons JA, Fathi H, Westland C, Chanda S, Lambkin-
Williams R, Smith P, Zhang Q, Beigelman L, Blatt LM, Fry J. Activity of Oral ALS-


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 130 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
008176 in a Respiratory Syncytial Virus Challenge Study. N Engl J Med. 2015 Nov 
19;373(21):2048-58. doi: 10.1056/NEJMoa1413275. PubMed PMID: 26580997. 
 
44. 
Kim YI, DeVincenzo JP, Jones BG, Rudraraju R, Harrison L, Meyers R, Cehelsky 
J,Alvarez R, Hurwitz JL. Respiratory syncytial virus human experimental infection 
model: provenance, production, and sequence of low-passaged memphis-37 challenge 
virus. PLoS One. 2014 Nov 21; 9(11):e113100. doi: 10.1371/journal.pone.0113100. 
eCollection 2014. PubMed PMID: 25415360; PubMed Central PMCID: PMC4240712. 
 
45. 
DeVincenzo JP, Wilkinson T, Vaishnaw A, Cehelsky J, Meyers R, Nochur S, Harrison 
L, Meeking P, Mann A, Moane E, Oxford J, Pareek R, Moore R, Walsh E, Studholme 
R, Dorsett P, Alvarez R, Lambkin-Williams R. Viral load drives disease in humans 
experimentally infected with respiratory syncytial virus. Am J Respir Crit Care Med. 2010 
Nov 15; 182(10):1305-14. doi: 10.1164/rccm.201002-0221OC. Epub 2010 Jul 9. 
PubMed PMID: 20622030; PubMed Central PMCID: PMC3001267. 
 
46. 
DeVincenzo J, Lambkin-Williams R, Wilkinson T, Cehelsky J, Nochur S, Walsh E, 
Meyers R, Gollob J, Vaishnaw A. A randomized, double-blind, placebo-controlled study 
of an RNAi-based therapy directed against respiratory syncytial virus. Proc Natl Acad 
Sci U S A. 2010 May 11;107(19):8800-5 
 
47. 
DeVincenzo JP, Whitley RJ, Mackman RL, Scaglioni-Weinlich C, Harrison L, Farrell E, 
McBride S, Lambkin-Williams R, Jordan R, Xin Y, Ramanathan S, O'Riordan T, Lewis 
SA, Li X, Toback SL, Lin SL, Chien JW. Oral GS-5806 activity in a respiratory syncytial 
virus challenge study. N Engl J Med. 2014 Aug 21; 371(8):711-22. doi: 
10.1056/NEJMoa1401184. PubMed PMID: 25140957 
 
48. 
Chapman J, Abbott E, Alber DG, Baxter RC, Bithell SK, Henderson EA, Carter MC, 
Chambers P, Chubb A, Cockerill GS, Collins PL, Dowdell VC, Keegan SJ, Kelsey RD, 
Lockyer MJ, Luongo C, Najarro P, Pickles RJ, Simmonds M, Taylor D, Tyms S, Wilson 
LJ, Powell KL (2007). RSV604, a novel inhibitor of respiratory syncytial virus 
replication. Antimicrob Agents Chemother; 51 (9):3346-3353. 
 
49. 
halla S, Scott AD, Yuzhakov O, Zhou Y, Tiong-Yip CL, Gao N, Thresher J, Yu Q 
(2015). Mechanism of action for respiratory syncytial virus inhibitor RSV604. 
Antimicrob Agents Chemother; 59 (2):1080-1087. 
50. 
Carter MC, Alber DG, Baxter RC, Bithell SK, Budworth J, Chubb A, Cockerill GS, 
Dowdell VC, Henderson EA, Keegan SJ, Kelsey RD, Lockyer MJ, Stables JN, Wilson 
LJ, Powell KL (2006). 1,4-Benzodiazepines as inhibitors of respiratory syncytial virus. J 
Med Chem;  49 (7):2311-2319. 
 
51. 
Chapman J, Cockerill GS (2011). Discovery and development of RSV604. In: 
Kazmierski WM (ed) Antiviral Drugs: From Basic Discovery Through Clinical Trials, 
First Edition. John Wiley & Sons, Inc. 
52. 
Henderson EA, Alber DG, Baxter RC, Bithell SK, Budworth J, Carter MC, Chubb A, 
Cockerill GS, Dowdell VC, Fraser IJ, Harris RA, Keegan SJ, Kelsey RD, Lumley JA, 
Stables JN, Weerasekera N, Wilson LJ, Powell KL (2007). 1,4-benzodiazepines as 
inhibitors of respiratory syncytial virus. The identification of a clinical candidate. J Med 
Chem 50 (7):1685-1692. 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 131 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
53.      Directive 2016/679 of the European Parliament and of the Council of 14 April 2016 on 
the protection of natural persons with regard to the processing of personal data and on 
the free movement of such data, and repealing Directive 95/46/EC (General Data 
Protection Regulation)  
 
 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 132 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
21 
APPENDICES 
Appendix 1: Patient Health Questionnaire (PHQ-9)40 ................................................................. 133 
Appendix 2: Generalised Anxiety Disorder Questionnaire (GAD-7)41 ........................................ 134 
Appendix 3: Normal ranges ........................................................................................................ 135 
Appendix 4: hVIVO Symptom Diary Card ................................................................................... 136 
Appendix 5: AE and Toxicity Grading Scales ............................................................................. 137 
Appendix 6: Assessment of Baseline by Investigator for Clinical Conduct ................................ 138 
Appendix 7: PK Blood Sampling Schedule ................................................................................. 140 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV  
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
 
 
CONFIDENTIAL 
Page 133 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
Appendix 1: Patient Health Questionnaire (PHQ-9)40 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
CONFIDENTIAL 
Page 134 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
Appendix 2: Generalised Anxiety Disorder Questionnaire (GAD-7)41 






Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV : 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
  
CONFIDENTIAL 
Page 137 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
Appendix 5: AE and Toxicity Grading Scales 
Common Terminology Criteria for Adverse Events (CTCAE); Version 5.0. Published: 
November 27, 2017 (v50: November 27, 2017). U.S. Department of Health and Human 
Services, National Institutes of Health National Cancer Institute. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV : 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
 
CONFIDENTIAL 
Page 139 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
Patient Health Questionnaire (PHQ-9) 
Nearest to Inoculation 
Generalised Anxiety Disorder Questionnaire (GAD-7) 
Nearest to Inoculation 
Note: Nearest to inoculation is defined as the nearest assessment pre-inoculation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Safety, Pharmacokinetics and Antiviral Activity of Orally Administered EDP-938 Against RSV : 
ENANTA Protocol No: EDP 938-101 
 
 
hVIVO Protocol No: ENA-CS-001 
 
 
Version: Amendment 4.0 (v5.0)_07NOV2019 
  
 
 
  
CONFIDENTIAL 
Page 140 of 144 
hVIVO Clinical Study Protocol Template (G_0687) v2.0 
Appendix 7: PK Blood Sampling Schedule 
Blood (plasma) samples for the evaluation of PK parameters of EDP-938 will be collected at the following time points based on the schedule of 
dosing.  
Based on the dose selection for Part 2 (i.e. a combination of different dosing schedule i.e. OD and BD dosing for 5 days), the PK Blood sampling 
for 5 days TWICE a day dosing for Part 1 will be used for Part 2.  
The allowable time windows for the sampling are as follows: 
 
▪ 
± 5 minutes from the scheduled time for time points ≤ 1 hour from dosing; 
 
▪ 
± 15 minutes from the scheduled time for time points > 1 hour from dosing, with NOTE below: 
o 24 hours timepoints: +/- 1 hour window 
o 30 hours timepoint: +/- 1 hour window 
o 36 hours timepoint: +/- 1 hour window 
o 48 hours timepoint: +/- 2 hours window 
o 60 hours timepoint: +/- 2 hours window 
o 72 hours timepoint: +/- 2 hours window 
 
▪ 
There is no time window requirement for the pre-dose sample. The pre-dose sample must be taken prior to dose. 









SAP_001.pdf: 
Protocol Number:  EDP 938-101 
 
Official Title:  Randomised, Phase 2a, Double-Blind, Placebo-Controlled Study to 
Evaluate the Safety, Pharmacokinetics and Antiviral Activity of 
Multiple Doses of Orally Administered EDP-938 Against Respiratory 
Syncytial Virus Infection in the Virus Challenge Model 
 
NCT Number: NCT03691623 
 
Document Date:  01 NOV 2019 


hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 Statistical Analysis Plan Page 1 of 154 
Version  02-00, 01 NOV2019 
 
 
STATISTICAL ANALYSIS PLAN 
VERSION 02.00, 01 NOV 2019 
 
A Randomised, Phase 2a, Double-Blind, Placebo-Controlled Study to 
Evaluate the Safety, Pharmacokinetics and Antiviral Activity of 
Multiple Doses of Orally Administered EDP-938 Against Respiratory 
Syncytial Virus Infection in the Virus Challenge Model 
ENA-CS-001 
(Sponsor Protocol Number: EDP 938-101) 
 
 
 
Prepared by: 
 
For: hVIVO Services Limited (hVIVO) 
Sponsor: ENANTA Pharmaceuticals, Inc 
 
 


 hVIVO Services Ltd/ENA-CS-001 
 
 
CONFIDENTIAL
 
 
 Statistical Analysis Plan Page 2 of 154 
 
 
Version 02-00, 01 NOV 2019 
 
CONTENTS 
1. 
STATISTICAL ANALYSIS PLAN APPROVAL FORM ............................................................................... 5 
2. 
STATISTICAL ANALYSIS PLAN AUTHOR(S) ......................................................................................... 6 
3. 
LIST OF ABBREVIATIONS ................................................................................................................... 7 
4. 
INTRODUCTION ................................................................................................................................ 9 
5. 
STUDY OBJECTIVES .........................................................................................................................10 
5.1. Primary Objective(s) ...............................................................................................................10 
5.2. Secondary Objective(s) ...........................................................................................................10 
5.3. Exploratory Objective(s) .........................................................................................................10 
6. 
STUDY DESIGN ................................................................................................................................11 
6.1. Summary of Study Design ......................................................................................................11 
Table 1: Summary of study phases and procedures .......................................................................12 
Figure 1: Study Design ....................................................................................................................13 
6.2. Randomisation and Blinding...................................................................................................14 
6.3. Time and Events Schedule ......................................................................................................14 
Table 2: Time and Events Schedule ................................................................................................15 
6.4. Interim Analysis / Data Monitoring ........................................................................................23 
7. 
STUDY ENDPOINTS .........................................................................................................................24 
7.1. Primary Endpoint ....................................................................................................................24 
7.2. Secondary Endpoints ..............................................................................................................24 
7.2.1. Efficacy .......................................................................................................................24 
7.2.2. Safety .........................................................................................................................24 
7.2.3. Pharmacokinetics .......................................................................................................25 
7.3. Exploratory Endpoints ............................................................................................................25 
8. 
SAMPLE SIZE ...................................................................................................................................26 
9. 
STUDY ANALYSIS SETS.....................................................................................................................27 
9.1. Intent to Treat (ITT) Analysis Set ............................................................................................27 
9.2. Intent to Treat Infected (ITT-I) Analysis Set ...........................................................................27 
9.3. Intent to Treat Infected Pre-Dose (ITT-A) Analysis Set ...........................................................28 
9.4. Intent to Treat Infected Post-Dose (ITT-B) Analysis Set .........................................................28 
 
 


 hVIVO Services Ltd/ENA-CS-001 
 
 
CONFIDENTIAL
 
 
 Statistical Analysis Plan Page 3 of 154 
 
 
Version 02-00, 01 NOV 2019 
 
9.6. Safety Analysis Set ..................................................................................................................28 
9.7. PK Analysis Set ........................................................................................................................28 
10. PLANNED STATISTICAL METHODS ..................................................................................................29 
10.1. Statistical Considerations .......................................................................................................29 
10.1.1. General definitions .....................................................................................................29 
10.1.2. Data Presentation ......................................................................................................29 
10.1.3. Statistical Testing and Estimation ..............................................................................31 
10.1.4. Handling of Dropouts or Missing Data .......................................................................31 
10.1.5. Multiple Comparison/Multiplicity ..............................................................................31 
10.1.6. Examination of Subgroups .........................................................................................31 
10.1.7. Model checking and sensitivity analyses....................................................................31 
10.1.8. Software .....................................................................................................................31 
10.1.9. Data Conversion (CDISC) ............................................................................................31 
10.2. Subject Disposition .................................................................................................................32 
10.3. Protocol Deviations ................................................................................................................32 
10.4. Demographic and other baseline characteristics ...................................................................32 
10.4.1. Demographics ............................................................................................................32 
10.4.2. Other Baseline Characteristics ...................................................................................32 
10.4.3. Medical History ..........................................................................................................32 
10.5. Prior and Concomitant medications .......................................................................................32 
10.6. Treatment and Inoculation exposure .....................................................................................33 
10.7. Efficacy Analysis......................................................................................................................33 
10.7.1. Primary Efficacy Analysis............................................................................................33 
10.7.2. Secondary Efficacy Analyses ......................................................................................35 
10.7.3. Exploratory Efficacy Analysis ......................................................................................38 
10.8. Safety Analysis ........................................................................................................................41 
10.8.1. Adverse Events ...........................................................................................................41 
10.8.2. Laboratory Variables ..................................................................................................42 
10.8.3. Vital Signs ...................................................................................................................43 
10.8.4. Physical Examination .................................................................................................43 
10.8.5. Spirometry ..................................................................................................................43 
10.8.6. 12-Lead ECG ...............................................................................................................43 
10.9. Pharmacokinetic Analysis .......................................................................................................44 


 hVIVO Services Ltd/ENA-CS-001 
 
 
CONFIDENTIAL
 
 
 Statistical Analysis Plan Page 4 of 154 
 
 
Version 02-00, 01 NOV 2019 
 
11. CHANGES TO THE PROTOCOL SPECIFIED ANALYSIS DETAILED IN THE STATISTICAL ANALYSIS PLAN
 
46 
12. REFERENCES ....................................................................................................................................48 
13. TABLES, FIGURES AND LISTINGS .....................................................................................................49 
13.1. Specific Presentation Details ..................................................................................................49 
13.2. List of Tables ...........................................................................................................................50 
13.3. List of Figures ..........................................................................................................................59 
13.4. List of Listings .........................................................................................................................67 
14. TABLE AND LISTING SHELLS ............................................................................................................70 
15. APPENDICES ..................................................................................................................................153 
15.1. Study ENA-CS-001 assay cut-offs and reporting ..................................................................153 
 




 hVIVO Services Ltd/ENA-CS-001 
 
 
CONFIDENTIAL
 
 
 Statistical Analysis Plan Page 6 of 154 
 
 
Version 02-00, 01 NOV 2019 
 
2. STATISTICAL ANALYSIS PLAN AUTHOR(S) 
 
 
 
 
 
 
 
 
 
 


 hVIVO Services Ltd/ENA-CS-001 
 
 
CONFIDENTIAL
 
 
 Statistical Analysis Plan Page 7 of 154 
 
 
Version 02-00, 01 NOV 2019 
 
3. LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ANCOVA 
Analysis of covariance 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate transaminase 
AUC 
Area under the curve 
BD 
Twice daily 
BDRM 
Blinded data review meeting  
β-HCG 
Beta human chorionic gonadotropin 
BLQ 
Below level of quantification 
BMI 
Body mass index 
Bpm 
Beats per minute 
Cmax 
Maximum (peak) observed concentration  
CRF 
Case Report Form 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
%CV 
Coefficient of variation, expressed as a percentage 
DBP 
Diastolic blood pressure 
DPE 
Direct Physical Examination 
ECG 
Electrocardiogram 
FEV1 
Forced expiratory volume in 1 second  
FI 
Febrile Illness 
FSH 
Follicle stimulating hormone 
FU 
Follow-up 
FVC 
Forced vital capacity  
%GCV 
Geometric coefficient of variation, expressed as a percentage 
GGT 
Gamma glutamyl transferase  
HR 
Heart Rate 
hVIVO 
hVIVO Services Limited 
HVC 
Human Viral Challenge 
IMP 
Investigational medicinal product 
ITT 
Intention-to-treat 
ITT-I 
Intention-to-treat infected 
ITT-A 
Intention-to-treat infected pre-dose 
ITT-B 
Intention-to-treat infected post-dose 
LDH 
Lactate dehydrogenase  
LRT 
Lower Respiratory Tract 
LRTI 
Lower Respiratory Tract Illness 
LS 
Least squares 
LSLV 
Last Subject Last Visit 
MCH 
Mean corpuscular haemoglobin  
MCHC 
Mean corpuscular haemoglobin concentration  
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NDA 
No detectable antibody 
OD 
Once daily 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 
PFU 
Plaque forming units 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PP 
Per protocol 


 hVIVO Services Ltd/ENA-CS-001 
 
 
CONFIDENTIAL
 
 
 Statistical Analysis Plan Page 8 of 154 
 
 
Version 02-00, 01 NOV 2019 
 
PT 
Prothrombin time 
Q1 
Lower Quartile 
Q3 
Upper Quartile 
qicPCR 
Qualitative integrated cycler polymerase chain reaction 
RR 
Respiratory rate 
RT-qPCR 
Quantitative reverse transcriptase polymerase chain reaction  
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
RSV 
Respiratory Syncytial Virus 
RVAT 
Rapid Viral Antigen Test 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Standard Deviation 
SE 
Standard Error  
SI 
Systemic Illness 
SOC 
System Organ Class 
SpO2 
Peripheral arterial oxygen saturation 
T1/2 
Terminal plasma half-life  
TDL 
TDL Pathology (vendor for safety laboratory assessments) 
TEAE 
Treatment emergent adverse event 
TFL 
Tables, Figures and Listings 
Tmax 
Observed timepoint of Cmax  
TSS 
Total symptom score 
URT 
Upper Respiratory Tract 
URTI 
Upper Respiratory Tract Illness 
WBC 
White blood cell 
WHO 
World Health Organisation 
 


 hVIVO Services Ltd/ENA-CS-001 
 
 
CONFIDENTIAL
 
 
 Statistical Analysis Plan Page 9 of 154 
 
 
Version 02-00, 01 NOV 2019 
 
4. INTRODUCTION 
 
This statistical analysis plan (SAP) explains in detail the statistical analyses that will be performed for 
the hVIVO ENA-CS-001 (EDP 938-101) study. The analysis is outlined within the final study protocol 
V1.0, dated 23 July 2018 (and protocol amendment 1 (V2.0), dated 04 September 2018, protocol 
amendment 2 (V3.0), dated 30 October 2018) and protocol amendment 3 (V4.0), dated 11 July 2019.  
This SAP was approved on 12 February 2019 (Version 01.00) and amended on 01 November 2019 
(Version 02.00) and contains a more technical and detailed description of those analyses outlined in 
the Protocol. In particular, information is provided on the definitions of the analysis sets, and it also 
details the list of Tables, Figures and Listings (TFL) that will be produced by S-cubed Biometrics for 
use and inclusion with the Clinical Study Report (CSR). The SAP has been written and finalised before 
any unblinding of the study.  
This study is designed to have up to 2 Parts. Both Parts, together, will not exceed the number of 
subjects planned for this study (i.e. up to 198 evaluable subjects). Part 2 commenced after an 
evaluation by the Sponsor and Investigator of the virology, clinical symptom score, pharmacokinetics 
(PK), and safety data from Part 1. Part 1 data analysis was reported after completion of Part 1, and 
based on these results, Part 2 of the study has commenced. Data presentations will be the same in 
both parts of the study, unless otherwise stated.   
SAP Version 01.00 contains the pre-planned analysis for Part 1 of the study, this version was 
amended after analysis of Part 1 to create Version 02.00, which includes clarifications of the planned 
analysis prior to the unblinding of Part 2.  
Any deviations from the protocol specified analyses, and also deviations from analyses stated within 
this SAP, will be described within the CSR. 


 hVIVO Services Ltd/ENA-CS-001 
 
 
CONFIDENTIAL
 
 
 Statistical Analysis Plan Page 10 of 154 
 
 
Version 02-00, 01 NOV 2019 
 
5. STUDY OBJECTIVES 
5.1. Primary Objective(s) 
The primary objective is to evaluate the antiviral activity of EDP-938 compared to placebo in healthy 
adult subjects inoculated with RSV (Respiratory Syncytial Virus)-A Memphis 37b. 
5.2. Secondary Objective(s) 
 
• 
To evaluate EDP-938 compared to placebo in healthy adult subjects inoculated with RSV-
A Memphis 37b in terms of: 
 
o Clinical symptoms 
o Viral load 
o Safety and Tolerability 
 
• 
To characterise the PK profile of multiple doses of EDP-938 and metabolites in healthy 
adult subjects inoculated with RSV-A Memphis 37b. 
 
• 
To characterise the relationship between Plasma PK of EDP-938 and viral load AUC (RT-
qPCR) and total symptom score AUC  
5.3. Exploratory Objective(s) 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 hVIVO Services Ltd/ENA-CS-001 
 
 
CONFIDENTIAL
 
 
 Statistical Analysis Plan Page 11 of 154 
 
 
Version 02-00, 01 NOV 2019 
 
6. STUDY DESIGN 
6.1. Summary of Study Design 
This is a randomised, Phase 2a, double-blind, placebo-controlled study in healthy subjects inoculated 
with RSV-A Memphis 37b.  
The study is divided into 2 parts: 
• 
In Part 1: 
o 
5 consecutive days of dosing in one of three treatment groups: 
 
Group 1: Placebo (n=38); subjects in this group will receive placebo dose BD 
(every 12 hours (±1 hour) interval) for a total of 10 doses. 
 
Group 2: EDP-938 oral 
 loading dose group (n=38): subjects in this 
group will receive 500mg first dose, and at 12 hours (±1 hour) interval receive 
300mg second dose, then 300mg doses BD for a total of 10 doses. 
 
Group 3: EDP-938 oral 
, 600mg dose group (n=38): subjects in this 
group will receive a daily 600mg dose followed by a placebo dose at 12 hours 
(±1 hour) interval for a total of 10 doses.  
o IMP dosing to start on confirmation of positive result by qualitative integrated cycler 
polymerase chain reaction (qicPCR) on nasal wash. Nasal wash for qicPCR will be 
performed BD on Study Days 2-5 (Study Day 5 morning only), or until a positive result is 
achieved, whichever is sooner. 
 
o Earliest start of IMP dose will be in the evening on Study Day 2 post viral challenge 
(IMP will be initiated 12 ± 1-hour post nasal wash confirmation of a positive qicPCR 
result). 
 
OR 
 
o Dosing will start in the evening of Study Day 5 if no positive result is obtained by 
qicPCR. 
• 
In Part 2:  
63 subjects will be randomised equally into 1 of 3 treatment groups as below.  
o Group 1 (n=21): Placebo dosed BD for 5 days, with dosing at 12 hours (± 1 hour) interval 
o Group 2 (n=21): A single Loading Dose of 400mg (Dose 1), followed by 200mg second 
dose at 12 hours (± 1-hour interval), then 200mg doses BD, and with dosing for 5 days,  
o Group 3 (n=21): A single Loading Dose of 600mg (Dose 1), followed by a 300mg dose OD 
(every 24 hours (±1 hour) interval) dosing, and with dosing for 5 days. 
The study is divided into three phases as shown in Table 1. The overall study design is depicted in Figure 
1: Study Design for Subjects. 






hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 Statistical Analysis Plan Page 14 of 154 
Version 02-00, 01 NOV 2019 
 
6.2. Randomisation and Blinding 
 
In Part 1 of the study, dosing will be triggered once the decision to dose is established based on 
confirmation of RSV infection by qicPCR between Study Day 2 and Study Day 5 (Day 5 morning only). 
If infection is not confirmed by positive qicPCR by Study Day 5 morning, subjects will be randomised 
on Study Day 5 and will commence IMP dosing in the evening of Study Day 5.  
 
Following an analysis and emerging data from Part 1, Part 2 of the study started in which up to 84 
subjects will be assigned to 1 of 3 treatment groups of up to 28 subjects each, randomised in a 1:1:1 
ratio. Up to a maximum of 84 subjects in total will be enrolled in Part 2. 
 
Randomisation numbers will be assigned sequentially in ascending order; and once assigned, that 
randomisation number shall not be reassigned. The study site will keep a log of the randomisation 
number assigned to each subject. 
 
The randomisation schedule will be used to assign the subject to one of the three treatment arms in 
Part 1 of the study (EDP-938 at 600mg OD or 500mg LD followed by 300 mg BD or placebo).  A 
randomization number will be used to link the subjects place in the randomization schedule to their 
identity in the EDC system. The randomisation schedule and assigned randomisation number in Part 
2 of the study will determine whether a subject receives EDP-938 at 400mg LD followed by 200mg BD 
or 600mg LD followed by 300mg OD or placebo.  
 
For the purposes of statistical analysis, placebo subjects from Part 1 will be analysed as a single placebo 
treatment group, as will placebo subjects from Part 2 based on the assumptions that the placebo 
substance is expected to be completely inert and have no antiviral properties and subsequently no 
effect on the efficacy endpoints and their analyses. 
 
A designated unblinded statistician, separate from the conduct or analysis of the study, will be 
responsible for the computer-generated randomisation schedule. Sealed copies of the randomisation 
code will be stored in a secure location.  
Randomisation numbers will follow a 5-digit format e.g. Part 1 will start with 10001, 10002, etc, and 
Part 2 will start with 20001, 20002, etc. A copy of the randomisation code list will be sent to the 
unblinded pharmacist/designee preparing the IMP, so that EDP-938/placebo can be prepared for each 
subject as appropriate. 
6.3. Time and Events Schedule 
Details of the timing of study assessments and procedures can be found in Table 2 below. Where 
appropriate, additional safety procedures may be performed at the Study Physician’s discretion. 










 hVIVO Services Ltd/ENA-CS-001 
 
 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 19 of 154 
 
 
Version 02-00, 01 NOV 2019 
 
KEY NOTES FOR TIME AND EVENTS SCHEDULE 
 
X 
Once 
BD 
Twice Daily, 12 hours between assessments (± 1 hour). 
TDS 
Three Times Daily, at the same time each day (± 1 hour). 
T 
To determine tolerance of the procedure only (sample will not be tested). 
+ 
Only the applicable Inclusion/Exclusion criteria will be reviewed at each time point. 
a 
Subjects will be assigned a randomisation number once the decision to dose is confirmed (i.e. RSV RNA positive confirmed by 
qicPCR). 
b 
Subjects will be randomised to a dose group after RSV infection has been confirmed by qicPCR. qicPCR will be conducted on 
study Day 2 AM through to Day 5 (Study Day 5 morning only), or until a positive result is achieved, whichever is sooner. For 
subjects who still have no positive result obtained by qicPCR, dosing will then start in the evening of Study Day 5.   
 
Part 1:  
• 
5 consecutive days of dosing in three treatment groups: 
o 
Group 1: Placebo (n=38); subjects in this group will receive placebo dose BD every 12 hours (±1 hour) interval 
for a total of 10 doses. 
o 
Group 2: EDP-938 oral 
 loading dose group (n=38): subjects in this will receive 500mg first dose, 
and at 12 hours (±1 hour) interval receive 300mg second dose, then 300mg doses BD for a total of 10 doses. 
o 
Group 3: EDP-938 oral 
 600mg dose group (n=38): subjects in this group will receive a daily  
600mg dose followed by a placebo dose at 12 hours (±1 hour) interval for a total of 10 doses.   
 
Part 2: 
• 
5 consecutive days of dosing in three treatment groups: 
o 
Group 1 (n=21): Placebo dosed TWICE daily (BD) for 5 days, with dosing at 12 hours (± 1 hour) interval,   
o 
Group 2 (n=21): A single Loading Dose of 400mg (Dose 1) and at 12 hours (± 1 hour) interval receive a 
200mg second dose, then 200mg doses BD every 12 hours (± 1-hour interval) and with dosing for 5 days, 
o 
Group 3 (n=21): A single Loading Dose of 600mg (Dose 1), followed by a 300mg dose ONCE a day (OD) 
(every 24 hours (±1 hour) interval) dosing, and with dosing for 5 days. 
 


 hVIVO Services Ltd/ENA-CS-001 
 
 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 20 of 154 
 
 
Version 02-00, 01 NOV 2019 
 
In order to maintain the study blind, subjects in the active OD dosing group will have their regimen supplemented by the 
administration of a placebo matched to EDP-938 in order to mimic the BD dosing group. 
c 
Height will be taken at Screening only.  
d 
Distribution of paper issues and bags will start on Day -1, with the first collection on Day 0. Thereafter distribution 
and collection of tissues will occur at 08:00 (± 1 hour). Tissues will be handed out daily and collection will occur until discharge 
from quarantine. 
e 
Spirometry will be performed at the same time each day during quarantine (± 1 hour). 
f 
A serum follicle stimulating hormone (FSH) test will be performed in all post-menopausal women 
g 
Blood serum pregnancy test (ß-HCG) will be performed in all female subjects 
h 
Blood will be drawn under non-fasted conditions.  
Repeat bloods may be drawn under fasted conditions if a lipid profile (cholesterol and triglyceride) or glucose is required (at PI 
discretion).  
i 
Virus serology (RSV neutralisation antibody assay) will be performed within 90 days of inoculation to determine eligibility, on 
entry to Quarantine, and at Day 28 Follow-up Visit 
j 
Nasopharyngeal swab for respiratory virus screen to assess for the presence of other respiratory viruses. 
k 
Nasal wash virology/ Pharmacokinetics samples will be collected at the same time each day during quarantine (± 1 hour) and 
used for RT-qPCR, and may be used for other secondary or exploratory assessments 
 
  
Samples collected between Days 2 and 5 (Study Day 5 Morning) will also be used for qicPCR until a positive result is received 
(to support dosing decisions). 
l 
Plasma Pharmacokinetics: plasma samples for IMP assay will be collected as outlined in Appendix 7 (PK Blood Sampling 
Schedule): 
 
The allowable time windows for the sampling are as follows: 




 hVIVO Services Ltd/ENA-CS-001 
 
 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 22 of 154 
 
 
Version 02-00, 01 NOV 2019 
 
p 
When historical pre-screening data collected through the hVIVO generic screening process within 56 days to 3 days prior to 
inoculation (90 days for viral serology) is used for screening procedures, the study specific ICF will be obtained at quarantine 
admission (Day -2/-1) from each subject before any study specific procedures are performed. 
q 
Only Subjects who started IMP dosing on the evening of Study Day 5 (up to Day 8 evening) post Viral Challenge for up to 7 days 
dosing regimen (Part 2) will return for PK sampling on Study Day 13, 14,  15, 16, 17 and 18 (as applicable) in order to obtain the 
PK sample(s) associated with the final dose of IMP, for the pre-dose, 0.5-hour, 1-hour, 2-hour, 3-hour, 4-hour, 5-hour, 6-hour, 8-
hour, 10-hour, 12-hour, 15-hour, 24-hour, 30-hour, 36-hour, 48-hour, 60-hour, and 72-hour post final dose time points as 
applicable. 
r 
ECGs will also be recorded:  
 
• 
First IMP dose (Dose 1): pre-dose, 4 and 8 hours after the initial dose  
• 
Dose 2 to Dose 6: pre-dose  
• 
Last IMP dose: 24 and 48 hours post last dose  
 
All pre-dose ECGs can be obtained up to 2 hours prior to dosing.  Post dose ECGs will be obtained ± 30 minutes of the target 
time.  
Notes: 
Parenthesis indicates the assessment may be optional, or at the PI/Investigator's discretion, or as required relative to the start of 
IMP dosing. 
For all subjects TDS assessments will commence on Day 0, the first assessment will be pre-virus challenge. 
The PI/Investigator may perform additional safety assessments as required. 
Where any nasal sampling time points occur together, the order of sampling will typically be (1) Nasopharyngeal swab followed 
by (2) Nasal wash. 


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 Statistical Analysis Plan Page 23 of 154 
Version 02-00, 01 NOV 2019 
6.4. Interim Analysis / Data Monitoring 
No interim analysis of the data will be performed, as the results from Part 1 are not to be combined 
with Part 2. However, as specified in the protocol, an analysis of Part 1 data will be performed prior to 
starting Part 2 of the study, as described below: 
Part 1 data analysis will be reported after completion of Part 1, and based on these results, Part 2 of 
the study will commence. The Part 1 data analysis will produce the full set of data presentations for all 
Part 1 endpoints as presented in this SAP. This SAP will be finalised before any unblinding of Part 1 of 
the study. 
Part 2 will commence after an evaluation by the Sponsor and Investigator of the virology, clinical 
symptom score, PK, and safety data from Part 1. The Sponsor will review the emerging data to confirm 
dose(s) and dose frequencies to be evaluated in Part 2.  


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 24 of 154 
Version 02-00, 01 NOV 2019 
7. STUDY ENDPOINTS 
Note: This section is based on the Study Objective and Endpoints Section (Section 6) of the protocol. 
For further detail on specific endpoint definitions and/or methods of analysis please refer to SAP 
Section 10. 
In order to look at the antiviral effect of EDP-938, all efficacy endpoints will use the measurement 
collected at the time of the first dose of IMP as the starting point in their derivations. For viral load 
endpoints this will be the last measurement collected prior to first dose of IMP, but for symptoms and 
temperature this will be from the assessment at the time of the first dose of IMP (which can be prior 
to or after dosing, depending on whether the subject is dosed in the morning or evening).  
7.1. Primary Endpoint 
The primary endpoint is the Area Under the Curve (AUC) of RSV viral load measured in nasal washes 
by quantitative reverse transcription polymerase chain reaction (RT-qPCR), in subjects inoculated with 
RSV-A Memphis 37b. 
7.2. Secondary Endpoints 
7.2.1. Efficacy 
The secondary efficacy endpoints include, but are not limited to: 
• 
Clinical symptoms:  
o Effect of EDP-938 compared to placebo on RSV symptoms, (using the 10- item diary 
card), with endpoints including:  
 AUC of total symptom score 
 Peak total symptom score over the duration of quarantine 
 Total symptom score  
 Time to peak symptom score after IMP dosing.  
 Time to resolution from peak symptom. 
 
o Total weight of nasal mucus produced (via weighed paper tissues)  
• 
Viral load: 
o Additional viral load endpoints calculated separately using data from RT-qPCR of 
nasal wash comparing EDP-938 and placebo including:  
 
Peak viral load  
 
Time to peak viral load  
 
Time to resolution from peak  
 
Time to cessation of virus quantifiable post first dosing 
7.2.2. Safety 
Secondary endpoints relating to safety include, but are not limited to: 
• 
AEs 
• 
Physical Examinations 
• 
Vital signs 
• 
12-lead ECGs 


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 25 of 154 
Version 02-00, 01 NOV 2019 
• 
Spirometry 
• 
Clinical laboratory results (including biochemistry, haematology, coagulation (if required), 
cardiac enzymes and urine analysis 
7.2.3. Pharmacokinetics 
 
Secondary endpoints related to PK include, but are not limited to: 
• 
Plasma PK parameters of EDP-938 (and metabolites, i.e. EP-024636, EP-024594, and EP-
024595) following repeat dose administration in healthy adult subjects inoculated with RSV-A 
Memphis 37b: Cmax, Tmax, t1/2, CL/F (parent only), λz, Vd/F (parent only), C12, C24, AUClast, AUC0-
tau, or AUC0-inf. 
Note: The details of the PK calculations and non-compartmental analysis will be provided in a 
separate PK Analysis Plan (which is shown in Appendix 15.2). 
• 
Plasma PK (AUC) correlations with viral load AUC (e.g. RT-qPCR) and TSS AUC 
7.3. Exploratory Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 26 of 154 
Version 02-00, 01 NOV 2019 
8. SAMPLE SIZE 
The protocol specified (Section 16.2) sample size details are as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Note: The results for Part 1 showed that the sample size assumptions above were a reasonable and/or 
a conservative approximation, hence for Part 2, two active treatment arms and one placebo group 
were selected, and described above, each group will include 21 subjects (63 subjects in total).  
 


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 27 of 154 
Version 02-00, 01 NOV 2019 
9. STUDY ANALYSIS SETS 
Analysis sets defined below will be reviewed against the study database at a blinded data review 
meeting (BDRM). The database at this time will be nearly final (i.e. the meeting may result in further 
data queries/changes post meeting), so inclusion/exclusion of subjects from analysis sets defined at 
this meeting will be further checked (post meeting) against a final locked database, and will then be 
finalised prior to unblinding each study Part. 
For all analysis sets, subjects who receive a different treatment (EDP-938 or placebo) to the one they 
were randomised to, will be presented against the treatment they actually received.  
The following analysis sets should be taken in combination with the relevant pre-defined subgroups 
stated in Section 10.1.6, as collectively they show all populations and subgroups to be used in the 
analyses described in this SAP. 
9.1. Intent to Treat (ITT) Analysis Set 
The Intent to Treat (ITT) Analysis Set is defined as all randomised subjects receiving Challenge Virus 
and at least one dose of IMP. The ITT analysis set will be considered a secondary analysis population 
for efficacy endpoints. 
9.2. Intent to Treat Infected (ITT-I) Analysis Set 
The Intent to Treat Infected (ITT-I) Analysis Set is defined as all randomised subjects receiving Challenge 
Virus and at least one dose of IMP, and meeting the criterion for laboratory confirmed RSV infection 
(see below for definition of laboratory confirmed RSV infection). The ITT-I analysis set will be 
considered the primary analysis population for efficacy endpoints. 
As per Section 4.2 in the protocol, a laboratory-confirmed RSV infection is defined as the presence of 
viral shedding, measured in nasal wash. Subjects with incomplete data and no recorded data meeting 
the definition of this endpoint will be treated as not having met the endpoint. 
A subject will fulfil the criteria for viral shedding if: 
• 
At least two positive detections by viral load RT-qPCR assay specific for the challenge virus, 
reported within two consecutive study days 
and/or 
• 
One positive detection by viral load RT-qPCR assay, specific for the challenge virus, in which an 
aliquot of the same sample has also tested positive in a cell based infectivity assay appropriate 
for detecting the challenge virus. 
For RT-qPCR and the cell based infectivity assay a positive detection is any positive numeric or 
“detected” value. 
Note: ’Not Detected’ log10 copies/mL titre values as reported from RT-qPCR analysis correspond to 
‘No’ for the reporting of occurrence of viral shedding. 
 


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 28 of 154 
Version 02-00, 01 NOV 2019 
9.3. Intent to Treat Infected Pre-Dose (ITT-A) Analysis Set 
The Intent to Treat Infected (ITT-A) Analysis Set is defined as all randomised subjects receiving 
Challenge Virus and at least one dose of IMP, and meeting the criterion for laboratory confirmed RSV 
infection (see Section 9.2 for definition of laboratory confirmed RSV infection) using only assessments 
prior to taking IMP. The ITT-A analysis set will be considered a secondary analysis population for 
efficacy endpoints. ITT-A will be a subset of ITT-I. 
Note: The assessments prior to dosing with IMP will include all RT-qPCR assessments performed before 
dosing, including the assessment immediately prior to dosing. In addition, if the infection is seen (via 
a positive RT-qPCR value) prior to first dose of IMP but the confirmatory value (as per the first part of 
the viral shedding definition in Section 4.2 of the protocol) is taken after IMP, then that the subject is 
declared as infected prior to IMP, and hence will fall into the ITT-A Analysis Set.  
9.4. Intent to Treat Infected Post-Dose (ITT-B) Analysis Set 
The Intent to Treat Infected (ITT-B) Analysis Set is defined as all randomised subjects not already in the 
ITT-A Analysis Population, receiving Challenge Virus and at least one dose of IMP, and meeting the 
criterion for laboratory confirmed RSV infection (see Section 9.2 for definition of laboratory confirmed 
RSV infection) using only assessments after IMP. The ITT-B analysis set will be considered a secondary 
analysis population for efficacy endpoints. ITT-B will be a subset of ITT-I. 
Note: The assessments after dosing with IMP will include all RT-qPCR assessments that are after the 
RT-qPCR assessment that is immediately prior to dosing. 
9.5. Per Protocol (PP) Analysis Set 
The Per Protocol (PP) Analysis Set is defined as all ITT-I Analysis Set subjects who have no major 
protocol deviations (as defined in Section 10.3), and who complete the quarantine period up to the 
final day of Quarantine (Study Day 12) and receive all doses of IMP. Subject exclusions will be 
determined at a BDRM, which will take place prior to database lock.  The PP Analysis Set will be 
considered a secondary analysis population for efficacy endpoints. 
9.6. Safety Analysis Set 
The Safety Analysis Set is defined as all subjects receiving Challenge Virus, regardless of whether they 
have received IMP or not. The baseline and safety analyses will be performed on the Safety Analysis 
Set. 
9.7. PK Analysis Set 
The PK Analysis Set is defined as all ITT subjects with at least one post-dose PK result. The PK analyses 
will be performed on the PK Analysis Set. 
 


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 29 of 154 
Version 02-00, 01 NOV 2019 
10. PLANNED STATISTICAL METHODS 
10.1. Statistical Considerations 
10.1.1. General definitions 
In all applicable summary/analysis presentations of safety endpoints, Baseline is defined as the last 
non-missing assessment value for a subject, for that particular parameter, that is prior to inoculation 
of challenge virus unless over-ruled after review of data at the BDRM or otherwise stated in the 
appropriate endpoint section(s) below, whatever the reason for that assessment (e.g. if it is a repeat 
assessment, then it should be used as the baseline). For efficacy endpoints, the baseline definition is 
as per the appropriate endpoint sections below. For the derivation of most efficacy endpoints, the first 
assessment to be used should be the assessment that was taken at the time of first dose. For example, 
if a subject was first dosed in the morning of Day 3 then the first RT-qPCR value to be used in the AUC 
of RT-qPCR viral load (from time of first dose) derivation should be the Day 3 morning assessment. 
For subjects that extend their time in quarantine beyond Day 12, the additional assessments beyond 
Day 12 will be listed only, and will not be used for the derivation of any efficacy endpoints. For the 
avoidance of doubt, the last scheduled efficacy assessment for those subjects not extending their time 
in quarantine, will be the Day 12 morning assessment. So, if additional assessments are taken on Day 
12, then they will be listed only. 
A subject will be considered to have completed the study after his/her attendance at the last planned 
study visit (Day 28 (+ 3 days)), or the last unscheduled visit (if any occur), as applicable. 
Within summary presentations/analyses it is envisaged that only scheduled protocol visit values will 
be used for post-baseline time points. On the clinical database a number of data points have been 
labelled as unscheduled/additional recordings of data. These data points will be included within 
subject Listings only. However, at the BDRM the occurrence of such non-scheduled data will be 
reviewed for each subject to decide if (and how) any such data point(s) should be included within 
summary presentations/analyses. Any such decisions will be documented in the BDRM minutes. 
Where endpoints with assessments on Day 0 (either pre or post challenge) data is to be reported or 
used in algorithms, the assessments on Day 0 for those endpoints will be compared to the date and 
time of inoculation to ensure they are pre or post challenge, respectively. 
10.1.2. Data Presentation 
The full list of TFLs to be produced for the final study analysis are shown in Section 13, and the specific 
format and content of each data Table/Listing presentation is shown in Section 14. 
Summary Tables and Figures will be presented by treatment group (and also for all subjects, for 
selected data presentations). Parts 1 and 2 will be presented separately. Within all Tables and Figures 
values for treatment in Part 1 will be labelled as follows: 
• 
“EDP-938 600mg OD” 
• 
“EDP-938 500mg LD/300mg BD” 
• 
“Placebo” 
The ordering of treatments shown here represents the order they will appear in Tables.  


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 30 of 154 
Version 02-00, 01 NOV 2019 
Within all Tables and Figures, treatment in Part 2 will be labelled as follows: 
• 
“EDP-938 600mg LD/300mg OD” 
• 
 “EDP-938 400mg LD/200mg BD” 
• 
 “Placebo” 
The ordering of treatments shown here represents the order they will appear in Tables. 
The scheduled protocol visits will be labelled in (applicable) report presentations as follows: 
• 
Screening 
• 
Day -2 or Day -1 or “Admission”, as appropriate 
• 
Day 0 
Note: Within some summary Tables only “Baseline” may be shown (as applicable) instead of the above 
scheduled visits. 
• 
Day x (x=1,…12, as collected, to be included within summary Table) 
• 
Day 28 (FU) 
• 
Withdrawal 
Unscheduled visit data will be labelled as “Unscheduled” together with a date in data Listings. 
Where duplicate information is collected on both the database and on the vendor data transfer(s) (e.g. 
sampling date and time) this information will be reconciled by data management and then the 
information from the vendor data transfer(s) will be included in subject Listings. 
All variables will be listed to the same number of decimal places as reported.  Descriptive statistics for 
all endpoints that are continuous data will have the following summary statistics presented in the 
following order:  n, (arithmetic) mean (rounded to one more decimal place than recorded), geometric 
mean (for pre-specified endpoints only) (rounded to one more decimal place than recorded), standard 
deviation (rounded to two more decimal places than recorded), %CV (coefficient of variation) (rounded 
to one decimal place), %GCV (geometric coefficient of variation, for pre-specified endpoints only) 
(rounded to one decimal place), standard error (for pre-specified endpoints only) (rounded to two 
more decimal places than recorded), median (rounded to one more decimal place than recorded), 
lower and upper quartiles (rounded to one more decimal place than recorded), minimum (as 
recorded), and maximum (as recorded). 
Note: for endpoint(s) that require a geometric mean to be produced, and those endpoint(s) can have 
raw values of 0 (zero), the geometric mean calculation will add an appropriate constant value to all 
raw values prior to logging and will subtract that constant value from the final calculated anti-logged 
mean. The constant value used will be documented in the footnote of the tables. An example of such 
a calculation is shown below: 
Geometric Mean = anti-log {mean (logged (base 10) endpoint values + 1)} - 1  
Categorical variables will be summarised using proportions (counts and percentages). The specific 
approach to calculating percentages (relevant denominator) is detailed within each (relevant) Table 
template (Section 14). 


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 31 of 154 
Version 02-00, 01 NOV 2019 
Unless otherwise stated in the appropriate endpoint section(s) below, laboratory/efficacy parameter 
values that are below the level of quantification (BLQ) will be set to zero in computations for summary 
presentations and analysis but will be noted as below the limit of quantification in subject Listings.  
10.1.3. Statistical Testing and Estimation 
Hypothesis testing will be performed for the primary and secondary efficacy endpoints, as specified 
and described in Sections 10.7.1 and 10.7.2. Analyses will be performed between each EDP-938 
treatment group and the placebo group, and also between the two EDP-938 treatment groups.  
All statistical analyses will be performed using appropriate two-sided hypothesis tests. P-values will be 
rounded to 3 decimal places. All p-values that round to 0.000 will be presented as <0.001 and p-values 
that round to 1.000 will be presented as >0.999. 
10.1.4. Handling of Dropouts or Missing Data 
In general, missing data will not be imputed and all summary statistics will be reported based upon 
observed data. For a limited number of summary presentations, missing data rules will be introduced. 
In particular methods of handling missing data for the efficacy endpoints (Section 10.7), incomplete 
dates for adverse events (Section 10.8.1) and incomplete dates for concomitant medications (Section 
10.5) are presented. For any other data which has partial dates, which are required for use in time 
related calculations, these dates will be completed using a suitably conservative approach. Dates will 
be shown in subject Listings as they have been recorded. 
10.1.5. Multiple Comparison/Multiplicity 
As this is an early phase study, with the main objectives being safety and PK, no adjustments will be 
made to handle multiplicity. 
10.1.6. Examination of Subgroups 
It was intended that certain pre-selected endpoints were to be repeated for the subgroup ‘Laboratory 
confirmed infected’. This subgroup is defined as those subjects who are laboratory-confirmed infected 
(by viral shedding, see Section 9.2). However, the ITT-I, ITT-A and ITT-B analysis sets already 
incorporate this subgrouping definition, and hence there is no need to subgroup any analysis sets 
further.  
10.1.7. Model checking and sensitivity analyses 
No model checking will be performed.  For each comparison between treatment group performed 
using an ANCOVA, the Wilcoxon rank-sum test with two-sided 5% statistical significance, will also be 
provided. 
10.1.8. Software 
Data will be reported using SAS (version 9.4 or later). 
10.1.9. Data Conversion (CDISC) 
For the reporting of this study both CDISC SDTM (SDTM Implementation Guide version 3.2) and ADaM 
(ADaM Implementation Guide version 1.1) standards will be applied. One set of CDISC data sets will be 
provided containing data from Part 1 and Part 2. 


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 32 of 154 
Version 02-00, 01 NOV 2019 
10.2. Subject Disposition 
The subjects inoculated, randomised, receiving at least one dose of IMP, withdrawing (including reason 
for withdrawal) from and completing the study, and the analysis populations will be summarised by 
treatment group and across all subjects. 
The number of subjects attending each of the following scheduled visits will be listed for all subjects: 
Screening, Day -2/-1 (or Admission), Day 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 28 (FU) and Withdrawal. 
10.3. Protocol Deviations  
Subject data will be reviewed for major protocol deviations by a qualified clinical reviewer prior to 
database lock and unblinding, at the blinded data review meeting (BDRM). Subjects with any major 
protocol deviations will be documented within the BDRM minutes, and such subjects will be excluded 
from the PP analysis set.  
Protocol deviations will be listed. 
10.4. Demographic and other baseline characteristics 
The Safety Analysis Set will be used in all presentations of demographic and baseline data. No statistical 
testing will be used to compare treatments for different baseline characteristics. 
10.4.1. Demographics 
Demographic variables at screening (sex, age, ethnicity, race, height (cm), weight (kg), and body mass 
index (BMI) (kg/m2) [BMI is recorded on the case report form (CRF) and included within the study 
database, therefore it does not require derivation]), will be summarised by treatment group and across 
all subjects.  
10.4.2. Other Baseline Characteristics 
Smoking history and alcohol consumption will be summarised by treatment group and across all 
subjects for the following items: 
• 
Smoking history status (Never smoked / current smoker / previous smoker) 
• 
Alcohol history status (Never / current / previous) 
All substance use history data will also be listed. Recreational drugs of abuse will also be listed. 
10.4.3. Medical History 
As stated in the protocol, medical history data will be listed. Medical History will be coded using 
MedDRA, Version 21.1. 
10.5. Prior and Concomitant medications 
Concomitant medication terms will be coded using the World Health Organisation (WHO) Drug 
Dictionary Enhanced (WHO Drug Global Version 2018:3, September 1, 2018). Medications will be 
assigned as being prior to or concomitant with IMP treatment (i.e. given prior to or after receiving IMP 


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 33 of 154 
Version 02-00, 01 NOV 2019 
treatment) based on the start and stop dates of the medication and the date of receiving IMP 
treatment. 
If the medication stop date is before the date of inoculation, the medication will be assigned as being 
prior to inoculation. If the medication stop date is before the date of IMP treatment, the medication 
will be assigned as being prior to IMP treatment. In all other situations, the medication will be assigned 
as being concomitant with the IMP treatment.  
Note: Start and Stop times will not be used for determining if a medication is concomitant or not. 
All concomitant medications will be separately summarised, using the Safety Analysis Set, by treatment 
group (and across all subjects), Drug Class (L2) and generic name. Prior (to inoculation and IMP) 
medications will be identified in a subject listing. If a subject has separate periods of taking specific 
medications, then that medication is only counted once within the period of observation (i.e. prior to 
inoculation, prior to IMP or concomitant) where it is taken. 
10.6. Treatment and Inoculation exposure  
The number of subjects inoculated and the number of subjects receiving IMP treatment will be 
summarised (as part of the Subject Disposition data presentations (Section 10.2)). 
10.7. Efficacy Analysis 
In terms of the efficacy analysis, the primary analysis will be based on the ITT-I analysis set, with 
secondary analyses populations based on the ITT-A, ITT-B, ITT and PP analysis sets. Only the primary 
and main secondary efficacy endpoints, as stated in Sections 7.1 and 7.2.1, will be presented on all of 
these analysis sets if they contain different subjects. All efficacy endpoints that relate to symptom 
scores will be based on the 10-item symptom diary card 
 
 
10.7.1. Primary Efficacy Analysis 
The primary endpoint is the AUC of RSV-A Memphis 37b viral load measured in nasal washes by RT-
qPCR, from the measurement collected at the time of the first dose of IMP until the last measurement 
collected up to Day 12 (Quarantine discharge). The viral load data will be supplied as log10 copies/mL 
and will be used for this primary efficacy analysis and to calculate the AUC using the trapezoid rule [1]. 
AUC will be compared between each dose level of EDP-938 and placebo, separately, and also between 
the two active dose levels of EDP-938, by means of a full set of descriptive statistics and an ANCOVA 
with treatment group as a main effect and the baseline value as a covariate. The baseline value will be 
the RT-qPCR viral load value from the last measurement collected prior to the first dose of IMP. The 
three treatment comparisons will be presented, including the LS means of the treatment differences 
for each comparison together with the corresponding two-sided 95% confidence interval and the p-
values will be presented. The equivalent Wilcoxon rank-sum tests will also be provided. 
The analysis will be performed by the PROC MIXED procedure in SAS using code similar to that below. 
 
proc mixed data=XXXXX; 
class treatment; 
model AUC= baseline treatment / ddfm=kr; 
lsmeans treatment / diff cl; 
run; 


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 34 of 154 
Version 02-00, 01 NOV 2019 
As nasal washes are scheduled to be taken twice daily for Days 2 to 11 (and once on Day 12), in order 
to calculate the AUC, the actual time that the assessment was collected will be used within the AUC 
calculation. The AUC calculation will be based on the available non-missing assessment values between 
the start and end of the defined AUC time period. However, for an AUC to be derived, the subject must 
have at least one non-missing data recording at the start of the AUC period (e.g. date of first dose of 
IMP) and also at the end of the AUC time period (e.g. Day 12). In addition, the subject must have at 
least 1 non-missing data recording on each day between the start and end of the defined AUC time 
period (i.e. at least 1 out of the 2 possible assessments on each Day)). Any missing RT-qPCR data will 
be reviewed at the BDRM, for its potential impact on this endpoint, and any decisions to include 
subjects that fail these criteria above will be documented in the BDRM minutes. 
Note: For the reporting of AUC, where appropriate, RT-qPCR values that are ‘Not Detected’ or are at 
or below the limit of quantification will be re-assigned using the substitution values shown in the table 
in Appendix 15.1.  
As an additional sensitivity analysis, the AUC of RSV viral load measured in nasal washes by RT-qPCR 
will be presented for a fixed time period, from the measurement collected at the time of the first dose 
of IMP to the scheduled assessment occurring 6.5 days afterwards (e.g. if a subject does not have a 
positive qicPCR then they will be dosed on Day 5 (evening) and they will be followed up until Day 12 
(morning) 14 assessments in total) – which represents the longest possible AUC time period where all 
subjects are followed for the same fixed period of time.  
A second sensitivity analysis of AUC of RSV viral load measured in nasal washes by RT-qPCR will be 
presented for a fixed time period, which will include data from the morning assessment on Day 2 (i.e. 
the first RT-qPCR assessment measured) through to Day 12.  
A third sensitivity analysis of AUC of RSV viral load measured in nasal washes by RT-qPCR, from the 
measurement collected at the time of the first dose of IMP until the last measurement collected up to 
Day 12 (Quarantine discharge), will be presented where the AUC will be calculated using a linear scale 
(unlogged) viral load data (i.e. the supplied value will be anti-logged to get a value as copies/mL).   
The AUC analyses will be summarised by treatment group. The same statistical testing methods as 
applied to the main analysis of the primary endpoint will be applied to each sensitivity analysis. For the 
third sensitivity analysis, the individual AUC data will be log-transformed (base 10) prior to statistical 
analysis and the geometric mean and %GCV will be shown. 
As well as a descriptive statistics summary of RT-qPCR values, the mean RT-qPCR values (+/- 1 Standard 
Error (SE)) will be displayed graphically by day (relative to first dose of IMP) and assessment, and 
treatment group. In order to calculate the time point that each assessment will be presented against, 
the last RT-qPCR measurement collected prior to the first dose of IMP will be assigned to be the value 
at time point 1, while measurements collected on subsequent assessments and days will be assigned 
to subsequent time points in sequential order (i.e. time point 2, 3 and so on). Time point 1 will be 
presented against Day 0 assessment 1, while subsequent time points will be presented against Day 0 
assessment 2, Day 1 assessment 1, and so on. 
[Line graph: y-axis = mean of RT-qPCR (log10 copies/mL), x-axis = day relative to dosing, one line for 
each treatment group on same plot]. 
Note: For multiple assessments taken within each day, so as to be able to plot mean values across 
subjects (within a treatment group) by day, the actual collection time point (which may differ across 
subjects) will not be used. Rather all 1st /2nd assessments will have mean values separately calculated 


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 35 of 154 
Version 02-00, 01 NOV 2019 
and plotted as two separate means within each day. These two means will be shown equally spaced 
along the x-axis within the graph.   
10.7.2. Secondary Efficacy Analyses 
Secondary efficacy analyses will be performed on the following endpoints:  
10.7.2.1 
AUC of total symptom score 
Total symptom scores (from the 10-item symptom diary card) will be used to calculate the AUC, from 
the assessment at the time of the first dose of IMP (can be prior to or after dosing, depending on 
whether dosed in the morning or evening), i.e. baseline, until Day 12 (Quarantine discharge), for each 
subject using the trapezium rule [1]. 
Symptoms are recorded on the symptom diary cards, assessed 3 times daily for Day 1 to Day 11 (and 
once for Day 12). The following types of symptoms are recorded (on a grading scale, 0 to 3 (or 0 to 4 
for the Shortness of Breath symptom)): 
• 
Upper Respiratory Tract (URT): runny nose, stuffy nose, sore throat, sneezing, earache. 
• 
Lower Respiratory Tract (LRT): cough, shortness of breath. 
• 
Systemic: headache, malaise, muscle/joint ache/stiffness. 
A total symptom score will be derived for each subject, separately for each assessment (symptom diary 
card) on each day (Day 0 to Day 12) as follows: 
• 
For each assessment, sum the 10 observed symptom grade values for each symptom diary 
card to obtain a total symptom score for each symptom diary card. If the subject does not 
have all 10 observed values on a specific symptom diary card being considered, then total 
symptom score will not be calculated for that symptom diary card. It is expected that subjects 
will not have missing data.  
• 
The AUC calculation will be based on the available non-missing calculated total symptom 
scores between the start and end of the defined AUC time. However, for an AUC to be derived, 
the subject must have at least 1 non-missing calculated total symptom scores at the start of 
the AUC period (e.g. date of first dose of IMP) and also at the end of the AUC time period (e.g. 
Day 12). In addition, the subject must have at least 2 non-missing data recording on each day 
between the day after the start, and the day before the end, of the defined AUC time period 
(i.e. at least 2 out of the 3 possible assessments on each Day)). Any missing total symptom 
score data will be reviewed at the BDRM, for its potential impact on this endpoint, and any 
decisions to include subjects that fail these criteria above will be documented in the BDRM 
minutes. 
• 
As symptoms are scheduled to be taken 3 times daily for Days 0 to 11 (and once on Day 12), 
in order to calculate the AUC, the actual time that the assessment was collected will be used 
within the AUC calculation. 
As an additional sensitivity analysis, the AUC of total symptom score will be presented for a fixed time 
period, from the assessment at the time of the first dose of IMP (can be prior to or after dosing, 
depending on whether dosed in the morning or evening), to the scheduled assessment occurring 6.5 
days afterwards.  
A second sensitivity analysis of AUC of total symptom score will be presented for a fixed time period, 
which will include data from the Day 0 (Pre-Challenge) assessment through to Day 12.  


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 36 of 154 
Version 02-00, 01 NOV 2019 
The AUC of the total symptom score will be summarised by treatment group and modelled in the same 
way as the main analysis of the primary endpoint. 
The total symptom scores will be summarised (including a geometric mean) by timepoint (i.e. day 
relative to first dose of IMP and assessment) and treatment group, and symptom scores from the 
symptom diary card will be listed. 
As well as a descriptive statistics summary of total symptom score values, the mean total symptom 
score values (+/- 1 Standard Error (SE)) will be displayed graphically by day (relative to first dose of 
IMP) and assessment, and treatment group. In order to calculate the time point that each assessment 
will be presented against, the last total symptom score measurement collected at the time of the first 
dose of IMP will be assigned to be the value at time point 1, while measurements collected on 
subsequent assessments and days will be assigned to subsequent time points in sequential order (i.e. 
time point 2, 3 and so on). Time point 1 will be presented against Day 0 assessment 1, while subsequent 
time points will be presented against Day 0 assessment 2, Day 0 assessment 3, Day 1 assessment 1, 
and so on. 
[Line graph: y-axis = mean of total symptoms score, x-axis = day relative to dosing, one line for each 
treatment group on same plot]. 
Note: For multiple assessments taken within each day, so as to be able to plot mean values across 
subjects (within a treatment group) by day, the actual collection time point (which may differ across 
subjects) will not be used. Rather all 1st /2nd /3rd assessments will have mean values separately 
calculated and plotted as three separate means within each day. These three means will be shown 
equally spaced along the x-axis within the graph. 
10.7.2.2 
Peak total symptom score over the duration of quarantine 
Using the scheduled protocol assessments from the assessment at the time of the first dose of IMP 
(can be prior to or after dosing, depending on whether dosed in the morning or evening) to Day 12 
(Quarantine discharge), this endpoint corresponds to the highest total symptom score (defined as the 
sum of all 10 individual composite symptoms). Subjects who had no symptoms will be given a peak of 
0. 
The peak symptom score will be summarised by treatment group and modelled in the same way as the 
main analysis of the primary endpoint. 
10.7.2.3 
Time to peak symptom after IMP dosing 
This endpoint corresponds to the time (days) from the assessment at the time of the first dose of IMP 
(can be prior to or after dosing, depending on whether dosed in the morning or evening) until the 
peak (as defined in Section 10.7.2.2) is observed. If the peak occurs on more than one day then the 
first occurrence is selected. Subjects who stay symptom free during quarantine will have their peak 
assigned to the time of their last assessment. 
The time to peak symptom will be summarised by treatment group and modelled in the same way as 
the main analysis of the primary endpoint. 
10.7.2.4        
Time to resolution from peak symptom 
This endpoint corresponds to the time (days) to resolution of symptoms, which is from time of peak 
symptom until the start of the first 24 hour symptom-free period after the peak. Note: the 24 hour 
symptom-free period has to be a minimum of 24 hours (as measured by the exact assessment dates 


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 37 of 154 
Version 02-00, 01 NOV 2019 
and times) and no symptoms must have occurred during that time period. Subjects who did not have 
a 24 hour symptom-free period after their peak will be assigned to the time of their last assessment. 
Subjects who had no symptoms will be excluded from this analysis. 
The Time to resolution will be summarised by treatment group and modelled in the same way as the 
main analysis of the primary endpoint. 
10.7.2.5        
Total weight of nasal mucus produced  
Total weight of nasal discharge (grams) will be calculated as the sum of mucus weights taken from the 
assessment at the time of the first dose of IMP (can be prior to or after dosing, depending on whether 
dosed in the morning or evening) to Day 12 (Quarantine discharge). Total mucus weight will be 
summarised by treatment group. The same statistical testing methods as applied to the main analysis 
of the primary endpoint will be applied. 
As well as a descriptive statistics summary of total weight of nasal discharge, the mean weight of nasal 
discharge values (+/- 1 Standard Error (SE)) will be displayed graphically by day (relative to first dose 
of IMP) and assessment, and treatment group. In order to calculate the time point that each 
assessment will be presented against, the last weight of nasal discharge measurement collected prior 
to the first dose of IMP will be assigned to be the value at time point 1, while measurements collected 
on subsequent days will be assigned to subsequent time points in sequential order (i.e. time point 2, 3 
and so on). Time point 1 will be presented against Day 0, while subsequent time points will be 
presented against Day 1, Day 2, and so on. Also, given that weight of nasal discharge values span a 24 
hour period, the point used for each timepoint will be set midway between each day that forms the 
boundary of each 24 hour time period. 
[Line graph: y-axis = mean weight of nasal discharge, x-axis = day relative to dosing, one line for each 
treatment group on same plot]. 
10.7.2.6 Peak viral load measured in nasal washes by RT-qPCR 
Using the scheduled protocol assessments from the last measurement collected prior to the first dose 
of IMP to Day 12 (Quarantine discharge), this endpoint corresponds to the highest observed RT-qPCR 
viral load value for each subject. Subjects who stay undetectable (i.e. a ’Not Detected’ value) during 
quarantine will be given a peak equivalent to an undetectable value (as shown in Appendix 15.1). 
The peak will be summarised by treatment group and modelled in the same way as the main analysis 
of the primary endpoint. 
10.7.2.7 
Time to peak viral load measured in nasal washes by RT-qPCR 
This endpoint corresponds to the time (days) from the last measurement collected prior to the first 
dose of IMP until the peak is observed. If peak is seen on more than one day, then take first occurrence. 
Subjects who stay undetectable during quarantine will have their peak assigned to the time of their 
last assessment. 
The time to peak will be summarised by treatment group and modelled in the same way as the main 
analysis of the primary endpoint. 
10.7.2.8 
Time to resolution from peak viral load measured in nasal washes by RT-qPCR 
This endpoint corresponds to the time (days) from when the peak value was observed until the first 
confirmed undetectable assessment timepoint (after which no further virus is detected) after the peak 


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 38 of 154 
Version 02-00, 01 NOV 2019 
viral load. Subjects who did not have a confirmed undetectable after their peak will be assigned to the 
time of their last detectable assessment. Subjects who stay undetectable during quarantine will be 
excluded from this analysis. 
The time to resolution will be summarised by treatment group and modelled in the same way as the 
main analysis of the primary endpoint. 
10.7.2.9 
Time to cessation of virus detection post first dosing measured in nasal washes by RT-
qPCR 
This endpoint corresponds to the time (days) from the last measurement collected prior to the first 
dose of IMP until the first confirmed undetectable assessment timepoint (after which no further virus 
is detected) after the peak viral load measured in nasal washes by RT-qPCR. Subjects who did not have 
a confirmed undetectable assessment after their peak are censored at their last detectable 
assessment. Subjects who stay undetectable during quarantine will be excluded from this analysis. 
The time to cessation will be summarised by treatment group. 
Kaplan-Meier plots [2] will be displayed by treatment group showing the time to cessation of virus 
detection (with the time axis as days since peak). A table will accompany the plot and will display the 
Kaplan-Meier estimates of the cumulative proportion of subjects’ event free at specific time points by 
treatment group. In addition, the lower quartile, median and upper quartile of the survival times in 
each treatment group will be presented. A log rank test will be performed to compare the survival 
times between each dose level of EDP-938 and placebo, and also between the two active dose levels 
of EDP-938, and the corresponding p-values will be presented. 
10.7.3. Exploratory Efficacy Analysis 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 39 of 154 
Version 02-00, 01 NOV 2019 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 42 of 154 
Version 02-00, 01 NOV 2019 
severity and the strongest relationship to IMP among those events for the summaries in which those 
characteristics are considered.   
Pre-treatment adverse events will be identified in a subject listing, indicating whether they started 
before or after inoculation of the challenge virus. Treatment emergent adverse events will be 
summarised by: 
• 
Treatment group showing number of events, number of subjects with events (also split by 
severity; mild, moderate, severe, life-threatening, death), number of subjects with SAEs, 
number of subjects with related events, number of subjects with events leading to 
discontinuation from the study, number of subjects with events leading to discontinuation of 
dosing;   
• 
Treatment group, system organ class, and preferred term;   
• 
Treatment group, system organ class, preferred term and severity (Mild / Moderate / Severe); 
• 
Treatment group, system organ class, preferred term and relationship to IMP; 
This Table will only include the subset of adverse events that are judged as being ‘Related’ to 
treatment, i.e. correspond to adverse events where relationship to IMP is recorded on the 
adverse event page as being ‘Unlikely to be related’, ‘Possibly related’, ‘Probably related’, 
‘Definitely related’, or a relationship is not given.  Relationship sub-categories will be displayed 
in addition to overall numbers. 
The summary by relationship to IMP will be repeated for all adverse events by relationship to challenge 
virus. 
Serious adverse events (SAEs) and adverse events directly resulting in withdrawal from study will be 
listed by treatment group.  
In all adverse event summary tables results will be displayed ordered alphabetically by SOC and also 
preferred term within SOC.  
10.8.2. Laboratory Variables 
The following haematology, biochemistry, coagulation (if required), cardiac enzyme, thyroid function 
tests, human immunodeficiency virus and hepatitis A, B and C and urinalysis parameters (as shown 
within Section 14 of the protocol) will be included within subject listings (and presented in the units as 
shown) and summary tables where relevant: 
• 
Haematology: platelet count (10^9/L), white blood cell (WBC) count (absolute) (10^9/L), 
neutrophils (% and absolute (10^9/L)), lymphocytes (% and absolute (10^9/L)), monocytes (% 
and absolute (10^9/L)), eosinophils (% and absolute (10^9/L)), basophils (% and absolute 
(10^9/L)), red blood cell (RBC) count (10^12/L), reticulocyte count (% and absolute (10^9/L), 
haemoglobin (g/L), haematocrit (%), mean corpuscular volume (MCV) (fL), mean corpuscular 
haemoglobin (MCH) (PG), mean corpuscular haemoglobin concentration (MCHC) (g/L). 
• 
Biochemistry: sodium (mmol/L), potassium (mmol/L), glucose (mmol/L), serum albumin (g/L), 
chloride (mmol/L), bicarbonate (mmol/L), calcium (mmol/L), uric acid (umol/L), total protein 
(g/L), creatinine (umol/L), total bilirubin (umol/L), indirect bilirubin (umol/L), direct bilirubin 
(umol/L), phosphate (mmol/L), blood urea nitrogen (mg/dL), C-reactive protein (CRP) (mg/L),  
gamma glutamyl transferase (GGT) (IU/L), alkaline phosphatase (ALP) (IU/L), alanine 


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 43 of 154 
Version 02-00, 01 NOV 2019 
transaminase (ALT) (IU/L), lactate dehydrogenase (LDH) (IU/L),  aspartate transaminase (AST) 
(IU/L), urea (mmol/L). 
• 
Coagulation: prothrombin time (PT) (secs), activated partial thromboplastin time (APTT) (secs). 
• 
Cardiac Enzymes: creatine kinase (IU/L), CK-MB (ug/L), troponin T (ng/L) 
• 
Thyroid Function Tests: Free thyroxine (pmol/L), Thyroid Stimulating Hormone (mIU/L) 
• 
Human Immunodeficiency Virus and Hepatitis A, B and C: HIV-1 and HIV-2 antibodies, hepatitis 
A antibodies (HepA IgM), hepatitis B surface antigen (HBsAg), hepatitis C antibodies (HCAb).  
• 
Urinalysis: colour, specific gravity, appearance, pH, blood, glucose, leukocytes, ketones, nitrite, 
protein, urobilinogen, bilirubin. 
 
Laboratory data collected in different units to that shown will be converted to the above specified units 
(if possible) for presentation in subject Listings. 
Summary statistics for absolute and changes from baseline by timepoint will be tabulated, by 
treatment group, for absolute laboratory parameters (i.e. haematology, biochemistry, coagulation, 
cardiac enzymes and thyroid function tests). 
Laboratory parameters (Haematology, Biochemistry, Coagulation (if required), Cardiac Enzymes, 
Human Immunodeficiency Virus, Hepatitis A, B and C and Urinalysis) will be included in subject listings. 
Laboratory values outside the normal range will be identified in subject listings as above or below the 
normal range.  
Unscheduled visit assessments will be included within subject listings. 
10.8.3. Vital Signs 
Summary statistics for absolute and changes from baseline will be tabulated, by timepoint and by 
treatment group, for vital signs parameters (systolic blood pressure (SBP) (mmHg), diastolic blood 
pressure (DBP) (mmHg), respiratory rate (RR) (breaths per minute), heart rate (HR) (beats per minute) 
and SpO2 (%)) and will be included within subject listings. 
10.8.4. Physical Examination 
Physical examination findings (both for complete examination and also directed examination 
assessments) will be included within subject listings. 
10.8.5. Spirometry 
Summary statistics for absolute values and change from baseline by time point will be tabulated, by 
treatment group and all subjects, for spirometry parameters (FEV1(absolute), FEV1(% predicted), 
Forced vital capacity (FVC) (absolute), FVC (% predicted), FEV1/FVC ratio (absolute), FEV1/FVC ratio (% 
predicted)) and will also be included within subject listings. 
For the calculation of baseline, the mean of all assessments between Day -2 and Day 0 (pre-
inoculation), inclusive, will be used.   
10.8.6. 12-Lead ECG 
Summary statistics for absolute values and change from baseline by time point will be tabulated, by 
treatment group and all subjects, for ECG parameters (Heart Rate (bpm), PR interval (sec), QRS 


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 44 of 154 
Version 02-00, 01 NOV 2019 
duration (sec), QT interval (sec), QTc interval (sec), QTcB interval (sec), QTcF interval (sec) and RR 
interval (sec)) and will also be included within subject listings. 
10.9. Pharmacokinetic Analysis 
The PK analysis set will be used for all PK presentations. No statistical analysis of PK data will be 
performed. 
10.9.1.1  
Plasma EDP-938 PK Parameters 
Plasma PK parameters for EDP-938 and its metabolites will be calculated for the first dose and last 
dose of EDP-938 by PRA, and will be supplied to S-cubed for data presentation purposes. The details 
of the PK calculations and non-compartmental analysis will be provided in a separate PK Analysis Plan.  
The summaries described in this section will be repeated for the first and last dose of EDP-938. 
Summary statistics for the plasma PK parameters of EDP-938 following administration in healthy adult 
subjects inoculated with RSV-A Memphis 37b will be tabulated, by treatment group, and will also be 
included within subject listings. The PK parameters to be summarised will include: Cmax, Tmax, t1/2, 
CLss/F, λz, Vss/F, C12, C24, AUC0-last, tlast, AUC0-12 (BD group only), AUC0-24 (OD group only), AUC0-tau, and 
and metabolite-to-parent ratio. 
Similarly, summary statistics for the plasma PK parameters of EDP-938 metabolites (i.e. EP-024636, EP-
024594, and EP-024595) following repeat dose administration in healthy adult subjects inoculated with 
RSV-A Memphis 37b will be tabulated, by treatment group, and will also be included within subject 
listings. The PK parameters for the EDP-938 metabolites to be summarised will include: Cmax, Tmax, t1/2, 
λz, C12, C24, AUClast, tlast, AUC0-12 (BD group only), AUC0-24 (OD group only), and AUC0-tau. 
Where a PK parameter is flagged by PRA, the parameter will be included in the Listings but not included 
in the descriptive summary statistics. Flagging rules are described in the PK Analysis Plan.  
In listings, PK data will be presented with the same precision as the original data. Derived data will be 
rounded for presentation purposes. For summary statistics, PK parameters will be rounded to 3 
significant figures except for Tmax, which will be reported with 2 decimals. 
10.9.1.2  
Plasma EDP-938 Concentrations 
Summary statistics for plasma concentration values by time point will be tabulated, by treatment 
group, for EDP-938 and its 3 metabolites, and will also be included within subject listings. 
Plasma concentrations of EDP-938 and its metabolites below the limit of quantification (BLQ) will be 
set to zero in the computation of mean concentration values. Descriptive statistics will not be 
presented for a given treatment and timepoint if over half the subjects have values BLQ. Instead, BLQ 
will display for the median and minimum and, with the exceptions of n and maximum, and all other 
descriptive statistics will be missing.  
The mean (± SD) plasma concentration of EDP-938 and its 3 metabolites (linear and logarithmic (base 
10) scale) versus scheduled sampling time profiles, by treatment group, will be displayed graphically. 
For the semi-logarithmic scale plot of concentrations, the plasma concentration data will not be 
transformed, but the scale of the y-axis will be in log form, and no error bars will be presented. Mean 
plots will use the BLQ handling procedures described above.  
In addition, individual subject EDP-938 concentration (linear and semi-logarithmic (base 10) scale) 
verses actual time profiles, by treatment group, will be displayed graphically using spaghetti plots. 


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 45 of 154 
Version 02-00, 01 NOV 2019 
For the semi-logarithmic scale plot of concentrations, the plasma concentration data will not be 
transformed, but the scale of the y-axis will be in log form. Individual plots will use the BLQ handling 
procedures described above. These plots will be presented on separate axes for after first dose, after 
last dose, pre-dose troughs, and all timepoints.  The time axes will be broken, as necessary, where 
the scale is not linear (i.e. all timepoints). 
10.9.2  
Plasma PK (AUC) correlations with viral load RT-qPCR AUC and TSS AUC 
For the plots described in this section, the plasma EDP-938 AUC in this section is in relation to the 24-
hour period after the last dose of treatment.  For the OD group this is AUC0-24 and for the BD group an 
equivalent is estimated from AUC0-12 multiplied by 2.  Both treatment groups will be presented on the 
same axis and colour coded. 
A scatterplot (together with a regression line and a correlation coefficient) will be produced displaying 
viral load RT-qPCR AUC (y axis) versus plasma EDP-938 AUC (x axis). 
Similarly, a scatterplot (together with a regression line and a correlation coefficient) will be produced 
displaying (10-item and separately the 11-item) TSS AUC (y axis) versus plasma EDP-938 AUC (x axis). 
Secondly, a quartile plot will be produced displaying viral load RT-qPCR AUC box plots (y axis) versus 
plasma EDP-938 AUC by quartile (Q1, Q2, Q3, Q4) (x axis). 
Similarly, a quartile plot will be produced displaying (10-item) TSS AUC box plots (y axis) versus plasma 
EDP-938 AUC by quartile (Q1, Q2, Q3, Q4) (x axis). 
Thirdly, an Emax model plot will be produced displaying viral load RT-qPCR AUC (y axis) versus plasma 
EDP-938 AUC (x axis).  
Similarly, an Emax model plot will be produced displaying TSS AUC (y axis) versus plasma EDP-938 AUC 
(x axis). 
Fourthly, an Emax model plot will be produced displaying viral load RT-qPCR AUC (y axis) versus plasma 
EDP-938 Ctrough (C12 for BD, C24 for OD relative to the last dose) (x axis). 
Similarly, an Emax model plot will be produced displaying TSS AUC (y axis) versus plasma EDP-938 
Ctrough (C12 for BD, C24 for OD relative to the last dose) (x axis). 
10.9.3  
Nasal Wash EDP-938 Concentrations 
 
 
 


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 46 of 154 
Version 02-00, 01 NOV 2019 
11. CHANGES TO THE PROTOCOL SPECIFIED ANALYSIS DETAILED IN THE 
STATISTICAL ANALYSIS PLAN 
 
• 
The following exploratory endpoints have been defined in the protocol, but will be presented 
outside of this SAP: 
o 
 
 
 
 
 
• 
The secondary PK endpoints: 
o  of AUC0-inf will not be presented    
o CLss/F and Vss/F will be presented instead of CL/F and Vd/F. 
• 
 
 
 
 
 
 
 
 
 
 
 
• 
The following changes were documented at the BDRM prior to data lock and unblinding of 
Part 1 of this study.  These changes are included in the current SAP Amendment. 
o The following clarifications were made to the definition of viral shedding. 
A subject will fulfil the criteria for viral shedding if: 
• 
At least two positive quantifiable detections by viral load RT-qPCR assay specific 
for the challenge virus, reported within two or more consecutive study days 
and/or 
• 
One positive detection by viral load RT-qPCR assay, specific for the challenge virus, 
in which an aliquot of the same sample has also tested positive in a cell-based 
infectivity assay appropriate for detecting the challenge virus. 
 
o If an infection is seen (via a positive RT-qPCR value) prior to first dose of IMP but the 
confirmatory value (as per the first part of the viral shedding definition in Section 4.2 
of the protocol) is taken after IMP, then that the subject is declared as infected prior 
to IMP, and hence will fall into the ITT-A Analysis Set.  


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 47 of 154 
Version 02-00, 01 NOV 2019 
 
 
o The AUC time period for qPCR was originally based on the assumption that the RT-
qPCR assessment at the time of the first IMP dose was taken immediately prior to 
IMP being given, however, 4 subjects in Part 1 had their qPCR assessment 
immediately after the first dose of IMP. In order to calculate consistent AUCs, qPCR 
measurement taken at the time of the first dose of IMP is used as the first value for 
the AUC.  
 


 hVIVO Services Ltd/ENA-CS-001 
CONFIDENTIAL 
 
 Statistical Analysis Plan Page 48 of 154 
Version 02-00, 01 NOV 2019 
12. REFERENCES 
[1] Matthews JNS, Altman DG, Campbell MJ, Royston P. Analysis of serial measurements in medical 
research. Br Med J (1990); 300: 230-5. 
(2) Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. Journal of American 
Statistical Association. 1958; 53:457-481. 




 
ENA-CS-001 
CONFIDENTIAL 
. Statistical Analysis Plan Page 50 of 154
Version 02-00, 01 NOV 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 


 
ENA-CS-001 
CONFIDENTIAL 
 Statistical Analysis Plan Page 51 of 154
Version 02-00, 01 NOV 2019 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
/ENA-CS-001 
CONFIDENTIAL 
 Statistical Analysis Plan Page 52 of 154
Version 02-00, 01 NOV 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
/ENA-CS-001 
CONFIDENTIAL 
 Statistical Analysis Plan Page 53 of 154
Version 02-00, 01 NOV 2019 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 


 
/ENA-CS-001 
CONFIDENTIAL 
 Statistical Analysis Plan Page 54 of 154
Version 02-00, 01 NOV 2019 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


 
/ENA-CS-001 
CONFIDENTIAL 
 
. Statistical Analysis Plan Page 55 of 154 
Version 02-00, 01 NOV 2019 
 
 
  
 
  
 
 
  
 
 
  
 
 
  
 
  
 
  
 
  
 
  
 
  
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
ENA-CS-001 
CONFIDENTIAL 
 Statistical Analysis Plan Page 56 of 154
Version 02-00, 01 NOV 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
/ENA-CS-001 
CONFIDENTIAL 
. Statistical Analysis Plan Page 57 of 154
Version 02-00, 01 NOV 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
ENA-CS-001 
CONFIDENTIAL 
. Statistical Analysis Plan Page 58 of 154
Version 02-00, 01 NOV 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
/ENA-CS-001 
CONFIDENTIAL 
 
. Statistical Analysis Plan Page 59 of 154 
Version 02-00, 01 NOV 2019 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
ENA-CS-001 
CONFIDENTIAL 
 Statistical Analysis Plan Page 60 of 154
Version 02-00, 01 NOV 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
/ENA-CS-001 
CONFIDENTIAL 
 Statistical Analysis Plan Page 61 of 154
Version 02-00, 01 NOV 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
ENA-CS-001 
CONFIDENTIAL 
 Statistical Analysis Plan Page 62 of 154
Version 02-00, 01 NOV 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
ENA-CS-001 
CONFIDENTIAL 
 Statistical Analysis Plan Page 63 of 154
Version 02-00, 01 NOV 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
ENA-CS-001 
CONFIDENTIAL 
 Statistical Analysis Plan Page 64 of 154
Version 02-00, 01 NOV 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
ENA-CS-001 
CONFIDENTIAL 
 Statistical Analysis Plan Page 65 of 154
Version 02-00, 01 NOV 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
ENA-CS-001 
CONFIDENTIAL 
. Statistical Analysis Plan Page 66 of 154
Version 02-00, 01 NOV 2019 
 
 


 
ENA-CS-001 
CONFIDENTIAL 
. Statistical Analysis Plan Page 67 of 154
Version 02-00, 01 NOV 2019 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
ENA-CS-001 
CONFIDENTIAL 
. Statistical Analysis Plan Page 68 of 154
Version 02-00, 01 NOV 2019 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


 
ENA-CS-001 
CONFIDENTIAL 
 Statistical Analysis Plan Page 69 of 154
Version 02-00, 01 NOV 2019 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
/ENA-CS-001 
CONFIDENTIAL 
 Statistical Analysis Plan Page 70 of 154
Version 02-00, 01 NOV 2019 








































































































































































 
ENA-CS-001 
 CONFIDENTIAL 
 
. Statistical Analysis Plan
   Page 154 of 154 
Version 02-00, 01 NOV 2019