Clinical trial NCT04488575
Conditions: Covid19
Keywords: SARS-CoV-2 corona virus coronavirus corona
Sponsor: Evelo Biosciences, Inc.
Start date: 2020-08-26; Completion date: 2021-05-19
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Evelo will investigate the safety and efficacy of EDP1815 in the treatment of patients hospitalized with SARS-CoV-2 Infection

Detailed description:
This is a randomized, placebo-controlled clinical study to assess the safety and efficacy of EDP1815 in patients hospitalized with COVID-19 infection.

The study is designed to evaluate the efficacy of EDP1815 at reducing time to resolution of symptoms, preventing progression of COVID-19 symptoms and preventing COVID-Related Complications (CRC)

Arms: arm 1: Patients will receive EDP1815 in addition to standard of care arm 2: Patients will receive placebo in addition to standard of care
Interventions: intervention 1: EDP1815 intervention 2: Placebo
Intervention descriptions: intervention 1: EDP1815 is an orally administered monoclonal microbe intervention 2: Placebo oral capsule

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
Official Title: 
A Phase 2 Double-blind Placebo-
controlled Study Investigating the 
Safety and Efficacy of EDP1815 in 
the Treatment of Patients 
Hospitalized With SARS-CoV-2 
Infection 
  
 
NCT Number: 
 
NCT04488575 
 
Document date:  
05 August 2020 
 








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Investigator Agreement 
I confirm that I have read and that I understand this clinical protocol, the Investigator’s 
Brochure, and other product information provided by the Sponsor. I agree to conduct this study 
in accordance with the requirements of this clinical protocol and also protect the rights, safety, 
privacy, and wellbeing of study participants in accordance with the following: 
• Ethical principles originating from the Declaration of Helsinki. 
• International Council for Harmonisation (ICH) E6 and Good Clinical Practice (GCP). 
• All applicable laws and regulations including data privacy laws and regulations. 
 
 
 
Signature of Investigator 
Date 
Investigator Name 
Investigator Title 
Name of Facility 
Location of Facility (City) 
 
 
 


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Table of Contents 
1. 
Protocol Summary ........................................................................................................10 
1.1. 
Synopsis ..........................................................................................................................10 
1.2. 
Schema ............................................................................................................................14 
1.3. 
Schedule of Activities (SoA) ..........................................................................................15 
2. 
Introduction ...................................................................................................................18 
2.1. 
Background .....................................................................................................................18 
2.2. 
Mechanism of Action......................................................................................................19 
2.3. 
Rationale for Use ............................................................................................................20 
2.4. 
Benefit/Risk Assessment ................................................................................................21 
3. 
Objectives and Endpoints ............................................................................................22 
4. 
Study Design ..................................................................................................................24 
4.1. 
Overall Design ................................................................................................................24 
4.2. 
Scientific Rationale for Study Design ............................................................................24 
4.3. 
Dose Justification ............................................................................................................25 
4.4. 
End of Study Definition ..................................................................................................25 
5. 
Study Population ...........................................................................................................26 
5.1. 
Inclusion Criteria ............................................................................................................26 
5.2. 
Exclusion Criteria ...........................................................................................................27 
5.3. 
Lifestyle Restrictions ......................................................................................................28 
5.4. 
Screen Failures ................................................................................................................28 
6. 
Study Interventions.......................................................................................................29 
6.1. 
Study Interventions Administered ..................................................................................29 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................29 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................30 
6.4. 
Study Intervention Compliance ......................................................................................30 
6.5. 
Concomitant Therapy .....................................................................................................31 
6.6. 
Study stopping criteria ....................................................................................................32 
6.6.1. 
Safety ..............................................................................................................................32 
6.7. 
Intervention after the End of the Study ...........................................................................32 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................33 
8. 
Study Assessments and Procedures.............................................................................35 
8.1. 
Efficacy Assessments .....................................................................................................35 
8.1.1. 
Oxygen Saturation ..........................................................................................................35 
8.1.2. 
WHO Ordinal Scale ........................................................................................................36 
8.2. 
Safety Assessments .........................................................................................................37 
8.2.1. 
Physical Examinations ....................................................................................................37 
8.2.2. 
Vital Signs .......................................................................................................................37 
8.2.3. 
Strain-specific PCR for EDP1815 ..................................................................................37 
8.2.4. 
Gastrointestinal Assessment ...........................................................................................37 
8.2.5. 
Clinical Safety Laboratory Assessments ........................................................................37 
8.3. 
Adverse Events and Serious Adverse Events .................................................................38 


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8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................38 
8.3.2. 
Method of Detecting AEs and SAEs ..............................................................................39 
8.3.3. 
Follow-up of AEs and SAEs ...........................................................................................39 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...............................................................39 
8.3.5. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs.............................................................................................39 
8.4. 
Treatment of Overdose ...................................................................................................39 
8.5. 
Biomarkers ......................................................................................................................40 
8.5.1. 
Biomarkers to be measured on all subjects .....................................................................40 
8.5.2. 
Additional plasma biomarkers ........................................................................................40 
8.5.3. 
Transcription analysis .....................................................................................................40 
8.5.4. 
Microbiome Research .....................................................................................................40 
9. 
Statistical Considerations .............................................................................................41 
9.1. 
Sample Size Determination ............................................................................................41 
9.2. 
Populations for Analyses ................................................................................................42 
9.3. 
Estimands and Intercurrent Events .................................................................................43 
9.3.1. 
Primary Efficacy Estimand .............................................................................................43 
9.3.2. 
Secondary Efficacy Estimands .......................................................................................43 
9.4. 
Statistical Analyses .........................................................................................................45 
9.4.1. 
Efficacy Analyses ...........................................................................................................45 
9.4.2. 
Safety Analyses ...............................................................................................................48 
9.5. 
Interim Analyses and Safety Monitoring ........................................................................49 
10. 
Supporting Documentation and Operational Considerations ..................................50 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................50 
10.1.1. Regulatory and Ethical Considerations ...........................................................................50 
10.1.2. Financial Disclosure........................................................................................................50 
10.1.3. Informed Consent Process ..............................................................................................50 
10.1.4. Data Protection................................................................................................................51 
10.1.5. Committees Structure......................................................................................................51 
10.1.6. Dissemination of Clinical Study Data.............................................................................52 
10.1.7. Data Quality Assurance ..................................................................................................52 
10.1.8. Source Documents ..........................................................................................................52 
10.1.9. Study and Site Closure ....................................................................................................52 
10.1.10. Publication Policy ...........................................................................................................53 
10.2. 
Appendix 2: Contraceptive Guidance and Collection of 
Pregnancy Information ...................................................................................................54 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................57 
10.4. 
Appendix 4: Summary of Protocol Amendments ...........................................................62 
11. 
References ......................................................................................................................68 
 
 
 


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Table of Tables 
Table 1: Clinical Trial Objectives and Endpoints ......................................................................... 10 
Table 2: Clinical Trial Objectives and Endpoints ......................................................................... 22 
Table 3: Treatment Arms .............................................................................................................. 29 
Table 4: Estimated Size of Confidence Intervals of Treatment Difference in Change from 
Baseline in Trough S/F Ratio ........................................................................................................ 42 
Table 5: Description of Patient Populations ................................................................................. 42 
Table 6: Intercurrent Event Strategies for the Primary Estimand ................................................. 43 
Table 7: Intercurrent Event Strategies for the Secondary Estimands ........................................... 44 
Table 8: Population Level Summary Measures for the Secondary Estimands ............................. 45 
Table 9: Highly Effective Contraceptive Methods ....................................................................... 55 
Table of Figures 
Figure 1: Clinical Trial Design ..................................................................................................... 14 
Figure 2: Schedule of Activities ................................................................................................... 15 
Figure 3: WHO ordinal scale for clinical improvement (OSCI) of COVID-19 ........................... 36 
 
 
 


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ABBREVIATIONS 
AE                   Adverse Event 
ACE2               Angiotensin-converting Enzyme 2 
ALP                 Alkaline Phosphatase 
ALT                Alanine Aminotransferase  
ANCOVA       Analysis of Covariance 
ARDS              Acute Respiratory 
AST                 Aspartate Aminotransferase 
CI                    Confidence Interval 
CIOMS            Council for International Organizations of Medical Sciences  
CONSORT      Consolidated Standards of Reporting Trials  
CRF                 Case Report Form 
CRP                 C-reactive Protein 
CRC                Covid Related Complications 
CSR                 Clinical Study Report 
eCRF               Electronic Case Report Form 
DAD                Diffuse Alveolar Damage 
eGFR               Estimated Glomerular Filtration Rate 
Evelo               Evelo Biosciences Inc. (the Sponsor company)  
FDA                Food and Drug Administration 
FiO2                Fraction of Inspired Oxygen 
FoxP3              Forkhead Box P3 
FSH                 Follicle Stimulating Hormone  
GCP                Good Clinical Practice 
GI                    Gastrointestinal 
HIPAA            Health Insurance Portability and Accountability Act  
HLA                Human Leukocyte Antigen 
HRT                Hormonal Replacement Therapy 
IB                    Investigator’s Brochure 
ICF                  Informed Consent Form 
ICH                 International Council for Harmonisation  
ICU                 Intensive Care Unit 
IEC                  Independent Ethics Committee 
IL                    Interleukin 
IRB                 Institutional Review Board 
iDMC              Independent Data Monitoring Committee 
IUD                 Intrauterine Device 
IUS                  Intrauterine Hormone-Releasing System 
LFT                 Liver Function Test 
LPS                 Lipopolysaccharide 
KLH                Keyhole limpet haemocyanin 
OSCI               WHO Ordinal Scale for Clinical Improvement 
MedDRA        Medical Dictionary for Regulatory Activities  
O2                   Oxygen 
OTC                Over-The-Counter 
PBMC             Peripheral Blood Mononuclear Cell 


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PIS                   Patient Information Sheet 
PCR                 Polymerase Chain Reaction 
QC                   Quality Control 
RNA                Ribonucleic Acid 
SAE                 Serious Adverse Event 
SaO2               Oxygen Saturations 
SAP                 Statistical Analysis Plan 
SARS-Cov-2   Severe Acute Respiratory Syndrome Coronavirus 2 
SD                   Standard Deviation 
SF                    SaO2 / FiO2 ratio 
SINTAX         Small Intestinal Axis 
SoA                 Schedule of Activities 
SpO2               Saturation of Oxygen 
SRC                 Safety Review Committee 
SUSAR           Suspected Unexpected Serious Adverse Reactions  
ULN                Upper Limit of Normal 
WHO               World Health Organization 
WOCBP          Woman of Child-Bearing Potential 
 
 


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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: A Phase 2 double-blind placebo-controlled study investigating the safety and 
efficacy of EDP1815 in the treatment of patients hospitalized with SARS-CoV-2 Infection 
 
Short Title: Safety and efficacy of EDP1815 in the treatment of patients hospitalized with SARS-
CoV-2 Infection. 
 
Rationale: EDP1815 is a single strain of a small-intestine targeted, systemically immune-
modulating, monoclonally-expanded commensal gut bacteria.  Preclinical and clinical data have 
demonstrated that EDP1815 reduces levels of IL-6, TNFα and IL-8, while elevating epithelial 
expression of IL-10 and FoxP3. At the same time, EDP1815 is well tolerated with no overall 
difference from placebo in human trials to date. This profile could be highly relevant with respect 
to treating COVID-Related Complications (CRC). 
 
An exaggerated host immune response leads to the life-threatening complications of COVID-19 
infection. The cytokine IL-6 and chemokine IL-8 have been shown to be increased in subjects 
hospitalized with coronaviral infections, infections with influenza A, and in secondary HLH, and 
their exaggerated levels are pathogenic in the development of complications such as ARDS.  The 
host immune response is clearly important in the initial anti-viral response of the host and IL-6 in 
particular has been shown to be important in the early phase of the infection.  A prolonged and 
exaggerated immune response is however associated with pulmonary complications, 
hospitalization and ultimately death.  A therapeutic agent that does not abrogate the host immune 
response entirely, but instead modulates multiple pathways and returns it back to a state of immune 
homeostasis, could offer significant clinical benefit to subjects with coronaviral infections. 
 
The profile of EDP1815 as an oral agent with good tolerability modulating multiple key immune 
pathways without blocking them completely – that is, immune normalization rather than immune 
suppression – could offer significant clinical benefit to patients at risk of developing serious 
complications secondary to COVID-19. 
 
Table 1: Clinical Trial Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the effect of EDP1815 on 
pulmonary function as measured by the 
change in Oxygen Saturation (SpO2) / 
Fraction of Inspired Oxygen (FiO2) [S/F 
ratio] 
• 
Change from baseline to the lowest S/F ratio 
measured in days 1-14 
 
 


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Secondary 
 
• 
To evaluate the effect of EDP1815 on the 
development and severity of complications 
of COVID-19 infection 
• 
Change in S/F ratio at days 4, 7, 10 and 
14/discharge day. 
• 
Percentage change in S/F ratio at days 4, 7, 10 
and 14/discharge day. 
• 
Percentage of participants at each level on the 
WHO OSCI score at days 4, 7, 14, 21 and 42. 
• 
Percentage of participants with shifts from each 
level of the WHO OSCI score at baseline at 
days 4, 7, 14, 21 and 42. 
• 
Percentage of participants remaining at their 
baseline score on the WHO OSCI (or lower) at 
days 4, 7, 14, 21 and 42. 
• 
Percentage of participants reporting each level 
of the WHO OSCI score at their worst post-
baseline day. 
• 
The time in days spent at each participant’s 
worst reported WHO OSCI score (excluding 
death). 
• 
Intubation and mechanical-ventilation free 
survival, defined as the time in days from start 
of treatment to first occurrence of a WHO OSCI 
score of 6 or more.  
• 
Overall survival, defined as the time in days 
from start of treatment to death by any cause 
• 
Number of days requiring oxygen therapy. 
• 
Number of days with pyrexia ≥ 38oC. 
• 
Maximum daily temperature. 
• 
Minimum SpO2 level. 
• 
Maximum SpO2 level. 
• 
To evaluate the effect of EDP1815 on length 
of hospitalization and recovery in 
participants with COVID-19 
• 
Time to discharge, defined as the time in days 
from start of treatment to first occurrence of a 
WHO OSCI score of 2 or less. 
• 
Time to oxygen saturation (SpO2) ≥94% on 
room air without further requirement for oxygen 
therapy.  
• 
Time to recovery, defined as the time in days 
from symptom onset to alleviation of all 
COVID-19 symptoms. 
 
 




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from this study, after discussion with the chief investigator. Inclusion in concurrent interventional 
studies will not be permitted. Inclusion in observational studies in parallel to this study is allowed. 
Number of Participants: 
Sixty subjects will be enrolled into the study and randomized in a 1:1 ratio.  A further 40 subjects 
may be enrolled on the request of the DMC if it was felt likely to provide further beneficial 
information to take forward into planning future studies. 
 
Participant Trial Duration: 
This study will consist of a 14-day treatment period followed by a 28-day post-treatment follow-
up visit, as described below: 
 
• Up to 2 days for Screening and Baseline assessment period. Note: Due to the urgent nature 
of the study, screening, baseline and Day 1 assessments can occur on the same day. Eligible 
patients will be randomized and dosed as soon as possible after eligibility is confirmed. 
• A 14-day treatment period (treatment will be stopped if the participant is admitted to ICU). 
• A 28-day post-treatment period, with final follow-up via telephone assessment at Day 42. 
 
Number of Centers: 
The study will be run at multiple centers in the United States. 
 
 


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1.2. 
Schema 
 
Figure 1: Clinical Trial Design 
 
 
 


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1.3. 
Schedule of Activities (SoA) 
 
Figure 2: Schedule of Activities 
Data 
Screening^ 
(Day -1 to Day 
0) 
Baseline^ 
(Day -1 to Day 
0) 
D 
1^ 
D 
2 
D 
3 
D 
4 
D 
5 
D 
6 
D 
7 
D 
8 
D 
9 
D  
10 
D  
11 
D  
12 
D  
13 
D14  
or day of 
discharge&  
D21 ~ 
 (Follow-up 
Telephone 
Visit)  
D42 (Final 
Follow-Up 
Telephone 
Visit) 
Informed 
consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion 
criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
and 
anthropomorph
ic data (e.g. 
age, height, 
weight) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking 
status 9 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Significant 
Covid-19 
Comorbidities 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(blood/urine) 1 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Vital signs#* 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Concomitant 
Medications# 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Oxygen 
therapy status# 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SaO2/FiO2 
status#2* 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Blood tests 
(FBC, CRP, 
LFT, 
Creatinine, 
Urea and 
Electrolytes, 
Ferritin, D-
 
x 
 
 
 
x3 
 
 
x3 
 
 
 
 
 
 
 
 
 


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Data 
Screening^ 
(Day -1 to Day 
0) 
Baseline^ 
(Day -1 to Day 
0) 
D 
1^ 
D 
2 
D 
3 
D 
4 
D 
5 
D 
6 
D 
7 
D 
8 
D 
9 
D  
10 
D  
11 
D  
12 
D  
13 
D14  
or day of 
discharge&  
D21 ~ 
 (Follow-up 
Telephone 
Visit)  
D42 (Final 
Follow-Up 
Telephone 
Visit) 
dimer, 
Troponin) #* 
HIV test 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cytokine Panel, 
Paxgene 
sample, and 
Biobanking 
sample* 
 
x 
 
 
 
x3 
 
 
x3 
 
 
 
 
 
 
 
 
 
Plasma PCR 
for EDP1815 
 
 
 
 
 
 
 
 
x3 
 
 
 
 
 
 
 
 
 
Day since onset 
of symptoms# 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8-point ordinal 
scale# 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
COVID-19 
RTPCR# 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of 
adverse 
events#*@ 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Retrieval of 
relevant 
clinical data4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Outpatient 
questionnaire5 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x6 
x6 
x6 
Telephone call5 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
x 
Discharge 
status# 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mortality 
status# 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Faecal sample 
for microbiome 
analysis 
 
x7 
 
 
 
 
 
 
x7 
 
 
 
 
 
 
 
 
 
EDP1815 or 
Placebo 
administration8 
 
 
x8 
x8 
x8 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
^ Due to the urgent nature of the study, screening, baseline and Day 1 assessments can occur on the same day. Eligible patients will be randomized and dosed as soon as possible 
after eligibility is confirmed. 
~ This assessment can be performed between days 20-22. 


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#Results will be extracted from the patient record where available – no research specific test may be required. 
*If a patient is discharged then these assessments may not be performed. 
@Whilst an inpatient, participants should have a daily assessment for evidence of nausea, vomiting, diarrhoea, bloating and abdominal pain. This information will be collected for 
outpatients in the patient questionnaire. 
& If a participant is not discharged at Day 14 and remains in hospital, Day 14 assessments will be performed until a participant is discharged from hospital or they reach the final 
follow-up visit (Day 42). 
1 Pregnancy test will only be performed in women of child-bearing potential (Appendix 2). 
2 If the patient is on 3L/min oxygen flow or less, this assessment should be performed after the patient is at rest on room air for 10 minutes, as detailed in section 8.1.1. 
3 If the patient is discharged prior to these blood tests, where possible outpatient blood testing will be organised. 
4 Extraction of relevant clinical data from the patient’s medical record (such as but not limited to symptoms, concomitant medications, other relevant blood tests, and radiology 
reports such as chest radiograph or CT scan). 
5 If the patient is discharged, they will be given a daily questionnaire to complete; a telephone call will be made on day 7, 14, 21 and 42 (telephone call has a window of +/- 1 day). 
6 The patient will be asked to continue to fill the questionnaire daily until their symptoms have fully resolved for 48 hours or until the day 42 telephone visit (whichever is earlier). 
7 This is an optional sample for research purposes but will be collected whenever possible once at the Baseline visit and then again once between Days 5-14. If the patient is 
discharged prior to this faecal test, where possible, an outpatient sample will be collected. 
8 Administered twice daily for six doses) and then once daily for the remaining days (17 doses total). Treatment will be stopped if the participant is admitted to ICU, meets 
individual stopping criteria, or is withdrawn from the study. 
9 Smoking status to include whether current-smoker, ex-smoker, or never-smoker; and to quantify current usage and total pack-year history.


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2. 
Introduction 
2.1. 
Background 
The COVID-19 pandemic, as declared on 11th March 2020 by World Health Organization (WHO), 
is caused by a novel coronavirus (SARS-Cov-2). It is estimated to result in ~50,000 – 160,000 
deaths in the USA, if optimal healthcare can be delivered, and up to in excess of 2.2 million deaths 
if healthcare resources such as ventilated beds are exhausted (Cookson 2020). It is the pulmonary 
complications of the viral infection that results in the majority of hospitalizations, admissions to 
ICU and ultimately death (Guan 2020; Huang 2020; Liu 2020; Wang 2020). The COVID-Related 
Complications (CRC) include acute respiratory distress syndrome (ARDS), arrhythmia, shock, 
acute kidney injury, acute cardiac injury, liver dysfunction and secondary infection (Huang 2020; 
Maharaj 2020). There are no vaccines, prophylactic or therapeutic agents of proven efficacy. 
Significant symptoms that do not result in hospitalization are also common and result in significant 
illness even short of hospitalization. 
 
Study of coronavirus infections in tissue culture and animal models and of historical, SARS-
coronavirus outbreaks, provide insights into the likely pathophysiology of infection with COVID-
19 (Guan 2020; Gralinski 2015). The majority of tissue damage following infection with SARS-
Cov1 appears to be due to a later, exaggerated, host immune response (Gralinski 2015). The host 
anti-viral response is driven by the induction of type I interferons which inhibit transcription and 
translation of the viral genome and reduce the threshold for activation of natural killer cells. Type 
I interferons also decrease expression of Serping1, a regulator of the complement system and 
coagulation proteases; this may lead to complement-mediated tissue damage and a prothrombotic 
tendency. In airway epithelial cells, type I IFNs upregulate expression of ACE2 in airway epithelial 
cells. Whereas ACE2 has been shown to be protective in models of acute lung injury, it is also the 
receptor for the spike protein of COVID-19 and is used by the virus for binding to its target cells. 
 
While SARS-CoV-2 infection evades detection by the immune system in the first 24h of infection, 
after 7-14 days following symptom onset an exaggerated response from the host immune system 
occurs in a subgroup of people. This leads to progressive lung damage leading to the need for 
hospitalization and oxygen therapy that can progress to severe pulmonary complications requiring 
ventilation and even death. It is important to note that the development of Diffuse Alveolar 
Damage (DAD) is often independent of high-titer viral replication (Peiris 2003). Other end organ 
damage can also occur secondary to the host immune response. This abnormal immune and 
inflammatory response in affected lungs includes production of high levels of IL-6, IL-8, TNFα, 
IL-1β, influx of neutrophils and cytotoxic T cells. A Th2 (IL4, IL13) response from alternatively-
activated macrophages, and an associated profibrotic phenotype (including increased TGF β and 
PDGFα production) can lead to lung fibrosis and chronic sequelae (Ruan 2020). Activation of the 
coagulation cascade is associated with development of fibrin clots in the alveoli. IL- 6 and IL-8 
are increased in subjects hospitalized with coronaviral infections (Mehta 2020). A therapeutic 
agent with anti-inflammatory effects across IL-6, IL-8 and TNFα could prevent this host immune 
mediated organ damage. The host immune response is clearly important in the initial anti-viral 
response of the host. A prolonged and exaggerated immune response as measured by these 
cytokines / chemokines is however associated with pulmonary complications, hospitalization and 
ultimately death. A therapeutic agent that does not abrogate the initial host anti-viral immune 


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response but modulates the delayed excess immune response via multiple pathways, restoring a 
state of immune homeostasis, could offer significant clinical benefit to subjects with COVID-19 
infections. 
2.2. 
Mechanism of Action 
EDP1815 is an orally administered pharmaceutical preparation of a single strain of Prevotella 
histicola isolated from the duodenum of a human donor. Prevotella is the genus of human 
commensal organisms commonly found on oral, nasopharyngeal, gastrointestinal, and genito-
urinary mucosal surfaces. It has been found in all human population groups studied so far. 
EDP1815 is currently in phase 2 clinical development and has European and US approval to 
initiate a multinational psoriasis study, scheduled for 2Q2020. 
 
Preclinical and clinical data have demonstrated that EDP1815 can systemically suppress IL-6, 
TNFα and IL-8, while elevating epithelial expression of IL-10 and FoxP3. At the same time, 
EDP1815 is well tolerated with no overall difference from placebo in human trials to date. This 
profile could be highly relevant with respect to treating CRC. 
 
EDP1815 works via the small intestinal axis (SINTAX): a network of anatomical and functional 
connections between the small intestine and the rest of the body. SINTAX links small intestinal 
mucosal immunology with systemic inflammation, accessible with oral medicines. EDP1815 is 
non-pathogenic, not genetically modified, does not colonize or persist in the gut, and does not 
modify the colonic microbiome. It acts locally in the gut - which is, in effect, on the outside of the 
body - but has pharmacodynamic activity throughout the inside of the body modulating the 
immune system without any systemic exposure. 
 
EDP1815 is not systemically absorbed and there are no expected ADRs. Safety and tolerability 
have been indistinguishable from placebo, with no SAEs or AEs of severe intensity reported. The 
nature of the pharmaceutical preparation of EDP1815 ensures that there is no unwanted persistence 
of the drug after administration. It does not modify the colonic microbiome as assessed by 16S 
ribosomal RNA sequencing of stool samples from patients, and the drug is undetectable in stool 
samples once dosing has ceased. Importantly, there has been no increased risk of infections 
observed in the phase 1 program. 
 
The therapeutic effects of these orally delivered medicines come from their interaction with pattern 
recognition receptors on immune cells in the lining of the small intestine. These cells, in turn, 
modulate immune cells circulating throughout the body. Preclinical and clinical data provide 
evidence that EDP1815 is capable of modulating multiple immune pathways in humans, and 
therefore has the potential to become an attractive therapeutic strategy in patients with 
inflammatory diseases: including the abnormal host immune responses to acute viral infections. 
 
Preclinical studies using EDP1815 have been carried out across a range of human and mouse cell 
in vitro assays, as well as in 5 key in vivo models, which all support the use of this agent in the 
treatment of immunoinflammatory diseases. In vitro, EDP1815 has been found to stimulate 
secretion of anti-inflammatory cytokines such as interleukin (IL)-10, IL-27, and IL-1RA, from 
human macrophages and dendritic cells. Furthermore, pre-clinical results have also shown that 
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In human testing EDP1815 improves psoriasis lesions (a condition due to abnormal Th17 activity) 
and reduces the inflammatory response to keyhole limpet hemocyanin (KLH) challenge (a Th1 
driven healthy volunteer model).  In addition, in ex-vivo testing EDP1815 has been shown to 
reduce, or normalize, the secretion of both IL-6 and IL-8, which are 2 of the key cytokines / 
chemokines involved in exaggerated host responses to viral infections. This confirmed the 
preclinical findings that EDP1815, despite being gut restricted, can modulate systemic immune 
biology along multiple pathways, and this unique profile and mechanism makes EDP1815 an ideal 
candidate for this trial. 
 
2.3. 
Rationale for Use 
As has been discussed above, exaggerated host immune responses lead to the life-threatening 
complications of COVID-19 infection.  
 
Systemic cytokine interleukin (IL)-6 and chemokine IL-8 levels have been shown to be elevated 
in subjects hospitalised with coronaviral infections, infections with influenza A (de Jong  2006; 
Hagau 2010) and in secondary haemophagocytic lymphohistiocytosis (Wong 2004; Ruan 2020). 
These exaggerated levels are pathogenic in the development of complications such as acute 
respiratory distress syndrome (ARDS). Although host immune response is important in the initial 
anti-viral response, prolonged and exaggerated immune response is associated with pulmonary 
complications, hospitalisation and death. A therapeutic agent that modulates multiple pathways 
back to a state of immune homeostasis without frank immunosuppression could offer significant 
clinical benefit to subjects with SARS-CoV-2 infection. 
 
The profile of EDP1815 as an oral agent with good tolerability modulating multiple key immune 
pathways without abrogating them completely – that is, immune normalization rather than immune 
suppression – could offer significant clinical benefit to patients at risk of developing serious 
complications secondary to COVID-19. Its safety profile positions it as an appropriate treatment 
to use early in the disease course, prior to the onset of these significant symptoms or complications. 
 
 


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2.4. 
Benefit/Risk Assessment 
EDP1815 is a specific pharmaceutical preparation of Prevotella histicola, a natural human 
commensal organism, commonly found on oral, nasopharyngeal, GI, and genito-urinary mucosal 
surfaces. 
 
EDP1815 is being investigated for its potential benefit in immunoinflammatory disorders, 
including the cytokine storm associated with COVID-19. There is significant morbidity and 
mortality benefit to be derived from reducing COVID-Related Complications. 
 
The safety profile of EDP1815 has been indistinguishable from placebo in both the EDP1815-101 
and EDP1815-102 studies, with no serious adverse events (SAEs) or adverse events (AEs) of 
severe intensity reported in either study. Mild and transient AEs have included headache and 
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3. 
Objectives and Endpoints 
Table 2: Clinical Trial Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the effect of EDP1815 on 
pulmonary function as measured by the 
change in Oxygen Saturation (SpO2) / 
Fraction of Inspired Oxygen (FiO2) [S/F 
ratio] 
• 
Change from baseline to the lowest S/F ratio 
measured in days 1-14 
Secondary 
 
• 
To evaluate the effect of EDP1815 on the 
development and severity of complications 
of COVID-19 infection 
• 
Change in S/F ratio at days 4, 7, 10 and 
14/discharge day. 
• 
Percentage change in S/F ratio at days 4, 7, 10 
and 14/discharge day. 
• 
Percentage of participants at each level on the 
WHO OSCI score at days 4, 7, 14, 21 and 42. 
• 
Percentage of participants with shifts from each 
level of the WHO OSCI score at baseline at 
days 4, 7, 14, 21 and 42. 
• 
Percentage of participants remaining at their 
baseline score on the WHO OSCI (or lower) at 
days 4, 7, 14, 21 and 42. 
• 
Percentage of participants reporting each level 
of the WHO OSCI score at their worst post-
baseline day. 
• 
The time in days spent at each participant’s 
worst reported WHO OSCI score (excluding 
death). 
• 
Intubation and mechanical-ventilation free 
survival, defined as the time in days from start 
of treatment to first occurrence of a WHO OSCI 
score of 6 or more.  
• 
Overall survival, defined as the time in days 
from start of treatment to death by any cause 
• 
Number of days requiring oxygen therapy. 
• 
Number of days with pyrexia ≥ 38oC. 
• 
Maximum daily temperature. 
• 
Minimum SpO2 level. 
• 
Maximum SpO2 level. 


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• 
To evaluate the effect of EDP1815 on length 
of hospitalization and recovery in 
participants with COVID-19 
• 
Time to discharge, defined as the time in days 
from start of treatment to first occurrence of a 
WHO OSCI score of 2 or less. 
• 
Time to oxygen saturation (SpO2) ≥94% on 
room air without further requirement for oxygen 
therapy.  
• 
Time to recovery, defined as the time in days 
from symptom onset to alleviation of all 
COVID-19 symptoms. 
• 
To evaluate the safety and tolerability of 
EDP1815 in participants with COVID-19 
• 
Incidence and severity of treatment emergent 
adverse events and serious adverse events.  
• 
Incidence of clinically significant abnormal 
changes in safety laboratory parameters. 
Exploratory 
 
• 
To evaluate the effect of EDP1815 on the 
exaggerated host cytokine response to 
COVID-19 infection 
• 
Change from baseline in cytokine levels 
(including IL-6) at day 4 and day 7 (and/or at 
additional timepoints if samples are available). 
• 
Change from baseline in inflammatory response 
at day 4 and day 7 (and/or at additional 
timepoints if samples are available). 
 
• 
To identify clinical or biochemical predictors 
of response to EDP1815, and to confirm lack 
of systemic absorption. 
• 
Statistical significance of each potential 
predictor-treatment interaction in exploratory 
models based on the final selected model for the 
primary efficacy analysis. 
• 
To identify the presence of EDP1815 in stool 
and/or blood using PCR primers 
 


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4. 
Study Design 
4.1. 
Overall Design 
This is a randomized placebo-controlled clinical study to assess the safety and efficacy of 
EDP1815 in patients hospitalized with COVID-19 infection, to determine the efficacy of EDP1815 
at reducing time to resolution of symptoms, preventing progression of COVID-19 symptoms and 
preventing COVID-Related Complications (CRC). The study will be fully blinded to the 
participants, investigator, and sponsor. This is a pilot study with a primary objective of 
investigating the potential of EDP1815 in the prevention of COVID-19 disease progression. The 
secondary objective is to evaluate multiple endpoints for clinical relevance and sensitivity, while 
informing the sample size for future studies. Where possible, all assessments will be taken from 
those performed as part of the participant’s routine clinical care in this pragmatic study. 
 
Participants who have been recently hospitalized for confirmed COVID-19 disease and are 
confirmed to be eligible for the study will be randomised to either the active (EDP1815) or placebo 
group, in addition to standard of care, and dosing will be initiated on a twice daily regime for the 
first 6 doses, then once daily for the remaining days. The treatment course is 14 days. The trial 
hypothesis is that treatment with EDP1815 in hospitalized patients reduces oxygen requirements 
by normalizing the exaggerated host immune response to COVID-19. This will be measured by 
assessing the Oxygen Saturation (SpO2) / Fraction of Inspired Oxygen (FiO2) [S/F] ratio. 
 
Dosing will be stopped if participants are admitted to ICU. Efficacy and safety data will continue 
to be collected according to the schedule of activities, where possible. However, if the participant 
is eligible for another interventional trial at this point, they may be enrolled into it and withdrawn 
from this study, after discussion with the chief investigator.  Inclusion in concurrent interventional 
studies will not be permitted. Inclusion in observational studies in parallel to this study is allowed. 
4.2. 
Scientific Rationale for Study Design 
The exaggerated immune response to COVID-19 infection can affect multiple organs, causing 
pulmonary, renal and cardiac complications.  Pulmonary complications are the most common CRC 
and progression to ARDS is the most common cause of death.  The study therefore focusses on 
pulmonary function as the primary endpoint and the ratio of the Oxygen Saturation (SpO2) / 
Fraction of Inspired Oxygen (FiO2) is a validated measure of severity of ARDS (Villar 2013).  
Due to the lack of established literature on the progression of COVID-19 infection, a large number 
of secondary endpoints are being collected to understand the potential of EDP1815 in the treatment 
of this disease. As this is a pilot study an initial sample size of 60 subjects has been used with the 
potential to expand this to a maximum of a 100 should that be required to understand the effects 
of EDP1815 and inform future larger-scale studies. 
 
There is no approved treatment for the immunological response to COVID-19 infection and so a 
placebo-controlled study in addition to best standard of care is the optimal design. 
 
 


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4.3. 
Dose Justification 
EDP1815 will be administered in the EDP1815-205 study as an enteric coated powder in capsule 
formulation; this formulation has already been dosed in humans in EDP1815-101 (EudraCT 
Number: 2018-002807-32), a study currently ongoing in the UK with data from completed cohorts 
reported in the Investigator’s Brochure. 
The treatment regimen for this study will be 1.6x1011 cells of EDP1815 (2 capsules) given twice a 
day for 3 days (6 doses) then once a day for 11 days (14-day total course). 
 
The doses of EDP1815 tested in humans to date (1.6x1011 cells to 8.0x1011 cells in EDP1815-101) 
were based on allometric scaling from the preclinical in vivo experimental data. Both doses had 
clear effects on IL-6 and IL-8 based on lipopolysaccharide (LPS) stimulation of whole blood 
samples taken at baseline and after a course of daily administration of EDP1815. The study 
included patients with mild to moderate psoriasis, and improvements in their skin condition were 
also demonstrated. There was no clear difference between the 2 dose levels tested on IL-6 and IL-
8 and so the lower dose has been selected for this study. These data are presented in the 
Investigator’s Brochure. 
 
An initial twice daily (bd) dosing regimen has been selected to maximise the speed of response. 
EDP1815 works via direct interaction with immune cells in the epithelium of the upper small 
intestine. A twice a day regimen doubles the duration of exposure of the microbes to the immune 
cells in the upper small intestine per 24 hours and will increase the speed of response. The total 
daily dose is less than half the maximum daily dose tested for 28 days in EDP1815-101.  
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed the treatment 
period and completed their final safety follow-up visit 28 days after their last dose. A participant 
is also considered to have completed the study if they are withdrawn from the study. If a participant 
is admitted to ICU and is enrolled in a subsequent study then they are deemed to have completed 
this study at the point of signing the informed consent. 
 
The end of the study is defined as the date of the last visit of the last participant in the study or last 
scheduled procedure shown in the Schedule of Activities (SoA).  
 


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5. 
Study Population 
This protocol contains participants with a confirmed diagnosis of COVID-19 viral infection. 
 
Potential participants will be identified by reviewing hospital admissions, as well as reviewing the 
positive results from COVID-19 testing. Potential participants will be referred to the research team 
if they are interested in participating in this clinical trial. Once contact has been made with the 
patient, the research team will outline and explain the aims of the trial. An electronic or paper copy 
of the Patient Information Sheet (PIS) will then be given to the patient who will have the 
opportunity to consider the information and discuss the trial with the trial staff, and raise any 
queries before consenting to participate in the trial. 
 
Prospective approval of protocol deviations, also known as protocol waivers or exemptions, is not 
permitted. 
 
5.1. 
Inclusion Criteria  
Each participant must meet all of the following study criteria to be enrolled in this study: 
 
1. Capable of giving signed informed consent as described in Appendix 1 which includes 
compliance with the requirements and restrictions listed in the informed consent form (ICF) 
and in this protocol. Informed consent will be obtained prior to any Screening procedures and 
in accordance with national, local, institutional guidelines. 
2. Hospitalized within the last 36 hours. 
3. Receiving any form of supplementary oxygen therapy at baseline. 
4. Confirmed COVID-19 viral infection by RTPCR at screening. 
5. Age: 
a.  18-65 years old, OR 
b. >65 year-olds can be included after DMC approval (see section 10.1.5) 
6. Contraception: 
Male participants: 
A male participant must agree to use contraception as detailed in Appendix 2 of this 
protocol during their participation in this study and for a period of 90 days after the last 
dose; and also refrain from donating sperm during this period. 
 
Female participants: 
A female participant is eligible to participate if she is not pregnant, and at least one of the 
following conditions applies: 
 
a. Not a woman of child-bearing potential (WOCBP) as defined in Appendix 2. 
 
OR 
 
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 2 during their 
participation in this study for at least 1 complete menstrual cycle (≥30 days) after last dose. 
 


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5.2. 
Exclusion Criteria  
Participants meeting any of the following criteria will be excluded from the study: 
 
1. Contraindications/hypersensitivity to P histicola or any of the capsule excipients 
2. Patients with chronic hypoxia or underlying significant chronic respiratory disease (such as 
COPD, Pulmonary Fibrosis, or Bronchiectasis). 
3. Admission to ICU at time of screening. 
4. Mechanically ventilated, on CPAP, or on non-invasive ventilation at the time of screening. 
5. Patient is taking a systemic immunosuppressive agent such as, but not limited to, oral steroids, 
methotrexate, azathioprine, ciclosporin, or tacrolimus, unless these are given as part of COVID 
standard of care treatment. 
6. Patient has a diagnosed primary immunodeficiency. 
7. Patient has a diagnosis of HIV/AIDS 
8. Patient has pre-existing known chronic kidney disease stage 4 or 5 or requiring renal 
replacement therapy (i.e. estimated glomerular filtration rate (eGFR) <30ml/min/1.73m2); 
[Laboratory results within the last 48 hours may be used]. 
9. Patient has pre-existing known significant liver disease with Alanine aminotransferase (ALT) 
or aspartate aminotransferase (AST) ≥ 5.0 x upper limit of normal (ULN); [Laboratory results 
within the last 48 hours may be used]. 
10. Patient has pre-existing known significant gastrointestinal tract disease expected to affect 
absorption within the small intestine (e.g. short bowel syndrome, inflammatory bowel disease 
affecting the small intestine, gastroparesis); or prior malabsorptive bariatric surgery that could 
interfere with GI delivery and transit time. 
11. GI signs or symptoms equivalent to CTCAE v5.0, gastrointestinal disorders, grade 3 or 4 event. 
12. Patient has pre-existing known substantially impaired cardiac function or pre-existing 
clinically significant cardiac diseases, including unstable angina or acute myocardial infarction 
≤ 6 weeks prior to Screening. 
13. Currently participating in an interventional clinical trial (observational studies allowed). 
14. Moribund at time of screening 
15. Female participant who is currently pregnant at time of screening 
16. Female participant who is unwilling to stop breastfeeding during treatment period 
17. Any medical history or clinically relevant abnormality that is deemed by the principal 
investigator and/or medical monitor to make the patient ineligible for inclusion because of a 
safety concern.  
18. Unwilling to comply with study procedures, including follow-up, as specified by this protocol; 
or unwillingness to cooperate fully with the investigator. 
 
 


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5.3. 
Lifestyle Restrictions 
Participants must refrain from consuming acidic drinks for 1 hour either side of dosing and from 
eating 2 hours before dosing and 1 hour after dosing. 
 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention/entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants 
to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAEs. 
 
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6. 
Study Interventions 
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1. 
Study Interventions Administered 
All study interventions in this study will be administered orally. EDP1815 will be supplied as 
capsules that are enteric coated to release the contents in the duodenum and jejunum. The drug 
product is manufactured by 
.  
 
The EDP1815 drug product is available as enteric coated hydroxylpropyl methylcellulose 
(HPMC) hard capsules in white to off-white color.  The formulation of EDP1815 consist of 
freeze-dried powder of P histicola and excipients.  The excipients include mannitol, magnesium 
stearate and colloidal silicon dioxide. Each EDP1815 PIC contains 8.0x 1010 cells of P histicola.  
 
The matching placebo are identical in appearance but do not contain P histicola or any other 
bacteria. Matching placebo is supplied by 
. The placebo excipients include 
microcrystalline cellulose and magnesium stearate.  
 
Treatment with EDP1815 or placebo will be twice daily for 6 doses and then once daily for 11 
doses (14-day total course). There should be a minimum of two hours between the twice daily 
doses. For subjects who are discharged within the 14-day period, medication will be dispensed to 
take at home. 
 
Table 3: Treatment Arms 
 
Participants must refrain from consuming acidic drinks 1 hour either side of dosing and from eating 
2 hours before dosing and 1 hour after dosing. Refer to the Pharmacy Manual for further details. 
6.2. 
Preparation/Handling/Storage/Accountability 
All capsules will be supplied in blister packs and must be kept in controlled conditions of 2-8°C 
while at the study site.  
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during storage and transit for all study interventions received and any 
excursions are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive the study intervention and only 
authorised site staff may supply the study intervention. While at the study site, all study 
intervention must be stored in a secure, environmentally controlled, and monitored area 
 
Arm 
 
Dosage 
EDP1815 
1.6 x 1011 cells as 2 capsules twice daily for 6 doses, then once daily to 14 days 
Placebo 
2 capsules twice daily for 6 doses, then once daily to 14 days 


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(manual or automated with the ability to show minimum and maximum temperatures 
daily), in accordance with the labelled storage conditions with access limited to the 
investigator and authorised site staff. 
3. If the study intervention is given to participants to take at home, the participants should be 
instructed to take it straight home from the hospital, and then to store it at home in the 
refrigerator and out of reach of children. 
4. The investigator is responsible for study intervention accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation, and final disposition records). 
5. Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual.  
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is a randomized controlled study and therefore, the treatment allocation is random. 
Randomized treatment ensures minimisation of selection bias, so that the individuals in the two 
treatment groups are not systematically different, other than the treatment that they receive. A 
paper randomisation will be used to assign participants to study interventions. 
 
Blind Break (Scratch-off 
code breaks) 
A scratch-off code break that contains the study intervention 
assignment for each participant will be provided to each site 
investigator. The scratch-off code breaks will be retained by the 
investigator (or representative) in a secured area. In case of an 
emergency, the investigator has the sole responsibility for determining 
if unblinding of a participant’s treatment assignment is warranted. 
Participant safety must always be the first consideration in making such 
a determination. If a participant’s treatment assignment is unblinded, 
the Sponsor must be notified within 24 hours after breaking the blind. 
Once the study is complete, all scratch-off code breaks (revealed and 
non-revealed) must be inventoried and returned to the Sponsor. 
The investigational drug blind shall not be broken by the investigator unless information 
concerning the study intervention is necessary for the medical treatment of the participant.  
For unblinding a participant, the investigational drug blind can be obtained by scratching off the 
blinded area to reveal the treatment information. 
The Sponsor must be notified immediately (within 24 hours) if the investigational drug blind is 
broken. The date, time, and reason the blind was broken must be recorded on the appropriate Case 
Report Form (CRF). 
6.4. 
Study Intervention Compliance 
Drug supplies will be counted and reconciled at the study site before being returned. 
The investigator must maintain 100% accountability for all study intervention received and 
dispensed during the entire duration of the study. Proper drug accountability includes, but is not 
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• Continuously monitoring expiration dates if expiry date or retest date is provided to the 
investigator. 
• Frequently verifying that actual inventory matches documented inventory. 
• Verifying that the log is completed for the drug lot used to prepare each dose. 
• Verifying that all containers and/or packs used are documented accurately on the log. 
• Verifying that required fields are completed accurately and legibly. 
If any dispensing errors or discrepancies are discovered, the Sponsor must be notified immediately. 
The investigator must maintain a current inventory (Drug Accountability Log) of all study 
intervention delivered to the site, inventory at the site, dispensing log, and participants’ use 
records. This log must accurately reflect the drug accountability of the study intervention at all 
times. The following information will be recorded at a minimum: protocol number and title, name 
of investigator, site identifier and number, description of study intervention, kit numbers, expiry 
or retest date (if applicable) and amount dispensed, and the date and amount returned to the site by 
the participant, including the initials of the person dispensing and receiving the study intervention. 
The log should include all required information as a separate entry for each participant to whom 
study intervention is dispensed. 
Prior to site closure or at appropriate intervals, a representative from the Sponsor or its designee 
will perform clinical study material accountability and reconciliation before clinical study 
materials are returned to the Sponsor or its designee for destruction. The investigator will retain 
the original documentation regarding clinical study material accountability, return, and/or 
destruction, and copies will be sent to the Sponsor. 
The investigator will be notified of any change in expiry date or retest date of clinical study 
material during the study conduct. On expiry date notification from the Sponsor or designee, the 
site must complete all instructions outlined in the notification, including segregation of expired 
clinical study material for return to the Sponsor or its designee for destruction. In the event of 
expiry date extension of supplies already at the study site, supplies may be relabeled with the new 
expiry date at that site. In such cases, the Sponsor or its designee will prepare additional labels, 
certificates of analyses, and all necessary documentation for completion of the procedure at the 
sites. 
6.5. 
Concomitant Therapy 
All standard of care therapy is permitted for use any time during the study. 
 
There are no contraindications to treatment. There are no prohibited concomitant medications and 
no anticipated drug-drug interactions. Of note, no significant inhibition or induction of any of the 
CYP450 enzymes were observed in vitro after EDP1815 treatment. 
 
Any medication or vaccine (including OTC or prescription medicines, probiotics, and/or herbal 
supplements) that the participant is receiving at the time of enrolment or receives during the study 
must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 


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Any diagnostic, therapeutic, or surgical procedure performed during the study period should be 
recorded, including the dates, description of the procedure(s), and any clinical findings, if 
applicable. The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
6.6. 
Study stopping criteria 
6.6.1. 
Safety 
Safety data will be evaluated on an ongoing basis by a Data Monitoring Committee (DMC) which 
will consist of at least; a chairperson, 2 physicians independent of the study team, and an unblinded 
statistician. The DMC support staff for the blinded sessions will include the Principal Investigator, 
the Evelo medical monitor, a blinded statistician, and an Evelo clinical operations representative.  
 The DMC will review the data in a blinded manner but can request unblinded data if required.  
Any unblinded data will be reviewed only by the chairperson, 2 independent clinicians, and the 
unblinded statistician.  The DMC can halt the study at any point for safety concerns. Further details 
can be found in the DMC charter. 
 
The study should be terminated if either of the following conditions are met: 
1. One (or more) subjects on treatment with EDP1815 has symptoms of a clinically significant 
bacteremia and has a positive blood culture for the EDP1815 strain of P. histicola.(Note: 
the study will be paused and dosing held in all participants while identifying the specific 
strain of P.histicola).   
2. The DMC believe that EDP1815 is potentially detrimental to patient outcomes. 
 
6.7. 
Intervention after the End of the Study 
No specific interventions are planned after the end of the study, which is the visit 28 days after 
the last dose of the study drug (Day 42). 
 


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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
7.1 Discontinuation from Study Treatment and/or Withdrawal from the Study 
Participants may discontinue from study treatment or withdraw from the study at any time and for 
any reason without prejudice to their future medical care by the investigator or at the study site. 
Every effort should be made to keep participants in the study. The reasons for participants 
discontinuing treatment and/or withdrawing from the study will be recorded in the CRF. A 
participant may discontinue from the study drug or withdraw for the following reasons: 
 
1. The participant does not meet the protocol inclusion or exclusion criteria. 
2. The participant is non-compliant with the protocol. 
3. The participant is admitted to ICU. At this point, dosing for this individual subject will be 
stopped, but they will remain in the study until Day 42 for data collection where practical. 
However, if the subject is eligible for another interventional trial, they may be enrolled into this 
trial after discussion with the chief investigators. The participant is deemed to have completed this 
study at the point of signing the informed consent of this other study. 
4. The participant has a serious or intolerable AE that in the investigator’s opinion requires 
discontinuation from study treatment or withdrawal from the study (see section 7.2). 
5. The participant has laboratory safety results that reveal clinically significant changes from the 
baseline values that are not, in the opinion of the investigator, explained by COVID-19 infection 
or CRCs. 
6. The participant is lost to follow-up. 
7. Other reasons (e.g. pregnancy). 
8. The participant withdraws consent, or the investigator or sponsor decides to discontinue the 
participant’s participation in the study. 
 
7.2 Discontinuation from Study Treatment 
7.2.1 Temporary Cessation of Dosing in an Individual Participant: 
- 
Subjects with grade 3 GI-related AEs will pause dosing for up to 72 hours. Dosing may be 
restarted when/if symptoms improve, after discussion with the sponsor medical monitor. If 
symptoms do not improve within 72 hours then the subject will be withdrawn from the 
study. 
- 
Subjects with non GI-related grade 3 adverse events, not attributed to Covid-19 infection, 
will pause dosing for up to 72 hours, unless the baseline value was grade 2. Dosing may be 
restarted when/if symptoms improve, on discussion with the sponsor medical monitor. If 
symptoms do not improve within 72 hours then the subject will be withdrawn from the 
study. 
 
The participant should discontinue treatment permanently if the AE occurs a second time on 
restarting treatment. 
 


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7.2.2  Permanent Cessation of Dosing in an Individual Participant 
It may be necessary for a participant to permanently discontinue study treatment. If study drug is 
definitively discontinued, the participant will be encouraged by the investigator to continue to 
participate in all scheduled study visits and assessments, so that study data will be collected for 
the participant per protocol. Every effort should be made to keep participants in the study. 
Individual treatment stopping rules are: 
 
- 
“Any CTCAE grade 4 gastrointestinal-related adverse event.” 
- 
“Any non GI-related CTCAE grade 4 adverse event, not attributed to Covid-19 infection.” 
- 
“A new diagnosis of HIV / AIDS” 
 
 
7.3 Withdrawal from the Study 
Participants may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. The investigator will also withdraw participant(s) if Evelo terminates the 
study.  
 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.  
 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the CRF.  
 
Participants who withdraw from the study should complete the assessments for the follow-up visit.  
 
7.4 Lost to Follow Up  
A participant will be considered lost to follow-up if he or she has been discharged or transferred 
to another hospital, and the study site is unable to contact the participant for their telephone visit. 
 
Before a participant is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the participant by telephone. These contact attempts should be 
documented in the CRF.  
 
If the participant continues to be unreachable after 3 attempts, he/she will be considered to have 
withdrawn from the study.  
 
7.5 Replacements  
Participants who withdraw or are withdrawn from the study within 1 week of randomisation may 
be replaced in order to have approximately 60 participants provide at least 7 days of post baseline 
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8. 
Study Assessments and Procedures 
• Study procedures and their timing are summarised in the SoA (section 1.3). Protocol waivers 
or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
• All Screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to record 
details of all participants screened and to confirm eligibility or record reasons for screening 
failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management (e.g. blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures meet the protocol-specified criteria and were performed 
within the time frame defined in the SoA. Likewise, procedures conducted as part of the 
participant’s routine clinical management may be utilised for any of the study data provided 
the procedures meet the protocol-specified criteria and were performed within the time frame 
defined in the SoA. 
• The maximum amount of blood collected from each participant over the duration of the study, 
for the purposes of the study, including any extra assessments that may be required, will not 
exceed 140mL. Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the samples. 
• 
Repeat or unscheduled visits may be conducted at the investigator's discretion but all details 
must be recorded in the CRF. 
8.1. 
Efficacy Assessments  
Planned timepoints for all efficacy assessments are provided in the SoA. This data can be collected 
from the patient’s medical records if performed at the same time-point, and need not be repeated 
for research purposes. Where possible, all assessments will be taken from those performed as part 
of the participant’s routine clinical care. 
8.1.1. 
Oxygen Saturation 
Oxygen saturation will be measured using a peripheral pulse oximeter and will also be analysed 
as a ratio with the oxygen flow (SpO2 /FiO2).  The measurement will ideally be performed with 
the subject sitting and having been rested for at least 10 minutes. 
 
If the subject is on 3litres/min oxygen flow or less, and the investigator feels it is safe to do so, the 
investigator will remove the subject’s supplemental oxygen for 10 minutes while they remain 
seated, and while continuously monitoring the oxygen saturation. After 10 minutes the oxygen 
saturation reading will be taken to calculate the S/F ratio on room air. If, during this process, the 
saturations drop by greater than 4%, the oxygen will be immediately replaced and the ratio 
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8.1.2. 
WHO Ordinal Scale 
The WHO ordinal scale will be collected throughout the study.  This is an accepted instrument 
which has been developed specifically for trials in patients with COVID-19. 
 
Figure 3: WHO ordinal scale for clinical improvement (OSCI) of COVID-19 
 
 
 
8.1.3 Participant Questionnaire and Diary 
When participants are discharged, they will be given a daily questionnaire and diary to complete. 
The purpose is to record if the participant changes their current medications, starts taking any new 
medication, whether they are on home oxygen therapy, whether they continue to have COVID-19 
symptoms, and whether these symptoms interfere with their usual activities (to enable calculation 
of the OSCI score) and to record any adverse events. 
 
These questionnaires and diary should be completed once daily, until the patient is symptom free 
and off oxygen therapy for at least 48 hours, or until Day 42 (whichever is sooner). 
 
8.1.4 Telephone call 
If patients are discharged, they will be contacted by telephone on days 7, 14, 21 and 42 (+/- 1 day). 
The purpose of this call is to seek reporting of AEs, remind the participant to continue to fill their 
daily questionnaire (until symptoms have resolved or Day 42, whichever is sooner), and to offer 
the opportunity for any study-related questions. 
 
 


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8.2. 
Safety Assessments  
Planned timepoints for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations 
• A physical examination will include, at a minimum, assessments of the cardiovascular, 
respiratory, and GI systems. Height and weight will also be measured and recorded.  The 
physical examination data will be recorded from the admission record and medical notes 
where possible.  
8.2.2. 
Vital Signs 
• Blood pressure, pulse rate, respiratory rate, oxygen saturations and temperature will be 
assessed. 
8.2.3. 
Strain-specific PCR for EDP1815 
• Plasma samples will be taken from participants at day 7, to assess for the presence of 
EDP1815 levels by PCR with strain-specific primers that can detect EDP1815 
specifically, even when other strains of Prevotella Histicola are present. 
• If a participant has a positive blood culture for P. histicola identified as part of their 
clinical care, then isolates will be tested for the EDP1815 strain.   
Note: the study will be paused, and dosing held in all participants while identifying the specific 
strain of P. histicola. 
8.2.4. 
Gastrointestinal Assessment 
• Inpatients will have a daily assessment for evidence of any severity of nausea, vomiting, 
diarrhoea, bloating and abdominal pain. This will be recorded as an adverse event and an 
assessment of causality will be made. 
• Outpatients will complete the daily diary card (section 8.1.3), where they will be 
prompted to record GI side-effects such as nausea, vomiting, diarrhoea, bloating and 
abdominal pain as AEs. 
8.2.5. 
Clinical Safety Laboratory Assessments 
• An HIV test will be performed at screening. Subjects with a positive result will be excluded 
or withdrawn from the study. 
• The safety laboratory assessments are Full blood count, Creatinine, Urea and Electrolytes 
and Liver function test, performed at baseline, Day 4 and Day 7. 
• The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition. 
• All laboratory tests with values considered clinically significantly abnormal and which are 
not associated with the underlying disease during participation in the study or within 
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or baseline or are no longer considered clinically significant by the investigator or Medical 
Monitor. 
o If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the aetiology should be identified and the Sponsor 
notified. 
o All protocol-required laboratory assessments must be conducted in accordance with 
the laboratory manual and the SoA in addition to local procedures.  
o If laboratory values from non-protocol specified laboratory assessments performed 
at the institution’s local laboratory require a change in participant management or 
are considered clinically significant by the investigator (e.g. SAE or AE or dose 
modification), then the results must be recorded in the CRF.  
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3. 
 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorised representative).  Due to the nature of the patient population and 
disease only SAEs and AEs of severe (CTCAE Grade 3) and potentially life threatening 
(CTCAE Grade 4) intensity will be documented in the CRF. AEs of mild (CTCAE Grade 1) or 
moderate (CTCAE Grade 2) intensity should be documented in the medical notes. However, 
adverse events relating to nausea, vomiting, diarrhoea, bloating and abdominal pain of any grade 
will be recorded and assessed as an adverse event. 
 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7). 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information  
All SAEs will be collected from the signing of the ICF at Screening until the follow--up visit (28 
days after last dose) at the timepoints specified in the SoA (Section 1.3). 
 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the CRF, 
not the AE section. 
 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 3. The investigator will submit any updated SAE data to the Sponsor within 24 hours 
of it being available. 
 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify the 
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The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3. 
8.3.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.  
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilisation, the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is given in Appendix 3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. The Sponsor will inform all study 
sites of any SAEs as soon as possible after an SAE has been reported. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary. 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g. summary or listing of SAEs) from the Sponsor will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements. 
8.3.5. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
Death, progression to ICU, mechanical ventilation and organ failure can all result from COVID 19 
infection and are endpoints within the study.  These events will not be reported according to the 
standard process for expedited reporting of SAEs even though the event may meet the definition 
of an SAE, unless deemed drug related by the PI or sponsor. 
 
8.4. 
Treatment of Overdose 
For this study, any dose of EDP1815 taken which is more than 8.0x1011 cells (10 capsules) 
within a 24-hour time period will be considered an overdose. 
 
The Sponsor does not recommend specific treatment for an overdose unless there is evidence of 
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would recommend the use of a penicillin--based antibiotic (e.g. Penicillin V) which may be used 
in case of overdose. If the patient is allergic to penicillins, then alternatives including 
cephalosporins; macrolides (e.g. clarithromycin or erythromycin); or tetracyclines (eg. 
Doxycycline) may be used as an alternative. 
 
In the event of an overdose, the investigator should: 
1. Contact the Medical Monitor immediately upon becoming aware of the overdose. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities for 
72 hours or until they have resolved, whichever is the longer. 
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5. 
Biomarkers 
Biomarker samples will be collected at baseline, day 4 and day 7.  A small panel of biomarkers 
will be conducted on all subjects at these time points.  Additional biomarkers may be measured 
based on the results of the trial. 
8.5.1. 
Biomarkers to be measured on all subjects 
Specific biomarkers have been associated with progression and poor outcome following infection 
with COVID-19. These include differential white cell count, neutrophil to lymphocyte ratio, CRP, 
IL-6, IL-8, Ferritin, D-Dimer, and Troponin levels. These will be measured in all subjects at 
baseline, day 4 and day 7. 
8.5.2. 
Additional plasma biomarkers  
Additional plasma biomarkers may be analysed subject to the clinical data in the trial. These 
biomarkers may help understand the response to EDP1815 and / or the progression of COVID-19 
disease.  These markers could include Eotaxin, Eotaxin-3, GM-CSF, IFN-γ, IL-1α, IL-1β, IL-2, 
IL-4, IL-5, IL-7, IL-8 (HA), IL-10, IL-12/IL-23p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, IP-
10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, TARC, TNF-α, TNF-β, VEGF-A.  Additional 
plasma biomarkers may be analysed if emerging data suggests they could be useful in 
understanding the drug response and / or disease progression. 
8.5.3. 
Transcription analysis 
RNA will be collected from PBMCs and may be analysed subject to the clinical data in the trial.  
The exact genes to be analysed will be defined by an expert sub-group of the study but will include 
genes related to host immune response as well as those related to the disease pathology. 
8.5.4. 
Microbiome Research  
The microbiome composition of stool samples will be assessed as an optional research test 
collected at baseline and once more between Days 5-14. EDP1815 is not expected to alter the 
composition of the microbiome, but the microbiome will be evaluated for separate research 
purposes. Microbiome analysis may be performed through 16s ribosomal RNA sequencing and/or 
whole genome microbial sequencing depending on the question being asked. 
 


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8.5.5. 
Biobanking Sample 
Blood will be stored in a research tissue bank for up to 
 for future research of COVID-19.  
Samples will be labelled with a code and if shared with others, will be deidentified.  The samples 
may be used by the Sponsor, the participating investigators or other IRB-approved investigators at 
the participating institutions. 
 
8.6 Additional Baseline Information 
 
8.6.1 Smoking Status 
Data on whether the participant is a current-smoker, past-smoker, or never-smoker will be 
collected. For past- or current-smokers, a pack year history will be collected (packs of cigarettes 
smoked per day * years the patient has smoked). 
 
8.6.2 Significant Covid-19 Co-morbidities 
Information on the presence or absence of current comorbidities that are relevant as prognostic 
factors for Covid-19 will be collected. This includes the presence/absence of diabetes, 
hypertension, chronic other cardiovascular disease, chronic respiratory disease, and cancer. 
9. 
Statistical Considerations  
The SAP will be developed and finalised before database lock and will fully describe the 
participant populations to be included in the analyses, procedures for accounting for missing, 
unused, and spurious data and the statistical methods to be applied to the data.  
 
All analyses will be performed using SAS® version 9.3 or later (SAS Institute, Cary, NC, USA). 
9.1. 
Sample Size Determination  
 
60 participants will be randomly assigned to EDP1815 or matching placebo in a 1:1 ratio.   
 
This is a pilot study designed to give an initial evaluation of the efficacy and safety of EDP1815 
in treating Covid-19 and in evaluating multiple endpoints for clinical relevance and sensitivity, 
while informing the sample size for future studies. A formal power calculation was not performed 
and the number of participants was selected based on feasibility. 
 
Based on this sample size, the table below indicates the expected size of a 95% confidence interval 
for the difference between the treatments based on possible observed sample variation and drop-
out rates. 
 
 










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in a model of trough S/F ratio and selected as covariates for the relevant model at a 5% level of 
significance using forward stepwise selection. 
 
Baseline S/F will be the first fitted term in the model regardless of significance. A maximum of 3 
further covariates may be included in the model in order to avoid over-parameterisation and a 
reduction in the efficiency of the treatment estimates.  
 
This approach to the inclusion of baseline covariates which may have a prognostic effect on 
response will also be used for the Cox proportional hazards and Fine and Gray models to be used 
for the secondary analyses. 
9.4.1.1. 
Primary Efficacy Analysis 
 
Change from baseline in trough S/F ratio will be analysed with an analysis of covariance 
(ANCOVA) model.  The model will include fixed effect parameters for treatment and baseline S/F 
ratio together with the additional baseline covariates which were identified during the blinded 
review.  
 
Least square (LS) estimates of the mean change from baseline trough S/F ratio together with the 
standard error and 95% confidence interval will be reported. The LS mean treatment difference 
and 95% confidence interval will also be presented. 
 
Distributional assumptions underlying the model used for analysis will be examined by obtaining 
a normal probability plot of the residuals and a plot of the residuals versus the fitted values (i.e. 
checking the normality assumption and constant variance assumption of the model respectively) 
to gain confidence that the model assumptions are reasonable. 
 
If during the course of the study, a newly approved medication for COVID-19 becomes part of the 
standard of care treatment at the investigational site, a further sensitivity analysis will be 
performed. A new-medication covariate (yes, no for use before Day 14) and an interaction for 
treatment*new medication will be included in the ANCOVA model described above. 
9.4.1.2. 
Secondary Efficacy Analyses 
 
Change from baseline in S/F ratio at Days 4, 7, 10 and 14 will be analysed separately ANCOVA 
models.  The models will include treatment, baseline S/F ratio together with the additional baseline 
covariates included in the primary model for trough S/F ratio. Two models will be fitted, one with 
S/F ratio as the response variable and one with change from baseline in S/F ratio as the response 
variable. 
 
If more than one S/F ratio measurement is provided at the relevant study day, the lowest S/F 
measurement within each study day will be used.  Participants who are discharged from hospital 
will have their last observed S/F ratio prior to discharge carried forward to replace missing data at 
later timepoints.  Data missing for reasons other than discharge will be imputed with the closest 
S/F ratio recorded within one day of the missing visit if such a value exists, otherwise the 
participant will be excluded from the analysis for that visit.   
 


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Other mechanisms for dealing with this missing not at random (MNAR) data may be further 
investigated for informing on the most credible methods to take forward into a future study. These 
methods will be further discussed in the SAP. 
 
LS mean and LS mean change from baseline in S/F ratio will be reported with their corresponding 
standard error and 95% confidence interval.  Estimated treatment difference for the mean change 
from baseline and corresponding 95% confidence interval will also be reported. 
 
If during the course of the study, a newly approved medication for COVID-19 becomes part of the 
standard of care treatment at the investigational site, a further sensitivity analysis will be 
performed. A new-medication covariate (yes, no for use prior to the relevant study day) and an 
interaction for treatment*new medication will be included in the ANCOVA models described 
above at timepoint. 
 
Percentage change from baseline in S/F ratio will be analysed in the same manner as the change 
from baseline in S/F ratio described above. 
 
A Cochran-Mantel Haenszel (CMH) test for ordinal data will be used to compare the treatment 
groups with respect the percentage of participants reporting each WHO OSCI score at Days 4, 7, 
10, 14, 21 and 42.   
 
Shift tables showing the shifts from Baseline to each of Days 4, 7, 10, 14, 21 and 42 in WHO OSCI 
score will be provided. 
 
The difference in proportions between the treatment groups in the percentage of participants 
remaining at or below their baseline WHO OSCI score will be reported together with the 
corresponding 95% confidence interval at Days 4 7, 10, 14, 21 and 42. 
 
A CMH test for ordinal data will be used to compare the treatment groups with respect to the 
maximum WHO OSCI score recorded by each participant. Within each maximum score, the time 
in days spent at that score will also be summarised. 
 
Overall survival will be analysed using a Cox proportional hazards (Cox-PH) model. The model 
will include parameters for treatment together with the additional baseline covariates which were 
identified during the blinded review of the overall survival model.  Participants who are still alive 
at the end of the 42-day study period or who withdraw prematurely from the study for reasons 
other than death will be censored on the day of their study completion/withdrawal. The hazard 
ratio for treatment difference with corresponding 95% confidence interval will be presented. 
 
If during the course of the study, a newly approved medication for COVID-19 becomes part of the 
standard of care treatment at the investigational site, a further sensitivity analysis will be 
performed. A time-dependent covariate for use of the new medication (yes, no) will be included 
in the model described above together with its interaction with treatment. 
 
Intubation and mechanical ventilation free survival will be analysed in the same manner as 
described for overall survival above. 
 


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Number of days requiring oxygen therapy, number of days with pyrexia, maximum daily 
temperature, minimum and maximum SpO2 values will be summarised only. 
 
Time to discharge will be analyzed using the Fine and Gray subdistributional hazards model to 
allow for the competing risk of death (Fine 1999). The model will include parameters for treatment 
together with the additional baseline covariates which were identified during the blinded review 
of the time to discharge model.  
 
Subjects who are not discharged and are still alive at the end of the 42-day study period or those 
who withdraw prematurely from the study without being discharged or dying will be censored on 
the day of study completion/withdrawal.  
 
The number and percentage of participants who are discharged, who die and who are censored will 
be reported together with the estimated subdistributional hazard ratio (with 95% confidence 
interval) for treatment difference in risk of recovery and its p-value from the model. Cumulative 
incidence functions for time to full recovery will also be plotted by treatment group. 
 
If during the course of the study, a newly approved medication for COVID-19 becomes part of the 
standard of care treatment at the investigational site, a further sensitivity analysis will be 
performed. A time-dependent covariate for use of the new medication (yes, no) will be included 
in the model described above together with its interaction with treatment. 
 
Time to SpO2 ≥94% on room air without further requirement for oxygen therapy and time to 
recovery will be analysed in the same manner as described above for time to discharge. 
9.4.1.3. 
Exploratory Efficacy Analysis 
 
Exploratory endpoints will be summarized. 
 
Exploratory modelling will be performed to look for potential predictors of response. This will use 
the model for change from baseline in trough S/F ratio from the primary analysis, including any 
baseline covariates found to be significant.  For each potential predictor, the variable and its 
interaction with treatment will be added to the base model from the primary analysis and look for 
significant interactions. If during the course of the study, a newly approved medication for 
COVID-19 becomes part of the standard of care treatment at the investigational site, the interaction 
between treatment and the covariate defined by use of the new medication will also be investigated 
as part of this exploratory analysis.  
 
Full details will be provided in the SAP. 
 
9.4.2. 
Safety Analyses  
 
All safety endpoints will be tabulated by treatment group and will be performed on the Safety 
Population. Further details will be described in the SAP. 


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9.5. 
Interim Analyses and Safety Monitoring 
 
The independent Data Monitoring Committee (DMC) will consist of at least; a chairperson, 2 
physicians independent of the study team, and an unblinded statistician. The DMC support staff 
for the blinded sessions will include the Principal Investigator, the Evelo medical monitor, a 
blinded statistician, and an Evelo clinical operations representative.  
 
After 20 patients are enrolled, the DMC will review the safety data and decide whether to open 
recruitment to subjects aged  >65 years. 
 
The DMC can also recommend increasing the sample size of the study to a further 40 participants 
if their review of the data suggests that there would be substantial added benefit to the likelihood 
of meeting the trial objectives. 
 
Interim results of the analysis, beyond the recommendations to continue or stop the study, will not 
be shared with the sponsor prior to the end of the study in order to avoid any bias or potential 
alpha-spending issues as per the FDA guidance on Adaptive Designs for Clinical Trials of Drugs 
and Biologics. 
 
Full details of the disposition and responsibilities of the DMC together with the frequency of 
reviews will be provided in the DMC charter. 


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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents 
(e.g. advertisements) must be submitted to an IRB/IEC by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants or changes considered non-substantial by the Sponsor.  
• The investigator is responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
• The investigator or designee must ensure that each trial participant, or his/her legally 
acceptable representative, is fully informed about the nature and objectives of the trial and 
possible risks associated with their participation. 
• The investigator or designee will obtain electronic or paper written informed consent from 
each participant or the participant’s legally acceptable representative before any trial-
specific activity is performed. The informed consent form used for this trial and any change 
made during the course of this trial, must be prospectively approved by the ethics 


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committee. The investigator will retain the original electronic or paper copy of each 
participant signed informed consent form.  
• Any new information which becomes available, which might affect the participant’s 
willingness to continue participating in the trial, will be communicated to the participant 
and/or their legally accepted representative as soon as possible. 
• The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.  
• Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study site.  
• The medical record must include a statement that written informed consent and assent, 
where applicable, was obtained before the participant was enrolled in the study and the 
date the written consent was obtained. The authorized person obtaining the informed 
consent must also sign the informed consent form. 
• Participants must be reconsented to the most current version of the informed consent 
form(s) during their participation in the study.  
• A copy of the informed consent form(s) must be provided to the participant or the 
participant’s legally authorized representative.  
10.1.4. 
Data Protection 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.  
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with applicable data protection laws. The level of disclosure 
must also be explained to the participant.  
• The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Committees Structure 
The only committee that will be set-up for this study is an independent Data Monitoring Committee 
(DMC). The DMC will consist of at least; a chairperson, 2 physicians independent of the study 
team, and an unblinded statistician. The DMC support staff for the blinded sessions will include 
the Principal Investigator, the Evelo medical monitor, a blinded statistician, and an Evelo clinical 
operations representative.  
 
After 20 patients are enrolled, the DMC will review the safety data and decide whether to open 
recruitment to subjects aged >65 years. 
 


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Full details of the disposition and responsibilities of the DMC together with the frequency of 
reviews will be provided in the DMC charter. 
10.1.6. 
Dissemination of Clinical Study Data 
The Sponsor and the investigator are committed to publish data in accordance with applicable 
regulations and transparency guidance. Results will be published within 2 years of finalization of 
the CSR and will only be delayed to the second year if earlier publication may be detrimental to 
the financial position or intellectual property rights of the Sponsor. 
10.1.7. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on electronic CRF (eCRF) unless 
transmitted to the Sponsor or designee electronically (e.g. laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.  
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations 
or institutional policies require a longer retention period. No records may be destroyed 
during the retention period without the written approval of the Sponsor. No records may 
be transferred to another location or party without written notification to the Sponsor.  
10.1.8. 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at each investigator site. 
• Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
• Definition of what constitutes source data can be found in the source data agreement form 
for each site. 
10.1.9. 
Study and Site Closure 
The Sponsor reserves the right to close a study site or terminate the study at any time for any reason 
at the sole discretion of the Sponsor. Study sites will be closed upon study completion. A study 


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site is considered closed when all required documents and study supplies have been collected and 
a study site closure visit has been performed. 
 
The investigator may initiate study site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
 
Reasons for the early closure of a study site by the Sponsor or investigator may include but are not 
limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate enrolment of participants by the investigator 
• Discontinuation of further study intervention development 
10.1.10. 
Publication Policy 
• Full details on the publication policy are provided in the contract between the Sponsor and 
the investigator. In summary: the results of this study may be published or presented at 
scientific meetings. If this is foreseen, the investigator agrees to submit all manuscripts or 
abstracts to the Sponsor at least 30 days before submission. This allows the Sponsor to 
protect proprietary information, delay the publication if necessary to protect its patent 
rights, and to provide comments.  
• The Sponsor will comply with the requirements for publication of study results as detailed 
in Section 10.1.6. In accordance with standard editorial and ethical practice, the Sponsor 
will generally support publication of multisite studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by mutual 
agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 
 


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10.2. 
Appendix 2: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Child-Bearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.  
• Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-oestrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  
Contraception Guidance: 
Male participants with a female partner of child-bearing potential must either 
• Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
• Use a male condom during each episode of penile penetration during their participation 
in the study and for 90 days after the last dose of study drug.  
• Have a confirmed vasectomy. 
 
In addition, all male participants must refrain from donating sperm for the duration of the study 
and for at least 90 days following their final visit. 
Female participants 
Female participants of child-bearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in Table 9. 
 
 


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Table 9: Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of < 1% per year when used consistently and correctly.  
Combined (oestrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationb  
• Oral  
• Intravaginal  
• Transdermal  
Progestogen only hormonal contraception associated with inhibition of ovulation 
• Oral  
• Injectable  
Highly Effective Methods That Are User Independent a  
• Implantable progestogen only hormonal contraception associated with inhibition of 
ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
Vasectomised partner  
A vasectomised partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.  
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.  
NOTES:  
a) Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies.  
b) Hormonal contraception may be susceptible to interaction with the study intervention, which 
may reduce the efficacy of the contraceptive method. In this case, a highly effective method 
of contraception plus condoms should be utilised during their participation in the study up to 
and including at least 1 complete menstrual cycle (≥ 30 days) for women and 90 days for men 
post last dose.  
Pregnancy Testing: 
• WOCBP should only be included after a confirmed menstrual period and a negative 
pregnancy test. 
• Pregnancy testing is required at screening.  
• Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
 
 


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Collection of Pregnancy Information: 
Male participants with partners who become pregnant  
• The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies to all male participants who receive EDP1815. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to the Sponsor. Generally, the follow-
up will be no longer than 8 weeks following the estimated delivery date. Any termination 
of the pregnancy will be reported regardless of foetal status (presence or absence of 
anomalies) or indication for the procedure.  
Female participants who become pregnant  
• The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The investigator will collect follow-up information on the participant and the 
neonate and the information will be forwarded to the Sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of foetal status (presence or absence 
of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE. A 
spontaneous abortion is always considered to be an SAE and will be reported as such. 
Any post-study pregnancy related- SAE considered reasonably related to the study 
intervention by the investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.  
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 












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10.4. 
Appendix 4: Summary of Protocol Amendments 
 
Protocol Amendment 1, Protocol version 2.0, dated 24 June 2020 
 
The study protocol has been amended to address comments raised by the FDA and IRB 
following their review of the original protocol, Protocol version 1.0, dated 06 May 2020. Major 
changes are summarised below.  
 
Administrative and minor grammatical, editorial, and formatting changes were made for 
clarification purposes only. 
 
Section 1.1 
 
• Secondary endpoints were revised to include data at Day 21 and Day 42, and not Day 28. 
• Exploratory objective and endpoints revised to include detection of EDP1815 in stool and/or 
in blood.  
• Participant Trial Duration revised to 42 days post first dose. 
 
Section 1.2 
 
• Schema revised to indicate longer study duration to 42 days post first dose. 
 
Section 1.3 
 
• Schedule of Assessments revised to indicate longer study duration to 42 days post first dose, 
including assessments to be performed. 
• The following assessments were added to the Schedule of Assessments: 
o Smoking status. 
o Significant Covid-19 Comorbidities. 
o Plasma PCR for EDP1815. 
• The timing of the following assessment was changed: 
o Faecal sample for microbiome analysis 
• Schedule of Assessments footnotes revised: 
o to add surveillance for potential GI symptoms. 
o to clarify assessments to be collected in the event of remaining in hospital longer than 
14 days. 
o to clarify faecal sample collection. 
o to add information on smoking status. 
 
Section 3 
 
• Secondary endpoints were revised to include data at Day 21 and Day 42, and not day 28. 


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• Exploratory objective and endpoints revised to include detection of EDP1815 in stool and/or 
in blood.  
• Participant Trial Duration revised to 42 days post first dose. 
 
Section 4.4 
• End of Study Definition revised to indicate longer study duration to 42 days post first 
dose. 
Section 5.1 
 
• Inclusion criteria revised/clarified: 
o to include participants receiving any form of supplementary oxygen therapy at 
baseline. 
o to include participants with confirmed COVID-19 viral infection by RTPCR at 
screening. 
o Age: 
 18-75 years old., OR 
 15 - 17 year-olds can be included after DMC approval (see section 10.1.5), 
OR 
 .>75 year-olds can be included after DMC approval (see section 10.1.5). 
• Removed the following inclusion criterion: 
o Are considered an appropriate subject for intervention with EDP1815 in the opinion 
of the investigator. 
Section 5.2 
 
• Exclusion criteria revised/clarified; 
o to exclude participants with a diagnosed primary immunodeficiency. 
o to allow the use of laboratory results reported in the last 48 hours. 
o to exclude participants with GI signs or symptoms equivalent to CTCAE v5.0, 
gastrointestinal disorders, grade 3 or 4 event. 
o clarified the exclusion if participants are currently participating in an 
interventional study. 
Section 6.1 
 
• Clarified the minimum time allowed between the twice daily doses. 
 
Section 6.6.1 
 
• Amended the study stopping criteria: 
o One (or more) subjects on treatment with EDP1815 has symptoms of a clinically 
significant bacteremia and has a positive blood culture for the EDP1815 strain of 


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P. histicola.(Note: the study will be paused and dosing held in all participants 
while identifying the specific strain of P.histicola). 
Section 7.2 
 
• Revised to include sub section 7.2.1, Temporary Cessation of Dosing in an Individual 
Participant and section 7.2.2, Permanent Cessation of Dosing in an Individual Participant. 
  Section 8.1.3 
 
• Clarified that the dairy should be completed until the participant is asymptomatic and off 
oxygen for at least 48 hours or to Day 42, whichever is sooner. 
 
  Section 8.1.4 
 
• Revised in line with longer duration of study. 
 
Section 8.2 
 
• Revised to include sub section 8.2.3: Strain-specific PCR for EDP1815 and section 8.2.4: 
Gastrointestinal Assessment. 
 
Section 8.3 
 
• Revised to include reference to the CTCAE grading of adverse events, including addition 
of wording related to collection of adverse events relating to GI adverse events. 
 
Section 8.6 
 
• Addition of section on Additional Baseline Information. 
 
Section 9.4.1.1 
 
• Addition of wording on handling newly approved medication for COVID-19 becoming a 
potential covariate. 
Section 9.4.1.2 
 
• Revised days in relation to the longer study duration. 
• Addition of wording on handling newly approved medication for COVID-19 becoming a 
potential covariate. 
 
Section 9.4.1.3 
 


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• Addition of wording on handling newly approved medication for COVID-19 becoming a 
potential covariate. 
 
Section 9.5 
 
• Revised wording to indicate the DMC involvement prior to enrolling participants aged 
15-17, as well as participants aged >75 years.  
 
Section 10.1.5 
 
• Revised wording to clarify DMC membership and to indicate the DMC involvement prior 
to enrolling participants aged 15-17, as well as participants aged >75 years. 
 
Section 10.3 
 
• Revised classification of adverse events to use the CTCAE classification. 
• Revised the SAE reporting wording with inclusion of contact telephone numbers and 
email address. 
 
 


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Protocol Amendment 2, Protocol version 3.0, dated 09 July 2020 
 
The study protocol has been amended to address comments raised by the FDA following their 
review of Protocol version 2.0, dated 24 June 2020. Major changes are summarised below.  
 
Administrative and minor grammatical, editorial, and formatting changes were made for 
clarification purposes only. 
 
Section 1.3 
 
• An HIV assessment at the time of screening was added to the Schedule of activities 
• An ‘x’ was added to the screening visit for concomitant medications and adverse event 
checks.  
 
Section 5.1 
• The inclusion criteria were amended to an age range of 18-65 years old. Inclusion of subjects 
aged 15-17 years was removed; and text related to possible inclusion of subjects older than 
65 after DMC review was added. 
 
Section 5.2 
• The exclusion criteria were amended to add individuals with HIV/AIDS. 
 
Section 7.2.2 
• Permanent cessation of dosing in an individual participant criteria were updated to include a 
diagnosis of HIV/AIDS. 
 
Section 8.4 
• Additional antibiotic options added in case of penicillin allergy. 
 
Sections 9.5 and 10.1.5 
• An update was made to the DMC review criteria, to include assessment after 20 subjects are 
enrolled for consideration of enrolling patients older than 65, and removal of consideration of 
enrolling adolescents aged 15-17. 
 
 


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Protocol Amendment 3, Protocol version 4.0, dated 03 August 2020 
 
The study protocol has been amended to include biobanking language and to clarify the 
collection of the microbiome sample and what the site should do in the event of a positive blood 
culture during the study. Major changes are summarised below.  
 
Administrative and minor grammatical, editorial, and formatting changes were made for 
clarification purposes only. 
 
Page 13, Section Number of Centers 
• Language changed to accommodate increase in number of potential sites to be utilized in 
the study to meet enrolment goals. 
 
Section 1.3 
• Biomarker sample added to the Schedule of Activities (SOA) 
• SOA Footnote #7: language added to clarify when the Microbiome Sample should be 
collected. 
 
Section 8.2.3 
• Language added to clarify what should be done at the site level should there be a 
participant showing signs of bacteremia with a positive blood culture. 
 
Section 8.5.4 
• Language added to clarify when the Microbiome Sample should be collected. 
 
Section 8.5.5 
• New section added to describe the Biobanking samples, how long it will be retained, how 
the samples will be used, and who has access to these samples. 
 
 


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11. 
References 
Cookson C. UK’s original coronavirus plan risked ‘hundreds of thousands’ dead. Financial 
Times. 16 March 2020. 
Fine JP and Gray RJ. A Proportional Hazards Model for the Subdistribution of a Competing 
Risk. J Amer Stat Assn, vol. 94, no. 446, 1999, pp. 496–509. 
Gralinski LE, and Baric RS. Molecular pathology of emerging coronavirus infections. J Pathol, 
2015: 235: 185-195. 
Guan WJ, Ni ZY, Hu Y et al. Clinical Characteristics of Coronavirus Disease 2019 in China. 
NEJM, 2020: 382(18):1708-1720. 
Hagau N, Slavcovici A, Gonganau DN et al. Clinical aspects and cytokine response in severe 
H1N1 influenza A virus infection. Crit Care, 2010: 14(6) R203. 
Huang C, Wang Y, Li X et al. Clinical features of patients infected with 2019 novel coronavirus 
in Wuhan, China. Lancet. 2020; 395(10223):497–506.  
de Jong MD, Simmons CP, Thanh TT et al. Fatal outcome of human influenza A (H5N1) is 
associated with high viral load and hypercytokinemia. Nat Med, October 2006: 12(10) 1203-7. 
Maharaj R. King’s Critical Care - Evidence Summary Clinical Management of COVID-19. 
King’s Critical Care. 09 March 2020: 1-24. 
Liu Y, Yang Y, Zhang C et al. Clinical and biochemical indexes from 2019-nCoV infected 
patients linked to viral loads and lung injury. Sci. China Life Sci. 2020: 63, 364–374. 
Mehta P, McAuley DF, Brown M et al. Covid-19: consider cytokine storm syndromes and 
immunosuppression; The Lancet. 2020: 395, 1033-4. 
Peiris JS, Chu CM, Cheng VC et al. Clinical progression and viral load in a community outbreak 
of coronavirus-associated SARS pneumonia: a prospective study. Lancet. 2003: 361: 1767-72. 
Ruan Q, Yang K, Wang W et al. Clinical predictors of mortality due to COVID-19 based on an 
analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 03 Mar 2020. 
Villar J, Pérez-Méndez L, Blanco J, et al. Spanish Initiative for Epidemiology, Stratification, and 
Therapies for ARDS (SIESTA) Network. A universal definition of ARDS: the PaO2/FiO2 ratio 
under a standard ventilatory setting--a prospective, multicenter validation study. Intensive Care 
Med. 2013 Apr;39(4):583-92. 
Wang D. Hu B, Hu C et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 
Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA. 2020: 323, 1061–1069.  
Wong CK, Lam CWK, Wu AKL et al. Plasma inflammatory cytokines and chemokines in severe 
acute respiratory syndrome. Clin Exp Immunol. 2004: 136, 95-103 

SAP_001.pdf: 
 
 
 
 
 
 
Official Title: 
A Phase 2 Double-blind Placebo-
controlled Study Investigating the 
Safety and Efficacy of EDP1815 in 
the Treatment of Patients 
Hospitalized With SARS-CoV-2 
Infection 
  
 
NCT Number: 
 
NCT04488575 
 
Document date:  
11 February 2022 
 


Statistical Analysis Plan  
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EDP1815-205 
 
  
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Page 1 of 61 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol: EDP1815-205 
Protocol version: V4.0 05AUG2020 
 
A Phase 2 double-blind placebo-controlled study investigating the safety and 
efficacy of EDP1815 in the treatment of patients hospitalized with SARS-CoV-2 
Infection 
 
SAP/Amendment Number 
Date 
Final SAP v1.0 
30 July 2020 
Final SAP v2.0 
11 February 2022 
 
 
 
Prepared for: 
Evelo Biosciences Inc. 
 
 
Prepared by: 
 
 
 
 
 
 
 
 
Approved by 
Signature 
Date 
 
Immunology Clinical Lead, 
Evelo Biosciences Inc. 
 
 
 
Consultant Statistician 
. 
 
 
 
Senior Statistician,      
 
 
 
 


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1 
Table of Contents 
1 
Table of Contents ..................................................................................................................................... 2 
2 
Abbreviations and Definitions .................................................................................................................. 6 
3 
Introduction .............................................................................................................................................. 7 
4 
Study Objectives and Endpoints ............................................................................................................... 7 
4.1 
Study Objectives ............................................................................................................................ 7 
4.2 
Endpoints ....................................................................................................................................... 7 
5 
Study Methods ......................................................................................................................................... 9 
5.1 
General Study Design and Plan ...................................................................................................... 9 
5.2 
Randomization and Blinding ........................................................................................................ 10 
5.3 
Derived variables ......................................................................................................................... 10 
5.3.1 
General ............................................................................................................................ 10 
5.3.2 
Demographic and Background Data ............................................................................... 11 
5.3.3 
Efficacy ............................................................................................................................ 14 
5.3.4 
Safety ............................................................................................................................... 19 
6 
Sample Size ............................................................................................................................................. 20 
7 
General Considerations .......................................................................................................................... 21 
7.1 
Analysis Populations .................................................................................................................... 21 
7.1.1 
Enrolled Population ......................................................................................................... 21 
7.1.2 
Intention to Treat (ITT) Population ................................................................................. 21 
7.1.3 
Safety Population ............................................................................................................ 22 
7.2 
Covariates and Subgroups ........................................................................................................... 22 
7.3 
Missing Data ................................................................................................................................ 23 
7.3.1 
General ............................................................................................................................ 23 
7.3.2 
Partial Dates/Times ......................................................................................................... 24 
7.3.3 
Adverse Event Information ............................................................................................. 25 
7.4 
Interim Analyses and Data Monitoring ........................................................................................ 25 
7.4.1 
Purpose of Interim Analyses ........................................................................................... 25 
7.4.2 
Planned Schedule of Interim Analyses ............................................................................ 26 
7.4.3 
Scope of Adaptations ...................................................................................................... 26 
7.4.4 
Stopping Rules ................................................................................................................. 27 
7.4.5 
Practical Measures to Minimize Bias .............................................................................. 27 
7.4.6 
Documentation of Interim Analyses ............................................................................... 27 


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7.5 
Multiple Testing ........................................................................................................................... 28 
8 
Summary of Study Data .......................................................................................................................... 28 
8.1 
Subject Disposition ...................................................................................................................... 28 
8.2 
Protocol Deviations ...................................................................................................................... 29 
8.3 
Demographic and Baseline Variables .......................................................................................... 29 
8.4 
Concurrent Illnesses and Medical Conditions ............................................................................. 29 
8.5 
Prior and Concomitant Therapy .................................................................................................. 30 
8.6 
Compliance .................................................................................................................................. 31 
9 
Efficacy Analyses .................................................................................................................................... 32 
9.2 
Primary Efficacy Analysis ............................................................................................................. 33 
9.2.1 
Primary Efficacy Estimand ............................................................................................... 33 
9.2.2 
Main Analytical Approach ............................................................................................... 33 
9.2.3 
Sensitivity Analyses ......................................................................................................... 34 
9.2.4 
Subgroup Analyses .......................................................................................................... 34 
9.3 
Secondary Efficacy Analyses ........................................................................................................ 34 
9.3.1 
Change from Baseline in S/F Ratio .................................................................................. 34 
9.3.2 
Percentage Change from Baseline in S/F Ratio ............................................................... 36 
9.3.3 
WHO OSCI Score .............................................................................................................. 36 
9.3.4 
Overall Survival and Intubation and Mechanical Ventilation Free Survival .................... 38 
9.3.5 
Time to Discharge, Time to SpO2 ≥94% on Room Air and Time to Recovery ................. 39 
9.3.6 
Other Secondary Endpoints ............................................................................................ 40 
9.4 
Exploratory Efficacy Analyses ...................................................................................................... 40 
9.4.1 
Biomarkers ...................................................................................................................... 40 
9.4.2 
Potential Predictors of Response to EDP1815 ................................................................ 40 
10 Safety Analyses ....................................................................................................................................... 41 
10.1 Extent of Exposure ....................................................................................................................... 41 
10.2 Adverse Events............................................................................................................................. 41 
10.3 Deaths, Serious Adverse Events and other Significant Adverse Events ...................................... 42 
10.3.1 Adverse Events of Special Interest .................................................................................. 42 
10.4 Clinical Laboratory Evaluations .................................................................................................... 42 
10.5 Other Safety Measures ................................................................................................................ 43 
10.5.1 Vital Signs ........................................................................................................................ 43 
10.5.2 Physical Examination ....................................................................................................... 44 


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10.5.3 Pregnancy Tests ............................................................................................................... 44 
11 Pharmacokinetics ................................................................................................................................... 44 
12 Reporting Conventions ........................................................................................................................... 44 
13 Technical Details ..................................................................................................................................... 45 
14 Summary of Changes to the Protocol .................................................................................................... 45 
15 References .............................................................................................................................................. 45 
16 Appendix 1: List of Tables, Figures and Listings ..................................................................................... 46 
16.1 Study Population .......................................................................................................................... 46 
16.1.1 Tables .............................................................................................................................. 46 
16.2 Efficacy ......................................................................................................................................... 47 
16.2.1 Tables .............................................................................................................................. 47 
16.2.2 Figures ............................................................................................................................. 50 
16.3 Safety ........................................................................................................................................... 52 
16.3.1 Tables .............................................................................................................................. 52 
16.4 Listings ......................................................................................................................................... 54 
17 Appendix 2: MedDRA Internationally Agreed Order for System Organ Class ........................................ 57 
18 Cytokines and Inflammatory Response Markers ................................................................................... 58 
19 Appendix 3: Safety Laboratory Evaluations ........................................................................................... 60 
 
 
 


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Table of Tables 
Table 1 
List of endpoints associated with each study objective .............................................................. 7 
Table 2 
Conversion to Cigarette-equivalent use for Other Tobacco Products ...................................... 12 
Table 3 
Calculation of Expected Dose .................................................................................................... 13 
Table 4 
Derivation of FiO2 values .......................................................................................................... 14 
Table 5 
Rules for Imputation of Missing S/F Ratios on Individual Study Days 1-14 ............................... 15 
Table 6 
WHO Ordinal Scale for clinical Improvement ............................................................................ 15 
Table 7 
Derivation of WHO OSCI using the Outpatient Daily Covid-19 diary ........................................ 16 
Table 8 
Estimated Size of Confidence Intervals for the Primary Endpoint ............................................ 21 
Table 9 
Intercurrent Event Strategies for the Primary Estimand ........................................................... 33 
Table 10 
Intercurrent Event Strategies for the Change from Baseline in S/F Ratio Secondary Estimands
 ................................................................................................................................................ 35 
Table 11 
Intercurrent Event Strategies for the WHO OSCI Score Secondary Estimands ......................... 37 
Table 12 
Intercurrent Event Strategies for Overall Survival and Intubation and Mechanical Ventilation 
Free Survival Secondary Estimands ........................................................................................ 38 
Table 13 
Intercurrent Event Strategies for Time to Discharge, Time to SpO2 ≥94% on Room Air and 
Time to Recovery Secondary Estimands ................................................................................. 39 
Table 14 
PCI Criteria for Vital Signs .......................................................................................................... 43 
Table 15 
MedDRA Internationally Agreed SOC Order.............................................................................. 57 
Table 16 
Biomarker Parameters and Units .............................................................................................. 58 
Table 17 
Safety Laboratory Parameters and Units .................................................................................. 60 
 
Table of Figures 
Figure 1 
 Study Schema ........................................................................................................................... 10 
 
 
 


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2 
Abbreviations and Definitions 
 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
BMI 
Body mass index 
CI 
Confidence interval 
CRC 
Covid related complications 
CRF 
Case report form 
CRP 
C-reactive protein 
CSR 
Clinical study report 
CTCAE 
Common terminology criteria for adverse events 
dp 
Decimal place 
eCRF 
Electronic case report form 
FiO2 
Fraction of inspired oxygen 
GI 
Gastrointestinal 
iDMC 
Independent data monitoring committee 
ICU 
Intensive care unit 
IMP 
Investigational medical product 
ITT 
Intention to treat 
LDH 
Lactate dehydrogenase 
LS 
Least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model for repeated measures 
MNAR 
Missing not at random 
O2 
Oxygen 
OSCI 
Ordinal scale for clinical improvement 
PCI 
Potentially clinically important 
RTPCR 
Reverse transcription polymerase chain reaction 
SAE 
Serious adverse event 
S/F Ratio 
SpO2/FiO2 ratio 
SOC 
System organ class 
SpO2 
Oxygen saturation by pulse oximetry  
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
 
 








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Figure 1 
 
Study Schema 
 
 
 
5.2 
Randomization and Blinding 
Participants will be randomly allocated, in a 1:1 ratio, to EDP1815 or matched placebo using a pre-
prepared, blocked randomization list.  Randomization numbers will be allocated sequentially. If more than 
one site is used in this study each site will be given complete blocks of randomization numbers.  
 
The study will be fully blinded to the participants, site staff and sponsor.  An independent statistics and 
programming group will be used to prepare all unblinded outputs for the iDMC which will be held in a 
secure area until the study has completed.  
 
The Sponsor must be notified immediately (within 24 hours) if the investigational drug blind is broken. The 
date, time, and reason the blind was broken must be recorded on the appropriate Case Report Form 
(CRF). 
 
5.3 
Derived variables 
5.3.1 
General 
5.3.1.1 
Relative Day and Time 
The relative day of an assessment will be calculated as: 
• 
For measurement performed on or after the date of first dose: 
Date of assessment – date of start of treatment +1  
 
• 
For measurements performed before the date of first dose: 
Date of assessment – date of study treatment 
 


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5.3.1.2 
Baseline 
The last non-missing value collected before first study dose will be taken as the baseline measurement for 
all parameters. If data is collected on Day 1 without an associated time being provided, it will be assumed 
to be pre-dose.  
 
5.3.1.3 
Change and Percentage Change from Baseline 
Change from baseline will be calculated as: 
change from baseline = value at timepoint – baseline value 
Change from baseline will be presented to the same level of precision as the original value in the listings. 
 
Percentage change from baseline will be calculated as: 
 
percentage change from baseline = 100*(change from baseline / baseline value) 
Percentage change from baseline will be presented to 1 decimal place (dp) in the listings. 
 
5.3.2 
Demographic and Background Data 
5.3.2.1 
Age 
Age (years) will not be recalculated using year of birth but will be taken directly from the CRF. 
 
If participants aged >65 years are allowed to be entered into the study, then age (years) will be 
categorized as follows: 
• 
18-65 years 
• 
66-75 years 
• 
>75 years 
 
In addition, for age as a prognostic marker for COVID-19, a further categorization will be performed as 
follows: 
• 
18-59 years 
• 
≥ 60 years 
 
5.3.2.2 
Race and Ethnicity 
Participants who select multiple races on the CRF will be coded as ‘Mixed race’. 
 
Race and ethnicity will also be combined in the ‘Non-white or Hispanic/Latino’ covariate as follows: 
• 
‘Non-Hispanic/Latino white’ – participants who select only race=’White’ and no other race and 
who select ethnicity =’Not Hispanic/Latino’ 
• 
‘Non-white or Hispanic/Latino’ – all other participants 
 
5.3.2.3 
Height, Weight and Body Mass Index 
Height may be recorded in cm or inches. Height in inches will be converted to height in cm as follows: 












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Intubation and mechanical ventilation free survival (IMVFS) is defined as the time in days from 
randomization until the earliest event of death by any cause or requirement for intubation and/or 
mechanical ventilation as indicated by the first occurrence of a WHO OSCI score of 6 or above. 
 
Participants who complete the 42-day study period or prematurely withdraw from the study without 
experiencing the relevant event will be censored on the date of study completion/withdrawal. 
 
Participants who prematurely withdraw from treatment but remain in the study will not be censored and 
will continue to be followed up until the first occurrence of the relevant event, study completion or 
withdrawal from the study. 
 
Time to the relevant event will be calculated as:  
 
Time to event (days) = Date of event/censoring – date of randomization +1 
 
5.3.3.6 
Time to Discharge, Time to SpO2 ≥94% on Room Air and Time to Recovery 
Time to discharge is defined as the time in days from randomization until the date of discharge. 
 
Time to SpO2 ≥94% on room air is defined as the time in days from randomization to the first day at which 
an SpO2 measurement ≥94% on room air is reported after which there were no further requirements for 
oxygen therapy during the study. 
 
Time to recovery is defined as the time in days from the date of symptom onset until the first day on 
which a WHO OSCI score of 0 is reported with no further increase above 0 during the study.  
 
Participants who die during the study before the relevant event occurring will be given a status of ‘death’ 
which will be considered as a competing risk rather than an event or a censored observation in the 
analysis. 
 
Participants who are still alive at the end of the 42-day study period or who withdraw prematurely from 
the study for reasons other than death without experiencing the relevant event will be censored on the 
date of study completion/withdrawal.  
 
As the endpoint of SpO2 ≥94% on room air without further requirement for oxygen therapy cannot be 
measured after discharge (as SpO2 is not measured after discharge), any participants who have not 
achieved this before discharge will be considered as having met the endpoint criterion at the discharge 
date if they are discharged without oxygen for home use and will be censored at the discharge date if they 
are discharged with oxygen for home use. Note that these rules only apply for participants who are 
discharged  before study completion/withdrawal. 
 
Time to discharge and time to SpO2 will be calculated as: 
 
Time to event (days) = Date of event/censoring/death – date of randomization +1 


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Time to recovery will be calculated as: 
 
Time to event (days) = Date of event/censoring/death – date of symptom onset +1 
 
5.3.3.7 
Number of Days Requiring Oxygen Therapy 
For participants who are discharged with ongoing oxygen therapy, any changes to their oxygen therapy 
are to be reported in the participant diary they complete daily.  This data will be transcribed to the oxygen 
therapy page of the main CRF.  
 
Each study day will be flagged as with or without oxygen therapy based on the start and stop dates for 
relevant records in oxygen therapy page.  For example, if a record for oxygen therapy is shown as starting 
on Day 2 and ending on Day 6 then Days 2-6 inclusive will all be flagged as with oxygen therapy. 
 
Number of days with oxygen therapy will be reported for the following intervals: 
• 
Days 1-14 
• 
Days 1-28 
• 
Days 1-42 
 
For each interval, the percentage of days with oxygen therapy will be calculated, using the number of days 
in the interval prior to death or premature withdrawal as the denominator.  
 
For participants who die or withdraw prematurely from the study, a sensitivity variable will be created 
which counts study days after death/early withdrawal as ‘with oxygen therapy’ up to Day 42. 
 
5.3.3.8 
Temperature and Number of Days with Pyrexia ≥ 38°C 
Temperature will be reported daily for participants prior to discharge.  The daily temperature reported on 
the CRF should be the highest recorded in the participant notes for that day. 
 
After discharge, participants are asked to report their temperature daily while they are still experiencing 
symptoms if they have a thermometer at home. If they do not have a thermometer at home, they should 
answer a question on the daily diary to say if they feel like they have a fever. 
 
In the event that a subject reports data in both the patient diary and on the vital signs CRF for a single 
study day, both measurements will be listed but the temperature collected on the CRF vital signs page will 
be used in the tables and figures. 
 
Temperature may be recorded in °C or °F.  Temperature recorded in °F will be converted to temperature 
in °C as follows: 
 
Temperature (°C) = (Temperature (°F) – 32)*(5/9) 
Temperature (°C) will be presented to 1 dp in the listings. 
 


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Each study day will be flagged as with or without pyrexia ≥ 38°C based on the actual data reported. 
 
Number of days with pyrexia ≥ 38°C will be reported for the following intervals: 
• 
Days 1-14 
• 
Days 1-28 
• 
Days 1-42 
 
For each interval, the percentage of days with pyrexia ≥ 38°C reported will be calculated, using the 
number of days with a temperature measurement recorded as the denominator. 
As temperature data is expected to be missing not at random (MNAR), i.e. that the reason for missingness 
may be dependent on the missing value (were it to have been observed), an alternative method for 
counting days with pyrexia will be used for sensitivity analyses as detailed below: 
 
• 
Missing temperature measurements because a participant has died or withdrawn from the study 
o Days after death/withdrawal will be counted as having pyrexia ≥ 38°C 
 
• 
Missing temperature measurements while participant is still in hospital 
o If there exists at least one temperature measurement within 1 day of the missing 
measurement, it will be imputed with the average of the measurements reported within the 
window of +/- 1 day    
o If there is no recorded temperature on the day before or after the missing measurement, 
then carry forward the response from the last day on which temperature was measured. 
 
• 
Missing temperature after participant was discharged 
o If the participant has answered the question ‘Do you feel like you have a fever?’ as ‘Yes’ then 
count the day as with pyrexia ≥ 38°C 
o If the participant has answered the question ‘Do you feel like you have a fever?’ as ‘No’ then 
count the day as without pyrexia ≥ 38°C 
o If the participant had stopped completing the daily diary as they had already reported no 
after 2 consecutive days of no symptoms and a return to their usual activities, then count the 
day as without pyrexia ≥ 38°C 
o Otherwise carry forward the response from the last day on which either temperature was 
measured or the daily diary question about fever was answered 
 
5.3.3.9 
Cytokines 
Any values expressed as <x or >x will be imputed as a value of x for the summary tables and for calculating 
changes from baseline.  The actual value will be displayed in the listings. 
 
5.3.4 
Safety 
5.3.4.1 
Duration of Exposure 
The duration of exposure will be calculated as 


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Duration of exposure (days) = Treatment stop date – treatment start date + 1 
 
5.3.4.2 
Treatment-Emergent Adverse Events 
An adverse event (AE) will be classified as ‘treatment-emergent’ if the onset date/time was on or after the 
start date/time of study treatment. Where dates or times are missing or partially missing, AEs will be 
assumed to be treatment-emergent, unless there is clear evidence (through comparison of partial 
dates/times, see Section 7.3.2) to suggest that the AE started prior to dosing. 
 
AEs will be classified into the following study phases based on the onset date/time of the AE after any 
imputations: 
• 
Pre-Treatment Phase: All AEs with onset date/time prior to the first dose of randomized study 
treatment 
• 
Treatment Phase: All AEs with onset date/time at the time of or after the first dose of randomized 
study treatment (Day 1) up to and including the date of the last dose of treatment received.  
• 
Follow-up Phase: All AEs with onset date after the date of the last dose of treatment received.  
 
For participants who complete 14 days of dosing per protocol the Treatment Phase will be from Day 1 to 
Day 14 and the Follow-up Phase will be from Day 15 to Day 42. In all cases the day will be assumed to start 
at 00:00 hours and end at 23:59 hours. Adverse events occurring in both the Treatment Phase and 
Follow-up Phase are classified as treatment emergent. 
 
The onset phase of all AEs will be included in the relevant data listings. 
 
5.3.4.3 
Hematology Differentials 
The database allows the white blood cell differential results (neutrophils, lymphocytes, monocytes, 
eosinophils and basophils) to be entered on to the CRF as either absolute values or relative values 
(percentage of white blood cells). If both absolute and relative values are provided in the lab report then 
the expectation is that the absolute values will be entered, and the relative values marked as ‘Not done’. 
 
In order to summarize all differential values together, all relative values will be converted to absolute 
values as follows: 
   Absolute value = (Relative value (%) /100) x White Blood Cell Count 
The units for the absolute value will be the same as for the white blood cell count (x10^/uL). 
 
6 
Sample Size  
This is a pilot study designed to give an initial evaluation of the efficacy and safety of EDP1815 in treating 
Covid-19 and in evaluating multiple endpoints for clinical relevance and sensitivity, while informing the 
sample size for future studies. A formal power calculation was not performed, and the number of 
participants was selected based on feasibility. 
 




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Participants will be analyzed according to the study treatment group to which they were randomized. 
 
7.1.3 
Safety Population 
All participants randomly assigned to a study treatment group who take at least one dose of study 
medication will be included in the Safety population. 
 
Participants will be analyzed according to the intervention they received. 
If a participant takes both placebo and EDP1815, due to an error in dosing, they will be assigned to the 
EDP1815 treatment group for all analyses using the Safety population. 
 
7.2 
Covariates and Subgroups 
The following covariates will be considered as possible prognostic factors for inclusion in the analysis 
models described in Section 7.2: 
• 
Age ≥60 years (yes, no) 
• 
Gender (male, female) 
• 
Race (Non-Hispanic/Latino white, non-white or Hispanic/Latino) 
• 
Baseline WHO OSCI score (4, 5) 
• 
Time since onset of symptom at Baseline (days) 
• 
Presence of obesity: BMI ≥30 kg/m2 (yes, no) 
• 
Current type 1 diabetes (yes, no) 
• 
Current type 2 diabetes (yes, no) 
• 
Current hypertension (yes, no) 
• 
Other current chronic cardiovascular disease (yes, no) 
• 
Current chronic respiratory disease (yes, no) 
• 
Active cancer, excluding skin basal cell carcinoma or localized squamous cell carcinoma (yes, 
no) 
• 
Smoking status (current smoker, not current smoker) 
• 
Neutrophils > 8.0 x103/uL 
• 
C-Reactive protein (CRP) > 40 mg/dL 
 
Other covariates may also be considered if emerging research into COVID-19 suggests other possible 
prognostic factors for outcome that can be determined from the data captured on the CRF. 
 
Prior to database lock, the inferential primary analysis model described in Section 9.2.2 will be examined 
on the blinded data in order to determine which baseline factors may have a prognostic effect on the 
efficacy endpoints. Covariates will be selected for inclusion in the model using forward stepwise selection 
procedure with a 5% level of significance applied for both the selection and deselection of variables from 
the model. 
 
Where applicable, the baseline value of the endpoint will be automatically fitted first, regardless of 
significance before additional covariates are considered. A maximum of 3 covariates, in addition to the 


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baseline value where applicable, may be selected for each model in order to avoid over-parameterization 
and a reduction in the efficiency of treatment estimates. 
If, during the study, a new treatment is approved for use in COVID-19 and becomes part of the standard of 
care for hospitalized participants at the study site(s), additional sensitivity analyses will be performed 
using covariates defined by use of this treatment. 
• 
For ANCOVA analyses of trough S/F ratio 
o New SOC covariate: ‘yes’ if taken at any time before Day 14, ‘no’ otherwise  
• 
For ANOVA analyses of S/F ratio at Day X 
o New SOC covariate: ‘yes’ if taken prior to Day X, ‘no’ otherwise 
• 
For time-to-event analyses 
o New SOC covariate will be fitted as a time-dependent covariate with value ‘yes’ at time t if 
taken prior to time t, ‘no’ otherwise. 
 
Note that the purpose of this sensitivity analysis is to account for any biases to the endpoints caused by a 
standard of care treatment that was available to later participants but not to those first entered. Any new 
medication that becomes standard of care and is available for use by all participants before Day 14 will not 
meet the criteria for performing this sensitivity analysis. 
 
Subgroup analyses based on use of any new SOC medication may also be performed, depending on results 
seen from the sensitivity analyses using this covariate.  
 
In addition to the covariates mentioned above, other baseline biomarkers will be examined for a 
prognostic effect on treatment response as part of the exploratory analysis. These will be fitted as 
continuous variables in the model and include the following: 
• 
CRP (mg/dL) 
• 
Neutrophils (103/uL) 
• 
IL-6 (pg/mL) 
• 
Ferritin (ng/mL) 
• 
D-dimer (ng/mL) 
• 
Neutrophil/Lymphocyte ratio (fraction of 1) 
• 
Lactate Dehydrogenase (LDH) (IU/L) 
• 
Troponin I (ng/mL) 
 
7.3 
Missing Data 
7.3.1 
General 
Participants who discontinue treatment before the end of the scheduled 14 days treatment period will 
remain in the study and complete assessments as scheduled unless they die, start an alternate 
experimental treatment, or withdraw consent.  Data collected at scheduled visits following 
discontinuation of study treatment will be included in all analyses. 
 


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Participants who are discharged from hospital before the end of the 42-day study period will be asked to 
complete a participant diary everyday with details of their symptoms, any AEs experienced and any 
changes to their concomitant medications.   
 
Imputation rules for individual variables with missing data have been provided in Section 5.3. 
 
7.3.2 
Partial Dates/Times 
Partial dates and times for AEs, medical conditions and concomitant medications will be imputed for the 
purpose of assigning study phases and calculating duration. Listings will always include the reported 
date/time information rather than any imputations. 
 
Partial AE onset and concomitant medication start dates will be imputed as follows: 
• 
If only the month and year are specified, and the month and year of the start of treatment are not 
the same as the month and year of the start date, then use the 1st of the month. 
• 
If only the month and year are specified, and the month and year of the start of treatment are the 
same as the month and year of the start date, then use the date of start of treatment. If this 
results in a start date after a known or partial end date, then use the 1st of the month. 
• 
If only the year is specified, and the year of the start of treatment is not the same as the year of 
the start date, then use January 1 of the year of the start date. 
• 
If only the year is specified, and the year of the start of treatment is the same as the year of the 
start date, then use the date of the start of treatment. If this results in a start date after a known 
or partial end date, then use January 1 of the year of the start date. 
• 
If the start date is completely unknown, then use the date of the start of treatment. If this results 
in a start date after a known or partial end date, do not impute the start date. 
 
Partial AE onset and concomitant medication start times will be imputed as follows: 
• 
If the actual or imputed start date is the same as the treatment start date, and the start time is 
completely missing, then use the time of start of treatment. 
• 
If the actual or imputed start date is not the same as the treatment start date, and the start time 
is completely missing, then use 00:00 h. 
• 
If the actual or imputed start date is the same as the treatment start date, and the start time is 
partially missing then use the following: 
o If the hour is missing (XX:mm) then use the complete time of the start of treatment (i.e., 
both hours and minutes) 
o If the minutes are missing (hh:XX), use hh:59 h. 
• 
If the actual or imputed start date is not the same as the treatment start date, and the start time 
is partially missing then use the following: 
o If the hour is missing (XX:mm) then use the 00:mm h 
o If the minutes are missing (hh:XX), use hh:00 h 
 
Partial medical conditions start dates will be imputed as follows: 
• 
If only the month and year are specified, then use the 1st day of the month. 


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• 
If only the year is specified, then use January 1st of that year. 
• 
If the start date is completely unknown, do not impute the stop date. 
 
Partial AE resolution, medical condition stop dates and concomitant medication stop dates and date last 
smoked will be imputed as follows: 
• 
If only the month and year are specified, then use the last day of the month. 
• 
If only the year is specified, then use December 31 of that year. 
• 
If the stop date is completely unknown, do not impute the stop date. 
 
Partial AE resolution and concomitant medication stop times will be imputed as follows: 
• 
If the actual or imputed stop date is non-missing, and the stop time is completely missing, then 
use 23:59h on that date. 
• 
If the actual or imputed stop date is non-missing, and the stop time is partially missing, then use 
23:mm h for missing hours and hh:59 h for missing minutes. 
• 
If the actual or imputed stop date is missing, do not impute the stop time. 
 
7.3.3 
Adverse Event Information 
AEs with missing severity will be considered as ‘Severe’ for summary purposes but recorded as missing in 
the listings. 
 
AEs with missing relationship will be considered ‘Related’ for summary purposes but recorded as missing 
in the listings. 
 
7.4 
Interim Analyses and Data Monitoring 
An independent data monitoring committee (DMC), consisting of at least a chairperson, two physicians 
independent of the study team and an unblinded statistician will monitor the safety for the study in an 
ongoing fashion.  DMC support staff for blinded sessions will include the Principal Investigator, the Evelo 
medical monitor, a blinded statistician, the Evelo Chief Medical Officer and an Evelo clinical operations 
representative. 
 
7.4.1 
Purpose of Interim Analyses 
The purpose of the planned interim analyses will be to: 
• 
Allow for the ongoing safety monitoring of the study. 
• 
Provide information for the DMC recommendation on whether recruitment can be open to 
participants aged >65. 
• 
Provide information for the DMC recommendation on whether recruitment should be increased 
to a further 40 participants. 
 


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7.4.2 
Planned Schedule of Interim Analyses 
Interim analyses are planned after 10, 20, 30, 40 and 60 participants have completed 7 days follow-up 
after their last dose (Day 21 for participants who complete dosing as scheduled).  
 
At all interim analyses, the DMC will review safety and study disposition data to assess the safety of the 
interventions and to monitor the overall conduct of the study.  Safety review will focus on the number and 
details of severe and serious adverse events, gastrointestinal (GI) events of any grade and laboratory data 
which meets the criteria for potentially clinically important (PCI). 
 
At the second interim, after 20 participants have completed 7 days of follow-up after their last dose, the 
DMC will also specifically address the question of recruitment can be opened to participants aged >65 
years.  
 
At the final interim, after 60 participants have completed 7 days of follow-up after their last dose, the 
DMC will also review the efficacy data in order to make a recommendation on whether recruitment 
should be extended to a further 40 participants.  
 
7.4.3 
Scope of Adaptations 
At all DMC meetings, the iDMC can recommend one of the following options for the study: 
• 
The study may continue 
• 
The study may continue with modifications (to be provided in the minutes) 
• 
Temporary suspension of the study 
• 
Termination of the study 
 
Their recommendation will be based on a review of relevant unblinded safety data and where appropriate 
unblinded efficacy data for them to review the risk/benefit profile of EDP1815 in comparison with 
placebo. 
 
At the second DMC (20 participants at Day 21) meeting, the DMC members will be asked to make 
additional recommendations, based on safety data, on whether the eligibility criteria should be extended 
to allow adults aged >65 years to enter the study.   
 
At the final DMC (60 participants at Day 21) meeting, the DMC members will be asked to make a 
recommendation as to whether an additional 40 participants should be recruited into the study. There are 
no precise or pre-defined rules for this recommendation and DMC members will be asked to use their 
clinical expertise and experience. The option to extend to 100 participants should be strongly considered 
where there appears to be an emerging clinically meaningful treatment difference, but where the size of 
variation means that no significant conclusions can be drawn on efficacy.  If there is clear efficacy shown, 
no evidence of efficacy shown or a concern regarding safety then no further recruitment should be 
recommended. Guidance on this decision, including some hypothetical scenarios provided for illustrative 
guidance to the DMC are provided in the DMC Charter. 
 


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7.4.4 
Stopping Rules 
The study stopping criteria, in Section 6.6.1 of the protocol, specify that the study should be terminated if 
either of the following conditions are met: 
• 
One (or more) participants on treatment with EDP1815 has symptoms of a clinically significant 
bacteremia and has a positive blood culture for the EDP1815 strain of P. histicola. 
• 
The iDMC believes that EDP1815 is potentially detrimental to participant outcomes. 
 
In addition, the DMC may recommend stopping the study for the following reasons: 
• 
The data show a distinct increased risk of serious adverse effects in the active treatment group. 
• 
It becomes clear that successful completion of the study is not feasible (e.g. there is an excess of 
participant dropout, missing data, lack of recruitment, etc.) 
• 
Other important safety finding(s) as identified by the Sponsor or iDMC. 
• 
The risk/benefit profile for the product is deemed to have changed and is considered 
unacceptable for the study to continue. 
 
7.4.5 
Practical Measures to Minimize Bias 
The unblinded interim summaries and analyses will be performed by an unblinded team led by the 
unblinded statistician who sits on the iDMC as a non-voting member.  The members of the unblinded 
team will not be involved in any aspects of study trial conduct, including the development of the final 
summaries and analyses for the study. 
 
No unblinded data, either as individual participant results or as aggregated summaries will be shared by 
with any study personnel involved in the conduct or final reporting of the study. 
 
Interim results of the analysis, beyond the recommendations to continue, modify, suspend or stop the 
study, will not be shared with the sponsor prior to the end of the study in order to avoid any bias or 
potential alpha-spending issues as per the FDA guidance on Adaptive Designs for Clinical Trials of Drugs 
and Biologics. 
 
The expected summaries and listings which will be provided to the iDMC, both in blinded and unblinded 
form will be a subset of those expected for the final analysis and will be flagged as such in the list of 
tables, figures and listings in Appendix 1: List of Tables, Figures and Listings. 
  
7.4.6 
Documentation of Interim Analyses 
All unblinded data and summaries together with minutes from the closed sessions will be held in a 
restricted file structure by the unblinded statistician until after the study has finished and the data has 
been unblinded after database lock. 
 
A DMC charter is available to provide further details of the required documentation, content and structure 
of the iDMC meetings. 
 


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7.5 
Multiple Testing 
No adjustments for alpha spending will be performed. 
8 
Summary of Study Data 
All continuous variables will be summarized using the following descriptive statistics: n (non-missing 
sample size), mean, SD, median, maximum and minimum. The frequency and percentages (based on the 
non-missing sample size) of observed levels will be reported for all categorical measures. 
 
In general, all data will be listed, sorted by randomized treatment (Placebo, EDP1815) and participant 
number.  If additional sites are added, then data will be sorted by participant number within site. Relevant 
listings will include whether the assessment was performed and the date, study day/visit and time of the 
assessment as applicable. 
 
Unless otherwise specified below, all summary tables will be structured with a column for each treatment 
(placebo, EDP1815) and, for data collected prior to dosing, will include an overall total column where 
appropriate. 
 
Columns will be ordered and labelled as follows: 
• 
Placebo 
• 
EDP1815 
• 
Total 
 
Except for disposition tables in which it is appropriate to include screened subjects, the enrolled 
population will be used, otherwise the ITT population will be used for all summaries of disposition, 
demographic and baseline data and efficacy. 
 
The safety population will be used for all summaries of safety. 
 
Unless otherwise specified, all listings will be produced using the ITT population. 
 
8.1 
Subject Disposition 
All subject disposition summaries will be presented by treatment group and overall.  The ITT population 
will be used unless otherwise specified. 
 
Completion/withdrawal from the study and completion/discontinuation from treatment, together with 
reasons for withdrawal from the study or discontinuation from treatment will be listed and the following 
will also be tabulated 
• 
Number and percentage of participants who completed the study 
• 
Number and percentage of participants withdrawn from the study and the reported reason for 
withdrawal 


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• 
For the interim analyses, the number and percentage of participants still ongoing in the study will 
also be presented 
• 
Number and percentage of participants who completed the 14-day treatment period 
• 
Number and percentage of participants who discontinued treatment early and reason for 
discontinuation 
• 
For the interim analyses, the number and percentage of participants who have treatment ongoing 
will also be presented 
 
For subjects who fail screening, the reasons for screen failure including details on which inclusion/ 
exclusion criteria were not met will be summarized and listed. 
 
For the enrolled population, the number and percentage of participants in each analysis population will be 
presented.  Inclusion/exclusion in each study population will also be listed, together with reasons for 
exclusion. 
 
The number and percentage of participants with data available for each study day, broken down by 
inpatient or outpatient status will be summarized. 
 
8.2 
Protocol Deviations 
The number and percentage of participants in the ITT population with at least one major protocol 
deviation will be summarized by treatment group and overall, together with the number and percentage 
of participants reporting at least one major protocol deviation within each category. 
All protocol deviations will also be listed. 
 
8.3 
Demographic and Baseline Variables 
All summaries of demographic and baseline variables will be presented by treatment group and overall 
using the ITT population. 
 
The following summaries will be produced, using appropriate summary statistics as specified in Section 8: 
• 
Demographic variables: age, sex, race, ethnicity, height weight and BMI 
• 
Smoking status (never, former, current), type of smoking product used, years since last smoked 
and pack-years. 
• 
Baseline disease characteristics: time since start of symptoms, time since first positive RTPCR test, 
SpO2, S/F ratio, WHO OSCI score and temperature 
 
8.4 
Concurrent Illnesses and Medical Conditions 
All summaries of concurrent illnesses and medical conditions will be presented by treatment group and 
overall using the ITT population. 
 


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Concurrent illnesses and medical conditions will be classified as ‘current’ if the end date is on or after the 
date of first dose of study drug, or the condition has been marked as ongoing.  Otherwise they will be 
classified as ‘past’. 
 
Targeted questions will be used to report the following known comorbidities for COVID-19 as part of the 
medical history CRF page: 
• 
Type 1 diabetes  
• 
Type 2 diabetes 
• 
Hypertension 
• 
Other chronic cardiovascular disease  
• 
Chronic respiratory disease  
• 
Ongoing diagnosis of cancer 
 
In addition, other medical history and concurrent illnesses will be captured and coded using the v23.0 of 
the Medical Dictionary for Regulatory Activities (MedDRA®). 
 
The number and percentage of participants reporting each relevant medical condition will be summarized 
together with the following potential risk factors for severe illness with COVID-19 which will be assessed 
from the demographic and baseline data: 
• 
Age ≥60 years 
• 
Male 
• 
Non-white or Hispanic/Latino  
• 
Obesity (BMI ≥30 kg/m2) 
• 
Current smoker 
• 
Baseline WHO OSCI score of 5 
• 
Baseline neutrophils > 8.0 x103/uL 
• 
Baseline CRP >40 mg/dL 
 
In addition, the number and percentage of participants reporting 0, 1, 2, 3, 4, ≥5 potential risk factors will 
be summarized. 
 
All medical history will be summarized, individually for past and current conditions. All medical history will 
be listed. 
 
8.5 
Prior and Concomitant Therapy 
Medications will be coded according to the World Health Organization Drug Dictionary (WHODD) Version 
dated 01Mar2020. Medical procedures will not be coded.  
 
Oxygen therapy will be collected on a separate CRF page and will be considered part of the efficacy data 
with the reporting described in Section 9.3.6. 
 


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Concomitant medications are defined as any medications taken during the treatment period or follow-up 
period after treatment.  This includes any medications started before the first dose and ongoing after the 
first dose. Prior medications are defined as any medication taken before or during the screening period 
which were stopped before the first dose of study medication. 
 
Missing and partial start and stop dates will be imputed using the rules specified in Section 7.3.2 before 
classifying therapies as prior or concomitant. If the classification is still ambiguous after missing and partial 
dates have been imputed, then the medication will be considered concomitant. 
 
Medications will be summarized using the ITT population, by treatment group and overall and the 
WHODD Anatomical Main Group (Level 1), Therapeutic Subgroup (Level 2) and preferred term.  The 
summaries will report incidence within each relevant level so that a participant taking multiple 
medications coded to the same relevant Level 1, Level 2 or preferred term would only be counted once 
within the incidence count for that level or term. 
 
Concomitant medications taken for COVID-19 will be defined using the indication field on the CRF. 
 
Separate summaries will be produced for each of the following: 
• 
Prior medications 
• 
Concomitant medications taken for COVID-19 
• 
Concomitant medications taken for COVID-19 started pre-treatment  
• 
Concomitant medications taken for COVID-19 during the treatment period (including any which 
started pre-treatment) 
• 
Concomitant medications taken for COVID-19 started during the follow-up period 
• 
Concomitant medications not taken for COVID-19 
• 
Concomitant medications not taken for COVID-19 started pre-treatment 
• 
Concomitant medications not taken for COVID-19 during the treatment period (including any 
which started pre-treatment) 
• 
Concomitant medications not taken for COVID-19 started during the follow-up period 
 
All prior and concomitant medications will be listed. Concomitant medical procedures carried out during 
the study will be listed separately. 
 
8.6 
Compliance 
Treatment compliance will be summarized for the safety population and daily diary compliance will be 
summarized for the ITT population, by treatment group and overall. 
 
Treatment and daily diary compliance data will also be listed. 
 


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9 
Efficacy Analyses 
Unless otherwise specified, all efficacy summaries and analyses will be presented by treatment group and 
overall.  The ITT population will be used for all summaries and analyses of efficacy. 
 
In addition to the inferential analyses described below, descriptive statistics will be provided to summarize 
all efficacy endpoints by treatment group.  
 
For categorical variables, summary tabulations of frequency and percentage of participants within each 
category will be presented.  
 
For continuous variables, the number of participants, mean, median, standard deviation (SD), minimum, 
and maximum values will be presented. 
 
For time to event endpoints, the number of participants with the event, the number of participants 
censored will be presented together with Kaplan-Meier estimates of median time to event and the 
predicted proportion of subjects with the event at Days 4, 7, 14, 21 and 42 as appropriate to the endpoint. 
Kaplan-Meier curves of time to event will also be presented. 
 
All analyses will be considered as descriptive only and no adjustment for multiple testing will be performed. 
 
9.1.1.1 
Early Stopping 
In the case of stopping the study early due to low recruitment, no inferential efficacy analysis will be 
carried out. Figures will not be presented. Only summaries and listings of the study population, primary 
and secondary efficacy endpoints, and safety data will be produced.  
 
The list of outputs produced in case of early stopping of the study is provided in Appendix 1: List of Tables, 
Figures and Listings. 
 
9.1.1.2 
Blinded Model Fitting 
Prior to database lock the models to be used in the primary analysis will be examined on the blinded data 
in order to determine which baseline factors may have a prognostic effect and should be included in the 
models. The covariates defined in Section 7.2 will be examined in a model of trough S/F ratio and selected 
as covariates for the relevant model at a 5% level of significance using forward stepwise selection. 
 
Baseline S/F ratio will be the first fitted term in the model regardless of significance. A maximum of 3 
further covariates may be included in the model in order to avoid over-parameterization and a reduction 
in the efficiency of the treatment estimates. 
 
Distributional assumptions underlying the models used for analysis will be also be examined during the 
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Change from baseline in trough S/F ratio will be analyzed with an analysis of covariance (ANCOVA) model.  
The model will include fixed effect parameters for treatment and baseline S/F ratio together with the 
additional baseline covariates which were identified during the blinded review.  
 
Least square (LS) estimates of the mean change from baseline trough S/F ratio together with the standard 
error and 95% confidence interval will be reported. The LS mean treatment difference and 95% confidence 
interval will also be presented. 
 
The distributional assumptions for the final unblinded model will be checked in the same manner as 
described above in Section 9.1.1.2.  If the inclusion of treatment effect causes the models to no longer be 
valid compared to the blinded data models, a Wilcoxon test will be used to compare the treatments 
instead and only a p-value will be produced for the comparison. 
 
9.2.3 
Sensitivity Analyses 
A sensitivity analysis will be performed where no imputation of trough S/F ratio will be made for 
participants who die. Instead the lowest reading recorded prior to death will be used. 
 
If a newly approved medication for COVID-19 becomes part of the standard of care treatment at the 
investigational site during the study an additional sensitivity analysis will be performed. A new medication 
covariate (yes, no for use before Day 14) will be fitted into the ANOCOVA model used for the main 
analytical approach together with its interaction with the EDP1815 treatment term. 
 
In addition to the estimates of LS means for effect of each treatment group and their difference, the p-
values for the significance of the new medication*treatment interaction will be provided.   
 
9.2.4 
Subgroup Analyses 
If the sensitivity analysis for a newly approved COVID-19 medication described in Section 9.2.3 is 
performed and the p-value for the new medication*treatment interaction is found to be significant at the 
5% level, the analysis described for the main analytical approach will be performed by use of the new 
medication prior to Day 14. 
  
9.3 
Secondary Efficacy Analyses 
9.3.1 
Change from Baseline in S/F Ratio  
9.3.1.1 
Estimands 
The endpoints will be the change from baseline in S/F ratio as measured on Days 4, 7, 10 and 14.  The 
population summary measure of interest will be the difference in mean change from baseline in  
S/F ratio between EDP1815 and placebo at the relevant study day. 
 
The intercurrent event strategy for these estimands is described in Table 10. 




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LS mean (95% CI) change from baseline in S/F ratio will be plotted against time for Days 4, 7, 10 and 14. 
 
The distributional assumptions for the final unblinded model will be checked in the same manner as 
described above in Section 9.1.1.2.   
 
A sensitivity analysis will be performed where no imputation will be used for participants who die.  These 
participants will be excluded from the analysis at any timepoints after death has occurred. 
If at least 10% of participants have withdrawn from the study before Day 14, a sensitivity analysis will be 
performed.  Data for participants who have either been discharged or died will be imputed as per the 
rules in Table 5, but no other imputation will be performed. The change from baseline in S/F ratio will be 
analyzed in a mixed model for repeated measurements including treatment, baseline S/F ratio, study day, 
study day*treatment and study day*baseline S/F ratio and any additional covariates identified during the 
blinded modelling phase.  Data from all study days between Day 1 and Day 14 would be included. 
LS mean change from baseline in S/F ratio will be reported with their corresponding standard error and 
95% confidence interval at Days 4, 7, 10 and 14. Estimated treatment difference for the mean change 
from baseline and corresponding 95% confidence interval will also be reported at these study days. 
 
If a newly approved medication for COVID-19 becomes part of the standard of care treatment at the 
investigational site during the course of the study an additional sensitivity analysis will be performed at 
each visit in the same manner as described in Section 9.2.3. A new medication covariate (yes, no for use 
before the relevant study day) will be fitted into the ANOCOVA models at each visit together with its 
interaction with the EDP1815 treatment term. 
 
In addition to the estimates of LS means for effect of each treatment group and their difference, the p-
values for the significance of the new medication*treatment interaction will be provided at each visit. 
Mean (+/- standard deviation) S/F ratio at each study day will also be plotted once using only available 
data and once after the rules specified in Table 5 have been applied. 
 
9.3.2 
Percentage Change from Baseline in S/F Ratio 
Percentage change from baseline in S/F ratio at Days 4, 7, 10 and 14 will be summarized and analyzed in 
the same manner as described for mean change from baseline in S/F ratio in Section 9.3.1. 
 
9.3.3 
WHO OSCI Score 
9.3.3.1 
Estimands 
The endpoints will be recorded (inpatients) or derived (outpatients) WHO OSCI score at Days 4, 7, 14, 21 
and 42.  Population summary methods will be: 
• 
Percentage of participants at each level of the WHO OSI score   
• 
Percentage of participants with each possible shift from Baseline in WHO OSCI score 
• 
Percentage of participants remaining at their baseline WHO OSCI score (or lower) 








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9.3.5.2 
Analytical Approach 
Time to discharge will be analyzed using a Fine and Gray subdistributional hazards model to allow for the 
competing risk of death (Fine, 1999). The model will include a parameter for treatment together with any 
additional baseline covariates identified during the blinded review of the time to discharge model. 
 
The number and percentage of participants who are discharged, who die and who are censored will be 
reported together the estimate of median time to the event, and the predicted proportion of participants 
who were discharged at Days 4, 7, 14, 21 and 42. The estimated subdistributional hazard ratio (with 95% 
confidence interval) for treatment difference in risk of recovery and its p-value from the model will also be 
presented. Cumulative incidence functions for time to full recovery will also be plotted by treatment group. 
 
Time to discharge information will be listed including event status and time to event/censoring or death. 
 
Time to SpO2 ≥94% on room and time to recovery will be analyzed in the same manner as described 
above for time to discharge. 
 
9.3.6 
Other Secondary Endpoints 
Number and percentage of days requiring oxygen therapy and the sensitivity variable described in Section 
0 will be summarized for days 1-14, 1-28 and 1-42 and listed. Details of all oxygen therapy used will also 
be listed. 
 
Number and percentage of days with pyrexia ≥ 38°C and the sensitivity variable described in Section 
5.3.3.8 will be summarized for days 1-14, 1-28 and 1-42 and listed. Maximum temperature for each 
participant will also be summarized. Daily temperature data will also be listed. 
 
Minimum and maximum SpO2 for each participant will be summarized and listed. Daily SpO2 values will 
be included in the listing of daily S/F ratio data. 
 
9.4 
Exploratory Efficacy Analyses 
9.4.1 
Biomarkers 
Table 16 shows the parameters which will be collected and the units in which they will be supplied. 
 
Actual values and change from baseline in cytokine levels will be summarized at Days 4 and 7. All cytokine 
level data will also be listed. 
 
Actual values and change from baseline in inflammatory response markers will be summarized at Days 4 
and 7.  All inflammatory response marker data will also be listed. 
 
9.4.2 
Potential Predictors of Response to EDP1815 


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To identify clinical and biochemical predictors of response to EDP1815 exploratory modelling will be 
performed to identify potential interactions between treatment and each covariate defined in Section 7.2.  
The model fitted for the primary analysis of change from baseline in trough S/F ratio will be considered as 
the base model for this.  For each potential predictor, the covariate (if not already fitted) and the 
treatment-covariate interaction will be added to the base model and the p-value for the treatment-
covariate interaction will be reported.  Each potential predictor will be considered in a separate model 
independently of other potential predictors. 
 
In the event that a predictor is found to have a significant treatment interaction with EDP1815 on the 
primary endpoint, further exploratory analyses will be performed to find the extent and direction of the 
interaction as well as looking at the effect on other secondary endpoints. Any such analyses will be 
considered as adhoc and will not be further described here. 
 
10 Safety Analyses 
10.1 Extent of Exposure 
The duration of exposure (days) and number of doses taken will be summarized by treatment for the 
Safety population using summary statistics for continuous data as well as the number and percentage of 
participants with: 
• 
≥ 7 days exposure 
• 
14 days exposure (completed treatment) 
 
Treatment start and stop dates, exposure duration (days) and number of doses administered will be listed 
by participant. 
 
10.2 Adverse Events 
Due to the nature of the participant participation and disease, only serious AEs (SAEs), AEs of severe 
(Common Terminology Criteria for Adverse Events (CTCAE) Grade 3) and potentially life-threatening 
(CTCAE Grade 4) intensity, and AEs relating to nausea, vomiting, diarrhea, bloating and abdominal pain of 
any grade will be documented in the CRF. Other AEs of mild (CTCAE Grade 1) or moderate (CTCAE Grade 
2) intensity are to be documented in the medical notes.  
 
Only treatment emergent AEs and SAEs reported in the CRF will be included in the summaries, pre-
treatment AEs and SAEs reported in the CRF will be included in the listings of all AEs.   
 
All AEs will be coded using version 23.0 of MedDRA. 
 
Treatment-emergent AEs will be summarized by treatment, system organ class (SOC) and preferred term. 
Summary tables will contain the number and percentage of participants and the number of events. A 
participant who has multiple events in the same SOC or the same preferred term will be counted only 
once in the participant counts but all events will be counted in the event counts. Adverse event 


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summaries will be sorted by the internationally agreed SOC order (Table 15) and decreasing incidence of 
preferred term within SOC in the EDP1815 column. 
 
The above summary will be repeated for Treatment Phase AEs and for Follow-up Phase AEs. 
 
AEs considered related to study treatment will also be summarized by treatment, SOC and preferred term 
in the same manner as described above. 
 
All AEs, SAEs, fatal AEs, AEs leading to discontinuation of study treatment or withdrawal from the study 
will be listed separately by participant. Adverse events of special interest will be flagged in the listings. 
 
10.3 Deaths, Serious Adverse Events and other Significant Adverse Events 
Treatment emergent SAEs, TEAEs leading to discontinuation of study treatment or withdrawal from the 
study will be summarized separately by treatment, SOC and preferred term. 
 
10.3.1 Adverse Events of Special Interest 
TEAEs of nausea, vomiting, diarrhea, bloating and abdominal pain will be considered as adverse events of 
special interest (AESI). 
 
AESI will be summarized by treatment, preferred term, and CTCAE grade.  The summary will contain the 
number and percentage of participants and the number of events.   
 
AESI will also be summarized by treatment, preferred term and relationship to study drug in the same 
manner. 
 
10.4 Clinical Laboratory Evaluations 
Local laboratory data will be used for all safety laboratory evaluations.  Blood samples for safety 
laboratory evaluations will be collected at Baseline, Day 4 and Day 7. Table 17 shows the parameters 
which will be collected and the units in which they will be supplied. 
Laboratory data (hematology and chemistry parameters) will be summarized by treatment and visit.  
Changes from baseline at Day 4 and Day 7 will also be summarized. 
 
Relative differentials (neutrophils, lymphocytes, monocytes, eosinophils and basophils) will be converted 
to absolute values as described in Section 5.3.4.3.   
 
The number and percentage of participants showing shifts from baseline to worst-case post-baseline with 
respect to the normal ranges will also be summarized for each parameter. Categories will be: 
• 
Low 
• 
Normal 
• 
High 
 




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The number and percentage of participants showing shifts from baseline to worst-case post-baseline with 
respect to the PCI criteria will also be summarized for each parameter. Categories will be: 
• 
Within range 
• 
High 
 
The determination of worst-case post-baseline will consider both scheduled (Day 4 and Day 7) and any 
unscheduled assessments which occur after the first dose of study treatment.  Percentages will use the 
number of participants with at least one post-baseline assessment available. If the baseline value is 
missing it will be assumed to be within range for this summary.   
 
All vital signs data will be listed, including flags for values which meet the PCI criteria. In addition, a 
separate listing of all vital signs assessments for any participant who meet has at least one value meeting 
the PCI criteria will be produced. 
 
10.5.2 Physical Examination 
All data collected at the physical examination performed at the Screening visit will be listed. 
 
10.5.3 Pregnancy Tests 
Pregnancy test results will be listed together with female fertility status. 
 
11 Pharmacokinetics 
Analyses of the pharmacokinetics exploratory endpoints including the presence of EDP1815 in stool 
and/or blood using PCR primers will be addressed in a separate analysis plan and will not be further 
discussed in this document. 
12 Reporting Conventions 
When reporting relative frequencies or other percentage values, the following rules apply: 
• 
For values where all subjects fulfil certain criteria, the percentage value will be displayed as 100 
• 
For values where the absolute frequency is 0, there will be no percentage presented at all 
• 
All other percentage displays will use 1 decimal place 
 
When reporting descriptive statistics, the following rules will apply in general: 
• 
n will be an integer 
• 
Mean and median will use 1 decimal place more than the original data 
• 
Standard deviation will use 2 decimal places more than then original data 
• 
Minimum and maximum will be reported using the same number of decimal places as the original 
value 


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• 
If no subjects have data at a given timepoint, for example, then only n=0 will be presented. 
However, if n<3, present the n, min and maximum only. If n=3, n, mean, median, minimum and 
maximum will be presented only. The other descriptive statistics will be left blank 
 
Where reporting estimated statistics from inferential tests and models, the following rules will apply in 
general: 
• 
P-values ≥0.001 will be reported to 3 decimal places; p-values less than 0.001 will be reported as 
“<0.001”. 
• 
Estimated parameters and 95% confidence intervals on the same scale as raw observations will be 
reported to 1 decimal place more than the original data, standard errors will be reported to  
decimal places more 
• 
Estimated parameters and 95% confidence intervals of percentage change variables will be 
reported to 2 decimal places, standard errors will be reported to 3 decimal places 
• 
Estimated parameters and 95% confidence intervals, not on the same scale as raw observations or 
for percentage change statistics (e.g. regression coefficients) will be reported to 3 significant 
figures, standard errors will be reported to one further decimal place. 
 
13 Technical Details 
Statistical evaluation will be performed by 
. 
 
CDISC standards will not be used for this study.  The analysis datasets will be produced using a similar 
structure to those described for the analysis dataset model (ADaM) but will be not be fully validated and 
will be programmed directly from the source CRF and external data rather than from SDTM datasets. 
 
All analyses will be performed using SAS version 9.2 or higher (SAS Institute, Cary, NC, USA). 
 
14 Summary of Changes to the Protocol 
Not applicable. 
 
15 References 
Fine, J. a. (1999). A Proportional Hazards Model for the Subdistribution of a Competing Risk. Journal of 
American Statistics Association, 94(446), 496-509. 
 
 
































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Note: If local lab provides both absolute and relative differentials, only absolute differentials should be 
completed on the CRF and relative differentials should be marked as not done.  If relative differentials 
only are provided these will be converted to absolute values in the analysis data sets as described in 
Section 5.3.4.3.