Clinical trial NCT04603027
Conditions: Psoriasis Plaque Psoriasis
Keywords: PSO mild psoriasis moderate psoriasis plaque psoriasis psoriasis EDP1815
Sponsor: Evelo Biosciences, Inc.
Start date: 2020-09-21; Completion date: 2021-12-06
Enrollment: 249 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase 2 study has been designed to investigate the clinical safety and efficacy of EDP1815 and to identify an optimal dose in subjects with mild to moderate psoriasis.

Detailed description:
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-cohort, dose-ranging study of participants with mild to moderate plaque psoriasis. This Phase 2 study has been designed to investigate the clinical safety and efficacy of EDP1815 and to identify an optimal dose in subjects with mild to moderate psoriasis.

Arms: arm 1: 75 subjects with mild to moderate psoriasis; 50 on EDP1815, 25 on placebo. Dose = 0.8 x 10\^11 cells, capsule, once daily, 16 weeks arm 2: 75 subjects with mild to moderate psoriasis; 50 on EDP1815, 25 on placebo. Dose = 3.2 x 10\^11 cells, capsule, once daily, 16 weeks arm 3: 75 subjects with mild to moderate psoriasis; 50 on EDP1815, 25 on placebo. Dose = 8.0 x 10\^11 cells, capsule, once daily, 16 weeks
Interventions: intervention 1: EDP1815 intervention 2: Placebo
Intervention descriptions: intervention 1: EDP1815 is an orally administered, pharmaceutical preparation of a single strain of bacteria intervention 2: Placebo oral capsule

Protocol documents:
Prot_000.pdf: 
Cover Page 
 
CLINICAL STUDY PROTOCOL 
 
NCT04603027  
 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Cohort, Dose-Ranging Study Investigating the Effect of EDP1815 
in the Treatment of Mild to Moderate Plaque Psoriasis 
 
PROTOCOL EDP1815-201  
Version 5.0 (Amendment 4), 17 November 2020 
 
 
 
 






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Protocol Amendment 1 – Summary of Major Changes 
The study has been amended to enhance the safety of all participants and the safety of 
potential offspring of male participants.  
The major change enhancing the safety of all participants has been made with the addition of 
a new section. It reads, in its entirety: 
11.3.1    Study Halting Criteria 
The study will be terminated if any of the following occur: 
• One death considered definitely, probably, or possibly related to the study drug 
• Two or more subjects with an SAE considered definitely, probably, or possibly 
related to the study drug 
• Three or more subjects with grade 3 AEs of the same type considered definitely, 
probably, or possibly related to the study drug 
The major change affecting the safety of potential offspring of male participants has been 
made with the addition of a new bullet point to the contraception guidance for male 
participants in Section 13.1:  
• Have had a vasectomy, and the absence of sperm has been confirmed in the 
ejaculate. 
Administrative and minor grammatical, editorial, and formatting changes were made for 
clarification purposes only.  
 
 


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Protocol Amendment 2 – Summary of Major Changes 
Please note that Protocol Amendment 2 was not submitted to regulatory authorities or 
investigative sites. 
The study has been amended to reduce the number of cohorts in the study from 3 to 2, to 
amend the ratio of patients receiving EDP1815 or matching placebo from 3:1 to 2:1, to 
remove the secondary objectives to evaluate efficacy dose response and optimal dose of 
EDP1815, to include the option for study visits to be conducted remotely in exceptional 
circumstances (and where operationally possible), to clarify the addition of BMI calculation, 
to add IND number and change the study title. Sections 7.9 through 7.10.3.4 were deleted as 
information was already present in Sections 6.3 through 6.4.3.4.  
Administrative and minor grammatical, editorial, and formatting changes were made for 
clarification purposes only. 
The major changes listed above have been made in addition to the edits in the following 
sections (and the corresponding text in the Protocol Synopsis).  
Changes have been marked as follows: new text as bold and deleted text as strikethrough. 
Title Page (and globally, where applicable): 
IND number 19576 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort, 
Dose Ranging Study Investigating the Effect of EDP1815 in the Treatment of Mild to 
Moderate Plaque Psoriasis. 
Section 1: 
This Phase 2 study has been designed to investigate the clinical response to treatment with 
EDP1815 and to identify an optimal dose. 
Section 2.2: 
The secondary objectives of this study are the following: 
• To evaluate the efficacy dose response of EDP1815 at Week 16 


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• To evaluate the maximal clinical benefit of EDP1815 at Week 16 
• To evaluate the optimal dose of EDP1815 based on efficacy and safety up to Week 16 
• To evaluate the safety and tolerability of EDP1815 (all dose levels) throughout the 
study 
Section 3.1: 
After eligibility is confirmed during the screening period (Section 4.1), participants will be 
randomly assigned in a 1:1:1 ratio to one1 of the following 3 2 parallel cohorts: 
• Cohort 1: 1.6 × 1011 cells of EDP1815 or matching placebo administered as 
2 mini tablets in capsules (MICs), once daily (Section 5.2).  
• Cohort 2: 4.8 × 1011 cells of EDP1815 or matching placebo administered as 6 MICs, 
once daily (Section 5.2).  
• Cohort 3: 8.0 × 1011 cells of EDP1815 or matching placebo administered as 10 MICs, 
once daily (Section 5.2). 
In each cohort, approximately 60 69 participants will be randomly assigned in a 32:1 ratio to 
receive either EDP1815 or matching placebo once daily for 16 weeks. 
The study design figure (Figure 3.1) was updated accordingly to remove Cohort 3. 
Section 3.1.1: 
The doses tested in the program are based on predictions from the preclinical data and the 
clinical and biomarker data obtained in EDP1815-101, the Phase 1 study. All doses tested up 
to 8.0 × 1011 cells have been equally well tolerated. No clear difference in efficacy was 
observed between the 1.6 × 1011 cells and the 8.0 × 1011 cells in EDP1815-101 over the 
28-day dosing period, but at the 14-day follow up (Day 42) the participants receiving the 
higher dose had a continued improvement in their psoriasis compared to participants who had 
received the lower dose. This suggests a more sustained and potentially deeper response in 
the high dose group. Evelo is therefore proposing to include the highest feasible dose (based 
on capsule load) in this study to establish the maximum clinical benefit and to assess 


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participant acceptability of the doses tested. The dose response relationships found in this 
study are expected to enable the selection of appropriate dosing for future studies. This 
suggests additional efficacy could be obtained at doses above the dose of 1.6 × 1011 cells. 
Therefore, 4.8 × 1011 cells will be tested as well as 1.6 × 1011 cells in this study. 
Section 4.1: 
Approximately 180 138 participants will be enrolled (randomly assigned to treatment) in 
multiple countries, including (but not limited to) sites in the United States, the United 
Kingdom, and Poland. 
Section 4.2.4: 
Participants who withdraw or are withdrawn from the study within 4 weeks of randomization 
may be replaced in order to have approximately 180 138 participants provide at least 4 weeks 
of postbaseline data.  
Section 5.1: 
Participants will be randomly assigned at the baseline visit (Visit 2) to 1 of 3 2 cohorts (in a 
1:1:1 allocation ratio) that are distinguishable to participants and study staff by the number of 
capsules administered per once-daily dose. Within each the cohort, participants will be 
randomly assigned in a 3 2:1 allocation ratio to receive either EDP1815 or matching placebo 
treatment (Section 3.1). Interactive response technology (IRT) will be used to administer the 
randomization schedule. 
Section 6: 
The SoA is presented in Table 6 1. Detailed instructions for study site activities will be 
provided in the study manual. High level descriptions of the study assessments are presented 
in the subsections of Section 6. In exceptional circumstances, study assessments may be 
conducted remotely (ie, at a participant’s home), except for baseline, Visit 9, and 
Visit 10. Remote visits can only occur if operationally possible. 


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Section 6.2.3: 
A complete physical examination will be conducted, including assessments of the skin and 
cardiovascular, respiratory, GI, and neurological systems. Height (at screening only) and 
weight will also be measured and recorded (without shoes, street clothing). Body mass index 
will be calculated from the height and weight. Investigators should pay special attention to 
clinical signs related to previous serious illnesses. 
The SoA (Table 6-1) was also updated to include a footnote clarifying the BMI calculation. 
Section 6.4.2: 
Systemic exposure following oral EDP1815 dosing is estimated to be very low based on lack 
of detection in blood (<0.01% of administered dose). However, plasma samples will be taken 
from all participants for the estimate of systemic EDP1815 levels by PCR with strain-specific 
primers that can detect EDP1815 specifically, even when other strains of Prevotella histicola 
are present. Any effects of EDP1815 on the gut microbiome will be investigated using 16S 
ribosomal RNA sequencing, which measures both the presence and quantity of microbes at 
the genus level. Sampling will be performed as specified in the SoA (Table 6-1, blood 
sample for systemic levels of microbes).  
Section 7.2: 
As a further supplementary analysis, a dose response model will be fitted using Bayesian 
techniques as fully described in Section 7.8.1. This model will be fitted for the primary 
endpoint of percentage change from baseline at Week 16. Data collected after discontinuation 
of treatment will be considered missing and imputed using an LOCF approach in order to 
include all participants who had at least one evaluable on treatment percentage change from 
baseline in PASI score available. A sensitivity analysis, including only participants who have 
evaluable percentage change from baseline in PASI score at Week 16 will also be performed. 
If the results of the supportive MMRM analyses show substantial differences to the primary 
MMRM analysis, further sensitivity analyses may also be performed excluding data 
following protocol deviations which may affect efficacy or including all data collected during 
the study regardless of treatment discontinuation.  


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Section 7.5: 
The sample size of 180 138 participants in total, has been chosen to explore the tolerability 
and safety of EDP1815. “…” 
Participants in the placebo arm of each cohort will be pooled for the statistical analysis in 
order to compare active and control arms resulting in 45 46 participants will be randomized 
to each treatment group (pooled placebo, EDP1815 1.6 × 1011 cells, and EDP1815 4.8 × 1011 
cells, and EDP1815 8.0 × 1011 cells). Assuming that no more than 15% of participants will 
discontinue treatment before the Week 16 visit, at least 38 39 participants in each treatment 
group are expected to provide data through the Week 16 visit. 
Each pairwise comparison between placebo and active dose would be expected to have more 
than 90% power to detect a difference between the treatment groups at the 5% significance 
level under the assumption that pooling the placebo groups is a valid strategy. If the 
3 2 placebo cohorts are considered to be too heterogeneous for pooling into a single reference 
group, the power to detect a difference in each pairwise comparison between active and 
placebo doses within a cohort falls to approximately 70 80%. 
Section 7.7: 
If the placebo groups from the 3 2 cohorts are found to be too heterogeneous to be pooled 
(Section 7.8.1), the primary and secondary analyses will be performed using within-cohort 
comparisons of active and placebo treatments, and summary tables may also be produced by 
cohort. 
Section 7.8.1: 
The assumption that the 3 2 cohorts of placebo participants can be pooled into a single 
placebo group to be used as a control for all active doses will be examined using mean (±SD) 
plots of percent change in PASI score against time. A decision will be made by the Evelo 
study team on whether the pooling strategy is appropriate. 
The primary analysis will be performed using an MMRM. The model will include parameters 
for treatment*visit and baseline PASI score*visit interactions. Body mass index, gender, and 
other baseline covariates will also be considered and included as parameters if found to be 
significant (p<0.05). The model will not include an intercept. Visit will consist of 6 levels 


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(Weeks 1, 2, 4, 8, 12 and 16) and treatment will consist of 4 3 levels (pooled placebo, 
EDP1815 1.6 x 1011 cells, and EDP1815 4.8 x 1011 cells and EDP1815 8.0 x) if the placebo 
pooling strategy is considered appropriate or 6 4 levels (Placebo matching 1.6 x 1011 cells, 
Placebo matching 4.8 x 1011 cells, EDP1815 1.6 x 1011 cells, and EDP1815 4.8 x 1011 cells 
and EDP1815 8.0x) if the placebo pooling strategy is not considered appropriate. “…” 
If the assumption of similarity between the 3 2 placebo cohorts is considered appropriate, the 
placebo cohorts will be pooled, and a single placebo control group will be used for the 
pairwise differences for each active dose to placebo. “…” 
If the assumption of similarity between the placebo cohorts is supported, a supplementary 
analysis will be performed on the percent change from baseline to Week 16 in PASI score 
using a dose response model on the pooled cohorts. The log linear, 3 parameter and 
4 parameter Emax models will be fitted and compared, with the best fitting model (lowest 
DIC) selected for use in the outputs.  
The dose response model will be fitted to the data using Bayesian techniques with 
non informative priors for E0 and Emax and an FUP for ED50 (3  and 4 parameter models 
only) and the slope parameter m (4 parameter model only). The rationale for this choice of 
inference is that the FUP shrinks the dose response towards a flat line throughout the dose 
range, therefore providing more conservative estimates of the dose response relationship 
compared to maximum likelihood (Bornkamp 2014). The models will be fully described in 
the SAP. 
Based on the selected model, the posterior mean with associated 95% HDP CrI, for the 
difference from placebo for each active dose will be produced for the pairwise differences 
between each active dose and placebo, together with the posterior mean and 95% HDP CrI of 
the treatment difference from placebo for each active dose and posterior probabilities that 
difference from placebo is less than 0, 20%, 30% and 50%. 
Section 7.8.2: 
All secondary analyses will be performed either using the pooled placebo group if the 
assumption of similarity for the placebo cohorts is considered appropriate or using the 3 
2 cohort-level placebo groups if it is not considered appropriate. 




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• Blood or plasma analytes: urea, creatinine, sodium, potassium, ALT, AST, total and 
direct bilirubin, CRP, creatine kinase, fasting glucose, fasting lipid panel (total 
cholesterol, HDL, LDL, triglycerides) 
• Hematologic analyses: full blood count, including hemoglobin, MCV, MCH, MCHC, 
hematocrit, percent reticulocytes, platelet count; differential white blood cell count 
including neutrophils, lymphocytes, monocytes, and eosinophils 
• Urinalysis by dip stick: protein, blood, glucose, ketones, bilirubin, pH, nitrites, and 
specific gravity 
Other screening tests include the following:  
• Serology (HIV antibody, HBsAg, and HCV antibody) 
• Serum pregnancy test (HCG) at screening, urine test thereafter 
Blood samples for assessment of fasting blood glucose and lipid panel will be obtained after 
the participant has fasted for at least 8 hours.  
A central laboratory (or specialized central laboratories) will be used for all laboratory 
analyses. Details of sample collection and handling procedures will be provided in the study 
manual.  
The investigator must review the laboratory reports, document this review, and record any 
clinically relevant changes occurring during the study. If the laboratory reports are not 
transferred electronically, the values must be filed with the source information (including 
reference ranges). In most cases, clinically significant abnormal laboratory findings are those 
that 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 during 
participation in the study or within 30 days after the last dose of study drug should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor. If such values do not return to 
normal/baseline within a time judged reasonable by the investigator, the etiology should be 
identified, and the sponsor notified. 


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All protocol required laboratory assessments, as defined in this section, must be conducted in 
accordance with the laboratory manual and the SoA (Table 6 1). If laboratory values from 
nonprotocol specified laboratory assessments performed at the institution’s local laboratory 
require a change in participant management or are considered clinically significant by the 
investigator (eg, SAE or AE or dose modification), then the results must be recorded in the 
eCRF. 
Section 7.10.1: 
The planned maximum amount of blood collected from each participant over the duration of 
the study is less than 130 mL. Repeat or unscheduled samples may be taken for safety 
reasons or for technical issues with the samples. The planned maximum amount of blood 
collected from each participant at a single visit is less than 46mL, and the planned maximum 
amount of blood collected from each participant over 30 days is less than 58 mL.  
Section 7.10.2: 
Systemic exposure following oral EDP1815 dosing is estimated to be very low based on lack 
of detection in blood (<0.01% of administered dose). However, plasma samples will be taken 
from all participants for the estimate of systemic EDP1815 levels by PCR using 
EDP1815 specific primers. Sampling will be performed as specified in the SoA (Table 6 1, 
blood sample for systemic levels of microbes).  
Systemic exposure of EDP1815 will be measured using specific PCR with strain specific 
primers which can detect EDP1815 specifically even when other strains of Prevotella 
histicola are present. Any effects of EDP1815 on the gut microbiome will be investigated 
using 16S ribosomal RNA sequencing, which measures both the presence and quantity of 
microbes at the genus level. 
Section 7.10.3: 
Procedures for sample collection, processing, storage, and shipment will be detailed in the 
study manual. Biomarkers are exploratory endpoints and analytical results for biomarkers 
will not be included in the CSR. They will be reported separately from the CSR.  
Digital photographs should be taken of up to 6 lesion sites that have a lesion area 
≥2 cm × 2 cm at baseline. The same locations photographed at baseline should be followed 


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throughout the study for each participant. Procedural details for digital photography will be 
provided in the study manual.  
Section 7.10.3.1: 
Standard histology will be performed on skin plaque biopsies (including epidermal thickness, 
basal mitotic counts and immune cell infiltrates, immunohistochemistry) from approximately 
15 participants in each cohort. Details will be provided in the study manual. The histologic 
evaluations are exploratory and are outside the scope of the CSR.  
Section 7.10.3.2: 
An mRNA transcription analysis will be performed on the skin plaque biopsies.  
Section 7.10.3.3: 
Blood samples will be stimulated ex vivo and analyzed for levels of cytokines and 
chemokines, including IL 1 beta, IL 2, IL 4, IL 6, IL 8, IL 10, IL 12p40, IL 17A, TNFα, and 
IFNγ. 
Section 7.10.3.4: 
The microbiome composition of stool samples will be assessed by 16S ribosomal RNA 
sequencing, which looks at the diversity and abundance of microbes in the colonic 
microbiome (Human Microbiome Project Consortium 2012). EDP1815 is not expected to 
alter the composition of the microbiome, but it is being evaluated as a safety biomarker.  
 
 


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Protocol Amendment 3 – Summary of Major Changes 
The study has been amended to increase the number of cohorts in the study from 2 to 3, to 
adjust the doses per cohort, to add secondary objectives to evaluate efficacy dose response 
and optimal dose of EDP1815, to change some exploratory endpoints to be secondary 
endpoints, to update the criteria by which AE severity are rated, to update the sponsor 
medical monitor details, and to change the study title.  
Administrative and minor grammatical, editorial, and formatting changes were made for 
clarification purposes only. 
The major changes listed above have been made in addition to the edits in the following 
sections (and the corresponding text in the Protocol Synopsis).  
Changes have been marked as follows: new text as bold and deleted text as strikethrough. 
Title Page (and globally, where applicable): 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort, 
Dose-Ranging Study Investigating the Effect of EDP1815 in the Treatment of Mild to 
Moderate Plaque Psoriasis. 
Section 1: 
Evelo Biosciences Inc. (Evelo) is developing medicines based on monoclonal single strains 
of bacteria as a new class of therapeutic agents known as monoclonal microbials. 
Monoclonal microbials. These therapeutic agents are human commensal organisms that 
offer the potential of systemic immune system modulation following oral administration, 
without systemic exposure. “…” 
Several studies (de Groot et al 2017; Hindson et al 2017; Yan et al 2017; Felix et al 2018) 
suggest that host-microbe interactions in the gut, and particularly in the small intestine, can 
influence systemic inflammation. Evelo is seeking to develop oral anti-inflammatory 
medicines based on this emerging science. Preclinical data confirms that individual strains of 
microbes exhibit unique pharmacological profiles. This is thought to be based on multiple 
distinct microbial structural pattern motifs interacting with varying combinations of host 
pattern recognition receptors in small intestinal epithelium.  


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Studies of EDP1815 in vitro in a range of human and mouse assays and studies in vivo in 
model symptoms support the use of EDP1815 in the treatment of inflammatory diseases 
including psoriasis (Evelo Biosciences 2019). EDP1815 increases secretion of 
anti-inflammatory cytokines such as IL-10, IL-1RA, and IL-27 from human immune cells, 
while inducing minimal production of pro-inflammatory cytokines such as IL-6, TNFα, and 
IFNγ. 
Oral administration of EDP1815 to mice results in striking pharmacodynamic effects on 
animal models of delayed-type hypersensitivity, fluorescein isothiocyanate cutaneous 
hypersensitivity, collagen-induced arthritis (Marietta et al 2016) and experimental acute 
encephalomyelitis (Mangalam et al 2017). The high degree of consistency of both effect and 
dose suggests the potential for clinical benefit across multiple type 1, type 2, and type 3 
immunoinflammatory conditions. No potentially related adverse effects were seen in the 
animals used in these experiments with daily dosing for up to 3 weeks or with alternate day 
dosing for over 7 weeks. Immunophenotyping ex vivo in these models shows increased 
regulatory T cell numbers and regulatory dendritic cells in spleen and mesenteric lymph 
nodes, as well as decreases in pro-inflammatory cytokines such as IL-23p40, IL-17, TNFα, 
IL-6, and IL-13. Treatment also led to enhancement of gut intestinal barrier integrity, which 
is often disrupted in patients with inflammatory diseases. These effects on immune 
parameters have been observed both within and outside the GI tract, which demonstrates that 
host-microbe interactions in the gut can affect the immune response in peripheral tissues. 
Psoriasis is a chronic immune-mediated type 1/3 inflammatory skin disease in which 
hyperactive T cells trigger excessive keratinocyte proliferation. “…” 
This Phase 2 study has been designed to investigate the clinical safety and efficacy of 
response to treatment with EDP1815 and to identify an optimal dose. 
Section 2: 
All objectives are related to understanding the safety, efficacy, and dose effects of EDP1815 
treatment of mild to moderate plaque psoriasis in adult participants (Section 4.1). 


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Section 2.1: 
The primary objective of this study is to evaluate the safety and efficacy of 3 different doses 
of EDP1815 for the treatment of psoriasis following daily dosing for 16 weeks. 
Section 2.2: 
The secondary objectives of this study are the following: 
• To evaluate the efficacy dose response of EDP1815 at Week 16 
• To evaluate the maximal clinical benefit of EDP1815 at Week 16 
• To evaluate the optimal dose of EDP1815 based on efficacy and safety up to 
Week 16 
• To evaluate the safety and tolerability of EDP1815 (all dose levels) throughout the 
study 
Section 2.3: 
The exploratory objectives of this study are the following: 
• To evaluate the time to onset of clinical response to EDP1815  
• To evaluate the effect of EDP1815 treatment on patient-reported outcomes including 
quality of life and pain 
• To evaluate the effect of EDP1815 treatment on biomarkers in blood 
• To evaluate the effect of EDP1815 treatment on biomarkers in skin plaques 
• To evaluate the effect of EDP1815 treatment on fecal microbiome composition 


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Section 3.1: 
After eligibility is confirmed during the screening period (Section 4.1), participants will be 
randomly assigned in a 1:1:1 ratio to 1 of the following 3 2 parallel cohorts: 
• Cohort 1: 0.81.6 × 1011 cells of EDP1815 or matching placebo administered as 1 PIC 
2 MICs, once daily (Section 5.2).  
• Cohort 2: 3.24.8 × 1011 cells of EDP1815 or matching placebo administered as 
4 PICs6 MICs, once daily (Section 5.2).  
• Cohort 3: 8.0 × 1011 cells of EDP1815 or matching placebo administered as 
10 PICs, once daily (Section 5.2). 
In each cohort, approximately 7569 participants will be randomly assigned in a 2:1 ratio to 
receive either EDP1815 or matching placebo once daily for 16 weeks. 
The study design figure (Figure 3.1) was updated accordingly to add Cohort 3. 
Section 3.1.1: 
The doses tested in the program are based on predictions from the preclinical data and the 
clinical and biomarker data obtained in EDP1815-101, the Phase 1 study. All doses tested up 
to 8.0 × 1011 cells have been equally well tolerated. No clear difference in efficacy was 
observed between the 1.6 × 1011 cells and the 8.0 × 1011 cells in EDP1815-101 over the 
28-day dosing period, but at the 14-day follow up (Day 42) the participants receiving the 
higher dose had a continued improvement in their psoriasis compared to participants who had 
received the lower dose. This suggests a more sustained and potentially deeper response 
in the high dose group. Evelo is therefore proposing to include the lowest and highest 
feasible doses (based on capsule load) in this study to establish the dose response, the 
maximum clinical benefit, and to assess participant tolerability and acceptability of the 
doses tested. additional efficacy could be obtained at doses above the dose of 1.6 × 1011 
cells. Therefore, 4.8 × 1011 cells will be tested as well as 1.6 × 1011 cells in this study. 


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Section 4.1: 
Approximately 225138 participants will be enrolled (randomly assigned to treatment) in 
multiple countries, including (but not limited to) sites in the United States, the United 
Kingdom, and Poland. 
Section 4.1.1: 
4. Have mild to moderate plaque psoriasis with plaque covering body surface area (BSA) 
of ≥3% and ≤10% and meet both at least 1 of the following additional criteria:  
a. PASI score of ≥6 and ≤15., and  
b. PGA score of 2 or 3.  
 
All parameters in this criterion should be reconfirmed at baseline visit prior to 
randomization. 
Section 4.1.2: 
10. Have used topical medications/treatments that could affect psoriasis or PGA 
evaluation (including [but not limited to] high- and mid-potency corticosteroids 
[Appendix 13.2], anthralin, calcipotriene, topical vitamin D derivatives, retinoids, 
tazarotene, methoxsalen, trimethylpsoralens, picrolimus, and tacrolimus) within 
2 weeks of the first administration of study drug. Topical unmedicated emollients and 
low-potency topical corticosteroids are not excluded. 
Section 4.2: 
A participant may discontinue from the study drug or withdraw from the study for any of the 
following reasons: 
1. The participant does not meet the protocol inclusion or exclusion criteria. 
2. The participant is noncompliant with the protocol. 
3. The participant experiences treatment failure, demonstrated by the participant 
commencing an oral agent, biological, or intermediate or high-potency dose topical 
therapy for plaque psoriasis.  
4. “...” 


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Section 4.2.4: 
Participants who withdraw or are withdrawn from the study within 4 weeks of randomization 
may be replaced in order to have approximately 225138 participants provide at least 4 weeks 
of postbaseline data.  
Section 5.1: 
Participants will be randomly assigned at the baseline visit (Visit 2) to 1 of 32 cohorts (in a 
1:1:1 allocation ratio) that are distinguishable to participants and study staff by the number of 
capsules administered per once-daily dose. Within the cohort, participants will be randomly 
assigned in a 2:1 allocation ratio to receive either EDP1815 or matching placebo treatment 
(Section 3.1). Interactive response technology (IRT) will be used to administer the 
randomization schedule. 
Section 5.3: 
The EDP1815 drug product is a blend of freeze dried powder of P histicola and excipients.  
For this study, EDP1815 is formulated as multiple available as enteric-coated HPMC hard 
capsules in minitablets of EDP1815 drug product filled into Swedish-Orange color HPMC 
capsules (MICs). The EDP1815 PIC consists of freeze-dried powder of P histicola, 
mannitol, magnesium stearate, and colloidal silicon dioxide. The excipients include 
mannitol, colloidal silicon dioxide, hydroxypropyl cellulose, crospovidone, and magnesium 
stearate. Each EDP1815 PICMIC contains 8.0 × 1010 cells of P histicola. 
The matching placebo is MICs are identical in appearance but do not contain P histicola or 
any other bacteria. The placebo excipients include mannitol, microcrystalline cellulose, 
colloidal silicon dioxide, sodium starch glycolate, and magnesium stearate.  
Section 5.4.1: 
EDP1815 PICsMICs and matching placebo will be prepared in blister wallets of 10 or 
20 capsules each (cohort dependent). Blister wallets will be packaged in packs that contain 
approximately 1 week’s supply of study drug for 1 randomized participant, identified by a 
numeric code. When appropriate for the interval between study visits, multiple packs will be 
assigned and dispensed for each participant throughout the treatment period.  


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Section 5.8.2: 
Anti-histamines and acetaminophen/paracetamol following labeled dosing instructions are 
permitted for use at any time during the study. Topical unmedicated emollients and 
low-potency topical steroids are also permitted if participants were already using them as part 
of their care prior to study entry (exclusion criterion #10, Section 4.1.2). Participants will be 
advised to continue to use these therapies as they were prior to study entry. 
Non-live vaccines are permitted in this study. 
Section 5.8.2.1: 
Prior therapies restricted for participants eligible for this study as detailed in the exclusion 
criteria (Section 4.1.2) are prohibited concomitant therapy during the study.  
Live or live-attenuated vaccines are contra-indicated in this study. 
Section 6: 
Footnote h was amended in the SoA (Table 6-1): 
h 
Blood pressure, pulse, respiratory rate, and oral temperature are to be checked on the morning of the visit. 
 
A new footnote was added in the SoA (Table 6-1): 
n 
Inclusion criterion #4 (mild to moderate plaque psoriasis with plaque covering BSA of ≥3% and 
≤10%, PASI score of ≥6 and ≤15, and PGA score of 2 or 3) should be reconfirmed at the baseline visit 
prior to randomization. 
Participants meeting eligibility criteria at screening will return to the study site on Day 1. 
The PASI, BSA involvement, and PGA scores must be available to reconfirm eligibility 
prior to randomization and administration of the first dose of study drug on Day 1 (Visit 2). 
Section 6.2.1.2: 
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 drug or study participation, the investigator must promptly notify the sponsor (or 
designee). 


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Section 6.2.1.2.1: 
The severity, or intensity, of an AE refers to the extent to which an AE affects the 
participant’s daily activities or their health. The intensity of the AE will be rated in 
accordance with the CTCAE version 5.0. as mild, moderate, or severe using the following 
criteria: 
Mild: 
These events require minimal or no treatment and do not interfere with the 
participant’s daily activities.  
Moderate: These events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
normal functioning.  
Severe: 
These events interrupt a participant’s usual daily activity and may require 
systemic drug therapy or other treatment Severe events are usually 
incapacitating. 
 
Section 6.2.1.3: 
All AEs reported or observed during the study will be recorded on the AE page in the eCRF. 
Information to be collected includes the following:  
• “...” 
• Lot/batch number 
• Any required treatment or evaluations 
• Action taken with the study drug due to the event 
• Outcome 


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Section 6.2.4: 
Blood pressure, pulse rate, respiratory rate, and oral temperature will be assessed. Blood 
pressure and pulse measurements will be assessed in a sitting position with a completely 
automated device. Blood pressure and pulse measurements should be preceded by at least 
5 minutes of rest for the participant in a quiet setting without distractions (eg, television, 
mobile phones). 
Section 7.1: 
The primary estimand will be the effect of EDP1815 on the percent change in PASI score 
from baseline to Week 16 in the mITT set of all treated participants, regardless of deviations 
from the protocol. Only data collected while on treatment will be used to account for the 
intercurrent event of treatment discontinuation (hypothetical strategy based on adherence to 
treatment only). The posterior mean difference between each active dose and the pooled 
placebo group will be estimated. 
For the primary analysis, 2 supportive estimands will also be considered: 
• To assess the impact of intercurrent events related to protocol deviations believed to 
impact efficacy, a supportive analysis will be performed where all data collected after 
any such identified protocol deviations will be excluded. Participants who had a 
protocol deviation believed to impact efficacy prior to the first dose of treatment 
(hypothetical strategy based on adherence to treatment and the aspects of the protocol 
which impact efficacy) will be completely excluded from this analysis. 
• To assess the impact of treatment discontinuation, a supportive analysis will be 
performed in which all data collected during the study, including any data collected 
after treatment discontinuation will be included (treatment policy strategy). 
Estimands for the analyses of all secondary endpoints are shown in Table 7 1. 
Table 7-1 
Summary of Secondary Estimands 


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Population of interest 
Endpoint 
Consideration of 
intercurrent events 
Summary measure 
mITT set 
Mean change from baseline 
in PASI Score at Week 16 
To include all data collected 
prior to treatment 
discontinuation, regardless 
of protocol deviations 
Posterior mean difference 
between each active 
treatment group and pooled 
placebo group 
mITT set 
Achievement of PASI-50 at 
Week 16 
To include all data collected 
prior to treatment 
discontinuation, regardless 
of protocol deviations 
Posterior odds ratio for 
response between each 
active treatment group and 
pooled placebo group  
mITT set 
Achievement of PASI 75, 
PASI 90 and PASI 100 at 
Week 16 
To include all data collected 
prior to treatment 
discontinuation, regardless 
of protocol deviations 
Proportion of response for 
each endpoint in each 
treatment group  
mITT set 
Achievement of PGA of 0 
or 1 with a ≥2-point 
improvement from baseline 
at Week 16 
To include all data collected 
prior to treatment 
discontinuation, regardless 
of protocol deviations 
Posterior odds ratio for 
response between each 
active treatment group and 
pooled placebo group 
mITT set 
Achievement of PGA of 0 
at Week 16 
To include all data collected 
prior to treatment 
discontinuation, regardless 
of protocol deviations 
Posterior odds ratio for 
response between each 
active treatment group and 
pooled placebo group 
mITT set 
Mean change from baseline 
in PGA×BSA at Week 16 
To include all data collected 
prior to treatment 
discontinuation, regardless 
of protocol deviations 
Posterior mean difference 
between each active 
treatment group and pooled 
placebo group  
mITT set 
Mean change from baseline 
in LSS at Week 16 
To include all data collected 
prior to treatment 
discontinuation, regardless 
of protocol deviations 
Posterior mean difference 
between each active dose 
and pooled placebo group 
 
Section 7.1.1 (previously Section 7.2): 
The primary estimand will be the effect of EDP1815 on the percent change in PASI 
score from baseline to Week 16 in the mITT set of all treated participants, regardless of 
deviations from the protocol. Only data collected while on treatment will be used to 
account for the intercurrent event of treatment discontinuation (hypothetical strategy 
based on adherence to treatment only). The posterior mean difference between each 
active dose and the pooled placebo will be estimated. The primary efficacy endpoint is the 
percent change from baseline in PASI score at Week 16. 
Percent change from baseline in PASI score at each visit will be calculated as: 
100*(PASI score at Visit – baseline PASI score) / baseline PASI score. 
A negative percentage change from baseline will indicate an improvement. 


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For the primary analysis, 2 supportive estimands will also be considered: 
• To assess the impact of intercurrent events related to protocol deviations 
believed to impact efficacy, a supportive analysis will be performed where all 
data collected after any such identified protocol deviations will be excluded. 
Participants who had a protocol deviation believed to impact efficacy prior to 
the first dose of treatment (hypothetical strategy based on adherence to 
treatment and the aspects of the protocol which impact efficacy) will be 
completely excluded from this analysis. 
• To assess the impact of treatment discontinuation, a supportive analysis will be 
performed in which all data collected during the study, including any data 
collected after treatment discontinuation will be included (treatment policy 
strategy).  
For the primary analysis, the mITT set with all data collected prior to treatment 
discontinuation will be used, regardless of any protocol deviations. 
“...” 
Supportive analyses will also be performed in the same manner, using the 2 alternative 
estimands as defined abovein Section 7.1.1. These will explore the possible impact of the 
intercurrent events of treatment discontinuation and events relating to protocol deviations 
that may have an impact on efficacy. 
Section 7.1.2 (previously Section 7.3): 
The secondary efficacy endpoints are: 
• Mean change from baseline in PASI score at Week 16 
• Percentage of participants achieving PASI 50, PASI 75, PASI 90 and PASI 100 at 
Week 16 
• Percentage of participants achieving PGA of 0 or 1 with a ≥2-point improvement at 
Week 16 


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• Percentage of participants achieving PGA of 0 at Week 16 
• Mean change from baseline in PGA×BSA score at Week 16 
• Mean change from baseline in LSS at Week 16.  
All summaries and analyses of interest will be performed on the mITT set, with data 
collected after discontinuation of treatment excluded, without consideration of any protocol 
deviations.  
Estimands for the analyses of all secondary endpoints are shown in Table 7-1. 
Table 7-1 
Summary of Secondary Estimands 
Population of 
interest 
Endpoint 
Consideration of intercurrent 
events 
Summary measure 
mITT set 
Mean percentage change 
from baseline in PASI 
Score at Weeks 4, 8, and 
12 
To include all data collected prior 
to treatment discontinuation, 
regardless of protocol deviations 
Posterior mean difference 
between each active 
treatment group and pooled 
placebo at each visit 
mITT set 
Mean absolute change 
from baseline in PASI 
Score at Weeks 4, 8, 12, 
and 16 
To include all data collected prior 
to treatment discontinuation, 
regardless of protocol deviations 
Posterior mean difference 
between each active 
treatment group and pooled 
placebo at each visit 
mITT set 
Achievement of PASI-50 
at Weeks 4, 8, 12, and 16 
To include all data collected prior 
to treatment discontinuation, 
regardless of protocol deviations 
Posterior odds ratio for 
response between each active 
treatment group and pooled 
placebo at each visit  
mITT set 
Time to first 
achievement of PASI-50 
To include all data collected prior 
to treatment discontinuation, 
regardless of protocol deviations 
Hazard ratio for each active 
group versus placebo 
mITT set 
Achievement of PASI-
75, PASI-90 and PASI-
100 at Week 16 
To include all data collected prior 
to treatment discontinuation, 
regardless of protocol deviations 
Proportion of response for 
each endpoint in each 
treatment group at each visit 
mITT set 
Achievement of PGA of 
0 or 1 with a ≥2-point 
improvement from 
baseline at Week 16 
To include all data collected prior 
to treatment discontinuation, 
regardless of protocol deviations 
Posterior odds ratio for 
response between each active 
treatment group and pooled 
placebo  
mITT set 
Achievement of PGA of 
0 at Week 16 
To include all data collected prior 
to treatment discontinuation, 
regardless of protocol deviations 
Posterior odds ratio for 
response between each active 
treatment group and pooled 
placebo  
mITT set 
Mean percentage change 
from baseline in 
PGA×BSA at Weeks 4, 
8, 12, and 16 
To include all data collected prior 
to treatment discontinuation, 
regardless of protocol deviations 
Posterior mean difference 
between each active 
treatment group and pooled 
placebo at each visit 


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Population of 
interest 
Endpoint 
Consideration of intercurrent 
events 
Summary measure 
mITT set 
Mean absolute change 
from baseline in 
PGA×BSA at Weeks 4, 
8, 12, and 16 
To include all data collected prior 
to treatment discontinuation, 
regardless of protocol deviations 
Posterior mean difference 
between each active 
treatment group and pooled 
placebo at each visit 
mITT set 
Mean percentage change 
from baseline in LSS at 
Weeks 4, 8, 12, and 16 
To include all data collected prior 
to treatment discontinuation, 
regardless of protocol deviations 
Posterior mean difference 
between each active dose and 
pooled placebo at each visit 
mITT set 
Mean absolute change 
from baseline in LSS at 
Weeks 4, 8, 12, and 16 
To include all data collected prior 
to treatment discontinuation, 
regardless of protocol deviations 
Posterior mean difference 
between each active dose and 
pooled placebo at each visit 
mITT set 
Mean percentage change 
from baseline in DLQI 
score at Weeks 4, 8, 12, 
and 16 
To include all data collected prior 
to treatment discontinuation, 
regardless of protocol deviations 
Posterior mean difference 
between each active dose and 
pooled placebo at each visit 
mITT set 
Mean absolute change 
from baseline in DLQI 
score at Weeks 4, 8, 12, 
and 16 
To include all data collected prior 
to treatment discontinuation, 
regardless of protocol deviations 
Posterior mean difference 
between each active dose and 
pooled placebo at each visit 
mITT set 
Mean percentage change 
from baseline in 
mNAPSI total score at 
Weeks 4, 8, 12, and 16 
To include all data collected prior 
to treatment discontinuation, 
regardless of protocol deviations 
Posterior mean difference 
between each active dose and 
pooled placebo at each visit 
mITT set 
Mean absolute change 
from baseline in 
mNAPSI total score at 
Weeks 4, 8, 12, and 16 
To include all data collected prior 
to treatment discontinuation, 
regardless of protocol deviations 
Posterior mean difference 
between each active dose and 
pooled placebo at each visit 
 
Section 7.2 (previously Section 7.4): 
The exploratory endpoints include the following: 
• Mean percentage change from baseline in PASI score at Weeks 4, 8 and 12 
• Mean change from baseline in PASI score at Weeks 4, 8, and 12 
• Percentage of participants achieving PASI-50, PASI-75, PASI-90, and PASI-100 at 
Weeks 4, 8, and 12 
• Time to first achievement of PASI 50 
• Percentage of participants achieving PGA of 0 or 1 with a ≥2-point improvement at 
Weeks 4, 8, and 12  


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• Percentage of participants achieving PGA of 0 at Weeks 4, 8, and 12  
• Mean change from baseline in PGA×BSA score at Weeks 4, 8, and 12  
• Mean change from baseline in LSS at Weeks 4, 8 and 12 
• Mean change from baseline in DLQI and PSI quality of life scores at Weeks 12 
and 16 
• Mean percentage change from baseline in PSI quality of life scores at Weeks 12 
and 16 
• Mean change from baseline in Pain and Fatigue scores at Weeks 4, 8, 12, and 16 
• Mean percentage change from baseline in Pain and Fatigue scores at Weeks 4, 8, 
12, and 16 
• Mean change from baseline in mNAPSI total score at Weeks 4, 8, 12 and 16 
• Mean change from baseline in fasting blood glucose and fasting lipid panel at 
Weeks 8 and 16 
Section 7.3 (previously Section 7.5): 
The sample size of 225138 participants in total, has been chosen to explore the tolerability 
and safety of EDP1815. “…” 
Participants in the placebo arm of each cohort will be pooled for the statistical analysis in 
order to compare active and control arms resulting in 75 participants randomized to the 
pooled placebo group and 5046 participants randomized to each active treatment group 
(pooled placebo, EDP1815 0.81.6 × 1011 cells, and EDP1815 3.24.8 × 1011 cells, and 
EDP1815 8.0 × 1011 cells). Assuming that no more than 15% of participants will discontinue 
treatment before the Week 16 visit, at least 42 active and 21 placebo39 participants in each 
treatment group of the 3 cohorts are expected to provide data through the Week 16 visit. 
Each pairwise comparison between pooled placebo and active dose would be expected to 
have more than 9590% power to detect a difference between the treatment groups at the 5% 


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significance level under the assumption that pooling the placebo groups is a valid strategy. If 
the 32 placebo cohorts are considered to be too heterogeneous for pooling into a single 
reference group, the power to detect a difference in each within-cohort pairwise comparison 
between active and placebo doses within a cohort falls to approximately would be greater 
than 80%. 
Section 7.4 (previously Section 7.6): 
mITT set: The mITT set will consist of all participants who were randomized to treatment 
and who received at least one dose of study treatment. Participants who withdraw from the 
study before the end of Week 4 and are replaced will be included in this analysis set. All 
analyses using the mITT will group participants according to randomized treatment.  
PPS: The PPS will consist of all mITT participants who were not replaced (following study 
withdrawal before the end of Week 4) and who do not have a protocol deviation which 
that may impact efficacy with a start date for the deviation before initiation of study 
treatment. “...” 
Section 7.5 (previously Section 7.7): 
If the placebo groups from the 32 cohorts are found to be too heterogeneous to be pooled 
(Section 7.6.1), the primary and secondary analyses will be performed using within-cohort 
comparisons of active and placebo treatments, and summary tables may also be produced by 
cohort. 
Section 7.6 (previously Section 7.8): 
Statistical analysis will be performed using SAS software Version 9.3 or later.  
In addition to the inferential analyses described in Sections 7.6.1 and 7.6.2, descriptive 
statistics will be provided to summarize all endpoints by treatment group. 
Section 7.6.1 (previously Section 7.8.1): 
The assumption that the 32 cohorts of placebo participants can be pooled into a single 
placebo group to be used as a control for all active doses will be examined using mean (±SD) 


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plots of percent change in PASI score against time. A decision will be made by the Evelo 
study team on whether the pooling strategy is appropriate. 
The primary analysis will be performed using an Bayesian MMRM. The model will include 
parameters for treatment*visit and baseline PASI score*visit interactions. Body mass index, 
gender, and other baseline covariates will also be considered and included as parameters if 
found to be significant (p<0.05). The model will not include an intercept. Visit will consist of 
6 levels (Weeks 1, 2, 4, 8, 12, and 16) and treatment will consist of 43 levels (pooled placebo, 
EDP1815 0.81.6 × 1011 cells, EDP1815 3.2 × 1011 cells, and EDP1815 8.04.8 × 1011 cells) if 
the placebo pooling strategy is considered appropriate or 64 levels (Placebo matching 
EDP1815 0.81.6 × 1011 cells, Placebo matching EDP1815 3.24.8 × 1011 cells, Placebo 
matching EDP1815 8.01.6 × 1011 cells, and EDP1815 04.8 × 1011 cells, EDP1815 3.2 × 1011 
cells, and EDP1815 8.0 × 1011 cells) if the placebo pooling strategy is not considered 
appropriate. “…” 
If the assumption of similarity between the 32 placebo cohorts is considered appropriate, the 
placebo cohorts will be pooled, and a single placebo control group will be used for the 
pairwise differences for each active dose to placebo. If the assumption of similarity is 
considered inappropriate, each placebo dose will be included in the model as a separate dose 
level and pairwise comparisons between each active dose and placebo will be performed 
using only the matching placebo dose data for the relevant active dose. 
The adjusted posterior mean percentage change from baseline and the associated 95% HDP 
CrI for each treatment at Week 16each visit will be reported, together with. In addition, the 
adjusted mean difference from placebo and the associated 95% HDP CrI for each active dose 
at each visit will also be reported together withand the probability that each treatment 
difference is less than 0%, -20%, -30%, and -50% for each active dose at Week 16. 
Model checking and diagnostic plots, including posterior density plots of the posterior 
samples for all parameters in the model and residual plots to evaluate the distributional 
assumptions underlying the model, will be produced. The assumption that data are 
missing at random will be evaluated by plotting the mean percentage change in PASI 
score against visit, by treatment group, for the subgroups of participants who 
completed 16 weeks of study drug compared with those who discontinued study drug 
before the Week 16 visit. 


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If model checking and diagnostic plots show a violation of the assumptions underlying 
the analysis, alternative statistical methods will be considered, appropriate to the type 
of violation observed. “…” 
A further sensitivity analysis will be performed on the model with the primary 
estimand, in which participants who withdrew from study drug due to treatment failure 
(demonstrated by the participant commencing an oral agent, biological, or intermediate 
or high-potency topical therapy for plaque psoriasis) will have their percentage change 
from PASI imputed at all visits after study drug was discontinued as the maximum 
on-treatment value reached (ie, worst score carried forward). 
If the assumption of similarity between the placebo cohorts is supported, a 
supplementary analysis will be performed on the percent change from baseline to 
Week 16 in PASI score using a dose-response model on the pooled cohorts. The 
log-linear, 3-parameter, and 4-parameter Emax models will be fitted and compared, with 
the best fitting model (lowest DIC) selected for use in the outputs. 
The dose-response model will be fitted to the data using Bayesian techniques with 
noninformative priors for E0 and Emax and an FUP for ED50 (3- and 4-parameter 
models only) and the slope parameter m (4-parameter model only). The rationale for 
this choice of inference is that the FUP shrinks the dose response towards a flat line 
throughout the dose range, therefore providing more conservative estimates of the 
dose-response relationship compared to maximum likelihood (Bornkamp 2014). The 
models will be fully described in the SAP. 
Based on the selected model, the posterior mean with associated 95% HDP CrI, for the 
difference from placebo for each active dose will be produced for the pairwise 
differences between each active dose and placebo, together with the posterior mean and 
95% HDP CrI of the treatment difference from placebo for each active dose and 
posterior probabilities that difference from placebo is less than 0, -20%, -30%, 
and -50%. A further sensitivity analysis will be performed on the dose response model, 
in which participants who withdrew from study drug due to treatment will have their 
Week 16 percentage change from PASI imputed as 100% after study drug was 
discontinued. 


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Section 7.6.2 (previously Section 7.8.2): 
All secondary analyses will be performed either using the pooled placebo group if the 
assumption of similarity for the placebo cohorts is considered appropriate or using the 
32 cohort-level placebo groups if it is not considered appropriate. 
Unless otherwise specified, aAll secondary analyses will be performed on the mITT set, 
excluding data collected after treatment discontinuation, without consideration of any 
protocol deviations. Dose will be treated as a categorical variable and no dose response 
modelling will be done. Comparisons of interest will be between individual EDP1815 doses 
and placebo. All posterior probabilities and CrI calculated will be considered as descriptive 
with no further adjustments for multiplicity performed. “…” 
Mean percentage change from baseline in PASI score at Weeks 4, 8, and 12 will be 
analyzed as part of the MMRM for the primary estimand. The same statistics produced 
for the Week 16 time point will also be produced at Weeks 4, 8, and 12.summarized by 
visit. A Bayesian MMRM model will be used to estimate treatment difference at Week 16 in 
the same manner as that described in Section 7.8.1 for the primary efficacy analysis. 
The following secondary endpoints will be analyzed in the same manner as described 
for the primary analysis: 
• Mean absolute change from baseline in PASI score at Weeks 4, 8, 12, and 16  
• Mean percentage change from baseline in LSS at Weeks 4, 8, 12, and 16 
• Mean absolute change from baseline in LSS at Weeks 4, 8, 12, and 16 
• Mean percentage change from baseline in PGA×BSA at Weeks 4, 8, 12, and 16 
• Mean absolute change from baseline in PGA×BSA at Weeks 4, 8, 12, and 16 
• Mean percentage change from baseline in DLQI score at Weeks 4, 8, 12, and 16 
• Mean absolute change from baseline in DLQI score at Weeks 4, 8, 12, and 16 


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• Mean percentage change from baseline in mNAPSI total score at Weeks 4, 8, 12, 
and 16 
• Mean absolute change from baseline in mNAPSI total score at Weeks 4, 8, 12, 
and 16 
Percentage of participants achieving PASI 50, PASI 75, PASI 90 and PASI 100 at Weeks 4, 
8, 12, and 16 will be summarized by visit. 
For the PASI-50, a Bayesian generalized linear mixed effects model with a logit link function 
will be fitted using data from all visits. Treatment*visit and baseline PASI score*visit 
interactions will be included in the model as fixed effects. Body mass index, gender, and 
other baseline covariates will also be considered and fitted as fixed effects if found to be 
significant (p<0.05). Odds ratios and 95% HDP CrI Credible intervals for each active dose 
compared to placebo at each visit Week 16 will be presented.  
A sensitivity analysis for the PASI-50 will also be performed, in the same manner as 
described above, in which participants who withdraw from study drug before Week 16 
due to treatment failure will be included in the model with the PASI-50 endpoint 
imputed as ‘not achieved’ at all visits after study drug withdrawal. 
Percentage of participants achieving PGA of 0 or 1 with a ≥2-point improvement and 
percentage of participants achieving a PGA of 0 will be analyzed summarized by visit. 
Bayesian GLM will be used to estimate treatment differences in the same manner as 
described above for the PASI-50 endpoint. 
For the time to first achievement of PASI-50, a Bayesian Cox proportional hazards 
model will be fitted with treatment and baseline PASI score as covariates. Hazard ratios 
and 95% HDP CrI for each active dose compared to placebo will be presented. Mean 
change from baseline in PGA×BSA and LSS will be summarized by visit. Bayesian MMRM 
models will be used to estimate treatment differences at Week 16 in the same manner as that 
described in Section 7.8.1 for the primary efficacy analysis. 
Section 7.6.3 (previously Section 7.8.3): 
Exploratory endpoints will be summarized using the mITT population, with data collected 
after discontinuation of treatment excluded but without consideration of any protocol 


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deviations. Details of all analyses to be performed on the exploratory endpoints will be 
detailed in the SAP No inferential analyses will be performed on the exploratory endpoints. 
Section 7.6.7 (previously Section 7.8.7): 
An interim analysis may be undertaken during the conduct of the study after at least 50% of 
participants have completed at least 12 weeks of treatment or withdrawn from treatment. The 
purpose of this analyses will be to aid in the planning of future studies and for a better 
understanding of the benefit/risk profile of EDP1815. If the recruitment is such that the full 
study is expected to report out before the end of 2020, this interim analysis may not be 
performed. “...” 
The interim analysis will look at the primary endpoint of percentage change from baseline in 
PASI score, secondary, and safety endpoints. The posterior predictive probability 
(Spiegelhalter et al 2004) of the percent change from baseline in PASI score being at least 
20% lower in each active dose compared to the pooled placebo group will also be calculated, 
using the estimates of treatment difference found at Week 12 using the Bayesian MMRM 
model described for the primary analysis. If the posterior predictive probabilities for all 
active doses are found to be <30%, then the study may be stopped for futility. 
Section 8.1: 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the participants treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. These source documents may include diaries, laboratory reports, 
ECG strips, etc. Electronic devices will be used for the administration of investigator and 
participant responses to Clinical Outcome Assessments. Data collected via these devices 
will be uploaded directly to a central database for storage and analysis for administering 
questionnaires will upload data directly to the clinical database. Details will be provided in 
the study manual.  
Section 11.3.1: 
The study will be haltedterminated if any of the following occur: 
• One death considered definitely, probably, or possibly related to the study drug 


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• Two or more participantssubjects with an SAE considered definitely, probably, or 
possibly related to the study drug 
• Three or more participantssubjects with grade 3 AEs of the same type considered 
definitely, probably, or possibly related to the study drug 
Section 12: 
Bornkamp B. Practical considerations for using functional uniform prior distributions 
for dose-response estimation in clinical trials. Biom J. 2014;56(6):947-62. 
 
 


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Protocol Amendment 3.1 Hungary Specific – Summary of Major Changes 
The protocol was amended to clarify the language around study drug discontinuations or 
study withdrawals in Section 4.2 as per request from the National Institute of Pharmacy and 
Nutrition (ie, Országos Gyógyszerészeti és Élelmezés-egészségügyi Intézet). 
Changes have been marked as follows: new text as bold and deleted text as strikethrough. 
Minor grammatical and formatting changes were made for clarification purposes only. 
A participant may will be discontinued from the study drug or withdrawn from the study for 
any of the following reasons: 
1. 
The participant does not meet the protocol inclusion or exclusion criteria. 
2. 
The participant is noncompliant with the protocol. 
3.1. 
The participant experiences treatment failure, demonstrated by the participant 
commencing an oral agent, biological, or intermediate or high-potency topical therapy for 
plaque psoriasis.  
4.2. 
The participant has a serious or intolerable AE that in the investigator’s opinion 
requires discontinuation from study treatment or withdrawal from the study.  
5. 
The participant has laboratory safety results that reveal clinically significant 
hematological or biochemical changes from the baseline values. 
6.3. 
The participant has symptoms or an intercurrent illness not consistent with the 
protocol requirements or that justifyies withdrawal. 
7.4. 
The participant is lost to follow-up. 
8.5. 
Other reasons (eg, pregnancy, development of contraindications toof use of study 
drug). 
9.6. 
The participant withdraws consent, or the investigator or sponsor decides to 
discontinue the participant’s participation in the study. 
A participant may be discontinued from the study drug or withdrawn from the study for any 
of the following reasons: 


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1. 
The participant does not meet the protocol inclusion or exclusion criteria. 
2.1. 
The participant is noncompliant with the protocol. 
3. 
The participant experiences treatment failure, demonstrated by the participant 
commencing an oral agent, biological, or intermediate or high potency topical therapy for 
plaque psoriasis.  
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.  
5.2. 
The participant has laboratory safety results that reveal clinically significant 
hematological or biochemical changes from the baseline values. 
6. 
The participant has symptoms or an intercurrent illness not consistent with the 
protocol requirements or that justify withdrawal. 
7. 
The participant is lost to follow up. 
8. 
Other reasons (eg, pregnancy, development of contraindications of use of study drug). 
9. 
The participant withdraws consent, or the investigator or sponsor decides to 
discontinue the participant’s participation in the study. 
3. 
If the participant is required to start therapy for a concurrent condition that 
may affect the study endpoints, eg, a disease-modifying agent for psoriatic arthritis. 
In all of these instances, if the participant is to remain in the study, then the investigator 
should confirm that the participant is suitable to continue in the study with the medical 
monitor. 
 
 


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Protocol Amendment 4 – Summary of Major Changes 
The study has been amended to include local Amendment 3.1 (Hungary) and to extend 
post-treatment follow-up for a maximum of up to 6 months; to add one secondary and one 
exploratory objective; to add definitions of response, relapse, and rebound based on PASI 
score; to update statistical analyses, endpoints, and supportive analyses; to add skin plaque 
biopsy description; to add instructions for participants on withholding emollients or 
moisturizers; to add clarification and remove Vitamin D and analogues from exclusion 
criterion #8 and add clarification to exclusion criterion #21; to clarify pre- and probiotic use; 
to update allowed and prohibited vaccines; to clarify that eligibility confirmation at 
Baseline/Visit 2 will be based on screening laboratory results; to clarify maximum dose 
(overdose management); to add clarification on blinding; to change ‘on the morning of the 
visit’ ECGs and vital signs to ‘on the day of the visit’ in footnotes of the Schedule of 
Assessments (SoA); to update the ideal size of lesion area for digital photography.  
Administrative and minor grammatical, editorial, and formatting changes were made for 
clarification purposes only. 
The major changes listed above have been made in addition to the edits in the following 
sections (and the corresponding text in the Protocol Synopsis).  
Changes have been marked as follows: new text as bold and deleted text as strikethrough. 
 
Section 2.2    Secondary Objectives 
The secondary objectives of this study are the following: 
• To evaluate the efficacy dose response of EDP1815 at Week 16 
• To evaluate the maximal clinical benefit of EDP1815 at Week 16 
• To evaluate the optimal dose of EDP1815 based on efficacy and safety up to Week 16 
• To evaluate the safety and tolerability of EDP1815 (all dose levels) throughout the 
study 


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• To evaluate relapse and rebound of plaque psoriasis after cessation of EDP1815 
Section 2.3    Exploratory Objectives 
The exploratory objectives of this study are the following: 
• To evaluate the time to onset of clinical response to EDP1815  
• To evaluate the effect of EDP1815 treatment on patient-reported outcomes including 
quality of life and pain 
• To evaluate the duration of remission, treatment success, and therapeutic effect 
of EDP1815 
• To evaluate the effect of EDP1815 treatment on biomarkers in blood 
• To evaluate the effect of EDP1815 treatment on biomarkers in skin plaques 
• To evaluate the effect of EDP1815 treatment on fecal microbiome composition 
 
Section 3.1    Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-cohort, 
dose-ranging study of participants with mild to moderate plaque psoriasis (Section 4.1).  
Part A of the study comprises a screening period of up to 4 weeks, a baseline visit, a 
treatment period of 16 weeks (8 planned study site visits), and a follow-up visit at Week 20 
(4 weeks after cessation of dosing). Part A of the study therefore comprises a total of 
11 scheduled study visits, and on completion of Part A, the primary analysis will be 
performed. 
Part B of the study is designed to assess the durability of treatment response and 
incidence of rebound of psoriasis following cessation of dosing. All participants will 
attend for skin assessments at Weeks 24 and 28, unless they have previously 
experienced treatment failure and/or had rebound of disease. A final visit at Week 40 
will also be performed for those participants who experienced treatment response at 


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Week 16 of treatment, but have not yet met the definition of disease relapse. Part B of 
the study therefore comprises a maximum of 3 additional scheduled study visits with a 
follow-up of up to 40 weeks (24 weeks after cessation of dosing), and on completion of 
Part B, the final analysis will be performed. period of 4 weeks (1 planned study site visit at 
EOS). There are a total of 11 scheduled study visits.  
The study design is presented in Figure 3-1, and the SoA is presented in Table 6-1 for 
Part A, and in Table 6-2 for Part B.  
Three paragraphs without changes 
After the planned 16 weeks of treatment, all participants will have an initial follow-up visit 
at Week 20 (ie, 4 weeks post last dose of study treatment), completing Part A of the 
study; and enter Part B with continued follow-up for a maximum of 20 additional 
weeks (up to Week 40). The duration of follow up will depend on the initial response to 
study therapy and any relapse or rebound experienced after cessation of study 
treatment. enter a 4 week post treatment follow up period and undergo end of treatment 
evaluations.  
The maximum planned duration of study participationfor each participant will be 
24 44 weeks, and the duration of the study is defined for each participant as the date signed 
written informed consent is provided through theto their last follow-up visit. Participants 
will be considered to have completed the study with after the completion of all required 
visits.phases of the study, culminating with their EOS follow up visit.  
 
Figure 3-1 Study Design 
 
 


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Figure 3-1     Study Design 
 
Note: All dosing is once daily.  
 
 


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Section 3.1.1    Rationale for Study Design 
Added the following as last paragraph of this subsection: 
Part B of the study, which includes additional visits at Weeks 24, 28, and 40, is designed 
to help understand the durability of treatment effect, including time to relapse and 
incidence of any rebound of psoriasis after treatment has completed. These are 
important aspects to understand regarding a psoriasis therapy (EMA guideline 
CHMP/EWP/2454/02, 2004). 
 
Section 4.1    Selection of Study Population 
Countries updated in the first paragraph: 
Approximately 225 participants will be randomized enrolled (randomly assigned to 
treatment) in multiple countries, including (but not limited to) sites in the United States, the 
United Kingdom, and Poland, and Hungary. Participants will be assigned to study treatment 
only if they meet all inclusion criteria and no exclusion criteria during screening. 
 
Section 4.1.2 Exclusion Criteria 
8. Have received phototherapy or any systemic medications/treatments that could affect 
psoriasis or PGA evaluation (including, but not limited to oral or injectable 
corticosteroids, retinoids, 1,25 dihydroxy vitamin D3 and analogues, psoralens, 
sulfasalazine, hydroxyurea, or fumaric acid derivatives) within 4 weeks of first 
administration of study drug. This includes therapeutic doses of non-steroidal anti-
inflammatory drugs such as ibuprofen, although intermittent as required use as 
an analgesic is permitted when required. Chronic use of low dose aspirin for 
cardiovascular protection is permitted. 
Exclusion criteria 9 to 13 without changes: 
14. Have received live or live-attenuated replicating vaccineation within 6 weeks prior to 
screening or intend to have such a vaccination during the study. 


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Exclusion criteria 15 to 20 without changes: 
21. Current acute or chronic inflammatory disease other than psoriasis or psoriatic 
arthritis (eg, inflammatory bowel disease, rheumatoid arthritis, systemic lupus 
erythematosus). If a subject is off all treatment and is disease and has been 
symptom free for greater than 12 months, then the inflammatory disease is 
considered to be in remission and they may be enrolled. 
Exclusion criteria 22 to 27 without changes: 
28. Initiating any OTC or prescription medication including vitamins, herbal supplements 
and nutraceuticals (eg, supplements including high doses of probiotics and prebiotics 
as usually found in capsules/tablets/powders), except acetaminophen/paracetamol and 
anti-histamines, within 14 days prior to baseline or anticipates change in dosage for 
the duration of the study period.  
Note: Probiotic and prebiotic foods that contain low doses are allowed (eg, yoghurt, 
kefir, kombuca),. however, supplements containing high doses of probiotics and 
prebiotics are not allowed at any point during the study. 
 
Section 4.2    Discontinuation From Study Treatment and/or Withdrawal From the Study 
Clarified 3rd bullet: 
• Early withdrawal from the study is defined as failing to complete the required 
follow-up periodvisit scheduled for Week 20.  
 
Section 4.2.2    Withdrawal From the Study 
Last paragraph updated:  
Participants who withdraw from the study during Part A should complete the final 
assessments listed under the Follow-up Visit (Week 20) at an unscheduled for the 
follow-up visit, as detailed in the SoA (Table 6-1). Participants who withdraw from the 
study during Part B should complete the final assessments at the Early Withdrawal 
Visit, as detailed in Table 6-2. 


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Section 5.4.1 and 5.4.2 
Replaced ‘study manual’ with ‘IMP handling manual’ 
 
Section 5.5    Overdose Management 
First paragraph: 
An overdose is any dose of study treatment given to a participant or taken by a participant 
that exceeds the maximum dose described in the protocol (10 capsules per day). 
 
Section 5.6    Blinding 
Added last paragraph: 
The data will be unblinded and the primary analysis will be performed once all 
participants have completed 4 weeks of post-treatment follow-up at Visit 11 (Week 20; 
at the end of Part A). Study site staff, participants, and clinical monitors who will be 
involved in the collection and review of individual study data will remain blinded until 
Part B is completed. 
 
Section 5.8.2    Concomitant Therapy 
Second paragraph: 
Non-live and non-replicating vaccines are permitted in this study. 
 


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Section 5.8.2.1 Prohibited Concomitant Therapy 
Last paragraph: 
Live or live-attenuated replicating vaccines are contra-indicated in this study. 
 
Section 6    Study Assessments and Procedures 
Before performing any study procedures, all potential participants will sign an ICF. 
Additional procedural details related to the ICF are provided in Section 9.3.  
The SoA is presented in Table 6-1. Detailed instructions for study site activities will be 
provided in the appropriate specific user manualstudy manual, where applicable. High 
level descriptions of the study assessments are presented in the subsections of Section 6. In 
exceptional circumstances, study assessments may be conducted remotely (ie, at a 
participant’s home), except for screening, baseline, Visit 9, and Visit 10. Remote visits can 
only occur if operationally possible. 
 
Table 6-1    Schedule of Assessments Study Site Activities 
The title of this Table 6-1 was updated to ‘Schedule of Assessments’ as per protocol template.  
Updated and clarified footnote a on final assessments for participant who withdraw during 
Part A of this study. 
Added footnote b, to add reference to the added Schedule of Post-Treatment Follow-up 
Assessments – Part B in Table 6-2. 
Added text to footnote c (previously footnote b) to clarify that the laboratory results for 
eligibility confirmation (ie, at Baseline/Visit 2) will be the results from laboratory tests 
performed at the Screening Visit 1. 
Replaced the word ‘morning’ with ‘day’ in footnotes h and i (previous footnotes g and h) and 
updated all other footnote letters (after the addition of new footnote b). 


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Updated and clarified text on skin plaque biopsies in footnote k (previous footnote j) to 
match the added new Section 6.1.10 (as described separately further below).  
Updated ideal size for lesion area in footnote l (previous footnote k) to ‘ideally greater than 
2 cm by 2 cm’.  
Added text to clarify withholding emollients or moisturizers, at the end of footnote n 
(previous footnote m): Participants will be asked to withhold all emollients or 
moisturizers on the day of these study visits until all study assessments are completed. 
 


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Table 6-1 
Schedule of Assessments Study Site Activities – Part A 
Procedure 
Screening Baseline 
Treatment Period 
Follow-upa, b 
Day 
-28 to -7 
1 
8 
15 
22 
29 
43 
57 
85 
113 
141 
Week 
-4 
0 
1 
2 
3 
4 
6 
8 
12 
16 
20 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Visit window (days) 
-- 
-- 
5-11 
12-18 
19-25 
26-32 
40-46 
54-60 
82-88 
110-116 
134-148 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria  
X 
X cb 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
HbsAg, HCV and HIV screening 
X 
 
 
 
 
 
 
 
 
 
 
HLA sample dc 
 
X 
 
 
 
 
 
 
 
 
 
Medical history and current medical conditions 
(including duration of psoriasis) 
X 
X 
 
 
 
 
 
 
 
 
 
Full physical examination (height only at 
screening) ed 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
Pregnancy test fe 
X 
X 
 
 
 
 
 
 
 
X 
X 
Laboratory assessments (hematology, serum 
biochemistry and CRP, and urinalysis)  
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
Fasting gf blood sampling 
 
X 
 
 
 
 
 
X 
 
X 
 
12-lead ECG hg 
X 
X 
 
 
 
X 
 
 
 
X 
X 
Vital signs ih 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Dosing ji 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense study drug 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Collect/count unused study drug 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Skin plaque biopsies kj 
 
X 
 
 
 
 
 
 
 
X 
 


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Procedure 
Screening Baseline 
Treatment Period 
Follow-upa, b 
Day 
-28 to -7 
1 
8 
15 
22 
29 
43 
57 
85 
113 
141 
Week 
-4 
0 
1 
2 
3 
4 
6 
8 
12 
16 
20 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Visit window (days) 
-- 
-- 
5-11 
12-18 
19-25 
26-32 
40-46 
54-60 
82-88 
110-116 
134-148 
Digital photography of lesion sites lk 
 
X 
 
 
 
X 
 
X 
 
X 
X 
Stool samples for microbiome investigation ml 
 
X 
 
 
 
 
 
 
 
X 
X 
Dispense stool diary 
X 
 
 
 
 
 
 
 
 
 
 
Collect/record stool diary 
 
X 
 
 
 
 
 
 
 
 
 
Blood sample for detection of systemic EDP1815 
 
X 
 
 
 
 
 
 
 
X 
 
Samples for blood biomarkers  
 
X 
 
 
 
 
 
 
 
X 
 
BSA involvement (%), PGA, PASI nm, on 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
LSS, mNAPSI nm 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
PSI, DLQI, PA-VAS, SF-36 (vitality and pain), 
Fatigue po 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
AE/SAE review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense dosing diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Collect/review dosing diary qp 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
a 
Participants who withdraw from the study during Part Aearly should complete these final assessments listed under the Follow-up Visit (Week 20), at an 
unscheduled follow-up visit. Where relevant and when possible, this should be arranged within 72 hours of the start of a new psoriasis treatment. In 
the event of early withdrawal from the study, unused study drug is to be collected/counted at this visit.  
b 
All participants will attend additional follow-up Visits 12 and 13 (see Table 6-2), unless they are considered a ‘treatment failure’ or meet the criteria 
for rebound. 
cb 
Recheck inclusion/exclusion criteria at Baseline, before first dose of study drug. Screening laboratory results will be used to confirm eligibility at 
Baseline.  
dc 
Predose optional genetic samples. 


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ed 
BMI will be calculated from the height and weight. 
fe 
Women of child-bearing potential only. Serum HCG at screening, urine thereafter. Pregnancy testing will be performed at the visits indicated or if a 
menstrual cycle is missed or if pregnancy is otherwise suspected. 
gf 
Participants will fast for at least 8 hours before glucose and lipid blood sampling  
hg 
A single ECG tracing is to be obtained on the morningday of the visit. If, in the opinion of the investigator, there appear to be clinically significant findings, 
a second tracing should be obtained during the visit. 
ih 
Blood pressure, pulse, respiratory rate, and temperature are to be checked on the morningday of the visit. 
ji 
The first dose will be given at the baseline visit, following random assignment to treatment. Subsequent doses are to be taken (away from the study site) once 
daily in the morning at approximately the same time ±2 hours. Participants should refrain from consuming acidic drinks 1 hour either side of dosing and 
from eating 2 hours before dosing and 1 hour after dosing. On days of study site visits during the treatment period (Visit 3 through Visit 10, inclusive), 
participants may dose at home.  
kj 
Skin plaque biopsies (ie, a 4 mm punch biopsy, performed pre-dose by a suitably trained study personnel and processed as per laboratory manual) 
are to be performed after all other assessments have been completed at the end of Visits 2 and 10. are to be taken after all other assessments at visit 
have been completed in participating participants. A 7 day window is allowed at baseline and a +7 day window at Week 16 to accommodate availability of 
the dermatologist. 
lk 
Digital photographs should be taken of up to 6 lesion sites that have a lesion area ideally greater than ≥2 cm by× 2 cm at baseline. The same locations 
photographed at baseline should be followed throughout the study for each participant. 
ml 
Stool samples are to be collected within the 48 hours preceding each visit of stool sample collection.  
nm Investigator rating scales. Participants will be asked to withhold all emollients or moisturizers on the day of these study visits until all study 
assessments are completed. 
on 
Inclusion criterion #4 (mild to moderate plaque psoriasis with plaque covering BSA of ≥3% and ≤10%, PASI score of ≥6 and ≤15, and PGA score of 2 or 3) 
should be reconfirmed at the baseline visit prior to randomization. 
po 
Participant-reported assessments. 
qp 
Study staff will review the dosing diaries with participants at each visit when diaries are collected. Diaries will be reviewed for completeness and accuracy, 
and participants will be coached as needed on compliance with the protocol. 


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Table 6-2    Schedule of Post-Treatment Follow-Up Assessments – Part B 
Table 6-2 was added in its entirety: 
Table 6-2 
Schedule of Post-Treatment Follow-Up Assessments – Part B  
Procedure 
Post-Treatment Follow-Up – Part B a 
Visit number 
12 b 
13 b 
14 c 
Early  
Withdrawal 
Visit a 
Months (after the End of Treatment) 
2 
3 
6 
Weeks 
24 
28 
40 
Day 
169 
197 
218 
– 
Visit window (days) 
162-176 
190-204 
204-232 
– 
BSA involvement (%), PGA, PASI d 
X 
X 
X 
X 
LSS, mNAPSI d 
X 
X 
X 
X 
PSI, DLQI e  
X 
X 
X 
X 
Concomitant medication review  
X 
X 
X 
X 
a 
Participants who withdraw from the study during Part B should complete the final assessments at the Early 
Withdrawal Visit (where relevant and when possible, this should be arranged within 72 hours of the start of 
a new psoriasis treatment).  
b 
All participants will attend Visits 12 and 13, unless they are considered a ‘treatment failure’ or meet the 
criteria for rebound. 
c 
Only participants who are classified as responders at Week 16 (Visit 10) and have not relapsed at Week 28 
(Visit 13) will be eligible for Visit 14 (Week 40). 
d 
Investigator rating scales. Participants will be asked to withhold all emollients or moisturizers on the day of 
study visits until all study assessments are completed.  
e 
Participant-reported assessments. 
 
During the screening period, participants will be advised to monitor their psoriasis symptoms 
and remain on a stable regimen of topical emollients and low-dose topical corticosteroid 
medications (if they are already taking any). Participants will be asked to withhold the 
application of any emollients or moisturizers on the day of any site visit until after all 
the study assessments have been performed. As part of the screening, PASI, BSA 
involvement, and PGA scores will be measured (inclusion criterion #4, Section 4.1.1). 
 


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Section 6.1.1 Psoriasis Area and Severity Index Score 
The PASI score will be assessed as described by Langley and Ellis (2004). The PASI is a 
physician assessment that combines the assessment of the severity of and area affected by 
psoriasis into a single score in the range 0 (no disease) to 72 (maximal disease). The absolute 
PASI score in this study is used as part of inclusion criterion #4. The PASI percentage 
response rates are efficacy endpoints (ie, PASI-50, PASI-75, PASI-90, and PASI-100). For 
example, the percentage of participants who achieve a 75% or greater reduction in PASI 
score from baseline is represented by the PASI-75 value. Details of the PASI assessment will 
be provided in the relevant training material. study manual  
The below Response Definitions were added in their entirety: 
Response Definitions based on PASI score at Week 16: 
• Responders: Participants on treatment achieving PASI-50 or greater at week 16 visit 
• Relapse: Increase in PASI score to baseline value or greater, or participant begins a 
new treatment for psoriasis 
• Partial Relapse: Loss of PASI-50 response after cessation of study treatment 
• Rebound: Increase in PASI score to 125% of baseline value or above, or onset of 
new pustular/erythrodermic psoriasis within 3 months of cessation of study treatment 
• Duration of remission: Time from first achievement of PASI-100 to loss of 
PASI-100 
• Duration of treatment success: Time from first achievement of PASI-50 to loss of 
PASI-50 
• Duration of therapeutic effect: Time from cessation of study treatment until 
increase of PASI to 50% of maximum improvement from baseline 
 


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Section 6.1.4    Percent of Body Surface Area Involvement 
First paragraph: 
The percent of BSA involvement will be estimated for each participant, where 1% is 
approximately the area of the participant’s handprint (Walsh et al 2013). Details of the BSA 
assessment will be provided in the relevant training materialstudy manual. 
 
Section 6.1.5    Modified Nail Psoriasis Severity Index 
First paragraph: 
The mNAPSI is a numeric, reproducible, objective, and simple tool for physicians to evaluate 
the severity of nail bed psoriasis and nail matrix psoriasis by area of involvement in the nail 
unit (Cassell et al 2007). Details of conducting the mNAPSI will be provided in the relevant 
training materialstudy manual. 
 
Section 6.1.6, 6.1.8, and 6.1.9 
Deleted the last sentence in all three subsections 
 
Section 6.1.7    Psoriasis Symptom Inventory 
The PSI is a patient reported outcomes instrument that is used to assess the severity of plaque 
psoriasis symptoms (Bushnell et al 2013). All symptoms (itch, redness, scaling, burning, 
cracking, stinging, flaking, and pain) are rated on a 5-point severity scale. The PSI 
demonstrated good construct validity and was sensitive to within-subject change (p<0.0001). 
Details of administering the PSI will be provided in the specific user manualstudy manual. 
 


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Section 6.1.10    Biopsy of Skin Plaque (this subsection was added in its entirety) 
Skin plaque biopsies (ie, a 4 mm punch biopsy, performed pre-dose by a suitably 
trained study personnel and processed as per laboratory manual) are to be performed 
after all other assessments have been completed at the end of Visits 2 and 10.  
 
Section 6.2.1.2    Eliciting and Documenting Adverse Events 
Adverse events will be reported from the date of signed informed consent and through for 
28 days after the cessation of dosing. Adverse events occurring after the 28 days post-
treatment would only be reported if the investigator considers it to be related to the 
study treatment.through the final follow up visit. 
 
Section 6.2.1.3    Reporting Adverse Events 
Added the following two bullets: 
• Investigator-specific assessment if the AE is related to a recent/current COVID 
infection 
• If a COVID positive PCR test received within last 14 days 
 
Section 6.4 Laboratory Analyses 
Last paragraph 
All protocol-required laboratory assessments, as defined in this section, must be conducted in 
accordance with the laboratory manual and the SoA (Table 6-1). Screening laboratory 
results will be used to confirm eligibility at Baseline (Visit 2). 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 


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investigator (eg, SAE or AE or dose modification), then the results must be recorded in the 
eCRF. 
 
Section 6.4.3   Pharmacodynamics and Biomarkers 
Procedures for sample collection, processing, storage, and shipment will be detailed in the 
study specific laboratory manual. Biomarkers are exploratory endpoints and analytical 
results for biomarkers will not be included in the CSR. They will be reported separately from 
the CSR.  
Digital photographs should be taken of up to 6 lesion sites that have a lesion area ideally 
greater than ≥2 cm by × 2 cm at baseline. The same locations photographed at baseline 
should be followed throughout the study for each participant. Procedural details for digital 
photography will be provided in the specific user manualstudy manual.  
 
Section 6.4.3.1   Histologic Assessment 
A 4 mm punch biopsy will be taken by suitably trained study personnel (see Section 
6.1.10). Standard histology will be performed on skin plaque biopsies (including epidermal 
thickness, basal mitotic counts and immune cell infiltrates, immunohistochemistry) from 
approximately 15 participants in each cohort. Details will be provided in the study specific 
laboratory manual. The histologic evaluations are exploratory and are outside the scope of 
the CSR.  
 
Section 7   Statistical Considerations 
Added as last paragraph: 
The primary analysis for the study will occur after all participants have completed 4 
weeks of follow-up after their last dose of study medication (end of Part A). The final 
analysis for the study will occur when all participants have completed the required 
relapse and rebound follow-up period of up to 24 weeks post-treatment (end of Part B). 


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Section 7.1.1    Primary Efficacy Estimand 
Added after first paragraph: 
For the primary analysis, 3 2 supportive estimands will also be considered: 
• To assess the impact of intercurrent events related to protocol deviations believed to 
impact efficacy, a supportive analysis will be performed where all data collected after 
any such identified protocol deviations will be excluded. Participants who had a 
protocol deviation believed to impact efficacy prior to the first dose of treatment 
(hypothetical strategy based on adherence to treatment and the aspects of the protocol 
which impact efficacy) will be completely excluded from this analysis. 
• To assess the impact of treatment discontinuation for any reason, a supportive 
analysis will be performed in which all data collected during up to the studyend of 
Week 16, including any data collected after treatment discontinuation will be 
included (treatment policy strategy).  
• To assess the impact of treatment discontinuation due to a requirement for 
alternative therapy, a supportive analysis will be performed where the highest 
PASI score recorded prior to treatment discontinuation will be applied to all 
expected visits after treatment discontinuation up to Week 16.  
The primary analysis will be performed using a Bayesian MMRM as fully described in 
Section 7.6.1. Data from visits prior to Week 16 will be included in the model and missing 
data will not be explicitly imputed.  
Supportive analyses will also be performed in the same manner, using the 2 alternative 
3 supportive estimands as defined above. These will explore the possible impact of the 
intercurrent events of treatment discontinuation for any reason, treatment discontinuation 
due to requirement for alternative treatment, and events relating to protocol deviations 
that may have an impact on efficacy. 
 


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Table 7-1    Summary of Secondary Estimands 
Added the following 3 rows as last rows of this table: 
Population of 
interest 
Endpoint 
Consideration of 
intercurrent events 
Summary measure 
 
 
 
 
mITT set 
Mean absolute change 
from baseline in mNAPSI 
total score at Weeks 4, 8, 
12, and 16 
To include all data 
collected prior to treatment 
discontinuation, regardless 
of protocol deviations 
Posterior mean difference 
between each active dose and 
pooled placebo at each visit 
Week 16 
responders set 
Cumulative incidence of 
partial relapse at 
Weeks 20, 24, 28, and 40 
To include all data 
collected after treatment 
discontinuation 
Proportion of participants to 
relapse in each treatment 
group at each visit 
Week 16 
responders set 
Cumulative incidence of 
complete relapse at 
Weeks 20, 24, 28 and 40 
To include all data 
collected after treatment 
discontinuation 
Proportion of participants to 
relapse in each treatment 
group at each visit 
mITT set  
Cumulative incidence of 
rebound at Weeks 20, 24, 
28 and 40 
To include all data 
collected after treatment 
discontinuation 
Proportion of participants to 
rebound in each treatment 
group at each visit 
 
Section 7.2    Exploratory Endpoints 
The exploratory endpoints include the following: 
• Percentage of participants achieving PASI-50, PASI-75, PASI-90, and PASI-100 at 
Weeks 4, 8, and 12  
• Percentage of participants achieving PGA of 0 or 1 with a ≥2-point improvement at 
Weeks 4, 8, and 12  
• Percentage of participants achieving PGA of 0 at Weeks 4, 8, and 12  
• Mean change from baseline in PSI quality of life total and itch scores at Weeks 12 
and 16 
• Mean percentage change from baseline in PSI quality of life total and itch scores at 
Weeks 12 and 16 
• Mean change from baseline in Pain and Fatigue scores at Weeks 4, 8, 12, and 16 


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• Mean percentage change from baseline in Pain and Fatigue scores at Weeks 4, 8, 12, 
and 16 
• Mean change from baseline in fasting blood glucose and fasting lipid panel at 
Weeks 8 and 16 
• Mean duration of remission in participants who achieve PASI-100 
• Mean duration of treatment success in participants who achieve PASI-50 
• Mean duration of therapeutic response in participants after cessation of study 
treatment 
 
Section 7.4    Analysis Sets 
Added definition for Week 16 Responders Set after PPS definition: 
Week 16 responders set: The Week 16 responders set will consist of all mITT 
participants who achieved a PASI-50 response at Week 16. 
 
Table 7-2    Deviations with a Potential Impact on Efficacy 
Description 
Evaluation Period 
Impact on PPS analyses 
Not meeting inclusion 
criteria 3, 4, or 6 or 
meeting any of exclusion 
criteria 1-12 or 27  
Baseline 
Exclude participant from PPS. 
Use of any prohibited 
medication 
(Section 5.8.2.1) 
Throughout study 
If start date of prohibited medication ≤ date of first dose 
of study drug then exclude participant from PPS. 
Otherwise, include participant in PPS but exclude all 
data collected on or after start date of prohibited 
medication. 


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Description 
Evaluation Period 
Impact on PPS analyses 
Compliance with study 
drug <80%  
Evaluated in 
48-week periods 
(Weeks 1-8,4, 5 8, 
9 12and 13 9-16) 
If participant is non-compliant within Week 1-84 
treatment period, then exclude from PPS. 
If participant is non-compliant only within 
Week 9-16 treatment periodOtherwise, include 
participant in PPS but exclude all data collected after the 
Week 8 visit date.  start of the first non compliant 4
week period. 
The 4 weekly treatment periods will be defined by the 
occurrence of the Week 4, 8, 12, and 16 visits (eg, Week 
5 8 compliance will look at compliance from the day 
after the Week 4 visit to the day of the). If visits are 
missed completely without withdrawal from the study, 
then the visit date will be approximated using the middle 
of the neighboring attended visits. 
More than 7 consecutive 
days with no study 
medication without 
participant being 
permanently withdrawn 
from study medication  
Throughout study 
Participant will not be excluded from PPS, but all 
data collected after the 8th consecutive day with no 
study medication will be excluded. 
More than 14 total days 
with no study 
medication (does not 
need to be continuous)  
Throughout study 
Exclude participant from PPS. 
 
Section 7.5    Description of Subgroups to be Analyzed 
No subgroup analyses are planned, but Results may be summarized by individual cohort.  
Subgroup analysis of the primary estimand will be performed based on the following 
subgroups: 
• Baseline PASI score (<10, ≥10) 
• Baseline PGA score (2, 3) 
• Baseline BMI (<30kg/m2, ≥30kg/m2) 
 


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Section 7.6.1    Analysis of Primary Efficacy Endpoint 
First paragraphs: 
The assumption that the 3 cohorts of placebo participants can be pooled into a single placebo 
group to be used as a control for all active doses will be examined using mean (±SD) plots 
and box plots of percent change in PASI score against time. In addition, a mixed model for 
repeated measures (MMRM) will be used to compare the 3 cohorts of placebo 
participants. The model will include parameters for cohort, visit and baseline PASI 
score together with cohort*visit and baseline PASI score*visit interactions. LS mean 
(95% CI) estimates for each placebo cohort will be plotted by visit. 
A decision will be made by the Evelo study team, based on examination of the above 
figures and model, on whether the pooling strategy is appropriate.  
The primary analysis will be performed using a Bayesian MMRM. The model will include 
parameters for treatment*visit and baseline PASI score*visit interactions. Body mass index, 
gender, country, and time since diagnosisother baseline covariates will also be considered 
and included as parameters if found to be significant (p<0.05). The model will not include an 
intercept. Visit will consist of 6 levels (Weeks 1, 2, 4, 8, 12, and 16) and treatment will 
consist of 4 levels (pooled placebo, EDP1815 0.8 × 1011 cells, EDP1815 3.2 × 1011 cells, and 
EDP1815 8.0 × 1011 cells) if the placebo pooling strategy is considered appropriate or 
6 levels (Placebo matching EDP1815 0.8 × 1011 cells, Placebo matching EDP1815 3.2 × 1011 
cells, Placebo matching EDP1815 8.0 × 1011 cells, EDP1815 0.8 × 1011 cells, EDP1815 
3.2 × 1011 cells, and EDP1815 8.0 × 1011 cells) if the placebo pooling strategy is not 
considered appropriate. 
Five paragraphs without changes 
This primary analysis will be repeated using the 2 3 supportive estimands defined in 
Section 7.1.1. 
Deleted the following paragraph: 
A further sensitivity analysis will be performed on the model with the primary estimand, in 
which participants who withdrew from study drug due to treatment failure (demonstrated by 
the participant commencing an oral agent, biological, or intermediate or high potency topical 


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therapy for plaque psoriasis) will have their percentage change from PASI imputed at all 
visits after study drug was discontinued as the maximum on treatment value reached (ie, 
worst score carried forward). 
Added as last paragraph: 
All summaries and analyses defined above for the primary estimand will be repeated 
using the subgroups defined in Section 7.5. 
 
Section 7.6.2    Analysis of Secondary Efficacy Endpoint 
Second paragraph, last sentence: 
All p-values, posterior probabilities, CI, and CrI calculated will be considered as descriptive 
with no further adjustments for multiplicity performed. 
Added third paragraph: 
The covariates selected for the Bayesian MMRM analysis for the primary estimand will 
also be used in all other analytical models including covariates. 
Two paragraphs without changes 
From fifth paragraph to end of this section: 
For the PASI-50, a Bayesian generalized linear mixed effects model with a logit link function 
will be fitted using data from all visits. Treatment, visit, and baseline PASI score terms 
will be included in the model as fixed effects, together with treatment*visit and baseline 
PASI score*visit interactions, will be included in the model as fixed effects. Body mass 
index, gender, and other any baseline covariates selected in the primary analysis model for 
the primary estimand.will also be considered and fitted as fixed effects if found to be 
significant (p<0.05). Odds ratios and 95% HDP CrICIs for each active dose compared to 
placebo at each visit will be presented.  
A sensitivity supportive analysis for the PASI-50 will also be performed, in the same manner 
as described above, in which participants who withdraw from study drug before Week 16 due 


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to treatment failure requirement for alternative therapy will be included in the model with 
the PASI-50 endpoint imputed as ‘not achieved’ at all expected visits after study drug 
withdrawal. 
A sensitivity analysis will also be performed on the PASI-50. Bayesian logistic regression 
models will be individually fitted at each of Weeks 4, 8, 12, and 16. The model will 
include parameters for treatment and baseline PASI score together with any baseline 
covariates selected in the primary analysis model for the primary estimand. The 
posterior odds-ratios for each pairwise comparison of an active EDP1815 dose and 
placebo with associated 95% HDP CrI will be presented together with the posterior 
probability that the true odds ratio >1. 
Percentage of participants achieving PGA of 0 or 1 with a ≥2-point improvement and 
percentage of participants achieving a PGA of 0 will be analyzed in the same manner as 
described above for PASI-50 with the exception that the sensitivity analysis using the 
Bayesian logistic regression model will only be fitted on the Week 16 data. 
For the time to first achievement of PASI-50, a Bayesian Cox proportional hazards 
modelnonparametric survival analysis for interval censored data will be performedfitted 
with treatment and baseline PASI score as covariates. Hazard ratios and 95% HDP CrI for 
each active dose compared to placebo will be presented. The expectation-maximization 
iterative complex minorant (EMICM) method for iterative computation of the 
nonparametric maximum likelihood estimator for the survival function (Wellner and 
Zahn 1997) will be used. The number and proportion of participants who meet the 
PASI-50 at least once during the study will be presented. A generalized log-rank test will 
be used to compare each active dose with placebo and the p-value for treatment 
difference will also be presented. The estimated survival curves for each treatment 
group will also be presented. 
Cumulative incidence of partial relapse and complete relapse at Weeks 20, 24, 28, and 
40 will be summarized by treatment group on the Week 12 responders set. 
Cumulative incidence of rebound after cessation of study treatment at Weeks 20, 24, 28, 
and 40 will be summarized by treatment group. 
 


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Section 7.6.3    Analyses of Exploratory Efficacy Endpoints 
Added as last paragraph: 
A further exploratory analysis will be performed on the Week 16 results. Adjusted 
indirect comparisons, pivoted around placebo, will be performed against publicly 
available data from two studies in apremilast in mild/moderate or moderate psoriasis. 
Further details will be provided in the study SAP. 
 
Section 12    References 
Added the below 2 references in alphabetical order: 
European Medicines Agency. Guideline on clinical investigation of medicinal products 
indicated for the treatment of psoriasis. European Medicines Agency 
CHMP/EWP/2454/02 corr, 18 November 2004. 
Wellner JA, Yihui Z. A hybrid algorithm for computation of the nonparametric 
maximum likelihood estimator from censored data. J Am Stat Assoc. 1997;92(439):945-
59. 


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Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Phase 2, Multicenter, 
Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort, Dose-Ranging Study 
Investigating the Effect of EDP1815 in the Treatment of Mild to Moderate Plaque Psoriasis” 
and the accompanying investigator’s brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with Protocol Version 5.0, dated 17 November 2020, the International Council for 
Harmonisation harmonised tripartite guideline E6(R2): Good Clinical Practice and all 
applicable government regulations. I will not make changes to the protocol before consulting 
with Evelo Biosciences Inc. or implement protocol changes without independent ethics 
committee approval except to eliminate an immediate risk to participants. I agree to 
administer study treatment only to participants under my personal supervision or the 
supervision of a subinvestigator. 
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Participant identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Evelo Biosciences Inc. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 


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Table of Contents 
Title Page ........................................................................................................................... 1 
Protocol Approval – Signatories ........................................................................................ 2 
Protocol Amendment 1 – Summary of Major Changes ..................................................... 3 
Protocol Amendment 2 – Summary of Major Changes ..................................................... 4 
Protocol Amendment 3 – Summary of Major Changes ................................................... 14 
Protocol Amendment 3.1 Hungary Specific – Summary of Major Changes ................... 35 
Protocol Amendment 4 – Summary of Major Changes ................................................... 37 
Declaration of Investigator .............................................................................................. 62 
Table of Contents ............................................................................................................. 63 
List of Tables .................................................................................................................... 67 
List of Figures .................................................................................................................. 67 
Protocol Synopsis............................................................................................................. 68 
List of Abbreviations and Definitions of Terms ............................................................... 83 
1 
Introduction .............................................................................................................. 86 
2 
Study Objectives....................................................................................................... 89 
2.1 
Primary Objective ........................................................................................... 89 
2.2 
Secondary Objectives...................................................................................... 89 
2.3 
Exploratory Objectives ................................................................................... 89 
3 
Investigational Plan .................................................................................................. 91 
3.1 
Study Design ................................................................................................... 91 
3.1.1 
Rationale for Study Design .............................................................. 94 
4 
Participant Selection and Withdrawal Criteria ......................................................... 96 
4.1 
Selection of Study Population ......................................................................... 96 
4.1.1 
Inclusion Criteria ............................................................................. 96 
4.1.2 
Exclusion Criteria ............................................................................ 97 
4.2 
Discontinuation From Study Treatment and/or Withdrawal From the Study
 ............................................................................................................... 100 


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4.2.1 
Discontinuation From Study Treatment ......................................... 102 
4.2.2 
Withdrawal From the Study ........................................................... 102 
4.2.3 
Lost to Follow Up .......................................................................... 103 
4.2.4 
Replacements ................................................................................. 103 
5 
Study Treatments .................................................................................................... 104 
5.1 
Method of Assigning Participants to Treatment Groups ............................... 104 
5.2 
Treatments Administered .............................................................................. 104 
5.3 
Identity of Study Drug .................................................................................. 104 
5.4 
Management of Clinical Supplies ................................................................. 104 
5.4.1 
Study Drug Packaging and Storage ............................................... 104 
5.4.2 
Study Drug Accountability ............................................................ 105 
5.4.3 
Other Supplies................................................................................ 105 
5.5 
Overdose Management ................................................................................. 105 
5.6 
Blinding......................................................................................................... 106 
5.6.1 
Breaking the Blind ......................................................................... 107 
5.7 
Compliance With Study Treatment ............................................................... 107 
5.7.1 
Dosing Diaries ............................................................................... 108 
5.8 
Prior, Concomitant, and Rescue Medications ............................................... 109 
5.8.1 
Prior Therapy ................................................................................. 109 
5.8.2 
Concomitant Therapy .................................................................... 109 
5.8.2.1 
Prohibited Concomitant Therapy ................................................... 109 
5.8.3 
Rescue Medicine ............................................................................ 110 
5.9 
Dose Modification ........................................................................................ 110 
6 
Study Assessments and Procedures ........................................................................ 111 
6.1 
Efficacy Assessments .................................................................................... 116 
6.1.1 
Psoriasis Area and Severity Index Score ....................................... 116 
6.1.2 
Lesion Severity Score .................................................................... 117 
6.1.3 
Physician’s Global Assessment ...................................................... 117 
6.1.4 
Percent of Body Surface Area Involvement .................................. 117 
6.1.5 
Modified Nail Psoriasis Severity Index ......................................... 117 
6.1.6 
Dermatology Life Quality Index.................................................... 117 
6.1.7 
Psoriasis Symptom Inventory ........................................................ 118 
6.1.8 
Pain ................................................................................................ 118 


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6.1.9 
Fatigue ........................................................................................... 118 
6.1.10 
Biopsy of Skin Plaque.................................................................... 118 
6.2 
Safety and Tolerability Assessments ............................................................. 118 
6.2.1 
Adverse Events .............................................................................. 118 
6.2.1.1 
Definitions ..................................................................................... 118 
6.2.1.2 
Eliciting and Documenting Adverse Events .................................. 120 
6.2.1.3 
Reporting Adverse Events ............................................................. 121 
6.2.1.4 
Follow-Up of Participants Reporting Adverse Events ................... 124 
6.2.2 
Bristol Stool Form Scale ................................................................ 124 
6.2.3 
Physical Examinations ................................................................... 124 
6.2.4 
Vital Signs ...................................................................................... 125 
6.2.5 
Electrocardiograms ........................................................................ 125 
6.3 
Pregnancy ...................................................................................................... 125 
6.4 
Laboratory Analyses ..................................................................................... 126 
6.4.1 
Blood Volume ................................................................................ 128 
6.4.2 
Pharmacokinetics ........................................................................... 128 
6.4.3 
Pharmacodynamics and Biomarkers .............................................. 128 
6.4.3.1 
Histologic Assessment ................................................................... 128 
6.4.3.2 
mRNA Transcription Analysis ....................................................... 129 
6.4.3.3 
Blood Cytokine and Chemokine Analysis ..................................... 129 
6.4.3.4 
Analysis of Fecal Microbiome ....................................................... 129 
7 
Statistical Considerations ....................................................................................... 130 
7.1 
Estimands and Intercurrent Events ............................................................... 130 
7.1.1 
Primary Efficacy Estimand ............................................................ 130 
7.1.2 
Secondary Efficacy Estimands ...................................................... 131 
7.2 
Exploratory Endpoints .................................................................................. 133 
7.3 
Sample Size Determination........................................................................... 134 
7.4 
Analysis Sets ................................................................................................. 135 
7.5 
Description of Subgroups to Be Analyzed .................................................... 137 
7.6 
Statistical Analysis Methodology ................................................................. 138 
7.6.1 
Analysis of Primary Efficacy Endpoint ......................................... 138 
7.6.2 
Analysis of Secondary Efficacy Endpoints ................................... 141 
7.6.3 
Analyses of Exploratory Efficacy Endpoints ................................. 143 


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7.6.4 
Pharmacokinetic Analyses ............................................................. 143 
7.6.5 
Safety Analyses .............................................................................. 144 
7.6.6 
Other Analyses ............................................................................... 144 
7.6.7 
Interim Analyses ............................................................................ 144 
8 
Data Quality Assurance .......................................................................................... 146 
8.1 
Data Management ......................................................................................... 146 
9 
Ethics ...................................................................................................................... 148 
9.1 
Independent Ethics Committee or Institutional Review Board .................... 148 
9.2 
Ethical Conduct of the Study ........................................................................ 148 
9.3 
Participant Information and Consent ............................................................ 148 
10 Investigator’s Obligations ...................................................................................... 150 
10.1 Confidentiality .............................................................................................. 150 
10.2 Financial Disclosure and Obligations ........................................................... 150 
10.3 Investigator Documentation .......................................................................... 150 
10.4 Study Conduct ............................................................................................... 151 
10.5 Adverse Events and Study Report Requirements ......................................... 151 
10.6 Investigator’s Final Report ........................................................................... 151 
10.7 Records Retention ......................................................................................... 151 
10.8 Publications and Results Disclosures............................................................ 151 
11 Study Management ................................................................................................. 153 
11.1 Monitoring .................................................................................................... 154 
11.1.1 
Safety Review Committee ............................................................. 154 
11.1.2 
Monitoring of the Study ................................................................. 154 
11.1.3 
Inspection of Records .................................................................... 154 
11.2 Management of Protocol Amendments and Deviations................................ 154 
11.2.1 
Modification of the Protocol .......................................................... 154 
11.2.2 
Protocol Deviations........................................................................ 155 
11.3 Study Termination ......................................................................................... 155 
11.3.1 
Study Halting Criteria .................................................................... 156 
11.4 Final Report .................................................................................................. 156 
12 References .............................................................................................................. 157 


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13 Appendices ............................................................................................................. 160 
13.1 Appendix: Contraceptive Guidance and Collection of Pregnancy Information
 ............................................................................................................... 160 
13.2 Appendix: World Health Organization Classification of Topical 
Corticosteroids ...................................................................................... 164 
 
List of Tables 
Table 6-1 
Schedule of Assessments – Part A .................................................................112 
Table 6-2 
Schedule of Post-Treatment Follow-Up Assessments – Part B .....................115 
Table 7-1 
Summary of Secondary Estimands ............................................................... 132 
Table 7-2 
Deviations with a Potential Impact on Efficacy ........................................... 137 
Table 11-1 
Study Administration .................................................................................... 153 
Table 13-1 
Highly Effective Contraceptive Methods ..................................................... 161 
 
List of Figures 
Figure 3-1 
Study Design ................................................................................................... 93 


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Protocol Synopsis 
Protocol Number: 
EDP1815-201 
Title: 
A Phase 2, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Parallel-Cohort, Dose-Ranging Study 
Investigating the Effect of EDP1815 in the Treatment of Mild to 
Moderate Plaque Psoriasis 
Sponsor: 
Evelo Biosciences Inc. 
620 Memorial Drive, Suite 500 
Cambridge, MA 02139 
USA 
Study Phase: 
Phase 2 
Study Sites: 
Multiple countries, including (but not limited to) sites in the United 
States, the United Kingdom, Poland, and Hungary.  
Indication: 
Treatment of mild to moderate plaque psoriasis 
Rationale: 
Evelo Biosciences Inc. (Evelo) is developing medicines based on 
single strains of bacteria as a new class of therapeutic agents. These 
therapeutic agents are human commensal organisms that offer the 
potential of systemic immune system modulation following oral 
administration, without systemic exposure. EDP1815 is a 
pharmaceutical preparation of a strain of Prevotella histicola isolated 
from a human duodenal biopsy: it has not been genetically modified.  
Studies of EDP1815 in vitro in a range of human and mouse assays 
and studies in vivo in model symptoms support the use of EDP1815 
in the treatment of inflammatory diseases including psoriasis.  
Oral administration of EDP1815 to mice results in striking 
pharmacodynamic effects on animal models of delayed-type 
hypersensitivity, fluorescein isothiocyanate cutaneous 
hypersensitivity, collagen-induced arthritis and experimental acute 
encephalomyelitis. The high degree of consistency of both effect and 
dose suggests the potential for clinical benefit across multiple type 1, 
type 2, and type 3 inflammatory conditions. No potentially related 
adverse effects were seen in the animals used in these experiments 
with daily dosing for up to 3 weeks or with alternate day dosing for 
over 7 weeks. Immunophenotyping ex vivo in these models shows 
increased regulatory T cell numbers and regulatory dendritic cells in 
spleen and mesenteric lymph nodes, as well as decreases in 
pro-inflammatory cytokines such as IL-23p40, IL-17, TNFα, IL-6, 
and IL-13. Treatment also led to enhancement of gut intestinal 
barrier integrity, which is often disrupted in patients with 
inflammatory diseases. These effects on immune parameters have 


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been observed both within and outside the GI tract, which 
demonstrates that host-microbe interactions in the gut can affect the 
immune response in peripheral tissues. 
Psoriasis is a chronic immune-mediated type 1/3 inflammatory skin 
disease in which hyperactive T cells trigger excessive keratinocyte 
proliferation. This results in the formation of raised erythematous 
plaques with scaling. Psoriatic lesions can appear anywhere on the 
body but are most often seen on the knees, elbows, scalp, and 
lumbar area. Critical events in the inflammatory process include 
activation of Langerhans cells and T cells, selective trafficking of 
activated T cells to the skin, and induction of an inflammatory 
cytokine and chemokine cascade in skin lesions. Clinical data have 
validated the role of anti-TNFα, anti-IL-17, and anti-IL-23 therapy 
in moderate to severe psoriasis. For patients with mild to moderate 
psoriasis, therapy usually involves topical agents (topical 
corticosteroids, vitamin D3 analogs), with topical corticosteroids 
providing the greatest range of efficacy and a wide range of 
formulations. More recently, physicians are prescribing apremilast, a 
first-in-class oral PDE4 inhibitor, ahead of biological therapy, which 
includes etanercept, infliximab, adalimumab, ustekinumab, and 
secukinumab. 
In Evelo study EDP1815-101, a total of 56 participants have 
participated in Cohorts 1-4, with 36 of these participants receiving 
EDP1815 once daily; 16 of these were treated for 14 days (healthy 
volunteers) and 20 participants with psoriasis were treated for 
28 days. Clinical responses, similar to apremilast and tofacitinib at 
the same time point, have been observed on the (psoriatic) LSS and 
PASI at Day 28. Furthermore, at the Day 42 follow-up visit, when 
participants were “off treatment” for 14 days, there was continued 
improvement in the pharmacodynamic response as measured by both 
LSS and PASI for participants administered the higher dose, but not 
the lower dose, suggesting a dose relationship on the durability of 
effect. The safety profile of EDP1815 was similar to placebo, with 
no SAEs or AEs of severe intensity.  
The evidence available so far suggests EDP1815 is very well 
tolerated and it continues to undergo clinical development in mild to 
moderate psoriasis. A well-tolerated oral therapy could offer 
significant benefit in the treatment of psoriasis and it is presently 
anticipated that EDP1815 would be used in established but early 
disease, before the use of biologic therapies.  
This Phase 2 study has been designed to investigate the clinical 
safety and efficacy of EDP1815 and to identify an optimal dose.  


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Objectives: 
Primary Objective: 
The primary objective of this study is to evaluate the safety and 
efficacy of 3 different doses of EDP1815 for the treatment of 
psoriasis following daily dosing for 16 weeks. 
Secondary Objectives: 
The secondary objectives of this study are the following: 
• To evaluate the efficacy dose response of EDP1815 at 
Week 16 
• To evaluate the maximal clinical benefit of EDP1815 at 
Week 16 
• To evaluate the optimal dose of EDP1815 based on efficacy 
and safety up to Week 16 
• To evaluate the safety and tolerability of EDP1815 (all dose 
levels) throughout the study 
• To evaluate relapse and rebound of plaque psoriasis after 
cessation of EDP1815  
Exploratory Objectives: 
The exploratory objectives of this study are the following: 
• To evaluate the time to onset of clinical response to 
EDP1815  
• To evaluate the effect of EDP1815 treatment on 
patient-reported outcomes including quality of life and pain 
• To evaluate the duration of remission, treatment success, and 
therapeutic effect of EDP1815  
• To evaluate the effect of EDP1815 treatment on biomarkers 
in blood 
• To evaluate the effect of EDP1815 treatment on biomarkers 
in skin plaques 
• To evaluate the effect of EDP1815 treatment on fecal 
microbiome composition 
Estimands: 
Primary Estimands 
The primary estimand will be the effect of EDP1815 on the percent 
change in PASI score from baseline to Week 16 in the mITT set of 
all treated participants, regardless of deviations from the protocol. 
Only data collected while on treatment will be used to account for 
the intercurrent event of treatment discontinuation (hypothetical 
strategy based on adherence to treatment only). The posterior mean 
difference between each active dose and the pooled placebo will be 
estimated. 


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For the primary analysis, 3 supportive estimands will also be 
considered: 
• To assess the impact of intercurrent events related to protocol 
deviations believed to impact efficacy, a supportive analysis 
will be performed where all data collected after any such 
identified protocol deviations will be excluded. Participants 
who had a protocol deviation believed to impact efficacy 
prior to the first dose of treatment (hypothetical strategy 
based on adherence to treatment and the aspects of the 
protocol which impact efficacy) will be completely excluded 
from this analysis. 
• To assess the impact of treatment discontinuation for any 
reason, a supportive analysis will be performed in which all 
data collected up to the end of Week 16, including any data 
collected after treatment discontinuation will be included 
(treatment policy strategy). 
• To assess the impact of treatment discontinuation due to a 
requirement for alternative therapy, a supportive analysis will 
be performed where the highest PASI score recorded prior to 
treatment discontinuation will be applied to all expected 
visits after treatment discontinuation up to Week 16. 
 
The primary analysis will be performed using a Bayesian MMRM. 
Data from visits prior to Week 16 will be included in the model and 
missing data will not be explicitly imputed. 
Supportive analyses will also be performed in the same manner, 
using the 3 supportive estimands as defined above. These will 
explore the possible impact of the intercurrent events of treatment 
discontinuation for any reason, treatment discontinuation due to 
requirement for alternative treatment, and events relating to protocol 
deviations that may have an impact on efficacy. 
Summary of Secondary Estimands: 
For all secondary estimands, the population of interest will be the 
mITT set, except for the two endpoints, which are based on the 
Week 16 responders analysis set.  
Endpoint 
Consideration of 
intercurrent events 
Summary measure 
Mean percentage change 
from baseline in PASI 
Score at Weeks 4, 8, and 
12 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior mean difference 
between each active 
treatment group and pooled 
placebo at each visit 


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Mean absolute change 
from baseline in PASI 
Score at Weeks 4, 8, 12, 
and 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior mean difference 
between each active 
treatment group and pooled 
placebo at each visit 
Achievement of PASI-50 
at Weeks 4, 8, 12, and 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior odds ratio for 
response between each 
active treatment group and 
pooled placebo at each visit 
Time to first achievement 
of PASI-50 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Hazard ratio for each active 
group versus placebo 
Achievement of PASI-75, 
PASI-90 and PASI-100 at 
Week 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Proportion of response for 
each endpoint  
in each treatment group at 
each visit 
Achievement of PGA of 0 
or 1 with a ≥2-point 
improvement from 
baseline at Week 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior odds ratio for 
response between each 
active treatment group and 
pooled placebo  
Achievement of PGA of 0 
at Week 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior odds ratio for 
response between each 
active treatment group and 
pooled placebo  
Mean percentage change 
from baseline in 
PGA×BSA at Weeks 4, 8, 
12, and 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior mean difference 
between each active 
treatment group and pooled  
placebo at each visit 
Mean absolute change 
from baseline in 
PGA×BSA at Weeks 4, 8, 
12, and 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior mean difference 
between each active 
treatment group and pooled 
placebo at each visit 
Mean percentage change 
from baseline in LSS at 
Weeks 4, 8, 12, and 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior mean difference 
between each active dose 
and pooled placebo at each 
visit 
Mean absolute change 
from baseline in LSS at 
Weeks 4, 8, 12, and 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior mean difference 
between each active dose 
and pooled placebo at each 
visit 
Mean percentage change 
from baseline in DLQI 
score at Weeks 4, 8, 12, 
and 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior mean difference 
between each active dose 
and pooled placebo at each 
visit 
Mean absolute change 
from baseline in DLQI 
score at Weeks 4, 8, 12, 
and 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior mean difference 
between each active dose 
and pooled placebo at each 
visit 
Mean percentage change 
from baseline in mNAPSI 
To include all data collected 
prior to treatment 
Posterior mean difference 
between each active dose 


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total score at Weeks 4, 8, 
12, and 16 
discontinuation, regardless of 
protocol deviations 
and pooled placebo at each 
visit 
Mean absolute change 
from baseline in mNAPSI 
total score at Weeks 4, 8, 
12, and 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior mean difference 
between each active dose 
and pooled placebo at each 
visit 
Week 16 responders set: 
 
Cumulative incidence of 
partial relapse at Weeks 
20, 24, 28, and 40 
To include all data collected 
after treatment 
discontinuation 
Proportion of participants 
to relapse in each treatment 
group at each visit 
Week 16 responders set: 
 
Cumulative incidence of 
complete relapse at 
Weeks 20, 24, 28, and 40 
To include all data collected 
after treatment 
discontinuation 
Proportion of participants 
to relapse in each treatment 
group at each visit 
Cumulative incidence of 
rebound at Weeks 20, 24, 
28, and 40 
To include all data collected 
after treatment 
discontinuation 
Proportion of participants 
to rebound in each 
treatment group at each 
visit 
Study Population: 
Inclusion Criteria 
Each participant must meet all the following criteria to be enrolled in 
this study: 
1. Give written informed consent (signed and dated) and any 
authorizations required by local law and be able to comply 
with all study requirements. 
2. Males or females ≥18 and ≤70 years old at the time of 
informed consent. 
3. A documented diagnosis of plaque psoriasis for ≥6 months. 
4. Have mild to moderate plaque psoriasis with plaque covering 
BSA of ≥3% and ≤10% and meet both of the following 
additional criteria:  
a. PASI score of ≥6 and ≤15, and  
b. PGA score of 2 or 3.  
 
All parameters in this criterion should be reconfirmed at 
baseline visit prior to randomization. 
5. Meet the following contraception criteria:  
a. Male participants: 
i. A male participant must agree to use 
contraception as detailed in Appendix 13.1 of 
this protocol during their participation in this 
study and for a period of 90 days after the last 


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dose and refrain from donating sperm during 
this period. 
b. Female participants:  
i. A female participant is eligible to participate 
if she is not pregnant (Appendix 13.1), not 
breastfeeding, and at least 1 of the following 
conditions applies: 
1. Not a WOCBP as defined in 
Appendix 13.1, OR 
2. A WOCBP who agrees to follow the 
contraceptive guidance in 
Appendix 13.1 during their 
participation in this study, 28 days 
prior to the first dose and for at least 
1 complete menstrual cycle (≥28 days) 
after the last dose. 
6. Agrees to not increase their usual sun exposure during the 
study. 
Exclusion Criteria 
Participants meeting any of the following criteria will be excluded 
from the study: 
1. Have received EDP1815 within the 3 months prior to 
screening. 
2. Have a diagnosis of non-plaque psoriasis. 
3. Plaque psoriasis restricted to scalp, palms and soles only.  
4. Evidence of skin conditions that would interfere with 
psoriasis evaluation or treatment response (eg, atopic 
dermatitis, fungal or bacterial superinfection).  
5. Having received systemic immunosuppressive therapy (MTX, 
apremilast, azathioprine, cyclosporine, 6-thioguanine, 
mercaptopurine, mycophenolate mofetil, hydroxyurea, and 
tacrolimus) within 4 weeks of first administration of study 
drug.  
6. Unresponsive to prior use of biologics (including, but not 
limited to, TNFα inhibitors, natalizumab, efalizumab, 
anakinra or agents that modulate B cells or T cells). 
7. If prior biologic therapy and responsive, participants must 
have been off therapy for at least 12 months prior to first 
administration of study drug. 


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8. Has received phototherapy or any systemic 
medications/treatments that could affect psoriasis or PGA 
evaluation (including, but not limited to oral or injectable 
corticosteroids, retinoids, psoralens, sulfasalazine, 
hydroxyurea, or fumaric acid derivatives) within 4 weeks of 
first administration of study drug. This includes therapeutic 
doses of non-steroidal anti-inflammatory drugs such as 
ibuprofen, although intermittent as required use as an 
analgesic is permitted when required. Chronic use of low dose 
aspirin for cardiovascular protection is permitted. 
9. Currently receiving lithium, antimalarials, leflunomide, or IM 
gold, or have received lithium, antimalarials, IM gold, or 
leflunomide within 4 weeks of first administration of study 
drug. 
10. Have used topical medications/treatments that could affect 
psoriasis or PGA evaluation (including [but not limited to] 
high- and mid-potency corticosteroids, anthralin, 
calcipotriene, topical vitamin D derivatives, retinoids, 
tazarotene, methoxsalen, trimethylpsoralens, picrolimus, and 
tacrolimus) within 2 weeks of the first administration of study 
drug. Topical unmedicated emollients and low-potency 
topical corticosteroids are not excluded. 
11. Gastrointestinal tract disease (eg, short-bowel syndrome, 
diarrhea-predominant irritable bowel syndrome) that could 
interfere with GI delivery and transit time. 
12. Active inflammatory bowel disease. 
13. Active infection requiring systemic antiviral or antimicrobial 
therapy that will not be completed prior to Day 1 (Visit 2). 
14. Has received live or live-attenuated vaccination within 
6 weeks prior to screening or intends to have such a 
vaccination during the study. 
15. Clinically significant abnormalities in screening laboratory 
values that would render a participant unsuitable for inclusion 
(per investigator judgment).  
16. For women, serum creatinine ≥125 µmol/L (1.414 mg/dL); 
for men, serum creatinine ≥135 µmol/L (1.527 mg/dL). 
17. ALT and AST >2 × ULN. 
18. Known history of or positive test for HIV, or active infection 
with hepatitis C or chronic hepatitis B. 
19. History of clinically significant acute cardiac or 
cerebrovascular event within 6 months before screening 


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(includes stroke, transient ischemic attack, and coronary heart 
disease [angina pectoris, myocardial infarction, heart failure, 
revascularization procedures]).  
20. In the opinion of the investigator, evidence of clinically 
important cardiac conduction abnormalities at screening as 
judged by ECG. 
21. Current acute or chronic inflammatory disease other than 
psoriasis or psoriatic arthritis (eg, inflammatory bowel 
disease, rheumatoid arthritis, systemic lupus erythematosus). 
If a subject is off all treatment and is disease and has been 
symptom free for greater than 12 months, then the 
inflammatory disease is considered to be in remission and 
they may be enrolled. 
22. Hypersensitivity to P histicola or to any of the excipients. 
23. Active untreated mental or psychiatric disorder. Participants 
who are on stable dosing of medication for a mental or 
psychiatric disorder for at least 6 months before screening and 
whose treating physicians consider them to be mentally stable 
may be enrolled.  
24. Any major or minor GI surgery within 6 months of screening. 
25. Any major surgery within 6 months of screening. 
26. Malignancy within 5 years, except for basal or squamous cell 
carcinoma of the skin or carcinoma in situ of the cervix that 
has been successfully treated. 
27. Treatment with another investigational drug, biological agent, 
or device within 1 month of screening, or 5 half-lives of 
investigational agent, whichever is longer. 
28. Initiating any OTC or prescription medication including 
vitamins, herbal supplements and nutraceuticals (eg, 
supplements including high doses of probiotics and prebiotics 
as usually found in capsules/tablets/powders), except 
acetaminophen/paracetamol and anti-histamines, within 
14 days prior to baseline or anticipates change in dosage for 
the duration of the study period. Note that probiotic and 
prebiotic foods that contain low doses are allowed (eg, 
yoghurt, kefir, kombucha). 
29. Blood donation of >100 mL within 30 days of screening or of 
>499 mL within 12 weeks of screening. 
30. Unwillingness 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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31. Have any other conditions, which, in the opinion of the 
investigator or sponsor, would make the participant unsuitable 
for inclusion or could interfere with the participant 
participating in or completing the study. 
Study Design: 
This is a multicenter, randomized, double-blind, placebo-controlled, 
parallel-cohort, dose-ranging study of participants with mild to 
moderate plaque psoriasis. 
Part A of the study comprises a screening period of up to 4 weeks, a 
baseline visit, a treatment period of 16 weeks (8 planned study site 
visits), and a follow-up visit at Week 20 (4 weeks after cessation of 
dosing). Part A of the study therefore comprises a total of 
11 scheduled study visits, and on completion of Part A, the primary 
analysis will be performed. 
Part B of the study is designed to assess the durability of treatment 
response and incidence of rebound of psoriasis following cessation 
of dosing. All participants will attend for skin assessments at Weeks 
24 and 28, unless they have previously experienced treatment failure 
and/or had rebound of disease. A final visit at Week 40 will also be 
performed for those participants who experienced treatment 
response at Week 16 of treatment, but have not yet met the definition 
of disease relapse. Part B of the study therefore comprises a 
maximum of 3 additional scheduled study visits with a follow-up of 
up to 40 weeks (24 weeks after cessation of dosing), and on 
completion of Part B, the final analysis will be performed. 
The study design is presented in Figure 3-1, and the SoA is 
presented in Table 6-1 for Part A, and in Table 6-2 for Part B. 
After eligibility is confirmed during the screening period, 
participants will be randomly assigned in a 1:1:1 ratio to 1 of the 
following 3 parallel cohorts:  
• Cohort 1: 0.8 × 1011 cells of EDP1815 or matching placebo 
administered as 1 PIC, once daily.  
• Cohort 2: 3.2 × 1011 cells of EDP1815 or matching placebo 
administered as 4 PICs, once daily.  
• Cohort 3: 8.0 × 1011 cells of EDP1815 or matching placebo 
administered as 10 PICs, once daily. 
In each cohort, approximately 75 participants will be randomly 
assigned in a 2:1 ratio to receive either EDP1815 or matching 
placebo once daily for 16 weeks.  
An interim analysis may be performed after at least 50% of 
participants have completed at least 12 weeks of treatment.  


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After the planned 16 weeks of treatment, all participants will have an 
initial follow-up visit at Week 20 (ie, 4 weeks post last dose of study 
treatment), completing Part A of the study; and enter Part B with 
continued follow-up for a maximum of 20 additional weeks (up to 
Week 40). The duration of follow up will depend on the initial 
response to study therapy and any relapse or rebound experienced 
after cessation of study treatment. 
Estimated Study 
Duration: 
The maximum planned duration of study participation will be 
44 weeks, and the duration of the study is defined for each 
participant as the date signed written informed consent is provided 
through to their last follow-up visit.  
Participants will be considered to have completed the study after the 
completion of all required visits. 
Efficacy 
Assessments: 
The efficacy assessments will include the PASI score, the LSS, the 
National Psoriasis Foundation Psoriasis Score version of a static 
PGA, the percent of BSA involvement, the mNAPSI, the DLQI, the 
PSI, the SF-36 Bodily Pain Scale, the VAS Pain assessment, the 
vitality subscale of the SF-36 (to assess fatigue), and a fatigue VAS. 
Pharmacokinetic or 
Pharmacodynamic 
Assessments: 
Pharmacokinetic assessments will be limited to a predose blood 
sample at baseline and another sample at the Week 16 visit (end of 
treatment).  
Pharmacodynamic and biomarker assessments are exploratory 
endpoints and analytical results for biomarkers will not be included 
in the CSR. They will be reported separately from the CSR. 
Pharmacodynamic and biomarker assessments include digital 
photography of up to 6 lesion sites, standard histologic assessments 
of skin plaque biopsies, mRNA transcription analysis of skin plaque 
biopsies, blood cytokine and chemokine analyses, and microbiome 
composition of the fecal microbiome. 
Safety and 
Tolerability 
Assessments: 
Safety and tolerability assessments include monitoring AEs 
(including SAEs), monitoring concomitant medications, BSFS 
categorization (recorded in a stool diary), physical examinations, 
vital sign measurements, and ECGs. 
Details of Applicable 
Monitoring 
Committee: 
There will be no safety review committee or data monitoring 
committee. 
Study drug, Dosage, 
and Route of 
Administration: 
The study drug will be capsules containing EDP1815 or matching 
capsules containing placebo.  
There will be 3 dosing cohorts, with dosages of 1 capsule, 
4 capsules, or 10 capsules; capsules of EDP1815 each contain 


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8.0 × 1010 cells of EDP1815, while placebo capsules contain no 
bacteria.  
Participants will self-administer their doses of study drug orally in 
the morning with water.  
Sample Size: 
The sample size of 225 participants in total, has been chosen to 
explore the tolerability and safety of EDP1815. Although the study 
will use a model-based probability inference approach in a Bayesian 
framework, the following power calculation was also performed 
(using a basic frequentist approach) in order to give confidence that 
enough participants are available to find a clinically meaningful 
difference between active dose and placebo if the below assumptions 
are met. 
The primary efficacy endpoint is the percent change from baseline in 
the PASI score at Week 16. Percent change from baseline relative to 
placebo will be estimated within the model as (percent change in 
active) - (percent change in placebo), with a negative value 
indicating a greater improvement for active than placebo. A percent 
change from baseline relative to placebo of at least 20% will be 
considered clinically meaningful. The pooled standard deviation 
across all doses is assumed to be 25%. 
Participants in the placebo arm of each cohort will be pooled for the 
statistical analysis in order to compare active and control arms 
resulting in 75 participants randomized to the pooled placebo group 
and 50 participants randomized to each active treatment group 
(EDP1815 0.8 × 1011 cells, EDP1815 3.2 × 1011 cells, and EDP1815 
8.0 × 1011 cells). Assuming that no more than 15% of participants 
will discontinue treatment before the Week 16 visit, at least 42 active 
and 21 placebo participants in each of the 3 cohorts are expected to 
provide data through the Week 16 visit. 
Each pairwise comparison between pooled placebo and active dose 
would be expected to have more than 95% power to detect a 
difference between the treatment groups at the 5% significance level 
under the assumption that pooling the placebo groups is a valid 
strategy. If the 3 placebo cohorts are considered to be too 
heterogeneous for pooling into a single reference group, the power 
to detect a difference in each within-cohort pairwise comparison 
between active and placebo doses would be greater than 80%. 
As the statistical inference for this study will focus on estimation 
rather than testing a formal hypothesis, no multiplicity adjustments 


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of the different comparisons between groups in order to control the 
study-wise type I error rate will be performed. 
Similarly, as there is no intention to use any interim analyses to stop 
the study early for efficacy, no adjustments for multiplicity will be 
made to account for any analyses performed as part of the interim 
analyses. 
Statistical Methods: 
Analysis methods for key endpoints are briefly described below. 
Further details on all analyses will be described in the SAP. 
No formal hypothesis will be tested. A model-based probability 
inference approach in a Bayesian framework will be used to guide 
decision-making around dose selection. Posterior estimates and 95% 
credible intervals (CrI) for the difference between each active dose 
and placebo will be produced for relevant primary and secondary 
endpoints. 
Unless otherwise specified, missing data will be considered as 
missing at random and will be accounted for using mixed models for 
repeated measures, with all time points collected for the relevant 
endpoint included in the model. This includes data which is excluded 
due to collection after treatment discontinuation or after a protocol 
deviation as applicable to the definition of the estimands used in the 
analysis. 
The primary analysis for the study will occur after all participants 
have completed 4 weeks of follow-up after their last dose of study 
medication (end of Part A). The final analysis for the study will 
occur when all participants have completed the required relapse and 
rebound follow-up period of up to 24 weeks post-treatment (end of 
Part B). 
Analysis Sets: 
The mITT set will consist of all participants who were randomized 
to treatment and who received at least one dose of study treatment.  
The PPS will consist of all mITT participants who were not replaced 
(following study withdrawal before the end of Week 4) and who do 
not have a protocol deviation that may impact efficacy with a start 
date for the deviation before initiation of study treatment.  
The safety set will consist of all participants who received any study 
drug. 
The mITT set will be the primary population of interest for the 
efficacy section, with some supportive analyses performed using the 
PPS. The safety set will be used for all safety summaries. 


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Statistical Analysis Methodology: 
Statistical analysis will be performed using SAS software 
Version 9.3 or later. Continuous variables will be summarized using 
the mean, standard deviation, median, minimum value, and 
maximum value. Categorical variables will be summarized using 
frequency counts and percentages. Time-to-event variables will be 
summarized using Kaplan-Meier estimates of the proportion of 
participants with the event at each visit. Data will be listed in data 
listings.  
Analysis of Primary Efficacy Endpoint: 
The primary analysis will be performed using a Bayesian MMRM. 
The model will include parameters for treatment*visit and baseline 
PASI score*visit interactions. Body mass index, gender, country, and 
time since diagnosis will also be considered and included as 
parameters if found to be significant (p<0.05). The model will not 
include an intercept. The priors for all parameters in the model will 
be non-informative and follow a normal distribution with mean 0 
and SD 1000. The prior for the variance-covariance matrix will 
follow an inverted Wishart distribution with degrees of freedom 
equal to the number of visits and an identity scale matrix. 
The adjusted posterior mean percentage change from baseline and 
the associated 95% HDP CrI for each treatment at Week 16 will be 
reported, together with the adjusted mean difference from placebo 
and the associated 95% HDP CrI for each active dose at each visit 
and the probability that each treatment difference is less than 
0%, -20%, -30%, and -50%. 
Analysis of Secondary Efficacy Endpoints:  
All secondary analyses will be performed on the mITT set, 
excluding data collected after treatment discontinuation, without 
consideration of any protocol deviations. Dose will be treated as a 
categorical variable and no dose response modelling will be done. 
Comparisons of interest will be between individual EDP1815 doses 
and placebo. All p-values, posterior probabilities, CI, and CrI 
calculated will be considered as descriptive with no further 
adjustments for multiplicity performed. 
Analyses of Exploratory Efficacy Endpoints 
Exploratory endpoints will be summarized using the mITT 
population, with data collected after discontinuation of treatment 
excluded but without consideration of any protocol deviations.  
Analyses of biomarkers will be addressed in a data analysis plan 
outside the study SAP. 


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Pharmacokinetic Analyses: 
The number and percentage of participants who have a quantifiable 
concentration of EDP1815 in their blood sample will be summarized 
using the safety set by visit. Placebo participants will be pooled into 
a single treatment group. If at least 20% of participants within a 
treatment group are found to have a quantifiable level at one of the 
visits, then the concentration will be summarized as a continuous 
variable for the relevant treatment group at that visit. 
Safety Analyses:  
All safety endpoints will be tabulated or plotted by treatment group 
using the safety set. All safety analyses will use the pooled placebo. 
Further details will be described in the SAP. 
Version and Date of 
Protocol: 
Version 5.0 (Amendment 4); 17 November 2020 


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List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BSA 
body surface area 
BSFS 
Bristol Stool Form Scale 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
COVID 
Corona virus disease 
CrI 
credible interval(s) 
CRP 
C-reactive protein 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DIC 
deviance information criterion 
DLQI 
Dermatology Life Quality Index 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EDP1815 
investigational study drug 
EMA 
European Medicines Agency 
EMICM 
expectation-maximization iterative complex minorant 
EOS 
end of study 
EU 
Europe 
FDA 
US Food and Drug Administration 
FSH 
follicle-stimulating hormone 
FUP 
functional uniform prior 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HbsAg 
hepatitis B surface antigen 
HCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 


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Abbreviation 
Definition 
HDL 
high-density lipoprotein 
HDP 
high-density probability 
HIV 
human immunodeficiency virus 
HPMC 
hydroxypropyl methylcellulose 
HRT 
hormone replacement therapy 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IFNγ 
interferon gamma 
IL 
interleukin 
IM 
intramuscular 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IRE 
Ireland 
IRT 
interactive response technology 
LDL 
low-density lipoprotein 
LSS 
lesion severity score 
MCV 
mean corpuscular volume 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MMRM 
mixed effects model with repeated measures 
mNAPSI 
modified Nail Psoriasis Severity Index 
mRNA 
messenger RNA 
MTX 
methotrexate 
OTC 
over-the-counter 
PASI 
Psoriasis Area and Severity Index 
PCR 
polymerase chain reaction 
PDE4 
phosphodiesterase type 4 
PGA 
Physician’s Global Assessment 


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Abbreviation 
Definition 
PIC 
powder in capsule 
PPS 
per-protocol set 
PSI 
Psoriasis Symptom Inventory 
QTcF 
QT interval corrected using Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SF-36 BPS 
SF-36 Bodily Pain Scale  
SoA 
schedule of assessments 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TNFα 
tumor necrosis factor alpha 
UK 
United Kingdom 
ULN 
upper limit of normal 
USA 
United States of America 
VAS 
visual analog scale 
WHO 
World Health Organization  
WOCBP 
woman/women of child-bearing potential 


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1 Introduction 
Evelo Biosciences Inc. (Evelo) is developing medicines based on single strains of bacteria as 
a new class of therapeutic agents. These therapeutic agents are human commensal organisms 
that offer the potential of systemic immune system modulation following oral administration, 
without systemic exposure. EDP1815 is a pharmaceutical preparation of a strain of 
Prevotella histicola isolated from a human duodenal biopsy: it has not been genetically 
modified. Strains of the Prevotella genus of microbes have been found in all human 
populations tested to date, at abundances ranging from less than 1% to nearly 50% of total 
fecal microbial load (Vandeputte 2017). Prevotella are gram-negative, obligate anaerobes that 
are natural human commensals in the oral cavity and GI tract. EDP1815 is a gram-negative 
bacterium sensitive to the major classes of antibiotics, eg, penicillins and cephalosporins. In 
non-clinical and clinical studies, its therapeutic effects have been dose-dependent. The IB 
describes the development of EDP1815, initially in the treatment of psoriasis and atopic 
dermatitis. Initial clinical data from the first-in-human study in psoriasis patients are 
presented in the IB (Evelo Biosciences 2019). 
Several studies (de Groot et al 2017; Hindson et al 2017; Yan et al 2017; Felix et al 2018) 
suggest that host-microbe interactions in the gut, and particularly in the small intestine, can 
influence systemic inflammation. Evelo is seeking to develop oral anti-inflammatory 
medicines based on this emerging science. Preclinical data confirms that individual strains of 
microbes exhibit unique pharmacological profiles. This is thought to be based on multiple 
distinct microbial structural pattern motifs interacting with varying combinations of host 
pattern recognition receptors in small intestinal epithelium.  
Studies of EDP1815 in vitro in a range of human and mouse assays and studies in vivo in 
model symptoms support the use of EDP1815 in the treatment of inflammatory diseases 
including psoriasis (Evelo Biosciences 2019). EDP1815 increases secretion of 
anti-inflammatory cytokines such as IL-10, IL-1RA, and IL-27 from human immune cells, 
while inducing minimal production of pro-inflammatory cytokines such as IL-6, TNFα, and 
IFNγ. 
Oral administration of EDP1815 to mice results in striking pharmacodynamic effects on 
animal models of delayed-type hypersensitivity, fluorescein isothiocyanate cutaneous 
hypersensitivity, collagen-induced arthritis (Marietta et al 2016) and experimental acute 
encephalomyelitis (Mangalam et al 2017). The high degree of consistency of both effect and 


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dose suggests the potential for clinical benefit across multiple type 1, type 2, and type 3 
inflammatory conditions. No potentially related adverse effects were seen in the animals used 
in these experiments with daily dosing for up to 3 weeks or with alternate day dosing for over 
7 weeks. Immunophenotyping ex vivo in these models shows increased regulatory T cell 
numbers and regulatory dendritic cells in spleen and mesenteric lymph nodes, as well as 
decreases in pro-inflammatory cytokines such as IL-23p40, IL-17, TNFα, IL-6, and IL-13. 
Treatment also led to enhancement of gut intestinal barrier integrity, which is often disrupted 
in patients with inflammatory diseases. These effects on immune parameters have been 
observed both within and outside the GI tract, which demonstrates that host-microbe 
interactions in the gut can affect the immune response in peripheral tissues. 
Psoriasis is a chronic immune-mediated type 1/3 inflammatory skin disease in which 
hyperactive T cells trigger excessive keratinocyte proliferation. This results in the formation 
of raised erythematous plaques with scaling. Psoriatic lesions can appear anywhere on the 
body but are most often seen on the knees, elbows, scalp, and lumbar area. Critical events in 
the inflammatory process include activation of Langerhans cells and T cells, selective 
trafficking of activated T cells to the skin, and induction of an inflammatory cytokine and 
chemokine cascade in skin lesions. Clinical data have validated the role of anti-TNFα, 
anti-IL-17, and anti-IL-23 therapy in moderate to severe psoriasis. For patients with mild to 
moderate psoriasis, therapy usually involves topical agents (topical corticosteroids, 
vitamin D3 analogs), with topical corticosteroids providing the greatest range of efficacy and 
a wide range of formulations. More recently, physicians are prescribing apremilast, a 
first-in-class oral PDE4 inhibitor, ahead of biological therapy, which includes etanercept, 
infliximab, adalimumab, ustekinumab, and secukinumab. 
In Evelo study EDP1815-101, a total of 56 participants have participated in Cohorts 1-4, with 
36 of these participants receiving EDP1815 once daily; 16 of these were treated for 14 days 
(healthy volunteers) and 20 participants with psoriasis were treated for 28 days. Clinical 
responses, similar to apremilast and tofacitinib at the same time point, have been observed on 
the (psoriatic) LSS and PASI at Day 28. Furthermore, at the Day 42 follow-up visit, when 
participants were “off treatment” for 14 days, there was continued improvement in the 
pharmacodynamic response as measured by both LSS and PASI for participants administered 
the higher dose, but not the lower dose, suggesting a dose relationship on the durability of 
effect. The safety profile of EDP1815 was similar to placebo, with no SAEs or AEs of severe 
intensity.  


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The evidence available so far suggests EDP1815 is very well tolerated and it continues to 
undergo clinical development in mild to moderate psoriasis. A well-tolerated oral therapy 
could offer significant benefit in the treatment of psoriasis and it is presently anticipated that 
EDP1815 would be used in established but early disease, before the use of biologic therapies.  
This Phase 2 study has been designed to investigate the clinical safety and efficacy of 
EDP1815 and to identify an optimal dose.  


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2 Study Objectives 
All objectives are related to understanding the safety, efficacy, and dose effects of EDP1815 
treatment of mild to moderate plaque psoriasis in adult participants (Section 4.1). 
2.1 Primary Objective 
The primary objective of this study is to evaluate the safety and efficacy of 3 different doses 
of EDP1815 for the treatment of psoriasis following daily dosing for 16 weeks.  
2.2 Secondary Objectives 
The secondary objectives of this study are the following: 
• To evaluate the efficacy dose response of EDP1815 at Week 16 
• To evaluate the maximal clinical benefit of EDP1815 at Week 16 
• To evaluate the optimal dose of EDP1815 based on efficacy and safety up to Week 16 
• To evaluate the safety and tolerability of EDP1815 (all dose levels) throughout the 
study 
• To evaluate relapse and rebound of plaque psoriasis after cessation of EDP1815 
2.3 Exploratory Objectives 
The exploratory objectives of this study are the following: 
• To evaluate the time to onset of clinical response to EDP1815  
• To evaluate the effect of EDP1815 treatment on patient-reported outcomes including 
quality of life and pain 
• To evaluate the duration of remission, treatment success, and therapeutic effect of 
EDP1815 


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• To evaluate the effect of EDP1815 treatment on biomarkers in blood 
• To evaluate the effect of EDP1815 treatment on biomarkers in skin plaques 
• To evaluate the effect of EDP1815 treatment on fecal microbiome composition 


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3 Investigational Plan 
3.1 Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-cohort, 
dose-ranging study of participants with mild to moderate plaque psoriasis (Section 4.1).  
Part A of the study comprises a screening period of up to 4 weeks, a baseline visit, a 
treatment period of 16 weeks (8 planned study site visits), and a follow-up visit at Week 20 
(4 weeks after cessation of dosing). Part A of the study therefore comprises a total of 
11 scheduled study visits, and on completion of Part A, the primary analysis will be 
performed. 
Part B of the study is designed to assess the durability of treatment response and incidence of 
rebound of psoriasis following cessation of dosing. All participants will attend for skin 
assessments at Weeks 24 and 28, unless they have previously experienced treatment failure 
and/or had rebound of disease. A final visit at Week 40 will also be performed for those 
participants who experienced treatment response at Week 16 of treatment, but have not yet 
met the definition of disease relapse. Part B of the study therefore comprises a maximum of 
3 additional scheduled study visits with a follow-up of up to 40 weeks (24 weeks after 
cessation of dosing), and on completion of Part B, the final analysis will be performed. 
The study design is presented in Figure 3-1, and the SoA is presented in Table 6-1 for Part A, 
and in Table 6-2 for Part B.  
After eligibility is confirmed during the screening period (Section 4.1), participants will be 
randomly assigned in a 1:1:1 ratio to 1 of the following 3 parallel cohorts: 
• Cohort 1: 0.8 × 1011 cells of EDP1815 or matching placebo administered as 1 PIC, 
once daily (Section 5.2).  
• Cohort 2: 3.2 × 1011 cells of EDP1815 or matching placebo administered as 4 PICs, 
once daily (Section 5.2).  
• Cohort 3: 8.0 × 1011 cells of EDP1815 or matching placebo administered as 10 PICs, 
once daily (Section 5.2). 


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In each cohort, approximately 75 participants will be randomly assigned in a 2:1 ratio to 
receive either EDP1815 or matching placebo once daily for 16 weeks.  
An interim analysis may be performed after at least 50% of participants have completed at 
least 12 weeks of treatment (Section 7.6.7).  
After the planned 16 weeks of treatment, all participants will have an initial follow-up visit at 
Week 20 (ie, 4 weeks post last dose of study treatment), completing Part A of the study; and 
enter Part B with continued follow-up for a maximum of 20 additional weeks (up to 
Week 40). The duration of follow up will depend on the initial response to study therapy and 
any relapse or rebound experienced after cessation of study treatment.   
The maximum planned duration of study participation will be 44 weeks, and the duration of 
the study is defined for each participant as the date signed written informed consent is 
provided through to their last follow-up visit. Participants will be considered to have 
completed the study after the completion of all required visits.  
The EOS is defined as the date of the last visit of the last participant in the study or last 
scheduled procedure shown in the SoA. 
 
 


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Figure 3-1 
Study Design 
 
 
Note: All dosing is once daily.  
 
 


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3.1.1 Rationale for Study Design 
The EDP1815 Phase 1 program evaluated doses of 1.6 × 1010 cells to 8.0 × 1011 cells given 
daily for 2 weeks in healthy volunteers and doses of 1.6 × 1011 cells and 8.0 × 1011 cells given 
daily for 4 weeks to participants with mild to moderate psoriasis. All doses were found to be 
well tolerated and doses of both 1.6 × 1011 and 8.0 × 1011 cells induced clinically relevant 
reductions in signs and symptoms of plaque psoriasis and psoriasis lesion severity.  
The doses tested in the program are based on predictions from the preclinical data and the 
clinical and biomarker data obtained in EDP1815-101, the Phase 1 study. All doses tested up 
to 8.0 × 1011 cells have been equally well tolerated. No clear difference in efficacy was 
observed between the 1.6 × 1011 cells and the 8.0 × 1011 cells in EDP1815-101 over the 
28-day dosing period, but at the 14-day follow up (Day 42) the participants receiving the 
higher dose had a continued improvement in their psoriasis compared to participants who had 
received the lower dose. This suggests a more sustained and potentially deeper response in 
the high dose group. Evelo is therefore proposing to include the lowest and highest feasible 
doses (based on capsule load) in this study to establish the dose response, the maximum 
clinical benefit, and to assess participant tolerability and acceptability of the doses tested.  
The clinical response to EDP1815 treatment will be evaluated using multiple assessments, 
facilitating appropriate selection of efficacy measures for future studies. 
The use of a placebo comparator is appropriate for this participant population of individuals 
with mild to moderate plaque psoriasis for the following reasons:  
• The limited proven efficacy of other treatments (topical corticosteroids, vitamin D3 
analogs, and apremilast) in patients with mild to moderate plaque psoriasis that could 
potentially serve as an active comparator 
• The limited duration of the study (maximum of 16 weeks of treatment) for each 
participant 
• A randomization ratio of 2:1 for EDP1815 treatment to placebo treatment in each 
cohort 
Part B of the study, which includes additional visits at Weeks 24, 28, and 40, is designed to 
help understand the durability of treatment effect, including time to relapse and incidence of 


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any rebound of psoriasis after treatment has completed. These are important aspects to 
understand regarding a psoriasis therapy (EMA guideline CHMP/EWP/2454/02, 2004). 
 


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4 Participant Selection and Withdrawal Criteria 
4.1 Selection of Study Population 
Approximately 225 participants will be randomized in multiple countries, including (but not 
limited to) sites in the United States, the United Kingdom, Poland, and Hungary. Participants 
will be assigned to study treatment only if they meet all inclusion criteria and no exclusion 
criteria during screening. 
Deviations from the inclusion and exclusion criteria are not allowed: adherence to the 
eligibility criteria as specified in the protocol is essential. 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study drug (EDP1815 or placebo). A minimal set 
of screen failure information is required to be entered in the eCRF to ensure transparent 
reporting of screen failure participants to meet the Consolidated Standards of Reporting 
Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
SAEs. 
Individuals who fail to satisfy inclusion and exclusion criteria at screening may be rescreened 
1 additional time with the agreement of the medical monitor before rescreening. Participants 
may also be rescreened if they initially pass the screening assessments but go beyond the 
screening period time limit. In exceptional circumstances, the screening window can be 
extended on a case-by-case basis after consultation with the sponsor: such an exceptional 
extension will not be considered a protocol deviation.  
4.1.1 Inclusion Criteria 
Each participant must meet all the following criteria to be enrolled in this study: 
1. Give written informed consent (signed and dated) and any authorizations required by 
local law and be able to comply with all study requirements. 
2. Males or females ≥18 and ≤70 years old at the time of informed consent. 
3. A documented diagnosis of plaque psoriasis for ≥6 months. 


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4. Have mild to moderate plaque psoriasis with plaque covering BSA of ≥3% and ≤10% 
and meet both of the following additional criteria:  
a. PASI score of ≥6 and ≤15, and  
b. PGA score of 2 or 3.  
 
All parameters in this criterion should be reconfirmed at baseline visit prior to 
randomization. 
5. Meet the following contraception criteria:  
a. Male participants: 
i. A male participant must agree to use contraception as detailed in 
Appendix 13.1 of this protocol during their participation in this study 
and for a period of 90 days after the last dose and refrain from 
donating sperm during this period. 
b. Female participants:  
i. A female participant is eligible to participate if she is not pregnant 
(Appendix 13.1), not breastfeeding, and at least 1 of the following 
conditions applies: 
1. Not a WOCBP as defined in Appendix 13.1, OR 
2. A WOCBP who agrees to follow the contraceptive guidance in 
Appendix 13.1 during their participation in this study, 28 days 
prior to the first dose and for at least 1 complete menstrual 
cycle (≥28 days) after the last dose. 
6. Agrees to not increase their usual sun exposure during the study.  
4.1.2 Exclusion Criteria 
Participants meeting any of the following criteria will be excluded from the study: 
1. Have received EDP1815 within the 3 months prior to screening. 
2. Have a diagnosis of non-plaque psoriasis. 
3. Plaque psoriasis restricted to scalp, palms, and soles only.  


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4. Evidence of skin conditions that would interfere with psoriasis evaluation or treatment 
response (eg, atopic dermatitis, fungal or bacterial superinfection).  
5. Have received systemic immunosuppressive therapy (MTX, apremilast, azathioprine, 
cyclosporine, 6-thioguanine, mercaptopurine, mycophenolate mofetil, hydroxyurea, 
and tacrolimus) within 4 weeks of first administration of study drug.  
6. Unresponsive to prior use of biologics (including, but not limited to, TNFα inhibitors, 
natalizumab, efalizumab, anakinra or agents that modulate B cells or T cells). 
7. If prior biologic therapy and responsive, participants must have been off therapy for at 
least 12 months prior to first administration of study drug. 
8. Have received phototherapy or any systemic medications/treatments that could affect 
psoriasis or PGA evaluation (including, but not limited to oral or injectable 
corticosteroids, retinoids, psoralens, sulfasalazine, hydroxyurea, or fumaric acid 
derivatives) within 4 weeks of first administration of study drug. This includes 
therapeutic doses of non-steroidal anti-inflammatory drugs such as ibuprofen, 
although intermittent as required use as an analgesic is permitted when required. 
Chronic use of low dose aspirin for cardiovascular protection is permitted. 
9. Currently receiving lithium, antimalarials, leflunomide, or IM gold, or have received 
lithium, antimalarials, IM gold, or leflunomide within 4 weeks of first administration 
of study drug. 
10. Have used topical medications/treatments that could affect psoriasis or PGA 
evaluation (including [but not limited to] high- and mid-potency corticosteroids 
[Appendix 13.2], anthralin, calcipotriene, topical vitamin D derivatives, retinoids, 
tazarotene, methoxsalen, trimethylpsoralens, picrolimus, and tacrolimus) within 
2 weeks of the first administration of study drug. Topical unmedicated emollients and 
low-potency topical corticosteroids are not excluded. 
11. Gastrointestinal tract disease (eg, short-bowel syndrome, diarrhea-predominant 
irritable bowel syndrome) that could interfere with GI delivery and transit time. 
12. Active inflammatory bowel disease. 
13. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Day 1 (Visit 2). 


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14. Have received live or live-attenuated replicating vaccine within 6 weeks prior to 
screening or intend to have such a vaccination during the study. 
15. Clinically significant abnormalities in screening laboratory values that would render a 
participant unsuitable for inclusion (per investigator judgment).  
16. For women, serum creatinine ≥125 µmol/L (1.414 mg/dL); for men, serum creatinine 
≥135 µmol/L (1.527 mg/dL). 
17. ALT and AST >2 × ULN. 
18. Known history of or positive test for HIV, or active infection with hepatitis C or 
chronic hepatitis B. 
19. History of clinically significant acute cardiac or cerebrovascular event within 
6 months before screening (includes stroke, transient ischemic attack, and coronary 
heart disease [angina pectoris, myocardial infarction, heart failure, revascularization 
procedures]).  
20. In the opinion of the investigator, evidence of clinically important cardiac conduction 
abnormalities at screening as judged by ECG. 
21. Current acute or chronic inflammatory disease other than psoriasis or psoriatic arthritis 
(eg, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus). 
If a subject is off all treatment and is disease and has been symptom free for greater 
than 12 months, then the inflammatory disease is considered to be in remission and 
they may be enrolled. 
22. Hypersensitivity to P histicola or to any of the excipients. 
23. Active untreated mental or psychiatric disorder. Participants who are on stable dosing 
of medication for a mental or psychiatric disorder for at least 6 months before 
screening and whose treating physicians consider them to be mentally stable may be 
enrolled.  
24. Any major or minor GI surgery within 6 months of screening. 
25. Any major surgery within 6 months of screening. 
26. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated. 


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27. Treatment with another investigational drug, biological agent, or device within 
1 month of screening, or 5 half-lives of investigational agent, whichever is longer. 
28. Initiating any OTC or prescription medication including vitamins, herbal supplements 
and nutraceuticals (eg, supplements including high doses of probiotics and prebiotics 
as usually found in capsules/tablets/powders), except acetaminophen/paracetamol and 
anti-histamines, within 14 days prior to baseline or anticipates change in dosage for 
the duration of the study period.  
Note: Probiotic and prebiotic foods that contain low doses are allowed (eg, yoghurt, 
kefir, kombucha), however, supplements containing high doses of probiotics and 
prebiotics are not allowed at any point during the study. 
29. Blood donation of >100 mL within 30 days of screening or >499 mL within 12 weeks 
of screening. 
30. Unwillingness to comply with study procedures, including follow-up, as specified by 
this protocol or unwillingness to cooperate fully with the investigator. 
31. Have any other conditions, which, in the opinion of the investigator or sponsor, would 
make the participant unsuitable for inclusion or could interfere with the participant 
participating in or completing the study.  
4.2 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 eCRF.  
There are 3 scenarios that result in interruption of the treatment regimen: interruption of 
study drug, early discontinuation of study drug, and early withdrawal from the study: 
• Interruption of treatment is defined as a temporary stopping of study drug that 
resumes during the treatment period, due to an AE or any other reason. The maximum 
permitted interruption is 1 week. 


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• Early discontinuation of treatment is defined as permanent stopping of study drug 
before completing the visit scheduled for Week 16. Investigators will strive to ensure 
that a participant who has interrupted treatment for a particular reason will not 
discontinue treatment unless discontinuation is medically imperative in the 
investigator’s judgment. However, a dose interruption of more than 1 week will result 
in mandatory discontinuation of treatment.  
• Early withdrawal from the study is defined as failing to complete the required follow-
up period.  
A participant will be discontinued from the study drug or withdrawn from the study for any 
of the following reasons: 
1. The participant experiences treatment failure, demonstrated by the participant 
commencing an oral agent, biological, or intermediate or high-potency topical therapy. 
2. The participant has a serious or intolerable AE that in the investigator’s opinion 
requires discontinuation from study treatment or withdrawal from the study. 
3. The participant has symptoms or an intercurrent illness not consistent with the 
protocol requirements or that justifies withdrawal. 
4. The participant is lost to follow-up. 
5. Other reasons (eg, pregnancy, development of contraindications to use of study drug). 
6. The participant withdraws consent, or the investigator or sponsor decides to 
discontinue the participant’s participation in the study. 
A participant may be discontinued from the study drug or withdrawn from the study for any 
of the following reasons: 
1. The participant is noncompliant with the protocol. 
2. The participant has laboratory safety results that reveal clinically significant 
hematological or biochemical changes from the baseline values. 
3. If the participant is required to start therapy for a concurrent condition that may affect 
the study endpoints, eg, a disease-modifying agent for psoriatic arthritis. 


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In all of these instances, if the participant is to remain in the study, then the investigator 
should confirm that the participant is suitable to continue in the study with the medical 
monitor. 
4.2.1 Discontinuation From Study Treatment 
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 site 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.  
Dosing may be interrupted at the investigator’s discretion due to AE or intercurrent illness for 
a period of up to 1 week, following which the participant may resume treatment if the 
investigator considers it safe to do so. The participant should discontinue treatment 
permanently if the AE occurs a second time. 
4.2.2 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 a participant 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 eCRF.  
Participants who withdraw from the study during Part A should complete the final 
assessments listed under the Follow-up Visit (Week 20) at an unscheduled follow-up visit, as 
detailed in the SoA (Table 6-1). Participants who withdraw from the study during Part B 
should complete the final assessments at the Early Withdrawal Visit, as detailed in Table 6-2. 


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4.2.3 Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the study site for a 
required study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 2 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
eCRF. 
If the participant continues to be unreachable, he/she will be considered to have withdrawn 
from the study. 
4.2.4 Replacements 
Participants who withdraw or are withdrawn from the study within 4 weeks of randomization 
may be replaced in order to have approximately 225 participants provide at least 4 weeks of 
postbaseline data.  
Replacement participants will be randomly assigned treatment in the respective cohorts of the 
participants they replace. 


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5 Study Treatments 
5.1 Method of Assigning Participants to Treatment Groups 
Participants will be randomly assigned at the baseline visit (Visit 2) to 1 of 3 cohorts (in a 
1:1:1 allocation ratio) that are distinguishable to participants and study staff by the number of 
capsules administered per once-daily dose. Within the cohort, participants will be randomly 
assigned in a 2:1 allocation ratio to receive either EDP1815 or matching placebo treatment 
(Section 3.1). Interactive response technology will be used to administer the randomization 
schedule. 
5.2 Treatments Administered 
Participants in each cohort (described in Section 3.1) will self-administer study drug doses 
orally in the morning with water, refraining from consuming acidic drinks 1 hour either side 
of dosing and from eating 2 hours before dosing and 1 hour after dosing (Table 6-1). The 
composition of capsules is described in Section 5.3. Strategy to improve compliance is 
presented in Section 5.7.  
5.3 Identity of Study Drug 
The EDP1815 drug product is available as enteric-coated HPMC hard capsules in Swedish-
Orange color. The EDP1815 PIC consists of freeze-dried powder of P histicola, mannitol, 
magnesium stearate, and colloidal silicon dioxide. Each EDP1815 PIC contains 8.0 × 1010 
cells of P histicola. 
The matching placebo is identical in appearance but do not contain P histicola or any other 
bacteria. The placebo excipients include microcrystalline cellulose and magnesium stearate.  
5.4 Management of Clinical Supplies 
5.4.1 Study Drug Packaging and Storage 
EDP1815 PICs and matching placebo will be prepared in blister wallets of 10 capsules. 
Blister wallets will be packaged in packs that contain approximately 1 week’s supply of study 
drug for 1 randomized participant, identified by a numeric code. When appropriate for the 
interval between study visits, multiple packs will be assigned and dispensed for each 
participant throughout the treatment period.  


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Study drug (EDP1815 and placebo) must be stored in a secure area (eg, a locked refrigerator) 
and kept at a controlled temperature of 2°C to 8°C. The investigator or designee must 
confirm appropriate temperature conditions have been maintained during transit and during 
storage at each site for all study drug received and any discrepancies are reported and 
resolved before use of the study drug. 
 
will supply study drug to each site in non-study descript shipping containers that will 
maintain temperature during transit within 2°C to 8°C. Temperature monitoring devices will 
be used to confirm adequate transit temperature. Site procedure for receipt of study drug will 
be provided in the IMP handling manual.  
5.4.2 Study Drug Accountability 
The investigator will maintain accurate records of receipt of all study drug, including dates of 
receipt. In addition, accurate records will be kept regarding when and how much test article 
is dispensed and used by each participant in the study. Study drug will be assigned using an 
IRT system. Only participants enrolled in the study may receive the study drug and only 
authorized site personnel may supply the study drug. Reasons for departure from the 
expected dispensing regimen must also be recorded. At the completion of the study, to satisfy 
regulatory requirements regarding drug accountability, all study drug will be reconciled and 
retained or destroyed according to applicable regulations. Further guidance and information 
for the final disposition of unused study drug are provided in the IMP handling manual. 
Accountability, reconciliation, and then shipment for destruction or for destruction on site 
will be documented through the IRT. 
5.4.3 Other Supplies 
Evelo will supply Bristol stool diaries (Section 6.2.2) and paper dosing diaries to all 
participants (Section 5.7.1). Electronic devices for administering questionnaires will be 
provided to all study sites.  
5.5 Overdose Management 
An overdose is any dose of study treatment given to a participant or taken by a participant 
that exceeds the maximum dose described in the protocol (10 capsules per day).  






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Before each visit (Visit 3 through Visit 10), study site staff will call participants to remind 
them to bring all study drug in the original containers to the study site for their visit, and to 
remind them to also bring their dosing diaries (Section 5.7.1).  
Compliance will be assessed by counting returned capsules during the site visits indicated in 
the SoA (Table 6-1), and the counts will be documented in the source documents and eCRF. 
Deviation from the prescribed dosage regimen should be recorded in the eCRF. 
A record of the number of study drug capsules dispensed to and taken by each participant 
must be maintained and reconciled with the study drug and compliance records. Study 
treatment start and stop dates, including dates for study treatment delays and/or dose 
reductions, will also be recorded in the eCRF. 
5.7.1 Dosing Diaries 
The primary purpose of the diary is to enhance participant compliance with the protocol. 
Participants will be asked to capture the following information in the diaries: 
• Dates of dosing with study drug 
• Times of dosing with study drug 
• Numbers of capsules in dose 
• Changes in concomitant medications 
• Changes in symptoms 
• Other comments 
Diaries will be dispensed and collected as detailed in the SoA (Table 6-1). Study staff will 
review the diaries with participants at each visit when diaries are collected. Diaries will be 
reviewed for completeness and accuracy, and participants will be coached as needed on 
compliance with the protocol.  


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5.8 Prior, Concomitant, and Rescue Medications  
Use of all concomitant medications will be recorded in the participant’s eCRF. The minimum 
requirement is that drug tradename, total daily dose, and the dates of administration are to be 
recorded. In addition, it is expected that the reason for use and dosage information (including 
dose and frequency) will also be recorded. This will include all prescription drugs, herbal 
products, vitamins, minerals, and OTC medications. Any changes in concomitant 
medications also will be recorded in the participant’s eCRF. The participant’s dosing diary 
may contain information relevant to the documentation of changes in concomitant 
medication.  
Any concomitant medication or therapy deemed necessary for the welfare of the participant 
during the study may be given at the discretion of the investigator. However, it is the 
responsibility of the investigator to ensure that details regarding the medication are recorded 
in full in the eCRF. 
5.8.1 Prior Therapy 
Prior therapies restricted for participants eligible for this study are detailed in the exclusion 
criteria (Section 4.1.2).  
5.8.2 Concomitant Therapy 
Anti-histamines and acetaminophen/paracetamol following labeled dosing instructions are 
permitted for use at any time during the study. Topical unmedicated emollients and 
low-potency topical steroids are also permitted if participants were already using them as part 
of their care prior to study entry (exclusion criterion #10, Section 4.1.2). Participants will be 
advised to continue to use these therapies as they were prior to study entry. 
Non-live and non-replicating vaccines are permitted in this study. 
Other concomitant medication may be considered on a case-by-case basis by the investigator 
in consultation with the medical monitor if required. 
5.8.2.1 Prohibited Concomitant Therapy 
Prior therapies restricted for participants eligible for this study as detailed in the exclusion 
criteria (Section 4.1.2) are prohibited concomitant therapy during the study.  


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Live or live-attenuated replicating vaccines are contra-indicated in this study. 
5.8.3 Rescue Medicine 
Although P histicola is a natural human commensal in the human GI tract, if a rare 
overgrowth condition is suspected the following rescue antibiotics may be used (supplied by 
the study site) if the clinical situation warrants such use: 
1. Penicillin V 
2. Amoxicillin 
Or, if allergic to the above antibiotics: 
3. Macrolides (eg, clarithromycin or erythromycin)  
4. Tetracyclines (eg, doxycycline) 
The date and time of rescue medication administration as well as the name and dosage 
regimen of the rescue medication must be recorded in the eCRF. 
5.9 Dose Modification 
Dose adjustments, including dose interruptions, and/or decreasing the dose frequency may be 
allowed for safety or tolerability (including capsule load) after consultation with the sponsor 
medical monitor. 


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6 Study Assessments and Procedures 
Before performing any study procedures, all potential participants will sign an ICF. 
Additional procedural details related to the ICF are provided in Section 9.3.  
The SoA is presented in Table 6-1. Detailed instructions for study site activities will be 
provided in the appropriate specific user manual, where applicable. High level descriptions of 
the study assessments are presented in the subsections of Section 6. In exceptional 
circumstances, study assessments may be conducted remotely (ie, at a participant’s home), 
except for screening, baseline, Visit 9, and Visit 10. Remote visits can only occur if 
operationally possible. 
 


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Table 6-1 
Schedule of Assessments – Part A 
Procedure 
Screening Baseline 
Treatment Period 
Follow-upa, b 
Day 
-28 to -7 
1 
8 
15 
22 
29 
43 
57 
85 
113 
141 
Week 
-4 
0 
1 
2 
3 
4 
6 
8 
12 
16 
20 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Visit window (days) 
-- 
-- 
5-11 
12-18 19-25 26-32 40-46 54-60 
82-88 
110-116 
141-148 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria  
X 
X c 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
HbsAg, HCV and HIV screening 
X 
 
 
 
 
 
 
 
 
 
 
HLA sample d 
 
X 
 
 
 
 
 
 
 
 
 
Medical history and current medical conditions 
(including duration of psoriasis) 
X 
X 
 
 
 
 
 
 
 
 
 
Full physical examination (height only at 
screening) e 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
Pregnancy test f 
X 
X 
 
 
 
 
 
 
 
X 
X 
Laboratory assessments (hematology, serum 
biochemistry and CRP, and urinalysis)  
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
Fasting g blood sampling 
 
X 
 
 
 
 
 
X 
 
X 
 
12-lead ECG h 
X 
X 
 
 
 
X 
 
 
 
X 
X 
Vital signs i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Dosing j 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense study drug 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Collect/count unused study drug 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Skin plaque biopsies k 
 
X 
 
 
 
 
 
 
 
X 
 


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Procedure 
Screening Baseline 
Treatment Period 
Follow-upa, b 
Day 
-28 to -7 
1 
8 
15 
22 
29 
43 
57 
85 
113 
141 
Week 
-4 
0 
1 
2 
3 
4 
6 
8 
12 
16 
20 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Visit window (days) 
-- 
-- 
5-11 
12-18 19-25 26-32 40-46 54-60 
82-88 
110-116 
141-148 
Digital photography of lesion sites l 
 
X 
 
 
 
X 
 
X 
 
X 
X 
Stool samples for microbiome investigation m 
 
X 
 
 
 
 
 
 
 
X 
X 
Dispense stool diary 
X 
 
 
 
 
 
 
 
 
 
 
Collect/record stool diary 
 
X 
 
 
 
 
 
 
 
 
 
Blood sample for detection of systemic EDP1815 
 
X 
 
 
 
 
 
 
 
X 
 
Samples for blood biomarkers  
 
X 
 
 
 
 
 
 
 
X 
 
BSA involvement (%), PGA, PASI n, o 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
LSS, mNAPSI n 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
PSI, DLQI, PA-VAS, SF-36 (vitality and pain), 
Fatigue p 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
AE/SAE review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense dosing diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Collect/review dosing diary q 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
a 
Participants who withdraw from the study during Part A should complete the final assessments listed under the Follow-up Visit (Week 20), at an unscheduled 
follow-up visit. Where relevant and when possible, this should be arranged within 72 hours of the start of a new psoriasis treatment. In the event of early 
withdrawal from the study, unused study drug is to be collected/counted at this visit.  
b 
All participants will attend additional follow-up Visits 12 and 13 (see Table 6-2), unless they are considered a ‘treatment failure’ or meet the criteria for 
rebound. 
c 
Recheck inclusion/exclusion criteria at Baseline, before first dose of study drug. Screening laboratory results will be used to confirm eligibility at 
Baseline/Visit 2 (ie, Day 1).  
d 
Predose optional genetic samples. 


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e 
BMI will be calculated from the height and weight. 
f 
Women of child-bearing potential only. Serum HCG at screening, urine thereafter. Pregnancy testing will be performed at the visits indicated or if a 
menstrual cycle is missed or if pregnancy is otherwise suspected. 
g 
Participants will fast for at least 8 hours before glucose and lipid blood sampling  
h 
A single ECG tracing is to be obtained on the day of the visit. If, in the opinion of the investigator, there appear to be clinically significant findings, a second 
tracing should be obtained during the visit. 
i 
Blood pressure, pulse, respiratory rate, and temperature are to be checked on the day of the visit. 
j 
The first dose will be given at the baseline visit, following random assignment to treatment. Subsequent doses are to be taken (away from the study site) once 
daily in the morning at approximately the same time ±2 hours. Participants should refrain from consuming acidic drinks 1 hour either side of dosing and 
from eating 2 hours before dosing and 1 hour after dosing. On days of study site visits during the treatment period (Visit 3 through Visit 10, inclusive), 
participants may dose at home.  
k 
Skin plaque biopsies (ie, a 4 mm punch biopsy, performed pre-dose by suitably trained study personnel and processed as per laboratory manual) are to be 
performed after all other assessments have been completed at the end of Visits 2 and 10. 
l 
Digital photographs should be taken of up to 6 lesion sites that have a lesion area ideally greater than 2 cm by 2 cm at baseline. The same locations 
photographed at baseline should be followed throughout the study for each participant.  
m 
Stool samples are to be collected within the 48 hours preceding each visit of stool sample collection.  
n 
Investigator rating scales. Participants will be asked to withhold all emollients or moisturizers on the day of these study visits until all study assessments are 
completed. 
o 
Inclusion criterion #4 (mild to moderate plaque psoriasis with plaque covering BSA of ≥3% and ≤10%, PASI score of ≥6 and ≤15, and PGA score of 2 or 3) 
should be reconfirmed at the baseline visit prior to randomization. 
p 
Participant-reported assessments. 
q 
Study staff will review the dosing diaries with participants at each visit when diaries are collected. Diaries will be reviewed for completeness and accuracy, 
and participants will be coached as needed on compliance with the protocol. 
 


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Table 6-2 
Schedule of Post-Treatment Follow-Up Assessments – Part B  
Procedure 
Post-Treatment Follow-Up – Part B a 
Visit number 
12 b 
13 b 
14 c 
Early  
Withdrawal 
Visita 
Months (after the End of Treatment) 
2 
3 
6 
Weeks 
24 
28 
40 
Day 
169 
197 
218 
– 
Visit window (days) 
162-176 
190-204 
204-232 
– 
BSA involvement (%), PGA, PASI d 
X 
X 
X 
X 
LSS, mNAPSI d 
X 
X 
X 
X 
PSI, DLQI e  
X 
X 
X 
X 
Concomitant medication review  
X 
X 
X 
X 
a 
Participants who withdraw from the study during Part B should complete the final assessments at the Early 
Withdrawal Visit (where relevant and when possible, this should be arranged within 72 hours of the start of 
a new psoriasis treatment).  
b 
All participants will attend Visits 12 and 13, unless they are considered a ‘treatment failure’ or meet the 
criteria for rebound. 
c 
Only participants who are classified as responders at Week 16 (Visit 10) and have not relapsed at Week 28 
(Visit 13) will be eligible for Visit 14 (Week 40). 
d 
Investigator rating scales. Participants will be asked to withhold all emollients or moisturizers on the day of 
these study visits until all study assessments are completed. 
e 
Participant-reported assessments. 
 
During the screening period, participants will be advised to monitor their psoriasis symptoms 
and remain on a stable regimen of topical emollients and low-dose topical corticosteroid 
medications (if they are already taking any). Participants will be asked to withhold the 
application of any emollients or moisturizers on the day of any site visit until after all study 
assessments have been performed. As part of the screening, PASI, BSA involvement, and 
PGA scores will be measured (inclusion criterion #4, Section 4.1.1). 
Participants meeting eligibility criteria at screening will return to the study site on Day 1. 
The PASI, BSA involvement, and PGA scores must be available to reconfirm eligibility prior 
to randomization and administration of the first dose of study drug on Day 1 (Visit 2).  


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6.1 Efficacy Assessments 
6.1.1 Psoriasis Area and Severity Index Score  
The PASI score will be assessed as described by Langley and Ellis (2004). The PASI is a 
physician assessment that combines the assessment of the severity of and area affected by 
psoriasis into a single score in the range 0 (no disease) to 72 (maximal disease). The absolute 
PASI score in this study is used as part of inclusion criterion #4. The PASI percentage 
response rates are efficacy endpoints (ie, PASI-50, PASI-75, PASI-90, and PASI-100). For 
example, the percentage of participants who achieve a 75% or greater reduction in PASI 
score from baseline is represented by the PASI-75 value. Details of the PASI assessment will 
be provided in the relevant training material.  
Response Definitions based on PASI score at Week 16: 
• Responders: Participants on treatment achieving PASI-50 or greater at Week 16 visit 
• Relapse: Increase in PASI score to baseline value or greater, or participant begins a 
new treatment for psoriasis 
• Partial Relapse: Loss of PASI-50 response after cessation of study treatment 
• Rebound: Increase in PASI score to 125% of baseline value or above, or onset of 
new pustular/erythrodermic psoriasis within 3 months of cessation of study treatment 
• Duration of remission: Time from first achievement of PASI-100 to loss of 
PASI-100 
• Duration of treatment success: Time from first achievement of PASI-50 to loss of 
PASI-50 
• Duration of therapeutic effect: Time from cessation of study treatment until 
increase of PASI to 50% of maximum improvement from baseline 
 


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6.1.2 Lesion Severity Score 
The LSS is used to score the severity of psoriasis plaques (Patel and Tsui 2011). The 
dimensions of scaling, erythema, and plaque elevation are each scored on a scale from 0 to 4, 
and the total LSS is the numerical sum of the 3-dimensional scores observed at a single study 
visit.  
6.1.3 Physician’s Global Assessment  
The National Psoriasis Foundation Psoriasis Score version of a static PGA is calculated by 
averaging the total body erythema, induration, and desquamation scores (Feldman and 
Krueger 2005). Erythema, induration, and desquamation will be scored on a 6-point scale, 
ranging from 0 (clear) to 5 (severe): the total PGA score is defined as the average of the 
erythema, induration, and desquamation scores. Details of the PGA assessment will be 
provided in the relevant training material. 
6.1.4 Percent of Body Surface Area Involvement 
The percent of BSA involvement will be estimated for each participant, where 1% is 
approximately the area of the participant’s handprint (Walsh et al 2013). Details of the BSA 
assessment will be provided in the relevant training material.  
Walsh and colleagues proposed the product of the PGA and the BSA involvement as a simple 
and effective alternative for measuring severity of psoriasis in clinical trials (Walsh et al 
2013).  
6.1.5 Modified Nail Psoriasis Severity Index 
The mNAPSI is a numeric, reproducible, objective, and simple tool for physicians to evaluate 
the severity of nail bed psoriasis and nail matrix psoriasis by area of involvement in the nail 
unit (Cassell et al 2007). Details of conducting the mNAPSI will be provided in the relevant 
training material. 
6.1.6 Dermatology Life Quality Index 
The DLQI is a patient reported outcomes instrument for assessing the impact of dermatologic 
conditions on patients’ quality of life (Finlay and Khan 1994).  


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6.1.7 Psoriasis Symptom Inventory 
The PSI is a patient reported outcomes instrument that is used to assess the severity of plaque 
psoriasis symptoms (Bushnell et al 2013). All symptoms (itch, redness, scaling, burning, 
cracking, stinging, flaking, and pain) are rated on a 5-point severity scale. The PSI 
demonstrated good construct validity and was sensitive to within-subject change (p<0.0001). 
Details of administering the PSI will be provided in the specific user manual.  
6.1.8 Pain 
Pain will be assessed by the SF-36 BPS and the VAS Pain (Hawker et al 2011).  
6.1.9 Fatigue 
Consistent with a recent study of fatigue in psoriasis (Skoie et al 2017), fatigue will be 
assessed by the vitality subscale of the SF-36 (van der Heijden et al 2003) and a fatigue VAS 
(Wolfe 2004). 
6.1.10 Biopsy of Skin Plaque 
Skin plaque biopsies (ie, a 4 mm punch biopsy, performed pre-dose by suitably trained study 
personnel and processed as per laboratory manual) are to be performed after all other 
assessments have been completed at the end of Visits 2 and 10.  
6.2 Safety and Tolerability Assessments 
6.2.1 Adverse Events 
6.2.1.1 Definitions 
6.2.1.1.1 
Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to the study drug or their clinical significance. 
An AE is defined as any untoward medical occurrence in a participant enrolled into this study 
regardless of its causal relationship to the study drug. Participants will be instructed to 
contact the investigator at any time after randomization if any symptoms develop. 


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A TEAE is defined as any event not present before exposure to the study drug or any event 
already present that worsens in either intensity or frequency after exposure to the study drug. 
6.2.1.1.2 
Serious Adverse Events 
An SAE is defined as any event that 
• results in death 
• is immediately life threatening 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize the participant or may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
6.2.1.1.3 
Suspected Unexpected Serious Adverse Reactions 
A SUSAR is a serious adverse reaction, the nature or severity of which is not consistent with 
the applicable product information (eg, IB for an unapproved IMP). By definition, an adverse 
reaction is considered causally related to the study drug.  
6.2.1.1.4 
Adverse Events of Special Interest 
There are no prespecified AEs of special interest for this study.  


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6.2.1.2 Eliciting and Documenting Adverse Events 
Adverse events will be reported from the date of signed informed consent and through for 
28 days after cessation of dosing. Adverse events occurring after the 28 days post-treatment 
would only be reported if the investigator considers it to be related to the study treatment. 
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 drug or study participation, the investigator must promptly notify the sponsor (or 
designee). 
Serious AEs that occur more than 30 days after the last dose of study drug need not be 
reported unless the investigator considers them related to the study drug. 
At every study visit, participants will be asked a standard nonleading question to elicit any 
medically related changes in their well-being. They will also be asked if they have been 
hospitalized, had any accidents, used any new medications, changed concomitant medication 
regimens (prescription or OTC medications), noticed any changes in bowel habits, or had 
unplanned visits to their general practitioner since the last visit. 
In addition to participant observations, AEs identified from any study data (eg, laboratory 
values, physical examination findings, ECG changes) or identified from review of other 
documents (eg, participant diaries) that are relevant to participant safety will be documented 
on the AE page in the eCRF. 
6.2.1.2.1 
Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the 
participant’s daily activities or their health. The intensity of the AE will be rated in 
accordance with the CTCAE version 5.0. 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. Adverse events characterized 
as intermittent do not require documentation of onset and duration of each episode. 


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6.2.1.2.2 
Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study drug is part of the 
documentation process. Regardless of the investigator's assessment of an AE's relationship to 
study drug, the AE must be reported.  
The relationship or association of the study drug in causing or contributing to the AE will be 
characterized using the following classification and criteria: 
Unrelated: 
There is no association between the study drug and the reported event. 
 
Possible: 
Treatment with the study drug caused or contributed to the AE, ie, the event 
follows a reasonable temporal sequence from the time of drug administration or 
follows a known response pattern to the study drug but could also have been 
produced by other factors. 
 
Probable: 
A reasonable temporal sequence of the event with drug administration exists 
and, based upon the known pharmacological action of the drug, known or 
previously reported adverse reactions to the drug or class of drugs, or judgment 
based on the investigator’s clinical experience, the association of the event with 
the study drug seems likely. The event disappears or decreases on cessation or 
reduction of the dose of study drug. 
 
Definite: 
A definite causal relationship exists between drug administration and the AE, 
and other conditions (concurrent illness, progression/expression of disease 
state, or concurrent medication reaction) do not appear to explain the event. The 
event reappears or worsens if the study drug is re-administered. 
6.2.1.3 Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page in the eCRF. 
Information to be collected includes the following: 
• Dose (number of capsules per day) 
• Description of the event / event term 
• Date and time of onset 
• Investigator-specified assessment of severity 


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• Investigator-specified assessment of causal relationship to study drug 
• Date and time of resolution of the event 
• Seriousness 
• Lot/batch number 
• Any required treatment or evaluations 
• Action taken with the study drug due to the event 
• Outcome 
• Investigator-specific assessment if the AE is related to a recent/current COVID 
infection 
• If a COVID positive PCR test received within last 14 days 
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, 
reactions to concurrent medications, or progression of disease states must also be reported. 
All AEs will be followed to adequate resolution. The then-current version of MedDRA will 
be used to code all AEs. 
Any medical condition that is present at the time that the participant is screened but does not 
deteriorate should not be reported as an AE, but it should be captured in the medical history 
page(s) of the eCRF. However, it should be recorded as an AE at any time during the study 
that it deteriorates to a greater extent than would be expected. 
If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. 
6.2.1.3.1 
Reporting Serious Adverse Events 
Any AE that meets SAE criteria (Section 6.2.1.1) must be reported to 
 
immediately (ie, within 24 hours) after the time site personnel first learn about the 
event.  




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event onset, comparing the severity of each SUSAR and the cumulative event frequency 
reported for the study with the severity and frequency reported in the EDP1815 IB. 
Reporting requirements will also be based on the investigator's assessment of causality and 
seriousness, with allowance for upgrading by the sponsor as needed. If an AE, after causality 
and expectedness assessment, is regarded as a potential SUSAR by the medical monitor and 
in agreement with the sponsor, unblinding for regulatory reporting purposes must be 
performed before notification of the SUSAR to the regulatory authorities and IRBs/ECs, as 
applicable. The procedure must ensure that the identity of the IMP is only revealed to those 
that need to obtain this information. 
6.2.1.4 Follow-Up of Participants Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not clinically 
significant, the event is considered stable, the participant dies, or the participant is lost to 
follow-up. 
6.2.2 Bristol Stool Form Scale 
The BSFS is a classification system for the form (appearance) of human feces (O’Donnell et 
al 1990) that has been determined to be a reliable and validated assessment that correlates 
well with stool water content (Blake et al 2016). In addition, the Prevotella enterotype has 
been found to be more abundant in subjects with looser stools (Vandeputte et al 2016).  
The BSFS classifies human feces into 7 consistency categories, with the highest scores 
corresponding to loose stools and fast colon transit and the lowest scores corresponding to 
hard stools (low stool water content) and slow colon transit.  
During the screening period, participants will complete a 7-day stool diary over the week 
before the baseline visit. Participants will record in the diary the date and time of each 
defecation, as well as its BSFS category. Participants will bring their completed diaries to the 
baseline visit, when study staff will collect it for entry in the eCRF.  
6.2.3 Physical Examinations 
A complete physical examination will be conducted, including assessments of the skin and 
cardiovascular, respiratory, GI, and neurological systems. Height (at screening only) and 


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weight will also be measured and recorded (without shoes, street clothing). Body mass index 
will be calculated from the height and weight. Investigators should pay special attention to 
clinical signs related to previous serious illnesses. 
6.2.4 Vital Signs 
Blood pressure, pulse rate, respiratory rate, and temperature will be assessed. Blood pressure 
and pulse measurements will be assessed in a sitting position with a completely automated 
device. Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (eg, television, mobile phones). 
Vital signs (to be checked prior to any procedures) will consist of 1 pulse rate and 3 blood 
pressure measurements (3 consecutive blood pressure readings will be recorded at intervals 
of at least 1 minute). The lowest of the 3 blood pressure readings will be recorded on the 
eCRF. 
6.2.5 Electrocardiograms 
Single 12-lead ECGs will be obtained as outlined in the SoA (Table 6-1) using an ECG 
machine that automatically calculates the heart rate and measures PR, RR, QRS, QT, and 
QTcF intervals.  
At each visit, a single individual ECG tracing should be obtained: if, in the judgment of the 
investigator, the ECG tracing appears to be clinically significant, it should be repeated. If the 
repeated tracing also appears clinically significant, the investigator should report the 
abnormality as an AE and consult with the medical monitor to decide whether the participant 
should continue treatment in the study.  
6.3 Pregnancy 
Pregnancy is not regarded as an AE unless there is a suspicion that a study drug may have 
interfered with the effectiveness of a contraceptive medication. Any pregnancy that occurs 
during study participation or up to 28 days after the final dose of study drug must be reported 
to 
 Safety by phone or email, within 2 weeks of learning of its occurrence. 
 Safety will send the Exposure in Utero Form to the site for completion 
within 24 hours. This form should be completed and returned to 
 Safety 
within 24 hours of receipt. The pregnancy must be followed up until the first “well-baby 


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visit” (or similarly purposed visit 6 to 8 weeks postpartum) to determine outcome (including 
spontaneous miscarriage, elective termination, normal birth, or congenital abnormality) and 
status of mother and child, even if the participant was discontinued from the study. If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE (ie, 
postpartum complication, spontaneous abortion, stillbirth, neonatal death, congenital 
anomaly, ectopic pregnancy), the investigator should follow the procedures for reporting an 
SAE. Pregnancy complications and elective terminations for medical reasons must be 
reported as an AE or SAE. Spontaneous miscarriages must be reported as an SAE. 
Any SAE occurring in association with a pregnancy, brought to the investigator’s attention 
after the participant has completed the study, and considered by the investigator as possibly 
related to the study treatment, must be promptly reported to 
. 
6.4 Laboratory Analyses 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECGs, vital sign measurements), including those that worsen from 
baseline or are clinically significant in the medical and scientific judgment of the 
investigator, are to be recorded as AEs or SAEs. However, any clinically significant safety 
assessments that are associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant’s condition, are not to be reported as AEs 
or SAEs. 
Standard laboratory analyses to understand safety and tolerability include the following:  
• Blood or plasma analytes: urea, creatinine, sodium, potassium, ALT, AST, total and 
direct bilirubin, CRP, creatine kinase, fasting glucose, fasting lipid panel (total 
cholesterol, HDL, LDL, triglycerides) 
• Hematologic analyses: full blood count, including hemoglobin, MCV, MCH, MCHC, 
hematocrit, percent reticulocytes, platelet count; differential white blood cell count 
including neutrophils, lymphocytes, monocytes, and eosinophils 
• Urinalysis by dip stick: protein, blood, glucose, ketones, bilirubin, pH, nitrites, and 
specific gravity 


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Other screening tests include the following:  
• Serology (HIV antibody, HbsAg, and HCV antibody) 
• Serum pregnancy test (HCG) at screening, urine test thereafter 
Blood samples for assessment of fasting blood glucose and lipid panel will be obtained after 
the participant has fasted for at least 8 hours.  
A central laboratory (or specialized central laboratories) will be used for all laboratory 
analyses. Details of sample collection and handling procedures will be provided in the 
specific laboratory manual.  
The investigator must review the laboratory reports, document this review, and record any 
clinically relevant changes occurring during the study. If the laboratory reports are not 
transferred electronically, the values must be filed with the source information (including 
reference ranges). In most cases, clinically significant abnormal laboratory findings are those 
that 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 during 
participation in the study or within 30 days after the last dose of study drug should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor. If such values do not return to 
normal/baseline within a time judged reasonable by the investigator, the etiology should be 
identified, and the sponsor notified. 
All protocol-required laboratory assessments, as defined in this section, must be conducted in 
accordance with the laboratory manual and the SoA (Table 6-1). Screening laboratory results 
will be used to confirm eligibility at Visit 2 (Baseline). 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 (eg, SAE or AE or dose modification), then the results must be recorded in the 
eCRF. 


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6.4.1 Blood Volume  
The planned maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 130 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples. The planned maximum amount of blood collected from each participant at a 
single visit will not exceed 46 mL, and the planned maximum amount of blood collected 
from each participant over 30 days will not exceed 58 mL.  
6.4.2 Pharmacokinetics 
Systemic exposure following oral EDP1815 dosing is estimated to be very low based on lack 
of detection in blood (<0.01% of administered dose). However, plasma samples will be taken 
from all participants for the estimate of systemic EDP1815 levels by PCR with strain-specific 
primers that can detect EDP1815 specifically, even when other strains of Prevotella histicola 
are present. Any effects of EDP1815 on the gut microbiome will be investigated using 16S 
ribosomal RNA sequencing, which measures both the presence and quantity of microbes at 
the genus level. Sampling will be performed as specified in the SoA (Table 6-1, blood sample 
for systemic levels of microbes).  
6.4.3 Pharmacodynamics and Biomarkers  
Procedures for sample collection, processing, storage, and shipment will be detailed in the 
study specific laboratory manual. Biomarkers are exploratory endpoints and analytical results 
for biomarkers will not be included in the CSR. They will be reported separately from the 
CSR.  
Digital photographs should be taken of up to 6 lesion sites that have a lesion area ideally 
greater than 2 cm by 2 cm at baseline. The same locations photographed at baseline should be 
followed throughout the study for each participant. Procedural details for digital photography 
will be provided in the specific user manual.  
6.4.3.1 Histologic Assessment 
A 4 mm punch biopsy will be taken by suitably trained study personnel (see Section 6.1.10). 
Standard histology will be performed on skin plaque biopsies (including epidermal thickness, 
basal mitotic counts and immune cell infiltrates, immunohistochemistry) from approximately 


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15 participants in each cohort. Details will be provided in the study specific laboratory 
manual. The histologic evaluations are exploratory and are outside the scope of the CSR.  
6.4.3.2 mRNA Transcription Analysis 
An mRNA transcription analysis will be performed on the skin plaque biopsies.  
6.4.3.3 Blood Cytokine and Chemokine Analysis 
Blood samples will be stimulated ex vivo and analyzed for levels of cytokines and 
chemokines, including IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-17A, TNFα, and 
IFNγ (ie, exploratory biomarkers). 
6.4.3.4 Analysis of Fecal Microbiome  
The microbiome composition of stool samples will be assessed by 16S ribosomal RNA 
sequencing, which looks at the diversity and abundance of microbes in the colonic 
microbiome (Human Microbiome Project Consortium 2012). EDP1815 is not expected to 
alter the composition of the microbiome, but it is being evaluated as a safety biomarker.  


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7 Statistical Considerations 
Analysis methods for key endpoints are described below. Further details on all analyses will 
be described in the SAP. 
No formal hypothesis will be tested. A model-based probability inference approach in a 
Bayesian framework will be used to guide decision-making around dose selection. Posterior 
estimates and 95% CrI for the difference between each active dose and placebo will be 
produced for relevant primary and secondary endpoints. 
Unless otherwise specified, missing data will be considered as missing at random and will be 
accounted for using mixed models for repeated measures, with all time points collected for 
the relevant endpoint included in the model. This includes data which is excluded due to 
collection after treatment discontinuation or after a protocol deviation as applicable to the 
definition of the estimands used in the analysis. 
The primary analysis for the study will occur after all participants have completed 4 weeks of 
follow-up after their last dose of study medication (end of Part A). The final analysis for the 
study will occur when all participants have completed the required relapse and rebound 
follow-up period of up to 24 weeks post-treatment (end of Part B). 
7.1 Estimands and Intercurrent Events 
7.1.1 Primary Efficacy Estimand 
The primary estimand will be the effect of EDP1815 on the percent change in PASI score 
from baseline to Week 16 in the mITT set of all treated participants, regardless of deviations 
from the protocol. Only data collected while on treatment will be used to account for the 
intercurrent event of treatment discontinuation (hypothetical strategy based on adherence to 
treatment only). The posterior mean difference between each active dose and the pooled 
placebo will be estimated. 
Percent change from baseline in PASI score at each visit will be calculated as: 
100*(PASI score at Visit – baseline PASI score) / baseline PASI score. 
A negative percentage change from baseline will indicate an improvement. 
For the primary analysis, 3 supportive estimands will also be considered: 


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• To assess the impact of intercurrent events related to protocol deviations believed to 
impact efficacy, a supportive analysis will be performed where all data collected after 
any such identified protocol deviations will be excluded. Participants who had a 
protocol deviation believed to impact efficacy prior to the first dose of treatment 
(hypothetical strategy based on adherence to treatment and the aspects of the protocol 
which impact efficacy) will be completely excluded from this analysis. 
• To assess the impact of treatment discontinuation for any reason, a supportive 
analysis will be performed in which all data collected up to the end of Week 16, 
including any data collected after treatment discontinuation will be included 
(treatment policy strategy).  
• To assess the impact of treatment discontinuation due to a requirement for alternative 
therapy, a supportive analysis will be performed where the highest PASI score 
recorded prior to treatment discontinuation will be applied to all expected visits after 
treatment discontinuation up to Week 16.  
The primary analysis will be performed using a Bayesian MMRM as fully described in 
Section 7.6.1. Data from visits prior to Week 16 will be included in the model and missing 
data will not be explicitly imputed.  
Supportive analyses will also be performed in the same manner, using the 3 supportive 
estimands as defined above. These will explore the possible impact of the intercurrent events 
of treatment discontinuation for any reason, treatment discontinuation due to requirement for 
alternative treatment, and events relating to protocol deviations that may have an impact on 
efficacy. 
7.1.2 Secondary Efficacy Estimands 
Estimands for the analyses of all secondary endpoints are shown in Table 7-1. 


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Table 7-1 
Summary of Secondary Estimands 
Population of 
interest 
Endpoint 
Consideration of 
intercurrent events 
Summary measure 
mITT set 
Mean percentage change from 
baseline in PASI Score at 
Weeks 4, 8, and 12 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior mean difference 
between each active treatment 
group and pooled placebo at 
each visit 
mITT set 
Mean absolute change from 
baseline in PASI Score at 
Weeks 4, 8, 12, and 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior mean difference 
between each active treatment 
group and pooled placebo at 
each visit 
mITT set 
Achievement of PASI-50 at 
Weeks 4, 8, 12, and 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior odds ratio for response 
between each active treatment 
group and pooled placebo at 
each visit  
mITT set 
Time to first achievement of 
PASI-50 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Hazard ratio for each active 
group versus placebo 
mITT set 
Achievement of PASI-75, 
PASI-90 and PASI-100 at 
Week 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Proportion of response for each 
endpoint in each treatment group 
at each visit 
mITT set 
Achievement of PGA of 0 or 
1 with a ≥2-point 
improvement from baseline at 
Week 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior odds ratio for response 
between each active treatment 
group and pooled placebo  
mITT set 
Achievement of PGA of 0 at 
Week 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior odds ratio for response 
between each active treatment 
group and pooled placebo  
mITT set 
Mean percentage change from 
baseline in PGA×BSA at 
Weeks 4, 8, 12, and 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior mean difference 
between each active treatment 
group and pooled placebo at 
each visit 
mITT set 
Mean absolute change from 
baseline in PGA×BSA at 
Weeks 4, 8, 12, and 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior mean difference 
between each active treatment 
group and pooled placebo at 
each visit 
mITT set 
Mean percentage change from 
baseline in LSS at Weeks 4, 
8, 12, and 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior mean difference 
between each active dose and 
pooled placebo at each visit 
mITT set 
Mean absolute change from 
baseline in LSS at Weeks 4, 
8, 12, and 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior mean difference 
between each active dose and 
pooled placebo at each visit 
mITT set 
Mean percentage change from 
baseline in DLQI score at 
Weeks 4, 8, 12, and 16 
To include all data collected 
prior to treatment 
Posterior mean difference 
between each active dose and 
pooled placebo at each visit 


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Population of 
interest 
Endpoint 
Consideration of 
intercurrent events 
Summary measure 
discontinuation, regardless of 
protocol deviations 
mITT set 
Mean absolute change from 
baseline in DLQI score at 
Weeks 4, 8, 12, and 16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior mean difference 
between each active dose and 
pooled placebo at each visit 
mITT set 
Mean percentage change from 
baseline in mNAPSI total 
score at Weeks 4, 8, 12, and 
16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior mean difference 
between each active dose and 
pooled placebo at each visit 
mITT set 
Mean absolute change from 
baseline in mNAPSI total 
score at Weeks 4, 8, 12, and 
16 
To include all data collected 
prior to treatment 
discontinuation, regardless of 
protocol deviations 
Posterior mean difference 
between each active dose and 
pooled placebo at each visit 
Week 16 
responders set 
Cumulative incidence of 
partial relapse at Weeks 20, 
24, 28, and 40 
To include all data collected 
after treatment 
discontinuation 
Proportion of participants to 
relapse in each treatment group 
at each visit 
Week 16 
responders set 
Cumulative incidence of 
complete relapse at 
Weeks 20, 24, 28, and 40 
To include all data collected 
after treatment 
discontinuation 
Proportion of participants to 
relapse in each treatment group 
at each visit 
mITT set  
Cumulative incidence of 
rebound at Weeks 20, 24, 28, 
and 40 
To include all data collected 
after treatment 
discontinuation 
Proportion of participants to 
rebound in each treatment group 
at each visit 
 
Summaries and analyses of the secondary endpoints are detailed in full in Section 7.6.2. 
7.2 Exploratory Endpoints 
The exploratory endpoints include the following: 
• Percentage of participants achieving PASI-50, PASI-75, PASI-90, and PASI-100 at 
Weeks 4, 8, and 12  
• Percentage of participants achieving PGA of 0 or 1 with a ≥2-point improvement at 
Weeks 4, 8, and 12  
• Percentage of participants achieving PGA of 0 at Weeks 4, 8, and 12  
• Mean change from baseline in PSI quality of life total and itch scores at Weeks 12 
and 16 


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• Mean percentage change from baseline in PSI quality of life total and itch scores at 
Weeks 12 and 16 
• Mean change from baseline in Pain and Fatigue scores at Weeks 4, 8, 12, and 16 
• Mean percentage change from baseline in Pain and Fatigue scores at Weeks 4, 8, 12, 
and 16 
• Mean change from baseline in fasting blood glucose and fasting lipid panel at 
Weeks 8 and 16 
• Mean duration of remission in participants who achieve PASI-100 
• Mean duration of treatment success in participants who achieve PASI-50 
• Mean duration of therapeutic response in participants after cessation of study 
treatment 
Biomarker endpoints (statistical analysis to appear separately from the CSR) include the 
following: 
• Histological assessment of skin plaque biopsies (including epidermal thickness, basal 
mitotic counts and immune cell infiltrates) at Week 16 versus baseline 
• mRNA transcription analysis on skin plaque biopsies at Week 16 versus baseline 
• Blood cytokine and chemokine levels at Week 16 versus baseline 
• Microbiome composition (in feces) at Week 16 and Week 20 versus baseline 
Exploratory endpoints will be summarized using the mITT set, with data collected after 
discontinuation of treatment excluded but without consideration of any protocol deviations. 
7.3 Sample Size Determination 
The sample size of 225 participants in total, has been chosen to explore the tolerability and 
safety of EDP1815. Although the study will use a model-based probability inference 
approach in a Bayesian framework, the following power calculation was also performed 


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(using a basic frequentist approach) in order to give confidence that enough participants are 
available to find a clinically meaningful difference between active dose and placebo if the 
below assumptions are met. 
The primary efficacy endpoint is the percent change from baseline in the PASI score at 
Week 16. Percent change from baseline relative to placebo will be estimated within the 
model (Section 7.6.1) as (percent change in active) - (percent change in placebo), with a 
negative value indicating a greater improvement for active than placebo. A percent change 
from baseline relative to placebo of at least 20% will be considered clinically meaningful. 
The pooled standard deviation across all doses is assumed to be 25%. 
Participants in the placebo arm of each cohort will be pooled for the statistical analysis in 
order to compare active and control arms resulting in 75 participants randomized to the 
pooled placebo group and 50 participants randomized to each active treatment group 
(EDP1815 0.8 × 1011 cells, EDP1815 3.2 × 1011 cells, and EDP1815 8.0 × 1011 cells). 
Assuming that no more than 15% of participants will discontinue treatment before the 
Week 16 visit, at least 42 active and 21 placebo participants in each of the 3 cohorts are 
expected to provide data through the Week 16 visit. 
Each pairwise comparison between pooled placebo and active dose would be expected to 
have more than 95% power to detect a difference between the treatment groups at the 5% 
significance level under the assumption that pooling the placebo groups is a valid strategy. If 
the 3 placebo cohorts are considered to be too heterogeneous for pooling into a single 
reference group, the power to detect a difference in each within-cohort pairwise comparison 
between active and placebo doses would be greater than 80%. 
As the statistical inference for this study will focus on estimation rather than testing a formal 
hypothesis, no multiplicity adjustments of the different comparisons between groups in order 
to control the study-wise type I error rate will be performed. 
Similarly, as there is no intention to use any interim analyses to stop the study early for 
efficacy (Section 7.6.7), no adjustments for multiplicity will be made to account for any 
analyses performed as part of the interim analyses. 
7.4 Analysis Sets 
The following analysis sets will be used in the statistical analyses. 


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Enrolled set: The enrolled set will consist of all participants who sign the ICF. 
mITT set: The mITT set will consist of all participants who were randomized to treatment 
and who received at least one dose of study treatment. Participants who withdraw from the 
study before the end of Week 4 and are replaced will be included in this analysis set. All 
analyses using the mITT will group participants according to randomized treatment.  
PPS: The PPS will consist of all mITT participants who were not replaced (following study 
withdrawal before the end of Week 4) and who do not have a protocol deviation that may 
impact efficacy with a start date for the deviation before initiation of study treatment. Note 
that in the case of participants who have a protocol deviation with a potential impact on 
efficacy after initiation of treatment, the participant will remain in the PPS but all data 
collected after the protocol deviation occurred will be excluded from any analyses performed 
using the PPS. All analyses using the PPS will group participants according to treatment 
received at the start of the study. Deviations that may affect efficacy are shown in Table 7-2.  
Week 16 responders set: The Week 16 responders set will consist of all mITT participants 
who achieved a PASI-50 response at Week 16. 
Safety set: The safety set will consist of all participants who received any study drug. All 
analyses using the safety set will group participants according to treatment received. If 
participants received multiple treatments during the study, they will be assigned to treatment 
group in the following manner: 
• If participant received both active EDP and placebo treatments, they will be assigned 
to the active treatment group. 
• If participant received 2 or more different active dose levels, they will be assigned to 
the treatment they received for the longest period. 
The mITT set will be the primary population of interest for the efficacy section, with some 
supportive analyses performed using the PPS. The safety set will be used for all safety 
summaries. 


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Table 7-2 
Deviations with a Potential Impact on Efficacy 
Description 
Evaluation Period 
Impact on PPS analyses 
Not meeting inclusion 
criteria 3, 4, or 6 or 
meeting any of exclusion 
criteria 1-12 or 27  
Baseline 
Exclude participant from PPS. 
Use of any prohibited 
medication 
(Section 5.8.2.1) 
Throughout study 
If start date of prohibited medication ≤ date of first dose 
of study drug then exclude participant from PPS. 
Otherwise, include participant in PPS but exclude all 
data collected on or after start date of prohibited 
medication. 
Compliance with study 
drug <80%  
Evaluated in 8-week 
periods (Weeks 1-8 
and 9-16) 
If participant is non-compliant within Week 1-8 
treatment period, then exclude from PPS. 
If participant is non-compliant only within Week 9-16 
treatment period, include participant in PPS but exclude 
all data collected after the Week 8 visit date.  
More than 7 consecutive 
days with no study 
medication without 
participant being 
permanently withdrawn 
from study medication  
Throughout study 
Participant will not be excluded from PPS, but all data 
collected after the 8th consecutive day with no study 
medication will be excluded. 
More than 14 total days 
with no study medication 
(does not need to be 
continuous)  
Throughout study 
Exclude participant from PPS. 
Incorrect study treatment 
taken 
Throughout study 
Participants will not be excluded from PPS. 
If a participant received a study drug other than that 
received at the start of the study, then exclude all data 
collected on or after the date at which the treatment 
change occurred. 
Study treatment blind 
broken 
Throughout study 
If participant’s blind is broken prior to first dose of 
study drug then exclude from PPS. 
Otherwise, include participant in PPS but exclude all 
data collected on or after the date on which the blind 
was broken. 
 
7.5 Description of Subgroups to Be Analyzed 
Results may be summarized by individual cohort.  
Subgroup analysis of the primary estimand will be performed based on the following 
subgroups: 


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• Baseline PASI score (<10, ≥10) 
• Baseline PGA score (2, 3) 
• Baseline BMI (<30 kg/m2, ≥30 kg/m2) 
If the placebo groups from the 3 cohorts are found to be too heterogeneous to be pooled 
(Section 7.6.1), the primary and secondary analyses will be performed using within-cohort 
comparisons of active and placebo treatments, and summary tables may also be produced by 
cohort. 
7.6 Statistical Analysis Methodology 
Statistical analysis will be performed using SAS software Version 9.3 or later.  
In addition to the inferential analyses described in Sections 7.6.1 and 7.6.2, descriptive 
statistics will be provided to summarize all endpoints by treatment group. 
Continuous variables will be summarized using the mean, standard deviation, median, 
minimum value, and maximum value. Categorical variables will be summarized using 
frequency counts and percentages. Time-to-event variables will be summarized using 
Kaplan-Meier estimates of the proportion of participants with the event at each visit. Data 
will be listed in data listings. 
Details of the statistical analyses, methods, and data conventions will be described in the 
SAP. 
7.6.1 Analysis of Primary Efficacy Endpoint 
The assumption that the 3 cohorts of placebo participants can be pooled into a single placebo 
group to be used as a control for all active doses will be examined using mean (±SD) plots 
and box plots of percent change in PASI score against time. In addition, an MMRM will be 
used to compare the 3 cohorts of placebo participants. The model will include parameters for 
cohort, visit and baseline PASI score together with cohort*visit and baseline PASI score*visit 
interactions. Least squares mean (95% CI) estimates for each placebo cohort will be plotted 
by visit. 


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A decision will be made by the Evelo study team, based on examination of the above figures 
and model, on whether the pooling strategy is appropriate.  
The primary analysis will be performed using a Bayesian MMRM. The model will include 
parameters for treatment*visit and baseline PASI score*visit interactions. Body mass index, 
gender, country, and time since diagnosis will also be considered and included as parameters 
if found to be significant (p<0.05). The model will not include an intercept. Visit will consist 
of 6 levels (Weeks 1, 2, 4, 8, 12, and 16) and treatment will consist of 4 levels (pooled 
placebo, EDP1815 0.8 × 1011 cells, EDP1815 3.2 × 1011 cells, and EDP1815 8.0 × 1011 cells) 
if the placebo pooling strategy is considered appropriate or 6 levels (Placebo matching 
EDP1815 0.8 × 1011 cells, Placebo matching EDP1815 3.2 × 1011 cells, Placebo matching 
EDP1815 8.0 × 1011 cells, EDP1815 0.8 × 1011 cells, EDP1815 3.2 × 1011 cells, and 
EDP1815 8.0 × 1011 cells) if the placebo pooling strategy is not considered appropriate. 
The priors for all parameters in the model will be non-informative and follow a normal 
distribution with mean 0 and SD 1000. The prior for the variance-covariance matrix will 
follow an inverted Wishart distribution with degrees of freedom equal to the number of visits 
and an identity scale matrix. The choice of Wishart distribution is based on it being the 
conjugate prior of the inverse-covariance matrix of a multivariate-normal random vector. 
If the assumption of similarity between the 3 placebo cohorts is considered appropriate, the 
placebo cohorts will be pooled, and a single placebo control group will be used for the 
pairwise differences for each active dose to placebo. If the assumption of similarity is 
considered inappropriate, each placebo dose will be included in the model as a separate dose 
level and pairwise comparisons between each active dose and placebo will be performed 
using only the matching placebo dose data for the relevant active dose. 
The adjusted posterior mean percentage change from baseline and the associated 95% HDP 
CrI for each treatment at Week 16 will be reported, together with the adjusted mean 
difference from placebo and the associated 95% HDP CrI for each active dose at each visit 
and the probability that each treatment difference is less than 0%, -20%, -30%, and -50%. 
Model checking and diagnostic plots, including posterior density plots of the posterior 
samples for all parameters in the model and residual plots to evaluate the distributional 
assumptions underlying the model, will be produced. The assumption that data are missing at 
random will be evaluated by plotting the mean percentage change in PASI score against visit, 


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by treatment group, for the subgroups of participants who completed 16 weeks of study drug 
compared with those who discontinued study drug before the Week 16 visit. 
If model checking and diagnostic plots show a violation of the assumptions underlying the 
analysis, alternative statistical methods will be considered, appropriate to the type of 
violation observed. 
This primary analysis will be repeated using the 3 supportive estimands defined in 
Section 7.1.1. 
If the assumption of similarity between the placebo cohorts is supported, a supplementary 
analysis will be performed on the percent change from baseline to Week 16 in PASI score 
using a dose-response model on the pooled cohorts. The log-linear, 3-parameter, and 
4-parameter Emax models will be fitted and compared, with the best fitting model (lowest 
DIC) selected for use in the outputs. 
The dose-response model will be fitted to the data using Bayesian techniques with 
noninformative priors for E0 and Emax and an FUP for ED50 (3- and 4-parameter models 
only) and the slope parameter m (4-parameter model only). The rationale for this choice of 
inference is that the FUP shrinks the dose response towards a flat line throughout the dose 
range, therefore providing more conservative estimates of the dose-response relationship 
compared to maximum likelihood (Bornkamp 2014). The models will be fully described in 
the SAP. 
Based on the selected model, the posterior mean with associated 95% HDP CrI, for the 
difference from placebo for each active dose will be produced for the pairwise differences 
between each active dose and placebo, together with the posterior mean and 95% HDP CrI of 
the treatment difference from placebo for each active dose and posterior probabilities that 
difference from placebo is less than 0, -20%, -30%, and -50%. A further sensitivity analysis 
will be performed on the dose response model, in which participants who withdrew from 
study drug due to treatment will have their Week 16 percentage change from PASI imputed 
as 100% after study drug was discontinued. 
Percent change from baseline in PASI score will be summarized by visit. 


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All summaries and analyses defined above for the primary estimand will be repeated using 
the subgroups defined in Section 7.5. 
7.6.2 Analysis of Secondary Efficacy Endpoints  
All secondary analyses will be performed either using the pooled placebo group if the 
assumption of similarity for the placebo cohorts is considered appropriate or using the 
3 cohort-level placebo groups if it is not considered appropriate.  
Unless otherwise specified, all secondary analyses will be performed on the mITT set, 
excluding data collected after treatment discontinuation, without consideration of any 
protocol deviations. Dose will be treated as a categorical variable and no dose response 
modelling will be done. Comparisons of interest will be between individual EDP1815 doses 
and placebo. All p-values, posterior probabilities, CI, and CrI calculated will be considered as 
descriptive with no further adjustments for multiplicity performed. 
Data will be analyzed as collected and no imputation of missing data will be performed. 
The covariates selected for the Bayesian MMRM analysis for the primary estimand will also 
be used in all other analytical models including covariates. 
Mean percentage change from baseline in PASI score at Weeks 4, 8, and 12 will be analyzed 
as part of the MMRM for the primary estimand. The same statistics produced for the Week 
16 time point will also be produced at Weeks 4, 8, and 12. 
The following secondary endpoints will be analyzed in the same manner as described for the 
primary analysis: 
• Mean absolute change from baseline in PASI score at Weeks 4, 8, 12, and 16  
• Mean percentage change from baseline in LSS at Weeks 4, 8, 12, and 16 
• Mean absolute change from baseline in LSS at Weeks 4, 8, 12, and 16 
• Mean percentage change from baseline in PGA×BSA at Weeks 4, 8, 12, and 16 
• Mean absolute change from baseline in PGA×BSA at Weeks 4, 8, 12, and 16 


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• Mean percentage change from baseline in DLQI score at Weeks 4, 8, 12, and 16 
• Mean absolute change from baseline in DLQI score at Weeks 4, 8, 12, and 16 
• Mean percentage change from baseline in mNAPSI total score at Weeks 4, 8, 12, and 
16 
• Mean absolute change from baseline in mNAPSI total score at Weeks 4, 8, 12, and 16 
For the PASI-50, a generalized linear mixed effects model with a logit link function will be 
fitted using data from all visits. Treatment, visit, and baseline PASI score terms will be 
included in the model as fixed effects, together with treatment*visit and 
baseline PASI score*visit interactions, and any baseline covariates selected in the primary 
analysis model for the primary estimand. Odds ratios and 95% CIs for each active dose 
compared to placebo at each visit will be presented.  
A supportive analysis for the PASI-50 will also be performed, in the same manner as 
described above, in which participants who withdraw from study drug before Week 16 due to 
requirement for alternative therapy will be included in the model with the PASI-50 endpoint 
imputed as ‘not achieved’ at all expected visits after study drug withdrawal. 
A sensitivity analysis will also be performed on the PASI-50. Bayesian logistic regression 
models will be individually fitted at each of Weeks 4, 8, 12, and 16. The model will include 
parameters for treatment and baseline PASI score together with any baseline covariates 
selected in the primary analysis model for the primary estimand. The posterior odds-ratios for 
each pairwise comparison of an active EDP1815 dose and placebo with associated 95% HDP 
CrI will be presented together with the posterior probability that the true odds ratio >1. 
Percentage of participants achieving PGA of 0 or 1 with a ≥2-point improvement and 
percentage of participants achieving a PGA of 0 will be analyzed in the same manner as 
described above for PASI-50 with the exception that the sensitivity analysis using the 
Bayesian logistic regression model will only be fitted on the Week 16 data. 
For the time to first achievement of PASI-50, a nonparametric survival analysis for interval 
censored data will be performed. The expectation-maximization iterative complex minorant 
(EMICM) method for iterative computation of the nonparametric maximum likelihood 


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estimator for the survival function (Wellner and Zahn 1997) will be used. The number and 
proportion of participants who meet the PASI-50 at least once during the study will be 
presented. A generalized log-rank test will be used to compare each active dose with placebo 
and the p-value for treatment difference will also be presented. The estimated survival curves 
for each treatment group will also be presented. 
Cumulative incidence of partial relapse and complete relapse at Weeks 20, 24, 28, and 40 will 
be summarized by treatment group on the Week 12 responders set. 
Cumulative incidence of rebound after cessation of study treatment at Weeks 20, 24, 28, and 
40 will be summarized by treatment group. 
7.6.3 Analyses of Exploratory Efficacy Endpoints 
Exploratory endpoints will be summarized using the mITT population, with data collected 
after discontinuation of treatment excluded but without consideration of any protocol 
deviations. Details of all analyses to be performed on the exploratory endpoints will be 
detailed in the SAP. 
Analyses of biomarkers will be addressed in a data analysis plan outside the study SAP.  
A further exploratory analysis will be performed on the Week 16 results. Adjusted indirect 
comparisons, pivoted around placebo, will be performed against publicly available data from 
two studies in apremilast in mild/moderate or moderate psoriasis. Further details will be 
provided in the study SAP. 
7.6.4 Pharmacokinetic Analyses 
The number and percentage of participants who have a quantifiable concentration of 
EDP1815 in their blood sample will be summarized using the safety set by visit. Placebo 
participants will be pooled into a single treatment group. If at least 20% of participants within 
a treatment group are found to have a quantifiable level at one of the visits, then the 
concentration will be summarized as a continuous variable for the relevant treatment group at 
that visit. 


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7.6.5 Safety Analyses 
All safety endpoints will be tabulated or plotted by treatment group using the safety set. All 
safety analyses will use the pooled placebo group. Further details will be described in the 
SAP. 
7.6.6 Other Analyses 
Tabulations will be provided for completion/withdrawal status, protocol deviations, study 
populations, demographic and other baseline characteristics, use of concomitant medications, 
and exposure of and compliance with study drug. 
7.6.7 Interim Analyses 
An interim analysis may be undertaken during the conduct of the study after at least 50% of 
participants have completed at least 12 weeks of treatment or withdrawn from treatment. The 
purpose of this analyses will be to aid in the planning of future studies and for a better 
understanding of the benefit/risk profile of EDP1815.  
For the interim analysis, unblinded aggregate results will be produced by an unblinded team 
within 
 and reviewed by Evelo personnel for strategic planning use. These will not 
be shared with any study site staff, participants, or clinical monitors who will be involved in 
the collection and review of individual study data. 
The interim analysis will look at the primary endpoint of percentage change from baseline in 
PASI score, secondary, and safety endpoints. The posterior predictive probability 
(Spiegelhalter et al 2004) of the percent change from baseline in PASI score being at least 
20% lower in each active dose compared to the pooled placebo will also be calculated, using 
the estimates of treatment difference found at Week 12 using the Bayesian MMRM described 
for the primary analysis. If the posterior predictive probabilities for all active doses are found 
to be <30%, then the study may be stopped for futility. 
No decisions regarding study conduct, other than the potential to stop the study early for 
futility, will be made based on these assessments and the study will not be stopped if superior 
efficacy is found. Outputs featuring unblinded treatment assignments will be created by the 
unblinded analysis group within 
 and shared with selective Evelo personnel (to be 
included in the data dissemination plan). 


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Further details of the outputs that will be produced will be described in the SAP. 


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8 Data Quality Assurance 
This study will be conducted according to the ICH E6(R2) risk and quality processes 
described in the applicable procedural documents. The quality management approach to be 
implemented in this study will be documented and will comply with the current ICH 
guidance on quality and risk management. The sponsor assumes accountability for actions 
delegated to other individuals (eg, Contract Research Organizations). 
The sites will maintain source documentation and enter participant data into the eCRF as 
accurately as possible and will rapidly respond to any reported discrepancies. Electronic 
CRFs are accessed through Medidata Rave® (Medidata Solutions Inc, New York, New York). 
This EDC system is validated and compliant with US Title 21 CFR Part 11. Each person 
involved with the study will have an individual username and password that allows for record 
traceability. Thus, the system, and subsequently any investigative reviews, can identify 
coordinators, investigators, and individuals who have entered or modified records, as well as 
the time and date of any modifications. A quality review of the data will be performed by the 
site with additional reviews by the clinical monitor through source data verification.  
Each eCRF is presented as an electronic copy, allowing data entry by site staff, who can 
add and edit data, identify and resolve discrepancies, and view records. This system provides 
immediate direct data transfer to the database, as well as immediate detection of 
discrepancies, enabling site coordinators to resolve and manage discrepancies in a timely 
manner.  
Paper copies of the eCRFs and other database reports may be printed by the investigator. 
This system provides site staff, monitors, and reviewers with access to hard copy audits, 
discrepancy reviews, and investigator comment information.  
After all data reviews and query resolutions are complete, the SAP is approved and signed, 
and any summary/analysis populations are approved, the database will be locked. 
8.1 Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the participants treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. These source documents may include diaries, laboratory reports, 


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ECG strips, etc. Electronic devices will be used for the administration of investigator and 
participant responses to Clinical Outcome Assessments. Data collected via these devices will 
be uploaded directly to a central database for storage and analysis. Details will be provided in 
the specific user manual.  
All eCRF information is to be completed. If an item is not available or is not applicable, this 
fact must be indicated. Blank spaces must not be present unless otherwise directed. Study site 
personnel will enter participant data into the Medidata Rave system. The analysis data sets 
will be a combination of these data and data from other sources (eg, laboratory data). 
Clinical data management will be performed in accordance with applicable 
standards 
and data cleaning procedures to ensure the integrity of the data (eg, removing errors and 
inconsistencies in the data). Adverse events and medical history will be coded using the 
then-current MedDRA terminology. Concomitant medications will be coded using the most 
current available WHO Drug Dictionary. 
After database lock, each study site will receive an electronic copy of their site-specific 
eCRF data as entered into the EDC system for the study, including full discrepancy and audit 
history. Additionally, an electronic copy of all the study site’s data from the study will be 
created and sent to the sponsor for storage. 
 will maintain a duplicate electronic copy for 
their records. In all cases, participant initials will not be collected or transmitted to the 
sponsor.  


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9 Ethics 
9.1 Independent Ethics Committee or Institutional Review Board 
Country regulations, US federal regulations, and the ICH guidelines require that approval be 
obtained from an IRB or IEC before participation of human participants in research studies. 
Before study onset, the protocol, ICF, advertisements to be used for the recruitment of study 
participants, and any other written information regarding this study to be provided to the 
participant or the participant’s legal guardian must be approved by the IRB/IEC. 
Documentation of all IRB/IEC approvals and of the IRB/IEC compliance with ICH 
harmonised tripartite guideline E6(R2): GCP and with applicable regulations in the countries 
where the study will be conducted will be maintained by the site and will be available for 
review by the sponsor or its designee. 
All IRB/IEC approvals must be signed by the IRB/IEC chairman or designee and must 
identify the IRB/IEC name and address, the clinical protocol by title or protocol number or 
both, and the date approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status of 
the study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The 
investigator must promptly supply the sponsor or its designee, the IRB/IEC, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to participants. 
9.2 Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, ICH GCP, and all applicable country and local regulations. 
9.3 Participant Information and Consent 
A written informed consent in compliance with regulatory authority regulations or US Title 
21 CFR Part 50 shall be obtained from each participant before entering the study or 
performing any unusual or nonroutine procedure that involves risk to the participant. An 
informed consent template may be provided by the sponsor to investigative sites. If any 
institution-specific modifications to study-related procedures are proposed or made by the 
site, the consent should be reviewed by the sponsor or its designee or both before IRB/IEC 


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submission. Once reviewed, the consent will be submitted by the investigator to his or her 
IRB/IEC for review and approval before the start of the study. If the ICF is revised during the 
study, all active participants must be reconsented by signing the revised form. 
Before recruitment and enrollment, each prospective participant or his or her legal guardian 
will be given a full explanation of the study, be allowed to read the approved ICF, and have 
any questions answered. Once the investigator is assured that the participant/legal guardian 
understands the implications of participating in the study, the participant/legal guardian will 
be asked to give consent to participate in the study by signing the ICF. The authorized person 
obtaining the informed consent also signs the ICF. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research (if applicable) and explain/address the exploratory 
research portion of the study. Participant medical records need to state that written informed 
consent was obtained.  
The investigator shall retain the signed original ICF(s) and give a copy of the signed original 
form to the participant or legal guardian. 


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10 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the 
IRB/IEC but will not result in protocol amendments. 
10.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain participant confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the participant (or the participant’s legal guardian), except as necessary for 
monitoring and auditing by the sponsor, its designee, the FDA, or the IRB/IEC. 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
10.2 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the sponsor to 
submit the complete and accurate certification or disclosure statements required under 
21 CFR 54. In addition, the investigator must provide to the sponsor a commitment to 
promptly update this information if any relevant changes occur during the investigation and 
for 1 year following the completion of the study. 
Neither the sponsor nor 
 is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither the sponsor nor 
 is financially responsible for 
further treatment of the participant’s disease. 
10.3 Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R2) 
Section 8.2 and Title 21 of the CFR by providing all essential documents. 


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10.4 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of ICH 
E6(R2). The investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations. Study information from this protocol will be 
posted on publicly available clinical trial registers before enrollment of participants begins. 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6(R2) and all applicable guidelines and regulations. 
10.5 Adverse Events and Study Report Requirements 
The investigator agrees to submit reports of SAEs to the sponsor and/or IRB/IEC according 
to the timeline and method outlined in the protocol (Section 6.2.1.3.1). In addition, the 
investigator agrees to submit annual reports to the study site IRB/IEC as appropriate. 
10.6 Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution. Also, the investigator/institution should provide the IRB/IEC with a summary of 
the study’s outcome and provide the sponsor and regulatory authority(ies) with any reports 
required. 
10.7 Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study drug. These documents should be 
retained for a longer period, however, if required by the applicable regulatory requirements 
or by an agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. No records 
may be transferred to another location or party without written notification to the sponsor. 
10.8 Publications and Results Disclosures 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the sponsor will be 


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responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and other related issues. The sponsor has final approval authority over all 
such issues. 
Data are the property of the sponsor and cannot be published without prior authorization 
from the sponsor, but data and publication thereof will not be unduly withheld. 




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11.1 Monitoring 
11.1.1 Safety Review Committee 
There will be no safety review committee or data monitoring committee. 
11.1.2 Monitoring of the Study 
This study will be monitored according to an approved monitoring plan based on the 
objectives, purpose, design, and complexity of the study. The investigator will allocate 
adequate time for all monitoring visits and between visits to facilitate the requirements of the 
study and study timelines. The investigator will also ensure that the monitor or other 
compliance or quality assurance reviewer is given direct access to all study-related 
documents and study-related facilities (eg, pharmacy, diagnostic laboratory), phone, fax, and 
internet and has adequate space to conduct the monitoring visit. Site monitoring is conducted 
to ensure that the rights of human participants are protected, that the study is implemented in 
accordance with the protocol and/or other operating procedures, and that the study uses high 
quality data collection processes. The monitor will evaluate study processes based on Evelo 
or designee standards, ICH E6, and all applicable, regulatory guidelines. 
11.1.3 Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB/IEC review, and regulatory inspections by providing direct access to all study 
records. In the event of an audit, the investigator agrees to allow the sponsor, representatives 
of the sponsor, or a regulatory agency (eg, FDA or other regulatory agency) access to all 
study records. 
The investigator should promptly notify the sponsor and 
 of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 
11.2 Management of Protocol Amendments and Deviations 
11.2.1 Modification of the Protocol 
Any changes in the required procedures defined in this protocol, except those necessary to 
remove an apparent, immediate hazard to the participant, must be reviewed and approved by 


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the sponsor or designee. Amendments to the protocol (including emergency changes) must be 
submitted in writing to the investigator’s IRB/IEC, along with any applicable changes to the 
ICF, for approval before participants can be enrolled into an amended protocol. 
11.2.2 Protocol Deviations 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB/IEC and agreed to by the 
investigator. A significant deviation occurs when there is nonadherence to the protocol or to 
local regulations or ICH GCP guidelines that may or may not result in a significant, 
additional risk to the participant or impacts the integrity of study data. 
The investigator or designee must document and explain in the participant’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard/safety risk to 
study participants without prior IRB/IEC approval. As soon as possible after such an 
occurrence, the implemented deviation or change, the reasons for it, and any proposed 
protocol amendments should be submitted to the IRB/IEC for review and approval, to the 
sponsor for agreement, and to the regulatory authorities, where required. 
In order to keep deviations from the protocol to a minimum, the investigator and relevant site 
personnel will be trained in all aspects of study conduct by the sponsor/sponsor 
representative. This training will occur either as part of the investigator meeting or site 
initiation. Ongoing training may also be performed throughout the study during routine site 
monitoring activities. 
11.3 Study Termination 
Although Evelo has every intention of completing the study, Evelo reserves the right to 
discontinue the study at any time for clinical or administrative reasons. 
If the study is prematurely terminated or suspended, the sponsor or investigator shall 
promptly inform the investigators, the IECs/IRBs, the regulatory authorities, and any contract 
research organization(s) used in the study of the reason for termination or suspension, as 
specified by the applicable regulatory requirements. The investigator shall promptly inform 
the participant and should assure appropriate participant therapy and/or follow-up. 


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The EOS is defined as the date on which the last participant completes the last visit (includes 
follow-up visit). 
11.3.1 Study Halting Criteria 
The study will be halted if any of the following occur: 
• One death considered definitely, probably, or possibly related to the study drug 
• Two or more participants with an SAE considered definitely, probably, or possibly 
related to the study drug 
• Three or more participants with grade 3 AEs of the same type considered definitely, 
probably, or possibly related to the study drug 
11.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
final data are summarized and provided to the regulatory agency(ies) as required by the 
applicable regulatory requirement(s). The sponsor will also ensure that the CSRs in 
marketing applications (as applicable) meet the standards of the ICH harmonised tripartite 
guideline E3: Structure and content of CSRs.  
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the CSR. The investigator will be provided reasonable access to 
statistical tables, figures, and relevant reports and will have the opportunity to review the 
complete study results. 
Upon completion of the final report, the sponsor will provide the investigator with the 
summary of the study results. The investigator is encouraged to share a summary of the 
results with the study participants, as appropriate. The study results will be posted on 
publicly available clinical trial registers.  


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Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire 


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(MPQ), Short‐Form McGill Pain Questionnaire (SF‐MPQ), Chronic Pain Grade Scale 
(CPGS), Short Form‐36 Bodily Pain Scale (SF‐36 BPS), and Measure of Intermittent and 
Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken). 2011;63 Suppl 
11:S240-52. 
Hindson J. Multiple sclerosis: A possible link between multiple sclerosis and gut microbiota. 
Nat Rev Neurol. 2017;13(12):705.  
Human Microbiome Project Consortium. A framework for human microbiome research. 
Nature. 2012;486:215-21.  
Langley RG, Ellis CN. Evaluating psoriasis with Psoriasis Area and Severity Index, Psoriasis 
Global Assessment, and Lattice System Physician's Global Assessment. J Am Acad 
Dermatol. 2004;51(4):563-9. 
Mangalam A, Shahi SK, Luckey D, et al. Human gut-derived commensal bacteria suppress 
CNS inflammatory and demyelinating disease. Cell Rep. 2017;20(6):1269-77. 
Marietta EV, Murray JA, Luckey DH, et al. Human gut-derived Prevotella histicola 
suppresses inflammatory arthritis in humanized mice. Arthritis Rheumatol. 
2016;68(12):2878-88.  
O’Donnell LJD, Virjee J, Heaton KW. Detection of pseudodiarrhoea by simple clinical 
assessment of intestinal transit rate. BMJ. 1990;300:439-40.  
Patel RV, Tsui CL. Evaluating psoriasis: a review of the assessments most commonly used in 
clinical trials. Psoriasis Forum. 2011;17(4):259-66. doi: 10.1177/247553031117a00403.  
Skoie IM, Dalen I, Ternowitz T, et al. Fatigue in psoriasis: a controlled study. Br J Dermatol. 
2017;177(2):505-12. 
Spiegelhalter DJ, Abrams KR, Myles JP. Bayesian approaches to clinical trials and health-
care evaluation. Chichester: John Wiley and Sons Ltd; 2004. 408 p. 
van der Heijden PG, van Buuren S, Fekkes M, et al. Unidimensionality and reliability under 
Mokken scaling of the Dutch language version of the SF-36. Qual Life Res. 2003;12:189–98. 


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Vandeputte D, Falony G, Vieira-Silva S, et al. Stool consistency is strongly associated with 
gut microbiota richness and composition, enterotypes and bacterial growth rates. Gut. 
2016;65:57-62. 
Vandeputte D, Kathagen G, D’hoe K, et al. Quantitative microbiome profiling links gut 
community variation to microbial load. Nature. 2017;551:507-11.  
Walsh JA, McFadden M, Woodcock J, et al. Product of the Physician Global Assessment and 
body surface area: a simple static measure of psoriasis severity in a longitudinal cohort. J Am 
Acad Dermatol. 2013;69(6):931-7. 
Wellner JA, Yihui Z. A hybrid algorithm for computation of the nonparametric maximum 
likelihood estimator from censored data. J Am Stat Assoc. 1997;92(439):945-59. 
Wolfe F. Fatigue assessments in rheumatoid arthritis: comparative performance of visual 
analog scales and longer fatigue questionnaires in 7760 patients. J Rheumatol. 
2004;31(10):1896-902.  
Yan D, Issa N, Afifi L, et al. The role of the skin and gut microbiome in psoriatic disease. 
Curr Dermatol Rep. 2017;6:94-103. 


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13 Appendices 
13.1 Appendix: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Women of Child-Bearing Potential 
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 FSH level in the postmenopausal range must be used to 
confirm a postmenopausal state in women not using hormonal contraception or 
HRT. However, in the absence of 12 months of amenorrhea, an 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.  


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Contraception Guidance: 
Male participants  
Male participants must participate according to one of the following criteria: 
• 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. In 
addition, male participants must refrain from donating sperm for the duration of 
the study and for at least 90 days following their final visit.  
• Have had a vasectomy, and the absence of sperm has been confirmed in the 
ejaculate. 
Female participants 
Female participants of child-bearing potential are eligible to participate if they agree to use a 
highly effective contraceptive method consistently and correctly as described in Table 13-1. 
Table 13-1 
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 (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationb  
• 
Oral  
• 
Intravaginal  
• 
Transdermal  
Progestogen only hormonal contraception associated with inhibition of ovulationb  
• 
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 sterilization 


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Vasectomized partner  
A vasectomized 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 
drug. 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.  
Table 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 drug, which 
may reduce the efficacy of the contraceptive method. In this case, a highly effective 
method of contraception plus condoms should be used during their participation in the 
study up to and including at least 1 complete menstrual cycle (≥28 days) for women and 
90 days for men post last dose.  
 
Pregnancy Testing: 
• A WOCBP should only be included after a negative serum HCG pregnancy test. 
• Pregnancy testing is required at screening, randomization, and 14 days after the last 
dose at the follow-up visit.  
• Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.  
Collection of Pregnancy Information: 
For 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 


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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 fetal status (presence or absence of anomalies) or indication for the procedure.  
For 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 fetal 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 drug by the investigator will be reported to the sponsor as described in 
Section 6.2.1.3.1. 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 drug. 
 


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13.2 Appendix: World Health Organization Classification of Topical 
Corticosteroids 
The potency of a topical corticosteroid depends on the formulation. Potency is also increased 
when a formulation is used under occlusive dressing or in intertriginous areas. In general, 
ointments are more potent than creams or lotions.  
Table 13-2 
WHO Classification of Topical Corticosteroids 
Ultra-High Potency 
Group I 
Clobestasol propionate cream (0.05%) 
Diflorasone diacetate ointment (0.05%) 
High Potency 
Group II 
Amcinonide ointment (0.1%) 
Betamethasone dipropionate ointment (0.05%) 
Desoximetasone (cream or ointment) (0.025%) 
Fluocinonide (cream, ointment, or gel) (0.05%) 
Halcinonide cream (0.1%) 
Group III 
Betamethasone dipropionate cream (0.05%) 
Betamethasone valerate ointment (0.1%) 
Diflorasone diacetate cream (0.05%) 
Triamcinolone acetonide ointment (0.1%) 
Moderate Potency 
Group IV 
Desoximetasone cream (0.05%) 
Fluocinonide acetonide ointment (0.025%) 
Hydrocortisone valerate ointment (0.2%) 
Triamcinolone acetonide cream (0.1%) 


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Moderate Potency (continued) 
Group V 
Betamethasone dipropionate lotion (0.02%) 
Betamethasone valerate cream (0.1%) 
Fluocinonide acetonide cream (0.025%) 
Hydrocortisone butyrate cream (0.1%) 
Hydrocortisone valerate cream (0.2%) 
Triamcinolone acetonide lotion (0.1%) 
Low Potency 
Group VI 
Betamethasone valerate lotion (0.05%) 
Desonide cream (0.05%) 
Fluocinolone acetonide solution (0.01%) 
Group VII 
Dexamethasone sodium phosphate cream (0.1%) 
Hydrocortisone acetate cream (1%) 
Methylprednisolone acetate cream (0.25%) 
Source: Bolognia JL, Jorizzo JL, Schaffer JV. Glucocorticosteroids. Dermatology. 3rd ed. 2012. Ch 125, 2075-
88. 
 

SAP_001.pdf: 
Cover Page 
 
STATISTICAL ANALYSIS PLAN 
V3.0 23Jul2021 
 
NCT04603027  
 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Cohort, Dose-Ranging Study Investigating the Effect of EDP1815 
in the Treatment of Mild to Moderate Plaque Psoriasis 
 
 
 
 
 


Statistical Analysis Plan  
Version 3.0, Final 23-July-2021 
 
EDP1815-201 
 
 
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Page 1 of 81 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol: EDP1815-201 
Protocol Version: V5.0 17NOV2020 
 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Cohort, Dose-Ranging Study Investigating the Effect of EDP1815 in the 
Treatment of Mild to Moderate Plaque Psoriasis 
 
SAP/Amendment Number 
Date 
Final SAP V1.0 
05NOV2020 
Final SAP V2.0 
02JUN2021 
Final SAP V3.0 
23JUL2021 
 
 
 
Prepared for: 
Evelo Biosciences Inc. 
 
 
Prepared by: 
 
 
 
 
 
 
 
Approved by 
Signature 
Date 
 
Immunology Clinical Lead, 
Evelo Biosciences Inc. 
 
 
 
Director of Statistics, 
Evelo Biosciences Inc. 
 
 
 
Senior Statistician,      
. 
 
 
 
 


Statistical Analysis Plan  
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EDP1815-201 
 
 
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Page 2 of 81 
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 .............................................................................................................................. 8 
5 
Study Methods ................................................................................................................................ 9 
5.1 
General Study Design and Plan ............................................................................................. 9 
5.2 
Randomisation and Blinding ............................................................................................... 10 
5.3 
Derived variables ................................................................................................................ 11 
5.3.1 
General ................................................................................................................... 11 
5.3.2 
Demographic and Background Data ...................................................................... 12 
5.3.3 
Efficacy ................................................................................................................... 14 
5.3.4 
Safety...................................................................................................................... 18 
6 
Sample Size ................................................................................................................................... 19 
7 
General Considerations ................................................................................................................. 20 
7.1 
Analysis Populations ........................................................................................................... 20 
7.1.1 
Enrolled Population ................................................................................................ 20 
7.1.2 
Modified Intention to Treat Population ................................................................. 20 
7.1.3 
Per-protocol Population ......................................................................................... 20 
7.1.4 
Safety Population ................................................................................................... 22 
7.1.5 
Week 16 Responders Population ........................................................................... 22 
7.1.6 
Part B Population ................................................................................................... 22 
7.2 
Covariates and Subgroups .................................................................................................. 22 
7.3 
Missing Data ........................................................................................................................ 23 
7.3.1 
Partial Dates/Times ................................................................................................ 23 
7.3.2 
Adverse Event Information .................................................................................... 24 
7.4 
Interim Analyses and Data Monitoring ............................................................................... 24 
7.4.1 
Purpose of Interim Analyses .................................................................................. 24 
7.4.2 
Planned Schedule of Interim Analyses ................................................................... 24 
7.4.3 
Endpoints to be Included in the Interim Analysis .................................................. 25 
7.4.4 
Adjustment of Confidence Intervals and p-values ................................................. 25 
7.4.5 
Practical Measures to Minimise Bias ..................................................................... 25 


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7.4.6 
Documentation of Interim Analyses ...................................................................... 26 
7.5 
Multi-centre Studies ........................................................................................................... 26 
7.6 
Multiple Testing .................................................................................................................. 26 
7.7 
Visit Windows ..................................................................................................................... 26 
8 
Summary of Study Data ................................................................................................................ 26 
8.1 
Study Disposition ................................................................................................................ 28 
8.2 
Protocol Deviations ............................................................................................................. 29 
8.3 
Demographic and Baseline Variables ................................................................................. 29 
8.4 
Medical History ................................................................................................................... 29 
8.5 
Prior and Concomitant Medications ................................................................................... 29 
8.6 
Treatment Compliance ....................................................................................................... 30 
9 
Efficacy Analyses ........................................................................................................................... 30 
9.1 
Pooling of Placebo Cohorts ................................................................................................. 31 
9.2 
Selection of Additional Covariates ...................................................................................... 31 
9.3 
Part B Analysis ..................................................................................................................... 31 
9.4 
Primary Efficacy Analysis ..................................................................................................... 32 
9.4.1 
Primary Efficacy Estimand ...................................................................................... 32 
9.4.2 
Supportive Estimands for the Primary Endpoint ................................................... 32 
9.4.3 
Main Analytical Approach ...................................................................................... 33 
9.4.4 
Sensitivity Analyses ................................................................................................ 35 
9.4.5 
Subgroup Analyses ................................................................................................. 36 
9.5 
Secondary Efficacy Analyses ............................................................................................... 36 
9.5.1 
Percentage Change from Baseline in PASI score at Weeks 4, 8 and 12 ................. 36 
9.5.2 
Other Continuous Secondary Endpoints ................................................................ 37 
9.5.3 
Response Endpoints with Inferential Analysis ....................................................... 37 
9.5.4 
PASI-75, PASI-90 and PASI-100 at Week 16 ........................................................... 39 
9.5.5 
Time to First Achievement of PASI-50 ................................................................... 40 
9.5.6 
Partial Relapse, Relapse and Rebound ................................................................... 40 
9.6 
Exploratory Efficacy Analyses ............................................................................................. 41 
9.6.1 
Exploratory Efficacy Endpoints .............................................................................. 41 
9.6.2 
Indirect Comparisons with Apremilast ................................................................... 42 
10 Safety Analyses ............................................................................................................................. 44 
10.1 Extent of Exposure .............................................................................................................. 44 
10.2 Adverse Events .................................................................................................................... 44 


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10.3 Deaths, Serious Adverse Events and other Significant Adverse Events .............................. 46 
10.4 Pregnancies ......................................................................................................................... 46 
10.5 Clinical Laboratory Evaluations ........................................................................................... 46 
10.6 Other Safety Measures ....................................................................................................... 47 
10.6.1 ECG ......................................................................................................................... 47 
10.6.2 Vital Signs ............................................................................................................... 47 
10.6.3 Physical Examination .............................................................................................. 48 
11 Reporting Conventions ................................................................................................................. 48 
12 Technical Details ........................................................................................................................... 49 
13 Summary of Changes from the Protocol ....................................................................................... 50 
14 References .................................................................................................................................... 50 
15 Appendix 1: List of Tables, Figures and Listings ............................................................................ 51 
15.1 Study Population ................................................................................................................. 51 
15.1.1 Tables ..................................................................................................................... 51 
15.2 Efficacy ................................................................................................................................ 52 
15.2.1 Tables ..................................................................................................................... 52 
15.2.2 Figures .................................................................................................................... 57 
15.3 Safety .................................................................................................................................. 61 
15.3.1 Tables ..................................................................................................................... 61 
15.4 Data Listings ........................................................................................................................ 63 
15.5 Part B Outputs ..................................................................................................................... 65 
15.5.1 Tables ..................................................................................................................... 65 
15.5.2 Figures .................................................................................................................... 66 
15.5.3 Data Listings ........................................................................................................... 67 
16 Appendix 2: Psoriasis Area and Severity Index Score ................................................................... 69 
17 Appendix 3: Physician Global Assessment .................................................................................... 71 
18 Appendix 4: Dermatology Quality of Life Index ............................................................................ 72 
19 Appendix 5: Modified Nail Psoriasis Severity Index ...................................................................... 73 
20 Appendix 6: Psoriasis Symptom Inventory ................................................................................... 75 
21 Appendix 7: SF-36 Pain and Vitality Scores ................................................................................... 76 
22 Appendix 8: MedDRA Internationally Agreed Order for System Organ Class .............................. 78 
23 Appendix 9: Safety Laboratory Evaluations .................................................................................. 79 
 
 
 


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Table of Tables 
Table 1 
Start and End Dates of Treatment Periods for Compliance Calculations ........................... 13 
Table 2 
Protocol Deviations with a Potential Impact on Efficacy .................................................... 21 
Table 3 
Intercurrent Event Strategies for the Primary Estimand .................................................... 32 
Table 4 
Supportive Estimands for the Primary Endpoint ................................................................ 32 
Table 5 
Intercurrent Event Strategy for Secondary Supportive Estimand for PASI-50 ................... 39 
Table 6 
Intercurrent Event Strategies for Partial Relapse, Relapse and Rebound Endpoints ......... 40 
Table 7 
PCI Criteria for Vital Signs ................................................................................................... 48 
Table 8 
Changes to the Protocol Specified Analysis ........................................................................ 50 
Table 9 
MedDRA Internationally Agreed SOC Order ....................................................................... 78 
Table 10 
Safety Laboratory Parameters and Units ............................................................................ 79 
 
 
Table of Figures 
Figure 1 
Study Schema ...................................................................................................................... 10 
 
 


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2 
Abbreviations and Definitions 
AE 
Adverse event 
BMI 
Body mass index 
BSA 
Body surface area 
BSFS 
Bristol Stool Form Scale 
CI 
Confidence interval 
CRF 
Case report form 
CrI 
Credible interval 
CRP 
C-reactive protein 
CSR 
Clinical study report 
CTCAE 
Common terminology criteria for adverse events 
dp 
Decimal place 
DIC 
Deviance information criterion 
DLQI 
Dermatology Life Quality Index 
eCOA 
Electronic clinical outcome assessment 
eCRF 
Electronic case report form 
EMICM 
Expectation-maximisation iterative complex minorant 
EOS 
End of study 
FUP 
Functional uniform prior 
GI 
Gastrointestinal 
HPD 
Highest posterior density  
IMP 
Investigational medical product 
IRT 
Interactive response technology 
ITT 
Intention to treat 
LDH 
Lactate dehydrogenase 
LS 
Least squares 
LSS 
Lesion severity score 
MCSE 
Monte Carlo standard error 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model for repeated measures 
mNAPSI 
Modified Nail Psoriasis Severity Index 
NPMLE 
Nonparametric maximum likelihood estimator 
PASI 
Psoriasis Area and Severity Index 
PCI 
Potentially clinically important 
PGA 
Physician’s Global Assessment 
PIC 
Powder in capsule 
PSI 
Psoriasis Symptom Inventory 
PT 
Preferred term 
SAE 
Serious adverse event 
SF-36 
36-Item Short Form Survey Instrument 
SOC 
System organ class 
SAP 
Statistical analysis plan 
SD 
Standard deviation 


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SE 
Standard error 
TEAE 
Treatment emergent adverse event 
ULN 
Upper limit of normal 
VAS 
Visual analogue scale 
WHO 
World Health Organization 
 
3 
Introduction 
The purpose of this SAP is to provide all information that is necessary to perform the required 
statistical analyses of study EDP1815-201. It also defines the summary TFLs to be included in the 
final clinical study report according to the protocol. The SAP is based upon, and assumes familiarity, 
with the study protocol, version 5.0, dated 17--Nov-2020.  
 
If a future protocol amendment necessitates a substantial change to the statistical analysis of the 
study data, this SAP will be amended accordingly. The content of this SAP is compatible with the ICH 
E9 Guidance document. 
 
4 
Study Objectives and Endpoints 
4.1 
Study Objectives 
The primary objective of the study is 
• 
To evaluate the safety and efficacy of 3 different doses of EDP1815 for the treatment of 
psoriasis following daily dosing for 16 weeks. 
 
The secondary objectives of the study are 
• 
To evaluate the efficacy dose response of EDP1815 at Week 16. 
• 
To evaluate the maximal clinical benefit of EDP1815 at Week 16. 
• 
To evaluate the optimal dose of EDP1815 based on efficacy and safety up to Week 16. 
• 
To evaluate the safety and tolerability of EDP1815 (all dose levels) throughout the study. 
• 
To evaluate relapse and rebound of plaque psoriasis after cessation of EDP1815. 
 
The exploratory objectives of the study are: 
• 
To evaluate the time to onset of clinical response to EDP1815.  
• 
To evaluate the effect of EDP1815 treatment on patient-reported outcomes including quality 
of life and pain. 
• 
To evaluate the effect of EDP1815 treatment on biomarkers in blood. 
• 
To evaluate the effect of EDP1815 treatment on biomarkers in skin plaques. 
• 
To evaluate the effect of EDP1815 treatment on faecal microbiome composition. 
• 
To evaluate the duration of remission, treatment success, and therapeutic effect of 
EDP1815. 
 


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4.2 
Endpoints 
The primary efficacy endpoint for the study is: 
• 
Percentage change in PASI score from baseline at Week 16. 
The secondary efficacy endpoints for the study are: 
• 
Percentage change in PASI score from baseline at Weeks 4, 8 and 12. 
• 
Absolute change from baseline in PASI score at Weeks 4, 8, 12 and 16. 
• 
Achievement of PASI-50 at Weeks 4, 8, 12 and 16. 
• 
Time to first achievement of PASI-50. 
• 
Achievement of PASI-75, PASI-90 and PASI-100 at Week 16. 
• 
Achievement of PGA of 0 or 1 with a ≥2-point improvement from baseline at Week 16. 
• 
Achievement of PGA of 0 at Week 16. 
• 
Percentage change from baseline in PGA*BSA at Weeks 4, 8, 12, and 16. 
• 
Absolute change from baseline in PGA*BSA at Weeks 4, 8, 12, and 16. 
• 
Percentage change from baseline in LSS at Weeks 4, 8, 12, and 16. 
• 
Absolute change from baseline in LSS at Weeks 4, 8, 12, and 16. 
• 
Percentage change from baseline in DLQI score at Weeks 4, 8, 12, and 16. 
• 
Absolute change from baseline in DLQI score at Weeks 4, 8, 12, and 16. 
• 
Percentage change from baseline in mNAPSI total score at Weeks 4, 8, 12, and 16. 
• 
Absolute change from baseline in mNAPSI total score at Weeks 4, 8, 12, and 16. 
• 
Cumulative incidence of partial relapse at Weeks 20, 24, 28, and 40. 
• 
Cumulative incidence of complete relapse at Weeks 20, 24, 28, and 40. 
• 
Cumulative incidence of rebound at Weeks 20, 24, 28, and 40. 
 
Exploratory efficacy endpoints are: 
• 
Achievement of PASI-50, PASI-75, PASI-90, and PASI-100 at Weeks 4, 8, and 12.  
• 
Achievement of PGA of 0 or 1 with a ≥2-point improvement at Weeks 4, 8, and 12. 
• 
Achievement of PGA of 0 at Weeks 4, 8, and 12. 
• 
Achievement of PGA of 0 or 1 at Weeks 4, 8, 12, and 16. 
• 
Percentage change from baseline in BSA at Weeks 4, 8, 12, and 16. 
• 
Absolute change from baseline in BSA at Weeks 4, 8, 12, and 16. 
• 
Achievement of BSA<3% and BSA-75 at Weeks 4, 8, 12, and 16. 
• 
Absolute change from baseline in PSI quality of life total and itch scores at Weeks 12 and 16. 
• 
Percentage change from baseline in PSI quality of life total and itch scores at Weeks 12 
and 16. 
• 
Absolute change from baseline in Pain and Fatigue scores at Weeks 4, 8, 12, and 16. 
• 
Percentage change from baseline in Pain and Fatigue scores at Weeks 4, 8, 12, and 16. 
• 
Absolute change from baseline in fasting blood glucose and fasting lipid panel at Weeks 8 
and 16. 
• 
Mean duration of remission in participants who achieve PASI-100. 
• 
Mean duration of treatment success in participants who achieve PASI-50. 
• 
Mean duration of therapeutic effect in participants after cessation of study treatment. 
 
 


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Other exploratory endpoints are: 
• 
Histological assessment of skin plaque biopsies (including epidermal thickness, basal mitotic 
counts and immune cell infiltrates) at Week 16 versus baseline. 
• 
mRNA transcription analysis on skin plaque biopsies at Week 16 versus baseline. 
• 
Blood cytokine and chemokine levels at Week 16 versus baseline. 
• 
Microbiome composition (in faeces) at Week 16 and Week 20 versus baseline. 
 
Note that analyses of the other exploratory endpoints will be addressed in a separate analysis plan 
and will not be further discussed in this document. 
 
5 
Study Methods 
5.1 
General Study Design and Plan 
This is a multicentre, randomised double-blind, placebo-controlled, parallel cohort dose ranging 
study of participants with mild to moderate plaque psoriasis.  
 
After eligibility is confirmed during the screening period (Protocol Section 4.1), participants will be 
randomly assigned in a 1:1:1 ratio to 1 of the following 3 parallel cohorts: 
• 
Cohort 1: 0.8 × 1011 cells of EDP1815 or matching placebo administered as 1 PIC, once daily.  
• 
Cohort 2: 3.2 × 1011 cells of EDP1815 or matching placebo administered as 4 PICs, once daily.  
• 
Cohort 3: 8.0 × 1011 cells of EDP1815 or matching placebo administered as 10 PICs, once 
daily. 
 
In each cohort, approximately 75 participants will be randomly assigned in a 2:1 ratio to receive 
either EDP1815 or matching placebo once daily for 16 weeks. 
 
As shown in Figure 1, Part A of the study comprises a screening period of up to 4 weeks, a baseline 
visit, a treatment period of 16 weeks, and a follow-up visit at Week 20, making 11 scheduled study 
visits in total. On completion of Part A, the primary analysis will be performed. 
Part B of the study is designed to assess the durability of treatment response and incidence of 
rebound of psoriasis following cessation of dosing. All participants will attend for skin assessments at 
Weeks 24 and 28, unless they have previously experienced treatment failure and/or had rebound of 
disease. A final visit at Week 40 will also be performed for those participants who experienced 
treatment response at Week 16 but have not yet met the definition of complete relapse. Part B 
therefore comprises a maximum of 3 additional scheduled study visits with a follow-up of up to 40 
weeks (24 weeks after cessation of dosing). On completion of Part B, the final analysis will be 
performed. 
‘Treatment failure’ is synonymous with ‘starting a new psoriasis treatment’ which is an oral agent, 
biological, or intermediate or high-potency dose topical therapy for plaque psoriasis. Starting topical 
unmedicated emollients and low-potency topical steroids which were not taken at baseline does not 
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Figure 1 
Study Schema 
 
 
 
Note: PIC=Powder in capsule (formulation). All dosing is once daily. 
Note: Since this figure was produced for the protocol, the Interim Analysis has been moved from 
Week 12 to when the last participant has received their last dose (Week 16).  
 
An interim analysis will be performed after the last participant was scheduled to receive their last 
dose (Week 16).  
 
Participants who withdraw from treatment in the first four weeks after randomisation may be 
replaced.  Replacement participants will be assigned to the same cohort as the withdrawn 
participant but will be randomly assigned to treatment within that cohort. 
 
5.2 
Randomisation and Blinding 
At the baseline visit (Visit 2), participants will be randomly allocated, in a 1:1:1 ratio to one of the 
three cohorts. Within the cohort, participants will then be randomly assigned in a 2:1 allocation ratio 
to receive either EDP1815 or matching placebo treatment.  
 
Interactive response technology (IRT) will be used to administer the randomization schedule 
centrally.  Successfully screened participants will be assigned to the next cohort randomisation 
number available at the time of their baseline visit to determine their cohort and then to the next 
treatment randomisation number available within that cohort.  
 
Note that if a participant has withdrawn from treatment within 4 weeks of randomisation and is to 
be replaced, the next participant to be randomised will automatically be assigned to the same 
cohort as the participant who was withdrawn instead of being randomly assigned to a cohort.  
Within the cohort, the replacement participant will be randomly assigned to treatment group with 
the next within-cohort treatment randomisation number. 


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The allocation to cohort is not blinded as it is distinguishable to participants and study staff by the 
number of capsules administered per once-daily dose. The treatment allocation within cohort will be 
fully blinded to participants, study staff and the sponsor with the exception of the personnel 
supporting the IRT system, the clinical supplies team, the clinical safety team at 
, and an 
unblinded team within 
who will produce the interim analysis but have no other 
involvement in the reporting of the study. 
 
A participant’s treatment assignment will not be unblinded for the investigator or study site staff 
until EOS unless medical treatment of the participant depends on knowing the study treatment the 
participant received. Participants who are unblinded will be allowed to continue their participation 
in the study; however, any data collected after the unblinding occurred will be excluded from per-
protocol analyses. 
 
For the interim analysis, unblinded aggregate results will be produced by the unblinded team within 
 and reviewed by Evelo personnel for strategic planning use. These results will not be 
shared with study site staff, participants, or clinical monitors who will be involved in the collection 
and review of individual study data. 
 
The data will be unblinded and the primary analysis will be performed once all participants have 
completed 4 weeks of post-treatment follow-up at Visit 11 (Week 20; at the end of Part A). Study 
site staff, participants, and clinical monitors who will be involved in the collection and review of 
individual study data will remain blinded until Part B is completed. 
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 
 
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. Efficacy data collected using the electronic clinical 
outcome assessment (eCOA) device on the same day as the first dose of study medication will also 
be assumed to be pre-dose data and can be used for the baseline assessment, regardless of whether 
the time indicates if it was before or after the time of first dose. 
 
 


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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 
Height may be recorded in cm or inches. Height in inches will be converted to height in cm as 
follows: 
 
Height (cm) = Height (inches)*0.3937 
Height (cm) will be presented to 1 dp in the listings. 
 
Weight may be recorded in kg or pounds.  Weight in pounds will be converted to weight in kg as 
follows: 
 
Weight (kg) = Weight (pounds) * 0.4536 
Weight (kg) will be presented to 1 dp in the listings. 
 
Body mass index (BMI) will be calculated as: 
BMI (kg/m2) = Weight (kg) / [height (cm)/100]2 
BMI (kg/m2) will be presented to 1 dp in the listings. 
 
BMI will also be categorised as: 
• 
≥30 kg/m2 
• 
<30 kg/m2 
 
5.3.2.1 
Time since Diagnosis 
Time since diagnosis in years at first dose will be calculated as: 
 
Time since diagnosis (years) = (Date of first dose – Date of diagnosis)/365.25 
 
Time since diagnosis will also be categorised as: 
• 
<2 years 
• 
≥2 years 
 
5.3.2.2 
Treatment Compliance 
Participants will be expected to dose once daily with 1, 4 or 10 capsules per dose respectively for 
cohorts 1, 2 and 3. 
 




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• 
Treatment with another investigational drug, biological agent, or device. 
 
Topical unmedicated emollients and low-potency topical steroids are permitted if participants were 
already using them as part of their care prior to study entry. The participant should not however 
start new medications or change the dose or frequency of this type during the course of the study. 
 
If a prohibited medication is found to have been used, this will be captured into the protocol 
deviations log. 
 
5.3.3 
Efficacy 
5.3.3.1 
General 
Participants who discontinue treatment but do not withdraw from the study should only have 
efficacy data collected after discontinuation of treatment included in the supportive estimand for 
the primary endpoint. For all other analyses, data collected after withdrawal of treatment should be 
considered as missing. 
 
5.3.3.2 
Psoriasis Area and Severity Index 
PASI score will be calculated within the eCOA system and taken directly from the supplied data.  
Further information on the scoring of the PASI is provided in Section 16. 
 
PASI-50, PASI-75, PASI-90 and PASI-100 responses are defined respectively by at least a 50%, 75%, 
90% and 100% reduction from Baseline in the PASI score.  
 
Response at Week 16 is defined as achieving PASI-50 or greater at the Week 16 visit. 
 
Partial relapse is defined, after the Week 16 visit, as loss of PASI-50 response after cessation of study 
treatment, or the participant begins a new treatment for psoriasis. 
 
Relapse is defined, after the week 16 visit, as an increase in PASI score to the baseline value or 
greater, or the participant begins a new treatment for psoriasis. 
Rebound is defined as an increase in PASI score to 125% of baseline value or above, or onset of new 
pustular/erythrodermic psoriasis, within 3 months of cessation of study treatment. 
 
5.3.3.3 
Time to First Achievement of PASI-50 
As the PASI score is only collected at each study visit, the time to first occurrence of PASI-50 should 
be considered as interval-censored data. It is only known that the participant achieved PASI-50 at 
some point at or before the assessment at which it was first observed and after the previous 
assessment.  
 
For participants who meet the criteria for PASI-50, the interval start and stop day for first 
achievement of PASI-50 will be defined as: 
 
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Interval end day = Study day of PASI assessment at which PASI-50 was first achieved 
 
Participants who do not meet the criteria for PASI-50 during the Part A of the study will be right-
censored at the last PASI assessment within 4 days of treatment discontinuation (for participants 
who did not complete the 16-week treatment period) or the last PASI assessment in Part A (for 
participants who did complete the 16-week treatment period).  For the purposes of the analysis data 
set, the interval start and stop dates will be defined as: 
 
Interval start day = Study day of last PASI assessment+1 
 
Interval end day = missing 
 
5.3.3.4 
Duration Endpoints 
The following duration endpoints will be defined: 
 
Duration of remission is defined as time from first achievement of PASI-100 to loss of PASI-100 or 
start of a new psoriasis treatment whichever occurs first. 
 
Duration of treatment success is defined as time from first achievement of PASI-50 to loss of PASI-50 
or start of a new psoriasis treatment whichever occurs first. 
 
Duration of therapeutic effect is defined as time from cessation of study treatment until increase of 
PASI to 50% of maximum improvement from baseline or start of a new psoriasis treatment 
whichever occurs first. Maximum improvement from baseline is a participant’s lowest post-baseline 
PASI score. Increase of PASI to 50% of maximum improvement from baseline can only occur at a visit 
after the visit where maximum improvement from baseline occurred. Any participant who showed 
no improvement in PASI score from baseline up to end of treatment will not have duration of 
therapeutic effect calculated. Any participant who showed an improvement prior to end of 
treatment and whose end of treatment PASI score had already gone above 50% of maximum 
improvement from baseline will have duration of therapeutic effect equal to zero. 
 
As the PASI score is only collected at each study visit, the duration endpoints should be considered 
as interval-censored data. Although an exact date of start of new psoriasis treatment will be 
collected, it is only known that the participant achieved and lost PASI-100/50 status, or achieved an 
increase of PASI to 50% of maximum improvement from baseline, at some point at or before the 
assessment at which it was first observed and after the previous assessment.  
 
Duration should be calculated as: 
Duration = End Day - Start Day 
 
For duration of remission and duration of treatment success: 
Start Day = Study day of PASI assessment at which PASI-100 or PASI-50, respectively, was first 
achieved 
End Day = Study day of PASI assessment at which PASI-100 or PASI-50, respectively, was first lost, or 
start of new psoriasis treatment whichever occurs first 
 


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For duration of therapeutic effect, duration should be calculated as: 
Start Day = Study day of end of study treatment 
End Day = Study day of PASI assessment at which increase of PASI to 50% of maximum improvement 
from baseline first occurred, or start of new psoriasis treatment, whichever occurs first 
 
If a participant does not meet the Start Day criteria relevant to a particular duration endpoint at any 
time during the study the endpoint will not be calculated.  
 
If a participant has not met the End Day criteria relevant to a particular duration endpoint by the 
final study visit the last PASI assessment in Part A or Part B will be used as the End Day in the 
calculations above. 
 
5.3.3.5 
Physician Global Assessment 
The physician will give a score on the participant’s psoriasis disease for each of induration 
(thickness), erythema (redness) and scaling on a scale of 0 to 5. Further information on the PGA is 
provided in Section 17. 
 
The PGA score will be calculated as the average of the three scores, rounded to the closest whole 
number. 
 
PGA score will be calculated within the eCOA system and taken directly from the supplied data prior 
to the rounding being applied. 
 
The rounded PGA value will be used in the calculation of the PGA*BSA variable and will also be used 
in any summaries and listings of the PGA data. 
 
5.3.3.6 
Percent of Body Surface Area Involvement 
The percent of BSA involvement will be estimated for each participant, where 1% is 
approximately the area of the participant’s handprint. 
 
BSA-75 response is defined by at least a 75% reduction from Baseline in the BSA.  
 
5.3.3.7 
Lesion Severity Score 
The lesion of interest, selected at the screening visit, will be scored for redness, induration 
(thickness) and scaling using a five-point scale: 
• 
0=None 
• 
1=Slight 
• 
2=Moderate 
• 
3=Severe 
• 
4=Very severe 
 


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The LSS is the sum of the redness, induration and scaling scores at each visit.  The LSS will not be 
calculated unless all three sub-scores are non-missing. 
 
All assessments must be performed throughout the study on the same lesion of interest as identified 
at Screening.  If a different lesion is scored, compared to the Screening visit, then the LSS will be 
considered missing. 
 
5.3.3.8 
Dermatology Life Quality Index 
The DLQI is a 10-item questionnaire with each item scored from 0 to 3.  Further information on the 
scoring of the DLQI is provided in Section 18. 
 
The DLQI score is the sum of the 10 individual items.  
 
During the course of the study it was found that question 7 of the DLQI had been asked incorrectly. 
Therefore the following action will be taken: DLQI questionnaires of all participants at all visits 
(including Baseline) will be assigned a score of 0 for question 7. This concurs with the questionnaire’s 
instructions on how to handle a question with a missing response. Up to one question can have a 
missing response and the total DLQI score is still considered valid. In the event that any 
questionnaire contains a missing response to another question, the DLQI score will be set to missing.  
 
Once the error was found it was decided not to correct the asking of the question going forward, 
since this would result in comparing a slightly different questionnaire at baseline to later time points 
for the majority of participants and therefore complicate interpretation of change from baseline. 
 
In order to investigate any potential effect of this error on conclusions drawn, sensitivity analyses of 
the DLQI will be carried out using the following scoring for question 7, based on the first part of the 
question: 
Answer to first part of question 7 
Score assigned 
Yes 
3 
No 
1.5 (median of the possible scores 0, 1, 2 and 3) 
Not relevant 
0 
The second part of the question will not be used as this was where the error occurred.  
 
5.3.3.9 
Modified Nail Psoriasis Severity Index 
The mNAPSI will only be collected in participants with psoriatic nail involvement.  
 
The mNAPSI is assessed for each of the participant’s 10 fingernails as detailed in Section 19. The 
mNAPSI score is the sum of the 10 scores for the individual nails. 
 
If the investigator indicates at a visit that there is no nail disease, a score of zero will be assigned. 
 
 
 


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5.3.3.10 Psoriasis Symptom Inventory 
The PSI will be completed daily by participants for the 7 days prior to each visit as detailed in Section 
20.  
 
For each of the 8 symptoms, the daily scores will be averaged to give a weekly symptom score for 
that visit. Data must be provided for at least 5 of the 7 days prior to the visit for a weekly symptom 
score to be calculated.  
 
The PSI total score at the visit will be the sum of the 8 weekly symptom scores.  
 
5.3.3.11 SF-36 Bodily Pain and Vitality Scores 
The SF-36 bodily pain and vitality scores will be calculated using the algorithms provided by the 
RAND corporation as detailed in Section 21. 
 
The SF-36 bodily pain score will be the average of the two question scores for pain and will be 
calculated if at least one of the two questions have been answered. 
 
The SF-36 vitality score will be the average of the four question scores for vitality/energy and will be 
calculated if at least two of the two questions have been answered. 
 
5.3.3.12 Pain and Fatigue Visual Analogue Scales 
The pain VAS will ask the question: How severe is your pain today? 
Participants will score this by marking a point on a line which goes from 0=no pain to 100=very 
severe pain 
 
The fatigue VAS will ask the question: How much of a problem has fatigue or tiredness been for you 
in the past week? 
Participants will score this by marking a point on a line which goes from 0=fatigue is no problem to 
100=fatigue is a major problem. 
 
5.3.4 
Safety 
5.3.4.1 
Duration of Exposure 
The duration of exposure will be calculated as 
 
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 7.3.1) to suggest that the AE started prior to dosing. 
 


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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 16 weeks of dosing per protocol the Treatment Phase will be from 
Day 1 to Day 112 and the Follow-up Phase will be from Day 113 until their last day in the study. 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. 
 
For the primary analysis which considers only data collected in Part A, only events which start on or 
prior to the end of Part A date will be included in the adverse event summaries. 
 
The onset phase of all AEs will be included in the relevant data listings. 
 
For the final analysis, only treatment related events which start in Part B will be included in the 
adverse event summaries.  
 
Only treatment related events which start in Part B and any Part A AEs which change in Part B will be 
included in the relevant data listings. 
 
6 
Sample Size  
The sample size of 225 participants in total, has been chosen to explore the tolerability and safety of 
EDP1815. Although the study will use a model-based probability inference approach in a Bayesian 
framework, the following power calculation was also performed (using a basic frequentist approach) 
in order to give confidence that enough participants are available to find a clinically meaningful 
difference between active dose and placebo if the below assumptions are met. 
 
The primary efficacy endpoint is the percent change from baseline in the PASI score at Week 16. 
Percent change from baseline relative to placebo will be estimated within the model (Section 9.4.3) 
as (percent change in active) - (percent change in placebo), with a negative value indicating a greater 
improvement for active than placebo. A percent change from baseline relative to placebo of at least 
20% will be considered clinically meaningful. The pooled standard deviation across all doses is 
assumed to be 25%. 
 
Participants in the placebo arm of each cohort will be pooled for the statistical analysis in order to 
compare active and control arms resulting in 75 participants randomized to the pooled placebo 
group and 50 participants randomized to each active treatment group (EDP1815 0.8 × 1011 cells, 
EDP1815 3.2 × 1011 cells, and EDP1815 8.0 × 1011 cells). Assuming that no more than 15% of 


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participants will discontinue treatment before the Week 16 visit, at least 42 active and 21 placebo 
participants in each of the 3 cohorts are expected to provide data through the Week 16 visit. 
 
Each pairwise comparison between pooled placebo and active dose would be expected to have 
more than 95% power to detect a difference between the treatment groups at the 5% significance 
level under the assumption that pooling the placebo groups is a valid strategy. If the 3 placebo 
cohorts are considered too heterogeneous for pooling into a single reference group (Section 9.1), 
the power to detect a difference in each within-cohort pairwise comparison between active and 
placebo doses would be greater than 80%. 
 
As the statistical inference for this study will focus on estimation rather than testing a formal 
hypothesis, no multiplicity adjustments of the different comparisons between groups in order to 
control the study-wise type I error rate will be performed. 
 
Similarly, as there is no intention to use any interim analyses to stop the study early for efficacy 
(Section 7.4), no adjustments for multiplicity will be made to account for any analyses performed as 
part of the interim analyses. 
 
7 
General Considerations 
7.1 
Analysis Populations 
7.1.1 
Enrolled Population 
The enrolled set will consist of all participants who sign the ICF. 
 
7.1.2 
Modified Intention to Treat Population 
The modified intention to treat (mITT) population will consist of all participants who were 
randomised to treatment and who received at least one dose of study treatment. Participants who 
withdraw from the study before the end of Week 4 and are replaced will be included in this analysis 
set.  
 
All analyses using the mITT population will group participants according to randomised treatment. 
 
7.1.3 
Per-protocol Population 
The per-protocol (PP) population will consist of all participants in the mITT population who had a 
duration of treatment exposure of at least 28 days (criteria for replacement) and who do not have a 
protocol deviation that may impact efficacy with a start date for the deviation before initiation of 
study treatment. 
 
Note that in the case of participants who have a protocol deviation with a potential impact on 
efficacy which occurs after initiation of treatment, the participant will remain in the PP population 
but all data collected after the protocol deviation occurred will be excluded from any analyses 
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For the exploratory analysis indirectly comparing the results from this study to those in the UNVEIL 
study (Section 9.6.2) the following subgroup of participants will be used: 
• 
Baseline PGA=3 and Baseline BSA 5-10% 
 
For the inferential models defined in Section 9, in addition to the relevant baseline score where 
applicable, the following covariates will be considered: 
• 
Body mass index (<30 kg/m2, ≥30 kg/m2) 
• 
Sex (male, female) 
• 
Country (UK, Poland, Hungary, USA) 
• 
Time since diagnosis (<2 years, ≥2 years) 
 
7.3 
Missing Data 
Missing efficacy data such as individual item scores will be dealt with as detailed in Section 5.3.3. 
Otherwise, no imputation of missing efficacy data will be performed, and the use of mixed models 
will account for missing data. 
 
7.3.1 
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 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. 
• 
If the actual or imputed start date is the same as the treatment start date, and the start time 
is partially missing (hh:XX) then use the following: 


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o If the hour is the same as the hour of the start of treatment time then use the 
complete time of the start of treatment (i.e., both hours and minutes) 
o If the hour is not the same as the hour of the start time than use hh:00. 
• 
If the actual or imputed start date is not the same as the treatment start date, and the start 
time is partially missing (hh:XX) then use hh:00 
 
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. 
• 
If only the year is specified, then use January 1st of that year. 
• 
If the start date is completely unknown, do not impute the start date. 
 
Partial AE resolution, medical condition stop dates and concomitant medication stop dates and date 
last smoked will be imputed as follows: 
• 
If the event, condition or medication is flagged as ongoing, do not impute the stop date 
• 
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 23:59 on that date. 
• 
If the actual or imputed stop date is non-missing, and the stop time is partially missing, then 
hh:59 for missing minutes. 
• 
If the actual or imputed stop date is missing, do not impute the stop time. 
 
7.3.2 
Adverse Event Information 
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 
7.4.1 
Purpose of Interim Analyses 
The interim analysis will be to aid in the planning of future studies and for a better understanding of 
the benefit/risk profile of EDP1815. 
 
No decisions regarding study conduct will be made based on the interim results and the study will 
not be stopped if superior efficacy is found. 
 
7.4.2 
Planned Schedule of Interim Analyses 
The interim analysis will be performed after the last participant has received their last dose 
(scheduled for the end of Week 16).  All Part A data collected at the time of the data cut will be 
included in the analysis, so some participants may have data from beyond the Week 16 visit. 
 


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7.4.3 
Endpoints to be Included in the Interim Analysis 
The following endpoints will be included in the interim analysis. Description of the analyses for these 
endpoints is described in Sections 8, 9 and 10.  The list of outputs which will be provided as part of 
the interim analysis is provided in Section 15. 
• 
Study disposition status 
• 
Treatment disposition status 
• 
Demography 
• 
Baseline disease status 
• 
Exposure to treatment 
• 
Percentage change from baseline in PASI (primary estimand only) main analytical approach 
(MMRM) and sensitivity analysis (dose response model) 
• 
Change from baseline in PASI - main analytical approach 
• 
Achievement of PASI-50 – main analytical approach 
• 
Achievement of PASI-75, PASI-90 and PASI-100 (summary only) 
• 
Achievement of PGA of 0 or 1 with a ≥2 point improvement (summary only) 
• 
Achievement of PGA of 0 (summary only) 
• 
Percentage change from baseline in PGA*BSA (summary only) 
• 
Incidence of adverse events 
 
7.4.4 
Adjustment of Confidence Intervals and p-values 
As the study will not be stopped if superior efficacy is demonstrated at the interim analysis, there 
will be no adjustments for alpha-spending. 
 
7.4.5 
Practical Measures to Minimise Bias 
Outputs featuring unblinded treatment assignments will be created by the unblinded analysis group 
within 
 and shared with selective Evelo personnel who are not directly involved in the 
conduct of the study.   
 
The members of the unblinded team will not be involved in any aspects of study conduct, including 
in the development of the final summaries and analyses for the study.  
 
Aggregate data from the unblinded results may be more widely shared, including into the public 
domain, but no data which may have the potential to unblind will be released beyond the unblinded 
personnel and DMC.  Data with the potential to unblind include: 
• 
Efficacy or safety event data where only participants from one treatment group have 
experienced the event 
• 
Categorical data where one or more categories contains only participants from one 
treatment group 
• 
Minimum and maximum values for continuous data 
• 
Time to event data where events at single timepoint occurred in only one treatment group 
 
 


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7.4.6 
Documentation of Interim Analyses 
All unblinded data and summaries, together with any meeting minutes in which unblinded data is 
discussed 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. 
 
7.5 
Multi-centre Studies 
Results will be presented for all centres combined.  For the inferential analyses the effect of country 
will be assessed for significance in the models. 
 
7.6 
Multiple Testing 
The statistical analysis for this study will focus on estimation rather than in testing a formal 
hypothesis. Therefore, no adjustments will be made to control the study-wise type I error rate. 
 
7.7 
Visit Windows 
All data will be reported according to nominal visits, except for subjects who complete the follow-up 
Week 20 assessments due to withdrawing from the study before the Week 16 visit.  For example, if a 
Week 2 visit occurred on Day 16 instead of the nominally expected Day 14 it will be reported and 
included in the summary statistics/statistical analyses for Week 2.  
 
Subjects who withdraw prematurely from the study should complete the assessments required for 
the follow-up visit (Week 20).  However, this data will only be included in tables and figures which 
are produced by visit for subjects who completed the 16-week treatment period and provided Week 
16 data prior to the Week 20/follow-up data being collected.  Tables and figures which do not show 
summaries by visit and all listings will include all collected Week 20/follow-up data regardless of 
whether the subject completed the 16-week treatment period.  
 
Scheduled visits which occur outside the protocol-specified visit window (e.g. if the Week 2 visit 
occurred on Day 19 outside of the Day 12-18 window), this will be noted as a protocol deviation but 
data collected will still be included in all summary and analysis tables. 
 
Unscheduled visits will not be included in summary or analysis tables, unless they are baseline 
measurements or provide data towards a safety endpoint which looks at worst-case post-baseline. 
 
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), cohort (1, 2, 
3), site number and participant number.  Relevant listings will include whether the assessment was 
performed and the date, study day/visit and time of the assessment as applicable. 


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Unless otherwise specified below, all summary tables will be structured with a column for each 
treatment. Where appropriate, columns combining all placebo participants, all EDP1815 participants 
and an overall total column may also be presented. 
 
For summaries of study disposition, demographic and baseline data and study treatment 
compliance, columns will be ordered and labelled as follows: 
• 
Placebo 1 capsule  
• 
EDP1815 1 capsule  
• 
Placebo 4 capsules 
• 
EDP1815 4 capsules 
• 
Placebo 10 capsules 
• 
EDP1815 10 capsules 
• 
All Placebo 
• 
All EDP1815 
• 
Total 
 
For concomitant medication, efficacy and safety outputs, columns will be ordered and labelled as 
follows: 
• 
All Placebo 
• 
EDP1815 1 capsule  
• 
EDP1815 4 capsules 
• 
EDP1815 10 capsules 
• 
All EDP1815 (concomitant medication and safety only) 
 
For the efficacy analyses, if the 3 cohorts of placebo participants are found to be too heterogeneous 
for pooling, selected efficacy tables will also be presented by treatment within cohort, in which case 
columns will be ordered and labelled as: 
• 
Placebo 1 capsule  
• 
EDP1815 1 capsule  
• 
Placebo 4 capsules 
• 
EDP1815 4 capsules 
• 
Placebo 10 capsules 
• 
EDP1815 10 capsules 
 
For the primary analysis: 
 
• 
For study disposition summaries where it is appropriate to report information on 
participants who failed screening, the enrolled population will be used. 
 
• 
For safety summaries, the safety population will be used. 
 
• 
For all other summaries and analyses the mITT population will be used, with selected 
efficacy outputs reproduced using the per-protocol population. 


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For the final analysis: 
 
• 
For partial relapse and complete relapse endpoints analysis Week 16 Responders population 
will be used. 
 
• 
For duration endpoints and rebound analysis mITT population will be used. 
 
• 
For or all other summaries and analyses the Part B population will be used. 
 
8.1 
Study Disposition 
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 (Part A for the primary 
analysis and Part B for the final analysis) 
• 
Number and percentage of participants withdrawn from the study and the reported reason 
for withdrawal (Part A for the primary analysis and Part B for the final analysis) 
• 
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 16-week treatment period 
(primary analysis) 
• 
Number and percentage of participants who discontinued treatment early and reason for 
discontinuation (primary analysis) 
 
For participants who fail screening, the reasons for screen failure including details on which 
inclusion/ exclusion criteria were not met will be summarised and listed. 
 
The number and percentage of participants enrolled within each country and within each site will be 
summarised. 
 
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 scheduled visit will be 
summarised. 
 
Missed visits and assessments due to COVID-19 will also be summarised and listed. 
 
 
 
 


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8.2 
Protocol Deviations 
The number and percentage of participants in the mITT population with at least one protocol 
deviation with a potential impact on efficacy in each category specified in Table 2 will be 
summarised.  
 
All protocol deviations will also be listed. 
 
8.3 
Demographic and Baseline Variables 
Demography data of age, sex, race, ethnicity will be summarised together with height, weight and 
BMI at screening. 
 
Baseline disease characteristics of time (years) since diagnosis and any current psoriasis treatment at 
the time of the Screening visit will be summarised. 
 
8.4 
Medical History 
Medical history and concurrent illnesses will be captured and coded using the v23.0 of the Medical 
Dictionary for Regulatory Activities (MedDRA®). 
 
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’. 
 
Past and current medical history will be summarised separately by System Organ Class (SOC) and 
Preferred Term (PT).  Summary tables will contain the number and percentage of patients. A patient 
who has multiple conditions in the same SOC or with the same PT will be counted only once in the 
patient counts. Medical history summaries will be sorted by the internationally agreed SOC order 
(Table 9) and decreasing frequency of PT within SOC in the Total column. 
 
All medical history data will be listed. 
 
8.5 
Prior and Concomitant Medications 
Medications will be coded according to the World Health Organization Drug Dictionary (WHODD) 
Version dated 01Mar2020. Medical procedures will not be coded.  
 
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 7.3.1 
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. 


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Medications will be summarised by 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. 
 
In the primary analysis separate summaries will be produced for each of the following: 
• 
Prior medications 
• 
All Concomitant medications  
• 
Concomitant medications started pre-treatment  
• 
Concomitant medications during the treatment period (including any which started pre-
treatment) 
• 
Concomitant medications started during the follow-up period 
 
All prior and concomitant medications will be listed.  
 
In the final analysis concomitant medications started during Phase B and medications from Phase A 
which changed during Phase B will be listed.  
 
8.6 
Treatment Compliance 
Treatment compliance will be summarised for each 8-week treatment period and for the whole 16-
week treatment period.   
 
Summary statistics (n, mean, SD, median and range) will be produced together with the number and 
percentage of participants within each of the categories defined in Section 5.3.2.2.  Percentages will 
use the number of participants who started the relevant treatment period as the denominator. 
 
Data from the dosing log and the calculated treatment compliance in each treatment period will also 
be listed. 
 
9 
Efficacy Analyses 
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 and duration endpoints, 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 time to 25% and 50% (median) 
of participants with event . Kaplan-Meier curves of time to event will also be presented. 


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9.1 
Pooling of Placebo Cohorts 
The assumption that the 3 cohorts of placebo participants can be pooled into a single placebo group 
to be used as a control for all active doses will be examined using mean (±SD) and box plots of 
percent change in PASI score against time. In addition, a mixed model for repeated measures 
(MMRM) model will be used to compare the 3 cohorts of placebo participants. The model will 
include parameters for cohort, visit and baseline PASI score together with cohort*visit and baseline 
PASI score*visit interactions. LS mean (95% CI) estimates for each placebo cohort will be plotted by 
visit. 
 
A decision will be made by the Evelo study team, based on examination of the above figures and 
model, on whether the pooling strategy is appropriate.   
 
If any placebo cohort is considered too different from the other placebo cohorts then no pooling will 
be used.  The pooling of 2 cohorts only will not be considered. 
 
If the pooling strategy is considered appropriate, then the placebo cohorts will be pooled into a 
single ‘all placebo’ group for all efficacy analyses and will be used as a common control group for 
each active EDP1815 treatment group. 
 
If the assumption of similarity across the placebo groups is found to be unreasonable, each placebo 
dose will be included in the model as a separate dose level and pairwise comparisons between each 
active EDP1815 dose and placebo will be performed using only the matching placebo dose data from 
the same cohort. 
 
All efficacy data will be listed, including both individual item scores and calculated questionnaire 
summary scores. 
 
9.2 
Selection of Additional Covariates 
The covariates described in Section 7.2 will be considered and included in the primary efficacy model 
described in Section 9.4.3 for the primary estimand if found to be significant (p<0.05).  A forward 
stepwise selection method will be used to include the covariates after the treatment*visit and 
baseline PASI score*visit interactions have already been fitted.  
 
The covariates selected for this primary model will also be used in all other analytical models 
including covariates. 
 
9.3 
Part B Analysis 
For the Part B endpoints other than those relating to relapse, rebound and duration of effects, a 
principal strata estimand will be used including all participants in the Part B population with all data 
included regardless of other intercurrent events.  
 






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capsules) if the placebo pooling strategy is not considered appropriate.  Visit will consist of 7 levels 
(Weeks 1, 2, 4, 8, 12,16 and 20). 
 
 As described in Section 9.2 additional covariates for baseline factors will be assessed using this 
model for inclusion in all efficacy models. 
 
The priors for all parameters in the model will be non-informative and follow a normal distribution 
with mean 0 and SD 1000. The prior for the variance-covariance matrix will follow an inverted 
Wishart distribution with degrees of freedom equal to the number of visits and an identity scale 
matrix. The choice of Wishart distribution is based on it being the conjugate prior of the inverse-
covariance matrix of a multivariate-normal random vector. 
 
The model will be blocked so that the MCMC procedure samples from the treatment*visit 
parameters first, then the baseline*visit parameters, then any additional fitted covariates and finally 
the variance-covariance matrix. 
 
100,000 MCMC samples will be generated with a thin of 20 to leave 5000 retained samples after a 
burn-in of 10,000 samples.  The number of samples or thin may be increased to reduce the ratio of 
the Monte Carlo standard error (MCSE) to the posterior SD, as deemed necessary. 
 
If the assumption of similarity between the 3 placebo cohorts is considered appropriate, the placebo 
cohorts will be pooled, and a common all placebo control group will be used for the pairwise 
differences or each active dose to placebo. If the placebo pooling strategy is not considered 
appropriate, each placebo dose will be included in the model as a separate dose level and pairwise 
comparisons between each active EDP1815 dose and its matching placebo dose will be used. 
 
The adjusted mean percentage change from baseline and the associated 95% highest posterior 
density (HPD) credible interval (CrI) for each treatment group at Week 16 will be reported, together 
with the adjusted mean difference from placebo and the associated 95% HPD CrI for each active 
dose at Week 16 and the probability that each active treatment difference is less than 0%, -20%, -
30% and -50%.   
 
At all other visits (Weeks 1, 2, 4, 8, 12 and 20) the adjusted mean percentage change from baseline 
and the associated 95% highest posterior density (HPD) credible interval (CrI) for each treatment 
group will be reported, together with the adjusted mean difference from placebo and the associated 
95% HPD CrI for each active dose and the probability that each active treatment difference is less 
than 0%.   
 
Posterior mean (with 95% HPD CrI) percentage change from baseline in PASI score will be plotted 
against time. 
 
Model checking and diagnostic plots, including posterior density plots of the posterior samples for all 
parameters in the model will be produced. The assumption that data are missing at random will be 
evaluated by plotting the mean percentage change in PASI score against visit by treatment group for 


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the subgroups of participants who completed 16 weeks of study drug compared with those who 
discontinued study drug before Week 16. 
 
If model checking and diagnostic plots show a violation of the assumptions underlying the analysis, 
alternative statistical methods will be considered, appropriate to the type of violation observed.  
This may include removing additional covariates even if they are found to be statistically significant if 
their inclusion causes issues with model inclusion, using an appropriate transformation (e.g. 
logarithmic) on the endpoint or changing the modelling strategy from MMRM. Requirements for 
alternative methods will be data driven and cannot be fully assessed until after the study has been 
unblinded and this document finalised.  Any changes to the modelling strategy will be fully described 
in a SAP addendum. 
 
The primary analysis approach will be repeated using the 3 supportive estimands described in 
Section 9.4.2. 
 
9.4.4 
Sensitivity Analyses 
If the assumption of similarity between the placebo cohorts is supported and placebo cohorts can be 
pooled, a sensitivity analysis will be performed on the percent change from baseline to Week 16 in 
PASI score using a Bayesian Emax dose response model on the pooled cohorts in the following form: 
Response = E0 + Emax*f(dose)  
 
Three possible models will be considered for the f(dose): 
• 
Log-linear: f(dose) = log(dose+0.01), where 0.01 is an offset to allow the model to fit for zero 
dose (placebo) 
• 
3-parameter model: f(dose) = dose/(dose+ED50) 
• 
4-parameter model: f(dose) = doseslope/(doseslope + ED50slope) 
Where: 
• 
Response = Percentage change from baseline in PASI at Week 16 
• 
E0 = the response at dose = 0 (placebo) 
• 
Emax = the maximal response over placebo 
• 
ED50 = the dose that yields 50% of the maximal response 
• 
slope = the dose-response slope parameter 
 
Dose will be fitted as a continuous variable with values of 0, 1, 4 and 10 used to denote the number 
of active capsules taken by each of the treatment groups. 
 
An inverse gamma prior with shape of 0.001 and scale of 0.001 will be used for the residual variance. 
Normal, non-informative priors will be used for the E0 and Emax parameters with mean 0 and SD 
1000. A functional uniform prior (FUP) will be used, when required, for the ED50 and slope 
parameters where the prior density of the FUP is based on all the parameters in the model.  For the 
FUP, the density will be calculated for values of dose from 0.01 to 10.01 in steps of 1. The use of a 
FUP shrinks the dose response towards a flat line throughout the dose range, therefore providing 
more conservative estimates of the dose-response relationship compared to maximum likelihood 
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Parameters will be blocked so that the MCMC procedure samples from E0 and Emax first, then the 
ED50 and slope parameters and finally the residual variance parameter. 
 
100,000 MCMC samples will be generated with a thin of 20 to leave 5000 retained samples after a 
burn-in of 10,000 samples.  The number of samples or thin may be increased to reduce the ratio of 
the MCSE to the posterior SD, as deemed necessary. 
 
The best-fitting (lowest DIC) of the three models will be selected and based on the selected model, 
the posterior mean with associated 95% HPD CrI while be displayed for the percentage change from 
baseline in PASI score at Week 16 and the pairwise treatment differences between each active dose 
and the pooled placebo group. Posterior probabilities will also be presented for the pairwise 
treatment differences between each active dose and placebo being less than 0%, -20%, -30% and -
50%. 
 
A figure will be presented of the fitted mean dose response model with the 95% HPD CrI for all 
possible doses (0 to 10 in steps of 0.5) in the dose range, overlaid with the Week 16 posterior means 
and 95% HPD CrI for the MMRM model specified in Section 9.4.3. 
 
If any of the results of the analyses using the supportive estimands are found to differ substantially 
from the primary estimand for the main analytical approach using the MMRM, this sensitivity 
analysis will be repeated using the supportive estimands. 
 
9.4.5 
Subgroup Analyses 
The analyses described in Section 9.4.3 will be repeated on the primary estimand only using the 
subgroups defined in Section 7.2 for baseline disease severity and obesity. There will be no figures 
for the subgroup analyses. 
 
9.5 
Secondary Efficacy Analyses 
The primary estimand approach will be applied to these endpoints, with the exception of the partial 
relapse, relapse and rebound endpoints, in the same manner as described in Section 9.4.1. No 
additional supportive or sensitivity analyses will be applied to these endpoints, with the exception of 
PASI-50 response which has a supportive estimand and DLQI score which has a supportive analysis. 
 
There will be no waterfall plots for the secondary endpoints, with the exception of absolute change 
from Baseline in PASI score at Week 16. 
 
9.5.1 
Percentage Change from Baseline in PASI score at Weeks 4, 8 and 12 
Mean percentage change from baseline in PASI score at Weeks 4, 8 and 12 will be analysed as part of 
the MMRM for the primary estimand.  The same statistics produced for the Week 16 time point will 
also be produced at Weeks 4, 8 and 12. 
 


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9.5.2 
Other Continuous Secondary Endpoints 
The following secondary endpoints will be analysed in the same manner as described for the main 
analytical approach for the primary analysis (Section 9.4.30): 
• 
Mean absolute change from baseline in PASI score at Weeks 4, 8, 12, and 16  
• 
Mean percentage change from baseline in LSS at Weeks 4, 8, 12, and 16 
• 
Mean absolute change from baseline in LSS at Weeks 4, 8, 12, and 16 
• 
Mean percentage change from baseline in PGA*BSA at Weeks 4, 8, 12, and 16 
• 
Mean absolute change from baseline in PGA*BSA at Weeks 4, 8, 12, and 16 
• 
Mean percentage change from baseline in DLQI score at Weeks 4, 8, 12, and 16 (main and 
sensitivity analysis) 
• 
Mean absolute change from baseline in DLQI score at Weeks 4, 8, 12, and 16 (main and 
sensitivity analysis) 
• 
Mean percentage change from baseline in mNAPSI total score at Weeks 4, 8, 12, and 16 
• 
Mean absolute change from baseline in mNAPSI total score at Weeks 4, 8, 12, and 16 
 
For the secondary endpoints the probability of each active treatment difference to placebo being 
less than 0 only will be presented. 
 
Note that for the mNAPSI, only participants with psoriatic nail involvement (mNAPSI score>0) will be 
included in the summaries and analyses for this endpoint. 
 
Similarly, if a participant has a zero score for any of the secondary scores at baseline, that participant 
will be excluded from any of the percentage change from baseline summaries and analyses as the 
percentage change from baseline cannot be calculated. 
 
As described in Section 9.2, any baseline covariates fitted into the primary analysis model will also be 
fitted in the models for these endpoints.  
 
9.5.3 
Response Endpoints with Inferential Analysis 
The following endpoints will be analysed in the same manner as described below: 
• 
Achievement of PASI-50 at Weeks 4, 8, 12 and 16 
• 
Achievement of PGA of 0 or 1 with a ≥2 point improvement from baseline at Week 16 
• 
Achievement of PGA of 0 at Week 16 
 
9.5.3.1 
Estimands 
The population summary measure of interest will be the odds ratio between each active dose and 
placebo for the achievement of response at the relevant time point. 
 
9.5.3.2 
Main Analytical Approach 
A generalised linear mixed effects model with a logit link function will be fitted using data from all 
visits. Treatment, visit and baseline score terms will be included in the model as fixed effects 


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together with treatment*visit and baseline score*visit interactions, where the baseline score of PASI 
or PGA is used as appropriate to the endpoint.  
 
Treatment will consist of 4 levels (all placebo, EDP1815 1 capsule, EDP1815 4 capsules and EDP1815 
10 capsules) if the placebo pooling strategy is considered appropriate or 6 levels (Placebo 1 capsule, 
Placebo 4 capsules, Placebo 10 capsules, EDP1815 1 capsule, EDP1815 4 capsules, and EDP1815 10 
capsules) if the placebo pooling strategy is not considered appropriate.  Visit will consist of 5 levels 
(Weeks 4, 8, 12,16 and 20). 
 
As described in Section 9.2, any baseline covariates fitted into the primary analysis model will also be 
fitted in the models for these endpoints. 
 
An unstructured covariance structure will be used.  If there are issues with model convergence, 
other covariance structures may be considered (e.g. compound symmetry). 
If the assumption of similarity between the 3 placebo cohorts is considered appropriate, the placebo 
cohorts will be pooled, and a common all placebo control group will be used for the pairwise 
differences or each active dose to placebo. If the placebo pooling strategy is not considered 
appropriate, each placebo dose will be included in the model as a separate dose level and pairwise 
comparisons between each active EDP1815 dose and its matching placebo dose will be used. 
 
If responder numbers are low and there are visits at which not all treatment groups have at least 
one response, the analysis may be modified to exclude one or more of the earlier visits and/or the 
Week 20 visit to ensure model convergence. Alternatively, the mixed effects model may be replaced 
with an individual logistic regression models at Week 16 or the baseline*visit interaction may be 
replaced by a fixed baseline effect only if either of these approaches appear to be more appropriate 
for the available data. Note that if there are insufficient responders to run the model with the Week 
16 visit included then no inferential analysis should be performed. 
 
The number and percentage of responders will be reported at each visit together with 95% CI for the 
percentage of responders, calculated using the exact method for binomial proportions. At each visit, 
the adjusted odds ratio, with 95% confidence interval (CI) associated p-value will also be presented. 
If the analysis is changed to exclude visits, then only the summary statistics for the number of 
subjects with data, the number and percentage of participants with a response and the 95% CI for 
the percentage of responders will be shown for any visits which were excluded from the model.  
Table footnotes will be added as appropriate to detail any changes to the planned analysis. 
 
The adjusted odds ratios (with 95% CI) will be plotted by visit for the 3 active doses compared to 
placebo.  
 
In addition, for the PASI-50 response endpoint only, a supportive analysis will be performed using 
the following supportive estimand.  The estimand will differ only in the intercurrent event strategy. 
 
 
 








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• 
Mean percentage change from baseline in PSI quality of life total and itch scores at Weeks 
12 and 16 
• 
Mean change from baseline in Pain and Fatigue scores at Weeks 4, 8, 12, and 16 
• 
Mean percentage change from baseline in Pain and Fatigue scores at Weeks 4, 8, 12, and 16 
• 
Mean change from baseline in fasting blood glucose and fasting lipid panel at Weeks 8 and 
16 
• 
Mean duration of remission in participants who achieve PASI-100 
• 
Mean duration of treatment success in participants who achieve PASI-50 
• 
Mean duration of therapeutic effect in participants after cessation of study treatment 
 
Note that if a participant has a zero score for any of the continuous measures (PSI score, 
Pain/Fatigue VAS or Bodily pain/Vitality SF-36 scores) at baseline, that participant will be excluded 
from any of the percentage change from baseline summaries and analyses as the percentage change 
from baseline cannot be calculated. 
 
In addition to the summary statistics as described in Section 9, response endpoints will also have 
95% CIs presented for percentage of participants responding.  
 
9.6.2 
Indirect Comparisons with Apremilast 
Adjusted indirect comparisons, pivoted around placebo, will be made with the Week 16 results and 
those from two studies in Apremilast in mild/moderate or moderate participants. 
 
Only efficacy endpoints which were specified as primary or secondary endpoints in both this study 
and the comparator study will be assessed. 
 
All indirect comparisons and their confidence intervals will be considered descriptive only.  No p-
values will be calculated. 
 
Each active dose of EDP1815 will be independently compared to Ampremilast. 
 
All data for the comparator studies will be taken from the published results for the study available 
on the clinicaltrials.gov website. 
 
9.6.2.1 
Binary (Response) Endpoints 
For binary endpoints (e.g. PASI-50), the indirect comparison will be based on the unadjusted relative 
risk (RR) statistics re-calculated from the number of participants in each treatment/trial with the 
relevant endpoint at Week 16.  Participants with missing data at Week 16 will have their last 
observed value before Week 16 carried forward. 
 
NA = number of participants evaluated on active treatment 
NP = number of participants evaluated on placebo treatment 
nA = number of participants with event on active treatment 
nP = number of participants with event on placebo treatment 


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Relative risk (RR) = 
𝑛𝑛𝐴𝐴𝑁𝑁𝐴𝐴
ൗ
𝑛𝑛𝑃𝑃𝑁𝑁𝑝𝑝
ൗ
 
 
SE(log RR) = √ቀ
1−𝑛𝑛𝐴𝐴
𝑛𝑛𝐴𝐴𝑁𝑁𝐴𝐴+ 
1−𝑛𝑛𝑃𝑃
𝑛𝑛𝑃𝑃𝑁𝑁𝑃𝑃ቁ 
 
RR for Indirect Comparison (RRIndirect) = 
𝑅𝑅𝑅𝑅𝐸𝐸𝐸𝐸𝐸𝐸1815
𝑅𝑅𝑅𝑅𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 
 
SE (log RR) for indirect comparison = √ቂ𝑆𝑆𝑆𝑆(log 𝑅𝑅𝑅𝑅𝐸𝐸𝐸𝐸𝐸𝐸1815)2 + 𝑆𝑆𝑆𝑆൫log 𝑅𝑅𝑅𝑅𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴൯
2ቃ 
 
95% CI for RR for indirect Comparison = exp (log 𝑅𝑅𝑅𝑅𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 ± 1.96 × 𝑆𝑆𝑆𝑆(log 𝑅𝑅𝑅𝑅𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼)) 
 
9.6.2.2 
Continuous Endpoints 
The indirect comparisons will use LS mean differences and their standard errors.   
In order to provide LS means similar in methodology to those seen in the UNVEIL study, the LS mean 
differences will be taken from simple ANOVA models at Week 16 with only treatment group and 
country included in the model.  Participants with missing data at Week 16 will have their last 
observed value before Week 16 carried forward. 
 
For comparison with ADVANCE study, the LS mean differences will be taken from a Bayesian mixed 
model for repeated measures as described for the main analytical approach for the primary analysis. 
No additional imputation will be done for this analysis. 
 
LSMDEDP1815 = LS mean difference from placebo for EDP1815 
LSMDApremilast = LS mean difference from placebo for Apremilast 
SEEDP1815 = SE of LSMDEDP1815 
SEApreimlast = SE of LSMDApremilast 
 
LSMD for Indirect Comparison (LSMDIndirect) = LSMDEDP1815 - LSMDApremilast 
 
SE for Indirect Comparison(SEIndirect) = SEIndirect = √ൣ𝑆𝑆𝑆𝑆𝐸𝐸𝐸𝐸𝐸𝐸1815
2 + 𝑆𝑆𝑆𝑆𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴)2൧ 
 
95% CI for LSMD for Indirect Comparison = LSMDIndirect ± 1.96 x SEIndirect 
 
9.6.2.3 
Apremilast UNVEIL study (NCT02425826) 
The UNVEIL study was performed on a population of moderate participants.  The population of 
interest was defined as those with baseline PGA=3 and baseline BSA 5-10%. For the indirect 
comparisons with data from this study, the subgroup of participants which match those criteria will 
be used. 
 
The following endpoints will be compared at Week 16: 
• 
Achievement of PASI-50 (binary) 


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• 
Achievement of PASI-75 (binary) 
• 
Achievement of PGA score of 0 or 1 (binary) – note that all participants achieving this must 
also have ≥2 point reduction from baseline as all participants in this analysis have PGA=3. 
• 
Percentage change from baseline in PGA*BSA (continuous) 
 
9.6.2.4 
Apremilast ADVANCE study (NCT03721172) 
The ADVANCE study was performed in a population of mild/moderate participants. The criteria 
specified for PGA, BSA or PASI for recruitment into this study were broadly similar to those for this 
study, therefore the results from the full mITT population will be used for comparison. 
 
The following endpoints will be compared at Week 16: 
• 
Achievement of PGA score of 0 or 1 with ≥2 point reduction from baseline (binary) 
• 
Change from baseline in PASI score (continuous) 
 
It should be noted that at the time of writing this SAP, the results were not yet available on 
clinicaltrials.gov for this study. This analysis will only be performed if these results are published 
prior to DB lock for this study. 
 
10 Safety Analyses 
The Safety population will be used for all summaries of Safety.  All safety endpoints will be listed. 
 
10.1  Extent of Exposure 
The duration of exposure (days) and number of doses taken will be summarized using summary 
statistics for continuous data.  The number and percentage of participants with at least 4, 8, 12 and 
16 weeks (28, 56, 84 and 112 days respectively) will also be presented. 
 
Treatment start and stop dates, exposure duration (days), number of doses administered, number of 
capsules taken and reasons for dose adjustments and dose interruptions will be listed by participant. 
 
10.2  Adverse Events 
Adverse events will be reported from the date of signed informed consent and through for 28 days 
after cessation of dosing. Adverse events occurring after the 28 days post-treatment would only be 
reported if the investigator considers it to be related to the study treatment. 
Only treatment emergent AEs (TEAEs) will be included in the summaries, pre-treatment AEs will be 
included in the listings of all AEs.   
 
In the primary analysis at the end of Part A, only adverse events which started on or before date of 
the end of Part A will be included in the summaries. 
 


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In the final analysis at the end of Part B, only adverse events which started during Part B will be 
included in the summaries. Treatment related events which start in Part B and any Part A AEs which 
change in Part B will be included in the relevant data listings. 
 
All AEs will be coded using version 23.0 of MedDRA.  Severity of event will be coded using the 
Common Terminology Criteria for Adverse Events v5.0 (CTCAE). 
 
An overview of TEAEs will be produced showing the number and percentage of participants with: 
• 
Any TEAEs (Part A) 
• 
Any TEAE of CTCAE grade 2 or above (Part A) 
• 
Any TEAE of CTCAE grade 3 or above (Part A) 
• 
Any TEAE of CTCAE grade 4 or above (Part A) 
• 
Any fatal TEAE (Part A) 
• 
Any serious TEAE (Part A) 
• 
Any TEAE leading to permanent discontinuation of study drug (Part A) 
• 
Any TEAE leading to withdrawal from the study (Part A) 
• 
Any related TEAE (Part A and Part B) 
• 
Any related TEAE of CTCAE grade 2 or above (Part A and Part B) 
• 
Any related TEAE of CTCAE grade 3 or above (Part A and Part B) 
• 
Any related TEAE of CTCAE grade 4 or above (Part A and Part B) 
• 
Any related fatal TEAE (Part A and Part B)  
• 
Any related serious TEAE (Part A and Part B) 
• 
Any related TEAE leading to permanent discontinuation of study drug (Part A and Part B) 
• 
Any related TEAE leading to withdrawal from the study (Part A and Part B) 
 
Related events are those which were considered by the investigator to be possibly, probably or 
definitely related to study drug. 
 
TEAEs will also be summarized by system organ class (SOC) and preferred term (PT). 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 summaries will 
be sorted by the internationally agreed SOC order (Table 9) and decreasing incidence of preferred 
term within SOC in the EDP1815 column. 
 
In the primary analysis the above summary will be repeated for treatment phase TEAEs and follow-
up phase TEAEs. 
 
Related TEAEs and TEAEs of CTCAE Grade 3 or above will also be summarized by SOC and PT in the 
same manner as described above. 
 
Non-serious TEAEs reported by at least 5% of participants in any treatment group will also be 
summarised by SOC and PT. 
 


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In the final analysis only related TEAEs will be summarized by SOC and PT in the same manner as 
described above. 
 
10.3 Deaths, Serious Adverse Events and other Significant Adverse Events 
Treatment emergent SAEs, TEAEs leading to discontinuation of study drug or withdrawal from the 
study will be summarized separately by treatment, SOC and preferred term. 
 
Serious AEs, fatal AEs and AEs leading to discontinuation of study drug will each be listed separately 
by participant. 
 
No specific adverse events are considered to be of special interest for EDP1815. 
 
10.4  Pregnancies 
Pregnancy test data will be listed only. 
 
10.5  Clinical Laboratory Evaluations 
Central laboratory data will be used for all safety laboratory evaluations. Table 10 (Section 23) shows 
the parameters which will be collected and the units in which they will be supplied. Lab data will be 
transformed as appropriate to the International System of Units (SI units) as part of the SDTM 
programming and SI units will be used for all summaries. 
 
Haematology and chemistry parameters will be summarised by visit, including change from baseline 
for all post-baseline visits. 
 
The number and percentage of participants showing shifts from baseline to worst-case post-baseline 
with respect to the normal ranges will also be summarised for each haematology and chemistry 
parameter.  Categories will be: 
• 
Low 
• 
Normal 
• 
High 
 
Haematology and chemistry values will also be flagged for potentially clinically important (PCI) 
values if they meet any of the criteria for Grade 2 or higher events according to CTCAE V5.0. The PCI 
criteria are listed in Table 10 (Section 23).  The number and percentage of participants showing shifts 
from baseline to worst-case baseline with respect to PCI criteria will be summarised for all 
parameters where PCI criteria have been defined. Categories will be: 
• 
Low 
• 
Within range 
• 
High 
 
For both the normal range and PCI summaries, the determination of worst-case post-baseline will 
consider both scheduled and unscheduled assessments which occur after the first dose of study 


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treatment.  Percentages will use the number of participants with at least one post-baseline 
assessment available as the denominator. If the baseline value is missing it will be assumed to be 
normal/within range.  Worst-case can be either High or Low and if a participant has post-baseline 
values both above and below the normal range/PCI criteria then they will be counted in both 
relevant categories. 
 
Haematology and chemistry data will be listed, including changes from baseline, normal ranges , 
flags for measurements outside the normal range, and flags for meeting PCI criteria.  In addition, for 
participants who meet at least one PCI criteria, all values within the laboratory type (haematology or 
chemistry) will be listed separately. 
 
Urinalysis data will be listed only.  
 
10.6 Other Safety Measures 
10.6.1 ECG  
Ventricular rate, PR interval, RR interval, QRS duration, QT interval and QTcF interval will be 
summarised by visit, including change from baseline. 
 
In addition, the QTcF interval will be flagged for PCI if it meets the CTCAE (v5.0) criteria for a Grade 3 
or above event (>500 ms or a >60 ms increase from baseline). 
The number and percentage of participants showing a shift from baseline to worst-case post-
baseline with respect to the QTcF PCI criteria will be summarised. Categories will be: 
• 
Within range 
• 
High 
 
The determination of worst-case post-baseline will consider all scheduled and 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 normal for this summary.   
 
All ECG data will be listed, including flags for values which meet the PCI criteria for QTcF. In addition, 
a separate listing of all ECG assessments for any participant who has at least one value meeting the 
QTcF PCI criteria will be produced. 
 
10.6.2 Vital Signs 
Systolic blood pressure (BP), diastolic BP, pulse rate, respiratory rate and temperature will be 
summarised by visit, including change from baseline.  
 
In addition, vital signs data will be flagged as potentially clinically important (PCI) if they meet the 
CTCAE (v5.0) criteria for a Grade 3 or above event as shown in Table 7. 
 
 
 




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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/credible 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 2 decimal places more 
• 
Estimated parameters and 95% confidence/credible intervals of percentage change variables 
will be reported to 2 decimal places, standard errors will be reported to 3 decimal places 
• 
Estimated odds ratios and 95% confidence/credible intervals will be reported to 2 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 decimal places, standard errors will be reported to one further decimal place. 
 
12 Technical Details 
Statistical evaluation will be performed by 
 
 
The datasets for the interim analysis will not use CDISC standards but will be programmed directly 
from the raw data supplied by 
 data management (eCRF data) and 
 (eCOA data). 
The analysis datasets will be produced using a similar structure to those described for ADaM but will 
be not be fully validated with respect to ADaM structure. 
 
The datasets for the final analysis will follow analysis dataset model (ADaM) data specifications and 
will used standard data tabulation model (SDTM) data sets provided by 
 data management as 
the source data. 
All analyses will be performed using SAS version 9.4 or higher (SAS Institute, Cary, NC, USA). 
 
For the Bayesian analyses, the production and quality control (QC) programmers will select different 
seeds and there is no expectation of an exact match between the production and QC programming. 
The statistical outputs will be confirmed as having passed QC as long as the differences between 
production and QC data is within the following tolerance limits: 
• 
Estimates and 95% Credible Intervals for percentage change from baseline (all scales) – QC 
data points must be within 5% (relative difference) or within 2 (absolute difference) of the 
relevant production data point. 
• 
Estimates and 95% Credible Intervals for change from baseline (all scales) – QC data points 
must be within 5% (relative difference) or within 0.5 (absolute difference) of the relevant 
production data point. 
• 
Odds ratios and 95% Credible Intervals for response data - QC data points must be within 5% 
(relative difference) or 0.1 (absolute difference) of the relevant production data point. 
• 
Probabilities - QC data points must be within 5% (relative difference) or 0.025 (absolute 
difference) of the relevant production data point. 








































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16 Appendix 2: Psoriasis Area and Severity Index Score  
Intensity 
A representative area of psoriasis is selected for each body region (head and neck, upper limbs, trunk, 
lower limbs). 
 
The intensity of erythema (redness), induration (thickness) and desquamation (scaling) of the psoriasis 
in each body region is scored as: 
• 
0 = None 
• 
1 = Mild 
• 
2 = Moderate 
• 
3 = Severe 
• 
4 = Very Severe 
 
An intensity score is calculated for each body region as the sum of the three scores for erythema, 
induration and desquamation. 
• 
A1 = Intensity score for head and neck 
• 
A2 = Intensity score for upper limbs 
• 
A3 = Intensity score for trunk 
• 
A4 = Intensity score for lower limbs 
 
Each subtotal is multiplied by the body surface area represented by that region as follows: 
• 
B1 = 0.1 x A1 
• 
B2 = 0.2 x A2 
• 
B3 = 0.3 x A3 
• 
B4 = 0.4 x A4 
 
Percentage area affected 
The percentage area affected by psoriasis is evaluated in each of the four body regions.  In each body 
region the area is expressed as: 
• 
0 = not affected at all 
• 
1 = >0% - <10% 
• 
2 = 10% - <30% 
• 
3 = 30% - <50% 
• 
4 = 50% - <70% 
• 
5 = 70% - <90% 
• 
6 = 90% - 100% 
 
PASI score calculation 
Each of the body area scores is multiplied by the intensity score for the relevant body region (B1-B4) to 
gives four area and intensity scores (C1-C4). 
 


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The PASI score is the sum of the four area and intensity scores: 
 
PASI score = C1 + C2 + C3 + C4. 
 
 
 


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17 Appendix 3: Physician Global Assessment  
The physician will give a score on the participant’s psoriasis disease activity, according to the following 
grades: 
 
Induration (I) (averaged over all lesions; use the National Psoriasis Foundation Reference card for 
measurement) 
• 
0 = no evidence of plaque elevation 
• 
1= minimal plaque elevation, =0.25mm 
• 
2 = mild plaque elevation, =0.5mm 
• 
3 = moderate plaque elevation, =0.75mm 
• 
4 = marked plaque elevation, =1mm 
• 
5 = severe plaque elevation, =1.25mm or more 
 
Erythema (E) (averaged over all lesions) 
• 
0 = no evidence of erythema, hyperpigmentation may be present 
• 
1 = faint erythema 
• 
2 = light red coloration 
• 
3 = moderate red coloration 
• 
4 = bright red coloration 
• 
5 = dusky to deep red coloration 
 
Scaling (S) (averaged over all lesions) 
• 
0 = no evidence of scaling 
• 
1 = minimal; occasional fine scale over less than 5% of the lesion 
• 
2 = mild, fine scale dominates 
• 
3 = moderate, course scale dominates 
• 
4 = marked, thick nontenacious scale dominates 
• 
5 = severe, very thick nontenacious scale dominates 
 
The PGA score will be the average of the three scores and will be rounded to the nearest whole number. 
 
 


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18 Appendix 4: Dermatology Quality of Life Index 
The DLQI consists of 10 questions: 
 
1. Over the last week, how itchy, sore, painful or stinging has your skin been? 
2. Over the last week, how embarrassed or self-conscious have you been because of your skin?  
3. Over the last week, how much has your skin interfered with you going shopping or looking after 
your home or garden? 
4. Over the last week, how much has your skin influences the clothes you wear? 
5. Over the last week, how much has your skin affected any social or leisure activities? 
6. Over the last week, how much has your skin made it difficult for you to do any sport? 
7. Over the last week, has your skin prevented you from working or studying? 
If “No”, over the last week how much has your skin been a problem at work or studying? 
8. Over the last week, how much has your skin created problems for your partner or any of your 
close friends or relatives? 
9. Over the last week, how much has your skin caused any sexual difficulties? 
10. Over the last week, how much of a problem has the treatment for your skin been, for example 
by making your home messy, or taking up time? 
 
Questions 1 and 2 is scored on a four-point Likert scale: 
• 
3 = Very much 
• 
2 = A lot 
• 
1 = A little 
• 
0 = Not at all 
 
Questions 3-6 and 8-10 also have an option of not relevant and are scored as: 
• 
3 = Very much 
• 
2 = A lot 
• 
1 = A little 
• 
0 = Not at all 
• 
0 = Not relevant 
 
Question 7 is a 2-part question and is scored as: 
• 
3 = Yes 
• 
3 = No; Very much 
• 
2 = No; A lot 
• 
1 = No; A little 
• 
0 = No; Not at all 
• 
0 = Not relevant 
 
Any unanswered question is scored as 0. 
The DLQI score is the sum of the 10 item scores. 


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19 Appendix 5: Modified Nail Psoriasis Severity Index 
The mNAPSI assesses each nail abnormality for each of the participant’s 10 fingernails. If the rater is 
unsure which grade to give they should select the lower of the grades. 
 
Three features or groups of features (pitting, onycholysis and oil-drop dyschromia, and crumbling) of 
each fingernail will be graded on a scale from zero to 3, according to the directions below. Four features 
(leukonychia, splinter haemorrhages, hyperkeratosis, and red spots in the lunula) will be graded as 
either present or absent for each fingernail. 
 
Onycholysis and oil-drop dyschromia 
Onycholysis: Separation of the nail plate from the nail bed. The separated part of the nail is opaque and 
can have white, yellow, or greenish tinge. If there is a piece of nail missing, estimate where the nail 
normally would have ended at the end of the nail bed, and count that missing part as involved in 
onycholysis.  
Oil-drop (salmon patch) dyschromia: Reddish-brown discoloration under the nail plate. 
 
Onycholysis and oil-drop dyschromia are considered together. When looking at the nail, combine the 
total percentage area of the nail that is affected by either and use that combined total to score the nail. 
 
Score: Percent of nail with onycholysis or oil-drop dyschromia present 
• 
0 = No onycholysis or oil drop dyschromia present 
• 
1= 1–10% of the nail has onycholysis or oil-drop dyschromia 
• 
2 =11–30% of the nail has onycholysis or oil-drop dyschromia 
• 
3 = > 30% of the nail has onycholysis or oil-drop dyschromia 
 
Pitting 
Small, sharply defined depressions in the nail surface. Pits are discrete abnormalities (“ice-pick-like”). If 
there is nail plate crumbling that is confluent with pits, do not score for pits. If the pits are separate from 
crumbling, they may be scored regardless of whether crumbling is present or not. 
 
Score: Number of pits 
• 
0 = 0 
• 
1 = 1–10 
• 
2 = 11–49 
• 
3 = > 50 
 
Nail plate crumbling 
Crumbling or fragmentation of friable nail plate which may be associated with confluent pitting. 
Crumbling involves alteration of the nail plate surface. Horizontal ridging of the nail, “wave-like” 
appearance, and horizontal lines are all features of crumbling. 
Score: Percent of nail with crumbling present 


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• 
0 = No crumbling 
• 
1 = 1–25% of the nail has crumbling 
• 
2 = 26–50% of the nail has crumbling 
• 
3 = > 50% of the nail has crumbling 
 
Additional features 
The next 4 abnormalities are scored only by their presence or absence. A score of 1 indicates present 
and a score of zero indicates not present. 
 
• 
Leukonychia: White spots in the nail plate due to psoriasis in the mid matrix. Leukonychia are 
just color changes. If it appears that there is depression or irregularity to the nail surface, this 
may be pitting or crumbling, not leukonychia. If the leukonychia is adjacent to, or confluent with 
crumbling or pits, it is counted as part of the crumbling or pitting and not as a separate 
abnormality. 
• 
Splinter hemorrhages: Small, longitudinal, linear, dark brown haemorrhage under the fingernail. 
• 
Nail bed hyperkeratosis: Thickened keratin in the nail bed. 
• 
Red spots in the lunula: Small pink or red macules in the lunula. 
 
mNAPSI score 
Each fingernail is scored as above to give a score of 0-13. The mNAPSI score is the total of the 10 
individual fingernail scores. 
 
 


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20 Appendix 6: Psoriasis Symptom Inventory 
The PSI is a patient reported outcome which assesses 8 symptoms of severity with a recall period of 24 
hours. It will be completed daily by participants in the 7 days before attending the site for a visit. 
 
The participant should answer each of the following questions every day: 
 
Overall, during the last 24 hours: 
• 
How severe was the itch from your psoriasis? 
• 
How severe was the redness from your lesions? 
• 
How severe was the scaling from your lesions? 
• 
How severe was the burning from your lesions? 
• 
How severe was the stinging from your lesions? 
• 
How severe was the cracking from your lesions? 
• 
How severe was the flaking from your lesions? 
• 
How severe was the pain from your lesions? 
 
Each question is scored on a 5-point scale as follows: 
• 
0 = Not at all 
• 
1 = Mild 
• 
2 = Moderate 
• 
3 = Severe 
• 
4 = Very Severe 
 
If the participant has answered the symptom question on at least 5 of the 7 days, a weekly symptom 
score will be calculated as the average of the available daily scores for each symptom. If less than 5 daily 
answers are provided, the weekly symptom score will be considered as missing. 
 
The PSI total score will be the sum of the 8 weekly symptom scores.  It will only be calculated when all 8 
weekly symptom scores are non-missing. 
 
 


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21 Appendix 7: SF-36 Pain and Vitality Scores 
Pain score 
The pain score will be calculated from questions 21 and 22 of the SF-36 questionnaire: 
 
Q21: How much bodily pain have you had during the past 4 weeks? 
• 
1 = None 
• 
2 = Very mild 
• 
3 = Mild 
• 
4 = Moderate 
• 
5 = Severe 
• 
6 = Very severe 
The Q21 score = 100*[(6-x)/5]  where x=1-6 is the Q21 item value as above. 
 
Q22: During the past 4 weeks, how much did pain interfere with your normal work (including both work 
outside the home and housework)? 
• 
1 = Not at all 
• 
2 = A little bit 
• 
3 = Moderately 
• 
4 = Quite a bit 
• 
5 = Extremely 
The Q22 score = 100*[(5-x)/4]  where x=1-5 is the Q22 item value as above. 
 
The SF-36 bodily pain score is the average of the Q21 and Q22 scores. If at least one of the two 
questions have been answered, the SF-36 bodily pain score will be calculated. 
 
Vitality score 
The vitality score will be calculated from questions 23, 27, 29 and 31 of the SF-36 questionnaire: 
 
How much of the time during the past 4 weeks… 
Q23: Did you feel full of pep? 
Q27: Did you have a lot of energy? 
Q29: Did you feel worn out? 
Q31: Did you feel tired? 
 
Each question has possible answers (x): 
• 
1 = All of the time 
• 
2 = Most of the time 
• 
3 = A good bit of the time 
• 
4 = Some of the time 
• 
5 = A little of the time 
• 
6 = None of the time 


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The Q23 score = 100*[(6-x)/5]  where x=1-6 is the Q23 item value as above. 
The Q27 score = 100*[(6-x)/5]  where x=1-6 is the Q27 item value as above. 
The Q29 score = 100*[x/5]  
where x=1-6 is the Q29 item value as above. 
The Q31 score = 100*[x/5]  
where x=1-6 is the Q31 item value as above. 
 
The SF-36 vitality score is the average of the Q23, Q27, Q29 and Q31 scores. If at least two of the four 
questions have been answered, the SF-36 bodily pain score will be calculated.