Clinical trial NCT03759041
Conditions: Ulcerative Colitis
Keywords: microbiome
Sponsor: Seres Therapeutics, Inc.
Start date: 2018-12-19; Completion date: 2021-10-13
Enrollment: 203 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Randomized, Double-Blind, Placebo-Controlled, Multiple Dose, Multicenter Study to Assess Efficacy and Safety of SER-287 in Adults with Active Mild-to-Moderate Ulcerative Colitis

Detailed description:
This is a Phase 2B randomized, double-blind, placebo-controlled, multiple dose, multicenter study designed to evaluate the efficacy, safety and microbiome alterations associated with two dose levels of SER-287, after pre-treatment with vancomycin, in adult subjects, age 18-80, with active mild-to-moderate ulcerative colitis (UC).

Arms: arm 1: Once-daily dosing of Placebo (after placebo pre-treatment) arm 2: Once-daily dosing of SER-287 (Induction Dose, after vancomycin pre-treatment) arm 3: Once-daily dosing of SER-287 (Step-Down Induction Dose, after vancomycin pre-treatment)
Interventions: intervention 1: Vancomycin Pre-Treatment intervention 2: Placebo for Vancomycin Pre-Treatment intervention 3: SER-287 intervention 4: Placebo for SER-287
Intervention descriptions: intervention 1: Four times per day dosing of vancomycin pre-treatment intervention 2: Four times per day dosing of placebo pre-treatment intervention 3: Once-daily dosing of SER-287 intervention 4: Once-daily dosing of Placebo for SER-287

Protocol documents:
SAP_002.pdf: 
 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
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v 1.0 
 
Microbiome Statistical Analysis Plan for the US Food and Drug 
Authority  
 
 
 
Protocol Number and Title: 
 
ECO-RESET: A Phase 2B, Randomized, Double-
Blind, Placebo-Controlled, Multiple Dose, 
Multicenter Study to Assess Efficacy and Safety of 
SER-287 in Adults with Active Mild-to-Moderate 
Ulcerative Colitis (SERES 201) 
 
 
Protocol Version and Date: 
Amendment 3 
8-October-2019 
 
 
  
  
 
  
  
 
  
 
 
 
mbSAP Version: 
1.0 
 
mbSAP Version Date:  
27 April 2021 
 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
2 of 61 
 
27-APR-2021 
Confidential 
v 1.0 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Seres Therapeutics, Inc. Acceptance of this 
document constitutes agreement by the recipient that no information contained herein will be published or disclosed 
without prior written authorization from an official of Seres Therapeutics, Inc.  However, this document may be 
disclosed to appropriate Institutional Review Board and Ethics Committees or duly authorized representatives of a 
national regulatory authority under the condition that they are requested to keep it confidential. In the event of an 
actual or suspected breach of this obligation, Seres Therapeutics, Inc. should be notified promptly. 
 
 
I confirm that I have reviewed this document and agree with the content. 
 
APPROVALS 
Seres Therapeutics 
 
 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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TABLE OF CONTENTS 
Glossary of Abbreviations ........................................................................................................ 6 
1. 
Purpose ............................................................................................................................ 7 
2. 
Timings of Analyses ......................................................................................................... 8 
2.1. 
At the end of the Induction Treatment period ..................................................................... 8 
2.2. 
At the end of the Maintenance Treatment period ................................................................ 8 
2.3. 
At the end of the Open-Label Treatment period .................................................................. 9 
3. 
Study Objectives ............................................................................................................ 10 
3.1. 
Other Secondary Objectives ............................................................................................. 10 
3.2. 
Exploratory Objectives .................................................................................................... 10 
4. 
Endpoints ....................................................................................................................... 11 
4.1. 
Other Secondary Efficacy Endpoints ............................................................................... 11 
4.2. 
Exploratory Efficacy Endpoints ....................................................................................... 11 
5. 
Study Design .................................................................................................................. 12 
5.1. 
Brief Description .............................................................................................................. 12 
5.2. 
Subject Selection .............................................................................................................. 14 
5.3. 
Determination of Sample Size .......................................................................................... 14 
5.4. 
Method of Assigning Subjects to Study Treatment .......................................................... 14 
5.5. 
Breaking The Study Blind ................................................................................................ 14 
5.6. 
Assessments and Procedures ............................................................................................ 15 
5.6.1. 
Schedule of Assessments for Microbiome Data Collection ................................................................. 15 
6. 
Analysis Populations ...................................................................................................... 18 
6.1. 
Microbiome Modified Intent-To-Treat (MCITT) Population .......................................... 18 
6.2. 
Microbiome As-Treated Induction Phase (MBAT_IP) Population .................................. 18 
6.3. 
Microbiome As-Treated Maintenance Phase (MBAT_MP) Population .......................... 18 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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6.4. 
Microbiome As-Treated Open-Label Phase (MBOL) Population .................................... 19 
7. 
General Aspects for Statistical Analysis .......................................................................... 20 
7.1. 
Planned Comparisons For Microbiome Endopoints ........................................................ 20 
7.1.1. 
Treatment-associated comparisons ...................................................................................................... 20 
7.1.2. 
Outcome-associated comparisons ........................................................................................................ 20 
7.2. 
Sample Acceptiability Criteria And Quality Control ....................................................... 21 
7.2.1. 
Whole metagenomic sequencing ......................................................................................................... 21 
7.2.2. 
Metabolomics ...................................................................................................................................... 22 
7.2.3. 
Transcriptomics ................................................................................................................................... 22 
7.3. 
Statistical Analysis -- General Methods ........................................................................... 22 
7.4. 
Key Definitions ................................................................................................................. 23 
7.4.1. 
Study Day ............................................................................................................................................ 23 
7.4.2. 
Baseline values .................................................................................................................................... 23 
7.4.3. 
SER-287 drug product species definitions ........................................................................................... 24 
7.5. 
Missing Data ..................................................................................................................... 25 
7.6. 
Visit Windows .................................................................................................................. 25 
7.7. 
Multiplicity Adjustments ................................................................................................. 27 
8. 
Endpoints For Microbiome Analysis ............................................................................... 28 
8.1. 
Microbiome Endpoints – Background And Overview ..................................................... 28 
8.2. 
Microbiome Endpoints – Molecular And Bioinformatic Methods ................................... 29 
8.2.1. 
Stool microbiome taxonomic profiling ................................................................................................ 29 
8.2.2. 
Stool metabolomics profiling ............................................................................................................... 30 
8.2.3. 
Host mucosal transcriptome profiling .................................................................................................. 30 
8.3. 
Secondary Endpoint: SER-287 Engraftment in Induction Phase .................................... 31 
8.4. 
Exploratory Endpoints: Effects of Treatment With SER-287 on the Intestinal 
Microbiome and Microbial Functional Responses ....................................................................... 32 
8.4.1. 
SER-287 engraftment .......................................................................................................................... 32 
8.4.2. 
Microbiome species composition and microbial functional response .................................................. 33 
8.4.3. 
Host mucosal functional response ....................................................................................................... 37 
8.5. 
Exploratory Endpoints: Association Between Clinical Outcome and the Intestinal 
Microbiome and Host and Microbial Functional Responses ........................................................ 41 
8.5.1. 
SER-287 engraftment .......................................................................................................................... 41 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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8.5.2. 
Microbiome species composition and microbial functional response .................................................. 42 
8.5.3. 
Host mucosal functional response ....................................................................................................... 45 
9. 
Changes From Analysis Planned in Protocol ................................................................... 50 
9.1. 
MCITT Population ........................................................................................................... 50 
10. 
References ................................................................................................................. 51 
11. 
Programming Considerations ..................................................................................... 52 
11.1. 
General Considerations .................................................................................................... 52 
11.2. 
Table, Listing, and Figure Format ................................................................................... 52 
11.2.1. 
General ............................................................................................................................................ 52 
11.2.2. 
Headers ........................................................................................................................................... 53 
11.2.3. 
Display Titles .................................................................................................................................. 53 
11.2.4. 
Column Header ............................................................................................................................... 53 
11.2.5. 
Table Conventions .......................................................................................................................... 54 
11.2.6. 
Listing Conventions ........................................................................................................................ 55 
11.2.7. 
Figure Conventions ......................................................................................................................... 55 
11.2.8. 
Footnotes ......................................................................................................................................... 55 
12. 
Index of Tables ........................................................................................................... 56 
13. 
Index of Figures .......................................................................................................... 60 
14. 
Index of Listings ......................................................................................................... 61 
 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
CRO 
Contract Research Organization 
CSP  
Clinical Study Protocol  
CSR  
Clinical Study Report  
eCRF 
Electronic Case Report Forms 
NGS  
Next Generation Sequencing  
SAP  
Statistical Analysis Plan  
mbSAP 
Microbiome Statistical Analysis Plan  
RNA-seq  
RNA sequencing  
TLF/s  
Tables, Lists, and Figures  
WMS  
Whole Metagenomic Sequencing 
Δm 
Fold-change in a metabolite 
ΔSobs_spore_dose 
A per-subject measure of the magnitude of engraftment (ie, total species) 
where the dose is defined as being species detected in any SER-287 drug lot. 
GSEA 
Gene set enrichment analysis 
UC 
Ulcerative colitis 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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1. 
PURPOSE 
This Microbiome Statistical Analysis Plan (mbSAP) details the statistical methodology to be 
used in analyzing secondary and exploratory microbiome endpoint study data and 
generate Tables, Listings and Figures (TLFs). It describes the variables and populations, 
anticipated data transformations and manipulations, and other details of the analyses not 
provided in the clinical SAP. This mbSAP addresses planned analysis and presentation of 
microbiome, transcriptomic, and metabolomic changes in subjects over the course of the study. 
The analysis of safety and clinical efficacy is described in the Clinical Statistical Analysis 
Plan, which is a separate document. The mbSAP will be finalized prior to database lock and 
describes the statistical analysis as it is foreseen when the study is being planned. Any deviations 
from the planned analyses will be described and justified in the final clinical study report (CSR).  
This mbSAP is based on SER-287-201 Protocol Amendment 3 dated 08 October 2019 and its 
associated electronic case report forms (eCRF) Version 3.0, dated 06 May 2019. 
This mbSAP is prepared for the United States Food and Drug Authority (FDA). A separate 
mbSAP will be provided for other regulatory authorities. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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2. 
TIMINGS OF ANALYSES  
2.1. 
AT THE END OF THE INDUCTION TREATMENT PERIOD 
Seres will conduct an unblinded analysis of the secondary and exploratory microbiome endpoints 
when all planned subjects in the study are enrolled, have completed their Induction Treatment 
(Week 11 [Visit 7]) or have terminated from the study prematurely prior to Week 11 [Visit 7], 
and have been evaluated for the primary/key secondary efficacy endpoints. Analyses of the 
microbiome endpoints (described herein) will be performed following completion of the clinical 
endpoints (described in the Clinical SAP). Unblinded microbiome endpoint tables, listings and 
figures (TLFs) will be generated at this time. Limited personnel at Seres will have access to the 
unblinded TLFs.  
Preprocessing and quality assessment of genomic, transcriptomic and metabolomic data may be 
conducted as data are generated and made available to Seres by qualified contract research 
organizations (CRO) to ensure that data are of appropriate quality and content to support 
secondary and exploratory endpoints. All data will first be analyzed in a blinded manner to 
ensure quality, and then unblinded to conduct the per mbSAP analysis. The mbSAP analyses 
described herein will be included in the CSR, or amended to the CSR as data, analyses, and 
reports are available.  
2.2. 
AT THE END OF THE MAINTENANCE TREATMENT PERIOD 
Seres will conduct an unblinded analysis of the exploratory microbiome endpoints when all 
subjects who were re-randomized in the Maintenance arm have been evaluated for the 
exploratory efficacy endpoints and have completed their Maintenance treatment (Week 37 
[VisitM-7]) or have terminated the study prematurely prior to Week 37 [Visit M-7]. Unblinded 
microbiome efficacy endpoint summary tables will be generated at this time. Limited personnel 
at Seres will have access to the unblinded tables, listings and figures (TLFs).  
Preprocessing and quality assessment of genomic, transcriptomic and metabolomic data may be 
conducted as data are generated and made available to Seres by qualified CRO to ensure that 
data are of appropriate quality and content to support exploratory endpoints. All data will first be 
analyzed in a blinded manner to ensure quality, and then unblinded to conduct the per mbSAP 
analysis. The mbSAP analyses described herein will be included in the CSR, or amended to the 
CSR as data, analyses, and reports are available. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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2.3. 
AT THE END OF THE OPEN-LABEL TREATMENT PERIOD 
Summary TLFs for relevant microbiome efficacy endpoint analyses for all subjects who entered 
the Open-Label Extension arm and have completed their Open-Label extension treatment 
(Week 0 [Visit OL-1] through Week 11 [Visit OL-5]) or have terminated the study prematurely 
prior to Week 11 [Visit OL-5] will be generated after final database lock. Preprocessing and 
quality assessment of genomic, transcriptomic and metabolomic data may be conducted as data 
are generated and made available to Seres by a qualified CRO to ensure that data are of 
appropriate quality and content to support exploratory endpoints. The mbSAP analyses described 
herein will be included in the CSR, or amended to the CSR as data, analyses, and reports are 
available. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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3. 
STUDY OBJECTIVES 
A comprehensive list of study objectives is provided in the CSP and Clinical SAP. The study 
objectives that are specifically addressed in this mbSAP are listed below. 
3.1. 
OTHER SECONDARY OBJECTIVES 
• To evaluate the engraftment of SER-287 bacteria from each SER-287 treatment arm into 
the intestinal microbial community over time 
3.2. 
EXPLORATORY OBJECTIVES 
• To evaluate changes in the composition of the intestinal microbiome over time  
• To evaluate changes in signatures of host and microbial functional responses over time  


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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4. 
ENDPOINTS 
A comprehensive list of endpoints is provided in the CSP and Clinical SAP. The endpoints that 
are specifically addressed in this Microbiome SAP are listed below. 
4.1. 
OTHER SECONDARY EFFICACY ENDPOINTS 
• Engraftment of SER-287 bacteria over time  
 
4.2. 
EXPLORATORY EFFICACY ENDPOINTS 
• Composition of the intestinal microbiome through the end of the Maintenance treatment 
and Open-Label treatment periods  
• Signatures of host and microbial functional responses through the end of the Maintenance 
treatment and Open-Label treatment periods  
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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5. 
STUDY DESIGN 
5.1. 
BRIEF DESCRIPTION 
SERES-201 is a Phase 2B randomized, double-blind, placebo-controlled, multiple dose, 
multicenter study designed to evaluate the efficacy, safety and microbiome alterations associated 
with a regimen of pre-treatment with vancomycin followed by treatment with two (2) dose levels 
of SER-287, in adult subjects, age 18-80, with active mild-to-moderate UC. Microbiome 
alterations encompass engraftment of SER-287 dose species, changes in microbiome 
composition and changes in microbiome function. 
The primary objective of the study is to assess the efficacy of once-daily dosing of SER-287 
(Induction Dose) for 10 weeks, after pre-treatment with vancomycin, to achieve Clinical 
Remission in subjects with active mild-to-moderate ulcerative colitis. In addition, the study will 
evaluate multiple dosing regimens of SER-287, the safety and efficacy of SER-287, subjects’ 
microbiome dynamics throughout treatment and post-treatment effects of SER-287.  
Subjects will be randomized to one (1) of three (3) study arms (Table 1), each of which contain a 
six-day pre-treatment period (vancomycin or matching placebo) and a 10-week Induction 
Treatment period (SER-287 or matching placebo). 
Table 1: SERES-201 Induction Treatment Arms 
Arm 
Pre-Treatment 
(QID for 6 days) 
Induction Treatment 
(QD for 10 weeks) 
A 
Placebo 
Placebo 
B 
Vancomycin 
SER-287 Induction Dose 
C 
Vancomycin 
SER-287 Step-Down Induction Dose 
 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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Subjects will be assessed for Clinical Remission status following 10 weeks of Induction 
Treatment.  
● Remitters will be re-randomized to one (1) of two (2) Maintenance Treatment study arms 
(Table 2): 
 
○ Arm D, treatment with placebo, to assess durability of Clinical Remission, and 
serve as a control 
○ Arm E, treatment with a SER-287 Maintenance Dose, to assess Maintenance of 
Clinical Remission with a once-weekly dosing regimen 
 
● Non-Remitters will be eligible to enter the Open-Label Extension arm, Arm F (Table 2). 
 
All subjects will be followed for long-term safety for 26 weeks following their last treatment 
dose. The study duration from Screening through last follow-up, will be up to 67 weeks. 
Table 2: SERES-201 Post-Induction Treatment Arms 
Arm 
Study Phase 
Pre-Treatment 
(QID for 6 days) 
Treatment 
Frequency of 
Treatment 
Treatment 
Duration  
D 
Maintenance 
Treatment 
N/A 
Placebo 
Once-
Weekly 
26 weeks 
E 
N/A 
SER-287 
Maintenance 
Dose 
Once-
Weekly 
26 weeks 
F 
Open-Label 
Extension 
Vancomycin 
SER-287  
Induction Dose 
Once-Daily 
10 weeks 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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5.2. 
SUBJECT SELECTION 
Detailed lists of inclusion and exclusion criteria are given in Section 4.7 of the Clinical SAP. 
 
5.3. 
DETERMINATION OF SAMPLE SIZE 
Details regarding the determination of sample size are given in Section 4.8 of the Clinical SAP. 
5.4. 
METHOD OF ASSIGNING SUBJECTS TO STUDY TREATMENT 
Subject identification, methods of assigning patients to study treatment arms are described in 
Section 4.9 and of the Clinical SAP. 
5.5. 
BREAKING THE STUDY BLIND 
After the mbSAP is final and the primary study period (Week 0 [Visit 3] to Week 11 [Visit 7]) 
data is declared complete and final, the study blind codes will be broken for the Induction period 
efficacy analyses. The Maintenance Treatment period will remain blinded until all data collected 
through M-Week 37 (Visit M-7) has been entered, cleaned and declared complete and final. Only 
limited personnel at Seres and the unblinded statistical and programming team will have access 
to the treatment code when the study blind is broken at the end of the Induction phase and at the 
end of the Maintenance phase. The remaining study team personnel (majority), PIs and subjects 
will remain blinded until the study is completed. A detailed unblinding plan will be implemented 
concurrently with the clinical SAP and mbSAP analyses 
Due to the time lag involved in generating microbiome data, clinical results by treatment group, 
but not subject by subject unblinded data, will be available prior to start of any microbiome 
analyses for each phase of the study. Samples will be processed in a fashion to ensure unbiased 
analysis of all populations. Specifically, blinded genomic, metabolomic, and transcriptomic data 
will be analyzed at the end of each phase of the study (i.e., Induction, Maintenance). Data for 
each treatment phase will be processed through predefined computational pipelines after the 
database lock to generate microbiome, metabolomic, and transcriptomic profiles. During these 
data generation and processing steps, the study blind will be maintained through the use of 
dummy randomization codes.  
Final TLFs for all subjects at the end of each treatment phase will be generated using true treatment 
codes upon unblinding, but before subjects have completed the following treatment phase or long-


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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term safety follow-up. Since the study is still ongoing, only a limited number of study team 
members will have access to the true treatment code at subject level.  
Microbiome genomic, metabolomic, and host transcriptomic datasets used for secondary and 
exploratory endpoints analyses will be generated 
 
. Data transfer from the vendors to Seres will occur via secure 
channels (e.g., encrypted and password-protected hard drive, secure cloud transfer, etc.). All TLFs 
will be stored in a secure network location, which only the unblinded genomic data team at Seres 
will be able to access. A change log will be maintained on the primary data files to ensure that they 
are not modified. If any samples need to be re-sequenced due to issues of poor quality, this will be 
noted in the final analysis.  
5.6. 
ASSESSMENTS AND PROCEDURES 
For a schedule of assessments and procedures (Induction treatment, Maintenance treatment for 
remitters and Open-Label extension arm for non-remitters), please refer to the Schedule of 
Events section of the Clinical SAP. The schedule of assessments for microbiome endpoints are 
summarized below, Table 3. 
5.6.1. 
Schedule of Assessments for Microbiome Data Collection 
This mbSAP documents the analysis and presentation of microbiome compositional and 
functional changes. For clarity, we present below the schedule of assessments (Table 3) filtered 
to show only samples collected for the endpoints addressed in this document.  
Metagenomic, metabolomic, and host transcriptomic data will be generated for the Induction 
phase. Metagenomic data will also be generated for the Maintenance and Open-label phases.  
In the Maintenance Phase, if clinical remission is significantly greater (p<0.05) in the SER-287 
arm (Arm E) compared to Placebo (Arm D) as assessed in the Clinical SAP, metabolomics and 
host transcriptomics data will be generated from the last scheduled visit (Week 37) or the last 
visit prior to Week 37 with a collected sample. In the Open Label phase, if at least 29% of 
subjects achieve Clinical Remission, as defined in the Clinical SAP, metabolomics and host 
transcriptomics data will be generated for the last time point in the Open Label phase (Week 11). 
Metabolomics and host transcriptomics data may also be generated for the Maintenance and 
Open-label phases at sponsor's discretion. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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Table 3. Schedule of sample collections and data types to be generated for microbiome 
endpoint analysis. 
 
Visit 
Number  
 
Week Number 
 
Study Phase 
 
Period 
 
Sample 
Type  
 
Metagenomics 
 
Metabolomics  
 
Transcriptomics 
1 
Week -4 to -1 
Induction 
Screening 
Stool 
x 
x 
  
2 
Week -4 to -1 
Induction 
Screening 
Biopsy 
  
  
x 
 
3 
 
Week 0 
 
Induction 
 
Pre-
Treatment 
  
  
  
  
4 
Week 1 
Induction 
Treatment 
Stool 
x 
x 
  
5 
Week 3 
Induction 
Treatment 
Stool 
x 
x 
  
6 
Week 7 
Induction 
Treatment 
Stool 
x 
x 
  
 
7 
 
Week 11 
 
Induction 
 
Treatment 
Stool 
x 
x 
  
Biopsy 
  
  
x 
M-1 
M-Week 12 
Maintenance 
Treatment 
  
  
  
  
M-2 
M-Week 16 
Maintenance 
Treatment 
Stool 
x 
 
  


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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M-3 
M-Week 20 
Maintenance 
Treatment 
Stool 
x 
 
  
M-4 
M-Week 24 
Maintenance 
Treatment 
Stool 
x 
 
  
M-5 
M=Week 28 
Maintenance 
Treatment 
Stool 
x 
 
  
M-6 
M-Week 32 
Maintenance 
Treatment 
Stool 
x 
 
  
 
M-7 
 
M-Week 37 
 
Maintenance 
 
Treatment 
Stool 
x 
* 
  
Biopsy 
  
  
* 
 
OL-1 
 
OL-Week 0 
 
Open-Label 
 
Pre-
Treatment 
  
  
  
  
OL-2 
OL-Week 1 
Open-Label 
Treatment 
Stool 
 
 
 
OL-3 
OL-Week 3 
Open-Label 
Treatment 
Stool 
x 
 
  
 
OL-5 
 
OL-Week 11 
 
Open-Label 
 
Treatment 
Stool 
x 
* 
  
Biopsy 
  
  
* 
 
x = Definitive sample analysis; * = Potential sample analysis pending trial outcome targets as outlined in Section 
5.6.1. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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6. 
ANALYSIS POPULATIONS 
There will be four (4) analysis populations used in the mbSAP listed below. 
6.1. 
MICROBIOME MODIFIED INTENT-TO-TREAT (MCITT) POPULATION 
The mcITT population is a subset of the mITT-1_IP population defined in the clinical SAP. The 
mcITT population will consist of all randomized subjects with a baseline evaluation for the 
induction phase, who have active mild-to-moderate UC when the induction phase starts, receive 
any amount of study drug during the induction phase, and have an evaluable stool sample 
collected at baseline and at least one (1) evaluable stool sample collected after the start of dosing. 
Evaluable stool samples are defined as samples that pass the sample acceptability and quality 
control criteria for WMS (see Section 7.2). Subjects will be analyzed based on the treatment to 
which they are randomized. 
6.2. 
MICROBIOME AS-TREATED INDUCTION PHASE (MBAT_IP) 
POPULATION 
The mbAT_IP population will consist of all randomized subjects with a baseline evaluation for 
the induction phase, who have active mild-to-moderate UC when the induction phase starts, 
receive any amount of study drug during the induction phase, and have an evaluable stool sample 
collected at baseline and at least one (1) evaluable stool sample collected after the start of dosing. 
Evaluable stool samples are defined as samples that pass the sample acceptability and quality 
control criteria for any of WMS, Metabolomics, or Transcriptomics data types (see Section 7.2). 
Subjects will be analyzed based on the treatment received, rather than the treatment to which 
they were randomly assigned. 
6.3. 
MICROBIOME AS-TREATED MAINTENANCE PHASE (MBAT_MP) 
POPULATION 
The mbAT_MP population will consist all subjects who were mITT-1 population during the 
induction phase, enter the maintenance phase, are re-randomized in the maintenance phase, 
receive any amount of study drug during the maintenance phase, and have an evaluable stool 
sample collected at baseline and at least one (1) evaluable stool sample collected after the start of 
dosing during the maintenance phase. Evaluable stool samples are defined as samples that pass 
the sample acceptability and quality control criteria for any of WMS, Metabolomics, or 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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Transcriptomics data types (see Section 7.2). Subjects will be analyzed based on the treatment 
received, rather than the treatment to which they were randomly assigned. 
6.4. 
MICROBIOME AS-TREATED OPEN-LABEL PHASE (MBOL) 
POPULATION 
The mbOL  population is a subset of the mITT-1_OL population defined in the clinical SAP. 
The mbOL population will consist of all subjects who were mITT-1 population during the 
induction phase, assigned to the open-label phase (as indicated in the “Status” CRF page), 
receive any amount of study drug during the open-label phase, and have an evaluable stool 
sample collected at baseline and at least one (1) evaluable stool sample collected after the start of 
dosing during the open-label phase. Evaluable stool samples are defined as samples that pass the 
sample acceptability and quality control criteria for any of WMS, Metabolomics, or 
Transcriptomics data types (see Section 7.2). 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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7. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
7.1. 
PLANNED COMPARISONS FOR MICROBIOME ENDPOINTS 
Unless otherwise stated, all the comparisons below will be performed for the indicated study 
phase. Specific metrics and hypotheses are outlined in Sections 10.3. and 10.4. 
7.1.1. 
Treatment-associated comparisons 
Treatment-associated comparisons will assess the effects of SER-287 on microbiome measures, 
based on the following comparisons. 
Induction phase:  
● Treatment Arms B and C separately compared to placebo (Arm A). Compares 
individual dosing regimens to placebo.  
● Treatment Arms B and C pooled together compared to placebo (Arm A). 
Compares both arms with SER-287 treatment to placebo.  
● Treatment Arms B vs C. Compares the Induction dose and the step-down 
Induction dose. 
 
Maintenance phase: 
● Treatment (Arm E) compared to placebo (Arm D). Compares Maintenance dosing 
to placebo. 
 
Open-label phase:  
● For engraftment and microbiome composition metrics, no hypothesis testing will 
be performed. Instead, descriptive statistics will be reported. 
● For stool metabolite composition and host mucosal functional response, 
hypothesis tests will be performed to assess change from baseline. 
 
7.1.2. 
Outcome-associated comparisons 
Outcome-associated comparisons will assess microbiome correlates of Clinical Remission and 
Endoscopic Improvement (as defined in the Clinical SAP). These comparisons will assess if 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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microbiome measures affect the likelihood of these clinical outcomes. For both Clinical 
Remission and Endoscopic Improvement, the following comparisons will be performed. 
Induction phase: 
● Subjects achieving the clinical outcome compared to subjects not achieving the 
clinical outcome within SER-287 treatment arms (Arms B and C). 
 
  
 
 
 
 
 
 
7.2. 
SAMPLE ACCEPTABILITY CRITERIA AND QUALITY CONTROL 
Samples are collected according to the time period described in the Schedule of Events (Table 3). 
Failure to meet quality thresholds (detailed below) will result in removal of a sample from 
analysis. Deviations in sample handling may result in removal of a sample from analysis.  
7.2.1. 
Whole metagenomic sequencing 
DNA will be extracted from stool samples at Seres via a qualified automated process on verified 
equipment. WMS on the extracted DNA will be performed 
. Sample 
quality control will be performed by the vendor and subject to their quality control procedures. 
Additional details regarding specific sample quality control procedures will be obtained in a 
statement of work. 
To ensure comparability between different subject samples, each sample will be subsampled to 
equalize the number of reads before subsequent analyses. If samples are sequenced multiple 
times (e.g., with multiple sample preparation methods; see Section 8.2.1), they will be merged to 
obtain one microbiome profile per sample; subsampling will occur either before or after profiles 
are merged and will be pre-specified in the analysis protocol. Before unblinding, the distribution 
of the number of reads per sample will be assessed; based on this distribution, a subsampling 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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level will be selected that maximizes the number of included samples while also maintaining a 
depth sufficient to characterize the microbiome profile. Any sample with a number of reads 
below this base level will be discarded from further analysis.  
7.2.2. 
Metabolomics 
Metabolomic samples will be processed, and quality control will be performed 
 
. Sample quality control will be performed by the vendor and subject to their quality 
control procedures. Additional details regarding specific sample quality control procedures will 
be obtained in a statement of work. 
7.2.3. 
Transcriptomics 
Transcriptomics samples will be processed 
. Sample quality control 
will be performed by the vendor and subject to their quality control procedures. Additional 
details regarding specific sample quality control procedures will be obtained in a statement of 
work. 
7.3. 
STATISTICAL ANALYSIS -- GENERAL METHODS 
● Continuous variables will be summarized using the number of subjects with evaluable 
data, mean, standard deviation (SD), median, minimum and maximum. 
● Categorical variables will be summarized using the number of observations (n), 
frequency and percentage of subjects. All percentages will be presented as one-decimal 
point, unless otherwise specified. Percentages equal to 100 will be presented as 100% and 
percentages will be presented as 0% for zero frequencies. Unless stated otherwise, the 
percentages will be based on the number of non-missing observations. 
● Any calculated p-values will be presented to 3 decimal places; p-values less than 0.001 
will be presented as ‘p<0.001’ and p-values greater than 0.999 will be presented as 
‘p>0.999’. 
● For statistical analyses involving hypothesis testing across multiple related variables (i.e., 
bacterial species, stool metabolites, and host transcripts), adjusted p-values will 
additionally be reported to estimate the false discovery rate (FDR). Any adjusted p-value 
will be presented to 3 decimal places; adjusted p-values less than 0.001 will be presented 
as ‘p<0.001’ and adjusted p-values greater than 0.999 will be presented as ‘p>0.999’. 
● Unless otherwise stated, all formal tests of hypotheses will be conducted at the two-sided 
level of significance with alpha=0.05.  


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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● All relevant subject data will be included in listings and sorted by treatment, Subject ID, 
and visit, as applicable, for all randomized subjects.  
● Unscheduled or repeat assessments will not be included in summary tables unless 
specified otherwise but will be included in the subject listings.  
● All tables, listings and figures will include footers that identify the name of the program 
that created the item, together with the date and time on which it was created. Headers 
will include the total number of pages that the presentation contains and, for each page, 
the number of the page within the presentation.  
 
7.4. 
KEY DEFINITIONS 
7.4.1. 
Study Day 
For the induction phase, Study Day 1 is defined as the first dosing day of induction study drug. 
Subsequent days are numbered consecutively (Day 2, Day 3, etc.). Before the day of study drug 
administration, study days are numbered sequentially with negative values (i.e., Day -1, Day -2, 
etc.). There is no Day 0. 
 
 
 
 
7.4.2. 
Baseline values 
For each study phase, baseline values will be taken as the last assessments within 30 days before 
dosing with any study drug for the specified phase. The baseline values for different phases of 
the study are defined as follows, unless otherwise specified: 
• For the Induction phase, baseline values are between Day -30 and Day 1. That is, baseline 
values are assessments done at screening or pre-dose assessments on Day 1 and within 30 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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days of Day 1, using the time point that is designated as the sample acquired at the Visit 1 
screening timepoint closest to but prior to dosing of any Induction treatment study drug. 
 
 
 
 
 
 
 
 
 
  
7.4.3. 
SER-287 drug product species definitions 
SER-287 is a formulation of bacterial Firmicute spores that are enriched and purified from 
human stool. Briefly, stool donations undergo Good Manufacturing Process-compliant 
manufacturing steps including clearance of non-spore forms of bacteria, fungi, parasites and 
viruses via solvent treatment and by sequential purification steps. 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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7.5. 
MISSING DATA 
Every effort will be made to collect all data at specified time points, according to the schedule of 
study events. Missing data will not be imputed. 
 
7.6. 
VISIT WINDOWS 
Samples collected at scheduled visits will be assigned to nominal visits if they fall within the 
visit windows delineated in Table 4 for that scheduled visit. The study visits scheduled after 
randomization should occur at the times delineated in the Schedule of Events section of the 
protocol amendment 3. Samples collected at unscheduled or end of treatment visits will not be 
assigned to nominal visits. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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Table 4: Visit Windows for mbSAP 
Visit Number in CSP  
Week Number in CSP 
Visit window for mbSAP 
1 
Week -4 to -1 
Days -30 to 1 
4 
Week 1 +/- 1 day 
Days 2-11 
5 
Week 3 + 3 day 
Days 13-35 
6 
Week 7 + 3 day 
Days 40-60 
7 
Week 11 + 3 day 
Days 65-100 
Visit M-2 
M-Week 16 + 3 days 
Days 14_MP-42_MP 
Visit M-3 
M-Week 20 + 3 days 
Days 43_MP-70_MP 
Visit M-4 
M-Week 24 + 3 days 
Days 71_MP-98_MP 
Visit M-5 
M-Week 28 + 3 days 
Days 99_MP-126_MP 
Visit M-6 
M-Week 32 + 3 days 
Days 127_MP-154_MP 
Visit M-7 
M-Week 37 + 3 days 
Days 155_MP-196_MP 
Visit OL-2 
OL-Week 1 +/- 1 day 
Days 2_OL-11_OL 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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Visit OL-3 
OL-Week 3 + 3 days 
Days 13_OL-35_OL 
Visit OL-5 
OL-Week 11 + 3 days 
Days 65_OL-100_OL  
 
7.7. 
MULTIPLICITY ADJUSTMENTS 
Adjustments for multiple testing will be made for hypotheses involving tests over multiple 
microbial species, metabolites, and transcripts; adjustments will be made within a given endpoint 
and timepoint and not across multiple timepoints or endpoints. The false discovery rate (FDR) at 
a given p-value cutoff will be controlled based on the Benjamini-Hochberg procedure; both p-
values and corrected p-values will be reported. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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8. 
ENDPOINTS FOR MICROBIOME ANALYSIS 
8.1. 
MICROBIOME ENDPOINTS – BACKGROUND AND OVERVIEW 
SER-287 is a formulation of bacterial Firmicute spores that are enriched and purified from 
human stool. The basic mechanism of action is thought to require engraftment of bacteria 
derived from SER-287 into the gastrointestinal tract of patients. We quantify engraftment, which 
is a measure of SER-287 pharmacokinetics (PK), based on whole metagenomic sequencing of 
both patient stool samples and SER-287 drug product. Engraftment of SER-287 is assessed as a 
secondary endpoint and further characterized in exploratory endpoints. 
Engraftment of SER-287 is then hypothesized to result in: a) compositional change in the 
microbiome, b) functional change in microbiome, including change in the fecal metabolome, and 
c) functional change in the host, including change in the host transcriptome. Each of these 
changes that follow engraftment are aspects of SER-287 pharmacodynamics (PD) and will be 
assessed as exploratory endpoints. 
Engraftment of SER-287 can result in other compositional changes in the microbiome through 
microbe-microbe and microbe-host interactions. This can manifest as some species becoming 
more prevalent while others become less prevalent. These broader compositional changes in the 
microbiome will be assessed based on whole metagenomic sequencing (WMS) of patient stool in 
exploratory endpoints. 
Microbial metabolism is a mechanism by which the microbiome can affect host inflammation 
and barrier integrity through multiple disease-relevant pathways. Production and consumption of 
metabolites by gut microbes changes the concentration of these metabolites in the intestinal 
lumen and host tissue. Metabolites that are modulated by gastrointestinal microbes can 
subsequently impact host inflammation and epithelial barrier integrity      (Brestoff and Artis, 
2013). The fecal metabolome of patients will be characterized by LC-MS and LC-MS/MS 
methods. Change in the concentration of microbially-modulated metabolites in patient fecal 
samples will be assessed in exploratory endpoints. 
The change in the molecular environment of the gastrointestinal tract due to change in the 
microbiome and metabolome in turn affects host gene expression. Some bacterially-modulated 
metabolites can directly regulate host gene expression; furthermore, bacterial antigens affect host 
gene expression. Thus, through several mechanisms, SER-287 is expected to alter gene 
expression in intestinal tissue. The host transcriptome of patients will be assessed by RNA-seq 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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from patient colonic biopsies and change in host transcriptome will be assessed in exploratory 
endpoints. 
In summary, a sequence of events is thought to underlie the therapeutic effect of SER-287 
starting from engraftment of SER-287 bacteria, and followed by broader compositional change 
in the microbiome, change in the fecal metabolome, and change in the host transcriptome. Each 
of these events will be separately assessed in this mbSAP.  
The assessments in the mbSAP are either treatment- or outcome-associated comparisons 
(Section 7.1). Treatment-associated comparisons will assess the effect of treatment arm on 
microbiome PK and PD measures. Outcome-associated comparisons will assess if microbiome 
PK or PD measures are associated with Clinical Remission and Endoscopic Improvement. 
Collectively, these two sets of comparisons aim to identify PK and PD effects of SER-287 that 
may affect the likelihood of clinical outcomes and may underlie the mechanism of action of 
SER-287. 
8.2. 
MICROBIOME ENDPOINTS – MOLECULAR AND BIOINFORMATIC 
METHODS 
8.2.1. 
Stool microbiome taxonomic profiling 
We will assess the bacterial taxonomic composition of SER-287 drug product lots and subject 
stool samples using whole metagenomic sequencing (WMS). WMS is a widely used method for 
profiling microbiomes which involves shotgun genomic sequencing of bulk DNA obtained from 
samples of interest. 
 
 
 
 
 
 The resulting WMS data 
can be used to identify specific species, subject to limitations due to assay sensitivity and the 
availability of complete bacterial genomes required for constructing reference databases.  
 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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To ensure comparability between different subject samples, each sample will be subsampled to 
equalize the number of reads before subsequent analyses based on methods outlined in 
Section 7.2.1. Any subject sample with a number of reads below this base level will be discarded 
from further analysis. Outputs from this computational pipeline will be referred to as the 
“microbiome profile” (i.e., the relative abundance of bacterial species) of a sample.  
8.2.2. 
Stool metabolomics profiling 
The fecal metabolome of patients will be characterized by LC-MS and LC-MS/MS through 
global profiling and targeted profiling of short-chain fatty acids. In targeted metabolomic 
profiling the concentrations of a specific set of metabolites is determined with well-defined 
limits of quantification. In global profiling, hundreds of metabolites across diverse classes are 
identified and quantitated in an unbiased manner, but the quantitative concentrations are not 
determined; instead, peaks are quantified using area-under-the-curve. Compounds will be 
identified based on retention index, mass and/or MS/MS spectrum in comparison to a library of 
purified standards and/or recurrent unknown entities. Determined concentrations (for targeted 
profiling) and peak areas (for global profiling) will be referred to as the “metabolomic profile” of 
a sample.  
8.2.3. 
Host mucosal transcriptome profiling 
The transcriptome of patients will be characterized by whole transcriptome sequencing using 
next-generation sequencing technology (NGS). RNA-Seq data from the mucosal biopsy samples 
from each subject will be generated. Total RNA will be extracted from biopsies and reverse 
transcribed to generate cDNA libraries that are sequenced using an Illumina sequencing 
platform. Sequence data will be processed for quality with well-established sequencing criteria 
and reads will be aligned to a current reference human genome. Following alignment to the 
human reference genome, mapped gene counts will be computed. Outputs from this 


TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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computational pipeline (i.e., mapped read counts for each detected human transcript) will be 
referred to as the “transcriptome profile” of a sample.  
8.3. 
SECONDARY ENDPOINT: SER-287 ENGRAFTMENT IN INDUCTION 
PHASE 
Engraftment of SER-287 into subject microbiomes is measured relative to subject baseline 
samples, as defined in Section 7.4.2. Baseline samples in this analysis represent subject 
microbiome composition prior to antibiotic pre-conditioning and treatment with SER-287. As 
SER-287 is derived from healthy, screened donor stool, some subset of SER-287 species are 
expected to be present in some subject baseline samples. Thus, microbiome engraftment will be 
measured by the number of spore-forming species detected in SER-287 that are absent in subject 
baseline samples, and present post-treatment, 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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8.4. 
EXPLORATORY ENDPOINTS: EFFECTS OF TREATMENT WITH SER-
287 ON THE INTESTINAL MICROBIOME AND MICROBIAL 
FUNCTIONAL RESPONSES 
8.4.1. 
SER-287 engraftment 
As outlined above, the magnitude of SER-287 engraftment will be assessed in the Induction 
phase using the spore_dose drug product definition (outlined in Section 7.4.3) as a secondary 
endpoint. 
 
 
  


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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8.4.2. 
Microbiome species composition and microbial functional response 
Engraftment of SER-287 spore-forming species is expected to mediate broader changes in the 
microbiome. In addition to engrafting species, the presence of other species (i.e., spore-forming 
bacterial species not detected in SER-287 and non-spore-forming species) are expected to change 
post-treatment. Some of these species are expected to appear after the start of treatment, or to 
disappear after the start of treatment. The gain and loss of species as a whole forms a broader 
characterization of how SER-287 treatment both directly and indirectly affects microbiome 
compositional change compared to the natural flux of species gains and losses that occur in 
placebo subjects. 
The change in the composition of the microbiome is in turn expected to alter patients’ fecal 
metabolome. Production and consumption of metabolites by gut microbes changes the 
concentration of these metabolites in the intestinal lumen. To assess this microbial functional 
response, we will evaluate changes in concentrations of metabolite levels in fecal samples due to 
SER-287 treatment.  
8.4.2.1. 
Frequency of species newly appearing post-treatment 
Newly appearing species will be defined for each subject and post-treatment time point as those 
species which are absent in a subject’s baseline sample and present post-treatment. These include 
both engrafting species and other species that newly appear post-treatment. 
To assess whether the frequency of newly appearing species differs across arms, we will first 
generate a 2x2 contingency table for each species based on the presence or absence of that 
species in subjects’ stool across the prespecified pairwise comparisons of treatment groups at a 
particular time point. The contingency table will have two categories: species absent at baseline 
and present post-treatment, and species absent at baseline and absent post-treatment. For each 
species, we will then calculate a two-sided p-value based on a Fisher’s Exact test to assess if the 
frequency of newly appearing species differs across arms at the given time point. FDR q-values 
will also be reported to correct for multiple hypotheses within each time point separately. 
Species detected in fewer than 5 subjects at a given time point across all treatment groups will 
not be assessed at that time point. 
We will test the following hypotheses at Week 1, Week 3, Week 7 and Week 11 for the 
mbAT_IP population and at M-Week 16, M-Week 20, M-Week 24, M-Week 28, M-Week 32, 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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and M-Week 37 for the mbAT_MP population for pairwise comparisons detailed in 
Section 7.1.1: 
● H0: The frequency of a newly appearing species does not differ between treatment arms. 
● HA: The frequency of a newly appearing species does differ between treatment arms. 
 
Descriptive statistics will be provided for newly appearing species for the mbOL population at 
OL-Week 3 and OL-Week 11; in the absence of a placebo arm in the Open-Label Phase, no p-
values will be reported. 
8.4.2.2. 
Frequency of species newly absent post-treatment 
Newly absent species will be defined for each subject and post-treatment time point as those 
species which are present in a subject’s baseline sample and absent post-treatment. 
To assess whether the frequency of inhibited species differs across arms, we will first generate a 
2x2 contingency table for each species based on the presence or absence of that species in 
subjects’ stool across pairwise comparisons of treatment groups. The contingency table will have 
two categories: species present at baseline and absent post-treatment, and species present at 
baseline and present post-treatment. For each species, we will then calculate a two-sided p-value 
based on a Fisher’s Exact test to assess if the frequency of newly absent species differs across 
arms at a given time point. FDR q-values will also be reported to correct for multiple hypotheses 
within each time point separately. Species detected in fewer than 5 subjects at a given time point 
not be assessed at that time point. 
We will test the following hypotheses at Week 1, Week 3, Week 7 and Week 11 for the 
mbAT_IP population and at M-Week 16, M-Week 20, M-Week 24, M-Week 28, M-Week 32, 
and M-Week 37 for the mbAT_MP population for pairwise comparisons detailed in 
Section 7.1.1: 
● H0: The frequency of a newly absent species does not differ between treatment arms.  
● HA: The frequency of a newly absent species does differ between treatment arms.  
 
Descriptive statistics will be provided for newly absent species for the mbOL population at OL-
Week 3 and OL-Week 11; in the absence of a placebo arm in the Open-Label Phase, no p-values 
will be reported. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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8.4.2.3. 
Stool metabolite composition 
The fecal metabolome of patients will be characterized by LC-MS and LC-MS/MS through 
global profiling and targeted profiling of short-chain fatty acids at baseline and post-treatment. 
For each detected metabolite, we will assess the log2 fold-change of metabolite abundance, Δm, 
from baseline compared to post-treatment. Undetected metabolites in samples will be imputed to 
the minimum observed level across all samples before fold-change calculation.  
To assess whether the fold-change in metabolite abundance from baseline, Δm, differs between 
prespecified treatment arm comparisons, we will use a linear model: 
Δm ~ 𝛃ArmArm 
FDR q-values will also be reported to correct for multiple hypotheses within each time point 
separately. 
We will test the following hypotheses at Week 3 and Week 11 for the mbAT_IP population and 
at M-Week 37 for the mbAT_MP population (pending trial outcome targets outlined in 
Section 5.6.1) for pairwise comparisons detailed in Section 7.1.1: 
● H0: The fold-change of metabolites (Δm) post-treatment does not differ between 
treatment arms. 
● HA: The fold-change of metabolites (Δm) post-treatment does differ between treatment 
arms. 
 
In the Open-Label phase, pending trial outcome targets outlined in Section 5.6.1 we will assess if 
the fold-change in metabolite abundance from baseline to OL-Week 11, Δm, is centered around 
zero using a linear model for the mbOL population. FDR q-values will also be reported to correct 
for multiple hypothesis correction within each time point separately. 
For all comparisons, in addition to reporting statistics for all measured metabolites, we will 
report the results for the following metabolites and ratios of metabolite concentrations that are 
specifically hypothesized to be affected by SER-287: 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
PLAN 
PROTOCOL NO. 
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TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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8.4.3. 
Host mucosal functional response 
Microbial species and metabolites that change as a result of treatment by SER-287 interface with 
the host intestinal mucosal layer and can directly or indirectly affect host gene expression. We 
will evaluate changes in gene expression from baseline to the end of treatment between subjects 
in SER-287 treatment arms versus placebo. Specifically, we will evaluate the change in 
aggregate in genes in specific pathways relevant to disease as well as in genes identified as being 
either positively or negatively associated with UC in the iHMP study (Lloyd-Price et al., 2019). 
8.4.3.1. 
Differential host gene expression and pathway enrichment 
To assess whether there are specific host genes associated with treatment with SER-287, we will 
compare the change in gene expression of subjects from baseline to post-treatment between 
prespecified treatment arm comparisons. 
 
 
 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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We will then test the association between treatment with SER-287 and the aggregate change in 
expression of genes in pre-specified gene sets (Table 6) with gene set enrichment analysis 
(GSEA). GSEA tests whether a predefined set of genes shows statistically significant differences 
between groups, which can be more powerful in detecting differences when a functionally 
related set of genes change in expression together, but individual genes may not reach the 
threshold of significance. GSEA will be run using the ‘fgsea’ R package.  
Genes relevant to disease will be composed of two types of gene sets: 1) Gene sets defined in 
prespecified KEGG [Kyoto Encyclopedia of Genes and Genomes] (Kanehisa et al., 2019) 
pathways of interest; and 2) Genes which are significantly differentially expressed between 
subjects with ulcerative colitis and non-IBD subjects in the iHMP study (Lloyd-Price et al., 
2019), applying the same linear model described above. For the latter (2), genes will also be 
partitioned into two categories: Those that are higher in UC vs. non-IBD subjects (N = 2901, 
FDR < 0.05), and those that are lower in UC vs. non-IBD subjects (N = 3924, FDR < 0.05). 
These will be tested as separate pathways. 
For all gene sets, the set of shared genes between this list and those detected after quality 
filtering in study samples will be used in the GSEA analysis. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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We will test the following hypotheses at Week 11 for the mbAT_IP population and at M-Week 
37 for the mbAT_MP population (pending trial outcome targets outlined in Section 5.6.1) for 
pairwise arm comparisons detailed in Section 7.1.1: 
● H0: Gene set expression does not shift differentially from baseline to post-treatment 
between prespecified treatment arm comparisons 
● HA: Gene set expression shifts differentially from baseline to post-treatment between 
prespecified treatment arm comparisons 
 
We will test the following hypotheses at OL-Week 11 for the mbOL population (pending trial 
outcome targets outlined in Section 5.6.1): 
● H0: Gene set expression does not shift differentially from baseline to OL-Week 11 
● HA: Gene set expression does not shift differentially from baseline to OL-Week 11      
 
In addition to gene set statistics, statistics for individual genes within gene sets with FDR<0.05 
will be reported.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
PLAN 
PROTOCOL NO. 
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TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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8.5. 
EXPLORATORY ENDPOINTS: ASSOCIATION BETWEEN CLINICAL 
OUTCOME AND THE INTESTINAL MICROBIOME AND HOST AND 
MICROBIAL FUNCTIONAL RESPONSES 
8.5.1. 
SER-287 engraftment 
The basic mechanism of action of SER-287 is thought to require engraftment of bacteria derived 
from SER-287 into the gastrointestinal tract of patients. We will assess if the magnitude of 
engraftment is associated with clinical outcome. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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8.5.1.1. 
Magnitude of engraftment 
We will evaluate the association of ΔSobs_spore_dose with clinical outcomes across arms. This 
measure will provide insight as to whether the magnitude of engraftment at particular timepoints 
are predictive of clinical outcome. 
We will perform logistic regression with arm and baseline richness of dose species in subject 
stool samples, Sobs_spore_dose_baseline, as covariates: 
Logit(Outcome) ~ 𝛃ΔSΔSobs_spore_dose + 𝛃ArmArm + 𝛃BaselineSobs_spore_dose_baseline 
We will test the following hypotheses for each time point at Weeks 3, 7 and 11 for the mbAT_IP 
and OL-Week 3 and OL-Week 11 for the mbOL populations pending trial outcome targets 
outlined in Section 7.1.1: 
● H0: The magnitude of engraftment is not associated with clinical outcome (i.e., 𝛃ΔS = 0). 
● HA: The magnitude of engraftment is associated with clinical outcome (i.e., 𝛃ΔS ≠ 0). 
 
8.5.2. 
Microbiome species composition and microbial functional response 
Changes in both microbiome species and metabolites composition are hypothesized to underlie 
SER-287 mechanism of action. We will assess if the presence of specific species and abundance 
of specific metabolites are associated with clinical outcome. 
8.5.2.1. 
Microbiome species composition 
We will evaluate the association of specific species with subject clinical outcome across arms. 
This measure will provide insight as to whether specific species (either engrafting from SER-287 
or changing as a result of treatment) are associated with clinical outcome. 
To assess whether specific species are associated with clinical outcome, we will perform logistic 
regression for individual species observed in subject stool samples using treatment arm and 
baseline observation of the species in subject stool samples as covariates: 
Logit(Outcome) ~ 𝛃ArmArm + 𝛃obs_spp_postIobs_spp_post+ 𝛃obs_spp_baselineIobs_spp_baseline 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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where Outcome = binary variable indicating clinical outcome status, Arm = treatment arm, 
Iobs_spp_post = binary variable indicating if species was observed post-treatment, Iobs_spp_baseline = 
binary variable indicating if species was observed at baseline. 
Species detected in fewer than 5 subjects at a given time point will not be assessed at that time 
point. FDR q-values will also be reported to correct for multiple hypotheses within each time 
point separately. 
We will test the following hypotheses for each time point at Week 1, Week 3, Week 7 and Week 
11 for the mbAT_IP population and OL-Week 3 and OL-Week 11 for the mbOL population 
pending trial outcome targets outlined in Section 7.1.1: 
● H0: The presence of a species post-treatment is not associated with clinical outcome (i.e., 
𝛃obs_spp_post = 0). 
● HA: The presence of a species post-treatment is associated with clinical outcome (i.e., 
𝛃obs_spp_post ≠ 0). 
 
8.5.2.2. 
Stool metabolite composition 
We will assess whether the concentration of metabolites in stool is associated with clinical 
outcome following treatment with SER-287. In order to assess whether log2 fold-changes of 
metabolite abundances, Δm, are associated with clinical outcome, we will perform logistic 
regression for each metabolite detected in any subject stool sample using treatment arm and log2 
baseline metabolite abundance as covariates: 
Logit(Outcome) ~ 𝛃ArmArm + 𝛃ΔmΔm +𝛃BaselinemBaseline 
where Outcome = binary variable indicating clinical outcome status, Arm = treatment arm, Δm = 
log2 fold-change of metabolite abundance and mBaseline = log2 baseline metabolite abundance. 
We will test the following hypotheses at Week 3 and Week 11 for the mbAT_IP population and 
OL-Week 11 for the mbOL population pending trial outcome targets outlined in Section 7.1.1: 
● H0: The fold-change of a metabolite (Δm) does not differ between responders and non-
responders (i.e., 𝛃Δm = 0). 
● HA: The fold-change of a metabolite (Δm) does differ between responders and non-
responders (i.e., 𝛃Δm ≠ 0). 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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For all comparisons, in addition to reporting statistics for all measured metabolites, we will 
report the results for the following metabolites that are specifically hypothesized to be associated 
with clinical outcome (Table 7). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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8.5.3. 
Host mucosal functional response 
Treatment-associated changes in both microbiome species composition and their complement of 
metabolites may also result in changes is host mucosal gene expression. We will evaluate 
changes in host mucosal gene expression are associated with clinical outcome.  
8.5.3.1. 
Differential host gene expression and pathway enrichment 
To assess whether there are specific host genes associated with clinical outcome, we will 
compare the change in gene expression from baseline to Week 11 of subjects achieving and not 
achieving a clinical outcome.  
The same approach as detailed in Section 8.4.3.1 will be applied, with raw counts data will be 
transformed to log2-counts per million (LC_M) with R function using the ‘voom’ function of the 
R ‘limma’ package. To test whether shifts from baseline of individual genes are associated with 
clinical outcomes, we will apply “lmFit” and “eBayes” functions in the R ‘limma’ package. We 
will fit the mixed linear model as shown below, with subject as a random effect. 
𝑐ൌ𝑋ை௨௧௖௢௠௘ି்௜௠௘௣௢௜௡௧𝛽ை௨௧௖௢௠௘ି்௜௠௘௣௢௜௡௧൅𝑋஺௥௠ି்௜௠௘௣௢௜௡௧𝛽஺௥௠ି்௜௠௘௣௢௜௡௧൅𝑢ௌ௨௕௝൅𝜀 
where  
• 𝑐 is the voom-transformed gene expression value for a single sample 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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• 𝑋ை௨௧௖௢௠௘ି்௜௠௘௣௢௜௡௧ is a nominal variable for each combination of clinical outcome and 
Timepoint 
• 𝛽ை௨௧௖௢௠௘ି்௜௠௘௣௢௜௡௧ is a vector of the fixed effects 
• 𝑋஺௥௠ି்௜௠௘௣௢௜௡௧ is a nominal variable for each combination of Arm and Timepoint 
• 𝛽஺௥௠ି்௜௠௘௣௢௜௡௧ is a vector of the fixed effects 
• 𝑢ௌ௨௕௝ is the vector of random effects 
• 𝜀 is the random error term 
For each transcript, we will evaluate the change in expression from baseline between pre-
specified treatment arm comparisons by evaluating the following contrast:  
(𝛽ோ௘௠௜௦௦௜௢௡ି௉௢௦௧்௫െ 𝛽ோ௘௠௜௦௦௜௢௡ି஻௔௦௘௟௜௡௘ሻെ ሺ𝛽ே௢௡௥௘௠௜௦௦௜௢௡ି௉௢௦௧்௫െ 𝛽ே௢௡௥௘௠௜௦௦௜௢௡ି஻௔௦௘௟௜௡௘ሻ. 
We will then test the association between clinical outcomes and the aggregate change in 
expression of pre-specified gene sets (Table 8) with gene set enrichment analysis (GSEA), as 
described in Section 8.4.3.1. For all gene sets, the set of shared genes between this list and those 
detected after quality filtering in study samples will be used in the GSEA analysis. 
We will test the following hypotheses at Week 11 for the mbAT_IP population and at OL-Week 
11 for the mbOL population pending trial outcome targets outlined in Section 5.6.1: 
● H0: Gene set expression does not shift differentially from baseline to Week 11 between 
responder and non-responder. 
● HA: Gene set expression shifts differentially from baseline to Week 11 between responder 
and non-responder. 
 
The following is the list of pathways, including the iHMP gene sets, specifically hypothesized to 
be differentially expressed between responder and non-responder. The hypothesized 
directionality of the enrichment score is given comparisons of responder and non-responder, 
where positive indicates greater enrichment (higher expression) in the former and negative 
indicates greater enrichment in the latter. 
 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
47 of 61 
 
27-APR-2021 
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v 1.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
48 of 61 
 
27-APR-2021 
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v 1.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
PLAN 
PROTOCOL NO. 
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In addition to gene set statistics, statistics for individual genes within gene sets with FDR<0.05 
will be reported.  


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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9. 
CHANGES FROM ANALYSIS PLANNED IN PROTOCOL 
9.1. 
MCITT POPULATION 
The mcITT population was modified to be a strict subpopulation of the mITT-1_IP population; 
this way, only subjects that have mild-to-moderate UC and receive any amount of study drug are 
analyzed. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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10. 
REFERENCES 
Brestoff J.R., and Artis D. (2013). Commensal bacteria at the interface of host metabolism and 
the immune system. Nat. Immunol. 14, 676–684. 
Kanehisa, M., Sato, Y., Furumichi, M., Morishima, K., and Tanabe, M. (2010) New approach for 
understanding genome variations in KEGG. Nucleic Acids Res. 47, D590-D595. 
Law, C.W., Chen ,Y., Shi, W., Smyth, G.K. voom: Precision weights unlock linear model 
analysis tools for RNA-seq read counts. (2014) Genome Biol. 15(2):R29. 
Lloyd-Price J., Arze C., Ananthakrishnan A.N., Schirmer M., Avila-Pacheco J., Poon T.W., 
Andrews E., Ajami N.J., Bonham K.S., Brislawn C.J., Casero D., Courtney H., Gonzalez A,. 
Graeber T.G., Hall A.B., Lake K., Landers C.J., Mallick H., Plichta D.R., Prasad M., Rahnavard 
G., Sauk J., Shungin D., Vázquez-Baeza Y., White R.A. 3rd; IBDMDB Investigators, Braun J., 
Denson L.A., Jansson J.K., Knight R., Kugathasan S., McGovern D.P.B., Petrosino J.F., 
Stappenbeck T.S., Winter H.S., Clish C.B., Franzosa E.A., Vlamakis H., Xavier R.J., 
Huttenhower C. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. 
(2019) Nature. May;569(7758):655-662. 
Segata, N., Waldron, L., Ballarini, A., Narasimhan, V., Jousson, O., and Huttenhower, C. (2012). 
Metagenomic microbial community profiling using unique clade-specific marker genes. Nat. 
Methods 9, 811–814. 
The Human Microbiome Project Consortium (2012). A framework for human microbiome 
research. Nature 486, 215–221. 
Truong, D.T., Franzosa, E.A., Tickle, T.L., Scholz, M., Weingart, G., Pasolli, E., Tett, A., 
Huttenhower, C., and Segata, N. (2015). MetaPhlAn2 for enhanced metagenomic taxonomic 
profiling. Nat. Methods 12, 902–903. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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11. 
PROGRAMMING CONSIDERATIONS 
All tables, data listings, figures (TLFs), and statistical analyses will be generated using R version 
3.2.3 or later. Computer-generated table, listing and figure output will adhere to the following 
specifications. 
11.1. 
GENERAL CONSIDERATIONS 
• One program can create several outputs or a separate program can be created for each 
output at statistical programmer’s discretion. 
• Each output will be stored in a separate file. 
• Output files will be delivered in Word format, rtf format, or pdf format. 
• Numbering of TFLs will follow International Conference to Harmonisation (ICH) E3 
guidance 
 
11.2. 
TABLE, LISTING, AND FIGURE FORMAT 
11.2.1. 
General 
• All TLFs will be produced using the Courier New font, sized as appropriate  
• Headers and footers for figures will be in Courier New font, sized as appropriate. 
• Legends will be used for all figures with more than 1 variable, group, or item displayed. 
• TLFs will be in black and white (no color), unless otherwise specified 
• Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TLFs, unless otherwise specified. On some 
occasions, superscripts 1, 2, or 3 may be used (see below). 
• Only standard keyboard characters will be used in the TLFs. Special characters, such as 
non-printable control characters, printer-specific, or font-specific characters, will not be 
used. Hexadecimal-derived characters will be used, where possible, if they are 
appropriate to help display math symbols (e.g., μ). Certain subscripts and superscripts 
(e.g., cm2, Cmax) will be employed on a case-by-case basis. 
• Mixed case will be used for all titles, footnotes, column headers, and programmer-
supplied formats, as appropriate. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
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11.2.2. 
Headers 
• All output should have the following header at the top left of each page: 
 
Seres Therapeutics, Inc. 
Protocol: SERES-287-201 
 
• All output should have Page n of N at the top or bottom right corner of each page. TLFs 
should be internally paginated in relation to the total length (i.e., the page number should 
appear sequentially as page n of N, where N is the total number of pages in the table). 
• The date (date output was generated) should appear along with program name and 
location as the last footer on each page. 
 
11.2.3. 
Display Titles 
• Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). ICH 
E3 numbering is strongly recommended but sponsor preferences should be obtained prior 
to final determination. A decimal system (x.y and x.y.z) should be used to identify TLFs 
with related contents. The title is centered. The analysis set should be identified on the 
line immediately following the title. The title and table designation are single spaced. A 
solid line spanning the margins will separate the display titles from the column headers. 
There will be 1 blank line between the last title and the solid line 
 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
Analysis Set 
11.2.4. 
Column Header 
• Column headings should be displayed immediately below the solid line described above 
in initial upper-case characters.  
• For numeric variables, include “unit” in column or row heading when appropriate. 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
54 of 61 
 
27-APR-2021 
Confidential 
v 1.0 
11.2.5. 
Table Conventions 
• Units will be included where available. 
• Where percentages are presented in these tables, zero percentages will not be presented 
and so any counts of 0 will be presented as 0 and not as 0 (0%). 
• Unless otherwise specified, the estimated mean and median for a set of values should be 
printed out to 1 more significant digit than the original values, and standard deviations 
should be printed out to 2 more significant digits than the original values. The minimum 
and maximum should report the same significant digits as the original values. For 
example: 
 
N 
 XX 
Mean 
XXX.X 
Std Dev 
 X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
 
• P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 3 
decimal places. Any p-value less than 0.001 will be presented as <0.001. If the p-value 
should be less than 0.0001 then present as <0.0001. If the p-value is returned as >0.999 
then present as >0.999 
• Percentage values should be printed to one decimal place, in parentheses with no spaces, 
one space after the count (e.g., 7 (12.8%), 13 (5.4%)). Values that round down to 0.0 will 
be displayed as '<0.1'. Unless otherwise noted, for all percentages, the number of subjects 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
55 of 61 
 
27-APR-2021 
Confidential 
v 1.0 
in the analysis set for the treatment group who have an observation will be the 
denominator. Percentages after zero counts should not be displayed and percentages 
equating to 100% should be presented as 100%.  
 
11.2.6. 
Listing Conventions 
• Listings will be sorted for presentation in order of treatment groups as above, subject 
number, visit/collection day, and visit/collection time. 
 
11.2.7. 
Figure Conventions 
• Unless otherwise specified, for all figures, study visits will be displayed on the X-axis 
and endpoint (e.g., treatment mean change from Baseline) values will be displayed on the 
Y-axis. 
 
11.2.8. 
Footnotes 
• A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
• All footnotes will be left justified with single-line spacing immediately below the solid 
line underneath the data display. 
• Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, etc. if 
a reference footnote. Each new footnote should start on a new line where possible. 
• Footnotes will be present on the page where they are first referenced and thereafter on 
each page of the table, unless the footnote is specific only to certain pages. Subject 
specific footnotes should be avoided. 
• Footnotes will be used sparingly and must add value to the table, figure, or data listing. If 
more than six lines of footnotes are planned, then a cover page may be used to display 
footnotes, and only those essential to comprehension of the data will be repeated on each 
page.  
• The last 2 lines of the footnote section will be a standard source that indicates the name 
of the program used to produce the data display, date the program was run, and the listing 
source (or data source for a listing) (i.e., ‘Program: myprogram.sas Listing source: 
16.x.y.z’). 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
56 of 61 
 
27-APR-2021 
Confidential 
v 1.0 
12. 
INDEX OF TABLES 
Table Number 
Table Title 
Population 
14.4.1.1 
Magnitude of Engraftment Post-Treatment 
mcITT 
14.4.1.2 
Magnitude of Engraftment Post-Treatment 
mbAT_IP 
14.4.1.3 
Magnitude of Engraftment Post-Treatment 
mbAT_MP 
14.4.1.4 
Magnitude of Engraftment Post-Treatment 
mbOL 
14.4.2.1 
Magnitude of Engraftment Association with Clinical Outcome mbAT_IP 
14.4.2.2 
Magnitude of Engraftment Association with Clinical Outcome mbOL 
14.4.3.1 
Microbiome Species Compositional Change Post-Treatment 
mbAT_IP 
14.4.3.2 
Microbiome Species Compositional Change Post-Treatment 
mbAT_MP 
14.4.3.3 
Microbiome Species Compositional Change Post-Treatment 
mbOL 
14.4.4.1 
Microbiome Species Composition Association with Clinical 
Outcome 
mbAT_IP 
14.4.4.2 
Microbiome Species Composition Association with Clinical 
Outcome 
mbOL 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
57 of 61 
 
27-APR-2021 
Confidential 
v 1.0 
14.4.5.1 
Stool Metabolite Change Post-treatment 
mbAT_IP 
14.4.5.2 
Stool Metabolite Change Post-treatment, all metabolites 
mbAT_IP 
14.4.5.3 
Stool Metabolite Change Post-treatment, short-chain fatty 
acids 
mbAT_IP 
14.4.5.4 
Stool Metabolite Change Post-treatment 
mbAT_MP 
14.4.5.5 
Stool Metabolite Change Post-treatment, all metabolites 
mbAT_MP 
14.4.5.6 
Stool Metabolite Change Post-treatment, short-chain fatty 
acids 
mbAT_MP 
14.4.5.7 
Stool Metabolite Change Post-treatment 
mbOL 
14.4.5.8 
Stool Metabolite Change Post-treatment, all metabolites 
mbOL 
14.4.5.9 
Stool Metabolite Change Post-treatment, short-chain fatty 
acids 
mbOL 
14.4.6.1 
Stool Metabolite Association with Clinical Outcome 
mbAT_IP 
14.4.6.2 
Stool Metabolite Association with Clinical Outcome, all 
metabolites 
mbAT_IP 
14.4.6.3 
Stool Metabolite Association with Clinical Outcome, short-
chain fatty acids 
mbAT_IP 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
58 of 61 
 
27-APR-2021 
Confidential 
v 1.0 
14.4.6.4 
Stool Metabolite Association with Clinical Outcome 
mbOL 
14.4.6.5 
Stool Metabolite Association with Clinical Outcome, all 
metabolites 
mbOL 
14.4.6.6 
Stool Metabolite Association with Clinical Outcome, short-
chain fatty acids 
mbOL 
14.4.7.1 
Host Biopsy Transcript Pathway Change Post-treatment, 
individual genes 
mbAT_IP 
14.4.7.2 
Host Biopsy Transcript Pathway Change Post-treatment, 
pathways 
mbAT_IP 
14.4.7.3 
Host Biopsy Transcript Pathway Change Post-treatment, 
individual genes 
mbAT_MP 
14.4.7.4 
Host Biopsy Transcript Pathway Change Post-treatment, 
pathways 
mbAT_MP 
14.4.7.5 
Host Biopsy Transcript Pathway Change Post-treatment, 
individual genes 
mbOL 
14.4.7.6 
Host Biopsy Transcript Pathway Change Post-treatment, 
pathways 
mbOL 
14.4.8.1 
Host Biopsy Transcript Pathway Association with Clinical 
Outcome, individual genes 
mbAT_IP 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
59 of 61 
 
27-APR-2021 
Confidential 
v 1.0 
14.4.8.2 
Host Biopsy Transcript Pathway Association with Clinical 
Outcome, pathways 
mbAT_IP 
14.4.8.3 
Host Biopsy Transcript Pathway Association with Clinical 
Outcome, individual genes 
mbOL 
14.4.8.4 
Host Biopsy Transcript Pathway Association with Clinical 
Outcome, pathways 
mbOL 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
60 of 61 
 
27-APR-2021 
Confidential 
v 1.0 
13. 
INDEX OF FIGURES 
Figure Number 
Figure Title 
Population 
14.4.1.1 
Magnitude of Engraftment Post-Treatment 
mcITT 
14.4.1.2 
Magnitude of Engraftment Post-Treatment 
mbAT_IP 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
MICROBIOME STATISTICAL ANALYSIS 
PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
61 of 61 
 
27-APR-2021 
Confidential 
v 1.0 
14. 
INDEX OF LISTINGS 
Listing Number 
Listing Title 
16.3.1.1 
Assignment to Microbiome Intent-to-Treat (mcITT) Population 
16.3.1.2 
Assignment to Microbiome As-Treated Induction Phase (mbAT_IP) Population 
16.3.1.3 
Assignment to Microbiome As-Treated Maintenance Phase (mbAT_MP) 
Population 
16.3.1.4 
Assignment to Microbiome Open-Label (mbOL) Population 
 

Prot_000.pdf: 






Seres Therapeutics, Inc. 
Clinical Study Protocol 
Protocol # SERES-201 
CONFIDENTIAL 
Amendment 3 
4 of 116 
08-Oct-2019
Declaration of the Investigator 
Title: ECO-RESET: A Phase 2B, Randomized, Double-Blind, Placebo-Controlled, 
Multiple Dose, Multicenter Study to Assess Efficacy and Safety of SER‑287 in 
Adults with Active Mild-to-Moderate Ulcerative Colitis 
I have received and read the SERES-201 Protocol dated 08-October-2019 and agree to 
conduct the study as outlined.  I agree to maintain the confidentiality of all information 
received or developed in connection with this protocol.   
_____________________________________ 
_____________________ 
Printed Name of Investigator 
Date 
_____________________________________ 
Signature of Investigator 


Seres Therapeutics, Inc. 
Clinical Study Protocol 
Protocol # SERES-201 
CONFIDENTIAL 
Amendment 3 
5 of 116 
08-Oct-2019
PROTOCOL SYNOPSIS  
Title 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, Placebo-Controlled, Multiple Dose, 
Multicenter Study to Assess Efficacy and Safety of SER‑287 in Adults with Active Mild-to-Moderate 
Ulcerative Colitis 
Sponsor 
Seres Therapeutics, Inc. 
Active Ingredient 
SER-287 (Eubacterial Spores, Purified Suspension, Encapsulated) 
Phase 
2B 
Sponsor Study 
No. 
SERES-201 
Population 
Male or female adult subjects 18-80 years of age, inclusive, with active mild-to-moderate Ulcerative 
Colitis 
Number of 
Subjects 
Approximately 201 subjects will be enrolled, approximately 67 subjects in each of three (3) treatment 
arms 
Study Centers 
Approximately 104 study centers in North America 
Planned 
Enrollment 
Duration: 
Approximately 17 months 
Objectives 
Primary Objective: 
•
To demonstrate the efficacy of SER-287, after 10 weeks of induction dosing (following
vancomycin pre-treatment), in achieving clinical remission
Key Secondary Objectives: 
•
To demonstrate the efficacy of SER-287, after 10 weeks of step-down induction dosing
(following vancomycin pre-treatment), in achieving clinical remission
•
To demonstrate the efficacy of SER-287, after 10 weeks of induction dosing (following
vancomycin pre-treatment), in achieving endoscopic improvement
•
To demonstrate the efficacy of SER-287, after 10 weeks of step-down induction dosing
(following vancomycin pre-treatment), in achieving endoscopic improvement
Other Secondary Objectives: 
•
To demonstrate the efficacy of each SER-287 treatment arm in achieving endoscopic remission
after 10 weeks of induction treatment
•
To demonstrate the efficacy of each SER-287 treatment arm in achieving histological mucosal
healing after 10 weeks of induction treatment
•
To demonstrate the efficacy of each SER-287 treatment arm in achieving clinical remission with
normalization of stool frequency after 10 weeks of induction treatment
•
To evaluate the efficacy of each SER-287 treatment arm on symptomatic remission (rectal
bleeding and stool frequency) after 10 weeks of induction treatment
•
To evaluate the engraftment of SER-287 bacteria from each SER-287 treatment arm into the
intestinal microbial community over time
•
For EMA consideration only (see Section 3, Definitions):
o
To demonstrate the efficacy of SER-287 to induce clinical remission, using less
stringent definition
o
To demonstrate the efficacy of SER-287 to induce clinical remission, using more
stringent definition
o
To demonstrate the efficacy of SER-287 to induce symptomatic remission and
endoscopic remission as co-endpoints
Safety Objective: 
To evaluate safety and tolerability of SER-287 


Seres Therapeutics, Inc. 
Clinical Study Protocol 
Protocol # SERES-201 
CONFIDENTIAL 
Amendment 3 
6 of 116 
08-Oct-2019
Exploratory Objectives: 
•
To evaluate clinical remission at the end of maintenance treatment
•
To evaluate endoscopic remission at the end of maintenance treatment
•
To evaluate histological mucosal healing at the end of maintenance treatment
•
To evaluate clinical remission at the end of open-label treatment
•
To evaluate endoscopic improvement at the end of open-label treatment
•
To evaluate endoscopic remission at the end of open-label treatment
•
To evaluate histological mucosal healing at the end of open-label treatment
•
To evaluate the effect of SER-287 treatment on symptomatic remission (rectal bleeding and stool
frequency) over time
•
To evaluate the clinical remission rate of SER-287, by donor, after 10 weeks of induction
treatment
•
To assess improvement in quality of life, as measured by the Inflammatory Bowel Disease
Questionnaire (IBDQ)
•
To assess changes in serum biomarkers (C-reactive protein [CRP]) and fecal biomarkers (fecal
calprotectin)
•
To evaluate changes in the composition of the intestinal microbiome over time
•
To evaluate changes in signatures of host and microbial functional responses over time
Efficacy 
Endpoints 
Primary Endpoint (See Section 3, Definitions): 
•
Clinical remission with SER-287, after 10 weeks of induction dosing, following vancomycin
pre-treatment (Treatment Arm B), compared to placebo, following placebo pre-treatment
(Treatment Arm A)
Key Secondary Endpoints (See Section 3, Definitions): 
•
Clinical remission with SER-287, after 10 weeks of step-down induction dosing, following
vancomycin pre-treatment (Treatment Arm C), compared to placebo, following placebo pre-
treatment (Treatment Arm A)
•
Endoscopic improvement with SER-287, after 10 weeks of induction dosing, following
vancomycin pre-treatment (Treatment Arm B), compared to placebo, following placebo pre-
treatment (Treatment Arm A)
•
Endoscopic improvement with SER-287, after 10 weeks of step-down induction dosing,
following vancomycin pre-treatment (Treatment Arm C), compared to placebo, following
placebo pre-treatment (Treatment Arm A)
Other Secondary Endpoints (See Section 3, Definitions): 
•
Endoscopic remission after 10 weeks of induction treatment
•
Histological mucosal healing after 10 weeks of induction treatment
•
Clinical remission with normalization of stool frequency after 10 weeks of induction
treatment
•
Symptomatic remission (rectal bleeding and stool frequency) after 10 weeks of induction
treatment
•
Engraftment of SER-287 bacteria over time
•
For EMA consideration only (See Section 3, Definitions):
o
Clinical remission (less stringent criteria) after 10 weeks of induction treatment
o
Clinical remission (more stringent criteria) after 10 weeks of induction treatment
o
Clinical remission co-endpoints: symptomatic remission and endoscopic remission
after 10 weeks of induction treatment
Exploratory Endpoints (See Section 3, Definitions): 
•
Clinical remission at the end of maintenance treatment and at the end of open-label
treatment
•
Endoscopic improvement at the end of open-label treatment


Seres Therapeutics, Inc. 
Clinical Study Protocol 
Protocol # SERES-201 
CONFIDENTIAL 
Amendment 3 
7 of 116 
08-Oct-2019
•
Endoscopic remission at the end of maintenance treatment and at the end of open-label
treatment
•
Histological mucosal healing at the end of maintenance treatment and at the end of open-
label treatment
•
Symptomatic remission (rectal bleeding and stool frequency) over time
•
Clinical remission after 10 weeks of induction treatment for each SER-287 donor used in the
induction treatment period
•
IBDQ scores after 10 weeks of induction, at the end of maintenance treatment, and at the
end of open-label treatment
•
Serum biomarkers: CRP after 10 weeks of induction treatment (Week 11), at the end of
maintenance treatment and at the end of open-label treatment
•
Fecal biomarkers: fecal calprotectin levels after 10 weeks of induction treatment (Week 11),
at the end of maintenance treatment and at the end of open-label treatment
•
Composition of the intestinal microbiome through the end of the maintenance treatment and
open-label treatment periods
•
Signatures of host and microbial functional responses through the end of the maintenance
treatment and open-label treatment periods
Evaluation of 
Safety 
The evaluation of safety data will be performed by comparing various safety parameters across 
treatment arms.  The following safety endpoints will be measured: 
•
Incidence of AEs, SAEs and AESIs
•
Laboratory evaluation results
•
Vital sign measurements
•
Physical examination findings
Incidence of AEs, SAEs and AESIs will be summarized for each SER-287 donor overall and within 
each treatment arm. 
Safety endpoints will be summarized at the end of the pre-treatment period (Week 1), Week 3, Week 
7, after 10 weeks of induction treatment (Week 11), at the end of maintenance treatment or open-
label treatment and at end-of-study. 
Study Design 
This is a Phase 2B, randomized, double-blind, placebo-controlled, multiple dose, multicenter study 
designed to evaluate the efficacy and safety of SER-287 in adult subjects, 18-80 years of age, 
inclusive, with active mild-to-moderate ulcerative colitis (UC).  
Approximately 201 subjects will be enrolled.  Enrollment in this trial, as well as the clinical 
endpoints, will be based upon a composite Three-Component Modified Mayo Score of 3 to 7, 
inclusive, which sums patient-reported rectal bleeding and stool frequency subscores with endoscopic 
subscore.  Endoscopic subscores will be determined by local and independent, blinded central 
readers.  The endoscopy central readers will remain blinded to subjects’ treatment assignments 
throughout the entire study. 
The key study phases after Screening and randomization are: Induction Treatment (three [3] 
treatment arms), Maintenance Treatment (for Remitters) or an Open-Label Extension Arm (for Non-
Remitters), and Long-Term Safety Follow-Up: 






Seres Therapeutics, Inc. 
Clinical Study Protocol 
Protocol # SERES-201 
CONFIDENTIAL 
Amendment 3 
10 of 116 
08-Oct-2019
reader will remain blinded to treatment assignment.  Subjects who experience a UC 
flare during the Open-Label treatment period will discontinue study drug and will 
be followed for safety for 26 weeks. 
5.
Long-Term Safety Follow-Up: All subjects will be followed for long-term safety for 26
weeks following their last treatment dose.  No office visits are required during this period.
Site personnel will conduct follow-up phone calls every four (4) weeks.  During the first
four (4) weeks of the Long-Term Safety Follow-Up Period, AEs/SAEs/AESIs, concomitant
procedures, and concomitant medications will be collected.  During subsequent follow-up
phone calls, subjects will be asked about any SAEs/AESIs and any concomitant medications
associated with an SAE/AESI.  Concomitant UC medications and UC procedures, and any
changes to these, will be collected throughout the entirety of the Long-Term Safety Follow-
Up Period.
Inclusion Criteria 
1.
Signed informed consent prior to initiation of any study-specific procedure or treatment.
The subject must be willing to provide written informed consent and understand the
potential risks and benefits from study enrollment and treatment.  The subject must also be
willing and able to comply with the scheduled visits, treatment plan, laboratory tests, daily
eDiary and other study procedures.
2.
Male or female (non-lactating), 18-80 years of age, inclusive
3.
Documented diagnosis of ulcerative colitis at least three (3) months prior to Screening.
Documentation should include lower endoscopic (flexible sigmoidoscopy or colonoscopy)
evidence or histological evidence (biopsy report) of UC; however, UC medical treatment
records may be sufficient, as determined by the PI.  Subjects must also have a minimum
disease extent of 15 cm from the anal verge, as determined at the Screening endoscopy.
4.
Active mild-to-moderate UC as determined by a Three-Component Modified Mayo Score of
3 to 7, inclusive, composed of endoscopic subscore (≥ 1, as determined by local and central
reader scores, with adjudication by a second central reader, if necessary), stool frequency
subscore (≥ 1) and rectal bleeding subscore (no eligibility requirement).  There will be a
maximum time of seven (7) business days between the Screening endoscopy and
randomization.
5.
Subjects must be willing to undergo a lower endoscopy (flexible sigmoidoscopy or
colonoscopy), including biopsy sample collection, at all specified timepoints.
6.
Subjects with an inadequate response to, loss of response to, or intolerance of, at least one
(1) of the following conventional therapies: 5-ASA compounds, corticosteroids, 6-
mercaptopurine (6-MP) or azathioprine (AZA), anti-TNFα, anti-integrin or tofacitinib (note
full definition within Section 5.1, Inclusion Criteria)
7.
If female, is either:
a.
Not of childbearing potential, defined as postmenopausal (≥ 12 continuous months
of amenorrhea with no other cause than menopause) or surgically sterile due to
bilateral tubal ligation, bilateral oophorectomy, or hysterectomy
b.
Of childbearing potential and participates in any activity associated with risk of
pregnancy: is practicing at least one (1) highly effective method of birth control,
including the barrier method, oral or parenteral contraceptives, a vasectomized
partner or abstinence from sexual intercourse.  The investigator will discuss with
the subject the option of practicing more than one (1) of the above methods for the
duration of the study.
8.
If male and partner is of childbearing potential, subject agrees to practice at least one (1)
highly effective method of birth control for the duration of the study.
Exclusion Criteria 
1.
Known history of Crohn’s disease
2.
No previous history of treatment for UC (treatment-naïve subjects should not be enrolled)
3.
Subjects on steroid medication (e.g. prednisone, budesonide, budesonide MMX®) who are
unable to have steroids tapered, and be completely off steroids at least two (2) weeks prior
to Screening


Seres Therapeutics, Inc. 
Clinical Study Protocol 
Protocol # SERES-201 
CONFIDENTIAL 
Amendment 3 
11 of 116 
08-Oct-2019
4.
Subjects who have received any investigational or approved biologic therapy
(e.g. infliximab, adalimumab, golimumab, certolizumab, vedolizumab, ustekinumab,
natalizumab) within eight (8) weeks prior to Screening or five (5) half-lives prior to
Screening (whichever is longer)
5.
Subjects who have received any investigational or approved non-biologic therapy
(e.g. cyclosporine, tacrolimus, thalidomide, methotrexate, tofacitinib), except for those
specifically listed in the Permitted Concomitant Medications (e.g. stable dose of 6-
mercaptopurine, azathioprine, methotrexate for ≥ 12 weeks prior to Screening), for the
treatment of underlying disease, within 30 days or five (5) half-lives prior to Screening
(whichever is longer)
6.
Major gastrointestinal surgery (not including appendectomy or cholecystectomy) within two
(2) months before Screening, or any history of total colectomy
7.
Subjects with active celiac disease (i.e., active diarrhea due to documented celiac disease)
8.
Subjects with evidence of, or treatment for, Clostridium difficile infection, or other intestinal
pathogen, within 30 days prior to Screening
9.
Subjects with Clostridium difficile positive stool, performed with a toxin enzyme
immunoassay (EIA) by the Central Laboratory.  Subjects who test positive for C. difficile
can be treated with standard of care antibiotics and rescreened for the study after 30 days, as
per Exclusion Criterion #8.
10. Oral antibiotic use within 30 days before Screening
11. Expected to receive antibiotics (i.e., for planned/anticipated procedure) within the Induction
Treatment period
12. Received an investigational drug or live vaccine within two (2) months before Screening
13. Previously enrolled in a Seres Therapeutics SER-109 or SER-287 study
14. Received a fecal microbiota transplant (FMT; includes human microbiota-based
therapeutics) within three (3) months prior to Screening
15. Poor concurrent medical risks with clinically significant co-morbid disease such that, in the
opinion of the investigator, the subject should not be enrolled including:
a.
Known hypogammaglobulinemia
b.
Known severe immunodeficiency
c.
Underlying liver function test (LFT) [Screening alanine aminotransferase (ALT) or
aspartate aminotransferase (AST)] abnormalities greater than 3x upper limit of
normal (ULN)
d.
Absolute neutrophil count (ANC) < 500 cells/mm3
e.
Hemoglobin levels < 9 g/dL
16. Subjects with anatomic or medical contraindications to lower endoscopy (flexible
sigmoidoscopy or colonoscopy), including but not necessarily limited to toxic megacolon,
gastrointestinal fistulas, immediate post-operative status from abdominal surgery, severe
coagulopathy, large or symptomatic abdominal aortic aneurysm, or any subject where study
physician deems subject at significant risk of complications of lower endoscopy (flexible
sigmoidoscopy or colonoscopy)
17. Unable to stop steroid enemas or suppositories, or 5-ASA enemas or suppositories, at least
two (2) weeks prior to Screening
18. Unable to stop probiotic treatment at least one (1) week prior to Screening.  Note: food
containing probiotics are permitted.
19. Known active malignancy, except for basal cell skin cancer or squamous cell skin cancer, or
concurrent intensive induction chemotherapy, radiotherapy, or biologic treatment for active
malignancy (subjects on maintenance chemotherapy may only be enrolled after consultation
with medical monitor)
20. Unable to comply with the protocol requirements, including the ability to take oral drugs; or
any condition that, in the opinion of the investigator, might interfere with study objectives or
compromise patient safety, including if the subject is likely to require surgery for UC during
the study period
21. Known allergy or intolerance to oral vancomycin
22. Current or recent history (six [6] months prior to Screening) of drug or alcohol abuse


Seres Therapeutics, Inc. 
Clinical Study Protocol 
Protocol # SERES-201 
CONFIDENTIAL 
Amendment 3 
12 of 116 
08-Oct-2019
Concomitant 
Medications 
Permitted Concomitant Medications: 
The below medications are allowed at study entry.  Doses must remain stable during the study 
treatment period. 
1.
Oral aminosalicylates (if taken for at least six [6] weeks prior to Screening, with a stable
dose for ≥ 2 weeks prior to Screening)
2.
Immunomodulator: 6-Mercaptopurine, Azathioprine, Methotrexate (Stable dose for ≥ 12
weeks prior to Screening)
3.
Pain medication (stable dose), including low-dose aspirin (81 mg); Note: temporary use of
pain medication is permitted during the treatment period (e.g. for minor surgery), and is
defined as no more than 48 hours.  Temporary use of opiates should be discussed with the
medical monitor.
4.
Inhaled steroids for non-UC-related treatment (taper-down is also acceptable)
5.
Inactivated influenza vaccine
Prohibited Concomitant Medications and Nutritional Supplements: 
The following prohibited concomitant medications may not be administered at any time through the 
study period.  Subjects who initiate the following treatments will be discontinued from further study 
drug administration. 
1.
Oral, intravenous (IV) and rectal steroids (e.g. prednisone, budesonide, budesonide MMX®)
2.
5-ASA enemas or suppositories
3.
Any investigational or approved biologic therapy (e.g. infliximab, adalimumab, golimumab,
certolizumab, vedolizumab, ustekinumab, natalizumab)
4.
Any investigational or approved non-biologic therapy (e.g. cyclosporine, tacrolimus,
thalidomide, methotrexate, tofacitinib)
5.
Anti-diarrheals (e.g. loperamide, diphenoxylate/atropine, or bile-salt sequestrant
[cholestyramine, colesevelam])
6.
Probiotics (food containing probiotics are permitted)
7.
Use of any nutritional supplement which claims to support or promote gut health should be
determined by medical monitor.
Statistical 
Methods 
Analysis Populations 
The Intent-to-Treat (ITT) Population will consist of all subjects who are randomly assigned, 
including those who are not exposed to any study drug, and will be analyzed based on the treatment 
to which they were randomized.  The ITT population will be the primary analysis population for all 
efficacy endpoints. 
The Modified Intent-to-Treat 1 (mITT-1) Population will consist of all randomized subjects with a 
baseline evaluation, who have active mild-to-moderate UC and receive any amount of study drug, 
and will be analyzed based on the treatment to which they were randomized. 
The Modified Intent-to-Treat 2 (mITT-2) Population will consist of all randomized subjects with a 
baseline evaluation, who have active mild-to-moderate UC and receive any amount of study drug, 
and will be analyzed based on the treatment to which they are randomized.  Subjects who are 
confirmed to have normal histology at baseline will be excluded from this analysis population.   
The Per Protocol (PP) Population will consist of subjects from the mITT-2 Population who do not 
have any major protocol deviations.  The details of the PP Population will be provided in the 
Statistical Analysis Plan (SAP) and defined before unblinding of the data. 
The Safety Population will consist of all subjects who receive any amount of study drug.  Subjects 
will be analyzed according to the treatment they actually received, rather than the treatment to which 
they are randomly assigned.  All safety analyses will be conducted based on the Safety Population. 


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Protocol # SERES-201 
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Amendment 3 
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The Microbiome Modified Intent-to-Treat (mcITT) Population will be used for analysis of 
microbiome data. It will consist of all randomized subjects with an evaluable stool sample collected 
at baseline, and at least one (1) evaluable stool sample collected after the start of dosing, who are 
exposed to any amount of study drug, and will be analyzed based on the treatment to which they are 
randomized. 
Analysis of the Primary Efficacy Endpoint 
The primary efficacy outcome measure for this study will be the difference in clinical remission rates 
after 10 weeks of induction treatment between SER-287 (Induction Dose after pre-treatment with 
vancomycin – Arm B) and placebo (Arm A).  The primary efficacy endpoint analysis will be based 
on the Cochran-Mantel-Haenszel (CMH) test, stratified by endoscopic score at baseline (1-2 vs. 3), 
and UC medications at baseline (5-ASA alone vs. immunomodulators with or without 5-ASA vs. 
none) in the ITT population. 
Analysis of the Key Secondary Efficacy Endpoints 
The key secondary efficacy endpoints will be analyzed using the same method used for the primary 
efficacy endpoint. 
Sensitivity Analyses for the primary and key secondary endpoint will be performed in the mITT-1, 
mITT-2, PP and Safety populations. 
Multiplicity Adjustment  
Adjustments for multiple testing will be made to test the primary efficacy and key secondary efficacy 
endpoints.  A fixed-sequence method will be used to maintain a study-wide 2-sided Type I error rate 
of 0.05.  Testing of the key hypotheses will be conducted in the following order, all at the same 
significance level (2-sided α = 0.05): 
1.
H01: No difference in clinical remission rates after 10 weeks of induction treatment between
Arm B (SER-287 at Induction Dose after pre-treatment with vancomycin) vs. Arm A (pre-
treatment with placebo followed by treatment with placebo) in the ITT population
2.
H02: No difference in clinical remission rates after 10 weeks of induction treatment between
Arm C (SER-287 at Step-Down Induction Dose after pre-treatment with vancomycin) vs.
Arm A (pre-treatment with placebo followed by treatment with placebo) in the ITT
population
3.
H03: No difference in endoscopic improvement rates after 10 weeks of induction treatment
between Arm B (SER-287 at Induction Dose after pre-treatment with vancomycin) vs. Arm
A (pre-treatment with placebo followed by treatment with placebo) in the ITT population
4.
H04: No difference in endoscopic improvement rates after 10 weeks of induction treatment
between Arm C (SER-287 at Step-Down Induction Dose after pre-treatment with
vancomycin) vs. Arm A (pre-treatment with placebo followed by treatment with placebo) in
the ITT population
Testing of later hypotheses in the sequence stops as soon as failure to show statistical significance at 
the 2-sided 0.05 level is observed in a hypothesis earlier in the sequence. 
Determination of Sample Size 
The planned sample size for this study is 67 subjects per treatment arm for a total sample size of 
201 subjects.  Assuming a clinical remission rate of 29% in the SER-287 arms and a clinical 
remission rate of 9% in the placebo arm, this sample size will provide 86% power to detect a 
difference of 20% in clinical remission rates between SER-287 to placebo, using a 2-sided 
significance level of 0.05. 






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Clinical Study Protocol 
Protocol # SERES-201 
CONFIDENTIAL 
Amendment 3 
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08-Oct-2019
Table 1: 
Schedule of Events: Induction Treatment 
Screening 
Pre-
Treatment 
Induction Treatment Period - 10 Weeks 
Long-Term Safety 
Follow-Upo 
Unscheduled 
Visit/EoTn 
WEEK NUMBER 
Week -4 to -1 
Week 0 
Week 1
+/-1d 
Week 3
+3d
Week 7
+3d
Week 11
+3d
Every 4 Weeks to 
Week 37/EoSm
+/-3d 
VISIT NUMBER 
1 
2* 
3 
4 
5 
6 
7 
8-14 
Visit Type 
Clinic 
Clinic/Endoscopy 
(max. 7 days between 
endoscopy and randomization) 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic/ 
Endoscopy 
Phone Calls 
Clinic 
(may include 
endoscopy) 
Procedure/Assessments 
Informed Consent 
X 
Inclusion/ Exclusion Criteria 
X 
X 
Medical History 
X 
UC History 
X 
Prior Medications & UC Therapies 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Procedures for UC a 
X 
X 
X 
X 
X 
X 
X 
X 
Demographic Data 
X 
Full Physical Exam 
X 
Focused Physical Exam 
Xi 
X 
X 
Vital signs  
X 
Xi 
X 
X 
Height (at Screening only), Weight 
X 
X 
X 
X 
Review lower endoscopy preparation instructions 
with subject prior to lower endoscopyb 
X 
X 
X 
Lower Endoscopy (Local and Central Reads) 
X 
X 
X 
Biopsies (4 samples) 
X 
X 
X 
Three-Component Modified Mayo Score c 
X 
X 
X 
IXRS Randomization 
X 
Dispense pre-treatment study drug 
Xg 
Administer study drug at clinic 
Xg 
Xg 
Return unused study drug 
X 
X 
X 
X 
X 
Review study drug compliance 
X 
X 
X 
X 
X 
Dispense study drug d 
Xj 
Xj 
Xj 
Adverse Event monitoring 
Xh 
X 
X 
X 
X 
Xl 
X 
Clinical Laboratory Tests 
Hematology 
X 
X i 
Xi 
X 
X 
Blood chemistry 
X 
Xi 
Xi 
X 
X 
Blood for CRP 
Xi 
X 
X 
Blood & Serum for Future Biomedical Research 
X 
X 
X 
X 
Urine Pregnancy test (WOCBP only) Note: Serum 
at Screening visit only 
X 
Xi 
Xi 
X 
X 
X 
X 
Routine Urine Dipsticke 
X 


Seres Therapeutics, Inc. 
Clinical Study Protocol 
Protocol # SERES-201 
CONFIDENTIAL 
Amendment 3 
17 of 116 
08-Oct-2019
Table 1: 
Schedule of Events: Induction Treatment (continued) 
Screening 
Pre-
Treatment 
Induction Treatment Period - 10 Weeks 
Long-Term Safety 
Follow-Upo 
Unscheduled 
Visit/EoTn 
WEEK NUMBER 
Week -4 to -1 
Week 0 
Week 1
+/-1d 
Week 3 
+3d
Week 7 
+3d
Week 11 
+3d
Every 4 Weeks to 
Week 37/EoSm
+/-3d 
VISIT NUMBER 
1 
2* 
3 
4 
5 
6 
7 
8-14 
Visit Type 
Clinic 
Clinic/Endoscopy 
(max. 7 days between 
endoscopy and randomization) 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic/ 
Endoscopy 
Phone Calls 
Clinic 
(may include 
endoscopy) 
Procedure/Assessments 
Provide Stool Collection Kit 
X 
X 
X 
X 
X 
X 
Stool Sample for C. diff. testing by toxin assay 
(EIA) 
Xf 
Review Stool Collection, Handling & Storage 
Instructions with Subject 
X 
X 
X 
Stool Sample for Microbiome, Metabolomics, 
Future Biomedical Research 
Xf 
X 
X 
X 
Xk 
Xk 
Fecal Calprotectin 
Xf 
X 
X 
IBDQ 
X i 
X 
X 
Review Subject eDiary Instructions with Subject 
X 
Subject eDiary (daily rectal bleeding and stool 
frequency)  
X 
X 
X 
X 
X 
X 
X 
X 
Review Subject eDiary for compliance 
X 
X 
X 
X 
X 
X 
X 
(*) A minimum of seven (7) days between Visit 1 and Visit 2 are required to ensure there are a sufficient quantity of eDiary entries to calculate the Stool Frequency subscore; (a) Lower endoscopies 
performed during study are not to be recorded as a concomitant procedure; (b) Remind subjects when to start clear liquid diet, overnight fast, and bowel prep prior to scheduled lower endoscopy; 
(c) Three-Component Modified Mayo Score will be calculated electronically from subject diary and central endoscopy read; (d) Instruct subject to take study medication at the same time every morning;
At Screening Visit 1, subjects should be asked about their stool frequency and rectal bleeding over the past seven (7) days. Subjects will be provided an electronic diary at Screening Visit 1 to begin
daily collection of rectal bleeding & stool frequency; (e) Urine dipstick performed at the study site; if positive for nitrates and/or leukocytes, send sample to central laboratory for analysis; (f) If possible, 
subjects should provide stool sample on site.  If not possible, subject should collect stool sample at home and return to the site as soon as possible.  C. diff test results must be received before performing
lower endoscopy at Screening Visit 2;  Remind subjects when to start clear liquid diet, overnight fast, and bowel prep prior to scheduled lower endoscopy; (g) first dose observe for one (1) hour post-
dosing (h) Recording of AEs for study will begin after first dose of pre-treatment IP; (i) Perform prior to dosing; (j) IP to be dispensed at this clinic visit; (k) Stool sample to be collected prior to subject
starting clear liquid diet for lower endoscopy; (l) During the first four (4) weeks of the Long-Term Safety Follow-Up Period, AEs/SAEs/AESIs, concomitant procedures,  and concomitant medications
will be collected.  Only SAEs/AESIs and concomitant medications associated with the treatment of SAEs/AESIs will be collected starting from the four (4) week follow-up call through the End of
Study.  Concomitant UC medications and UC procedures, and any changes to these, will be collected throughout the entirety of the Long-Term Safety Follow-Up Period; (m) The last safety follow-up
call will occur after six (6) weeks, rather than four (4); (n) To accommodate scheduling of clinic visit and/or endoscopy, assessments & procedures for an Unscheduled Visit do not need to take place
during one (1) clinic visit; The Unscheduled Visit may also be used for dispensation of study drug as needed; For subjects who experience disease worsening (as defined in Section 3.6, Disease
Worsening), an Unscheduled Visit may be used by the PI to determine if the subject is experiencing a UC flare; The Unscheduled Visit can serve as an 'End of Treatment' visit for a subject who ends
treatment early in the study but will continue to be followed for safety, or for subjects who decide to leave the study early and not be followed for safety.  If subjects decide to end treatment early or
early terminate from the study, all study IP should be returned by the subject; (o) Subjects who discontinue early and do not go into either the Maintenance arm or Open Label arm, will be followed for
long term safety for 26 weeks post last study drug dose.


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Clinical Study Protocol 
Protocol # SERES-201 
CONFIDENTIAL 
Amendment 3 
18 of 116 
08-Oct-2019
Table 2: 
Schedule of Events: Maintenance Treatment for Remitters 
Maintenance Treatment Period - 26 Weeks 
Long Term  
Safety Follow-Up 
Unscheduled 
Visit/EoT j
WEEK NUMBER
M-Week 12
+/-2d
M-Week 16
+3d
M-Week 20
+3d
M-Week 24
+3d
M-Week 28
+3d
M-Week 32
+3d
M-Week 37
+3d/EoT
Every 4 Weeks to 
M-Week 63/EoSh
+/-3d
VISIT NUMBER 
M-1
M-2
M-3
M-4
M-5
M-6
M-7
M-8 - M-13
Visit Type
Clinic
Clinic
Clinic
Clinic
Clinic
Clinic
Clinic/ 
Endoscopy
Phone Calls
Clinic 
(may include 
endoscopy) 
Procedure/Assessments 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Procedures for UCa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IXRS Re-Randomization 
X 
Focused Physical Exam 
X 
X 
X 
Vital signs  
X 
X 
Weight 
X 
Review lower endoscopy preparation 
instructions with subject prior to endoscopy b 
X
X
Lower Endoscopy (Local and Central Reads) 
X 
X 
Biopsies (4 samples) 
X 
X 
Three-Component Modified Mayo Scorec 
X 
X 
Return unused study drug 
X 
X 
X 
X 
X 
X 
X 
Review study drug compliance 
X 
X 
X 
X 
X 
X 
X 
Dispense study drugd 
X 
X 
X 
X 
X 
X 
Adverse Event monitoring 
X 
X 
X 
X 
X 
X 
X 
Xi 
X 
Clinical Laboratory Tests 
Hematology 
X 
X 
Blood chemistry 
X 
X 
Urine Pregnancy test (WOCBP only) 
X 
X 
X 
X 
X 
X 
X 
Blood & Serum for Future Biomedical 
Research 
X
X
Blood for CRP 
X 
X 


Seres Therapeutics, Inc. 
Clinical Study Protocol 
Protocol # SERES-201 
CONFIDENTIAL 
Amendment 3 
19 of 116 
08-Oct-2019
Table 2: 
Schedule of Events: Maintenance Treatment for Remitters (continued) 
Maintenance Treatment Period - 26 Weeks
Long Term  
Safety Follow-Up
Unscheduled 
Visit/EoT j
WEEK NUMBER
M-Week 12
+/-2d
M-Week 16
+3d
M-Week 20
+3d
M-Week 24
+3d
M-Week 28
+3d
M-Week 32
+3d
M-Week 37
+3d/EoT
Every 4 Weeks to M-
Week 63/EoSh
+/-3d
VISIT NUMBER 
M-1
M-2
M-3
M-4
M-5
M-6
M-7
M-8 - M-13
Visit Type
Clinic
Clinic
Clinic
Clinic
Clinic
Clinic
Clinic/ 
Endoscopy
Phone Calls
Clinic 
(may include 
endoscopy) 
Procedure/Assessments 
Provide Stool Collection Kit 
X 
X 
X 
X 
X 
X 
Stool sample for Microbiome, 
Metabolomics, Future Biomedical 
Research 
X
X
X 
X 
X 
Xg
X
Fecal Calprotectin 
Xg 
X 
IBDQ 
X 
X 
Subject eDiary (daily rectal bleeding and 
stool frequency) e 
X
X
X
X
X
X
X
X
Review subject eDiary for compliance 
X 
X 
X 
X 
X 
X 
Xf 
X 
(a) Lower endoscopies performed during study are not to be recorded as concomitant procedure; (b) Remind subjects when to start clear liquid diet, overnight fast, and bowel prep prior to
scheduled lower endoscopy; (c) Three-Component Modified Mayo Score will be calculated electronically from subject diary and central endoscopy read;  (d) IP for weekly dosing will be
dispensed at this clinic visit; Instruct subject to take study drug at the same time every morning; (e) Subjects will continue using same electronic diary; (f) Subjects use of eDiary complete
at this visit; subject to leave device on site; (g) Stool sample to be collected prior to subject starting clear liquid diet for lower endoscopy. An aliquot for Fecal Calprotectin is taken from
this one stool sample collected at M-Week 37 visit; (h) The last safety follow-up call will occur after six (6) weeks, rather than four (4); (i) During the first four (4) weeks of the Long-Term
Safety Follow-Up Period, AEs/SAEs/AESIs, concomitant procedures, and concomitant medications will be collected.  Only SAEs/AESIs and concomitant medications associated with the
treatment of the SAEs/AESIs, will be collected starting from the four (4) week follow-up call through the End of Study. Concomitant UC medications and UC procedures, and any changes
to these, will be collected throughout the entirety of the  Long-Term Safety Follow-Up Period; (j) To accommodate scheduling of clinic visit and/or endoscopy, assessments & procedures
for an Unscheduled Visit do not need to take place during one (1) clinic visit; The Unscheduled Visit may also be used for dispensation of study drug as needed; For subjects who experience
disease worsening (as defined in Section 3.6, Disease Worsening), an Unscheduled Visit may be used by the PI to determine if the subject is experiencing a UC flare; The Unscheduled
Visit can serve as an 'End of Treatment' visit for a subject who ends treatment early in the study but will continue to be followed for safety, or for subjects who decide to leave the study
early and not be followed for safety.  If subjects decide to end treatment early or early terminate from the study, all study IP should be returned by the subject.


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Clinical Study Protocol 
Protocol # SERES-201 
CONFIDENTIAL 
Amendment 3 
20 of 116 
08-Oct-2019
Table 3: 
Schedule of Events: Open-Label Extension Arm for Non-Remitters 
Open-Label Treatment Period - 11 Weeks 
Long-Term Safety 
Follow-Up 
Unscheduled 
Visit/EoT k 
WEEK NUMBER 
OL-Week 0 
+/-2d 
OL-Week 1 
+/-1d 
OL-Week 3 
+3d
OL-Week 7 
+3d
OL-Week 11 
+3d
Every 4 Weeks for 
26 Weeks/EoSj
+/-3d 
VISIT NUMBER 
OL-1 
OL-2 
OL-3 
OL-4 
OL-5/EoT 
OL-6 – OL-11 
Visit Type 
Clinic 
Stool Sample 
Home 
Collection 
Clinic 
Clinic 
Clinic/ 
Endoscopy 
Phone Calls 
Clinic 
(may include 
endoscopy)
Procedure/Assessments 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
Concomitant Procedures for UCa 
X 
X 
X 
X 
X 
X 
Focused Physical Exam 
X 
X 
Vital signs  
X 
X 
Weight 
X 
IXRS Registration for Open-Label 
X 
Dispense vancomycin pre-treatment 
X 
Administer vancomycin pre-treatment at clinic 
X 
Return unused study drug 
X 
X 
X 
X 
Review study drug compliance 
X 
X 
X 
Dispense SER-287 
Xe 
Xg 
Xg 
Adverse Event monitoring 
X 
X 
X 
X 
Xi 
X 
Clinical Laboratory Tests 
Hematology 
X 
X 
Blood chemistry 
X 
X 
Blood & Serum for Future Biomedical Research 
X 
X 
Blood for CRP 
X 
X 
Urine Pregnancy test (WOCBP) 
X 
X 
X 
X 
X 


Seres Therapeutics, Inc. 
Clinical Study Protocol 
Protocol # SERES-201 
CONFIDENTIAL 
Amendment 3 
21 of 116 
08-Oct-2019
Table 3: 
Schedule of Events: Open-Label Extension Arm for Non-Remitters (continued) 
Open-Label Treatment Period - 11 Weeks 
Long-Term Safety 
Follow-Up 
Unscheduled 
Visit/EoT k 
WEEK NUMBER 
OL-Week 0 
+/-2d 
OL-Week 1 
+/-1d 
OL-Week 3 
+3d
OL-Week 7 
+3d
OL-Week 
11 
+3d
Every 4 Weeks for 
26 Weeks/EoSj
+/-3d 
VISIT NUMBER 
OL-1 
OL-2 
OL-3 
OL-4 
OL-5/EoT 
OL-6 – OL-11 
Visit Type 
Clinic 
Stool Sample 
Home 
Collection 
Clinic 
Clinic 
Clinic/ 
Endoscopy 
Phone Calls 
Clinic 
(may include 
endoscopy)
Procedure/Assessments 
Provide Stool Collection Kit 
X 
X 
X 
X 
Stool sample for Microbiome, Metabolomics, Future 
Biomedical Research 
Xf 
X 
Xl 
X 
Fecal Calprotectin 
Xf 
X 
IBDQ 
X 
X 
Subject eDiary (daily rectal bleeding and stool frequency) b 
X 
X 
X 
X 
Xh 
X 
Review subject eDiary for compliance 
X 
X 
X 
X 
X 
Review lower endoscopy preparation instructions with 
subject prior to endoscopyc 
X 
X 
Lower Endoscopy (Local and Central Reads) 
X 
X 
Biopsies (4 samples) 
X 
X 
Three-Component Modified Mayo Scored 
X 
X 
(a) Lower endoscopies performed during study are not to be recorded as concomitant procedure; (b) Subjects will continue using same electronic diary;  Review pre-treatment
dosing and study drug dosing with subject; (c) Remind subjects when to start clear liquid diet, overnight fast, and bowel prep prior to scheduled lower endoscopy; Subjects will
return every four (4) weeks for re-supply of study drug that will be taken once-weekly; (d) Three-Component Modified Mayo Score will be calculated electronically from subject
diary and central endoscopy read;  (e) Two (2) weeks of IP is dispensed at clinic visit; subject should take Open-Label Week 3 dose on site; (f) Stool sample to be collected at
home.  Subject can return stool sample to clinic or it can be returned via courier to clinical site. An aliquot for Fecal Calprotectin is taken from this one stool sample collected at
OL-Week 11 visit; (g) IP is dispensed at this clinic visit; (h) Subjects use of eDiary complete at this visit; subject to leave device on site; (i) During the first four (4) weeks of the
Long-Term Safety Follow-Up Period, AEs/SAEs/AESIs, concomitant procedures, and concomitant medications will be collected.  Only SAEs/AESIs and concomitant medications
associated with the treatment of SAEs/AESIs will be collected starting from the four (4) week follow-up call through the End of Study.  Concomitant UC medications and UC
procedures, and any changes to these, will be collected throughout the entirety of the Long-Term Safety Follow-Up Period;  (j) The last safety follow-up call will occur after six
(6) weeks, rather than four (4); (k) To accommodate scheduling of clinic visit and/or endoscopy, assessments & procedures for an Unscheduled Visit do not need to take place
during one (1) clinic visit; The Unscheduled Visit may also be used for dispensation of study drug as needed; For subjects who experience disease worsening (as defined in Section
3.6, Disease Worsening), an Unscheduled Visit may be used by the PI to determine if the subject is experiencing a UC flare; The Unscheduled Visit can serve as an 'End of
Treatment' visit for a subject who ends treatment early in the study but will continue to be followed for safety, or for subjects who decide to leave the study early and not be
followed for safety.  If subjects decide to end treatment early or early terminate from the study, all study IP should be returned by the subject; (l) Stool sample to be collected prior
to subject starting clear liquid diet for lower endoscopy




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Clinical Study Protocol 
Protocol # SERES-201 
CONFIDENTIAL 
Amendment 3 
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08-Oct-2019
1 
Table of Contents 
PROTOCOL SYNOPSIS ................................................................................................. 5 
List of Study Personnel .................................................................................................. 22 
List of Abbreviations ...................................................................................................... 28 
1 
INTRODUCTION .................................................................................................. 31 
1.1 
Background ................................................................................................................ 31 
1.1.1 
Indication and Prevalence ........................................................................................ 31 
1.1.2 
Existing Practices .................................................................................................... 31 
1.1.3 
Disease Pathogenesis and Microbiome Involvement .............................................. 32 
1.1.4 
Pharmacological Concept for Microbiome Therapeutic .......................................... 33 
1.1.5 
Investigational Product ............................................................................................ 33 
1.2 
SER-287 SERES-101 Data in Active Mild-to-Moderate Subjects ......................... 33 
1.2.1 
Clinical Efficacy ...................................................................................................... 33 
1.2.2 
Clinical Safety ......................................................................................................... 35 
1.2.3 
Baseline Microbiome Composition ......................................................................... 36 
1.2.4 
Microbiome Engraftment and Post-Baseline Composition ..................................... 36 
1.3 
Phase 2B Overview ..................................................................................................... 38 
1.4 
Rationale ..................................................................................................................... 40 
1.4.1 
Rationale for Induction Dosing Regimen ................................................................ 40 
1.4.2 
Rationale for Maintenance Dosing Regimen ........................................................... 40 
1.4.3 
Rationale for Open-Label Extension Dosing Regimen ........................................... 41 
1.4.4 
Rationale for Antibiotic Pre-Treatment ................................................................... 41 
1.4.5 
Rationale for Endpoints ........................................................................................... 41 
2 
OBJECTIVES ......................................................................................................... 43 
2.1 
Primary Objective ...................................................................................................... 43 
2.2 
Key Secondary Objectives ......................................................................................... 43 
2.3 
Other Secondary Objectives ..................................................................................... 43 
2.4 
Safety Objective.......................................................................................................... 43 
2.5 
Exploratory Objectives .............................................................................................. 43 
3 
DEFINITIONS ........................................................................................................ 45 
3.1 
Clinical Remission ...................................................................................................... 45 
3.1.1 
U.S. FDA ................................................................................................................. 45
3.1.2 
EMA ........................................................................................................................ 45 
3.2 
Endoscopic Improvement .......................................................................................... 46 
3.3 
Endoscopic Remission ................................................................................................ 46 
3.3.1 
Endoscopic Remission for the Induction and Open-Label Treatment Periods ........ 46 
3.3.2 
Endoscopic Remission for the Maintenance Treatment Period (from Week 11 
through M-Week 37) ............................................................................................................ 46 
3.4 
Histological Mucosal Healing .................................................................................... 46 
3.5 
Three-Component Modified Mayo Score ................................................................ 46 
3.6 
Disease Worsening ..................................................................................................... 46 
3.7 
UC Flare ...................................................................................................................... 47 
3.8 
Engraftment ................................................................................................................ 47 
4 
STUDY DESIGN .................................................................................................... 48 
4.1 
Overview ..................................................................................................................... 48 
4.2 
Study Periods .............................................................................................................. 48 


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Clinical Study Protocol 
Protocol # SERES-201 
CONFIDENTIAL 
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08-Oct-2019
4.2.1 
Screening (Weeks -4 to -1; four [4] weeks) ............................................................. 48 
4.2.2 
Pre-Treatment (Week 0; six [6] days)...................................................................... 49 
4.2.3 
Induction Treatment (Week 1 – Week 11; 10 weeks) ............................................. 49 
4.2.4 
Maintenance Treatment (Week 11 – Week 37; 26 weeks) ...................................... 50 
4.2.5 
Open-Label Extension (OL-Week-0 – OL-Week-11; 11 weeks) ............................ 50 
4.2.6 
Long-Term Safety Follow-Up (26 weeks) ............................................................... 50 
5 
STUDY POPULATION ......................................................................................... 51 
5.1 
Inclusion Criteria ....................................................................................................... 51 
5.2 
Exclusion Criteria ...................................................................................................... 53 
5.3 
Subject Withdrawal and Replacement ..................................................................... 54 
5.3.1 
Reasons for Discontinuation of Treatment .............................................................. 54 
5.3.2 
Handling of Withdrawals and Discontinuation of Treatment .................................. 55 
5.4 
Termination of Study ................................................................................................. 55 
5.5 
Planned Sample Size and Number of Study Centers .............................................. 55 
5.6 
Subject Identification and Randomization .............................................................. 55 
5.6.1 
Subject Identification ............................................................................................... 55 
5.6.2 
Methods of Assigning Subjects to Study Treatment ............................................... 55 
5.6.3 
Maintaining the Randomization Codes and Breaking the Study Blind ................... 56 
6 
INVESTIGATIONAL PRODUCT ........................................................................ 58 
6.1 
SER-287 Drug Product Capsules .............................................................................. 58 
6.1.1 
Donor Screening ...................................................................................................... 58 
6.1.2 
SER-287 Manufacturing .......................................................................................... 58 
6.2 
Vancomycin HCl Hard Gelatin Capsules (“Vancomycin”) ................................... 58 
6.3 
SER-287 Placebo Capsules ........................................................................................ 58 
6.3.1 
SER-287 Placebo Manufacturing ............................................................................ 58 
6.4 
Vancomycin HCl Placebo Capsules (“Vancomycin Placebo”) .............................. 59 
6.4.1 
Vancomycin HCl Placebo Manufacturing and Storage ........................................... 59 
6.5 
Storage ........................................................................................................................ 59 
6.5.1 
SER-287 and SER-287 Placebo Storage ................................................................. 59 
6.6 
Study Drug Administration ....................................................................................... 59 
6.7 
Drug Accountability ................................................................................................... 60 
6.8 
Prior and Concomitant Medications ........................................................................ 60 
6.8.1 
Permitted Concomitant Medications ....................................................................... 60 
6.8.2 
Prohibited Concomitant Medications and Nutritional Supplements ....................... 61 
7 
VARIABLES AND METHODS OF ASSESSMENT ......................................... 62 
7.1 
Safety Variables ......................................................................................................... 62 
7.1.1 
Treatment Emergent Adverse Events ...................................................................... 63 
7.1.2 
Adverse Event of Special Interest ............................................................................ 64 
7.1.3 
Reporting Serious Adverse Events .......................................................................... 64 
7.1.4 
Follow-up of Serious Adverse Events and Adverse Events of Special Interest ...... 65 
7.1.5 
Pregnancy ................................................................................................................ 65 
7.1.6 
Laboratory Variables ............................................................................................... 66 
7.1.7 
Stool Samples .......................................................................................................... 66 
7.1.8 
Biopsy Samples ....................................................................................................... 66 
7.1.9 
Vital Signs ............................................................................................................... 67 
7.1.10 Physical Examinations ............................................................................................. 67 
7.2 
Demographics and Baseline Characteristics ........................................................... 67 
7.2.1 
Subject Demography ............................................................................................... 67 
7.2.2 
Disease History ........................................................................................................ 67 


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7.2.3 
Baseline Characteristics ........................................................................................... 68 
7.2.4 
Medical History ....................................................................................................... 68 
7.2.5 
Prior and Concomitant Medications ........................................................................ 68 
7.3 
Three-Component Modified Mayo Score ................................................................ 68 
7.3.1 
Stool Frequency Subscore ....................................................................................... 68 
7.3.2 
Rectal Bleeding Subscore ........................................................................................ 68 
7.3.3 
Endoscopic Subscore ............................................................................................... 68 
8 
STUDY CONDUCT ............................................................................................... 69 
8.1 
Study Schedule ........................................................................................................... 69 
8.2 
Procedures by Visit .................................................................................................... 69 
8.2.1 
Screening: Week -4 to -1 (Visit 1) ........................................................................... 69 
8.2.2 
Screening: Week -4 to -1:  Endoscopy Visit (Visit 2) ............................................. 70 
8.2.3 
Pre-Treatment: Week 0 (Visit 3) ............................................................................. 71 
8.2.4 
Induction Treatment: Week 1 +/-1d (Visit 4) .......................................................... 72 
8.2.5 
Induction Treatment: Week 3 +3d (Visit 5)............................................................. 72 
8.2.6 
Induction Treatment: Week 7 +3d (Visit 6)............................................................. 72 
8.2.7 
Induction Treatment: Week 11 +3d (End of Induction Treatment) (Visit 7) .......... 73 
8.2.8 
Induction Treatment: Unscheduled Visit ................................................................. 74 
8.2.9 
Maintenance Treatment: M-Week 12 +/-2d (Visit M-1) ......................................... 74 
8.2.10 Maintenance Treatment: M-Week 16 +3d (Visit M-2) ........................................... 75 
8.2.11 Maintenance Treatment: M-Week 20 +3d (Visit M-3) ........................................... 75 
8.2.12 Maintenance Treatment: M-Week 24 +3d (Visit M-4) ........................................... 75 
8.2.13 Maintenance Treatment: M-Week 28 +3d (Visit M-5) ........................................... 76 
8.2.14 Maintenance Treatment: M-Week 32 +3d (Visit M-6) ........................................... 76 
8.2.15 Maintenance Treatment: M-Week 37 +3d (Visit M-7) ........................................... 76 
8.2.16 Maintenance Treatment – Long-Term Safety Follow-Up: Phone Calls Every Four 
(4) Weeks +/-3d (Visits M-8 – M-13) .................................................................................. 77 
8.2.17 Maintenance Treatment: Unscheduled Visit ............................................................ 78 
8.2.18 Open-Label Extension: OL-Week 0 +/-2d (Visit OL-1) ......................................... 78 
8.2.19 Open-Label Extension: OL-Week 1 +/-1d (Visit OL-2) ......................................... 78 
8.2.20 Open-Label Extension: OL-Week 3 +3d (Visit OL-3) ............................................ 78 
8.2.21 Open-Label Extension: OL-Week 7 +3d (Visit OL-4) ............................................ 79 
8.2.22 Open-Label Extension: OL-Week 11 +3d (Visit OL-5) .......................................... 79 
8.2.23 Open-Label Extension – Long-Term Safety Follow-Up: Phone Calls Every Four (4) 
Weeks for 26 Weeks/EoS +/-3d (Visits OL-6 – OL-11) ...................................................... 80 
8.2.24 Open-Label Extension: Unscheduled Visit .............................................................. 80 
8.2.25 Unscheduled Visits .................................................................................................. 80 
8.2.26 End of Treatment Visit ............................................................................................ 81 
8.2.27 Handling of Withdrawals and Discontinuations of Treatment ................................ 82 
9 
STATISTICAL METHODS ................................................................................. 83 
9.1 
Study Endpoints ......................................................................................................... 83 
9.1.1 
Primary Efficacy Endpoint ...................................................................................... 83 
9.1.2 
Key Secondary Efficacy Endpoints ......................................................................... 83 
9.1.3 
Other Secondary Efficacy Endpoints ....................................................................... 83 
9.1.4 
Exploratory Efficacy Endpoints .............................................................................. 84 
9.1.5 
Safety Endpoints ...................................................................................................... 84 
9.2 
Study Subjects ............................................................................................................ 84 
9.2.1 
Disposition of Subjects ............................................................................................ 84 
9.2.2 
Protocol Deviations ................................................................................................. 84 
9.2.3 
Analysis Populations ............................................................................................... 84 


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9.3 
Multiplicity Adjustment ............................................................................................ 86 
9.4 
General Considerations ............................................................................................. 86 
9.5 
Efficacy Analyses........................................................................................................ 86 
9.5.1 
Timing of Analyses.................................................................................................. 86 
9.5.2 
Statistical Analysis and Significance Level ............................................................. 87 
9.5.3 
Missing or Spurious Data ........................................................................................ 88 
9.5.4 
Analysis of the Primary Efficacy Endpoint ............................................................. 88 
9.5.5 
Analysis of the Key Secondary Efficacy Endpoints ................................................ 88 
9.5.6 
Analyses of Other Secondary Efficacy Endpoints ................................................... 89 
9.5.7 
Analyses of Exploratory Endpoints ......................................................................... 89 
9.6 
Safety Analyses ........................................................................................................... 89 
9.6.1 
Adverse Events ........................................................................................................ 89 
9.6.2 
Clinical Laboratory Tests ........................................................................................ 90 
9.6.3 
Vital Signs ............................................................................................................... 90 
9.6.4 
Physical Examination Findings ............................................................................... 90 
9.6.5 
Pharmacokinetic Analyses ....................................................................................... 90 
9.7 
Gastrointestinal Tract Microbiome .......................................................................... 90 
9.7.1 
Microbiome Secondary Endpoint Data Analysis ..................................................... 90 
9.8 
Interim Analyses ........................................................................................................ 91 
9.9 
Determination of Sample Size ................................................................................... 91 
10 ADMINISTRATIVE REQUIREMENTS ............................................................ 92 
10.1 
Good Clinical Practice ............................................................................................... 92 
10.2 
Ethical Considerations ............................................................................................... 92 
10.3 
Subject Information and Informed Consent ........................................................... 92 
10.4 
Subject Confidentiality .............................................................................................. 93 
10.5 
Protocol Compliance .................................................................................................. 93 
10.6 
Future Use of Stored Specimens ............................................................................... 93 
10.7 
Study Monitoring ....................................................................................................... 93 
10.8 
Case Report Forms and Study Records ................................................................... 94 
10.9 
Study Completion ....................................................................................................... 95 
11 REFERENCE LIST ............................................................................................... 96 
12 APPENDICES ....................................................................................................... 101 
12.1 
Appendix 1: Mayo Score (Schroeder et al., 1987) ................................................. 101 
12.2 
Appendix 2: Stool Frequency and Rectal Bleeding Subscore Calculation 
Guidelines .............................................................................................................................. 102 
Stool Frequency Subscore .................................................................................................. 102 
Rectal Bleeding Subscore ................................................................................................... 103 
12.3 
Appendix 3: Inflammatory Bowel Disease Questionnaire (Guyatt et al., 1989) . 104 


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Tables in Text 
Table 1: Schedule of Events: Induction Treatment .................................................. 16 
Table 2: Schedule of Events: Maintenance Treatment for Remitters ...................... 18 
Table 3: Schedule of Events: Open-Label Extension Arm for Non-Remitters ....... 20 
Table 4: SERES-101 Treatment Arms ..................................................................... 33 
Table 5: SERES-201 Induction Treatment Arms .................................................... 39 
Table 6: SERES-201 Post-Induction Treatment Arms ............................................ 40 
Table 7: Doses, Route, and Schedule of Study Drug Administration ..................... 59 
Table 8: Study Schedule .......................................................................................... 69 
Figures in Text 
Figure 1: Subject Treatment Overview: Screening Through Week 11 ..................... 14 
Figure 2: Subject Treatment Overview: Week 11 Through End-of-Study ............... 15 
Figure 3: SERES-101 Efficacy Data – ITT ............................................................... 34 
Figure 4: SERES-101 High-Confidence Engraftment of SER-287 .......................... 38 
Figure 5: SERES-201 Treatment Arms ..................................................................... 48 


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List of Abbreviations 
Abbreviation 
Term 
5-ASA
5-aminosalicylate
6-MP
6-mercaptopurine
AE 
Adverse event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
AZA 
Azathioprine 
BP 
Blood pressure 
cc 
Cubic centimeter 
CD 
Crohn’s disease 
CDER 
Center for Drug Evaluation and Research 
CFR 
Code of Federal Regulations 
CHMP 
Committee for Medicinal Products for Human Use 
Cm 
Centimeter 
CMH 
Cochran-Mantel-Haenszel 
CRO 
Contract research organization 
CRP 
C-reactive protein
CSR 
Clinical Study Report 
D 
Day 
dL 
Deciliter 
DNA 
Deoxyribonucleic acid 
eCRF 
Electronic case report form 
EIA 
Enzyme immunoassay 
EMA 
European Medicines Agency 
EDC 
Electronic data capture 
eDiary 
Electronic diary 
EOT 
End-of-treatment 
ES 
Endoscopic subscore 
FDA 
Food and Drug Administration 
FMT 
Fecal microbiota transplantation 
g 
Grams 


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GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HCl 
Hydrogen chloride 
HDPE 
High-density polyethylene 
HR 
Heart rate 
IB 
Investigator’s Brochure 
IBD 
Inflammatory bowel disease 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
IP 
Investigational product 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat; Intention-to-Treat 
IXRS 
Interactive web/voice response system 
JAK 
Janus kinase 
LFT 
Liver function test 
LOCF 
Last observation carried forward 
mcITT 
Microbiome Modified Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MH 
Medical history 
mITT 
Modified Intent-to-Treat 
mL 
Milliliter 
mm3 
Cubic millimeter 
mmHg 
Millimeters of mercury 
MMX 
Multi-matrix system 
Pbo 
Placebo 
PE 
Physical examination 
PGA 
Physician Global Assessment 
PI 
Principal Investigator 
PP 
Per Protocol 
PT 
Preferred term 
QD 
Once-daily 






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1.1.3 Disease Pathogenesis and Microbiome Involvement 
The prevailing model of disease pathogenesis for UC is that in the genetically 
predisposed host, environmental factors are sufficient to generate an abnormally 
perpetuated immune response and inflammation (Xavier and Podolsky, 2007).  
Alterations in the intestinal microbiota parallel changes in environmental factors with 
evidence suggesting a role of the intestinal microbiota in immune modulation 
(Biedermann et al., 2013, 2014; Leone et al., 2013; Wu et al., 2013). 
The microbiomes of adults are comprised of four (4) principal bacterial phyla: 
Bacteroidetes, Firmicutes, Actinobacteria and Proteobacteria, of which Bacteroidetes and 
Firmicutes are the dominant members in healthy subjects (Human Microbiome Project 
Consortium, 2012).  Inflammatory bowel disease (IBD), including UC, is widely thought 
to be linked to the gut microbiome, and, in turn, to environmental factors which affect 
microbiome composition (Huttenhower et al., 2014).  Multiple cohort studies have 
characterized changes in fecal and mucosal microbiomes associated with UC using next 
generation sequencing methods including 16S rRNA and whole metagenomic shotgun 
sequencing (WMS) (Frank et al., 2007; Morgan et al., 2012; Papa et al., 2012; Walujkar 
et al., 2014; Willing et al., 2010; Wills et al., 2014, Halfvarson et al., 2017, Schirmer et 
al., 2018).   
The emerging picture from these studies is that the microbiome of UC patients tends to 
exhibit certain general features of dysbiosis, including: (1) lower microbial diversity, 
(2) a greater prevalence of facultative anaerobes in the family Enterobacteriaceae, and
(3) a depletion of commensal spore-forming taxa in the phylum Firmicutes (Frank et al.,
2007; Lepage et al., 2011; Machiels et al., 2014; Michail et al., 2012; Morgan et al.,
2012; Ott et al., 2004; Papa et al., 2012; Rajilić-Stojanović et al., 2013; Sartor, 2008;
Varela et al., 2013; Walujkar et al., 2014; Willing et al., 2010).  Importantly, however,
multiple studies have identified substantial variability in UC microbiomes related to
disease subtype and disease severity (Morgan et al., 2012; Papa et al., 2012, Halfverson
et al., 2017; Schirmer et al., 2018).  Studies focusing primarily on UC subjects in clinical
remission, or with mild forms of disease, find little differentiation between microbiomes
from UC subjects and those from healthy individuals (Willing et al., 2010), and other
studies have found a clear connection between increased disease severity and increased
dysbiosis (Papa et al., 2012; Walujkar et al., 2014).  A meta-analysis of four (4) cohort
studies (Morgan et al., 2012; Papa et al., 2012; Willing et al., 2010; Wills et al., 2014),
conducted by Seres, supports the above general conclusions from the literature.
Comparison of bacterial richness (α-diversity) and composition (β-diversity) of
microbiomes from UC subjects to 313 healthy individuals characterized with 16S rRNA
sequencing (The Human Microbiome Project Consortium, 2012) showed that UC
subjects with active disease tended to have less diverse microbiomes than individuals
with inactive disease, and that UC subject microbiomes were significantly enriched in
genera from the family Enterobacteriaceae, which have been implicated in several
studies as related to increased oxidative stress and host inflammatory response (Winter et
al., 2013; Caballero and Pamer, 2015; Morgan et al., 2012; Lawley and Walker, 2013).








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compared to placebo or the SER-287 weekly treatment arms.  This finding provides an 
independent assessment of efficacy as the GI AEs likely reflect ulcerative colitis disease 
activity. 
1.2.3 Baseline Microbiome Composition 
Comparison of the baseline microbiome of UC subjects enrolled in the SERES-101 
Phase 1B study to 202 healthy individuals characterized as part of the Human 
Microbiome Project (Lloyd-Price et al., 2017), based on high-resolution WMS genomics, 
demonstrates features of UC dysbiosis comparable to that reported in the literature.   
First, minimal differences in total diversity were observed between UC and healthy 
subjects; this is similar to findings in recent large cohort studies of the UC microbiome 
(Imhann et al., 2018, Halfverson et al., 2017, Schirmer et al., 2018).  Notably, since the 
SERES-101 subject population consists of subjects with mild-to-moderate disease, the 
expected baseline dysbiosis is less than observed in cohort studies which include subjects 
with severe disease.  Second, microbiomes from SERES-101 subjects at baseline tended 
to have a higher abundance of taxa from the family Enterobacteriaceae than healthy 
subjects (p=0.110, 2-tailed t-test), consistent with the findings of a meta-analysis of 
cohort studies conducted by Seres.  Additionally, the mean abundance of 
Enterobacteriaceae was higher in subjects with more severe disease at baseline (baseline 
endoscopic subscore [ES] ≥ 2), with the highest abundance in subjects with baseline ES 
of 3.  The mean abundance of Enterobacteriaceae was 2.2-fold higher in subjects with 
baseline ES of 3 than in subjects with baseline ES of 1.  Notably, several publications 
implicate an increased abundance of Enterobacteriaceae taxa with increased oxidative 
stress in the gastrointestinal tract, related to increased host inflammatory response 
(Winter et al., 2013; Caballero and Pamer, 2015; Morgan et al., 2012; Lawley and 
Walker, 2013). 
1.2.4 Microbiome Engraftment and Post-Baseline Composition 
The two microbiome primary objectives of the SERES-101 study were to (1) determine 
the engraftment of SER-287 bacteria into each of the treatment arms, relative to placebo, 
and (2) to compare the baseline composition of the intestinal microbiome to the post-
baseline composition after treatment with SER-287, or placebo.  The fecal microbiome of 
SERES-101 subjects and SER-287 drug product were characterized using WMS, a high-
resolution and widely utilized methodology (e.g. Lloyd-Price et al., 2017) which enables 
species-level taxonomic identifications (Truong et al., 2015).   
A statistically significant signal of engraftment of SER-287 bacteria in SERES-101 
subjects was observed following treatment with SER-287, which led to a rapid and 
durable change in subject microbiomes (Figure 4).  Vancomycin pre-treatment was 
associated with significantly higher levels of engraftment of SER-287 relative to placebo 
pre-treatment in subjects receiving a weekly dose of SER-287, starting at one (1) week 
after the start of dosing (p<0.007 for Vanco/SER287 Daily vs. Pbo/Pbo Daily, p<0.018 
for Vanco/SER287 Wkly vs. Pbo/Pbo Daily, one-sided Mann-Whitney U test).  
Engraftment was dose-dependent within vancomycin pre-treatment arms; the daily 
dosing arm showed significantly faster engraftment than the weekly dosing arm (p<0.012 
for Vanco/SER287 Wkly vs. Vanco/SER287 Daily).  Significant engraftment of 


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SER-287 in the vancomycin pre-treatment arms was observed as early as one (1) week 
after the initial SER-287 dose (p=0.004 for Vanco/SER287 Daily vs. Pbo/Pbo Daily, 
p=0.025 for Vanco/SER287 Wkly vs. Pbo/Pbo Daily).  Additionally, engraftment of 
SER-287 bacteria in the vancomycin pre-treatment arms was detectable four (4) weeks 
after the completion of SER-287 dosing (p=0.005 for Vanco/SER287 Daily vs. Pbo/Pbo 
Daily, p=0.007 for Vanco/SER287 Wkly vs. Pbo/Pbo Daily), at levels comparable to 
those observed during the dosing period, suggesting that SER-287 taxa can durably 
persist in subjects for at least four (4) weeks following cessation of drug administration 
(Figure 4). 
Treatment with SER-287 led to changes in the overall composition of the microbiome.  
The microbiome of subjects in the Vanco/SER-287 Daily dosing arm shifted and 
exhibited significantly greater similarity to SER-287 drug product one (1) week after the 
start of treatment (p=0.001); subjects in the SER-287 weekly dosing arm shifted, but did 
not show comparable similarity to the SER-287 dose until the study endpoint (p=0.016) 
(Figure 4).   
Notably, the composition of the microbiome in subjects in the daily dosing arm was 
stable from one (1) week after the start of treatment through four (4) weeks after the end 
of the dosing period.  Subjects in the daily dosing arm also showed significantly higher 
richness of spore-forming taxa at the end of the treatment period (p=0.037) relative to 
baseline, indicating that treatment with SER-287 was effective in shifting the 
composition of subject microbiomes.  Notably, comparison of the microbiomes from 
subjects who achieved clinical remission in the Vanco/SER-287 Daily arm to those who 
did not, revealed distinct patterns in microbial composition – subjects who achieved 
remission tended to demonstrate an increased prevalence of certain commensal species, 
including both species present and absent in SER-287 (Figure 4). 










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efficacy endpoints in this study include clinical remission (primary), endoscopic 
remission and endoscopic improvement (secondary).  In this study, clinical remission is 
based on the Three-Component Modified Mayo Scoring system and is defined as a stool 
frequency subscore of 0 or 1 with at least a one-point decrease from baseline, rectal 
bleeding subscore of 0 and endoscopic subscore of 0 or 1 (modified, excludes friability), 
with at least a one-point decrease from baseline.  All endpoints will be measured at 
1) baseline (Screening Visit 2) prior to randomization, 2) after 10 weeks of induction
treatment and 3) after Maintenance or Open-Label treatment.
Symptoms of disease will be assessed throughout the study via the patient reported 
outcome components of the Mayo score, rectal bleeding and stool frequency, using daily 
data from subjects’ electronic diary (eDiary) entries.   
Drug effects on mucosal healing will be assessed using lower endoscopy and histologic 
assessment of biopsies:  
1. Appearance of the mucosa will be assessed using lower endoscopy and the Mayo
scoring system
2. Histological mucosal healing will be assessed using Robarts Histopathological
Index (RHI; Mosli et al., 2017) and Geboes Score (Geboes et al., 2000)
Safety and tolerability will be evaluated by comparing safety parameters across treatment 
arms, including incidence of AEs, laboratory evaluations, vital sign measurements and 
physical examination findings, before and after treatment. 
SERES-101 provided safety on 47 subjects who received up to eight (8) weekly doses 
(32 subjects) or up to 56 daily doses (15 subjects) of SER-287.  The current study will 
add safety data for 67 subjects at approximately the same dose as the SERES-101 study 
(Arm B, Table 5), and for 67 subjects at a lower dose (Arm C, Table 5). 
This study will also evaluate microbiome changes.  Engraftment (a secondary endpoint) 
is defined as the outgrowth of bacteria that comprise the SER-287 drug product in a 
subject’s gastrointestinal tract, post-treatment.  This study will evaluate the engraftment 
of SER-287 bacteria in each treatment arm and will evaluate mechanism of action data 
for SER-287.  
There are several additional exploratory endpoints. 


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2 
OBJECTIVES 
2.1 
Primary Objective 
•
To demonstrate the efficacy of SER-287, after 10 weeks of induction dosing
(following vancomycin pre-treatment), in achieving clinical remission
2.2 
 Key Secondary Objectives 
•
To demonstrate the efficacy of SER-287, after 10 weeks of step-down induction
dosing (following vancomycin pre-treatment), in achieving clinical remission
•
To demonstrate the efficacy of SER-287, after 10 weeks of induction dosing
(following vancomycin pre-treatment), in achieving endoscopic improvement
•
To demonstrate the efficacy of SER-287, after 10 weeks of step-down induction
dosing (following vancomycin pre-treatment), in achieving endoscopic improvement
2.3 
Other Secondary Objectives 
•
To demonstrate the efficacy of each SER-287 treatment arm in achieving endoscopic
remission after 10 weeks of induction treatment
•
To demonstrate the efficacy of each SER-287 treatment arm in achieving histological
mucosal healing after 10 weeks of induction treatment
•
To demonstrate the efficacy of each SER-287 treatment arm in achieving clinical
remission with normalization of stool frequency after 10 weeks of induction
treatment
•
To evaluate the efficacy of each SER-287 treatment arm on symptomatic remission
(rectal bleeding and stool frequency) after 10 weeks of induction treatment
•
To evaluate the engraftment of SER-287 bacteria from each SER-287 treatment arm
into the intestinal microbial community over time
•
For EMA consideration only (see Section 3, Definitions):
o
To demonstrate the efficacy of SER-287 to induce clinical remission, using
less stringent definition
o
To demonstrate the efficacy of SER-287 to induce clinical remission, using
more stringent definition
o
To demonstrate the efficacy of SER-287 to induce symptomatic remission
and endoscopic remission as co-endpoints
2.4 
Safety Objective 
To evaluate safety and tolerability of SER-287 
2.5 
Exploratory Objectives 
•
To evaluate clinical remission at the end of maintenance treatment
•
To evaluate endoscopic remission at the end of maintenance treatment
•
To evaluate histological mucosal healing at the end of maintenance treatment
•
To evaluate clinical remission at the end of open-label treatment
•
To evaluate endoscopic improvement at the end of open-label treatment


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•
To evaluate endoscopic remission at the end of open-label treatment
•
To evaluate histological mucosal healing at the end of open-label treatment
•
To evaluate the effect of SER-287 treatment on symptomatic remission (rectal
bleeding and stool frequency) over time
•
To evaluate the clinical remission rate of SER-287, by donor, after 10 weeks of
induction treatment
•
To assess improvement in quality of life, as measured by the Inflammatory Bowel
Disease Questionnaire (IBDQ)
•
To assess changes in serum biomarkers (C-reactive protein [CRP]) and fecal
biomarkers (fecal calprotectin)
•
To evaluate changes in the composition of the intestinal microbiome over time
•
To evaluate changes in signatures of host and microbial functional responses over
time


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3 
DEFINITIONS 
3.1 
Clinical Remission 
Due to the differences in the definition of clinical remission in the U.S. FDA Guidance 
Ulcerative Colitis: Clinical Trial Endpoints (FDA CDER 2016) and the EMA “Guideline 
on the development of new medicinal products for the treatment of Ulcerative Colitis” 
(EMA/CHMP, 2018), the definitions for clinical remission, as well as associated 
endpoints, to be used for the U.S. FDA and the EMA analyses, are provided below. 
3.1.1 U.S. FDA
3.1.1.1 Clinical Remission for the Induction and Open-Label Treatment Periods: 
•
Stool Frequency subscore = 0 or 1, with at least one-point decrease from baseline
•
Rectal Bleeding subscore = 0
•
Endoscopic subscore = 0 or 1 on modified Mayo Score, with at least one-point
decrease from baseline
•
No occurrence of UC Flare during the treatment period
3.1.1.2 Clinical Remission for the Maintenance Treatment Period (Sustained from 
Week 11 through M-Week 37): 
•
Stool Frequency subscore = 0 or 1
•
Rectal Bleeding subscore = 0
•
Endoscopic subscore = 0 or 1 on modified Mayo Score
•
No occurrence of UC Flare during the treatment periods
3.1.1.3 Clinical Remission including normalization of stool frequency: 
•
Stool Frequency subscore = 0
•
Rectal Bleeding subscore = 0
•
Endoscopic subscore = 0 or 1 on modified Mayo Score, with at least one-point
decrease from baseline
•
No occurrence of UC Flare during the treatment period
3.1.2 EMA 
3.1.2.1 Clinical Remission – Less stringent: 
•
Stool Frequency subscore = 0 or 1
•
Rectal Bleeding subscore = 0
•
Endoscopic subscore = 0 or 1 on modified Mayo Score, with at least one-point
decrease from baseline
•
No occurrence of UC Flare during the treatment period
3.1.2.2 Clinical Remission – More stringent: 
•
Stool Frequency subscore = 0 or 1
•
Rectal Bleeding subscore = 0


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•
Endoscopic subscore = 0 on modified Mayo Score
•
No occurrence of UC Flare during the treatment period
3.1.2.3 Co-endpoints: 
•
Symptomatic remission:
a.
Stool Frequency subscore = 0 or 1
b. Rectal Bleeding subscore = 0
•
Endoscopic remission
a.
Endoscopic subscore = 0 or 1 on modified Mayo Score, with at least one-
point decrease from baseline
3.2 
Endoscopic Improvement 
Endoscopic subscore decrease from baseline of at least one (1) point, as assessed by 
flexible sigmoidoscopy or colonoscopy 
3.3 
Endoscopic Remission 
3.3.1 Endoscopic Remission for the Induction and Open-Label Treatment Periods 
Endoscopic subscore = 0 or 1 on modified Mayo Score, with at least one (1) point 
decrease from baseline, as assessed by flexible sigmoidoscopy or colonoscopy 
3.3.2 Endoscopic Remission for the Maintenance Treatment Period (from Week 11 
through M-Week 37) 
Endoscopic subscore = 0 or 1 on modified Mayo Score, as assessed by flexible 
sigmoidoscopy or colonoscopy 
3.4 
Histological Mucosal Healing 
Statistically significant decrease from baseline, using the Robarts Histopathological 
Index (RHI) scoring system 
3.5 
Three-Component Modified Mayo Score 
Sum of the below three (3) subscores: 
1. Endoscopic subscore
2. Stool frequency subscore
3. Rectal bleeding subscore
3.6 
Disease Worsening 
An increase by two (2) or more points, on two (2) days within a three (3) day period, of 
the patient reported outcomes (stool frequency and rectal bleeding) of the modified Mayo 
score, 
•
Compared to baseline score (Visit 2) if disease worsening is during the Induction
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•
Compared to the post-10-week induction treatment score if disease worsening is
after the Induction Treatment period
3.7 
UC Flare 
UC symptom changes (which may include disease worsening, as defined above), as 
determined by the principal investigator to be significant enough to warrant addition of a 
new UC medication, an increase in dose of a baseline UC medication, or surgery 
3.8 
Engraftment 
Outgrowth of bacteria that comprise the SER-287 drug product in a subject’s 
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5 
STUDY POPULATION 
Subjects must meet all the inclusion criteria and none of the exclusion criteria. 
5.1 
Inclusion Criteria 
To be eligible for enrollment, a subject must meet all the following criteria before 
undergoing any study-related procedures: 
1. Signed informed consent prior to initiation of any study-specific procedure or
treatment.  The subject must be willing to provide written informed consent and
understand the potential risks and benefits from study enrollment and treatment.
The subject must also be willing and able to comply with the scheduled visits,
treatment plan, laboratory tests, daily eDiary and other study procedures.
2. Male or female (non-lactating), 18-80 years of age, inclusive
3. Documented diagnosis of ulcerative colitis at least three (3) months prior to
Screening.  Documentation should include lower endoscopic (flexible
sigmoidoscopy or colonoscopy) evidence or histological evidence (biopsy report)
of UC; however, UC medical treatment records may be sufficient, as determined
by the PI.  Subjects must also have a minimum disease extent of 15 cm from the
anal verge, as determined at the Screening endoscopy.
4. Active mild-to-moderate UC as determined by a Three-Component Modified
Mayo Score of 3 to 7, inclusive, composed of endoscopic subscore (≥ 1, as
determined by local and central reader scores, with adjudication by a second
central reader, if necessary), stool frequency subscore (≥ 1) and rectal bleeding
subscore (no eligibility requirement).  There will be a maximum time of seven (7)
business days between the Screening endoscopy and randomization.
5. Subjects must be willing to undergo a lower endoscopy (flexible sigmoidoscopy
or colonoscopy), including biopsy sample collection, at all specified timepoints.
6. Subjects with an inadequate response to, loss of response to, or intolerance of, at
least one (1) of the following conventional therapies: 5-ASA compounds,
corticosteroids, 6-mercaptopurine (6-MP) or azathioprine (AZA), anti-TNFα,
anti-integrin or tofacitinib (note full definition later within Section 5.1)
7. If female, is either:
a.
Not of childbearing potential, defined as postmenopausal (≥ 12 continuous
months of amenorrhea with no other cause than menopause) or surgically
sterile due to bilateral tubal ligation, bilateral oophorectomy, or
hysterectomy
b. Of childbearing potential and participates in any activity associated with
risk of pregnancy: is practicing at least one (1) highly effective method of
birth control, including the barrier method, oral or parenteral
contraceptives, a vasectomized partner or abstinence from sexual
intercourse.  The investigator will discuss with the subject the option of
practicing more than one (1) of the above methods for the duration of the
study.
8. If male and partner is of childbearing potential, subject agrees to practice at least
one (1) highly effective method of birth control for the duration of the study.


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Note definition for Inclusion Criterion #6:  Subjects who have demonstrated, over the 
previous five (5) year period, an inadequate response to, loss of response to, or 
intolerance of, at least one (1) of the following agents, as defined below: 
•
5-ASA compounds:
o
Signs and symptoms of persistently active disease despite taking a 
therapeutic dose of a 5-ASA compound (based on the product label for 
each compound, per PI judgement) for a minimum of four (4) weeks, or
o
History of intolerance to at least one (1) 5-ASA (discontinuation due to 
side effects)
•
Corticosteroids:
o
Signs and symptoms of persistently active disease despite a history of at 
least one (1) four-week induction regimen that included a dose equivalent 
to prednisone ≥ 30 mg or budesonide ≥ 9 mg daily, orally for at least two
(2) weeks, or intravenously for at least one (1) week, or
o
Two (2) failed attempts to taper corticosteroids to below a dose equivalent 
to prednisone 10 mg daily, orally, on two (2) separate occasions, or
o
History of intolerance of corticosteroids (including, but not limited to 
Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, or 
neuropsychiatric side-effects, including insomnia, associated with 
corticosteroid treatment)
•
Immunomodulators:
o
Signs and/or symptoms of persistently active disease despite at least three
(3) months of treatment with one (1) of the following:

oral AZA (≥ 1.5 mg/kg/day) or 6-MP (≥ 0.75 mg/kg/day), or

oral AZA or 6-MP within a therapeutic range, as judged by 
thioguanine metabolite testing, or

a combination of a thiopurine and allopurinol within a therapeutic 
range, as judged by thioguanine metabolite testing, or

history of intolerance to at least one (1) immunomodulator
(including but not limited to nausea/vomiting, abdominal pain, 
pancreatitis, liver function test abnormalities and lymphopenia)
•
Pathway specific drugs for UC treatment, including anti-TNF antibodies, anti-
integrin antibodies, or janus kinase (JAK) inhibitors (such as tofacitinib):
o
Signs and symptoms of persistently active disease despite induction 
treatment at the approved induction dosing that was indicated in the 
product label at the time of use, or
o
Loss of response: Recurrence of signs and symptoms of active disease 
during approved maintenance dosing following prior clinical benefit
(discontinuation despite clinical benefit does not qualify as having failed 
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o
Intolerance: History of intolerance to infliximab, adalimumab,
golimumab, vedolizumab, tofacitinib or other approved biologics or JAK
inhibitors (including but not limited to infusion-related event,
demyelination, congestive heart failure, serious infection, or any other
drug-related AE that led to a reduction in dose or discontinuation of the
medication).
5.2 
Exclusion Criteria 
A subject will not be enrolled if the subject meets any of the following criteria: 
1. Known history of Crohn’s disease
2. No previous history of treatment for UC (treatment-naïve subjects should not be
enrolled)
3. Subjects on steroid medication (e.g. prednisone, budesonide, budesonide
MMX®) who are unable to have steroids tapered, and be completely off steroids
at least two (2) weeks prior to Screening
4. Subjects who have received any investigational or approved biologic therapy (e.g.
infliximab, adalimumab, golimumab, certolizumab, vedolizumab, ustekinumab,
natalizumab) within eight (8) weeks prior to Screening or five (5) half-lives prior
to Screening (whichever is longer)
5. Subjects who have received any investigational or approved non-biologic therapy
(e.g. cyclosporine, tacrolimus, thalidomide, methotrexate, tofacitinib), except for
those specifically listed in the Permitted Concomitant Medications (e.g. stable
dose of 6-mercaptopurine, azathioprine, methotrexate for ≥ 12 weeks prior to
Screening), for the treatment of underlying disease, within 30 days or five (5)
half-lives prior to Screening (whichever is longer)
6. Major gastrointestinal surgery (not including appendectomy or cholecystectomy)
within two (2) months before Screening, or any history of total colectomy
7. Subjects with active celiac disease (i.e., active diarrhea due to documented celiac
disease)
8. Subjects with evidence of, or treatment for, Clostridium difficile infection, or
other intestinal pathogen, within 30 days prior to Screening
9. Subjects with Clostridium difficile positive stool, performed with a toxin enzyme
immunoassay (EIA) by the Central Laboratory.  Subjects who test positive for C.
difficile can be treated with standard of care antibiotics and rescreened for the
study after 30 days, as per Exclusion Criterion #8.
10. Oral antibiotic use within 30 days before Screening
11. Expected to receive antibiotics (i.e., for planned/anticipated procedure) within the
Induction Treatment period
12. Received an investigational drug or live vaccine within two (2) months before
Screening
13. Previously enrolled in a Seres Therapeutics SER-109 or SER-287 study
14. Received a fecal microbiota transplant (FMT; includes human microbiota-based
therapeutics) within three (3) months prior to Screening
15. Poor concurrent medical risks with clinically significant co-morbid disease such
that, in the opinion of the investigator, the subject should not be enrolled
including:


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a.
Known hypogammaglobulinemia
b. Known severe immunodeficiency
c.
Underlying liver function test (LFT) [Screening alanine aminotransferase
(ALT) or aspartate aminotransferase (AST)] abnormalities greater than 3x
upper limit of normal (ULN)
d. Absolute neutrophil count (ANC) < 500 cells/mm3
e.
Hemoglobin levels < 9 g/dL
16. Subjects with anatomic or medical contraindications to lower endoscopy (flexible
sigmoidoscopy or colonoscopy), including but not necessarily limited to toxic
megacolon, gastrointestinal fistulas, immediate post-operative status from
abdominal surgery, severe coagulopathy, large or symptomatic abdominal aortic
aneurysm, or any subject where study physician deems subject at significant risk
of complications of lower endoscopy (flexible sigmoidoscopy or colonoscopy)
17. Unable to stop steroid enemas or suppositories, or 5-ASA enemas or
suppositories, at least two (2) weeks prior to Screening
18. Unable to stop probiotic treatment at least one (1) week prior to Screening.  Note:
food containing probiotics are permitted.
19. Known active malignancy, except for basal cell skin cancer or squamous cell skin
cancer, or concurrent intensive induction chemotherapy, radiotherapy, or biologic
treatment for active malignancy (subjects on maintenance chemotherapy may
only be enrolled after consultation with medical monitor)
20. Unable to comply with the protocol requirements, including the ability to take
oral drugs; or any condition that, in the opinion of the investigator, might
interfere with study objectives or compromise patient safety, including if the
subject is likely to require surgery for UC during the study period
21. Known allergy or intolerance to oral vancomycin
22. Current or recent history (six [6] months prior to Screening) of drug or alcohol
abuse
5.3 
Subject Withdrawal and Replacement 
5.3.1 Reasons for Discontinuation of Treatment 
A subject may discontinue treatment after discussion with the investigator and/or medical 
monitor for the following reasons: 
•
Pregnancy (see Section 7.1.5, Pregnancy)
•
Adverse event(s)
•
At the discretion of the Investigator
•
Subject choice (withdrawal of consent by subject; investigator will attempt to
ascertain reason)
•
Protocol violation
•
Non-compliance with study drug
•
Non-compliance with eDiary entries


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Subjects should continue to be followed for safety assessments up to 26 weeks after last 
study drug dose.  However, a subject may withdraw from the study at any time for any 
reason, without any consequence.  
5.3.2 Handling of Withdrawals and Discontinuation of Treatment 
Subjects who discontinue from treatment early will enter the long-term safety follow-up 
period.  The primary reason for discontinuation of treatment will be recorded in the 
subject’s clinical records and in the electronic data capture (EDC) system.  If a subject 
discontinues treatment, the Investigator must make every effort to perform the End of 
Treatment Visit, as described in Section 8.2.26, End of Treatment Visit. 
Subjects who withdraw from the study will have the reason for withdrawal documented 
in the EDC system.  A subject may also be withdrawn from study by the Sponsor, 
Regulatory Authorities, or Independent Ethics Committees (IECs)/Institutional Review 
Boards (IRBs).  Subjects will also be withdrawn if the entire study is terminated 
prematurely.   
If a subject fails to appear for a follow-up assessment, all attempts to contact the subject 
and information received during contact attempts must be documented in the subject’s 
medical record.  In any circumstance, every effort should be made to document subject 
outcome, if possible (i.e, three [3] documented contact attempts via phone calls, e-mail, 
etc., on separate occasions will be made to locate or contact them, or at least to determine 
their health status). 
5.4 
Termination of Study 
Although the Sponsor has every intention of completing the study, the Sponsor may 
terminate the study at any time for clinical or administrative reasons. 
5.5 
Planned Sample Size and Number of Study Centers 
Approximately 201 subjects will be enrolled at approximately 104 sites in North 
America.  
5.6 
Subject Identification and Randomization 
5.6.1 Subject Identification 
All screened subjects will be assigned a unique subject identification (SID) number that 
will be used through Screening, Pre-Treatment, Treatment and Follow-Up periods.  
5.6.2 Methods of Assigning Subjects to Study Treatment 
Randomization will be used to avoid bias in the assignment of subjects to double-blind 
treatment (SER-287 or placebo) and to increase the likelihood that known and unknown 
subject characteristics will be evenly distributed between the treatment groups.  
Eligible subjects are to be randomized at Week 0 (Visit 3), after all screening procedures 
have been performed and eligibility for the study is confirmed.  Subjects will be 


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randomized via the IXRS to one (1) of the three (3) study arms (Figure 5).  
Randomization will be stratified by subjects’ baseline endoscopic subscore (1-2 vs. 3) 
and by subjects’ concomitant use of UC medications at baseline (5-ASA alone vs. 
immunomodulators with or without 5-ASA vs. none).  An adaptive subject 
randomization algorithm will be employed to facilitate balance among the different 
donors within each of the SER-287 arms. 
Once a randomization number has been assigned to a subject, the number cannot be 
reused even if the subject discontinues from the study early or withdraws before 
receiving any study drug.  Subjects who discontinue from the study or who have been 
previously randomized in the study will not be permitted to re-enter.  Similarly, study 
drug assigned to a subject may not be re-used, even if the bottle is returned unopened. 
During the double-blind period, the following people will remain blinded to the treatment 
assignment: subjects, investigators, other study site personnel, clinical staff, medical 
monitor, study site monitors and other sponsor representatives involved in the clinical 
aspects of study conduct.  
5.6.3 Maintaining the Randomization Codes and Breaking the Study Blind 
A designated randomization administrator from an external, independent vendor will 
maintain the randomization codes in accordance with standard operating procedures to 
ensure that the blind is properly maintained and that only personnel who require 
knowledge of treatment assignments will be unblinded [e.g., staff involved in serious 
adverse event reporting].  
Investigators are not to break the study treatment blind except when information 
concerning the study drug is necessary for the medical treatment of the subject.  If a 
medical emergency requiring unblinding occurs, the investigator (or designated 
physician) is strongly encouraged to contact the medical or safety monitor to assess the 
necessity of breaking the study drug blind.  If unblinding is warranted, the investigator 
will obtain the treatment assignment information from the IXRS.  Every effort is to be 
made to limit study site personnel unblinding only to those individuals providing direct 
care to that subject.  Any intentional or unintentional breaking of the blind is to be 
reported immediately to the sponsor.  The other circumstances in which unblinding may 
be necessary are at the request of a subject who becomes pregnant during the study or for 
regulatory reporting purposes. 
If the blind is broken, the date, time, and reason must be recorded in the EDC system and 
any associated SAE report.  
If a subject is unblinded, they will not receive any additional study medications. 
After the statistical analysis plan (SAP) is final and the primary study period (Week 0 
[Visit 3] to Week 11 [Visit 7]) data is declared complete and final, the study blind codes 
will be broken for the induction period efficacy analyses.  The Maintenance Treatment 
period will remain blinded until all data collected through M-Week 37 (Visit M-7) has 
been entered, cleaned and declared complete and final.  Only limited study personnel will 


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have the access to the treatment code.  The remaining study team personnel (majority), 
PIs and subjects will remain blinded until the study is completed. 








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6.8.2 Prohibited Concomitant Medications and Nutritional Supplements 
The following prohibited concomitant medications and nutritional supplements may not 
be administered at any time through the study period.  Subjects who initiate the following 
treatments will be discontinued from further study drug administration. 
•
Oral, intravenous (IV) and rectal steroids (e.g. prednisone, budesonide,
budesonide MMX®)
•
5-ASA enemas or suppositories
•
Any investigational or approved biologic therapy (e.g. infliximab, adalimumab,
golimumab, certolizumab, vedolizumab, ustekinumab, natalizumab)
•
Any investigational or approved non-biologic therapy (e.g. cyclosporine,
tacrolimus, thalidomide, methotrexate, tofacitinib)
•
Anti-diarrheals (e.g. loperamide, diphenoxylate/atropine, or bile-salt sequestrant
[cholestyramine, colesevelam])
•
Probiotics (food containing probiotics are permitted)
•
Use of any nutritional supplement which claims to support or promote gut health
should be determined by medical monitor.


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7 
VARIABLES AND METHODS OF ASSESSMENT 
7.1 
Safety Variables 
Safety evaluations include medical history, assessment of AEs, clinical laboratory tests 
(chemistry, hematology and urinalysis), physical examination and vital signs.  
All AEs, including SAEs, will be graded for severity by using the following grading 
system: 
•
Mild: Events require minimal or no treatment and do not interfere with the subject’s
daily activities.
•
Moderate: Events result in a low level of inconvenience or concern and may require
treatment; moderate events may cause some interference with functioning.
•
Severe: Events interrupt a subject’s usual daily activity and may require systemic
drug therapy or other treatment; severe events are usually incapacitating.
Changes in the severity of an AE will be documented, and documentation will include 
assessment of the duration of the event at each level of intensity.  Adverse events 
characterized as intermittent will be documented based on the severity, onset and 
duration of each episode. 
An abnormal laboratory test finding that meets any of the criteria below will be 
considered an AE: 
•
Is associated with accompanying symptoms
•
Requires additional diagnostic testing or medical/surgical intervention
•
Leads to a concomitant drug treatment or any change in a concomitant medication or
therapy
•
Is considered an AE by the Investigator
Laboratory results that fall outside the reference range and do not meet one (1) of the 
criteria above will not be reported as AEs.  Repeating a test because of an abnormal 
result, in the absence of the above conditions, does not constitute as AE.  Any abnormal 
test result that is determined to be an error will not be reported as an AE. 
For all AEs, including SAEs, the Investigator will report on the relationship of the AE to 
the study drug by using the following definitions: 
•
Unrelated: There is little or no chance that the study drug caused the AE; other
conditions, including concurrent illnesses, progression or expression of the disease
state, or a reaction to a concomitant medication best explain the event.
•
Related or Possibly Related: The association of the AE with the study drug is
unknown; however, the AE is not clearly due to another condition, or a reasonable
temporal association exists between the AE and treatment administration and, based
on the Investigator’s clinical experience, the association of the AE with the study
drug seems likely.


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Adverse events, including local and systemic reactions not considered medically serious, 
will be recorded.  Information to be collected includes event description, time of onset, 
Investigator assessment of severity, relationship to study drug, date of resolution of the 
event, seriousness, and outcome. 
Any medical condition that is present at the time that the subject is screened will be 
considered as a baseline condition and not be reported as an AE. However, if it worsens 
at any time during the study, it should be recorded as an AE. 
The Investigator is responsible for: 
•
Informing the sponsor if a subject or a subject’s partner becomes pregnant during the
study.  A “Pregnancy Report Form” will be generated, and the pregnancy will be
documented in the safety database and outcome of the pregnancy will be
documented.
•
Evaluating subject safety including assessment of AEs for seriousness, severity, and
causality.
•
Informing the IRB/IEC of AEs as required, and SAEs as per IRB/IEC guidelines.
7.1.1 Treatment Emergent Adverse Events 
Collection of adverse events will begin following the first administration of study pre-
treatment medication on Week 0 (Visit 3) and will be collected through the first four (4) 
weeks of the Long-Term Safety Follow-Up Period. 
An adverse event is defined as any untoward medical occurrence in a subject who was 
administered study drug, regardless of its causal relationship to the study drug.  An AE 
can, therefore, be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of the study 
drug, whether it is related to the study drug, or not.   
A serious adverse event is any AE occurring at any dose and regardless of causality that: 
•
Results in death.
•
Is life-threatening.  Life-threatening means that the subject was at immediate risk of
death from the reaction as it occurred, i.e., it does not include a reaction that
hypothetically might have caused death had it occurred in a more severe form.
•
Requires inpatient hospitalization or prolongation of existing hospitalization; hospital
admissions and/or surgical operations scheduled to occur during the study period, but
planned before study entry are not considered AEs if the illness or disease existed
before the subject was enrolled in the study, provided that it did not worsen in any
unexpected manner during the study (e.g., surgery performed earlier than planned).
•
Results in persistent or significant disability/incapacity.  Disability is defined as a
substantial disruption of a subject’s ability to conduct normal life functions.
•
Is associated with a congenital anomaly/birth defect.






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If a female partner of a male study subject who has been exposed to the study drug 
becomes pregnant, the outcome of the pregnancy should be documented. 
7.1.6 Laboratory Variables 
All hematology and blood chemistry laboratory tests will be performed by the central 
laboratory.  The laboratory facilities for analysis of clinical laboratory samples obtained 
under this protocol will have adequate licensure and accreditation.  Urine pregnancy tests 
will be performed at the sites.  Details of sample handling, specific tests performed, and 
methodology will be provided in the laboratory manual. 
Blood samples for hematology, blood chemistry, and biomedical research will be 
obtained according to the Schedule of Events (Table 1, Table 2, Table 3).  Blood samples 
for hematology and blood chemistry obtained on Day 1 (pre-dose) will be used to 
determine baseline data but will not be used to confirm eligibility criteria. 
Any value outside the normal range will be flagged for the attention of the Investigator, 
or designee, at the site.  The Investigator, or designee, will indicate whether the value is 
of clinical significance and should be recorded as an AE.  Actual laboratory results will 
not be captured within the EDC system.  However, if any laboratory results meet the 
reporting requirements for an AE, the event term (e.g., elevated transaminase) will be 
recorded within the EDC system as an AE or SAE, as applicable. 
7.1.7 Stool Samples 
Stool samples will be collected by the subjects, as detailed in Section 8, Study Conduct.  
Stool sample collection, handling, storage and processing procedures will be defined in 
stool sample manuals for sites and study subjects.  When lower endoscopies are being 
performed, stool samples will be collected prior to the start of the clear liquid diet, in 
preparation for endoscopy.   
7.1.8 Biopsy Samples 
Four (4) biopsies will be obtained from the area of worst disease, with a minimum 
disease extent of 15 cm from the anal verge, before and after treatment, as detailed in 
Section 8, Study Conduct.  The biopsies collected after treatment will be from the same 
location as those collected before treatment.  Three (3) of the four (4) biopsy samples per 
visit will be placed in formalin, for histopathology, and one (1) will be placed in 
RNALater, for mucosal genomic analyses.  Samples will be processed at the clinical site, 
and then shipped to the central laboratory, according to the procedures defined in the 
endoscopy and histopathology charters.  Refer to the endoscopy and histopathology 
charters for full details. 


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7.1.9 Vital Signs 
The following vital signs will be assessed in accordance with the Schedule of Events 
(Table 1, Table 2, Table 3): 
•
Blood pressure (BP; systolic and diastolic; mmHg)
•
Heart rate (HR; beats per minute)
•
Body temperature (°C)
•
Respiration rate (breaths per minute)
The Investigator or designee will indicate whether a value is of clinical significance and 
should be recorded as an AE.   
7.1.10 Physical Examinations 
The physical examination includes an assessment of general appearance and evaluation 
of the following: Head/Eyes/Ears/Nose/Throat; Neck; Lungs and Heart; Abdomen; 
Lymph Nodes; Extremities; Neurological; Other. 
Abnormal clinically significant findings will be reported as medical history or AEs, as 
determined by the Investigator. 
7.2 
Demographics and Baseline Characteristics 
Demographics and Baseline Characteristics consist of those variables that are assessed 
only at Screening/baseline. 
7.2.1 Subject Demography 
•
Age at Screening
•
Sex
•
Height
•
Weight
•
Ethnic origin (Hispanic/Latino or not Hispanic/not Latino)
•
Race (White, American Indian/Alaska Native, Asian, Native Hawaiian or other
Pacific Islander, Black/African American)
7.2.2 Disease History 
•
UC history


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7.2.3 Baseline Characteristics 
•
General medical history
•
General surgical history
•
Smoking history
7.2.4 Medical History 
Any previous and concomitant diseases before Screening will be documented as medical 
history.  Medical history will be obtained by interviewing the subject and by inspecting 
his/her medical records. 
7.2.5 Prior and Concomitant Medications 
Prior and concomitant medication will be documented as described in Section 6.8, Prior 
and Concomitant Medications.  Prior and concomitant medications will be coded using 
the World Health Organization (WHO) Drug Dictionary.  Prior UC medications are of 
particular interest, as well as reason for stoppage – lack of efficacy or intolerance. 
7.3 
Three-Component Modified Mayo Score 
To be eligible for enrollment, a subject must have active mild-to-moderate UC as 
determined by a Three-Component Modified Mayo Score of 3 to 7, inclusive.  The total 
Three-Component Modified Mayo Score is the sum of the below three (3) subscores, 
which will be calculated electronically from subject eDiary entries and central endoscopy 
reads. 
7.3.1 Stool Frequency Subscore 
To be eligible for enrollment, a subject must have a stool frequency subscore ≥ 1.  Stool 
frequency will be recorded daily by enrolled subjects using an eDiary.  Subscore 
calculation guidelines can be found in Appendix 2. 
7.3.2 Rectal Bleeding Subscore 
There is no rectal bleeding subscore requirement for enrollment.  Rectal bleeding will be 
recorded daily by enrolled subjects using an eDiary.  Subscore calculation guidelines can 
be found in Appendix 2. 
7.3.3 Endoscopic Subscore 
To be eligible for enrollment, a subject must have an endoscopic subscore ≥ 1.  
Endoscopic subscores will be determined by qualified gastroenterologists – first locally, 
and then by an independent, blinded central reader.  If the scores are discordant, a second 
independent, blinded central reader will score the image (adjudication).  If all of the 
scores are different from one another, then the median of the three (3) scores will be used 
as the final endoscopic subscore.  
If the endoscopic subscore is missing, the subject will be assigned an outcome of failure 
for all endpoints which are derived using the endoscopic subscore. 




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Protocol # SERES-201 
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Amendment 3 
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•
Perform full physical exam
•
Assess vital signs (systolic and diastolic blood pressure, heart rate, respiratory
rate, temperature)
•
Obtain height and weight
•
Collect blood, urine and stool samples and ship to the central laboratory for
evaluation of:
o
Blood chemistry
o
Hematology
o
Serum pregnancy test for women of childbearing potential (WOCBP)
o
Blood & Serum for Future Biomedical Research
o
Urinalysis:  Urine dipstick performed at the study site; if positive for nitrates
and/or leukocytes, send sample to central laboratory for analysis
•
Subject should be asked to provide a stool sample on site, if possible, to be used
for Clostridum difficile testing (toxin enzyme immunoassay [EIA]), microbiome
and metabolomics.  If unable to produce a stool sample on site, subject should be
provided with a stool collection kit to take home.  Stool collection done at home
should be returned the next day by the subject or can be returned to the clinic via
courier.
•
Fecal calprotectin
•
Obtain history of stool frequency and rectal bleeding
•
Review subject eDiary Instructions with subject for recording of daily rectal
bleeding & stool frequency
•
Review stool collection handling and storage instructions with subject
•
Provide stool collection kit to subject for next clinic visit
•
Subject eDiary (daily rectal bleeding, stool frequency)
Note: A minimum of seven (7) days between Visit 1 and Visit 2 are required to 
ensure there are a sufficient quantity of daily eDiary entries to calculate the Stool 
Frequency subscore.  The SF score will be calculated electronically, from subject 
eDiary entries.  Sites will receive a notification from the IXRS that the subject meets 
the SF score requirement (SF ≥ 1) for performing the endoscopy at Screening Visit 2. 
8.2.2 Screening: Week -4 to -1:  Endoscopy Visit (Visit 2) 
•
Verify subject meets all the inclusion criteria and none of the exclusion criteria
•
Concomitant Medications
•
Concomitant Procedures for UC
•
Confirm subject has had no liquids six (6) hours prior to lower endoscopy
(flexible sigmoidoscopy or colonoscopy)
•
Confirm subject performed bowel preparation at PI discretion (e.g., two [2] Fleet
enemas 1.5 hours before procedure)
•
Perform lower endoscopy (flexible sigmoidoscopy or colonoscopy)


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Obtain biopsy for histopathology (3 samples)
•
Obtain biopsy for mucosal genomic analyses (1 sample)
•
Subject eDiary (daily rectal bleeding, stool frequency)
•
Review subject eDiary for compliance
Note: The Three-Component Modified Mayo Score will be calculated electronically, 
from subject eDiary entries and central endoscopy read, to determine subject 
eligibility.  Sites will receive an eligibility notification from the IXRS confirming if 
the subject is eligible to be randomized into the protocol (Three-Component 
Modified Mayo Score 3 to 7, inclusive), or is ineligible (screen failure).  
8.2.3 Pre-Treatment: Week 0 (Visit 3) 
8.2.3.1 Pre-dosing 
•
Concomitant Medications
•
Concomitant Procedures for UC
•
Confirm eligibility review has been completed by Medical Monitor, pre-
randomization, for final eligibility decision by PI
•
Perform focused physical exam
•
Assess vital signs (systolic and diastolic blood pressure, heart rate, respiratory
rate, temperature)
•
Obtain weight
•
Obtain urine sample pre-dose for pregnancy testing; should be performed and
reported as negative prior to dosing. (WOCBP only)
•
Blood sampling pre-dose for hematology, blood chemistry
•
Blood for CRP
•
Perform IBDQ
•
Subject eDiary (daily rectal bleeding, stool frequency)
•
Review subject eDiary for compliance
8.2.3.2 Dosing 
•
Perform randomization in IXRS
•
Dispense pre-treatment drug supply
•
Begin pre-treatment drug dosing (observe subject one [1] hour post-dosing)
•
Review stool sample collection, handling and storage instructions with subject
•
Provide stool sample collection kit to subject
•
Begin adverse event monitoring


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8.2.4 Induction Treatment: Week 1 +/-1d (Visit 4) 
8.2.4.1 Pre-dosing: 
•
Concomitant medications
•
Concomitant procedures for UC
•
Obtain urine sample for pregnancy testing (WOCBP only)
•
Return any remaining pre-treatment drug and all bottles dispensed
•
Review drug compliance
•
Subject eDiary (daily rectal bleeding, stool frequency)
•
Review subject eDiary for compliance
•
Blood sampling pre-dose for hematology, blood chemistry
•
Blood and Serum for future medical research
•
Subject to return stool sample collected at home and ship to the central
laboratory
•
Review stool sample collection, handling and storage instructions with
subject
8.2.4.2 Dosing: 
•
Begin treatment period drug dosing (observe subject one [1] hour post-dosing)
•
Dispense study drug for daily dosing
•
Continue adverse event monitoring
•
Provide stool collection kit to subject for next clinic visit
8.2.5 Induction Treatment: Week 3 +3d (Visit 5) 
•
Concomitant Medications
•
Concomitant Procedures for UC
•
Subject to return stool sample collected at home and ship to the central laboratory
•
Provide stool sample collection kit to subject
•
Obtain urine sample for pregnancy testing (WOCBP only)
•
Dispense study drug for daily dosing
•
Continue adverse event monitoring
•
Return all unused study drug and any bottles dispensed
•
Review drug compliance
•
Subject eDiary (daily rectal bleeding, stool frequency)
•
Review subject eDiary for compliance
8.2.6 Induction Treatment: Week 7 +3d (Visit 6) 
•
Concomitant Medications
•
Concomitant Procedures for UC


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Obtain urine sample for pregnancy testing (WOCBP only)
•
Return all unused study drug and any bottles dispensed
•
Review drug compliance
•
Dispense study drug for daily dosing
•
Continue adverse event monitoring
•
Provide stool collection kit to subject for next clinic visit
•
Subject to return stool sample collected at home and ship to the central laboratory
•
Subject eDiary (daily rectal bleeding, stool frequency)
•
Review Subject eDiary for compliance
8.2.7 Induction Treatment: Week 11 +3d (End of Induction Treatment) (Visit 7) 
•
Concomitant Medications
•
Concomitant Procedures for UC
•
Perform focused physical exam
•
Assess vital signs (systolic and diastolic blood pressure, heart rate, respiratory
rate, temperature)
•
Obtain weight
•
Obtain urine sample for pregnancy testing (WOCBP only)
•
IBDQ
•
Confirm subject has had no liquids six (6) hours prior to lower endoscopy
(flexible sigmoidoscopy or colonoscopy)
•
Confirm subject has performed bowel preparation at PI discretion (e.g. two [2]
Fleet enemas 1.5 hours before procedure)
•
Perform lower endoscopy (flexible sigmoidoscopy or colonoscopy)
•
Obtain biopsy for histopathology (3 samples)
•
Obtain biopsy for mucosal genomic analyses (1 sample)
•
Note: Three-Component Modified Mayo Score will be calculated electronically,
from subject eDiary entries and central endoscopy read
•
Return all unused study drug and any bottles dispensed
•
Review drug compliance
•
Collect blood and ship to the central laboratory for evaluation of:
o
Hematology
o
Blood Chemistry
o
CRP
o
Blood and Serum for Future Biomedical research
•
Subject to return stool sample collected at home (pre-liquid diet for endoscopy)
and ship to the central laboratory
•
Fecal calprotectin


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Protocol # SERES-201 
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Subject eDiary (daily rectal bleeding, stool frequency)
•
Review subject eDiary for compliance
•
Provide stool collection kit to subject for next clinic visit
•
Continue adverse event monitoring
8.2.8 Induction Treatment: Unscheduled Visit 
See Section 8.2.25, Unscheduled Visits. 
Determining Subjects’ Remitter vs. Non-Remitter Status 
The lower endoscopy performed at the Week 11 visit will be scored, and the Three-
Component Modified Mayo Score will be calculated electronically from subject eDiary 
entries and endoscopic subscore to determine if the subject achieved clinical remission 
(See Section 3, Definitions) at the end of the 10-week Induction Treatment period.   
Subjects who achieve clinical remission at the end of the 10-week Induction Treatment 
period will be re-randomized into the Maintenance Treatment period, to receive either a 
SER-287 Maintenance Dose, once-weekly, or matching placebo, for 26 weeks. 
Subjects who did not achieve clinical remission at the end of the 10-week Induction 
Treatment period will enter the Open-Label Extension arm, where they will receive six 
(6) days of vancomycin pre-treatment followed by 10 weeks of SER-287 (Induction
Dose), once-daily.
Maintenance Treatment Period – Remitters 
8.2.9 Maintenance Treatment: M-Week 12 +/-2d (Visit M-1) 
8.2.9.1 Pre-dosing: 
•
Concomitant medications
•
Concomitant procedures for UC
•
Subject eDiary (daily rectal bleeding, stool frequency)
•
Review subject eDiary for compliance
•
Provide stool collection kit to subject for next clinic visit
8.2.9.2 Dosing: 
•
Perform re-randomization in IXRS
•
Begin treatment period drug dosing.  Subject to take Week 12 dose on site
(observe subject one [1] hour post-dosing)
•
Dispense study drug for weekly dosing


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Clinical Study Protocol 
Protocol # SERES-201 
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Continue adverse event monitoring
8.2.10 Maintenance Treatment: M-Week 16 +3d (Visit M-2) 
•
Concomitant Medications
•
Concomitant Procedures for UC
•
Obtain urine sample for pregnancy testing (WOCBP only)
•
Return all unused study drug and any bottles dispensed
•
Review Study Drug Compliance
•
Dispense study drug for weekly dosing
•
Provide stool collection kit to subject for next clinic visit
•
Subject to return stool sample collected at home and ship to the central laboratory
•
Continue adverse event monitoring
•
Subject eDiary (daily rectal bleeding, stool frequency)
•
Review subject eDiary for compliance
8.2.11 Maintenance Treatment: M-Week 20 +3d (Visit M-3) 
•
Concomitant Medications
•
Concomitant Procedures for UC
•
Obtain urine sample for pregnancy testing (WOCBP only)
•
Return all unused study drug and any bottles dispensed
•
Review drug compliance
•
Dispense study drug for weekly dosing
•
Provide stool collection kit to subject for next clinic visit
•
Subject to return stool sample collected at home and ship to the central laboratory
•
Subject eDiary (daily rectal bleeding, stool frequency)
•
Review subject eDiary for compliance
•
Continue adverse event monitoring
8.2.12 Maintenance Treatment: M-Week 24 +3d (Visit M-4) 
•
Concomitant Medications
•
Concomitant Procedures for UC
•
Obtain urine sample for pregnancy testing (WOCBP only)
•
Perform focused physical exam
•
Return all unused study drug and any bottles dispensed
•
Review drug compliance
•
Dispense study drug for weekly dosing
•
Provide stool collection kit to subject for next clinic visit
•
Subject to return stool sample collected at home and ship to the central laboratory


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Clinical Study Protocol 
Protocol # SERES-201 
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Continue adverse event monitoring
•
Subject eDiary (daily rectal bleeding, stool frequency)
•
Review subject eDiary for compliance
8.2.13 Maintenance Treatment: M-Week 28 +3d (Visit M-5) 
•
Concomitant Medications
•
Concomitant Procedures for UC
•
Obtain urine sample for pregnancy testing (WOCBP only)
•
Return all unused study drug and any bottles dispensed
•
Review drug compliance
•
Dispense study drug for weekly dosing
•
Provide stool collection kit to subject for next clinic visit
•
Subject to return stool sample collected at home and ship to the central laboratory
•
Continue adverse event monitoring
•
Subject eDiary (daily rectal bleeding, stool frequency)
•
Review subject eDiary for compliance
8.2.14 Maintenance Treatment: M-Week 32 +3d (Visit M-6) 
•
Concomitant Medications
•
Concomitant Procedures for UC
•
Obtain urine sample for pregnancy testing (WOCBP only)
•
Return all unused study drug and any bottles dispensed
•
Review drug compliance
•
Dispense study drug for weekly dosing
•
Provide stool collection kit to subject for next clinic visit
•
Subject to return stool sample collected at home and ship to the central laboratory
•
Continue adverse event monitoring
•
Subject eDiary (daily rectal bleeding, stool frequency)
•
Review subject eDiary for compliance
8.2.15 Maintenance Treatment: M-Week 37 +3d (Visit M-7) 
•
Concomitant Medications
•
Concomitant Procedures for UC
•
Perform focused physical exam
•
Assess vital signs (systolic and diastolic blood pressure, heart rate, respiratory
rate, temperature)
•
Obtain urine sample for pregnancy testing (WOCBP only)
•
IBDQ


Seres Therapeutics, Inc. 
Clinical Study Protocol 
Protocol # SERES-201 
CONFIDENTIAL 
Amendment 3 
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08-Oct-2019
•
Confirm subject has had no liquids six (6) hours prior to lower endoscopy
(flexible sigmoidoscopy or colonoscopy)
•
Confirm subject has performed bowel preparation at PI discretion (e.g. two [2]
Fleet enemas 1.5 hours before procedure)
•
Perform lower endoscopy (flexible sigmoidoscopy or colonoscopy)
•
Obtain biopsy for histopathology (3 samples)
•
Obtain biopsy for mucosal genomic analyses (1 sample)
•
Note: Three-Component Modified Mayo Score will be calculated electronically,
from subject eDiary entries and central endoscopy read
•
Obtain weight
•
Return all unused study drug and any bottles dispensed
•
Review drug compliance
•
Subject to return stool sample collected at home and ship to the central laboratory
•
Fecal calprotectin
•
Collect blood and ship to the central laboratory for evaluation of:
o
Hematology
o
Blood chemistry
o
CRP
o
Blood and Serum for Future Biomedical Research
•
Continue adverse event monitoring
•
Subject eDiary (daily rectal bleeding, stool frequency)
•
Review subject eDiary for compliance
•
End of eDiary completion; subject to leave eDiary device on-site
NOTE: If a subject in the Maintenance Treatment Arm experiences a UC flare during 
the first 13 weeks of Maintenance Treatment (prior to M-Week 24), the subject will have 
the option to enter the Open-Label Extension Arm of the study and receive pre-treatment 
with vancomycin followed by 10 weeks of open-label treatment with SER-287.  
8.2.16 Maintenance Treatment – Long-Term Safety Follow-Up: Phone Calls Every 
Four (4) Weeks +/-3d (Visits M-8 – M-13) 
•
During the first four (4) weeks of the Long-Term Safety Follow-Up Period,
AEs/SAEs/AESIs, concomitant procedures, and concomitant medications will be
collected.
•
Continue adverse event monitoring; only SAEs/AESIs and concomitant
medications associated with SAEs/AESIs will be collected for the remainder of
the long-term safety follow-up period.   Concomitant UC medications and UC
procedures, and any changes to these, will be collected throughout the entirety of
the Long-Term Safety Follow-Up Period.


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8.2.17 Maintenance Treatment: Unscheduled Visit 
See Section 8.2.25, Unscheduled Visits. 
Open-Label Extension Arm – Non-Remitters 
8.2.18 Open-Label Extension: OL-Week 0 +/-2d (Visit OL-1) 
•
Concomitant Medications
•
Concomitant Procedures for UC
•
Obtain urine sample for pregnancy testing (WOCBP only)
•
Register subject in IXRS for Open-Label Extension arm
•
Dispense pre-treatment medication to subject
•
Administer first dose of vancomycin pre-treatment in clinic
•
Dispense two (2) weeks of Open-Label study drug for daily dosing and provide
instructions to subject to start study drug after completing pre-treatment
medication
•
Provide stool collection kit to subject for next clinic visit
•
Subject eDiary (daily rectal bleeding, stool frequency)
•
Review subject eDiary for compliance
•
Continue adverse event monitoring
8.2.19 Open-Label Extension: OL-Week 1 +/-1d (Visit OL-2) 
•
Provide stool collection kit to subject for next clinic visit
•
Subject eDiary (daily rectal bleeding, stool frequency)
•
Subject to return stool sample collected at home and ship to the central
laboratory.  The stool sample may be returned to clinical site via courier or by the
subject.
8.2.20 Open-Label Extension: OL-Week 3 +3d (Visit OL-3) 
•
Concomitant medications
•
Concomitant procedures for UC
•
Obtain urine sample for pregnancy testing (WOCBP only)
•
Return any remaining pre-treatment and study drug and all bottles dispensed
•
Review drug compliance
•
Dispense study drug for daily dosing
•
Subject to return stool sample collected at home and ship to the central
laboratory
•
Provide stool collection kit to subject for next clinic visits
•
Subject eDiary (daily rectal bleeding, stool frequency)
•
Review subject eDiary for compliance
•
Continue adverse event monitoring


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8.2.21 Open-Label Extension: OL-Week 7 +3d (Visit OL-4) 
•
Concomitant medications
•
Concomitant procedures for UC
•
Obtain urine sample for pregnancy testing (WOCBP only)
•
Return any remaining Open-Label study drug and all bottles dispensed
•
Review study drug compliance
•
Provide stool collection kit to subject for next clinic visits
•
Dispense study drug for daily dosing
•
Subject eDiary (daily rectal bleeding, stool frequency)
•
Review subject eDiary for compliance
•
Continue adverse event monitoring
8.2.22  Open-Label Extension: OL-Week 11 +3d (Visit OL-5) 
•
Concomitant Medications
•
Concomitant Procedures for UC
•
Perform focused physical exam
•
IBDQ
•
Assess vital signs (systolic and diastolic blood pressure, heart rate, respiratory
rate, temperature)
•
Subject to return stool sample collected at home and ship to the central laboratory
•
Obtain urine sample for pregnancy testing (WOCBP only)
•
Obtain weight
•
Confirm subject has had no liquids six (6) hours prior to lower endoscopy
(flexible sigmoidoscopy or colonoscopy)
•
Confirm subject has performed bowel preparation at PI discretion (e.g. two [2]
Fleet enemas 1.5 hours before procedure)
•
Perform lower endoscopy (flexible sigmoidoscopy or colonoscopy)
•
Obtain biopsy for histopathology (3 samples)
•
Obtain biopsy for mucosal genomic analyses (1 sample)
•
Note: Three-Component Modified Mayo Score will be calculated electronically,
from subject eDiary entries and central endoscopy read
•
Return all unused study drug and any bottles dispensed
•
Review study drug compliance
•
Collect blood and ship to the central laboratory for evaluation of:
o
Hematology
o
Blood chemistry
o
CRP
•
Blood and serum for future biomedical research


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Clinical Study Protocol 
Protocol # SERES-201 
CONFIDENTIAL 
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•
Continue adverse event monitoring
•
Subject eDiary (daily rectal bleeding, stool frequency)
•
Review subject eDiary for compliance
•
End of eDiary completion; subject to leave eDiary device on-site
8.2.23 Open-Label Extension – Long-Term Safety Follow-Up: Phone Calls Every 
Four (4) Weeks for 26 Weeks/EoS +/-3d (Visits OL-6 – OL-11) 
•
During the first four (4) weeks of the Long-Term Safety Follow-Up Period,
AEs/SAEs/AESIs, concomitant procedures, and concomitant medications will be
collected
•
Continue adverse event monitoring; only SAEs/AESIs and concomitant
medications associated with the treatment of SAEs/AESIs will be collected for
the remainder of the long-term safety follow-up period.  Concomitant UC
medications and UC procedures, and any changes to these, will be collected
throughout the entirety of the Long-Term Safety Follow-Up Period.
8.2.24 Open-Label Extension: Unscheduled Visit 
See Section 8.2.25, Unscheduled Visits. 
8.2.25 Unscheduled Visits 
To accommodate scheduling of clinic visits and/or endoscopies, assessments & 
procedures for an Unscheduled Visit do not need to take place during one (1) clinic visit. 
The Unscheduled Visit may be used for dispensation of study drug, as needed.   
For subjects who experience disease worsening (as defined in Section 3.6, Disease 
Worsening), an Unscheduled Visit may be used by the PI to determine if the subject is 
experiencing a UC flare. 
The Unscheduled Visit can serve as an 'End of Treatment' visit for a subject who ends 
treatment early in the study but will continue to be followed for safety, or for subjects 
who decide to leave the study early and not be followed for safety.  If subjects decide to 
end treatment early or early terminate from the study, all study IP should be returned by 
the subject. 
8.2.25.1 Unscheduled Visit for Reasons Other than UC Flare Assessment or EoT (Pre-
Treatment, Induction, Maintenance and Open-Label) 
•
Concomitant Medications
•
Concomitant Procedures for UC
•
Continue Adverse Event Monitoring
•
Focused Physical Exam
•
IBDQ
•
Assess Vital Signs (systolic and diastolic pressure, heart rate, respiratory rate,
temperature)
•
Collect blood and ship to the central laboratory for evaluation of:


Seres Therapeutics, Inc. 
Clinical Study Protocol 
Protocol # SERES-201 
CONFIDENTIAL 
Amendment 3 
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08-Oct-2019
o
Hematology
o
Blood Chemistry
o
Blood and Serum for Future Biomedical research
•
Subject to return stool sample collected at home and ship to the central laboratory
•
Fecal calprotectin
8.2.25.2 Unscheduled Visit for UC Flare Assessment (Pre-Treatment, Induction, 
Maintenance and Open-Label) 
•
Concomitant Medications
•
Concomitant Procedures for UC
•
Continue Adverse Event Monitoring
•
Focused Physical Exam
•
IBDQ
•
Obtain urine sample for pregnancy testing (WOCBP only)
•
Assess Vital Signs (systolic and diastolic pressure, heart rate, respiratory rate,
temperature)
•
Obtain weight
•
Confirm subject has had no liquids six (6) hours prior to lower endoscopy
(flexible sigmoidoscopy or colonoscopy)
•
Confirm subject has performed bowel preparation at PI discretion (e.g. two [2]
Fleet enemas 1.5 hours before procedure)
•
Perform lower endoscopy (flexible sigmoidoscopy or colonoscopy)
•
Obtain biopsy for histopathology (3 samples)
•
Obtain biopsy for mucosal genomic analyses (1 sample)
•
Note: Three-Component Modified Mayo Score will be calculated electronically,
from subject eDiary entries and central endoscopy read
•
Collect blood and ship to the central laboratory for evaluation of:
o
Hematology
o
Blood Chemistry
o
CRP
o
Blood and Serum for Future Biomedical research
•
Subject to return stool sample collected at home (pre-liquid diet for endoscopy)
and ship to the central laboratory
•
Fecal calprotectin
•
Subject eDiary (daily rectal bleeding, stool frequency)
•
Review subject eDiary for compliance
8.2.26 End of Treatment Visit 
Perform the following assessments and procedures: 
•
Concomitant Medications
•
Concomitant Procedures for UC


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•
Perform focused physical exam
•
Assess vital signs (systolic and diastolic blood pressure, heart rate, respiratory
rate, temperature)
•
Obtain weight
•
IBDQ
•
Obtain urine sample for pregnancy testing (WOCBP only)
•
Confirm subject has had no liquids six (6) hours prior to lower endoscopy
(flexible sigmoidoscopy or colonoscopy)
•
Confirm subject has performed bowel preparation at PI discretion (e.g. two [2]
Fleet enemas 1.5 hours before procedure)
•
Perform lower endoscopy (flexible sigmoidoscopy or colonoscopy)
•
Obtain biopsy for histopathology (3 samples)
•
Obtain biopsy for mucosal genomic analyses (1 sample)
•
Note: Three-Component Modified Mayo Score will be calculated electronically,
from subject eDiary entries and central endoscopy read
•
Return all unused study drug and any bottles dispensed
•
Review study drug compliance
•
Collect blood and ship to the central laboratory for evaluation of:
o
Hematology
o
Blood Chemistry
o
CRP
o
Blood and Serum for Future Biomedical research
•
Subject to return stool sample collected at home (pre-liquid diet for endoscopy)
and ship to the central laboratory
•
Subject eDiary (daily rectal bleeding, stool frequency)
•
Review subject eDiary for compliance
8.2.27 Handling of Withdrawals and Discontinuations of Treatment 
The primary reason for withdrawal from study treatment and/or withdrawal from the 
study will be recorded in an electronic case report form (eCRF).  
Subjects who voluntarily withdraw, or who are withdrawn from the study during 
treatment (Pre-Treatment/Induction/Maintenance/Open-Label) will be encouraged to 
complete the End of Treatment Visit.  The End of Treatment Visit procedures are listed 
in Section 8.2.26, End of Treatment Visit. Although subjects are free to withdraw at any 
time, subjects will be encouraged to remain in the study for long term follow-up safety 
evaluation. 




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Protocol # SERES-201 
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o
Clinical remission co-endpoints: symptomatic remission and endoscopic
remission after 10 weeks of induction treatment
9.1.4 Exploratory Efficacy Endpoints 
•
Clinical remission at the end of maintenance treatment and at the end of open-
label treatment
•
Endoscopic improvement at the end of open-label treatment
•
Endoscopic remission at the end of maintenance treatment and at the end of open-
label treatment
•
Histological mucosal healing at the end of maintenance treatment and at the end
of open-label treatment
•
Symptomatic remission (rectal bleeding and stool frequency) over time
•
Clinical remission after 10 weeks of induction treatment for each SER-287 donor
used in the induction treatment period
•
IBDQ scores after 10 weeks of induction treatment, at the end of maintenance
treatment and at the end of open-label treatment
•
Serum biomarkers: CRP after 10 weeks of induction treatment (Week 11), at the
end of maintenance treatment and at the end of open-label treatment
•
Fecal biomarkers: fecal calprotectin levels after 10 weeks of induction treatment
(Week 11), at the end of maintenance treatment and at the end of open-label
treatment
•
Composition of the intestinal microbiome through the end of the maintenance
treatment and open-label treatment periods
•
Signatures of host and microbial functional responses through the end of the
maintenance treatment and open-label treatment periods
9.1.5 Safety Endpoints 
•
Incidence of AEs, SAEs and AESIs for each treatment and each SER-287 donor
•
Laboratory evaluation results
•
Vital sign measurements
•
Physical examination findings
9.2 
Study Subjects 
9.2.1 Disposition of Subjects 
The number and percentage of subjects entering and completing the clinical study will be 
presented, by treatment group. 
9.2.2 Protocol Deviations 
Protocol deviations will be listed by subject. 
9.2.3 Analysis Populations 
Intent-to-Treat Analysis Population: The Intent-to-Treat (ITT) Population will consist of 
all subjects who are randomly assigned, including 
those who are not exposed to any study drug, and 


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will be analyzed based on the treatment to which 
they were randomized.  The ITT population will be 
the primary analysis population for all efficacy 
endpoints. 
Modified Intent-to-Treat 1 Population: The Modified Intent-to-Treat 1 (mITT-1) 
Population will consist of all randomized subjects 
with a baseline evaluation, who have active mild-
to-moderate UC and receive any amount of study 
drug, and will be analyzed based on the treatment 
to which they were randomized.   
Modified Intent-to-Treat 2 Population: The Modified Intent-to-Treat 2 (mITT-2) 
Population will consist of all randomized subjects 
with a baseline evaluation, who have active mild-
to-moderate UC and receive any amount of study 
drug, and will be analyzed based on the treatment 
to which they are randomized.  Subjects who are 
confirmed to have normal histology at baseline will 
be excluded from this analysis population. 
Per Protocol Population:  
The Per Protocol (PP) Population will consist of 
subjects from the mITT-2 Population who do not 
have any major protocol deviations.  The details of 
the PP Population will be provided in the SAP and 
defined before unblinding of the data. 
Microbiome Modified Intent-to-Treat: The Microbiome Modified Intent-to-Treat 
(mcITT) Population will be used for analysis of 
microbiome data.  It will consist of all randomized 
subjects with an evaluable stool sample collected at 
baseline, and at least one (1) evaluable stool sample 
collected after the start of dosing, who are exposed 
to any amount of study drug, and will be analyzed 
based on the treatment to which they are 
randomized. 
Safety Population: 
The Safety Population will consist of all subjects 
who receive any amount of study drug.  Subjects 
will be analyzed according to the treatment they 
actually received, rather than the treatment to which 
they are randomly assigned.  All safety analyses 
will be conducted based on the Safety Population. 
All clinical efficacy analyses will be conducted in the ITT population, and in the mITT-1, 
mITT-2, PP and Safety populations as sensitivity analyses, as appropriate. 
All microbiome alterations analyses will be conducted in the mcITT population. 


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9.3 
Multiplicity Adjustment 
Adjustments for multiple testing will be made to test the primary efficacy and key 
secondary efficacy endpoints.  A fixed-sequence method will be used to maintain a 
study-wide 2-sided Type I error rate of 0.05.  Testing of the key hypotheses will be 
conducted in the following order, all at the same significance level (2-sided α = 0.05): 
1.
H01: No difference in clinical remission rates after 10 weeks of induction
treatment between Arm B (SER-287 at Induction Dose after pre-treatment with
vancomycin) vs. Arm A (pre-treatment with placebo followed by treatment with
placebo) in the ITT population
2.
H02: No difference in clinical remission rates after 10 weeks of induction
treatment between Arm C (SER-287 at Step-Down Induction Dose after pre-
treatment with vancomycin) vs. Arm A (pre-treatment with placebo followed by
treatment with placebo) in the ITT population
3.
H03: No difference in endoscopic improvement rates after 10 weeks of induction
treatment between Arm B (SER-287 at Induction Dose after pre-treatment with
vancomycin) vs. Arm A (pre-treatment with placebo followed by treatment with
placebo) in the ITT population
4.
H04: No difference in endoscopic improvement rates after 10 weeks of induction
treatment between Arm C (SER-287 at Step-Down Induction Dose after pre-
treatment with vancomycin) vs. Arm A (pre-treatment with placebo followed by
treatment with placebo) in the ITT population
Testing of later hypotheses in the sequence stops as soon as failure to show statistical 
significance at the 2-sided 0.05 level is observed in a hypothesis earlier in the sequence. 
9.4 
General Considerations 
All clinical efficacy, safety and tolerability, intestinal microbiome, and biomarker data 
will be listed and presented in descriptive summaries by treatment arm, visit and time 
point. At a minimum, continuous data will be summarized by study arm using descriptive 
statistics (number of subjects, mean, standard deviation, minimum, median and 
maximum).  Categorical data will be summarized by study arm using frequency tables 
(number of subjects and percentage). 
Selected clinical efficacy and biomarker data will be presented in treatment mean (+/-
standard deviation [SD]) profile plots.   
All statistical analyses will be performed using SAS® Version 9.3 or later. 
9.5 
Efficacy Analyses 
9.5.1 Timing of Analyses 
9.5.1.1 At the end of the Induction Treatment period 
Seres will conduct an unblinded analysis of the efficacy and safety endpoints when all 
planned subjects in the study are enrolled, have been evaluated for the primary/key 


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secondary efficacy endpoints and have completed their Induction Treatment (Week 11 
[Visit 7]) or have terminated from the study prematurely prior to the Week 11 [Visit 7]. 
Key unblinded efficacy and safety summary tables will be generated at this time.  
Limited personnel at Seres will have access to the unblinded tables, listings and figures 
(TLFs).   A detailed unblinding plan will be drafted and finalized at the same time that 
the SAP is finalized.  
All clinical data generated during the primary study period (Screening Visit 1 through 
Week 11 [Visit 7]) for all subjects enrolled in the study will be entered in the database, 
cleaned and locked prior to the unblinding.  No changes to any locked data in the 
database will be permitted, unless deemed to be highly warranted. Therefore, all efficacy 
results evaluated up until this primary study period will be considered final.  A 
comparison of the data at the time of this unblinding and at the end of the study will be 
performed.  An audit trail of any changes made to the locked data will be available.  
9.5.1.2 At the end of the Maintenance Treatment period 
Seres will conduct an unblinded analysis of the safety and exploratory efficacy endpoints 
when all subjects who were re-randomized in the maintenance arm have been evaluated 
for the exploratory efficacy endpoints, and have completed their maintenance treatment, 
or have terminated the study prematurely prior to Week 37 (Visit M-7). 
Key unblinded efficacy and safety summary tables will be generated at this time.  
Limited personnel at Seres will have access to the unblinded tables, listings and figures 
(TLFs).    
All clinical data generated during the maintenance period (Week 11 through Week 37 
[Visit M-7]) for all subjects enrolled in the maintenance arm will be entered in the 
database, cleaned and locked prior to the unblinding.  No changes to any locked data in 
the database will be permitted, unless deemed to be highly warranted.  Therefore, all 
efficacy results evaluated up until this time for the maintenance arm will be considered 
final at the time of the analysis.  A comparison of the data at the time of this unblinding 
and at the end of the study will be performed.  An audit trail of any changes made to the 
locked data will be available. 
9.5.1.3 At the end of the Long-Term Safety Follow-Up period 
At the end of the Long-Term Safety Follow-Up period, after final database lock, all AE 
summary tables will be re-generated to include any additional safety findings from this 
period.  All other TLFs will also be re-run to ensure that any changes to the database that 
may have occurred since the earlier analyses are reflected in the final TLFs.  All changes 
in the efficacy results from the previous analyses will be described in the Clinical Study 
Report (CSR). 
9.5.2 Statistical Analysis and Significance Level 
Statistical significance tests, if reported, will be two-sided and will be presented as 
relative measures of the strength of association to the active SER-287 treatment arm 
(Arms B and C) for comparison with the placebo arm (Arm A) among study endpoints.  


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Details of the statistical analysis will be addressed in the SAP, finalized prior to the time 
the primary study period data is declared complete and final and any study unblinding. 
9.5.3 Missing or Spurious Data 
Every effort will be made to collect all data at specified timepoints, according to the 
schedule of study events. 
For analysis of the binary efficacy endpoints (i.e. clinical remission, endoscopic remission 
and clinical remission with normalization of stool frequency during the induction period), 
subjects with missing values will be assigned an outcome of failure for the endpoint, if  
(i)
the subject discontinued study treatment prior to Study Day 48, OR
(ii)
did not have a post-baseline endoscopy done during the induction period, OR
(iii)
if data is missing for any of the subscores needed for the Week 11 assessments
at the end of the induction period, such that the endpoint cannot be calculated.
The description of the handling of missing data for individual components of the Three-
Component Modified Mayo Score, specifically stool frequency and rectal bleeding, are 
described in Appendix 2. 
As sensitivity analyses, the primary endpoint and the key secondary endpoint will also be 
analyzed based on the last observation carried forward (LOCF) approach. Subjects who 
only have baseline values will be treated as failures for the endpoint in the LOCF 
analysis. The observed-case analyses will also be conducted where missing values will 
be excluded in the analyses. 
For continuous secondary endpoints, such as histological mucosal healing, missing 
values will not be imputed. The analyses will be based on the observed-case data where 
missing values will be excluded in the analyses. 
Handling of missing data for other endpoints will be specified in the SAP. 
9.5.4 Analysis of the Primary Efficacy Endpoint 
The primary efficacy outcome measure for this study will be the difference in clinical 
remission rates after 10 weeks of induction treatment between SER-287 (Induction Dose 
after pre-treatment with vancomycin – Arm B) and placebo (Arm A).  The primary 
efficacy endpoint analysis will be based on the CMH test, stratified by endoscopic score 
at baseline (1-2 vs. 3), and UC medications at baseline (5-ASA alone vs. 
immunomodulators with or without 5-ASA vs. none) in the ITT population. 
9.5.5 Analysis of the Key Secondary Efficacy Endpoints 
The key secondary efficacy endpoints will be analyzed using the same method used for 
the primary efficacy endpoint. 
Sensitivity Analyses for the primary and key secondary efficacy endpoint will be 
performed in the mITT-1, mITT-2, Safety and PP populations. 


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9.5.6 Analyses of Other Secondary Efficacy Endpoints 
All other dichotomous secondary efficacy endpoints will be analyzed using the same 
method used for the primary efficacy endpoint. 
For histological mucosal healing, analysis will be based on the change from baseline 
score using RHI (Mosli et al., 2017) and analyzed by an analysis of covariance 
(ANCOVA) test, with treatment, endoscopic score at baseline and UC medications at 
baseline as factors in the model.  The primary analysis population for this endpoint will 
be the mITT-2 population. 
All clinical efficacy analyses will be conducted in the ITT population, unless otherwise 
stated, and in the mITT-1, mITT-2 and PP populations as sensitivity analyses, as 
appropriate. 
9.5.7 Analyses of Exploratory Endpoints 
Details of the methods used for the analyses of the exploratory endpoints will be 
provided in the SAP. 
9.6 
Safety Analyses 
9.6.1 Adverse Events 
A TEAE is any adverse event (AE) that newly appeared, increased in frequency, or 
worsened in severity after initiation of study drug (including the pre-treatment period). 
Safety summaries of TEAEs will be presented by treatment group at the end of the pre-
treatment period (Week 1), Week 3, Week 7, after 10 weeks of induction treatment 
(Week 11), at the end of Maintenance Treatment or Open-Label Treatment and at end-of-
study, with selected safety summaries also presented by baseline endoscopic subscore 
and baseline UC medication stratum.  The number and percentage of subjects with 
TEAEs will be tabulated by system organ class and preferred term (PT) for each 
treatment group and stratum.  Serious TEAEs, AESIs and TEAEs leading to study 
discontinuation will be similarly tabulated.  Summaries of TEAEs by maximum severity 
and by maximum relationship to study drug will also be summarized by system organ 
class and PT.  
Selected safety summaries will also be provided by SER-287 donor. 
A listing of all TEAEs will be provided. 
All safety analyses will be conducted in the Safety Population, unless specified 
otherwise.  Subjects will be analyzed according to the treatment they actually received, 
rather than that to which they are randomly assigned.  Adverse events will be coded by 
using the Medical Dictionary for Regulatory Activities (MedDRA).   


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9.6.2 Clinical Laboratory Tests 
All scheduled and unscheduled laboratory results will be presented for each subject, 
sorted by category, subject, test and sample time.  Flags will be attached to values 
outside of the laboratory’s reference limits along with the Investigator’s assessment.  A 
separate listing of abnormal results will be presented, ordered by test, subject and sample 
time. 
Quantitative chemistry and hematology tests (observed values and change from baseline) 
will be summarized descriptively in tabular format.  A shift table will be presented for 
chemistry, hematology and urinalysis tests shift from baseline to each post-baseline visit 
and also the shift from baseline to highest and to lowest post-baseline assessment. 
9.6.3 Vital Signs 
Individual data listings of vital signs (observed and change from baseline) will be 
presented for each subject.  Descriptive statistics of the vital signs will be presented by 
treatment group for all study visits at which they were collected.  The change from 
baseline to each post-baseline visit will also be summarized by treatment group. 
9.6.4 Physical Examination Findings 
Abnormal clinically significant physical examination (PE) finding will be reported as 
medical history (MH) or as an AE.  
9.6.5 Pharmacokinetic Analyses 
Not applicable 
9.7 
Gastrointestinal Tract Microbiome 
The gastrointestinal microbiome of subjects will be characterized using genomic data 
sets generated from stool collected at the time points defined above in the Schedule of 
Events.  Genomic data sets will define the microbial composition of the microbiome of a 
subject at a given time point.  Genomic sequence read data sets will be analyzed to assign 
a taxonomic identity at the resolution of phylogenetic clade and/or species and further, to 
define the relative proportion of each species or taxon relative to all other species or taxa 
in a given sample.  Engraftment of SER-287 taxa will be measured and analyzed as 
defined in Section 9.7.1, Microbiome Secondary Endpoint Data Analysis. 
9.7.1 Microbiome Secondary Endpoint Data Analysis 
Engraftment of spore-forming bacteria in SER-287 will be assessed by examining the 
richness of spore-forming taxa found in drug product lots which appear newly in subject 
stool at one (1) or more timepoints after the initiation of treatment with SER-287 
(∆Sobs_spore_dose).  The nonparametric one-sided Mann-Whitney U test will be used to 
determine if there is a greater change in ∆Sobs_spore_dose in subjects receiving 
SER-287 relative to subjects receiving placebo. 
Further details will be included in the microbiome SAP. 


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9.8 
Interim Analyses 
Two unblinded analyses will be conducted prior to the completion of the entire study, 
specifically at the end of the induction period and at the end of the maintenance period.  
Please refer to Section 9.5.1, Timing of Analyses, for further details on these analyses.  
9.9 
Determination of Sample Size 
The planned sample size for this study is 67 subjects per treatment arm for a total sample 
size of 201 subjects. Assuming a clinical remission rate of 29% in the SER-287 arms and 
a clinical remission rate of 9% in the placebo arm, this sample size will provide 86% 
power to detect a difference of 20% in clinical remission rates between SER-287 to 
placebo, using a 2-sided significance level of 0.05. 
A placebo rate of 7% was derived from the weighted average of the placebo rates 
observed in the tofacitinib Phase 2 (Sandborn et al., 2012), 3A and 3B (Sandborn et al., 
2017) studies, and the ozanimod induction studies (Sandborn et al., 2016).  These 
four (4) studies were chosen as the basis for the placebo rate because each utilized a 
central reader to determine subjects’ endoscopic subscores.  However, due to the 
inclusion of mild subjects and those with an endoscopic subscore of 1 in the SERES-201 
study, who may have a higher placebo response rate, the assumed placebo rate was 
increased to 9%.  The clinical remission rate that was used for the SER-287 arm was 
based on the re-analysis of the clinical remission rate in the vancomycin/SER-287 daily 
arm in the SERES-101 Phase 1B study, and applying the definition of clinical remission 
for the SERES-201 study; additionally, only subjects with a baseline Three-Component 
Modified Mayo Score between 3 and 7, inclusive, and a baseline stool frequency 
subscore ≥1 were included, (38.5% with 95% CI: 15.1%, 67.7%).  The clinical remission 
rate was decreased to 29% to account for the small sample size in this SERES-101 arm 
(n=13).   


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10 ADMINISTRATIVE REQUIREMENTS 
10.1 Good Clinical Practice 
The study will be conducted in accordance with the International Conference on 
Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and the appropriate 
regulatory requirement(s).  The Investigator will be thoroughly familiar with the 
appropriate use of the Investigational product.  Essential clinical documents will be 
maintained to demonstrate the validity of the study and integrity of the data collected.  
Master files will be established at the beginning of the study, maintained for the duration 
of the study, and retained according to the appropriate regulations. 
•
The Principal Investigator has the overall responsibility for the conduct and
administration of the study at the clinical site and for contacts with the sponsor, the
IRB/IEC, and local authorities.
•
The Principal Investigator is responsible for ensuring the privacy, health, and welfare
of the subjects during and after the clinical study.
•
All Investigators are responsible for performing the study in accordance with the
protocol and the above guidelines and regulations, and for collecting, documenting,
and reporting the data accurately.
•
All Investigators must be familiar with the background and requirements of the study
and with the properties of the investigational product as described in the current
version of the Investigator’s Brochure
•
The Principal Investigator is responsible for distributing study information and
documentation to all appropriate staff members before and during the course of the
study as updated information becomes available.
10.2 Ethical Considerations 
The study will be conducted in accordance with ethical principles in the Belmont Report, 
and in compliance with local IRB/IEC requirements and institutional guidelines. 
The Investigator must obtain IRB/IEC approval of the protocol, informed consent form 
(ICF), and other required study documentation before starting the study.  It is the 
responsibility of the Investigator to ensure that all aspects of IRB/IEC review are 
conducted in accordance with current governmental regulations. 
A progress report must be submitted to the IRB/IEC at the required intervals and not less 
than annually.  At the completion or termination of the study, the Investigator must 
submit a closeout letter to the IRB/IEC. 
10.3 Subject Information and Informed Consent 
Before any testing under this protocol, including screening tests and assessments, written 
informed consent with the IRB/IEC-approved ICF must be obtained from the subject, in 
accordance with local practice and regulations. 


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The background of the proposed study, procedures, and benefits and risks of the study 
must be explained to the subject.  The subject must be given sufficient time to consider 
whether to participate in the study. 
A copy of the ICF, signed and dated by the subject, must be given to the subject.  Each 
ICF should contain an authorization allowing the Investigator to use and disclose subject 
health information (i.e., subject-identifiable health information) in compliance with local 
law. 
10.4 Subject Confidentiality 
Subject confidentiality is held strictly in trust by the Investigator and medical and 
laboratory staff.  This confidentiality is extended to cover testing of biological samples in 
addition to the clinical information relating to participating subjects.  The Investigator 
will grant regulatory authority(ies) access to the subject’s original medical records for 
verification of data gathered and to audit the data collection process.  The subjects’ and 
donors’ confidentiality will be maintained and will not be made publicly available to the 
extent permitted by the applicable laws and regulations. 
Subjects will not be identified by name in any study reports, and these reports will be 
used for research purposes only. 
10.5 Protocol Compliance 
The Investigator will conduct the study in compliance with the IRB/IEC-approved 
protocol without any changes or deviations.  Modifications to the protocol will require 
approval from the sponsor and written IRB/IEC approval before implementation, except 
when the modification is needed to eliminate an immediate hazard to the subject.  Any 
change, intentional or otherwise, must be reported immediately to the sponsor and to the 
relevant IRB/IEC and/or regulatory authority as required by guidelines or regulation.  
Sites that fail to comply may be terminated. 
10.6 Future Use of Stored Specimens 
The sponsor may, where permitted by local regulations, conduct future biomedical 
research on specimens (including blood, serum, stool and biopsies) routinely and 
specifically collected during this clinical study that may be used for potential commercial 
use by Seres Therapeutics and may be stored for up to 10 years.  This research may 
include genetic analyses (deoxyribonucleic acid [DNA]) and/or the measurement of other 
analytes. 
10.7 Study Monitoring 
Regular monitoring is defined in ICH Guidance for Industry E6 R2 Good Clinical 
Practice: Consolidated Guidance, Section 1.38, as “The act of overseeing the progress of 
a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance 
with the protocol, standard operating procedures, GCP, and the applicable regulatory 
requirement(s).”  The purpose of monitoring is to verify that: 


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•
Rights and wellbeing of the human subjects are protected.
•
The reported study data are accurate, complete, and verifiable from source
documents.
•
The conduct of the study is in compliance with the currently approved
protocol/amendment(s), with GCP, and with the applicable regulatory requirements.
It will be the responsibility of the Investigator to ensure that the essential documents are 
available at the investigator or institutional site.  Any or all of these documents may be 
pertinent to, and should be available for, monitoring by the sponsor or inspection by the 
regulatory authorities as defined in the monitoring plan. 
The sponsor or an authorized sponsor representative will conduct regular site monitoring 
visits to review and validate study data as defined in the monitoring plan by reviewing 
subjects’ medical records and eCRFs in accordance with written standard operating 
procedures, ICH guidelines, GCP, and applicable regulations and guidelines.  The 
Investigator will allow representatives of the sponsor or regulatory authorities to inspect 
facilities and records relevant to this study. 
10.8 Case Report Forms and Study Records 
Data will be collected for this study by using an eCRF.  The Investigator and study site 
staff will receive training and support on the use of the eCRF.  All eCRF data are to be 
completed by the study coordinator or other designated site personnel.  All data entry, 
modification, or deletion will be recorded automatically in the electronic audit trail.  All 
data changes will be clearly indicated with a means to locate prior values.  A unique user 
identification and password will be assigned to all personnel approved to enter or change 
data to prevent unauthorized access to the data.  
All electronic data entered by the site (including the electronic audit trail) will be 
maintained or made available at the site in compliance with Title 21 Part 11 of the Code 
of Federal Regulations (CFR) and other applicable retention regulations.  The 
computerized system must be able to generate accurate and complete copies of records in 
paper or electronic form for inspection and review by applicable regulatory authorities, 
the IRB/IEC/Research Ethics Board, and auditors or other designees authorized by the 
sponsor.  
In addition to capturing the user identification as part of the audit trail for all data entry, 
the eCRF will allow for application of electronic signatures.  The Investigator or 
designated Sub-Investigator, after review of the data in the eCRF, will confirm the 
validity of each subject’s data by electronic signature.  This electronic signature will be 
certified as outlined in 21 CFR Part 11. 
The sponsor will retain the original eCRF data and audit trail.  An electronic or certified 
paper copy of all completed eCRF data, including query resolution correspondence, will 
be provided to the Investigator at the end of the study. 


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10.9 Study Completion  
The sponsor requires the following data and materials to be submitted before a study can 
be considered complete or terminated: 
•
Laboratory findings, clinical data, and all special test results from informed consent
through End-of-Study
•
Electronic CRFs properly completed by appropriate study personnel and signed and
dated by the Investigator
•
Complete study drug accountability records
•
Copies of IRB/IEC approval and notification of the original protocol and of any
protocol amendments, if appropriate
•
A summary of the study prepared by the Investigator (an IRB/IEC summary letter is
acceptable)


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changes in the composition of the intestinal microbiota in humans. PloS One 8, e59260. 
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Loessner, M.J., Rogler, G., and Schuppler, M. (2014). Smoking cessation alters intestinal 
microbiota: insights from quantitative investigations on human fecal samples using 
FISH. Inflamm. Bowel Dis. 20, 1496–1501. 
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Panaccione, R., Steinhart, A.H., Tse, F., and Feagan, B. (2015). Clinical Practice 
Guidelines for the Medical Management of Nonhospitalized Ulcerative Colitis: The 
Toronto Consensus. Gastroenterology. 148, 1035-1058. 
Caballero, S., and Pamer, E.G. (2015). Microbiota-Mediated Inflammation and 
Antimicrobial Defense in the Intestine. Annual Review of Immunology 33, 227–256. 
Danese, S., and Fiocchi, C. (2011). Ulcerative colitis. N. Engl. J. Med. 365, 1713–1725. 
European Medicines Agency Committee for Medicinal Products for Human Use 
(CHMP). (2018). Guideline on the development of new medicinal products for the 
treatment of Ulcerative Colitis (EMA London, UK). 
Food and Drug Administration Center for Drugs Evaluation Research (CDER). (2016). 
Guidance for Industry: Ulcerative Colitis: Clinical Trial Endpoints (FDA Maryland). 
Frank, D.N., St. Amand, A.L., Feldman, R.A., Boedeker, E.C., Harpaz, N., and Pace, 
N.R. (2007). Molecular-phylogenetic characterization of microbial community 
imbalances in human inflammatory bowel diseases. Proc. Natl. Acad. Sci. U. S. A. 104, 
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Geboes K., Riddell R., Ost A., Jensfelt B., Persson T., Löfberg R. (2000). A reproducible 
grading scale for histological assessment of inflammation in ulcerative colitis. Gut. 
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Ghosh, S., and Mitchell, R. (2007). Impact of inflammatory bowel disease on quality of 
life: Results of the European Federation of Crohn’s and Ulcerative Colitis Associations 
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Grinspan, A., and Kornbluth, A. (2015). Positioning Therapy for Ulcerative Colitis. Curr. 
Gastroenterol. Rep. 17, 29. 
Guyatt G, Mitchell A, Irvine EJ, Singer J, Williams N, Goodacre R, Tompkins C. (1989). 
A New Measure of Health Status for Clinical Trials in Inflammatory Bowel Disease. 
Gastroenterology. 96(3), 804-10. 


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Halfvarson, J., Brislawn, C.J., Lamendella, R., Vázquez-Baeza, Y., Walters, W.A., 
Bramer, L.M., D’Amato, M., Bonfiglio, F., McDonald, D., Gonzalez, A., et al. (2017). 
Dynamics of the human gut microbiome in inflammatory bowel disease. Nature 
Microbiology 2, 17004. 
Human Microbiome Project Consortium (2012). Structure, function and diversity of the 
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Machiels, K., Joossens, M., Sabino, J., De Preter, V., Arijs, I., Eeckhaut, V., Ballet, V., 
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producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis 
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Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a 
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bowel disease. Nature 448, 427–434. 


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12 APPENDICES 
12.1 Appendix 1: Mayo Score (Schroeder et al., 1987) 
Stool frequency*  
0= Normal no. of stools for this patient 
1= 1-2 stools more than normal  
2= 3-4 stools more than normal  
3= 5 or more stools more than normal 
Rectal bleeding**
0= No blood seen 
1= Streaks of blood with stool less than half the time 
2= Obvious blood with stool most of the time 
3= Blood alone passed 
Findings of flexible proctosigmoidoscopy  
0= Normal or inactive disease 
1= Mild disease (erythema, decreased vascular pattern, mild friability)  
2= Moderate disease (marked erythema, absent vascular pattern, friability, erosions) 
3= Severe disease (spontaneous bleeding, ulceration)  
Physician’s global assessment*** 
0= Normal 
1= Mild disease 
2= Moderate disease  
3= Severe disease  
* Each patient served as his or her own control to establish the degree of abnormality of the stool
frequency.
** The daily bleeding score represented the most severe bleeding of the day. 
*** The physician’s global assessment acknowledged the three other criteria, the patient’s record of 
abdominal discomfort and general sense of well-being, and other observations, such as physical findings 
and the patient’s performance status. 
Schroeder, K.W., Tremaine, W.J., Ilstrup, D.M., (1987). Coated Oral 5-Aminosalicylic Acid Therapy for 
Mildly to Moderately Active Ulcerative Colitis. N. Engl. J. Med. 317(26), 1625-1629. 






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12.3 Appendix 3: Inflammatory Bowel Disease Questionnaire (Guyatt et al., 1989) 
INSTRUCTIONS FOR SELF-ADMINISTERED IBDQ 
This questionnaire is designed to measure the effects of your inflammatory bowel disease 
on your daily function and quality of life. You will be asked about symptoms you have 
been having as a result of your bowel disease, the way you have been feeling in general, 
and how your mood has been.  
There are two versions of this questionnaire, the IBDQ and IBDQ-Stoma. If you have a 
colostomy or ileostomy, you should complete the IBDQ-Stoma. Questions 1, 5, 17, 22, 
24 and 26 are slightly different in each version. Be sure you have the correct 
questionnaire.  
On this questionnaire there are 32 questions. Each question has a graded response 
numbered from I through 7. Please read each question carefully and answer the number 
which best describes how you have been feeling in the past 2 weeks.  
EXAMPLE 
How often have you felt unwell as a result of your bowel problem in the past 2 weeks? 
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  
If you are having trouble understanding a question, STOP for a moment! Think about 
what the question means to you. How is it affected by your bowel problem? Then answer 
the question as best you can. You will have the chance to ask the research assistant 
questions after completing the questionnaire. This takes only a few minutes to complete.  
Copyright © 1989 McMaster University, Hamilton, Ontario, Canada 
The Inflammatory Bowel Disease Questionnaire (IBDQ), authored by Dr. Jan Irvine et al, is the copyright of McMaster University 
(Copyright ©1989, McMaster University). The IBDQ has been provided under license from McMaster University and must not be 
copied, distributed or used in any way without the prior written consent of McMaster University.   
Contact the McMaster Industry Liaison Office at McMaster University, email: milo@mcmaster.ca for licensing details. 


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QUALITY OF LIFE IN INFLAMMATORY BOWEL DISEASE 
QUESTIONNAIRE (IBDQ) 
This questionnaire is designed to find out how you have been feeling during the last 
2 weeks. You will be asked about symptoms you have been having as a result of your 
inflammatory bowel disease, the way you have been feeling in general, and how your 
mood has been.  
1. How frequent have your bowel movements been during the last two weeks? Please
indicate how frequent your bowel movements have been during the last two weeks by
picking one of the options from
1 BOWEL MOVEMENTS AS OR MORE FREQUENT THAN THEY HAVE EVER 
BEEN  
2 EXTREMELY FREQUENT  
3 VERY FREQUENT  
4 MODERATE INCREASE IN FREQUENCY OF BOWEL MOVEMENTS  
5 SOME INCREASE IN FREQUENCY OF BOWEL MOVEMENTS  
6 SLIGHT INCREASE IN FREQUENCY OF BOWEL MOVEMENTS  
7 NORMAL, NO INCREASE IN FREQUENCY OF BOWEL MOVEMENTS 
2. How often has the feeling of fatigue or of being tired and worn out been a problem for
you during the last 2 weeks?  Please indicate how often the feeling of fatigue or tiredness
has been a problem for you during the last 2 weeks by picking one of the options from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  


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3. How often during the last 2 weeks have you felt frustrated, impatient, or restless?
Please choose an option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  
4. How often during the last 2 weeks have you been unable to attend school or do your
work because of your bowel problem?  Please choose an option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  
5. How much of the time during the last 2 weeks have your bowel movements been
loose?  Please choose an option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  


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6. How much energy have you had during the last 2 weeks?  Please choose an option
from
1 NO ENERGY AT ALL  
2 VERY LITTLE ENERGY  
3 A LITTLE ENERGY  
4 SOME ENERGY  
5 A MODERATE AMOUNT OF ENERGY 
6 A LOT OF ENERGY  
7 FULL OF ENERGY  
7. How often during the last 2 weeks did you feel worried about the possibility of
needing to have surgery because of your bowel problem.  Please choose an option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  
8. How often during the last 2 weeks have you had to delay or cancel a social
engagement because of your bowel problem?  Please choose an option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  


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9. How often during the last 2 weeks have you been troubled by cramps in your
abdomen? Please choose an option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  
10. How often during the last 2 weeks have you felt generally unwell?  Please choose an
option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  
11. How often during the last 2 weeks have you been troubled because of fear of not
finding a washroom?  Please choose an option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  


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12. How much difficulty have you had, as a result of your bowel problems, doing leisure
or sports activities you would have liked to have done during the last 2 weeks?  Please
choose an option from
1 A GREAT DEAL OF DIFFICULTY; ACTIVITIES MADE IMPOSSIBLE 
2 A LOT OF DIFFICULTY  
3 A FAIR BIT OF DIFFICULTY  
4 SOME DIFFICULTY  
5 A LITTLE DIFFICULTY  
6 HARDLY ANY DIFFICULTY  
7 NO DIFFICULTY; THE BOWEL PROBLEMS DID NOT LIMIT SPORTS OR 
LEISURE ACTIVITIES  
13. How often during the last 2 weeks have you been troubled by pain in the abdomen?
Please choose an option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  
14. How often during the last 2 weeks have you had problems getting a good night's
sleep, or been troubled by waking up during the night?  Please choose an option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  


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15. How often during the last 2 weeks have you felt depressed or discouraged? Please
choose an option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  
16. How often during the last 2 weeks have you had to avoid attending events where
there was no washroom close at hand?  Please choose an option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  
17. Overall, in the last 2 weeks, how much of a problem have you had with passing large
amounts of gas?  Please choose an option from
1 A MAJOR PROBLEM  
2 A BIG PROBLEM  
3 A SIGNIFICANT PROBLEM 
4 SOME TROUBLE  
5 A LITTLE TROUBLE  
6 HARDLY ANY TROUBLE  
7 NO TROUBLE  


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18. Overall, in the last 2 weeks, how much of a problem have you had maintaining or
getting to, the weight you would like to be at. Please choose an option from
1 A MAJOR PROBLEM  
2 A BIG PROBLEM  
3 A SIGNIFICANT PROBLEM 
4 SOME TROUBLE  
5 A LITTLE TROUBLE  
6 HARDLY ANY TROUBLE  
7 NO TROUBLE  
19. Many patients with bowel problems often have worries and anxieties related to their
illness. These include worries about getting cancer, worries about never feeling any
better, and worries about having a relapse.  In general, how often during the last 2 weeks
have you felt worried or anxious?  Please choose an option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  
20. How much of the time during the last 2 weeks have you been troubled by a feeling of
abdominal bloating?  Please choose an option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  


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21. How often during the last 2 weeks have you felt relaxed and free of tension?  Please
choose an option from
1 NONE OF THE TIME  
2 A LITTLE OF THE TIME  
3 SOME OF THE TIME  
4 A GOOD BIT OF THE TIME  
5 MOST OF THE TIME  
6 ALMOST ALL OF THE TIME 
7 ALL OF THE TIME  
22. How much of the time during the last 2 weeks have you had a problem with rectal
bleeding with your bowel movements?  Please choose an option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  
23. How much of the time during the last 2 weeks have you felt embarrassed as a result
of your bowel problem? Please choose an option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  


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24. How much of the time during the last 2 weeks have you been troubled by a feeling of
having to go to the bathroom even though your bowels were empty?  Please  choose an
option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  
25. How much of the time during the last 2 weeks have you felt tearful or upset?  Please
choose an option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  
26. How much of the time during the last 2 weeks have you been troubled by accidental
soiling of your underpants? Please choose an option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  


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27. How much of the time during the last 2 weeks have you felt angry as a result of your
bowel problem?  Please choose an option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  
28. To what extent has your bowel problem limited sexual activity during the last 2
weeks?  Please choose an option from
1 NO SEX AS A RESULT OF BOWEL DISEASE  
2 MAJOR LIMITATION AS A RESULT OF BOWEL DISEASE  
3 MODERATE LIMITATION AS A RESULT OF BOWEL DISEASE  
4 SOME LIMITATION AS A RESULT OF BOWEL DISEASE  
5 A LITTLE LIMITATION AS A RESULT OF BOWEL DISEASE  
6 HARDLY ANY LIMITATION AS A RESULT OF BOWEL DISEASE 
7 NO LIMITATION AS A RESULT OF BOWEL DISEASE  
29. How much of the time during the last 2 weeks have you been troubled by nausea or
feeling sick to your stomach?  Please choose an option. from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  


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30. How much of the time during the last 2 weeks have you felt irritable? Please choose
an option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  
31. How often during the past 2 weeks have you felt a lack of understanding from others?
Please choose an option from
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 HARDLY ANY OF THE TIME 
7 NONE OF THE TIME  


Seres Therapeutics, Inc. 
Clinical Study Protocol 
Protocol # SERES-201 
CONFIDENTIAL 
Amendment 3 
116 of 116 
08-Oct-2019
32. How satisfied, happy, or pleased have you been with your personal life during the
past 2 weeks? Please choose one of the following options from
1 VERY DISSATISFIED, UNHAPPY MOST OF THE TIME 
2 GENERALLY DISSATISFIED, UNHAPPY  
3 SOMEWHAT DISSATISFIED, UNHAPPY  
4 GENERALLY SATISFIED, PLEASED  
5 SATISFIED MOST OF THE TIME, HAPPY  
6 VERY SATISFIED MOST OF THE TIME, HAPPY  
7 EXTREMELY SATISFIED, COULD NOT HAVE BEEN MORE HAPPY OR 
PLEASED 
Copyright © 1989 McMaster University, Hamilton, Ontario, Canada 
The Inflammatory Bowel Disease Questionnaire (IBDQ), authored by Dr. Jan Irvine et al, is the copyright of McMaster University 
(Copyright ©1989, McMaster University). The IBDQ has been provided under license from McMaster University and must not be 
copied, distributed or used in any way without the prior written consent of McMaster University.   
Contact the McMaster Industry Liaison Office at McMaster University, email: milo@mcmaster.ca for licensing details. 
Guyatt G, Mitchell A, Irvine EJ, Singer J, Williams N, Goodacre R, Tompkins C. (1989). A New Measure 
of Health Status for Clinical Trials in Inflammatory Bowel Disease. Gastroenterology. 96(3), 804-10. 

SAP_001.pdf: 
 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
1 of 61 
 
21-APR-2021 
Confidential 
v 5.0 
 
Statistical Analysis Plan 
 
 
Protocol Number and Title: 
 
ECO-RESET: A Phase 2B, Randomized, Double-
Blind, Placebo-Controlled, Multiple Dose, 
Multicenter Study to Assess Efficacy and Safety of 
SER-287 in Adults with Active Mild-to-Moderate 
Ulcerative Colitis (SERES 201) 
 
 
Protocol Version and Date: 
Amendment 3 
8-October-2019 
 
 
Author(s): 
 
 
 
SAP Version: 
5.0 
 
SAP Version Date:  
21-April-2020 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Seres Therapeutics, Inc. Acceptance of this 
document constitutes agreement by the recipient that no information contained herein will be published or disclosed 
without prior written authorization from an official of Seres Therapeutics, Inc.  However, this document may be 
disclosed to appropriate Institutional Review Board and Ethics Committees or duly authorized representatives of a 
national regulatory authority under the condition that they are requested to keep it confidential. In the event of an 
actual or suspected breach of this obligation, Seres Therapeutics, Inc. should be notified promptly. 
 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
2 of 61 
 
21-APR-2021 
Confidential 
v 5.0 
 
 
I confirm that I have reviewed this document and agree with the content. 
 
APPROVALS 
Author 
 
 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
3 of 61 
 
21-APR-2021 
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v 5.0 
TABLE OF CONTENTS 
GLOSSARY OF ABBREVIATIONS ................................................................................ 7 
1. 
STUDY DESIGN .................................................................................................... 10 
2. 
PURPOSE .............................................................................................................. 11 
2.1. 
TIMINGS OF ANALYSES ............................................................................................................. 12 
2.1.1. 
At the end of the Induction Treatment period .................................................................................. 12 
2.1.2. 
At the end of the Maintenance Treatment and Open-Label Treatment periods, whichever is later ........ 12 
2.1.3. 
At the end of the Long-Term Safety Follow-Up period .................................................................... 13 
3. 
STUDY OBJECTIVES ........................................................................................... 13 
3.1. 
PRIMARY OBJECTIVE ................................................................................................................ 13 
3.2. 
KEY SECONDARY OBJECTIVE .................................................................................................. 14 
3.3. 
OTHER SECONDARY OBJECTIVES ........................................................................................... 14 
3.4. 
PRIMARY SAFETY OBJECTIVES ............................................................................................... 14 
3.5. 
EXPLORATORY OBJECTIVES ................................................................................................... 14 
3.6. 
SUBJECT SELECTION ................................................................................................................. 15 
3.6.1. 
Inclusion Criteria .......................................................................................................................... 15 
3.6.2. 
Exclusion Criteria ......................................................................................................................... 18 
3.7. 
DETERMINATION OF SAMPLE SIZE ........................................................................................ 20 
3.8. 
METHOD OF ASSIGNING SUBJECTS TO STUDY TREATMENT ............................................. 20 
3.9. 
MAINTAINING THE RANDOMIZATION CODES AND BREAKING THE STUDY BLIND ....... 21 
3.10. 
SCHEDULE OF EVENTS .............................................................................................................. 22 
4. 
ENDPOINTS .......................................................................................................... 22 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
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4.1. 
PRIMARY EFFICACY ENDPOINT .............................................................................................. 22 
4.2. 
KEY SECONDARY EFFICACY ENDPOINTS .............................................................................. 22 
4.3. 
OTHER SECONDARY EFFICACY ENDPOINTS ......................................................................... 22 
4.4. 
EXPLORATORY EFFICACY ENDPOINTS .................................................................................. 23 
4.5. 
SAFETY ENDPOINTS ................................................................................................................... 23 
5. 
ANALYSIS POPULATIONS .................................................................................. 24 
5.1.1. 
Intent-to-Treat (ITT) Populations ................................................................................................... 24 
5.1.2. 
Modified Intent-to-Treat 1 (mITT-1) Populations ............................................................................ 25 
5.1.3. 
Modified Intent-to-Treat 2 (mITT-2) Populations ............................................................................ 25 
5.1.4. 
Per Protocol (PP) Populations ........................................................................................................ 26 
5.1.5. 
Safety Populations ........................................................................................................................ 27 
5.1.6. 
Microbiome Modified Intent-to-Treat (mcITT) Populations ............................................................. 27 
5.2. 
PROTOCOL DEVIATIONS ........................................................................................................... 27 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ........................................ 28 
6.1. 
GENERAL METHODS .................................................................................................................. 28 
6.2. 
KEY DEFINITIONS ....................................................................................................................... 28 
6.2.1. 
Study Endpoints ........................................................................................................................... 28 
6.2.2. 
Study Day .................................................................................................................................... 32 
6.2.3. 
Baseline Values ............................................................................................................................ 32 
6.2.4. 
End of Treatment (EOT) Values .................................................................................................... 34 
6.3. 
MISSING DATA ............................................................................................................................ 36 
6.3.1. 
General Binary Efficacy Endpoint ................................................................................................. 36 
6.3.2. 
Mayo Score, Stool Frequency and Rectal Bleeding Subscores .......................................................... 37 
6.3.3. 
Imputation of Missing Data Using Last Observation Carries Forward (LOCF) Approach ................... 37 
6.3.4. 
Observed-Case Analyses ............................................................................................................... 37 
6.3.5. 
Robarts Histopathological Index .................................................................................................... 37 
6.3.6. 
Conventions for Missing AE Dates ................................................................................................ 38 
6.3.7. 
Conventions of Missing Concomitant Medications Dates ................................................................. 39 
6.4. 
VISIT WINDOWS .......................................................................................................................... 39 
6.5. 
POOLING OF CENTERS .............................................................................................................. 39 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
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6.6. 
MULTIPLICITY ADJUSTMENTS ................................................................................................ 40 
7. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS .................................... 40 
7.1. 
SUBJECT DISPOSITION AND WITHDRAWALS ........................................................................ 40 
7.2. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................................. 41 
7.3. 
MEDICAL AND SURGICAL HISTORY ....................................................................................... 42 
7.4. 
PRIOR THERAPY FOR ULCERATIVE COLITIS ....................................................................... 43 
7.5. 
PRIOR AND CONCOMITANT MEDICATION ............................................................................ 43 
8. 
EFFICACY ............................................................................................................ 44 
8.1. 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS .................................................................. 44 
8.1.1. 
Primary Analysis of the Primary Endpoint ...................................................................................... 44 
8.1.2. 
Sensitivity Analyses of the Primary Endpoint ................................................................................. 45 
8.2. 
SECONDARY EFFICACY ANALYSES ......................................................................................... 46 
8.2.1. 
Analysis of Key Secondary Endpoint ............................................................................................. 46 
8.2.2. 
Sensitivity Analyses ..................................................................................................................... 47 
8.2.3. 
Analyses of Other Secondary Efficacy Endpoints ............................................................................ 47 
8.3. 
EXPLORATORY EFFICACY ANALYSES ................................................................................... 48 
8.3.1. 
Additional Efficacy Analysis ......................................................................................................... 48 
8.3.2. 
Clinical Remission by Donor at the End of Induction ...................................................................... 48 
8.3.3. 
Clinical Remission by Histology at the End of Induction ................................................................. 48 
8.3.4. 
Clinical Remission, Endoscopic Improvement, Endoscopic Remission, Histological Mucosal Healing at 
the End of Maintenance Treatment and at the End of Open-Label Treatment .................................................. 48 
8.3.5. 
Symptomatic Remission Over Time ............................................................................................... 49 
8.3.6. 
Time to Symptomatic Remission (Symptom Scores), during the Induction Treatment ........................ 52 
8.3.7. 
Time to UC flare during Maintenance Phase ................................................................................... 53 
8.3.8. 
Inflammatory Bowel Disease Questionnaire (IBDQ) ....................................................................... 53 
8.3.9. 
Biomarker Analysis ...................................................................................................................... 54 
8.3.10. 
Microbiome Outcome Analysis ................................................................................................. 54 
9. 
SUBGROUP ANALYSES ....................................................................................... 55 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. 
SERES-201 
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10. 
SAFETY ............................................................................................................. 56 
10.1. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ................................................... 57 
10.2. 
ADVERSE EVENTS ....................................................................................................................... 58 
10.3. 
LABORATORY EVALUATIONS .................................................................................................. 59 
10.4. 
VITAL SIGNS ................................................................................................................................ 59 
10.5. 
PHYSICAL EXAMINATION ......................................................................................................... 59 
11. 
CHANGES FROM ANALYSIS PLANNED IN PROTOCOL ............................... 59 
11.1. 
STRATIFICATION FACTORS THAT ARE USED IN THE ANALYSIS....................................... 60 
11.2. 
SENSITIVITY ANALYSES ON SAFETY POPULATION ............................................................. 60 
12. 
REFERENCE LIST ............................................................................................ 60 
13. 
PROGRAMMING SPECIFICATIONS ............................................................... 61 
14. 
MOCK TABLES, LISTINGS AND FIGURES (TLFS) ......................................... 61 
 
 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
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21-APR-2021 
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GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
3CMMS 
Three-Component Modified Mayo Score 
5-ASA 
5-aminosalicylate 
6-MP 
6-mercaptopurine 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
AZA 
Azathioprine 
CI 
Confidence Interval 
cm 
Centimeter 
CMH 
Cochran-Mantel-Haenszel 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
D 
Day 
dL 
Deciliter 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
eDiary 
Electronic diary 
EIA 
Enzyme Immunoassay 
EOT 
End of treatment 
ES 
Endoscopic subscore 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
8 of 61 
 
21-APR-2021 
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Abbreviation 
Description 
FDA 
Food and Drug Administration 
FMT 
Fecal Microbiota Transplant 
g 
Grams 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
ICH 
International Conference to Harmonisation 
ITT 
Intent-To-Treat 
IXRS 
Interactive Voice or Web Response System 
JAK 
Janus kinase 
K-M 
Kaplan-Meier 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mITT 
Modified Intent-to-Treat 
mL 
Milliliter 
mm3 
Cubic millimeter 
mmHg 
Millimeters of Mercury 
Pbo 
Placebo 
PGA 
Physician Global Assessment 
PI 
Principal Investigator 
PP  
Per Protocol population 
PT 
Preferred Term 
QD 
Once a day 
QID 
Four (4) times a day 
QoL 
Quality of Life 
RB 
Rectal bleeding subscore 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
9 of 61 
 
21-APR-2021 
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v 5.0 
Abbreviation 
Description 
RHI 
Robarts Histopathological Index 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
 
 
SD 
Standard Deviation 
SF 
Stool frequency subscore 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-Emergent Adverse Event 
TLF 
Table, Listing and Figure 
TNF 
Tumor necrosis factor 
UC 
Ulcerative colitis 
ULN 
Upper limit of normal 
Vanco.  
Vancomycin 
WHO 
World Health Organization 
 
 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
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21-APR-2021 
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1. 
STUDY DESIGN 
The primary objective of the study is to assess the efficacy of once-daily dosing of SER-287 
(Induction Dose) for 10 weeks, after pre-treatment with vancomycin, to achieve clinical remission 
in subjects with active mild-to-moderate UC. In addition, the study will evaluate multiple dosing 
regimens of SER-287, the safety and efficacy of SER-287, subjects’ microbiome dynamics 
throughout treatment, and post-treatment effects of SER-287. 
Enrollment in this trial, as well as the clinical endpoints, will be based upon a composite Three-
Component Modified Mayo Score (3CMMS), which sums patient-reported rectal bleeding (RB) 
and stool frequency (SF) sub-scores, collected daily using an electronic diary (eDiary), with 
endoscopic subscore (ES). The ES will be determined by qualified gastroenterologists – first 
locally, and then by an independent, blinded central reader. The endoscopy central readers will 
remain blinded to subjects’ treatment assignments throughout the entire study.  If the local and 
central scores are discordant, a second independent, blinded central reader will score the video 
(adjudication).  If all of the scores are different from one another, then the median of the three (3) 
scores will be used as the final ES. 
This study will enroll subjects with a total 3CMMS of 3 to 7, inclusive, with inclusion requiring a 
SF ≥ 1 and an ES ≥ 1. 
Subjects will be randomized to 1 of 3 study arms (Table 1), each of which contain a 6-day pre-
treatment period (vancomycin or matching placebo) and a 10-week Induction Treatment period 
(SER-287 or matching placebo). 
Table 1: SERES-201 Induction Treatment Arms 
Arm 
Pre-Treatment 
(QID for 6 days) 
Induction Treatment 
(QD for 10 weeks) 
A 
Placebo 
Placebo 
B 
Vancomycin 
SER-287 Induction Dose 
C 
Vancomycin 
SER-287 Step-Down Induction Dose 
 
 
 
Subjects will be assessed for clinical remission status following 10 weeks of Induction Treatment. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
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21-APR-2021 
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• Remitters will be re-randomized to 1 of 2 Maintenance Treatment study arms 
(Table 2): 
o Arm D, treatment with placebo, to assess durability of clinical remission, 
and serve as a control 
o Arm E, treatment with a SER-287 Maintenance Dose, to assess 
maintenance of clinical remission with a once-weekly dosing regimen 
• Non-Remitters will enter the Open-Label Extension arm, Arm F (Table 2). 
 
Table 2: SERES-201 Post-Induction Treatment Arms 
Arm 
Study 
Phase 
Pre-Treatment 
(QID for 6 days) 
Treatment 
Frequency of 
Treatment 
Treatment 
Duration 
D 
 
Maintenance 
Treatment 
N/A 
Placebo 
Once-Weekly 
26 weeks 
E 
N/A 
SER-287 
Maintenance Dose 
Once-Weekly 
26 weeks 
F 
Open-Label 
Extension 
Vancomycin 
SER-287 
Induction Dose 
Once-Daily 
10 weeks 
 
 
All subjects will be followed for long-term safety for 26 weeks following their last treatment dose. 
The study duration, from Screening through last follow-up, will be up to 67 weeks. 
2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables 
and figures which will be produced, and the statistical methodologies that will be used, are 
complete and appropriate to allow valid conclusions regarding the study objectives. 
This SAP is based on SER-287-SERES-201Protocol Amendment 3, dated 08 October 2019 and 
its associated electronic case report forms (eCRF) Version 4.0, dated 14 Feb 2020.  


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
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2.1. 
TIMINGS OF ANALYSES  
2.1.1. 
At the end of the Induction Treatment period 
Seres will conduct an unblinded analysis of the primary and key secondary efficacy and selected 
safety endpoints when all planned subjects in the study are enrolled, have been evaluated for the 
primary/key secondary efficacy endpoints and have completed their Induction Treatment (Week 
11 [Visit 7]) or have terminated from the treatment prematurely prior to the Week 11 [Visit 7]. 
Key unblinded efficacy and safety summary tables will be generated at this time.  An unblinded 
separate pre-defined team will have access to the unblinded tables, listings and figures (TLFs).   A 
detailed unblinding plan will be implemented concurrently with the SAP.  
All clinical data generated during the induction treatment period (Screening Visit 1 through Week 
11 [Visit 7]) for all subjects enrolled in the study will be entered in the database, cleaned and 
locked prior to the unblinding.  No changes to the primary and key secondary efficacy data in the 
database will be permitted, unless deemed to be highly warranted (in such case, the decision, 
justification and the change will be documented). Therefore, all primary and key secondary 
efficacy results evaluated up until this primary study period will be considered final.  A comparison 
of the data at the time of this unblinding and at the end of the study will be performed, so it is clear 
which data points have been updated after the end of the primary study period. An audit trail of 
any changes made to the locked data will be available. 
2.1.2. 
At the end of the Maintenance Treatment and Open-Label Treatment periods, 
whichever is later 
Seres will conduct an unblinded analysis of the safety and exploratory efficacy endpoints at the 
end of the maintenance treatment and open-label treatment periods whichever is later, specifically 
when 
• All subjects who were re-randomized in the maintenance arm have been evaluated for the 
exploratory efficacy endpoints, and have completed their maintenance treatment, or have 
terminated the treatment prematurely prior to Week 37 (Visit M-7) 
and 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
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21-APR-2021 
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• All subjects who entered the Open-Label Extension arm have completed their open-label 
extension treatment (OL-Week 0 through OL-Week 11 [Visit OL-5]), or have terminated 
the treatment prematurely prior to Open-Label-Week 11 (Visit OL-5) 
whichever is later. 
Key unblinded efficacy and safety summary tables will be generated at this time.  An unblinded 
sub-team at Seres will have access to the unblinded tables, listings and figures (TLFs).    
Relevant clinical data generated during the maintenance treatment period (Week 11 through Week 
37 [Visit M-7]) and the open-label treatment period (OL-Week 0 through OL-Week 11 [Visit OL-
5]) for all subjects enrolled in the maintenance arms and the open-label arm will be entered in the 
database, cleaned and locked prior to the unblinding.  No changes to any locked data in the 
database will be permitted, unless deemed to be highly warranted.  Therefore, all efficacy results 
evaluated up until this time will be considered final at the time of the analysis.  A comparison of 
the data at the time of this unblinding and at the end of the study will be performed, so it is evident 
which data points have been updated after the end of the maintenance and the open-label treatment 
periods. An audit trail of any changes made to the locked data will be available. 
2.1.3. 
At the end of the Long-Term Safety Follow-Up period 
At the end of the Long-Term Safety Follow-Up period, after final database lock, all adverse event 
(AE) summary tables will be re-generated to include any additional safety findings from this 
period.  All other TLFs will also be re-run to ensure that any changes to the database that may have 
occurred since the earlier analyses are reflected in the final TLFs.  All changes in the efficacy 
results from the previous analyses will be described in the Clinical Study Report (CSR). 
3. 
STUDY OBJECTIVES 
3.1. 
PRIMARY OBJECTIVE 
To demonstrate the efficacy of SER-287, after 10 weeks of induction dosing (following 
vancomycin pre-treatment), in achieving clinical remission. 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. 
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21-APR-2021 
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3.2. 
KEY SECONDARY OBJECTIVE 
• To demonstrate the efficacy of SER-287, after 10 weeks of step-down induction dosing 
(following vancomycin pre-treatment), in achieving clinical remission 
• To demonstrate the efficacy of SER-287, after 10 weeks of induction dosing (following 
vancomycin pre-treatment), in achieving endoscopic improvement 
• To demonstrate the efficacy of SER-287, after 10 weeks of step-down induction dosing 
(following vancomycin pre-treatment), in achieving endoscopic improvement 
 
3.3. 
OTHER SECONDARY OBJECTIVES 
• To demonstrate the efficacy of each SER-287 treatment arm in achieving endoscopic 
remission after 10 weeks of induction treatment  
• To demonstrate the efficacy of each SER-287 treatment arm in achieving histological 
mucosal healing after 10 weeks of induction treatment  
• To demonstrate the efficacy of each SER-287 treatment arm in achieving clinical remission 
with normalization of stool frequency after 10 weeks of induction treatment  
• To evaluate the efficacy of each SER-287 treatment arm on symptomatic remission (rectal 
bleeding and stool frequency) after 10 weeks of induction treatment 
• To evaluate the engraftment of SER-287 bacteria from each SER-287 treatment arm into 
the intestinal microbial community over time 
3.4. 
PRIMARY SAFETY OBJECTIVES 
• To evaluate safety and tolerability of SER-287 
3.5. 
EXPLORATORY OBJECTIVES 
• To evaluate clinical remission at the end of maintenance treatment   


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
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21-APR-2021 
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• To evaluate endoscopic remission at the end of maintenance treatment   
• To evaluate histological mucosal healing at the end of maintenance treatment   
• To evaluate clinical remission at the end of open-label treatment  
• To evaluate endoscopic improvement at the end of open-label treatment   
• To evaluate endoscopic remission at the end of open-label treatment  
• To evaluate histological mucosal healing at the end of open-label treatment 
• To evaluate the effect of SER-287 treatment on symptomatic remission (rectal bleeding 
and stool frequency) over time 
• To evaluate the clinical remission rate of SER-287, by donor, after 10 weeks of induction 
treatment  
• To assess improvement in quality of life (QoL), as measured by the Inflammatory Bowel 
Disease Questionnaire (IBDQ)  
• To assess changes in serum biomarkers (C-reactive protein [CRP]) and fecal biomarkers 
(fecal calprotectin)  
• To evaluate changes in the composition of the intestinal microbiome over time  
• To evaluate changes in signatures of host and microbial functional responses over time  
 
3.6. 
SUBJECT SELECTION 
3.6.1. 
Inclusion Criteria 
To be eligible for enrollment, a subject must meet all the following criteria before undergoing 
any study-related procedures: 
1. Signed informed consent prior to initiation of any study-specific procedure or treatment.  
The subject must be willing to provide written informed consent and understand the 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
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potential risks and benefits from study enrollment and treatment. The subject must also 
be willing and able to comply with the scheduled visits, treatment plan, laboratory tests, 
daily eDiary and other study procedures. 
2. Male or female (non-lactating), 18-80 years of age, inclusive 
3. Documented diagnosis of ulcerative colitis at least three (3) months prior to Screening (, 
documentation should include lower endoscopic [flexible sigmoidoscopy or colonoscopy] 
evidence or histological evidence [biopsy report] of UC; however, UC medical treatment 
records may be sufficient, as determined by the Principal Investigator (PI)) and a 
minimum disease extent of 15 cm from the anal verge at the Screening endoscopy.   
4. Active mild-to-moderate UC as determined by a 3CMMS of 3 to 7, inclusive, composed 
of endoscopic subscore (≥ 1, as determined by local and central reader scores, with 
adjudication by a second central reader, if necessary), stool frequency subscore (≥ 1) and 
rectal bleeding subscore (no eligibility requirement).  There will be a maximum time of 
seven (7) business days between the Screening endoscopy and randomization. 
5. Subjects must be willing to undergo a lower endoscopy (flexible sigmoidoscopy or 
colonoscopy), including biopsy sample collection, at all specified timepoints. 
6. Subjects with an inadequate response to, loss of response to, or intolerance of, at least one 
(1) of the following conventional therapies: 5- aminosalicylate (5-ASA) compounds, 
corticosteroids, 6-mercaptopurine (6-MP) or azathioprine (AZA), anti-TNFα, anti-
integrin or tofacitinib. 
7. If female, is either: 
a. Not of childbearing potential, defined as postmenopausal (≥ 12 continuous 
months of amenorrhea with no other cause than menopause) or surgically sterile 
due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy 
b. Of childbearing potential and participates in any activity associated with risk of 
pregnancy: is practicing at least one (1) highly effective method of birth control, 
including the barrier method, oral or parenteral contraceptives, a vasectomized 
partner or abstinence from sexual intercourse.  The investigator will discuss with 
the subject the option of practicing more than one (1) of the above methods for 
the duration of the study. 
8. If male and partner is of childbearing potential, subject agrees to practice at least one (1) 
highly effective method of birth control for the duration of the study. 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
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Note definition for Inclusion Criterion #6:  Subjects who have demonstrated, over the previous 
five (5) year period, an inadequate response to, loss of response to, or intolerance of, at least one 
(1) of the following agents, as defined below: 
 
• 5-ASA compounds: 
o Signs and symptoms of persistently active disease despite taking a therapeutic 
dose of a 5-ASA compound (based on the product label for each compound, per 
PI judgement) for a minimum of four (4) weeks, or 
o History of intolerance to at least one (1) 5-ASA (discontinuation due to side 
effects) 
 
• Corticosteroids: 
o Signs and symptoms of persistently active disease despite a history of at least one 
(1) four-week induction regimen that included a dose equivalent to prednisone ≥ 
30 mg or budesonide ≥ 9 mg daily, orally for at least two (2) weeks, or 
intravenously for at least one (1) week, or  
o Two (2) failed attempts to taper corticosteroids to below a dose equivalent to 
prednisone 10 mg daily, orally, on two (2) separate occasions, or 
o History of intolerance of corticosteroids (including, but not limited to Cushing’s 
syndrome, osteopenia/osteoporosis, hyperglycemia, or neuropsychiatric side-
effects, including insomnia, associated with corticosteroid treatment) 
 
• Immunomodulators: 
o Signs and/or symptoms of persistently active disease despite at least three (3) 
months of treatment with one (1) of the following: 
 oral AZA (≥ 1.5 mg/kg/day) or 6-MP (≥ 0.75 mg/kg/day), or 
 oral AZA or 6-MP within a therapeutic range, as judged by thioguanine 
metabolite testing, or 
 a combination of a thiopurine and allopurinol within a therapeutic range, 
as judged by thioguanine metabolite testing, or 
 history of intolerance to at least one (1) immunomodulator (including but 
not limited to nausea/vomiting, abdominal pain, pancreatitis, liver function 
test abnormalities and lymphopenia) 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
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• Pathway specific drugs for UC treatment, including anti-TNF antibodies, anti-integrin 
antibodies, or janus kinase (JAK) inhibitors (such as tofacitinib):  
o Signs and symptoms of persistently active disease despite induction treatment at 
the approved induction dosing that was indicated in the product label at the time 
of use, or  
o Loss of response: Recurrence of signs and symptoms of active disease during 
approved maintenance dosing following prior clinical benefit (discontinuation 
despite clinical benefit does not qualify as having failed or being intolerant to UC 
biologic therapy), or 
o Intolerance: History of intolerance to infliximab, adalimumab, golimumab, 
vedolizumab, tofacitinib or other approved biologics or JAK inhibitors (including 
but not limited to infusion-related event, demyelination, congestive heart failure, 
serious infection, or any other drug-related AE that led to a reduction in dose or 
discontinuation of the medication). 
 
3.6.2. 
Exclusion Criteria 
A subject will not be enrolled if the subject meets any of the following criteria: 
1. Known history of Crohn’s disease 
2. No previous history of treatment for UC (treatment-naïve subjects should not be enrolled) 
3. Subjects on steroid medication (e.g. prednisone, budesonide, budesonide MMX®) who 
are unable to have steroids tapered, and be completely off steroids at least two (2) weeks 
prior to Screening 
4. Subjects who have received any investigational or approved biologic therapy (e.g. 
infliximab, adalimumab, golimumab, certolizumab, vedolizumab, ustekinumab, 
natalizumab) within eight (8) weeks prior to Screening or five (5) half-lives prior to 
Screening (whichever is longer) 
5. Subjects who have received any investigational or approved non-biologic therapy (e.g. 
cyclosporine, tacrolimus, thalidomide, methotrexate tofacitinib), except for those 
specifically listed in the Permitted Concomitant Medications (e.g. stable dose of 6-
mercaptopurine, azathioprine, methotrexate for ≥ 12 weeks prior to Screening), for the 
treatment of underlying disease, within 30 days or five (5) half-lives prior to Screening 
(whichever is longer) 
6. Major gastrointestinal surgery (not including appendectomy or cholecystectomy) within 
two (2) months before Screening, or any history of total colectomy 
7. Subjects with active celiac disease (i.e., active diarrhea due to documented celiac disease) 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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8. Subjects with evidence of, or treatment for, Clostridium difficile infection, or other 
intestinal pathogen, within 30 days prior to Screening 
9. Subjects with Clostridium difficile positive stool, performed with a toxin enzyme 
immunoassay (EIA) by the Central Laboratory.  Subjects who test positive for C. difficile 
can be treated with standard of care antibiotics and rescreened for the study after 30 days, 
as per Exclusion Criterion #8. 
10. Oral antibiotic use within 30 days before Screening 
11. Expected to receive antibiotics (i.e., for planned/anticipated procedure) within the 
Induction Treatment period  
12. Received an investigational drug or live vaccine within two (2) months before Screening 
13. Previously enrolled in a Seres Therapeutics SER-109 or SER-287 study 
14. Received a fecal microbiota transplant (FMT; includes human microbiota-based 
therapeutics) within three (3) months prior to Screening 
15. Poor concurrent medical risks with clinically significant co-morbid disease such that, in 
the opinion of the investigator, the subject should not be enrolled including: 
a. Known hypogammaglobulinemia 
b. Known severe immunodeficiency 
c. Underlying liver function test (LFT) [Screening alanine aminotransferase (ALT) 
or aspartate aminotransferase (AST)] abnormalities greater than 3x upper limit of 
normal (ULN) 
d. Absolute neutrophil count (ANC) < 500 cells/mm3 
e. Hemoglobin levels < 9 g/dL 
16. Subjects with anatomic or medical contraindications to lower endoscopy (flexible 
sigmoidoscopy or colonoscopy), including but not necessarily limited to toxic 
megacolon, gastrointestinal fistulas, immediate post-operative status from abdominal 
surgery, severe coagulopathy, large or symptomatic abdominal aortic aneurysm, or any 
subject where study physician deems subject at significant risk of complications of lower 
endoscopy (flexible sigmoidoscopy or colonoscopy) 
17. Unable to stop steroid enemas or suppositories, or 5-ASA enemas or suppositories, at 
least two (2) weeks prior to Screening 
18. Unable to stop probiotic treatment at least one (1) week prior to Screening.  Note: food 
containing probiotics are permitted. 
19. Known active malignancy, except for basal cell skin cancer or squamous cell skin cancer, 
or concurrent intensive induction chemotherapy, radiotherapy, or biologic treatment for 
active malignancy (subjects on maintenance chemotherapy may only be enrolled after 
consultation with medical monitor) 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
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20. Unable to comply with the protocol requirements, including the ability to take oral drugs; 
or any condition that, in the opinion of the investigator, might interfere with study 
objectives or compromise patient safety, including if the subject is likely to require 
surgery for UC during the study period 
21. Known allergy or intolerance to oral vancomycin 
22. Current or recent history (six [6] months prior to Screening) of drug or alcohol abuse 
 
3.7. 
DETERMINATION OF SAMPLE SIZE 
The planned sample size for this study is 67 subjects per treatment arm for a total sample size of 
201 subjects. Assuming a clinical remission rate of 29% in the SER-287 arms and a clinical 
remission rate of 9% in the placebo arm, this sample size will provide 86% power to detect a 
difference of 20% in clinical remission rates between SER-287 to placebo, using a 2-sided 
significance level of 0.05. 
A placebo rate of 7% was derived from the weighted average of the placebo rates observed in the 
tofacitinib Phase 2 (Sandborn et al., 2012), 3A and 3B (Sandborn et al., 2017) studies, and the 
ozanimod induction studies (Sandborn et al., 2016).  These four (4) studies were chosen as the 
basis for the placebo rate because each utilized a central reader to determine subjects’ ES 
subscores.  However, due to the inclusion of mild subjects and those with an ES subscore of 1 in 
the SERES-201 study, who may have a higher placebo response rate, the assumed placebo rate 
was increased to 9%.  The clinical remission rate that was used for the SER-287 arm was based on 
the re-analysis of the clinical remission rate in the vancomycin/SER-287 daily arm in the SERES-
101 Phase 1B study, and applying the definition of clinical remission for the SERES-201 study; 
additionally, only subjects with a baseline 3CMMS between 3 and 7, inclusive, and a baseline SF 
≥1 were included, (38.5% with 95% CI: 15.1%, 67.7%).  The clinical remission rate was decreased 
to 29% to account for the small sample size in this SERES-101 arm (n=13). 
3.8. 
METHOD OF ASSIGNING SUBJECTS TO STUDY TREATMENT 
Randomization will be used to avoid bias in the assignment of subjects to double-blind treatment 
(SER-287 or placebo) and to increase the likelihood that known and unknown subject 
characteristics will be evenly distributed between the treatment groups.  
Eligible subjects are to be randomized at Week 0 (Visit 3), after all screening procedures have 
been performed and eligibility for the study is confirmed.  Subjects will be randomized via the 
Interactive Voice or Web Response System (IXRS) to one (1) of the three (3) study arms.  


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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Randomization will be stratified by subjects’ baseline ES subscore (1-2 vs. 3), by subjects’ 
concomitant use of UC medications at baseline (5-ASA alone vs. immunomodulators with or 
without 5-ASA vs. none).  An adaptive subject randomization algorithm will be employed to 
facilitate balance among the different donors within each of the SER-287 arms.   
Once a randomization number has been assigned to a subject, the number cannot be reused even 
if the subject discontinues from the study early or withdraws before receiving any study drug.  
Subjects who discontinue from the study or who have been previously randomized in the study 
will not be permitted to re-enter.  Similarly, study drug assigned to a subject may not be re-used, 
even if the bottle is returned unopened.  
3.9. 
MAINTAINING THE RANDOMIZATION CODES AND BREAKING THE 
STUDY BLIND 
A designated randomization administrator from an external, independent vendor will maintain the 
randomization codes in accordance with standard operating procedures (SOPs) to ensure that the 
blind is properly maintained and that only personnel who require knowledge of treatment 
assignments will be unblinded [e.g., staff involved in serious adverse event (SAE) reporting].  
Investigators are not to break the study treatment blind except when information concerning the 
study drug is necessary for the medical treatment of the subject.  If a medical emergency requiring 
unblinding occurs, the investigator (or designated physician) is strongly encouraged to contact the 
medical or safety monitor to assess the necessity of breaking the study drug blind.  If unblinding 
is warranted, the investigator will obtain the treatment assignment information from the IXRS.  
Every effort is to be made to limit study site personnel unblinding only to those individuals 
providing direct care to that subject.  Any intentional or unintentional breaking of the blind is to 
be reported immediately to the sponsor.  The other circumstances in which unblinding may be 
necessary are at the request of a subject who becomes pregnant during the study or for regulatory 
reporting purposes. 
If the blind is broken, the date, time, and reason must be recorded in the Electronic Data Capture 
(EDC) system and any associated SAE report.  
If a subject is unblinded, they will not receive any additional study medications. 
After the SAP is final and the primary study period (Week 0 [Visit 3] to Week 11 [Visit 7]) data 
is declared complete and final, the study blind codes will be broken for the induction period 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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efficacy analyses.  The Maintenance Treatment period will remain blinded until all data collected 
through M-Week 37 (Visit M-7) has been entered, cleaned and declared complete and final.  Only 
limited personnel at Seres and the unblinded statistical and programming team at a biostatistics 
and statistical programming vendor will have access to the treatment code when the study blind is 
broken at the end of the induction phase and at the end of the maintenance phase.  The remaining 
study team personnel (majority), principal investigators and subjects will remain blinded until the 
study is completed. A detailed unblinding plan will be implemented concurrently with the SAP. 
3.10. 
SCHEDULE OF EVENTS 
For an updated schedule of events (induction treatment, maintenance treatment for remitters and 
open-label extension arm for non-remitters), please refer to Table 1, Table 2 and Table 3 of the 
SERES-201 clinical study protocol, Amendment 3 (08-October-2019). 
4. 
ENDPOINTS 
4.1. 
PRIMARY EFFICACY ENDPOINT 
• Clinical remission with SER-287, after 10 weeks of induction dosing, following 
vancomycin pre-treatment (Treatment Arm B), compared to placebo, following placebo 
pre-treatment (Treatment Arm A) 
4.2. 
KEY SECONDARY EFFICACY ENDPOINTS 
• Clinical remission with SER-287, after 10 weeks of step-down induction dosing, following 
vancomycin pre-treatment (Treatment Arm C), compared to placebo, following placebo 
pre-treatment (Treatment Arm A) 
• Endoscopic improvement with SER-287, after 10 weeks of induction dosing, following 
vancomycin pre-treatment (Treatment Arm B), compared to placebo, following placebo 
pre-treatment (Treatment Arm A) 
• Endoscopic improvement with SER-287, after 10 weeks of step-down induction dosing, 
following vancomycin pre-treatment (Treatment Arm C), compared to placebo, following 
placebo pre-treatment (Treatment Arm A) 
 
4.3. 
OTHER SECONDARY EFFICACY ENDPOINTS 
• Endoscopic remission after 10 weeks of induction treatment 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
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• Histological mucosal healing after 10 weeks of induction treatment 
• Clinical remission with normalization of stool frequency after 10 weeks of induction 
treatment 
• Symptomatic remission (rectal bleeding and stool frequency) after 10 weeks of induction 
treatment 
• Engraftment of SER-287 bacteria over time 
4.4. 
EXPLORATORY EFFICACY ENDPOINTS 
• Clinical remission at the end of maintenance treatment and at the end of open-label 
treatment 
• Endoscopic improvement at the end of maintenance treatment and at the end of open-label 
treatment 
• Endoscopic remission at the end of maintenance treatment and at the end of open-label 
treatment 
• Histological mucosal healing at the end of maintenance treatment and at the end of open-
label treatment 
• Symptomatic remission (rectal bleeding and stool frequency) over time  
• Clinical remission after 10 weeks of induction treatment for each SER-287 donor used in 
the induction treatment period 
• IBDQ scores after 10 weeks of induction treatment, at the end of maintenance treatment 
and at the end of open-label treatment 
• Serum biomarkers: CRP after 10 weeks of induction treatment (Week 11), at the end of 
maintenance treatment and at the end of open-label treatment 
• Fecal biomarkers: fecal calprotectin levels after 10 weeks of induction treatment (Week 
11), at the end of maintenance treatment and at the end of open-label treatment 
• Composition of the intestinal microbiome through the end of the maintenance treatment 
and open-label treatment periods 
• Signatures of host and microbial functional responses through the end of the maintenance 
treatment and open-label treatment periods 
 
4.5. 
SAFETY ENDPOINTS 
• Incidence of AEs, SAEs and Adverse Events of Special Interest (AESIs) for each treatment 
and each SER-287 donor  
• Laboratory evaluation results 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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• Vital sign measurements 
• Physical examination findings 
 
5. 
ANALYSIS POPULATIONS 
For the induction phase (IP), there will be 5 analysis populations: the Intent-to-Treat (ITT_IP) 
population, the modified Intent-to-Treat 1 (mITT-1_IP) population, the modified Intent-to-Treat 2 
(mITT-2_IP) population, the Per-Protocol (PP_IP) population, and the Safety population 
(Safety_IP). 
For the maintenance phase (MP), there will be 5 analysis populations: the ITT population 
(ITT_MP), the mITT-1 population (mITT-1_MP), the mITT-2 population (mITT-2_MP), the PP 
population (PP_MP), and the Safety population (Safety_MP). 
For the open-label phase (OL), there will be 4 analysis populations: the ITT population (ITT_OL), 
the mITT-1 population (mITT-1_OL), the mITT-2 population (mITT-2_OL), the PP population 
(PP_OL), and the Safety population (Safety_OL). 
5.1.1. 
Intent-to-Treat (ITT) Populations 
The ITT population will consist of all subjects who are randomly assigned, including those who 
are not exposed to any study drug, and will be analyzed based on the treatment to which they were 
randomized. The ITT population will be the primary analysis population for all efficacy endpoints. 
Specifically, the definitions for each study phase are listed below: 
• For the induction phase, the ITT population (ITT_IP) is defined as all subjects who are 
randomly assigned to the induction phase, including those who are not exposed to any 
study drug during the induction phase. 
• For the maintenance phase, the ITT population (ITT_MP) is defined as all subjects who 
enter the maintenance phase, and then are re-randomized in the maintenance phase, 
including those who are not exposed to any study drug during the maintenance phase. 
• For the open-label phase, the ITT population (ITT_OL) is defined as all subjects who are 
assigned to the open-label phase (as indicated in the “Status” CRF page), including those 
who are not exposed to any study drug during the open-label phase. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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The ITT_IP, ITT_MP, and ITT_OL populations will be the primary analysis populations for all 
efficacy endpoints for the induction, maintenance and open-label phases of the study, respectively.  
All analyses conducted in these populations will be analyzed based on the treatment to which 
subjects were randomized or assigned. 
5.1.2. 
Modified Intent-to-Treat 1 (mITT-1) Populations 
The mITT-1 population will consist of all randomized subjects with a baseline evaluation, who 
have active mild-to-moderate UC and receive any amount of study drug, and will be analyzed 
based on the treatment to which they were randomized. 
Specifically, the definitions for each study phase are listed below: 
• For the induction phase, the mITT-1 population (mITT-1_IP) is defined as all randomized 
subjects with a baseline evaluation for the induction phase, who have active mild-to-
moderate UC when the induction phase starts, and receive any amount of study drug during 
the induction phase. 
• For the maintenance phase, the mITT-1 population (mITT-1_MP) is defined as all subjects 
who were mITT-1 population during the induction phase, enter the maintenance phase, are 
re-randomized in the maintenance phase, and receive any amount of study drug during the 
maintenance phase. 
• For the open-label phase, the mITT-1 population (mITT-1_OL) is defined as all subjects 
who were mITT-1 population during the induction phase, assigned to the open-label phase 
(as indicated in the “Status” CRF page), and receive any amount of study drug during the 
open-label phase. 
All analyses in the mITT-1_IP, mITT-1_MP, and mITT-1_OL populations will be analyzed based 
on the treatment to which subjects were randomized or assigned. 
5.1.3. 
Modified Intent-to-Treat 2 (mITT-2) Populations 
The mITT-2 population will consist of all randomized subjects with a baseline evaluation, who 
have active mild-to-moderate UC and receive any amount of study drug, and will be analyzed 
based on the treatment to which they are randomized. Subjects who are confirmed to have normal 
histology at baseline will be excluded from this analysis population. Normal histology is defined 
as baseline Robarts Histopathological Index (RHI) score ≤3. 
Specifically, the definitions for each study phase are listed below: 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
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• For the induction phase, the mITT-2 population (mITT-2_IP) is defined as all randomized 
subjects with a baseline evaluation for the induction phase, who are confirmed to have 
normal histology at baseline for the induction phase, who have active mild-to-moderate 
UC when the induction phase starts, and receive any amount of study drug during the 
induction phase. 
• For the maintenance phase, the mITT-2 population (mITT-2_MP) is defined as all subjects 
who were mITT-2 population during the induction phase, enter the maintenance phase, are 
re-randomized in the maintenance phase, and receive any amount of study drug during the 
maintenance phase. 
• For the open-label phase, the mITT-2 population (mITT-2_OL) is defined as all subjects 
who were mITT-2 population during the induction phase, assigned to the open-label phase 
(as indicated in the “Status” CRF page), and receive any amount of study drug during the 
open-label phase. 
All analyses in the mITT-2_IP, mITT-2_MP, and mITT-2_OL populations will be analyzed based 
on the treatment to which subjects were randomized or assigned. 
5.1.4. 
Per Protocol (PP) Populations 
The PP population will consist of subjects from the mITT-2 Population who do not have any major 
protocol deviations. This definition will be applied to each study phase. The subjects excluded 
from the PP_IP, PP_MP, and PP_OL population will be determined and documented before the 
study is unblinded. Specifically, Seres has defined the following criteria as major deviations 
excluding subjects from the Per Protocol Population: 
1. Subject does not meet eligibility criteria which may impact subject safety or data integrity, 
including randomization >28 days from signing informed consent.  
2. Subject does not have documented informed consent prior to screening and enrollment.   
3. Subjects’ Induction Treatment Week 11 endoscopies were missing or not performed in 
compliance with protocol, i.e. >7 days outside of protocol specified window; endoscopy 
video performed in black and white (or other method not in line with protocol). 
4. Subject non-compliance with e-diary entry during Induction Treatment Week 11 and 
Induction Treatment Week 12 such that 3CMMS could not be calculated. 
5. Subject received prohibited concomitant medication(s) which may impact the validity of 
the primary endpoint assessment. 
6. Non-compliance with investigational product (<80% compliance in any treatment phase). 
7. Other:  deviations which may impact the validity of the primary endpoint assessment. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
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All analyses in the PP_IP, PP_MP, and PP_OL populations will be analyzed based on the treatment 
to which subjects were actually received. 
5.1.5. 
Safety Populations 
The Safety population will consist of all subjects who receive any amount of study drug.  Subjects 
will be analyzed according to the treatment they actually received, rather than the treatment to 
which they are randomly assigned.  This definition will be applied to each study phase.  
All safety analyses will be conducted based on the Safety population. All analyses in the Safety_IP, 
Safety_MP, and Safety_OL populations will be analyzed based on the treatment to which subjects 
were actually received. 
5.1.6. 
Microbiome Modified Intent-to-Treat (mcITT) Populations 
The mcITT Population will be used for analysis of microbiome data. It will consist of all 
randomized subjects with an evaluable stool sample collected at baseline, and at least one (1) 
evaluable stool sample collected after the start of dosing, who are exposed to any amount of study 
drug, and will be analyzed based on the treatment to which they are randomized. Microbiome 
analysis populations will be described in a separate microbiome SAP which will be written to 
address the microbiome endpoints. 
5.2. 
PROTOCOL DEVIATIONS 
Protocol deviations are entered into the 
 Clinical Trial Management System (CTMS). 
The protocol deviations will be further classified as major vs. minor in CTMS and reviewed by 
the medical monitors on an ongoing basis. This listing of 
-defined major and minor protocol 
deviations is reviewed by a Seres team including the Medical Monitor, Clinical Operations, Data 
Management, and statistical team prior to unblinding to identify deviations as either Major or 
Minor based on their impact to the primary efficacy analysis. Exclusion from the Per Protocol 
populations will be based on the occurrence of these major deviations. 
 
Protocol deviations will be presented by sponsor-defined major/minor category and deviation 
category within each major/minor category and summarized in 2 tables as follows: 1) with 
frequencies and percentages of subjects with at least one deviation in each major/minor category. 
Subjects with multiple deviations will only be counted once for a given major/minor category and 
once for the specific protocol deviation category within the major/minor category; and 2) with all 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
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incidences of the protocol deviations counted separately in each category. The total count of 
protocol deviations will be used as the denominator for percentages in this table. 
 
A special COVID-19 related protocol deviation category was created during the study. The 
protocol deviations summary  will present the number and percentage of subjects with COVID-19 
related deviations and the type of deviations. 
 
A listing of all protocol deviations by subject and deviation category will be provided.  
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6.1. 
GENERAL METHODS 
All statistical procedures will be completed using SAS® version 9.4. 
Hypothesis testing generally will be conducted at the two-sided α=0.05 level. Ninety-five percent 
(95%) confidence intervals (CIs) will be presented, where specified.  All P-values will be reported 
to three decimal places.  P-values less than 0.001 will be reported as ‘<0.001’ and P-values greater 
than 0.999 will be reported as ‘>0.999’. 
All summaries will be presented for each study phase separately. Within each phase, the 
summaries will be presented by treatment group, unless otherwise specified. For SER-287 
treatment groups, in addition to the induction dose and step-down induction dose arms, a “Total 
SER-287” column will also be added, combining the summaries from both SER-287 active 
treatment groups. Continuous variables will be summarized using descriptive statistics including 
number of subjects, mean, median, standard deviation (SD), minimum, and maximum.  For 
categorical variables, statistical summaries will include number of subjects and percentages. 
Supporting listing will be provided for each analysis parameter. 
6.2. 
KEY DEFINITIONS 
6.2.1. 
Study Endpoints 
6.2.1.1. 
Clinical Remission  
a) Clinical Remission for the Induction and Open-Label Treatment Periods: 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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o SF = 0 or 1, with at least one-point decrease from baseline 
o RB = 0  
o ES = 0 or 1 on modified Mayo Score, with at least one-point decrease from baseline 
o No occurrence of UC Flare during the treatment period 
 
b) Clinical Remission for the Maintenance Treatment Period (Sustained from Week 11 
through M-Week 37): 
o SF = 0 or 1 
o RB = 0  
o ES = 0 or 1 on modified Mayo Score 
o No occurrence of UC Flare during the treatment periods 
 
c) Clinical Remission including normalization of stool frequency: 
o SF = 0  
o RB = 0  
o ES = 0 or 1 on modified Mayo Score, with at least one-point decrease from baseline  
o No occurrence of UC Flare during the treatment period 
 
6.2.1.2. 
Symptomatic Remission: 
o SF = 0 or 1 
o RB = 0  
 
For the derivation of symptomatic remission over time as mentioned in Section 8.3.5, based on 
data from the included study days within each time point, the average of the 3 most recent scores 
for the SF subscore and the most severe RB subscore among the 3 most recent scores will be used 
to derive symptomatic remission. If only one score or less is available from the included study 
days, the subscore(s) will be considered missing. If one or both subscores are missing, 
symptomatic remission will be considered missing.  
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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6.2.1.3. 
Endoscopic Improvement 
ES subscore decrease from baseline of at least one (1) point, as assessed by flexible sigmoidoscopy 
or colonoscopy 
6.2.1.4. 
Endoscopic Remission 
a) Endoscopic Remission for the Induction and Open-Label Treatment Periods 
o ES = 0 or 1 on modified Mayo Score, with at least one (1) point decrease from 
baseline, as assessed by flexible sigmoidoscopy or colonoscopy 
 
b) Endoscopic Remission for the Maintenance Treatment Period (from Week 11 through M-
Week 37) 
o ES = 0 or 1 on modified Mayo Score, as assessed by flexible sigmoidoscopy or 
colonoscopy 
 
6.2.1.5. 
Histological Mucosal Healing 
Statistically significant decrease from baseline, using the RHI scoring system. The RHI score is 
computed based on Geboes score using the following formula (based on Mosli et al., 2017): 
RHI = 1 X chronic inflammatory infiltrate level (Geboes score item 1, 4 levels)  
+ 2 X lamina propria neutrophils (Geboes score item 2B, 4 levels)  
+ 3 X neutrophils in epithelium (Geboes score item 3, 4 levels)  
+ 5 X (erosion or ulceration (4 levels after combining Geboes score Item 5.1 and 5.2) 
 
The Geboes scores are defined as below: 
• 0: Structural - architectural change 
• 1: Chronic Inflammatory infiltrate 
• 2a: Lamina propria eosinophils 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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• 2b: Lamina propria neutrophils 
• 3: Neutrophils in epithelium 
• 4: Crypt destruction 
• 5: Erosion or ulceration 
For Geboes score Item 1, 2B and 3, the original scores are obtained from the histopathology data 
by removing the leading question index. For example, for Item 1, if the value in the histopathology 
data is 1.2, then the Geboes score Item 1 is 2 As another example, for Item 2B, if the value in the 
histopathology data is 2B.3, then the Geboes score Item 2B is 3. 
For Geboes score Item 5, the original scores are obtained from the histopathology data based on 
the following rules: 
• If histopathology data is 5.0, then Geboes score Item 5 is 0; 
• If histopathology data is 5.1, then Geboes score Item 5 is 1; 
• If histopathology data is 5.2, then Geboes score Item 5 is 1; 
• If histopathology data is 5.3, then Geboes score Item 5 is 2; 
• If histopathology data is 5.4, then Geboes score Item 5 is 3. 
 
6.2.1.6. 
Three-Component Modified Mayo Score 
Sum of the below three (3) subscores: 
1. 
ES (modified Mayo) 
2. 
SF  
3. 
RB  
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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6.2.1.7. 
Disease Worsening 
An increase by two (2) or more points, on two (2) days within a three (3) day period, of the patient 
reported outcomes (SF and RB subscores) of the modified Mayo score, 
o Compared to baseline score if disease worsening is during the Induction Treatment 
period, or 
o Compared to the post-10-week induction treatment score if disease worsening is 
after the Induction Treatment period 
 
6.2.1.8. 
UC Flare 
UC symptom changes (which may include disease worsening, as defined above), as determined 
by the principal investigator to be significant enough to warrant addition of a new UC medication, 
an increase in dose of a baseline UC medication, or surgery 
6.2.1.9. 
Engraftment 
Outgrowth of bacteria that comprise the SER-287 drug product in a subject’s gastrointestinal tract, 
post-treatment. 
6.2.2. 
Study Day 
For the induction phase, Study Day 1 is defined as the first dosing day of induction study drug. 
Subsequent days are numbered consecutively (Day 2, Day 3, etc.). Before the day of study drug 
administration, study days are numbered sequentially with negative values (i.e., Day -1, Day -2, 
etc.). There is no Day 0. 
For the maintenance phase, Study Day 1_MP is defined as the first dosing day of maintenance 
study drug, subsequent days are numbered consecutively (Day 2_MP, Day 3_MP, etc.).  
For the open-label phase, Study Day 1_OL is defined as the first dosing day of open-label study 
drug, subsequent days are numbered consecutively (Day 1_OL, Day 2_OL, etc.). 
6.2.3. 
Baseline Values 
Baseline values for SF, RB and ES are calculated in the following manner: 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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SF  
1. Baseline of the induction and the open-label phases (at screening prior to induction 
treatment) 
a. The scores from the three (3) most recent days, within the last seven (7) days prior 
to the day of the bowel preparation for endoscopy, will be averaged and rounded to 
the nearest integer. 
b. If only two (2) scores are available within the last seven (7) days prior to the day of 
the bowel preparation for endoscopy, the SF subscore will be considered missing 
and the subject will be ineligible for enrollment. 
2. Baseline of the maintenance (at the end of induction treatment) 
a. The scores from the three (3) most recent days, within the last seven (7) days prior 
to the day of the bowel preparation for endoscopy, will be averaged and rounded to 
the nearest integer. 
b. If only two (2) scores or less are available within the last seven (7) days prior to the 
day of the bowel preparation, then additional scores from three (3) to seven (7) days 
after the endoscopy procedure, choosing the scores closest to the day of endoscopy, 
can be used to obtain three (3) scores. These three (3) scores will be averaged and 
rounded to the nearest integer.  Scores available prior to the bowel preparation 
should be included in the calculation of the average SF subscore first, before using 
any scores after the endoscopy procedure. 
c. If three (3) scores from the two (2) preceding scenarios are not available, then the 
SF subscore will be considered missing and the subject will be assigned an outcome 
of failure for all endpoints which are derived using the SF subscore. 
RB  
The RB subscores are derived in the same manner as outlined in the preceding section for the 
calculation of the SF subscores.  However, instead of using the average of three (3) scores, the 
most severe RB score among the three (3) scores will be used to obtain the RB subscores. 
 
ES  


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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Endoscopic subscores are determined by qualified gastroenterologists – first locally, and then by 
an independent, blinded central reader. The endoscopy central readers were blinded to subjects’ 
treatment assignments throughout the entire study.  If the local and central scores were discordant, 
a second independent, blinded central reader scored the video (adjudication).  If all of the scores 
were different from one another, then the median of the 3 scores is used as the final ES.  The 
baseline ES for the induction phase and the open-label phase is calculated from the Screening Visit 
2 data. The baseline ES of the maintenance phase is calculated from the last ES assessment prior 
to the dosing of any maintenance study drug (generally this will be assessed at Week 11, at the end 
of the induction treatment period).  
If a subject discontinued the maintenance treatment and entered the open-label phase, baseline ES 
values would be at the time of discontinuation of the maintenance treatment prior to dosing of any 
open-label study drug, if available. If ES data is not available at the time of discontinuation at the 
end of maintenance treatment, baseline ES would be based from the Screening Visit 2 data. 
Other Endpoints 
In general, the baseline values for other endpoints (e.g. laboratory assessments) for different phases 
of the study are defined as follows, unless otherwise specified: 
• For the induction phase and the open-label phase, baseline values are assessments done at 
screening or pre-dose assessments on Day 1, using the timepoint that is closest to but prior 
to dosing of any induction treatment study drug. 
• For the maintenance phase, baseline values are the last assessments prior to dosing of any 
maintenance study drug (i.e. in general, these will be taken at Week 11, at the end of 
induction treatment period). 
• For the open-label phase, if subject discontinued the maintenance treatment and entered 
open-label phase, baseline values would be at the time of discontinuation of the 
maintenance treatment prior to dosing of any open-label study drug. If data is not available 
at the time of discontinuation at the end of maintenance treatment, baseline values would 
be based on assessments done at screening or pre-dose assessments on Day 1. 
6.2.4. 
End of Treatment (EOT) Values 
SF 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
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1. At the end of induction treatment (at Week 11 visit date, or the date of last visit if the 
subject early discontinued from the period) 
a. The scores from the three (3) most recent days, within the last seven (7) days prior 
to the day of the bowel preparation for endoscopy, will be averaged and rounded to 
the nearest integer. 
b. If only two (2) scores or less are available within the last seven (7) days prior to the 
day of the bowel preparation, then additional scores from three (3) to seven (7) days 
after the endoscopy procedure, choosing the scores closest to the day of endoscopy, 
can be used to obtain three (3) scores. These three (3) scores will be averaged and 
rounded to the nearest integer. Scores available prior to the bowel preparation 
should be included in the calculation of the average SF subscore first, before using 
any scores after the endoscopy procedure. 
c. If three (3) scores from the two (2) preceding scenarios are not available, then the 
SF subscore will be considered missing and the subject will be assigned an outcome 
of failure for all endpoints which are derived using the SF subscore. 
2. At the end of the maintenance treatment (at M-Week 37 visit date, or the date of last visit 
if the subject early discontinued from the period) and open-label treatment (at OL-Week 
11 visit date, or the date of last visit if the subject early discontinued from the period), 
a. The scores from the three (3) most recent days, within the last seven (7) days prior 
to the day of the bowel preparation for endoscopy, will be averaged and rounded to 
the nearest integer. 
b. However, if only two (2) scores are available within the last seven (7) days prior to 
the day of the bowel preparation for endoscopy, the SF subscore will be calculated 
as the average of these two (2) scores and rounded to the nearest integer. 
c. If one (1) score or less is available within the last seven (7) days prior to the day of 
the bowel preparation for endoscopy, the SF subscore will be considered missing 
and the subject will be assigned an outcome of failure for all endpoints which are 
derived using the SF subscore. 
 
RB 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
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The RB subscores are derived in the same manner as outlined in the preceding section for the 
calculation of the SF subscores.  However, instead of using the average of three (3) scores, the 
most severe RB score among the three (3) scores will be used to obtain the RB subscores. 
 
ES  
The end of treatment ES is calculated from the last available data on or before the date of last visit 
for the period.  
Due to onsite visit restrictions and closures of endoscopy facilities during the COVID-19 
pandemic, the Week 11 endoscopy visits for some subjects may be performed outside of the visit 
window as defined in the study protocol.  At the onset of the COVID-19 pandemic, a guidance 
document was issued to the sites, IRBs, and FDA to allow flexibility of the visit windows for 
endoscopies, including how to document delayed endoscopy visits.  
For the purpose of this analysis, endoscopies at the end of the induction, maintenance, and open 
label phases will be considered valid as long as the endoscopy was performed within 30 days of 
last dose of IP taken in each treatment phase.   
See Section 8.1.2.4 for sensitivity analyses related to the endoscopy visit window. 
Other Endpoints 
In general, the end of treatment values for other endpoints are defined as the last available data on 
or before the date of last visit for the period. 
6.3. 
MISSING DATA 
Every effort will be made to collect all data at specified timepoints, according to the schedule of 
study events. 
6.3.1. 
General Binary Efficacy Endpoint 
In general, unless otherwise specified, missing data will be imputed based on non-responder 
imputation (NRI), that is subjects with missing values such that the clinical binary efficacy 
endpoint cannot be calculated, the outcome will be assigned as a failure for the endpoint. In another 
words, subjects with missing value of a binary efficacy endpoint will be assigned an outcome of failure 
for the endpoint, if  


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
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• 
The subject did not have a post-baseline endoscopy done during the induction period, OR 
• 
Data is missing for any of the subscores needed for the Week 11 assessments at the end of the 
induction period, such that the endpoint cannot be calculated. 
6.3.2. 
Mayo Score, Stool Frequency and Rectal Bleeding Subscores 
The description of the handling of missing data for individual components of the 3CMMS, 
specifically SF and RB subscores, are described in Section6.2. 
6.3.3. 
Imputation of Missing Data Using Last Observation Carries Forward (LOCF) 
Approach 
The primary endpoint and the key secondary endpoint will also be analyzed based on the LOCF 
approach. The values before the last available visit of the period will be used when the subject 
early discontinued from the period. The end of treatment values, as discussed in Section 6.2, will 
be used. 
Subjects who only have baseline values will be treated as failures for the endpoint in the LOCF 
analysis. 
Note that when a subject had an increasing dose in UC medication including the use of new UC 
treatment medication, use of UC surgery, indicates that a subject had a UC flare based on the 
definition of UC flare in this study.  Therefore, since no occurrence of a UC flare is one of the 
criteria for achieving clinical remission, a value of failure will be assigned for this intercurrent 
event regardless of treatment arm in all the sensitivity analyses. 
6.3.4. 
Observed-Case Analyses 
For the observed-case analyses, the missing values will not be imputed. 
6.3.5. 
Robarts Histopathological Index 
When evaluating the change from baseline RHI score (as described in Section 8.2.3), two different 
approaches for RHI score imputation will be used: 
1) A multiple imputation approach using Markov Chain Monte Carlo (MCMC) method 
(Schafer, 1997) will be used to impute the missing values for RHI score at Week 11 [Visit 
7] using the distribution within each treatment group. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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2) As a sensitivity analysis approach, Baseline Observation Carried Forward (BOCF) will 
also be used for the imputation for RHI score at Week 11 [Visit 7].: Missing post-baseline 
data will be imputed to their respective baseline RHI scores. This assumes disease activity 
as measured by RHI scores remained at baseline value for subjects with early withdrawal, 
i.e. subject does not, in the long-term, derive benefit nor harm from treatment. 
6.3.6. 
Conventions for Missing AE Dates 
For AEs or SAEs, a missing or incomplete onset date will be imputed according to the following 
conventions: 
3) If an onset date is completely missing, the derived onset date will be calculated as the first 
non-missing date from the following list in the following order; 
o First study medication date 
o Date of informed consent 
4) If an onset date is partially missing, the derived onset date will be calculated following: 
o Missing day, but month and year present: the day will be imputed as the 15th of the 
month. If the month and year are equal to the month and year of the first study 
medication dose and the first study medication dose occurs after the imputed date, 
the derived onset date will be set equal to the first study medication date. If the AE 
end date occurs prior to the imputed date, the derived onset date will be set equal 
to the AE end date. 
o Missing day and month, but year present: the day and month will be imputed as the 
30th June of the year. If the year is equal to the year of the first study medication 
dose, the derived onset date will be set equal to the first study medication date. If 
the AE end date occurs prior to the imputed date, the derived onset date will be set 
equal to the AE end date. 
o If the imputed AE onset date occurs after the database lock date, the imputed AE 
onset date will be imputed as the database lock date. 
For AEs or SAEs which are not ongoing at the end of the study, a missing or incomplete end date 
will be imputed according to the following conventions: 
1) If an end date is missing, the derived end date will be imputed as the last assessment date, 
assuming that the last assessment occurs after the AE start. If the last assessment occurs 
prior to the AE start date, the derived end date will be imputed as the AE start date. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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2) If an end date is incomplete, the derived end date will be calculated following: 
o Missing day, but month and year present: the day will be imputed as the last date 
(for example February 2019 will be imputed as 28 February 2019) of the month 
o Missing day and month, but year present: the day and month will be imputed as the 
31st December of the year. 
o If the imputed AE end date occurs after the database lock date, the imputed AE end 
date will be imputed as the database lock date. 
6.3.7. 
Conventions of Missing Concomitant Medications Dates 
Start and stop dates for all concomitant medications are collected on the CRF. However, in case 
of missing or partial information in these dates, the following rules will be used: 
If the start date is missing or partial: 
- 
If the day is missing, the start day will be the first day of the month 
- 
If the month is missing, the start month will be the month of the randomization visit  
- 
If the year is missing, the start year will be the year of the randomization visit  
- 
If the entire date is missing, the start date will be the date of first study drug administration 
If the stop date is missing, partial and the medication is not “ongoing”: 
- 
If the day is missing, the stop day will be the last day of the month reported 
- 
If the month is missing, the stop month will be the month during which the last assessment 
occurred 
- 
If the year or the entire date is missing, the date will be the date of the last assessment. 
6.4. 
VISIT WINDOWS 
Nominal visits will be used for all by visit analyses. The study visits scheduled after randomization 
should occur at the times delineated in the Schedule of Events. 
6.5. 
POOLING OF CENTERS 
Data from all investigational centers/sites will be pooled for analyses since analyses will not be 
adjusted for investigator site. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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6.6. 
MULTIPLICITY ADJUSTMENTS 
Adjustments for multiple testing will be made to test the primary efficacy and key secondary 
efficacy endpoints. A fixed-sequence method will be used to maintain a study-wide Type I error 
rate of 0.05.  Testing of the key hypotheses will be conducted in the following order, all at the 
same significance level 2-sided α = 0.05). 
1. H01: No difference in clinical remission rates after 10 weeks of induction treatment between 
Arm B (SER-287 at Induction Dose after pre-treatment with vancomycin) vs. Arm A (pre-
treatment with placebo followed by treatment with placebo) in the ITT population 
2. H02: No difference in clinical remission rates after 10 weeks of induction treatment between 
Arm C (SER-287 at Step-Down Induction Dose after pre-treatment with vancomycin) vs. 
Arm A (pre-treatment with placebo followed by treatment with placebo) in the ITT 
population 
3. H03: No difference in endoscopic improvement rates after 10 weeks of induction treatment 
between Arm B (SER-287 at Induction Dose after pre-treatment with vancomycin) vs. Arm 
A (pre-treatment with placebo followed by treatment with placebo) in the ITT population 
4. H04: No difference in endoscopic improvement rates after 10 weeks of induction treatment 
between Arm C (SER-287 at Step-Down Induction Dose after pre-treatment with 
vancomycin) vs. Arm A (pre-treatment with placebo followed by treatment with placebo) 
in the ITT population 
Testing of later hypotheses in the sequence stops as soon as failure to show statistical significance 
at the 2-sided 0.05 level is observed in a hypothesis earlier in the sequence.  
7. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Summary tables for demographics (e.g., age, race, ethnicity, sex), baseline characteristics (e.g., 
weight, height, body mass index), UC medical history, treatment history, and other baseline 
disease characteristics will be summarized by treatment group for specified analysis populations 
outlined below. 
7.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
The following will be presented by treatment group: number of subjects who were screened; 
number and percentage of subjects who failed screening; number and percentage of subjects who 
were randomized; completion status for each period (pre-treatment, induction treatment, 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
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maintenance treatment, open-label treatment, and safety follow-up period); primary reason for 
premature discontinuation during each period (pre-treatment, induction treatment, maintenance 
treatment, open-label treatment, and safety follow-up period).   
The number and percentage of subjects included in each of the analysis populations will be 
presented.   
7.2. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Descriptive statistics will be used to summarize demographics and other baseline characteristics. 
The summary will be presented by treatment group and overall for each study population. 
Demographics information includes the following: 
• Age at informed consent (Year) 
• Sex at birth 
• Race 
• Ethnicity 
 
Baseline characteristics information includes the following: 
• Weight (kg) 
• Height (m) 
• Body mass index (BMI), calculated as BMI (kg/m2) = (Weight (kg)) / [Height (m)]2 
• Stratification information: 
o Baseline ES (1-2 vs. 3), based on IXRS. 
o Concomitant use of UC medications at baseline (5-ASA alone vs. immunomodulators 
with or without 5-ASA vs. none), based on IXRS and based on actual CRF 
information. 
o Concomitant use of UC medications at baseline (collapsed categories: 5-ASA or 
immunomodulators vs. none), based on IXRS and based on actual CRF information. 
 
The following variables will be summarized for smoking history: 
• Number of subjects who never smoked, were former smokers, and current smokers 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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• Number of years smoked for former smokers 
• Number of years smoked for current smokers 
• Time since the date stopped smoking for former smoker (from the date stopped to date of 
informed consent (months)) 
 
The following variables will be summarized for ulcerative colitis disease history information:  
• Time since symptoms began, calculated from date symptoms began to date of informed 
consent (months) 
• Time since UC diagnosis, calculated from date for diagnosis by physician to date of 
informed consent (months) 
• Number of patients with at least one (1) acute exacerbation within the past 12 months 
(including screening), number of acute exacerbations, status of last exacerbations 
• Number of patients with at least one (1) hospitalization for ulcerative colitis within the 
past 12 months (not including screening), number of hospitalizations 
• Number of patients who had at least one (1) colonoscopy or sigmoidoscopy within the 
last 18 months (not including screening), time since last colonoscopy or sigmoidoscopy 
• Location and extent of patient’s disease: Proctosigmoiditis, Left sided colitis, Extensive 
colitis, Pancolitis 
• Number of patients who had surgery for ulcerative colitis (not including screening), 
number of surgeries 
• Number of patients who had any extraintestinal manifestations (not including screening) 
and number of extraintestinal manifestations for each category (e.g. Arthritis/Arthralgia, 
Iritis/Uveitis etc.) 
• Number of weeks of corticosteroid use over the last 12 months 
 
7.3. 
MEDICAL AND SURGICAL HISTORY 
A by-treatment summary table of the number and percentage of subjects with medical and surgical 
history by system organ class (SOC) and preferred term (PT) will be produced for subjects in the 
Safety_IP. Medical history and surgical history will be sorted in alphabetical order of SOC and PT 
using the Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary, V21.0. For 
the summary tables, a subject may appear more than once if he has more than one medical 
history/surgical history finding coded under different SOC terms or more than one medical 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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history/surgical history finding with a different PT under the same SOC term. However, the subject 
will be counted only once in the overall category. 
A by-subject listing with coded SOC and PT along with verbatim eCRF term will also be provided. 
7.4. 
PRIOR THERAPY FOR ULCERATIVE COLITIS 
Prior therapy for Ulcerative Colitis will be summarized by treatment arm in the ITT_IP and 
ITT_MP population for the following therapies as outlined in the CRF. The summary table if 
applicable will also include status (ongoing/discontinued), duration of prior therapy (for 
ongoing/discontinued) and patient experience of the prior ongoing and prior discontinued therapy. 
• Systematic Corticosteroids 
• Immunomodulator: 6-Mercaptopurine, Azathioprine, Methotrexate 
• Anti-TNF biologics (approved and non-approved) 
• Anti-integrin biologics (approved and non-approved) 
• Anti-IL biologics (approved and non-approved) 
• Other orally active immunosuppressants (approved and non-approved) 
• Rectal Corticosteroids (enemas or suppositories) 
• Oral 5-ASA/Mesalamine/Mesalazine 
• Sulfasalazine 
• Balsalazide 
• Rectal 5-ASA (enemas or suppositories) 
• Probiotics 
• Antidiarrheals 
• Cyclosporine/Tacrolimus (FK506) 
• Enteral Feeds 
• Parenteral Nutrition 
 
A by-subject listing of prior therapy for ulcerative colitis will also be provided. 
7.5. 
PRIOR AND CONCOMITANT MEDICATION 
Prior medications are defined as medications that started before the date of dosing. Any medication 
that started on the date of dosing will not be considered prior. Concomitant medications are defined 
as all medications (excluding study treatment) taken on or after the date of dosing. This also 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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includes medications ongoing on the dosing date. Medications that started before the date of dosing 
and are ongoing after the date of dosing will be considered as both prior and concomitant. 
Separate summary tables will be provided for prior and concomitant medications in the Safety_IP 
population, presenting the number and percentage of subjects by treatment group, and will be 
sorted in alphabetical order of Anatomic Therapeutic Chemical (ATC) classification level 2 and 
then Preferred Term (PT) in the overall column. For concomitant medications, the summary will 
be presented for each phase (pre-treatment, induction treatment, maintenance treatment, open-label 
treatment, and safety follow-up period). For each subject, the medication will be counted only once 
within a given ATC level 2 and only once within a given preferred drug name level.  A subject 
may appear more than once if he/she has more than one concomitant medication coded under 
different ATC categories, however, the subject will be counted only once in the overall category. 
Prior and concomitant medications will be included in separate listings, coded by using the ATC 
classification codes and preferred drug name according to the World Health Organization (WHO) 
Drug Dictionary Global, (01SEP2018). 
8. 
EFFICACY 
8.1. 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS 
8.1.1. 
Primary Analysis of the Primary Endpoint 
The primary efficacy outcome measure for this study will be the difference in clinical remission 
rates after 10 weeks of induction treatment between SER-287 (Induction Dose after pre-treatment 
with vancomycin – Arm B) and placebo (placebo after pre-treatment placebo – Arm A). The 
number and percentage of subjects with clinical remission will be presented by treatment group.  
The primary efficacy endpoint analysis will be based on the Cochran-Mantel-Haenszel (CMH) 
test, stratified only by the ES score at baseline (1-2 vs. 3) and UC medications at baseline 
(collapsed categories based on IXRS: 5-ASA or immunomodulators vs. none). The CMH test p-
value, the adjusted treatment difference with CMH weight (Treatment B vs. Treatment A) along 
with its 2-sided 95% CI will be presented. The Breslow-Day Test of Homogeneity will be used to 
assess the homogeneity of the risk differences across the strata. 
As a supportive analysis, exact 2-sided Clopper Pearson binomial CIs will be computed for each 
treatment group. The difference of the clinical remission rate without adjustment for other 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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covariates between treatment groups will be computed. Asymptotic 2-sided 95% CIs will be 
computed using un-pooled variance estimates and approximation using Normal distribution. 
For the primary efficacy analysis, end of treatment values will be taken from Week 11 visit date, 
as discussed in Section 6.2. 
The primary efficacy analysis will be performed in the ITT_IP, mITT-1_IP, mITT-2_IP, and 
PP_IP Population. The results from the ITT_IP population will be deemed as the primary. 
 
8.1.2. 
Sensitivity Analyses of the Primary Endpoint 
8.1.2.1. 
Last Observation Carried Forward 
To assess the robustness of missing data imputation in the primary efficacy analysis, an additional 
sensitivity analysis will be performed for the primary endpoint while the missing data is imputed 
based on the last observation carried forward (LOCF) approach. Details of LOCF approach are 
described in Section 6.3.3. 
 
8.1.2.2. 
Re-randomization Test 
Following Han et al. 2013, we will also carry out a “Re-randomization Test” to evaluate the impact 
of the adaptive randomization algorithm used in the treatment allocation. This will be done through 
a Monte Carlo simulation process: 
1. Run 10000 simulation with the same treatment allocation algorithm (this will be done in 
SAS) for the enrolled subjects. 
2. Assign the observed primary endpoint results to each subject regardless of the treatment 
allocated in step 1. 
3. Calculate the CMH test statistic in each simulation. This will give us a null-distribution of 
the CMH test statistic 
4. Apply the observed CMH test statistic obtained in the primary efficacy analysis. 
5. Report the P-Value based on the quantiles of the observed CMH test statistic among the 
simulated CMH test statistics. P-Value will be defined as the proportion of CMH test 
statistic results that are more extreme than the observed CMH test statistic. 
 
Additionally, a 2-sided 95% interval estimate of treatment effect will be obtained by identifying a 
shift that leads to relevant p-values (0.025 and 0.975) using the same simulation approach as above. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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A grid search around the end point of this interval will be performed. This will be done in ITT_IP 
population. 
 
8.1.2.3      Logistic Regression Model 
 
For the ITT population, a multiple logistic regression model based on the binary clinical remission 
event (Yes, No) after 10 weeks of induction treatment between SER-287 (Induction Dose after 
pre-treatment with vancomycin – Arm B) and placebo (placebo after pre-treatment placebo – Arm 
A).  This model will contain as main effects the treatment factor (B vs A), and the stratification 
factors baseline ES strata, baseline UC medication strata (based on IXRS), and donor.  The model 
will also contain the 2-factor interactions treatment by ES strata, treatment by UC medication 
strata, and treatment by donor.  After fitting the full model, the best fitting reduced model will be 
obtained by first removing interaction terms having little effect (using entry α=0.2) on the log odds 
ratio, then removing any main effect stratification factors having little effect.  The resulting 
reduced model should fit the data as well as the full model. Conclusions regarding the comparison 
of B versus A from the reduced model will be compared with the conclusion resulting from the 
primary CMH analysis. The remission rate difference will be estimated using the difference in 
predicted rates from the logistic regression model. The confidence interval of the remission rate 
difference will be constructed by applying Delta Method to the results from logistic regression. 
 
8.1.2.4  
Sensitivity Analyses for COVID-19 Related Protocol Deviations. 
 
Additional sensitivity analyses based on the type of COVID-19 related protocol deviations and 
their impact to the primary analysis may also be conducted.  Subjects with Week 11 endoscopies 
conducted > 7 days outside of the protocol specified visit window will be assessed as non-
remitters. As the protocol allows a Week 11 +3 day window, the maximum number of days that 
a subject can be outside of the protocol specified window is 10 days for this sensitivity analysis.  
 
8.2. 
SECONDARY EFFICACY ANALYSES 
8.2.1. 
Analysis of Key Secondary Endpoint 
The key secondary efficacy endpoints will be analyzed using the same method used for the primary 
efficacy endpoint. 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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8.2.2. 
Sensitivity Analyses 
Similarly, a sensitivity analyses will be performed based on the LOCF imputation of the missing 
data. Sensitivity analyses adjusting for COVID-19 related protocol deviations and their impact to 
the secondary endpoints may also be conducted. 
8.2.3. 
Analyses of Other Secondary Efficacy Endpoints 
All other dichotomous secondary efficacy endpoints will be analyzed using the same method used 
for the primary efficacy endpoint. In general, the analyses are performed in the mITT-1_IP as well 
as mITT-2_IP population, unless otherwise stated.  
Histological mucosal healing will be analyzed using the RHI. The analysis will be based on the 
change from baseline RHI score (Mosli et al., 2017) and analyzed by an analysis of covariance 
(ANCOVA) test, with treatment, ES at baseline, UC medications at baseline (based on CRF) as 
factors and baseline score as a covariate in the model. Two different imputation methods as 
described in Section 6.3.5 will be used in this analysis. For imputation by using multiple 
imputation, 100 imputed data sets will be generated. And PROC MIANALYZE will be used to 
combine the results based on different imputed data sets. The analysis population for this endpoint 
will be the mITT-1 and mITT-2_IP population. 
In addition, histological mucosal healing will also be analyzed using a complete-case analysis in 
mITT-1. In this case, subjects with missing baseline or post-baseline data such that the change 
from baseline in RHI score cannot be calculated will be excluded from the analysis. This is 
assuming that the missing data is completely at random.  
Normalization status of post-baseline histological mucosal healing from baseline normalization 
status will be evaluated using a shift table.  
A by-subject listing with secondary efficacy data will also be provided. 
For the analysis of the engraftment of SER-287 bacteria over time, this will be provided in the 
microbiome SAP. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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8.3. 
EXPLORATORY EFFICACY ANALYSES 
8.3.1. 
Additional Efficacy Analysis 
Unless specified, all dichotomous exploratory efficacy endpoints will be analyzed using the same 
method used for the primary efficacy endpoint. The analyses are performed in the mITT-1 unless 
specified. It will be done for the induction, maintenance or the open-label periods, respectively, as 
appropriate.  
8.3.2. 
Clinical Remission by Donor at the End of Induction 
To evaluate the clinical remission rate of SER-287 by donor after 10 weeks of induction treatment, 
the primary analysis of the clinical remission rate of SER-287 by donor will be presented. This 
will be done for ITT_IP and mITT-1_IP populations only. 
8.3.3. 
Clinical Remission by Histology at the End of Induction 
To evaluate the clinical remission rate of SER-287 by histology after 10 weeks of induction 
treatment, the primary analysis of the clinical remission rate of SER-287 by histology will be 
presented.  This will be done for ITT_IP and mITT-1_IP populations only. 
8.3.4. 
Clinical Remission, Endoscopic Improvement, Endoscopic Remission, 
Histological Mucosal Healing at the End of Maintenance Treatment and at the 
End of Open-Label Treatment 
Clinical remission at the end of maintenance and open-label treatment will be analyzed using the 
same method used for the primary efficacy endpoint. 
Additionally, clinical remission at the end of open-label treatment will also be presented 
descriptively separating by their previous treatment in induction period and maintenance period.   
Endoscopic improvement, endoscopic remission, histological mucosal healing at the end of 
maintenance and open-label treatment will be analyzed using the same approach. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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8.3.5. 
Symptomatic Remission Over Time 
Symptomatic remission over time will be calculated weekly based on the SF and RB subscores as 
defined in Section 6.2.1.  The table below specifies the study days that will be included in the 
calculation of the SF and RB subscores for each time point: 
Induction Phase 
Time Point (Induction) 
Study Days Included in SF and RB 
Calculations 
Day 7 
1-7  
Day 14 
8 -14 
Day 21 
15- 21 
Day 28 
22-28 
Day 35 
29-35 
Day 42 
36-42 
Day 49 
43-49 
Day 56 
50-56 
Day 63 
57-63 
Day 70 
64-70 
Day 77 
71-77 
 
Maintenance Phase 
 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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Time Point (Maintenance: MP) 
Study Days Included in SF and RB 
Calculations 
Day 7_MP 
1_MP-7_MP 
Day 14_MP 
8_MP -14_MP 
Day 21_MP 
15_MP - 21_MP 
Day 28_MP 
22_MP -28_MP 
Day 35_MP 
29_MP -35_MP 
Day 42_MP 
36_MP -42_MP 
Day 49_MP 
43_MP -49_MP 
Day 56_MP 
50_MP -56_MP 
Day 63_MP 
57_MP -63_MP 
Day 70_MP 
64_MP -70_MP 
Day 77_MP 
71_MP -77_MP 
Day 84_MP 
78_MP -84_MP 
Day 91_MP 
85_MP -91_MP 
Day 98_MP 
92_MP -98_MP 
Day 105_MP 
99_MP -105_MP 
Day 112_MP 
106_MP -112_MP 
Day 119_MP 
113_MP -119_MP 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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Time Point (Maintenance: MP) 
Study Days Included in SF and RB 
Calculations 
Day 126_MP 
120_MP -126_MP 
Day 133_MP 
127_MP -133_MP 
Day 140_MP 
134_MP -140_MP 
Day 147_MP 
141_MP -147_MP 
Day 154_MP 
148_MP -154_MP 
Day 161_MP 
155_MP -161_MP 
Day 168_MP 
162_MP -168_MP 
Day 175_MP 
169_MP -175_MP 
Day 182_MP 
176_MP -182_MP 
 
 
Open-Label Phase 
 
Time Point (Open-Label: OL) 
Study Days Included in SF and RB 
Calculations 
Day 7_OL 
1_OL - 7_OL 
Day 14_OL 
8_OL -14_OL 
Day 21_OL 
15_OL - 21_OL 
Day 28_OL 
22_OL -28_OL 
Day 35_OL 
29_OL -35_OL 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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Time Point (Open-Label: OL) 
Study Days Included in SF and RB 
Calculations 
Day 42_OL 
36_OL -42_OL 
Day 49_OL 
43_OL -49_OL 
Day 56_OL 
50_OL -56_OL 
Day 63_OL 
57_OL -63_OL 
Day 70_OL 
64_OL -70_OL 
Day 77_OL 
71_OL -77_OL 
 
Symptomatic remission over time will be analyzed by generalized linear mixed effect model using 
the logit link and with treatment, visit, ES at baseline, UC medications at baseline, treatment group 
by visit interactions as fixed effects and subjects as random effect.  
A by-subject listing with symptomatic remission over time will also be provided. 
8.3.6. 
Time to Symptomatic Remission (Symptom Scores), during the Induction 
Treatment 
For the induction treatment period, Kaplan-Meier (K-M) plots of the time to symptomatic 
remission from the date of randomization will be produced for each treatment group, overall and 
by stratification factor. The median time to symptomatic remission and the corresponding 2-sided 
95% CI will be summarized for each treatment group. Time to symptomatic remission will be 
tested between each treatment arm and placebo overall using a stratified log-rank test and 
separately within stratification factor level by the log-rank test. This will be done for ITT_IP and 
mITT-1_IP populations only. 
For subjects with symptomatic remission during the induction treatment period, the date of 
symptomatic remission will be used as the event date. For subjects without symptomatic remission 
during the induction treatment period, the following censoring rules will be used: 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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• Subjects who are lost to follow-up or discontinued the trial prematurely during the 
induction treatment period are censored on the last date of contact during this period.  
• Subjects who die during the induction treatment period are censored on the date of death. 
• Subjects who complete the induction treatment period are censored on the date of last 
eDiary entry for SF/RB scores, or the date before entering Open-Label or Maintenance 
period, whichever is earlier. 
 
8.3.7. 
Time to UC flare during Maintenance Phase 
K-M plots of the time to UC flare from the date of re-randomization (maintenance treatment 
period) will be produced for each treatment group and overall. The median time to UC flare and 
the corresponding 2-sided 95% CI will be summarized for each treatment group. Time to UC flare 
will be tested between the treatment arm and placebo by the log rank test. This will be done for 
mITT-1_MP population only. 
For subjects with UC flare during the maintenance treatment period, the date of UC flare will be 
used as the event date. For subjects without UC flare during the induction treatment period, the 
following censoring rules will be used: 
• Subjects who are lost to follow-up or discontinued during the maintenance treatment 
period are censored on the last date of contact during this period.  
• Subjects who die during the maintenance treatment period are censored on the date of 
death.  
• Subjects who complete the maintenance treatment period are censored on the last date of 
contact during this period. 
8.3.8. 
Inflammatory Bowel Disease Questionnaire (IBDQ) 
Changes from baseline in IBDQ scores (total and sub-scale scores) will be assessed at the end of 
induction treatment, at the end of maintenance treatment and at the end of open-label treatment. 
Appropriate baseline values as defined in Section 6.2.3 will be used for each phase of the study. 
Descriptive statistics will be provided for the value and change from baseline in IBDQ scores. An 
ANCOVA model will be used with the change from baseline in IBDQ scores as the response 
variable, treatment group and stratification factors as the factors, and baseline IBDQ scores as a 
covariate. The least square means along with their 95% 2-sided CIs will be presented for the 
change from baseline in IBDQ scores for each treatment arm. The least square means along with 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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their 95% 2-sided CIs for the differences between treatment groups in changes from baseline in 
IBDQ scores will also be presented. 
 
The IBDQ 32-item questionnaire is summarized as a total score ranging from 32 to 224. The items 
are grouped into the following sub-scale scores: 
 
• IBDQ Bowel symptoms score = sum of (Q1, Q5, Q9, Q13, Q17, Q20, Q22, Q24, Q26, 
Q29), ranging from 10 to 70, 10 questions 
• IBDQ Emotional function score = sum of (Q3, Q7, Q11, Q15, Q19, Q21, Q23, Q25, Q27, 
Q30, Q31, Q32), ranging from 12 to 84, 12 questions 
• IBDQ Social function score = sum of (Q4, Q8, Q12, Q16, Q28), ranging from 5 to 35, 5 
questions 
• IBDQ Systemic symptoms score = sum of (Q2, Q6, Q10, Q14, Q18), ranging from 5 to 
35, 5 questions 
 
A by-subject listing with IBDQ scores will also be provided. 
 
8.3.9. 
Biomarker Analysis 
CRP change from baseline will be analyzed using the same method as for IBDQ scores. Both 
observed case and LOCF imputation for missing values will be used. It will be presented for mITT-
1 population only. 
Changes in fecal calprotectin will be summarized in a similar manner as CRP. In addition, 
normalization status (as evaluated by lab normal range) of post-baseline fecal calprotectin from 
baseline normalization status will be evaluated using a shift table.  
A by-subject listing with biomarker data will also be provided. 
8.3.10. 
Microbiome Outcome Analysis 
A separate Microbiome SAP will be provided by Seres Therapeutics for the following microbiome 
endpoints: 
• Engraftment of SER-287 bacteria over time 
• Composition of the intestinal microbiome through the end of the maintenance treatment 
and open-label treatment periods 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
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• Signatures of host and microbial functional responses through the end of the maintenance 
treatment and open-label treatment periods 
 
9. 
SUBGROUP ANALYSES 
There are specific subgroups of interest which will be performed for the primary endpoint and key 
secondary endpoints in induction phase. All subgroup analyses will be conducted for mITT-1 
population only. Endpoints will be summarized by treatment group and overall for the subgroups 
defined based on the categorized variables listed below: 
• Age (< 65 and ≥ 65 years and < 35 and ≥ 35 years) 
• Gender (Female, Male) 
• Race (Asian, Black of African American, White and Other) 
• Duration of UC (years from date of diagnosis to date of informed consent): < 1 years, ≥ 
1 - < 3 years, ≥ 3 - < 7 years, ≥ 7 years) 
• Country (US, Canada) 
• ES subscore (1-2 vs. 3) and (1 vs. 2 vs. 3) 
• Baseline UC Medication (collapsed categories based on IXRS: 5-ASA or 
immunomodulators vs. None) 
• Disease severity (Mild vs. Moderate) 
o Mild (Modified Mayo Score of 3-4) vs. Moderate (Modified Mayo Score of 5-7) 
o Mild (Modified Mayo Score of 3-5) vs. Moderate (Modified Mayo Score of 6-7) 
• Baseline RHI score:  missing, 0-3 (normal); 4-6 (mild); >6 Stratification factor levels: 
o 1 = ES 1 or 2 and 5-ASA or immunomodulators 
o 2 = ES 1 or 2 and none 
o 3 = ES 3 and 5-ASA or immunomodulators 
o 4 = ES 3 and none 
• Screening fecal calprotectin (≤ 500 and > 500 ug/g, ≤ 250 and > 250 ug/g) 
• Extent and location of disease localization (Proctosigmoiditis, Left sided colitis, 
Extensive colitis, Pancolitis) 
• Status of biologics therapy prior to entering the study (Yes vs. No, and Failed vs. Naïve 
or received and did not fail). 
o Anti-TNF 
o Anti-integrin 
o Anti-IL 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
56 of 61 
 
21-APR-2021 
Confidential 
v 5.0 
• Status of non-biologics therapy prior to entering the study (Yes vs. No, Failed vs. Naïve 
or  received and did not fail) 
o Non-biologics (e.g. tofacitinib, filgotinib, upadacitinib, apremilast, ameselimod, 
ozanimod, etrasimod) 
• Status of advanced therapy (including biologic therapy or non-biologic therapy) prior to 
entering the study (Yes. Vs. No., Failed at least one of the therapies vs. Naïve or received 
and did not fail). 
 
In addition, clinical remission and endoscopic improvement at the end of maintenance will be 
summarized by treatment group and overall for the subgroup defined below: 
• Subject’s treatment assignment in the induction phase (Arm A: Placebo/Placebo, Arm B: 
Vancomycin/SER-287 Induction Dose, Arm C: Vancomycin/SER-287 Step-Down 
Induction Dose) 
 
If the value of the grouping variable cannot be determined, the patient will be excluded from 
the corresponding subgroup analysis.  
10. 
SAFETY 
All safety analyses will be conducted in the Safety populations, unless specified otherwise. 
Subjects will be analyzed according to the treatment they receive, rather than that to which they 
are randomized.   
Safety endpoints will be summarized for each treatment period (pre-treatment, induction treatment, 
maintenance treatment, open-label treatment, and safety follow-up period). 
Each Safety table will have a variable identify the period. The total number (N) of subjects at each 
period will be: 
• For pre-treatment: N = # of subjects in Safety_IP 
• For induction treatment: N = # of subjects in Safety_IP 
• For maintenance treatment: N= # of subjects in Safety_MP 
• For open-label: N= # of subjects in Safety_OL 
• For safety follow-up: N= # of subjects entering follow-up period 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
57 of 61 
 
21-APR-2021 
Confidential 
v 5.0 
 
Note that, during the first four (4) weeks of the long-term safety follow-up period, 
AEs/SAEs/AESIs will be collected. Only SAEs/AESIs will be collected starting from the four (4) 
week follow-up call through the End of Study. For this period, summaries will be presented for 
subjects who enter the follow-up period from induction treatment, from maintenance treatment, 
and from open-label treatment. A total combining the numbers from all these 3 groups will also be 
provided. 
10.1. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
Duration of study drug exposure includes the study drug exposure during pre-treatment period, 
induction treatment period, maintenance treatment period, and open-label treatment period. The 
duration of exposure is computed as the following: 
• Duration of Exposure during Pre-Treatment Period = Last Dose Date during Pre-
Treatment Period (from “End of Treatment” CRF Page) – First Dose Date during 
Pre-Treatment Period (from “Status” CRF page) + 1. 
• Duration of Exposure during Induction Treatment Period = Last Dose Date 
during Induction Treatment Period (from “End of Treatment” CRF Page) – First 
Dose Date during Induction Treatment Period (from “Status” CRF page) + 1. 
• Duration of Exposure during Maintenance Treatment Period = Last Dose Date 
during Maintenance Treatment Period (from “End of Treatment” CRF Page) – 
First Dose Date during Maintenance Treatment Period (from “Status” CRF 
page) + 1. 
• Duration of Exposure during Open-Label Treatment Period = Last Dose Date 
during Open-Label Treatment Period (from “End of Treatment” CRF Page) – 
First Dose Date during Open-Label Treatment Period (from “Status” CRF page) 
+ 1. 
 
Duration of study drug exposure will be summarized by descriptive statistics by treatment group 
for each period. 
Compliance rates defined below will be summarized by treatment groups for induction, 
maintenance and open-label treatment periods. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
58 of 61 
 
21-APR-2021 
Confidential 
v 5.0 
Compliance rate (capsules) = (number of capsules dispensed – number of capsules returned) / 
capsules expected to be taken) * 100 
The number of capsules dispensed and returned are documented in the Cenduit Interactive 
Response Technology system in each period. 
The capsules expected to be taken is calculated by # of capsules expected for each day x # of 
days in each period. For the pre-treatment period, # of capsules will be capped at 24 capsules. 
The compliance rate will be summarized descriptively by treatment group for each period. The 
Total # of subjects (N) will be the # of subjects entering each corresponding period. 
10.2. 
ADVERSE EVENTS 
AEs will be coded by using the MedDRA V21.0. A Treatment-Emergent Adverse Event (TEAE) 
is any AE that newly appeared, increased in frequency, or worsened in severity after initiation of 
study drug (including the pre-treatment period).   
 
AE summaries will be presented by treatment group for each period. 
 
An overall summary of AEs will be presented by treatment group, including the number and 
percentage of subjects, and the number of events for: 
• Any TEAEs 
•  Study drug related (including related and possibly related) TEAEs 
• Serious TEAEs 
•  Treatment-emergent AESIs 
• Severe TEAEs 
•  TEAEs leading to study drug discontinuation 
• TEAEs leading to death 
 
The overall summary of AEs will also be presented by treatment group and by baseline ES and 
baseline UC medication (collapsed categories based on CRF) stratum. 
 
The number and percentage of subjects with TEAEs will be tabulated by system organ class (SOC) 
and preferred term (PT) for each treatment group and stratum.  Serious TEAEs, AESIs and TEAEs 
leading to study discontinuation will be similarly tabulated. For this study, UC Flare and invasive 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
59 of 61 
 
21-APR-2021 
Confidential 
v 5.0 
infections (e.g., bacteremia, abscess, meningitis) have been designated as AESIs. Summaries of 
TEAEs by maximum severity and by maximum relationship to study drug will also be summarized 
by SOC and PT.  
 
The overall summary of AEs, TEAE by SOC and PT and Serious TEAE by SOC and PT will also 
be provided by SER-287 donor. It will be for the induction period. 
 
A listing of all TEAEs and listings of deaths will be provided. 
10.3. 
LABORATORY EVALUATIONS 
Quantitative chemistry and hematology tests (observed values and change from baseline) will be 
summarized descriptively in tabular format by visit and treatment period.  For pre-treatment and 
induction treatment period, the baseline value before the first pre-treatment dose is used. For 
maintenance and open-label treatment periods, the value before the subject entering the period will 
be used as the baseline of the period, and a summary for the pre-treatment baseline will also be 
included in the summary. A shift table will be presented for chemistry, hematology and urinalysis 
tests shift from baseline to each post-baseline visit 
10.4. 
VITAL SIGNS 
Descriptive statistics of the vital signs will be presented by treatment group by visit and treatment 
period.  The change from baseline to each post-baseline visit will also be summarized by treatment 
group. For pre-treatment and induction treatment period, the baseline value before the first pre-
treatment dose is used. For maintenance and open-label treatment periods, the value before the 
subject entering the period will be used as the baseline. 
10.5. 
PHYSICAL EXAMINATION 
Abnormal clinically significant physical examination (PE) finding will be reported as medical 
history or as an AE. 
 
A by-subject listing of physical examination will also be provided. 
 
11. 
CHANGES FROM ANALYSIS PLANNED IN PROTOCOL 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
60 of 61 
 
21-APR-2021 
Confidential 
v 5.0 
11.1. 
STRATIFICATION FACTORS THAT ARE USED IN THE ANALYSIS 
For the analysis for efficacy endpoints using CMH method, the stratification factors as defined by 
the study protocol was by ES at baseline (1-2 vs. 3), and UC medications at baseline (5-ASA alone 
vs. immunomodulators with or without 5-ASA vs. none). Because there are few subjects in the 
category of “immunomodulators with or without 5-ASA”, the stratification factors for UC 
medications at baseline are collapsed to “5-ASA or immunomodulators” vs. “none” in the analysis. 
11.2. 
SENSITIVITY ANALYSES ON SAFETY POPULATION 
In protocol section 9.5.5, the following is stated: 
Sensitivity Analyses for the primary and key secondary efficacy endpoint will be 
performed in the mITT-1, mITT-2, Safety and PP populations. 
Since the Safety population is not relevant for efficacy analysis, the efficacy analysis will not be 
performed for Safety population. 
12. 
REFERENCE LIST 
Food and Drug Administration Center for Drugs Evaluation Research (CDER). (2016). Guidance 
for Industry: Ulcerative Colitis: Clinical Trial Endpoints (FDA Maryland). 
Han, B., Yu M., and McEntegart D., (2013), Weighted re-randomization tests for minimization 
with unbalanced allocation, Pharmaceut. Statist., 12 243–253.  
Lachin John M (2011). Biostatistical methods: the assessment of relative risks. New York, NY:  
John Wiley & Sons. 
Mosli, M.H., Feagan, B.G., Zou, G., Sandborn W.J., D'Haens, G.D., Khanna, R., Shackelton, 
L.M., Walker, C.W., Nelson, S., Vandervoort, M.K., et al. (2017). Development and validation 
of a histological index for UC. Gut 66, 50-58. 
Schafer, J. L. (1997). Analysis of Incomplete Multivariate Data. New York: Chapman & Hall. 
Sandborn, W.J., Ghosh, S., Panes, J., Vranic, I., Su, C., Rousell, S., and Niezychowski, W. 
(2012). Tofacitinib, an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis. N. Engl. J. Med. 
367, 616-624. 


 
TITLE 
ECO-RESET: A Phase 2B, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose, Multicenter Study to Assess 
Efficacy and Safety of SER-287 in Adults with Active Mild-to-
Moderate Ulcerative Colitis 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO. 
SERES-201 
PAGE NO 
61 of 61 
 
21-APR-2021 
Confidential 
v 5.0 
Sandborn, W.J., Feagan, B.G., Wolf, D.C., D'Haens, G., Vermeire, S., Hanauer, S.B., Ghosh, S., 
Smith, H., Cravets, M., Frohna, P.A., et al. (2016). Ozanimod Induction and Maintenance 
Treatment for Ulcerative Colitis. N. Engl. J. Med. 374, 1754-1762. 
Sandborn, W.J., Su, C., Sands, B.E., D'Haens, G.R., Vermeire, S., Schreiber, S., Danese, S., 
Feagan, B.G., Reinisch, W., Niezychowski, W., et. al. (2017). Tofacitinib as Induction and 
Maintenance Therapy for Ulcerative Colitis. N. Engl. J. Med. 376, 1723-1736. 
13. 
PROGRAMMING SPECIFICATIONS 
The Specification for analysis data sets will be presented in a separate document. 
14. 
MOCK TABLES, LISTINGS AND FIGURES (TLFS) 
The mock TLFs will be presented in a separate document.