Clinical trial NCT02618187
Conditions: Ulcerative Colitis
Sponsor: Seres Therapeutics, Inc.
Start date: 2016-01-13; Completion date: 2018-01-26
Enrollment: 58 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Multiple Dose Study to Evaluate the Safety, Tolerability and Microbiome Dynamics of SER-287 in Subjects with Mild-to-Moderate Ulcerative Colitis.

Detailed description:
This is a Phase 1b multicenter, randomized, double-blind, placebo-controlled multiple dose study designed to evaluate the safety and tolerability of SER-287, and to evaluate the microbiome alterations and pharmacodynamics associated with two dosing regimens of SER-287 in adult subjects with active mild-to-moderate ulcerative colitis (UC).

Arms: arm 1: Placebo pre-treatment, followed by once weekly dosing of SER-287 for 8 weeks arm 2: Placebo pre-treatment, followed by once daily placebo for 8 weeks arm 3: Vancomycin pre-treatment, followed by once daily dosing of SER-287 for 8 weeks arm 4: Vancomycin pre-treatment, followed by once weekly dosing of SER-287 for 8 weeks
Interventions: intervention 1: SER-287 intervention 2: Placebo intervention 3: Placebo Pre-Treat intervention 4: Vancomycin Pre-Treat
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
SAP_002.pdf: 


MICROBIOME STATISTICAL ANALYSIS PLAN 
 
 
SERES-101 
 
A Multiple Dose Study to Evaluate the Safety, Tolerability and Microbiome Dynamics of  
SER-287 in Subjects with Mild-to-Moderate Ulcerative Colitis 
 
Statistical Analysis Plan for Primary and Exploratory Microbiome Endpoints 
 
 
Version:  Final 1.0  
 
Date: 12 July 2017 


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REVISION HISTORY 
Final 1.0:  
12 July 2017 
 
 


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AUTHORS 
Primary Author: 
Sheri Simmons, Ph.D. 
Senior Scientist, Microbiome Sciences 
Seres Therapeutics, Inc. 
 
Contributors: 
Liyang Diao, Ph.D. 
Computational Scientist, Bioinformatics  
Seres Therapeutics, Inc. 
 
Edward O’Brien, Ph.D. 
Scientist, Microbiome Sciences 
Seres Therapeutics, Inc. 
 
Mauris Nnamani, Ph.D. 
Scientist, Molecular Technologies 
Seres Therapeutics, Inc.  
 
Alice Liou, DVM, Ph.D. 
Scientist, Immunology 
Seres Therapeutics, Inc.  
 
Matthew Henn, Ph.D. 
Senior VP, Head of Drug Discovery & Bioinformatics 
Seres Therapeutics, Inc. 
 


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SIGNATURE PAGE - Seres Therapeutics, Inc. 
 
Declaration 
The undersigned has/have reviewed and agree to the statistical analyses and procedures of this 
clinical study, as presented in this document. 
 
 
 
 
 
 
Jeff Zhao, Ph.D. 
 
Date (DD Mmm YY) 
Director, Biostatistics 
 
 
 
 
 
 
 
 
Michele Trucksis, MD, Ph.D.. 
 
Date (DD Mmm YY) 
Executive Vice President and Chief Medical Officer 
 
 
 
 
 
 
Matthew Henn, Ph.D. 
 
Date (DD Mmm YY) 
Senior Vice President, Head of Drug Discovery & 
Bioinformatics 
 
 
 


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TABLE OF CONTENTS 
REVISION HISTORY.................................................................................................................... 2 
AUTHORS ...................................................................................................................................... 3 
TABLE OF CONTENTS ................................................................................................................ 5 
ABBREVIATION AND ACRONYM LIST .................................................................................. 7 
1. 
MICROBIOME STATISTICAL ANALYSIS PLAN ....................................................... 8 
2. 
STUDY OBJECTIVES ..................................................................................................... 9 
2.1 
Primary Objectives ............................................................................................... 9 
2.2 
Secondary Objectives ........................................................................................... 9 
2.3 
Exploratory Objectives ......................................................................................... 9 
3. 
STUDY DESIGN ............................................................................................................ 10 
4. 
STUDY POPULATION .................................................................................................. 12 
5. 
STATISTICAL BASIS FOR SAMPLE SIZE ................................................................. 13 
6. 
SUBJECT IDENTIFICATION AND RANDOMIZATION ........................................... 14 
6.1 
Breaking the Study Blind at the End of Study ................................................... 14 
7. 
STATISTICAL ANALYSIS CONVENTIONS .............................................................. 16 
7.1 
Analysis Variables .............................................................................................. 16 
 
Primary Endpoints .......................................................................................... 16 
 
Schedule of Assessments for Primary and Exploratory 
Endpoints ......................................................................................... 16 
 
Sample and Sequencing Variables .................................................. 18 
 
Exploratory Endpoints .................................................................................... 18 
7.2 
Analysis Populations .......................................................................................... 18 
 
Microbiome Modified Intent-to-Treat (mcITT) Population ........................... 18 
 
Sensitivity Analysis Population - 1 ................................................................. 19 
 
Long-term Engraftment (LTE) Population ..................................................... 19 
 
Mucosal biopsy analysis population (MBP) ................................................... 19 
 
Metabolomic analysis population (MTP) ....................................................... 19 
7.3 
Statistical Analysis Methods .............................................................................. 19 
 
Statistical Analysis and Significance Level .................................................... 19 
 
Planned Comparisons for All Endpoints ........................................................ 20 
 
Sample and Sequencing Acceptability Criteria .............................................. 20 
 
Missing and Spurious Data ............................................................................. 21 
 
Endpoints for Analysis.................................................................................... 21 
 
Microbiome Primary Endpoints - Overview ................................... 21 
 
Microbiome Primary Endpoints- Methods ...................................... 22 
 
Microbiome Alteration Primary Endpoint ....................................... 23 
 
Microbiome Engraftment Primary Endpoint ................................... 25 
 
Exploratory Endpoints ..................................................................... 27 


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8. 
REFERENCES ................................................................................................................ 32 
9. 
TABLES AND LISTINGS TO BE INCLUDED IN SECTION 14 OF THE 
CLINICAL STUDY REPORT ........................................................................................ 34 
10. 
FIGURES TO BE INCLUDED IN SECTION 14 OF THE CLINICAL STUDY 
REPORT .......................................................................................................................... 37 
11. 
LISTINGS TO BE INCLUDED IN SECTION 16 OF THE CLINICAL STUDY 
REPORT .......................................................................................................................... 38 
 
 
 


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ABBREVIATION AND ACRONYM LIST  
Abbreviation / Acronym 
Definition / Expansion 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
NGS 
Next Generation Sequencing 
OTU 
Operational Taxonomic Unit 
SAP 
Statistical Analysis Plan 
RNA-seq 
RNA sequencing 
TLF/s 
Tables, Lists, and Figures 
WMS 
Whole Metagenomic Sequencing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. 
MICROBIOME STATISTICAL ANALYSIS PLAN 
This Microbiome Statistical Analysis Plan (SAP) details the statistical methodology to be used in 
analyzing primary and exploratory microbiome endpoint study data and outlines the analysis that 
will 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 Study Protocol (CSP).  This SAP addresses planned analysis and presentation of 
microbiome, transcriptomic, and metabolomic alterations. The analysis of safety and clinical 
efficacy is described in the Clinical Statistical Analysis Plan, which is a separate document.  
The SAP 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). 


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2. 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
• To evaluate the safety and tolerability of SER-287 vs. placebo in adult subjects ≥18 years of 
age with mild-to-moderate ulcerative colitis 
• To compare the baseline composition of the intestinal microbiome to the post-baseline 
composition after initiation of SER-287 or placebo 
• To determine the engraftment of SER-287 bacteria into the intestinal microbial community in 
each of the SER-287 arms compared to the placebo arm 
2.2 
Secondary Objectives 
• To determine the proportion of subjects in each of the treatment arms who, at 8 weeks post 
initiation of treatment, achieve a clinical response, complete remission, and endoscopic 
improvement 
• To assess changes in serum and fecal biomarkers from baseline throughout treatment 
2.3 
Exploratory Objectives 
• To compare the changes in exploratory biomarkers from mucosal biopsies and stool samples 
in each of the treatment arms from baseline throughout treatment. 
• To determine the complement of metabolic pathways from stool in each of the treatment 
arms from baseline throughout treatment. 


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3. 
STUDY DESIGN 
This is a Phase 1b multicenter, randomized, double-blind, placebo-controlled multiple dose study 
designed to evaluate the safety and tolerability of SER-287 and to evaluate the microbiome 
alterations and pharmacokinetics and pharmacodynamics associated with two dosing regimens of 
SER-287 in adult subjects with mild-to-moderate ulcerative colitis (UC). Subjects will be 
randomized to one of 4 study arms:  
A) Pre-treatment of placebo, followed by once weekly dosing of SER- 287 for 8 weeks;  
B) Pre-treatment of placebo, followed by once daily dosing of placebo for 8 weeks;  
C) Pre-treatment of vancomycin, followed by once daily dosing of SER-287 for 8 weeks;  
D) Pre-treatment of vancomycin, followed by once weekly dosing of SER-287 for 
8 weeks. 
The doses, route, and schedule of study drug administration are shown below: 
Group 
Pre-­treatment: Vanco or Pbo 
Treatment Period:  SER-­‐287 or Pbo 
Vanco or 
Pbo 
Regimen 
Admin 
Duration  SER-­287 
or Pbo 
Regimen 
Admin 
Duration 
A 
Pbo 
Pbo 
One capsule 
four times 
daily orally 
6 days 
SER-
287 + 
Pbo 
SER-287 Weekly 
(1x108 SporQs) +Pbo 
6d/wk 
Four capsules 
once daily 
orally 
8 wks 
B 
Pbo 
Pbo 
One capsule 
four times 
daily orally 
6 days 
Pbo 
Placebo Daily 
Four capsules 
once daily 
orally 
8 wks 
C 
Vanco 
Vanco 
125 mg 
qid 
One capsule 
four times 
daily orally 
6 days 
SER-
287 
SER-287 Daily 
(1x108 SporQs) 
Four capsules 
once daily 
orally 
8 wks 
D 
Vanco 
Vanco 
125 mg 
qid 
One capsule 
four times 
daily orally 
6 days 
SER- 
287 + 
Pbo 
SER-287 Weekly 
 (1x108 SporQs)+Pbo 
6d/wk 
Four capsules 
once daily 
orally 
8 wks 
 
The study has 5 study periods: Screening (Day-17 to Day-1), Pre-treatment, Treatment, a 4 Week 
Short Term Safety Follow-up and a Long Term Safety Follow-up.  The Schedule of Events is 
presented in Table 3 of the CSP. 
The Pre-Treatment Period (Day 1 to Day 7) includes administration of either oral vancomycin 
125 mg four times a day for 6 days or matching placebo. 
The Treatment Period (8 weeks, Day 8-63) includes administration of 4 capsules taken orally 
once a day of SER-287 or placebo according to the treatment group to which they have been 


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assigned: SER-287 once daily, SER-287 once weekly with matching placebo on other days, or 
placebo daily. 


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4. 
STUDY POPULATION 
The study population will consist of adult subjects with active mild-to-moderate ulcerative 
colitis. 
Detailed lists of inclusion and exclusion criteria are shown in Sections 4.1 and 4.2 of the CSP. 


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5. 
 STATISTICAL BASIS FOR SAMPLE SIZE 
No formal sample size calculation was performed. A sample size of approximately 55 subjects 
with 15 subjects randomized to each of the active arms (Treatment Groups A, C and D) and 
10 subjects in the placebo arm (Treatment Group B) is considered sufficient to evaluate the 
primary microbiome endpoints and exploratory endpoints of the study. 


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6. 
SUBJECT IDENTIFICATION AND RANDOMIZATION 
Subject identification, methods of assigning patients to study treatment, and randomization codes 
are described in Sections 6.1-6.3 of the Clinical SAP.  
6.1 
Breaking the Study Blind at the End of Study 
The primary study period (Visit 1 through Visit 13) will be conducted as a double-blind study. 
The final database for the primary study period will remain blinded until all clinical data 
collected through Visit 13 has been entered, cleaned and declared complete and final. The CSR 
will be finalized after results from the primary study period are complete; all available data post-
Visit 13 pertaining to mortality will be provided in the CSR. Because of the time lag involved in 
generating microbiome data, clinical results by treatment group, but not subject by subject 
unblinded data, will be available before microbiome analysis for Visit 12 and Visit 13 samples is 
complete. Below, we describe how we will maintain the study blind for analysis of microbiome 
data to ensure unbiased analysis of all populations.  
Samples from Visit 12 and Visit 13 will be processed in a fashion to ensure unbiased analysis of 
all populations. Specifically, blinded genomic data will be generated for samples from Visit 12 
and Visit 13 as samples become available. Data will be processed through a pre-defined 
computational pipeline prior to interim database lock to generate microbiome profiles. During 
this pre-processing step, the study blind will be maintained through the use of dummy 
randomization codes.  
Final TLFs for all patients at Visit 12 will be generated using true treatment codes upon 
unblinding after interim database lock when all subjects complete their Visit 13, but before all 
subjects have completed the long-term safety follow-up (Day 246). 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. To ensure unbiased analysis of Visit 13 samples, we will process blinded 
Visit 13 samples through the pre-defined computational pipeline using dummy randomization 
codes to check data quality and integrity. Generation of final TLFs for the Visit 13 samples using 
unblinded clinical data will not occur until TLFs for Visit 12 are final. 
The primary microbiome genomic sequence datasets will be generated by a team at our audited 
sequencing vendor. Data transfer from the vendor to Seres will occur via encrypted and 
password-protected hard drive and will be transferred to a secure, restricted-access location on a 
Seres server.  All TLFs will be stored in a- secure network location, which only the unblinded 
genomic data team at Seres will be able to access. After interim lock at Visit 13, all clinical data, 


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sequence data, and TLFs will remain unchanged and locked until the study is completed and all 
patients complete the long-term safety follow-up. 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. 


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7. 
STATISTICAL ANALYSIS CONVENTIONS 
7.1 
Analysis Variables 
 
Primary Endpoints 
The following primary endpoints are discussed in this SAP: 
•  Microbiome Alterations  
• Engraftment  
This SAP documents the presentation and analysis of genomic sequence results for assessment of 
microbiome alterations as measured by changes in the composition of the intestinal microbiome, 
and engraftment of SER-287 bacteria. For clarity, we present below the schedule of assessments 
(Table 7.1.1.1) filtered to show only samples collected for the primary and exploratory endpoints 
addressed in this document.  
For the purposes of all analyses described in this document, the baseline sample will be defined 
as the closest evaluable sample collected prior to the start of dosing with vancomycin or placebo 
during the pre-treatment period (Days 1-7).  
 
Schedule of Assessments for Primary and Exploratory Endpoints 
Table 7.1.1.1:  Schedule of Assessments for Primary and Exploratory Endpoints 
Visit 
Number 
Study 
Day 
Sample 
Type 
Study Phase 
Microbiome 
Metabolomics 
Mucosal 
transcriptomics 
Mucosal 
microbiome 
1  
Pre-Tx 
Stool 
Screening 
Y 
Y 
N 
N 
2  
Pre-Tx 
Biopsy 
Screening 
N 
N 
Y 
Y 
3 
1 
Any 
Randomization- 
Start of pre-
treatment 
period 
N 
N 
N 
N 
4 
8 
+/- 
1d 
Stool 
Initiation of 
treatment 
period 
Y 
Y 
N 
N 


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4 
11 +/- 
1d 
Stool 
Treatment 
period 
Y 
Y 
N 
N 
5 
15 +/- 
1d 
Stool 
Treatment 
period 
Y 
N 
N 
N 
5 
18 +/- 
1d 
Stool 
Treatment 
period 
Y 
N 
N 
N 
6 
22 +/- 
1d 
Stool 
Treatment 
period 
Y 
Y 
N 
N 
7 
29 +/- 
1d 
Any 
Treatment 
period 
N 
N 
N 
N 
8 
36 +/- 
1d 
Any 
Treatment 
period 
N 
N 
N 
N 
9 
43 +/- 
1d 
Any 
Treatment 
period 
N 
N 
N 
N 
10 
50 +/- 
1d 
Any 
Treatment 
period 
N 
N 
N 
N 
11 
57+/- 
1d 
Any 
Treatment 
period 
N 
N 
N 
N 
12 
64 +/- 
3d 
Stool + 
Biopsy 
End of 
treatment 
period 
Y 
Y 
Y 
Y 
13 
92 +/- 
2d 
Stool 
Short term 
safety follow-
up 
Y 
Y 
N 
N 
 


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Sample and Sequencing Variables  
The record of stool samples collected at Visit 1, Visit 4, Visit 5, Visit 6, Visit 12 and Visit 13 or 
the Early Termination Visit (if applicable), and any Unscheduled Visit will include record of 
date and time produced, refrigerated (Yes/No) and status (frozen, ambient or cooled).  
Sequencing quality variables will include the number of total sequencing reads, the number of 
reads mapping to human genome, and/or the number of reads mapping to a taxonomic marker 
database.  
 
Exploratory Endpoints 
The following exploratory endpoints are discussed in this SAP: 
• Stool metabolic pathways 
Samples collected for stool metabolomic profiling are described in Section 7.1.1.1 and will 
be analyzed as described in Section 7.3.5.5.1.   
• Mucosal microbiome profiling 
Mucosal microbiome profiling will be performed on biopsy samples collected at Visit 2 and 
Visit 12. Analysis of these results is described in Section 7.3.5.5.3. 
• Mucosal transcriptomic profiling  
Mucosal transcriptome profiling will be performed on biopsy samples collected at Visit 2 and 
Visit 12. Analysis of these results is described in Section 7.3.5.5.2. 
7.2 
Analysis Populations 
Populations for analysis are reported in Listings 16.2.1-16.2.5. 
 
Microbiome Modified Intent-to-Treat (mcITT) Population 
The Microbiome Modified Intent-to-Treat (mcITT) Population will consist of all randomized 
patients with an evaluable stool sample collected at baseline, and at least one evaluable stool 
sample collected on or between Visits 4 and 6, inclusive, who were exposed to any amount of 
study drug, and will be analyzed based on the treatment to which they were randomized. All 
primary endpoint analyses specified in this SAP will be carried out on the mcITT population or 
subsets thereof as defined below. The mcITT population is reported in Listing 16.2.1. 


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Sensitivity Analysis Population - 1  
The Sensitivity Analysis Population – 1 (SAP – 1) will consist of all randomized subjects with an 
evaluable stool sample collected at baseline and one evaluable stool sample collected at Visit 12 
or Early Termination (ET) visit collected within a 2 week window surrounding Visit 12. The 
SAP—1 population is reported in Listing 16.2.2. 
 
Long-term Engraftment (LTE) Population 
The LTE Population will be a subset of the SAP—1 population. It will consist of all patients 
meeting the criteria of the SAP—1 population with the additional requirement of an evaluable 
stool sample collected at Visit 13. If subjects terminated early from the treatment period but 
continued in the study and finished short-term safety follow-up, they will not be included in the 
LTE population. The LTE population is reported in Listing 16.2.3. 
 
Mucosal biopsy analysis population (MBP) 
The mucosal biopsy analysis population will consist of all randomized patients with evaluable 
biopsy samples collected at both Visit 2 and Visit 12, and will be analyzed based on the 
treatment to which they were randomized. If subjects terminated early from the treatment period 
with collection of an evaluable biopsy sample, then that subject will be included in the analysis. 
The MBP population is reported in Listing 16.2.5. 
 
Metabolomic analysis population (MTP)  
The metabolomic analysis population will consist of all randomized patients with an evaluable 
stool sample for metabolomics collected at baseline and at least one evaluable stool sample 
collected at Visit 12 or ET visit (provided that the ET visit occurred within a 2 week window 
surrounding Visit 12) and will be analyzed based on the treatment to which they were 
randomized. The MTP population is reported in Listing 16.2.5. 
7.3 
Statistical Analysis Methods 
 
Statistical Analysis and Significance Level 
Statistical analyses will be separately defined for each endpoint. There will be no adjustment of 
p-values for multiplicity unless specifically noted. P-values generated for this study are not 
intended to be conclusive, but provided for guidance only. 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’. 


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Planned Comparisons for All Endpoints  
In general, inferential analysis will be based on the following pairwise comparisons:  
• Treatment groups A, C and D separately compared to placebo (B). Compares individual pre-
treatment and dosing regimens to placebo.  
•  A and D pooled together compared to placebo (B).  Compares arms with weekly 
administration of SER-287 regardless of vancomycin pre-treatment with placebo.  
• A, C and D pooled together compared to placebo (B). Compares all arms with SER-287 
treatment to placebo.   
• The A vs D comparison examines the impact of vancomycin pre-treatment outcomes for 
subjects who received weekly doses of SER-287.  
• The C vs D comparison examines the impact of daily versus weekly dosing for subjects who 
received vancomycin pre-treatment.  
 
Sample and Sequencing Acceptability Criteria 
Samples are collected according to the time period described in the Schedule of Events. The 
samples collected out of visit window will be mapped to the closest appropriate visit.  A 
sensitivity analysis may be conducted after excluding those samples collected out of visit 
window which are considered as major protocol deviations.  Failure to meet sequencing quality 
thresholds defined prior to unblinding will result in removal of a sample from analysis. 
Deviations in sample handling may result in removal of a sample from analysis. If removal of a 
sample causes a subject to no longer meet the criteria defined for analysis populations as defined 
in Section 7.2, the subject will be removed from the analysis population prior to unblinded 
analysis. 
Specifically, sequencing quality thresholds will be assessed as follows. To ensure comparability 
between different drug product lots and between subject samples, each sample will be 
subsampled after read mapping to a taxonomic marker database to equalize the number of 
mapped reads before subsequent analyses. Subsampling will be performed to a read level which 
maximizes the number of included samples, but which is above a predefined base level of 
mapped reads to ensure sample quality. Any subject sample with a number of mapped reads 
below this base level will be discarded from further analysis, with the exception that drug 
product lots with mapped reads below the base level will be resequenced as appropriate until the 
base level of mapped reads is achieved. These criteria will be defined and pre-coded in the 
computational pipeline prior to the interim Visit 13 clinical database lock.  


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The number of samples from all subjects which pass quality criteria at each timepoint will be 
reported for the mcITT population in Table 14.4.1, the Sensitivity Analysis Population—1  in 
Table 14.4.2, the LTE population in Table 14.43, the MTP population in Table 14.4.4, and the 
MBP population in Table 14.4.5.  
 
Missing and Spurious Data  
For the purposes of primary and exploratory endpoint analyses, an ET visit will be considered to 
be equivalent to a Visit 12 visit if the ET visit occurred within a two week window surrounding 
Visit 12. In this subset of cases, the ET sample will be pooled with Visit 12 samples for analysis.  
Missing data will not be imputed. Any apparently spurious data will be verified. No verified data 
will be excluded from summaries or analyses. 
 
Endpoints for Analysis 
 
Microbiome Primary Endpoints - Overview  
Here we describe methods for analysis of genomic sequence results of the stool samples and 
assessment of microbiome alterations, composition of the intestinal microbiome and engraftment 
of SER-287 bacteria. Engraftment refers to the germination and outgrowth of the bacterial spores 
in the drug product. The analysis populations for the microbiome endpoints are the mcITT, 
Sensitivity Analysis Population-1, and LTE populations.  
Microbiome alteration and engraftment of SER-287 bacteria will be assessed between Study Day 
11 and Visit 12 or Early Termination, inclusive, as defined above. For the LTE population 
analysis, microbiome alteration and engraftment will be assessed additionally at Visit 13. If 
subjects have evaluable Study Day 8 samples (defined as the end of the pre-treatment period) we 
will also characterize the subject microbiome immediately prior to the initiation of SER-287 
dosing.  
All comparisons and statistics will be reported as described below for the mcITT, Sensitivity 
Analysis Population –1, and LTE populations.  P-values generated for this study are not intended 
to be conclusive, but are provided for guidance only.  
The composition of the microbiome will be measured in terms of both the number of unique 
types of spore-forming bacteria (i.e., α-diversity) and the microbial composition, including both 
spore-forming and non-spore-forming bacteria (i.e., β-diversity).  Differences between changes 
in the microbiome across treatment arms, as specified in Section 7.3.2, will be evaluated using 
both non-parametric tests for α-diversity and multivariate analysis of variances of dissimilarity 


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matrices for β-diversity. Engraftment of SER-287 bacteria will be measured in terms of the 
prevalence and richness of specific spore-forming bacteria found in SER-287 drug product in 
stool from subjects. 
We will perform sensitivity analyses comparing whether any use of antibiotics after initiation of 
treatment with SER-287 or placebo (Study Day 8) affected subject microbiome profiles for the 
mcITT and LTE populations, if applicable. The sensitivity population will be defined to exclude 
subjects who used any antibiotic during the treatment period (Visit 4 through Visit 12).  
 
Microbiome Primary Endpoints- Methods  
SER-287 is an ecology of bacterial spores enriched from human stool. We will assess the 
taxonomic composition of SER-287 drug product lots used in the SERES-101 trial 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. WMS data can be used to identify specific species in samples of interest 
(Franzosa et al., 2015), subject to limitations due to assay sensitivity and the availability of 
complete bacterial genomes required for constructing reference databases. 
Taxonomic profiling of WMS reads for both SER-287 drug product lots and subject samples will 
be performed using the MetaPhlAn2 software (Segata et al., 2012; Truong et al., 2015), a widely 
used and extensively evaluated method (Sczyrba et al., 2017) that was foundational to the 
Human Microbiome Project (The Human Microbiome Project Consortium 2012). The 
MetaPhlAn2 method involves mapping filtered sequencing reads to a set of ~1 million species-
specific genomic markers covering 7500 species, followed by estimation of the relative 
abundance of each species based on the distribution of mapped reads (Truong et al., 2015). Raw 
WMS sequence reads will be pre-processed to remove human sequences following methods used 
in the HMP (The Human Microbiome Project Consortium 2012) and to filter out technical 
artifacts before mapping.  
To ensure comparability between different drug product lots and between subject samples, each 
sample will be subsampled after read mapping to a taxonomic marker database to equalize the 
number of mapped reads before subsequent analyses. Subsampling will be performed to a read 
level which maximizes the number of included samples, but which is above a predefined base 
level of mapped reads to ensure sample quality. Any subject sample with a number of mapped 
reads below this base level will be discarded from further analysis, with the exception that drug 
product lots with mapped reads below the base level will be resequenced as appropriate until the 
base level of mapped reads is achieved. These criteria will be defined and pre-coded in the 


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computational pipeline prior to the interim Visit 13 clinical database lock. Outputs from this pre-
defined computational pipeline will be referred to as the “microbiome profile” of a sample. 
For analyses of the diversity of spore forming bacteria, the set of species identified by 
MetaPhlAn2 will be filtered against a proprietary, curated database of species experimentally 
demonstrated to form spores or identified in the literature as spore-forming species. For analyses 
of engraftment, the set of spore-forming species found in patients will be filtered against the set 
of spore-forming species identified in SER-287 drug product lots.  
 
Microbiome Alteration Primary Endpoint 
Richness of spore-forming bacteria (Alpha-diversity)  
 
We will explore whether treatment with SER-287 impacts bacterial richness (Sobs) in subject 
stool samples as compared with placebo. The strength of the Sobs index is that it accounts for the 
total number of species present in a sample, despite potential experimental bias in evaluating 
relative abundance, as is characteristic of microbial data sets (Chao, 1984; Colwell and 
Coddington, 1994; Hughes et al., 2001). Here, we will examine the change in bacterial richness 
from baseline for the visits specified below (∆Sobs). ∆Sobs is a quantitative measure of the change 
in the number of microbes in a subject relative to baseline. ∆Sobs will be calculated using WMS 
data subsampled as described above. To assess changes in α-diversity we will use the 
nonparametric two-sided Mann-Whitney U test to determine if there is a change in the ∆Sobs 
diversity metric in subjects receiving SER-287 relative to subjects receiving placebo. We will 
also report on the change in richness of spore-forming species only (∆Sobs_spore) and the change in 
richness of non-spore forming species (∆Sobs_nonspore).  
We will test the following hypotheses at Visits 4, 5, 6, 12, and 13 for the mcITT, SAP—1, and 
LTE populations (Section 7.2):  
• H0: The distribution of ∆Sobs values does not differ between subjects treated with SER-
287 and placebo subjects. 
• HA: The distribution of ∆Sobs values differs between subjects treated with SER-287 and 
placebo subjects. 
Two-sided non-parametric Mann-Whitney U tests will be applied to each comparison detailed in 
Section 7.3.2 and p-values will be reported. Summary statistics for changes in spore-former and 
non-spore former richness will also be reported for each analysis population. Results for the 
mcITT population are reported in Tables 14.5.1.1-14.5.1.2 and Figures 14.3.1.1 and 14.3.1.2. 


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Results for the Sensitivity Analysis Population – 1 are reported in Tables 14.5.1.3-14.5.1.4 and 
Figures 14.3.1.1 and 14.3.1.2.  Results for the LTE population are reported in Tables 14.5.1.4-
14.5.1.5 and Figure 14.3.2.1.  
 
Microbiome change (Beta-diversity)  
 
We will explore whether treatment with SER-287 leads to an overall shift in the microbiome 
profile in subjects after the initiation of dosing (Visit 4) relative to the microbiome profile in 
subjects receiving placebo. Specifically, we will apply two complementary and widely used beta-
diversity metrics (Binary Jaccard and Bray-Curtis) to microbiome profiles generated from 
subsampled WMS data. The Binary Jaccard distance ranges between 0 and 1, with 0 indicating 
samples sharing the exact same set of species, and 1 indicating samples that have no species in 
common. The abundance of species is not considered in calculations of the metric. The Bray-
Curtis metric uses the abundance of species in the calculation of distance between samples. 
These methods are widely used in the study of microbial communities and represents a balanced 
approach, with minimal bias to the presence of low- and high-abundance bacteria (Binary 
Jaccard) and sensitivity to changes in abundance (Bray-Curtis) (Parks and Beiko, 2013). 
We will calculate the Binary Jaccard and Bray-Curtis distances between baseline and each 
available post-treatment timepoint for each subject. A Mann-Whitney test will be used to assess 
whether the distributions of these baseline to post-treatment distances differ significantly 
between treatment arms for all the pairwise comparisons detailed in Section 7.3.2. The Mann-
Whitney test will be applied separately to each timepoint.   
Specifically, we will test the following hypotheses at each of Visits 4, 5, 6, 12, and 13 as defined 
for the mcITT, SAP—1, and LTE populations in Section 7.2: 
• H0: The microbiome profile of subjects receiving SER-287 does not differ from the 
microbiome profile of subjects receiving placebo.  
• HA: The microbiome profile of subjects receiving SER-287 differs from the microbiome 
profile of subjects receiving placebo. 
2-sided p-values and summary statistics for the mcITT population are reported in Table 14.5.2.1 
and Figure 14.3.2.1, results for the Sensitivity Analysis Population – 1 are reported in Table 
14.5.2.2 and Figure 14.3.2.2, and results for the LTE population are reported in Table 14.5.2.3 
and Figure 14.3.2.3. 


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Microbiome Engraftment Primary Endpoint  
The set of spore-forming bacteria present in clinical drug product lots of SER-287 will be 
defined by WMS sequencing followed by taxonomic profiling and filtering against a curated 
reference spore former species database as described in Section 7.3.5. Determinations of 
engraftment will be made on the basis of assessing the presence or absence of spore forming 
bacterial species present in SER-287 drug product lots in subject stool after the initiation of 
treatment. The abundance of spore-forming bacteria in SER-287 drug product lots will not be 
considered. Specifically, we will determine which spore-forming bacterial species in SER-287 
drug product lots are absent in subjects at baseline, and are present after the start of treatment 
with SER-287 or placebo. The prevalence and richness of these new SER-287 spore-forming 
species in subject stool will be assessed at each timepoint on or after Study Day 11, which is the 
day the first sample is collected after the initiation of dosing of SER-287 or placebo on Study 
Day 8. Engraftment will be assessed in all pairwise comparisons defined in Section 7.3.2.  
Prevalence of spore-forming species found in drug product lots  
Specifically, we will test the following hypotheses at each of Visits 4, 5, 6, 12, and 13 as defined 
for the mcITT, SAP—1, and LTE populations in Section 7.2: 
• H0: The prevalence of spore-forming species found in drug product lots absent at baseline 
and present after the start of treatment does not differ between subjects treated with SER-287 
versus placebo.   
• HA: The prevalence of spore-forming species found in drug product lots absent at baseline 
and present after the start of treatment differs between subjects treated with SER-287 versus 
placebo.   
To test these hypotheses, we will perform separate tests of significance for the distribution of 
each spore-forming species found in drug product lots across arms. For an overall test of 
engraftment across species, we will aggregate the resulting p-values using Fisher’s combined test 
(Fisher, 1932) to generate a single p-value for the pairwise comparison of each time point by 
subject and by cohort.  
The specific statistical methods used for each pairwise comparison are detailed below: 
• Identify the set of spore-forming species present in SER-287 drug product lots using 
microbiome profiles as described above.  


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• Generate 2x2 contingency tables for each spore-forming species found in drug product lots 
based on the presence or absence of that species in subjects’ stool across treatment groups. 
The contingency table will have two categories: SER-287 spore-forming species present after 
treatment, but absent at baseline, and SER-287 spore-forming species present at baseline.  
• Calculate the 2-sided p-value for Fisher’s exact test on each table. 
• Combine the p-values by Fisher’s combined test and calculate the overall p-value for the 
comparison. We assume that prevalence of individual species are independent of each other.  
Summary results for all pairwise comparisons for the mcITT population will be presented in 
Table 14.6.1. 2-sided p-values for individual species for all pairwise comparisons for the mcITT 
population will be reported in Table 14.6.2. Summary results for all pairwise comparisons for the 
Sensitivity Analysis Population – 1 will be presented in Table 14.6.3. 2-sided p-values for 
individual species for all pairwise comparisons for the Sensitivity Analysis Population – 1 will 
be reported in Table 14.6.4.  Summary results for all pairwise comparisons for the LTE 
population will be presented in Table 14.6.5. 2-sided p-values for individual species for all 
pairwise comparisons for the LTE population will be reported in Table 14.6.6.  
Appearance of new spore-forming species found in drug product lots   
We will also assess engraftment of spore-forming bacteria in SER-287 by examining the richness 
of spore-forming species found in drug product lots which appear newly in subject stool on or 
after Study Day 11 (∆Sobs_spore_dose). To assess changes in α-diversity of SER-287 species from 
baseline to each individual timepoint, we will use the nonparametric one-sided Mann-Whitney U 
test to determine if there is a greater change in ∆Sobs_spore_dose in subjects receiving SER-287 
relative to subjects receiving placebo. 
Specifically, we will test the following hypotheses at each of Visits 4, 5, 6, 12, and 13 as defined 
for the mcITT, SAP—1, and LTE populations in Section 7.2: 
•  H0: The change in richness of spore-forming species (∆Sobs_spore_dose) found in drug 
product lots absent at baseline and present after the start of treatment in subjects treated 
with SER-287 is smaller or equal to that found in placebo.  
• HA: The change in richness of spore-forming species (∆Sobs_spore_dose) found in drug 
product lots absent at baseline and present after the start of treatment is higher in subjects 
treated with SER-287 versus placebo.   


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Results for the mcITT population are reported in Table 14.6.7 and Figure 14.4.1. Results for the 
Sensitivity Analysis Population – 1 are reported in Table 14.6.8 and Figure 14.4.2. Results for 
the LTE population are reported in Table 14.6.9 and Figure 14.4.3.   
 
Exploratory Endpoints 
Results of the following exploratory endpoints collected at baseline and post-baseline visits will 
be listed and presented in descriptive summary tables. 
 
Stool Metabolomic Profiling 
Described here are the statistical methodologies that will be used to analyze stool metabolomic 
datasets from subjects enrolled in SERES-101. The analysis population for the stool 
metabolomic profiling endpoint is the MTP population as defined in Section 7.2.5. Statistics will 
be reported for comparisons outlined in Section 7.3.2.   
Gastrointestinal (GI) microbes produce metabolites that can impact the metabolic state of the 
human host; some of these microbial metabolites can be measured in the host feces. The 
metabolites that are produced and consumed by microbes change the environment of the GI tract 
and in turn affect the health and immune status of the host (Brestoff and Artis, 2013). Literature 
using metabolomic platforms including gas chromatography, LC-MS, and NMR spectroscopy 
support an association of altered microbial metabolite profiles between UC patients and healthy 
volunteers. In particular, in UC patients the fecal bile acid profiles have reduced levels of 
microbial-derived secondary bile acids and are differentially conjugated relative to healthy 
controls (Kruis et al, 1986; Jacobs et al 2016). Additionally, there are reported shifts in fecal 
tryptophan metabolites (e.g. serotonin, indoles, kynurenines), short chain fatty acids, branched-
chain amino acids, and polyamines in UC patients compared to healthy controls (Jacobs et al 
2016, Marchesi et al 2007, Le Gall et al 2011; Bjerrum et al 2015).   
The fecal metabolome of patients in the MTP population will be characterized by LC-MS and/or 
LC-MS/MS through global profiling. We may also perform targeted metabolomic profiling.  In 
targeted metabolomic profiling the concentrations of a specific set of metabolites (e.g., short 
chain fatty acids, bile acids, tryptophan 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. 
We will compare the change in the fecal metabolome of subjects between Visit 12 and baseline 
to determine whether treatment with SER-287 alters the fecal metabolome compared with 
placebo. We will additionally assess whether administration of vancomycin prior to treatment 


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with SER-287 alters the fecal metabolome compared with placebo, via comparison of the change 
in the fecal metabolome between Visit 12 and Study Day 8 for treatment and placebo arms. We 
may additionally assess the fecal metabolome on Study Day 11, Study Day 22, and/or Study Day 
92.  
Specifically, we will test the following hypotheses: 
• H0: The change in the fecal metabolomic profile from baseline and Day 8 to Day 64 does not 
differ between subjects treated with SER-287 versus placebo. 
• HA: The change in the fecal metabolomic profile from baseline and Day 8 to Day 64 differs 
between subjects treated with SER-287 versus placebo.   
We will perform sensitivity analyses comparing whether any use of antibiotics after initiation of 
treatment with SER-287 or placebo (Study Day 8) affected subject metabolome profiles for the 
MTP population, if applicable. The sensitivity population will be defined to exclude subjects 
who used any antibiotic during the treatment period (Visit 4 through Visit 12).  
The change in metabolome profiles (i.e., delta) from baseline to Visit 12 and from Study Day 8 
to Visit 12 for all pairwise comparisons will be assessed. The specific methods used for each 
comparison are detailed below: 
• Calculate the delta in metabolite abundance between timepoints (e.g., baseline to Visit 12, 
Study Day 8 to Visit 12) within each subject.  
• The significance of difference between the sets of delta values for the comparison arms will 
be assessed using a two-sided Mann-Whitney test.  
• Metabolites will be grouped according to pathways based on a proprietary functional 
database curated by the audited metabolomic vendor for the SERES-101 trial. This is referred 
to as the “pathway profile” of a sample.  
• A Fisher’s combined test will be used to assess whether there are overall differences between 
each pathway profile across arms, aggregating across metabolites within a profile. 
The p-values for the 25 most significantly different pathways for delta between baseline and 
Visit 12 will be reported in Table 14.7.1, and p-values for the 25 most significantly different 
pathways for delta between Study Day 8 and Visit 12 will be reported in Table 14.7.2. We will 
additionally report Fisher’s combined p-value aggregated across all metabolites to assess overall 
metabolomic change in Tables 14.7.3 (baseline to Visit 12) and 14.7.4 (Study Day 8 to Visit 12). 


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We may conduct additional exploratory analysis including correlation of metabolomic profiles 
with microbiome profiles and/or clinical biomarkers and outcomes.  
 
Biopsy Transcriptome Profiling 
Described here are the statistical methodologies that will be used to analyze human mucosal 
transcriptomic datasets from subjects enrolled in SERES-101. The analysis population for the 
mucosal transcriptomic profiling endpoint is the MBP population as defined in Section 7.2.4. 
Statistics will be reported for all the comparisons outlined in Section 7.3.2.   
The transcriptome of patients in the MBP population will be characterized with whole 
transcriptome sequencing using next-generation sequencing technology (NGS). RNA-Seq 
analysis on the NGS data from the mucosal biopsy samples from each subject will generate data 
on gene expression in host biopsy tissue, subject to the limit of detection of the RNA-Seq assay. 
Total RNA will be extracted from biopsies and reverse transcribed to generate cDNA libraries 
that are suitable for sequencing using Illumina’s high-throughput short read technology. 
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.  
We will compare the difference (delta) in transcriptome profiles of treatment subjects at Visit 12 
to paired baseline profiles, to the delta in transcriptome profiles of placebo subjects at Visit 12 to 
paired baseline profiles. This comparison of deltas will be made for each predefined comparison 
listed in Section 7.3.2 to determine whether treatment with SER-287 alters the host transcriptome 
profile in subjects compared with placebo.  
Specifically, we will test the following hypotheses: 
• H0: The change in the human transcriptomic profile from baseline to Visit 12 does not differ 
between subjects treated with SER-287 versus placebo. 
• HA: The change in the human transcriptomic profile from baseline to Visit 12 differs between 
subjects treated with SER-287 versus placebo. 
We will use DESeq2 (Love et al. 2014) to assess differential expression for all such comparisons 
to determine whether treatment with SER-287 alters the host transcriptome profile in subjects 
compared with placebo. We will report the top 100 protein-coding human genes differentially 
expressed for each pairwise comparison of deltas between Visit 12 and baseline in Table 14.8.1.  


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We may conduct additional exploratory analysis including correlation of specific differentially 
expressed genes with microbiome profiles and/or clinical biomarkers and outcomes.  
 
Mucosal Microbiome Profiling  
Described here are the statistical methodologies that will be used to analyze mucosal microbiome 
datasets from subjects enrolled in SERES-101. The analysis population for the mucosal 
microbiome profiling endpoint is the MBP population as defined in Section 7.2.4. Statistics will 
be reported for all the comparisons outlined in Section 7.3.2.   
The mucosal microbiome of subjects in the MBP population will be characterized by using 16S 
V4 genomic data sets generated from biopsies collected at the time points defined in Section 
7.1.1.1 (baseline and Visit 12). Genomic data sets will define the microbial composition of the 
mucosal microbiome of a subject at a given time point. We will analyze genomic sequence read 
data sets to assign a taxonomic identity at the resolution of species, the Operational Taxonomic 
Unit (OTU) and phylogenetic clade (clade) and, further, to define the relative proportion of each 
OTU and clade to all other OTUs and clades in a given sample. The resulting data are referred to 
below as the “mucosal microbiome profile.” 
For reference, an OTU is a genetically distinct bacterium as defined by nucleic acid sequence. 
OTUs that share at least 97% of average nucleotide identity across the 16S V4 variable region of 
the 16S are typically considered the same species (Achtman and Wagner, 2008; Konstantinidis et 
al., 2006) Generally, OTU taxonomic assignments derived by using 16S V4 cannot definitively 
resolve bacterial species because of insufficient information content in the 16S V4 region. To 
address this limitation in specificity of such data and to obtain robust taxonomic identities for 
cross-sample comparisons, 16S V4 sequence reads are additionally assigned to phylogenetic 
clades. A clade is a group of distinct bacteria that are phylogenetically more related to one 
another than bacteria in another clade. Clades are defined based on maximum-likelihood 
evolutionary analysis of a curated reference data set of 16S full-length sequences and mapping 
for 16S V4 sequences to this phylogeny. A clade is formally defined as a group of OTUs that 
cluster and are downstream of a statistically valid branch point (Wróbel, 2008) in a phylogenetic 
tree. Clades typically provide a taxonomic resolution that is greater than genus assignment but 
less than species; the resolution depends on the ability of different regions of the reference 
phylogenetic tree to distinguish OTUs at different taxonomic levels. Importantly, clades define 
the group of bacterial species that are not reliably distinguished from one another by using the 
16S V4 sequencing assay but can be distinguished from other bacterial species in other clades. 


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For statistical comparisons, we will compare the mucosal microbiome profile of subjects at the 
clade level. 
We will explore whether treatment with SER-287 leads to an overall shift in the mucosal 
microbiome of treated subjects at the end of the treatment period (Visit 12) relative to baseline, 
in comparison with the corresponding change in the mucosal microbiome profile of subjects 
receiving placebo.  
Specifically, we will test the following hypotheses: 
• H0: The change in the mucosal microbiome profile of subjects receiving SER-287 does 
not differ from the change in the microbiome profile of subjects receiving placebo 
between baseline and Visit 12.   
• HA: The change in the mucosal microbiome profile of subjects receiving SER-287 differs 
from the change in the microbiome profile of subjects receiving placebo between baseline 
and Visit 12.   
We will calculate the Binary Jaccard and Bray-Curtis distances between baseline and each 
available post-treatment timepoint for each subject. A Mann-Whitney test will be used to assess 
whether the distributions of these baseline to post-treatment distances differ significantly 
between treatment arms for all the pairwise comparisons detailed in Section 7.3.2. The Mann-
Whitney test will be applied separately to each timepoint.   
2-sided p-values and summary statistics will be reported for each comparison and beta diversity 
metric. Results will be reported in Table 14.9.1.  


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8. 
REFERENCES 
Achtman M, and Wagner M (2008). Microbial diversity and the genetic nature of microbial 
species. Nat. Rev. Microbiol. 6, 431–440. 
Bjerrum JT, Wang Y, Hao F, Coskun M, Ludwig C, Gunther U, Nielsen OH (2015). 
Metabonomics of human fecal extracts characterize ulcerative colitis, Crohn’s disease and 
healthy individuals. Metabolomics 11:122-133. 
Brestoff JR, and Artis D (2013). Commensal bacteria at the interface of host metabolism and the 
immune system. Nat. Immunol. 14, 676–684. 
Brooks JP, Edwards DJ, Harwich Jr. MD, et al. (2015). The truth about metagenomics: 
quantifying and counteracting bias in 16S rRNA studies. BMC Microbiology, 15:66. 
Chao, A. (1984). Non-parametric estimation of the number of classes in a population. Scand. J. 
Stat. 11, 265–270. 
Colwell, R.K., and Coddington, J.A. (1994). Estimating terrestrial biodiversity through 
extrapolation. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 345, 101–118. 
Hughes, J.B., Hellmann, J.J., Ricketts, T.H., and Bohannan, B.J.M. (2001). Counting the 
Uncountable: Statistical Approaches to Estimating Microbial Diversity. Appl. Environ. 
Microbiol. 67, 4399–4406. 
HMP 
WMS 
read 
pre-processing 
Standard 
Operating 
Procedure 
(SOP) 
http://hmpdacc.org/doc/ReadProcessing_SOP.pdf 
The Human Microbiome Project Consortium (2012) Structure, function and diversity of the 
healthy human microbiome. Nature, 486:207-214.  
Fisher RA, 1932. Statistical Methods for Research Workers, 4th Edition. Oliver and Boyd, 
Edinburgh. 
Love MI, Huber W and Anders S (2014). Moderated estimation of fold change and dispersion 
for RNA-seq data with DESeq2. Genome Biology 15:550. 
Jacobs JP, Goudarzi M, Singh N, Tong M, McHardy IH, Ruegger P, Asadourian M, Moon B0H, 
Ayson A, Borneman J, McGovern DPB, Fornace AJ, Braun J, Dubinsky M (2016). A Disease-
associated microbial and metabolomics state in relatives of pediatric inflammatory bowel disease 
in patients. Cell Mol Gastroenterol Hepatol 2:750-766. 


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Konstantinidis KT, Ramette A, and Tiedje JM (2006). The bacterial species definition in the 
genomic era. Philos. Trans. R. Soc. B Biol. Sci. 361, 1929–1940. 
Kruis W, Kalek HD, Stellaard F, Paumgartner G (1986). Altered fecal bile acid pattern in 
patients with inflammatory bowel disease. Digestion 35: 189-98. 
Le Gall G, Noor SO, Ridgway K, Scovell L, Jamieson C, Johnson IT, Colquhoun IJ, Kemsley 
EK, Narad A (2011). Metabolomics of fecal extracts detects altered metabolic activity of gut 
microbiota in ulcerative colitis and irritable bowel syndrome. J Proteome Res. 10: 4208-4218. 
Marchesi JR, Holmes E, Khan F, Kochhar S, Scanlan P, Shanahan F, Wilson ID, Wang Y 
(2007). Rapid and noninvasive metabonomic characterization of inflammatory bowel disease. J 
Proteome Res 6: 546-551. 
Parks, D.H., and Beiko, R.G. (2013). Measures of phylogenetic differentiation provide robust 
and complementary insights into microbial communities. ISME J. 7, 173–183. 
Sczyrba A, Hofmann P, Belmann P, Koslicki D, Janssen S, Droege J, Gregor I, Majda S, Fiedler 
J, Dahms E, et al. (2017). Critical Assessment of Metagenome Interpretation − a benchmark of 
computational metagenomics software. bioRxiv 99127. 
Segata N et al. (2012) Metagenomic microbial community profiling using unique clade-specific 
marker genes. Nature Methods, 8:811-814. 
Truong DT, Franzosa EA, Tickle TL, Scholz M, Weingart G, Pasolli E, Tett A, Huttenhower C, 
and Segata N (2015). MetaPhlAn2 for enhanced metagenomic taxonomic profiling. Nature 
Methods 12, 902–903. 
Wróbel B (2008). Statistical measures of uncertainty for branches in phylogenetic trees inferred 
from molecular sequences by using model-based methods. J. Appl. Genet. 49, 49–67. 
 
 
 


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9. 
TABLES AND LISTINGS TO BE INCLUDED IN SECTION 14 OF 
THE CLINICAL STUDY REPORT 
Sample and Sequencing Acceptability 
Table 14.4.1 Sample Acceptability Criteria for All Timepoints (mcITT population)  
Table 14.4.2 Sample Acceptability Criteria for All Timepoints (Sensitivity Analysis Population 
–1)  
Table 14.4.3 Sample Acceptability Criteria for All Timepoints (LTE population)  
Table 14.4.4 Sample Acceptability Criteria for All Timepoints (MTP population)  
Table 14.4.5 Sample Acceptability Criteria for All Timepoints (MBP population)  
Microbiome Alteration Primary Endpoint 
Table 14.5.1.1 P-values for Spore-Forming Species Richness Between All Planned Comparisons 
(mcITT population) 
Table 14.5.1.2 Summary Statistics for Spore-Forming Species Richness Between All Planned 
Comparisons (mcITT population) 
Table 14.5.1.3 P-values for Spore-Forming Species Richness Between All Planned Comparisons 
(Sensitivity Analysis Population—1) 
Table 14.5.1.4 Summary Statistics for Spore-Forming Species Richness Between All Planned 
Comparisons (Sensitivity Analysis Population—1) 
Table 14.5.1.5 P-values for Spore-Forming Species Richness Between All Planned Comparisons 
(LTE population) 
Table 14.5.1.6 Summary Statistics for Spore-Forming Species Richness Between All Planned 
Comparisons (LTE population) 
Table 14.5.2.1 Summary Statistics for Beta-Diversity Between All Planned Comparisons 
(mcITT population) 
Table 14.5.2.2 Summary Statistics for Beta-Diversity Between All Planned Comparisons 
(Sensitivity Analysis Population—1) 


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Table 14.5.2.3 Summary Statistics for Beta-Diversity Between All Planned Comparisons (LTE 
population) 
Microbiome Engraftment Primary Endpoint 
Table 14.6.1 P-Values for Overall Engraftment of SER-287 Drug Product Lot Species – mcITT 
population 
Table 14.6.2 P-Values for Engraftment of Individual SER-287 Drug Product Lot Species – 
mcITT population 
Table 14.6.3 P-Values for Overall Engraftment of SER-287 Drug Product Lot Species – 
Sensitivity Analysis Population –1  
Table 14.6.4 P-Values for Engraftment of Individual SER-287 Drug Product Lot Species – 
Sensitivity Analysis Population –1 
Table 14.6.5 P-Values for Overall Engraftment of SER-287 Drug Product Lot Species – LTE 
Population 
Table 14.6.6 P-Values for Engraftment of Individual SER-287 Drug Product Lot Species – LTE 
Population 
Table 14.6.7 P-values for Richness of Spore-Forming Species found in Drug Product Lots in 
mcITT population  
Table 14.6.8 P-values for Richness of Spore-Forming Species found in Drug Product Lots in 
Sensitivity Analysis Population –1 
Table 14.6.9 P-values for Richness of Spore-Forming Species found in Drug Product Lots in 
LTE Population  
Metabolome Exploratory Endpoint 
Table 14.7.1 25 Most Differentially Abundant Metabolites Between Baseline to Visit 12 For All 
Pairwise Comparisons 
Table 14.7.2 25 Most Differentially Abundant Metabolites Between Study Day 8 to Visit 12 For 
All Pairwise Comparisons  
Table 14.7.3 Fisher’s Combined P-Value Statistic for Pathway Profile Changes in All Pairwise 
Comparisons  - Baseline to Visit 12 


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Table 14.7.4 Fisher’s Combined P-Value Statistic for Pathway Profile Changes in All Pairwise 
Comparisons  - Study Day 8 to Visit 12 
Transcriptome Exploratory Endpoint 
Table 14.8.1 Top 100 Genes Differentially Expressed Between Arms Between Baseline And 
Visit 12 For All Comparisons  
Mucosal Microbiome Exploratory Endpoint  
Table 14.9.1 Summary Statistics for Mucosal Microbiome Beta Diversity  
 
 
 
 
 


Microbiome Statistical Analysis Plan 
Seres Therapeutics, Inc. 
SERES-101 
 
 
 
 
Final 1.0 
Confidential 
Page 37 of 38 
12 July 2017 
 
10. 
FIGURES TO BE INCLUDED IN SECTION 14 OF THE CLINICAL 
STUDY REPORT 
Microbiome Alteration Primary Endpoint 
Figure 14.3.1.1 Spore-Former Species Richness By Timepoint for the mcITT Population For All 
Pre-Specified Comparisons  
Figure 14.3.1.2 Spore-Former Species Richness By Timepoint for the Sensitivity Analysis 
Population – 1 For All Pre-Specified Comparisons  
Figure 14.3.1.3 Spore-Former Species Richness By Timepoint for the LTE Population For All 
Pre-Specified Comparisons 
Figure 14.3.2.1 Beta-Diversity Metrics for the mcITT Population 
Figure 14.3.2.2 Beta-Diversity Metrics for the Sensitivity Analysis Population – 1  
Figure 14.3.2.3 Beta-Diversity Metrics for the LTE Population 
Microbiome Engraftment Primary Endpoint 
Figure 14.4.1 Drug Product Lot-Specific Spore-Former Species Richness By Timepoint for the 
mcITT Population For All Pre-Specified Comparisons  
Figure 14.4.2 Drug Product Lot-Specific Spore-Former Species Richness By Timepoint for the 
Sensitivity Analysis Population – 1 For All Pre-Specified Comparisons  
Figure 14.4.3 Drug Product Lot-Specific Spore-Former Species Richness By Timepoint for the 
LTE Population For All Pre-Specified Comparisons 
 
 
 


Microbiome Statistical Analysis Plan 
Seres Therapeutics, Inc. 
SERES-101 
 
 
 
 
Final 1.0 
Confidential 
Page 38 of 38 
12 July 2017 
 
11. 
LISTINGS TO BE INCLUDED IN SECTION 16 OF THE CLINICAL 
STUDY REPORT 
Analysis Populations 
Listing 16.2.1 Assignment to Analysis Populations (mcITT)  
Listing 16.2.2 Assignment to Analysis Populations (Sensitivity Analysis Population – 1 ) 
Listing 16.2.3 Assignment to Analysis Populations (LTE) 
Listing 16.2.4 Assignment to Analysis Populations (MBP) 
Listing 16.2.5 Assignment to Analysis Populations (MTP) 
 
 
 

Prot_000.pdf: 
Clinical Study Protocol 
A Multiple Dose Study to Evaluate the Safety, Tolerability and 
Microbiome Dynamics of SER-287 in Subjects with Mild-to-
Moderate Ulcerative Colitis 
 
Sponsor: 
Seres Therapeutics, Inc. 
200 Sidney Street  
Cambridge, MA 02139 
Clinical Research Organization: 
PAREXEL International 
195 West Street 
Waltham, MA 02451 
 
Sponsor Protocol No.: 
SERES-101 
IND No.: 
16689 
Study Drug Name: 
SER-287 
Development Phase: 
1b 
Date of Protocol Amendment 3: 
10 Oct 2016 
Date of Previous Protocol: 
08 Dec 2015 
The study will be conducted according to the protocol and in compliance with Good 
Clinical Practice (GCP) and with other applicable regulatory requirements. 
This document contains confidential information of Seres Therapeutics, Inc. 
Do not copy or distribute without written permission from the Sponsor. 
CONFIDENTIAL 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  2 of 75                                                  10 Oct 2016  
SIGNATURE PAGE 
 
Declaration of Sponsor or Responsible Medical Officer 
Title: A Multiple Dose Study to Evaluate the Safety, Tolerability and Microbiome 
Dynamics of SER-287 in Subjects with Mild-to-Moderate Ulcerative Colitis 
 
This study protocol was subjected to critical review.  The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational product, 
as well as with the moral, ethical, and scientific principles governing clinical research as 
set out in the Declaration of Helsinki, 1989, and the guidelines on Good Clinical 
Practice. 
 
 
_____________________________________ 
_____________________ 
Michele Trucksis, PhD, MD 
Executive Vice President, Chief Medical Officer 
Seres Therapeutics, Inc. 
 
 
10/10/2016


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  3 of 75                                                  10 Oct 2016  
Declaration of the Investigator 
Title: A Multiple Dose Study to Evaluate the Safety, Tolerability and Microbiome 
Dynamics of SER-287 in Subjects with Mild-to-Moderate Ulcerative Colitis 
All documentation for this study that is supplied to me, and that has not been previously 
published will be kept in the strictest confidence.  This documentation includes this study 
protocol, Investigator's Brochure, electronic data capture (EDC) system, and other 
scientific data. 
The study will not be commenced without the prior written approval of a properly 
constituted Institutional Review Board (IRB) or Independent Ethics Committee (IEC). 
No changes will be made to the study protocol without the prior written approval of the 
Sponsor and the IRB or IEC, except where necessary to eliminate an immediate hazard to 
the subjects. 
I have read and understood and agree to abide by all the conditions and instructions 
contained in this protocol. 
 
Responsible Investigator of the local study center 
 
 
 
_____________________________________ 
_____________________ 
Signature 
Date 
 
_____________________________________ 
Name (block letters) 
 
_____________________________________ 
Title (block letters) 
 
_____________________________________ 
Institution (block letters) 
 
_____________________________________ 
Phone number 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  4 of 75                                                  10 Oct 2016  
PROTOCOL SYNOPSIS 
Title 
A Multiple Dose Study to Evaluate the Safety, Tolerability and Microbiome 
Dynamics of SER-287 in Subjects with Mild-to-Moderate Ulcerative Colitis 
Sponsor Study No. 
SERES-101 
Phase 
1b 
Sponsor 
Seres Therapeutics, Inc. 
Study Centers 
Approximately 20 Study Centers in the United States (US) 
Objectives 
Primary Objectives:  
•!
To evaluate the safety and tolerability of SER-287 vs. placebo in adult subjects 
≥18 years of age with mild-to-moderate ulcerative colitis 
•!
To compare the baseline composition of the intestinal microbiome to the post-
baseline composition after initiation of SER-287 or placebo  
•!
To determine the engraftment of SER-287 bacteria into the intestinal microbial 
community in each of the SER-287 arms compared to the placebo arm 
Secondary Objectives: 
•!
To determine the proportion of subjects in each of the treatment arms who, at 8 
weeks post initiation of treatment, achieve a clinical response, complete 
remission, and endoscopic improvement 
•!
To assess changes in serum and fecal biomarkers from baseline throughout 
treatment 
Exploratory Objectives:  
•!
To compare the changes in exploratory biomarkers from mucosal biopsies and 
stool samples in each of the treatment arms from baseline throughout treatment. 
•!
To determine the complement of metabolic pathways from stool in each of the 
treatment arms from baseline throughout treatment.  
 
Design 
This is a Phase 1b multicenter, randomized, double-blind, placebo-controlled 
multiple dose study designed to evaluate the safety and tolerability of SER-287, and 
to evaluate the microbiome alterations and pharmacodynamics associated with 2 
dosing regimens of SER-287 in adult subjects with mild-to-moderate ulcerative 
colitis (UC).  Subjects will be randomized to one of 4 study arms: 
Arm A: Placebo pre-treatment, followed by once weekly dosing of SER-287 for 8 weeks 
Arm B: Placebo pre-treatment, followed by once daily placebo for 8 weeks 
Arm C: Vancomycin1 pre-treatment, followed by once daily dosing of SER-287 for 8 weeks 
Arm D: Vancomycin pre-treatment, followed by once weekly dosing of SER-287 for 8 weeks 
 
This study has 5 study periods:  Screening (Day-17 to Day-1), Pre-treatment (Day 
1 to Day 7), 8-Week Treatment (Day 8-63), 4 Week Short Term Safety Follow-up 
(Day 64-92) and a Long Term Safety Follow-up (Day 93-246).   
 
Approximately 55 adult subjects with mild-to-moderate ulcerative colitis will be 
enrolled.   
Screening includes 2 screening visits.  At the first Screening visit, Visit 1, subjects 
will be checked for inclusion /exclusion criteria, and medical history and 
demographic data will be collected.  At the second Screening visit, Visit 2, eligible 
subjects will undergo a lower endoscopy (flexible sigmoidoscopy or colonoscopy) 
and biopsy within 17 days from the first Screening visit and prior to Study Day 1.  
For Baseline Mayo subscore measurement, the one closest to the randomization, 
Visit 2 should be used. 
Subjects will be on a clear liquid diet 1 day before the flexible lower endoscopy 
(flexible sigmoidoscopy or colonoscopy).  On the day of the procedure, the subject 
                                               
1 Full name of Vancomycin is Over-encapsulated (OE) Vancomycin HCl 125 mg capsules  


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  5 of 75                                                  10 Oct 2016  
will self-administer a bowel prep at the PI discretion (e.g., 2 Fleets enemas) and fast 
for 6 hours before the procedure.   
Endoscopy images will be obtained during each endoscopy and will be sent for 
independent central reading and determination of the modified Mayo endoscopic 
subscore.  A detailed image review charter from the central reading laboratory will 
outline the endoscopic procedures, video recordings, and equipment to be used for 
video capture and transmission of endoscopic recordings.  For each subject, video 
recording of the entire endoscopic procedure will be performed using a storage 
medium provided by the sponsor or designee.  The endoscopic recordings will be 
read centrally in a blinded manner by a qualified gastroenterologist according to the 
image review charter.  The Total modified Mayo score used for clinical endpoints in 
the trial will use the modified Mayo endoscopic subscore determined by the central 
reader. 
The total modified Mayo score is a composite score, including the modified Mayo 
endoscopic subscore, the patient report outcome (stool frequency and rectal 
bleeding) as well as physician’s rating.  The modified Mayo endoscopic subscore is 
determined by the central reader and provided to the clinical site.  Subjects who 
meet the inclusion criteria (Total modified Mayo score of 4 to 10, inclusive, and 
modified Mayo endoscopic subscore of > 1, with evidence of mucosal lesions), will 
be randomized using an interactive web/voice response system (IxRS) to 1 of 4 
treatment groups on Study Day 1 and initiate the pre-treatment regimen. 
 
During the Pre-Treatment period (Day 1 to Day 7) oral vancomycin 125 mg four 
times a day (qid) or matching placebo will be administered for 6 days.  
Following completion of the Pre-Treatment period, subjects will return to the clinic 
to begin the 8-Week Treatment Period (Day 8-63).  On Day 8, subjects will receive 
SER-287 or placebo according to the Treatment Group to which they have been 
assigned:  SER-287 once daily, SER-287 once weekly with matching placebo on the 
other days, or placebo daily. 
 
During the 8-Week Treatment Period, all subjects will come to the clinic weekly 
for drug dispensing and asked about adverse events (AEs), change in medications 
and the partial Mayo score assessment (scores should reflect the 24-hour period 
prior to reporting).  All subjects will have a lower endoscopy (flexible 
sigmoidoscopy or colonoscopy) at Visit 12/Early Termination +/- 3 days to evaluate 
endoscopic disease activity.  Subjects will be on a clear liquid diet the day before the 
lower endoscopy (flexible sigmoidoscopy or colonoscopy). On the day of the 
procedure, the subject will self-administer a bowel prep at the PI discretion (e.g., 2 
Fleets enemas) and fast for 6 hours before the procedure.   
All subjects will have an in-clinic visit at Visit 12/Early Termination +/- 3 days. 
 
Subjects will then enter the Short-Term Safety Follow-up Period in which 
subjects will be contacted by phone on Days 71, 78, 85 +/- 2 days.  Subjects will be 
asked about adverse events (AEs), concomitant medications and will complete 
disease activity assessment which includes stool frequency and rectal bleeding.  All 
subjects will have an in-clinic safety visit at Visit 13 +/- 2 days.  
 
Subjects will then enter the Long-Term Safety Follow-up Period in which subjects 
will be contacted by phone on Days 246 +/- 3 days. Following Visit 13 through Day 
246/ET only SAEs, and concomitant medications associated with SAEs will be 
collected. 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  6 of 75                                                  10 Oct 2016  
Data and Safety 
Monitoring 
Committee 
To ensure safe study conduct during the Phase 1b study, an independent, unblinded, 
external Data and Safety Monitoring Committee (DSMC) will be established to 
perform safety evaluations on an ongoing basis. A DSMC charter will be developed 
and will detail the review of the safety data.  
Treatment 
The Pre-Treatment Period includes administration of either oral vancomycin 125 
mg four times a day (over encapsulated Vancomycin HCl 125 mg) for 6 days or 
matching placebo. 
 
The Treatment Period includes administration of 4 capsules taken orally once daily 
of SER-287 or placebo according to the treatment group to which they have been 
assigned:  SER-287 once daily, SER-287 once weekly with matching placebo on 
other days, or placebo daily. 
 
The doses, route, and schedule of study drug administration are shown below: 
 
Group&
Pre)treatment:&Vanco&or&Pbo&
&&
Treatment&Period:&&SER)287&or&Pbo&
Vanco&
or&Pbo&
Regimen&
Admin&
Duration&
&&
SER6287&
or&Pbo&
Regimen&
Admin&
Duration&
A 
Pbo 
Pbo 
One 
capsule 
four 
times 
daily 
orally 
6 days 
  
SER-
287 + 
Pbo 
SER-287 
Weekly 
(1x108 
SporQs) 
+Pbo 6d/wk 
Four 
capsules 
once 
daily 
orally 
8 wks 
B 
Pbo 
Pbo 
One 
capsule 
four 
times 
daily 
orally  
6 days 
  
Pbo 
Placebo 
Daily 
Four 
capsules 
once 
daily 
orally 
8 wks  
C 
Vanco 
Vanco 
125 mg 
qid 
One 
capsule 
four 
times 
daily 
orally 
6 days 
  
SER-
287  
SER-287 
Daily 
(1x108 
SporQs)   
Four 
capsules 
once 
daily 
orally 
8 wks 
D 
Vanco 
Vanco 
125 mg 
qid 
One 
capsule 
four 
times 
daily 
orally 
6 days 
  
SER-
287 + 
Pbo 
SER-287 
Weekly 
(1x108 
SporQs) 
+Pbo 6d/wk   
Four 
capsules 
once 
daily 
orally 
8 wks 
d = day; Pbo = placebo; qid = Four times a day; wk = week; admin= administration; 
vanco=vancomycin; SporQs= spore equivalents 
 
Number of 
Subjects 
Approximately 55 subjects will be enrolled: 15 subjects in each of the three active 
arms (Groups A, C and D) and 10 subjects in the placebo arm (Group B). 
Population 
Male or female subjects with active mild-to-moderate Ulcerative Colitis ! 18 years 
of age. 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  7 of 75                                                  10 Oct 2016  
Criteria for 
Evaluation of 
Efficacy 
The evaluation of the efficacy data will be performed by comparison of the efficacy 
endpoints across treatment arms.  The following efficacy endpoints will be assessed 
for the comparison: 
 
Primary Endpoints 
•!
Composition of the intestinal microbiome  
•!
Engraftment of SER-287 bacteria in all treatment arms 
 
Secondary Endpoints 
•!
Clinical response defined as:  
o!
A decrease of ≥ 3 points in Total Modified Mayo score (TMMS) from 
baseline, along with EITHER a decrease of >1 point in rectal bleeding 
subscore or absolute rectal bleeding subscore of 0 or 1 
•!
Complete remission defined as: 
o!
A Total Modified Mayo Score <2 and an endoscopic subscore 0 with 
no erythema, no blood and no evidence of inflammation  
•!
Endoscopic improvement, defined as a decrease in endoscopic subscore > 1 
•!
Serum biomarkers [C-reactive protein (CRP)] 
•!
Fecal biomarkers (fecal calprotectin) levels 
 
Exploratory Endpoints 
•!
Stool and blood metabolic pathways 
•!
Serum cytokine profile 
•!
Mucosal Histopathology, including cytomegalovirus (CMV) 
Immunohistochemistry stains 
•!
Mucosal microbiome  
•!
Mucosal transcriptomic profile  
•!
Microbial Culture Endpoints: 
o! Candida titer and diversity 
 
Criteria for 
Evaluation of 
Safety 
The evaluation of the safety data will be performed by comparison of the safety 
endpoints across treatment arms.  The following safety parameters will be assessed 
for the comparison: 
•!
Incidence of adverse events 
•!
Incidence of adverse events of special interest 
•!
Laboratory evaluation results 
•!
Vital sign measurements 
•!
Physical examination findings 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  8 of 75                                                  10 Oct 2016  
Statistical 
Methods 
All safety and tolerability, intestinal microbiome, clinical efficacy, and biomarker 
data will be listed and presented in descriptive summaries by study arm, visit and 
time point. At a minimum, continuous data will be summarized by study arm using 
descriptive statistics (number, mean, standard deviation [SD], minimum, median and 
maximum).  Categorical data will be summarized by study arm using frequency 
tables (number and percentage). 
 
Analysis 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 were randomly assigned.  All safety analyses 
will be conducted based on the Safety Population. 
 
The Intent-to-Treat (ITT) Population will consist of all subjects who were randomly 
assigned, including those who were not exposed to any study drug, and will be 
analyzed based on the treatment to which they were randomized.   
 
The Modified Intent-to-Treat (mITT) Population will consist of all randomized 
patients with baseline and at least one post-baseline stool sample, including those 
who were not exposed to any study drug, and will be analysed based on the 
treatment to which they were randomized.   
 
All analyses on clinical response will be conducted in the ITT population and in the 
mITT population as sensitivity analyses. 
 
All microbiome alterations analyses will be conducted in the mITT Population. 
 
Analysis of Primary Endpoint 
Adverse Events 
The percentage of subjects with TEAEs will be tabulated by system organ class 
(SOC) and preferred term (PT) for each treatment group. The incidence of TEAEs 
based on the number of days the subjects in each treatment group were on study 
drug (per subject on therapy day) will also be presented by system organ class and 
preferred term for each treatment group, by severity, and by relationship to 
treatment. Tables of any TEAEs leading to study drug discontinuation, AESIs and 
SAEs will also be provided. 
 
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. 
 
Vital Signs 
Vital signs data include measurements of weight (kg), height (cm), blood pressure 
(mmHg), respiratory rate (breaths/minute), heart rate (bpm), body temperature 
(Celsius / Fahrenheit), and Body Mass Index (kg/m2). Descriptive statistics of the 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  9 of 75                                                  10 Oct 2016  
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 and to the 
overall worst post-baseline value will also be summarized by treatment group. 
 
Physical Examination Findings  
Abnormal clinically significant physical examination (PE) finding will be reported 
as Medical History (MH) or as an AE. 
 
Gastrointestinal tract Microbiome 
The gastrointestinal (GI) microbiome of subjects will be characterized by using at 
minimum recombinant deoxyribonucleic acid (rDNA) 16S V4 genomic data sets 
generated from stool collected for the various endpoints, and may include whole 
metagenome sequence (WMS) characterization. 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 an operational taxonomic unit (OTU) and phylogenetic clade 
(clade) and, further, to define the relative proportion of each OTU and clade to all 
other OTUs and clades in a given sample.  
Changes in the composition of the microbiome will be measured in terms of both the 
total number of unique types of bacteria (i.e., α-diversity) and the microbial 
composition (i.e., β-diversity). Engraftment is defined as the outgrowth of bacteria 
that comprise the SER-287 spore ecology in a subject’s gastrointestinal tract post-
treatment. Significant differences between changes in the microbiome across the 
various treatment arms will be evaluated using both non-parametric tests for α-
diversity and multivariate analysis of variances of dissimilarity matrices for β-
diversity. Dissimilarity will be defined by using the unweighted Unifrac 
dissimilarity metric, which evaluates changes in the overall phylogenetic 
composition between two samples; this method is widely used in the study of 
microbial communities and represents a balanced approach with minimal bias to the 
presence of low- and high-abundance bacteria. Additional measures of dissimilarity 
that are routinely used in the analysis of microbiome data sets will be evaluated. 
 
Determination of Sample Size 
No formal sample size calculation was performed.  A sample size of approximately 
55 subjects with 15 subjects randomized to each of the active arms (Treatment 
Groups A, C and D) and 10 subjects in the placebo arm (Treatment Group B) is 
considered sufficient to evaluate the safety, microbiome alterations, clinical response 
and exploratory objectives of the study. 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  10 of 75                                                  10 Oct 2016  
LIST OF STUDY PERSONNEL 
 
Sponsor 
Seres Therapeutics, Inc. 
200 Sidney Street 
Cambridge, MA 02139 
 
 
Contract Research 
Organization 
PAREXEL International 
195 West St. 
Waltham, MA 02451 
+1-781-487-9900 
 
Adverse Event Reporting 
PAREXEL International 
1 Federal Street 
Billerica, MA 01821 
Telephone Phone:  +1-781-434-5010 
Fax Number:  +1-781-434-5957 
 
Central Laboratory 
 
Eurofins Central Laboratory 
2430 New Holland Pike 
Lancaster, PA 17601 
 
Central lower endoscopy 
(flexible sigmoidoscopy or 
colonoscopy) Reader 
 
Robarts Clinical Trials  
PO Box 5015  
100 Perth Drive 
London, ON  
CANADA  N6A 5K8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  11 of 75                                                  10 Oct 2016  
Table of Contents 
PROTOCOL&SYNOPSIS&..................................................................................................&4!
List&of&Study&Personnel&..............................................................................................&10!
List&of&Abbreviations&..................................................................................................&14!
1!
Introduction&.......................................................................................................&17!
1.1!
Background&...........................................................................................................&18!
1.1.1!
Brief!Description!of!the!Indication!and!Existing!Practices!......................................!18!
1.1.2!
Rationale!for!the!Development!of!the!Compound,!and!Reasons!why!the!
Investigational!Product!is!Applicable!for!this!Disease!.........................................................!19!
1.1.3!
Pharmacological!Concept!for!the!Treatment!.........................................................!19!
1.1.4!
Name!and!Description!of!Investigational!Product!..................................................!20!
1.1.5!
Summary!of!Findings!from!NonNClinical!Studies!with!Potential!Clinical!Significance
!
20!
1.1.6!
Summary!of!Findings!from!Previous!Clinical!Studies!..............................................!20!
1.2!
Rationale&..............................................................................................................&22!
1.2.1!
Rationale!for!Regimen!............................................................................................!22!
1.2.2!
Rationale!for!dose!...................................................................................................!22!
1.2.3!
Rationale!for!Antibiotic!PreNTreatment!..................................................................!22!
1.2.4!
Rationale!for!Endpoints!..........................................................................................!23!
2!
Study&Objectives&................................................................................................&24!
2.1!
Primary&Objectives&................................................................................................&24!
2.2!
Secondary&Objectives&............................................................................................&24!
3!
Overall&Design&and&Plan&of&the&Study&.................................................................&25!
3.1!
Overview&..............................................................................................................&25!
3.2!
Criteria&for&Evaluation&of&the&Study&.......................................................................&26!
4!
Study&Population&...............................................................................................&28!
4.1!
Inclusion&Criteria&...................................................................................................&28!
4.2!
Exclusion&Criteria&..................................................................................................&28!
4.3!
Subject&Withdrawal&and&Replacement&..................................................................&30!
4.4!
Planned&Sample&Size&and&Number&of&Study&Centers&..............................................&30!
4.5!
Subject&Identification&and&Randomization&.............................................................&31!
4.5.1!
Subject!Identification!..............................................................................................!31!
4.5.2!
Methods!of!Assigning!Patients!to!Study!Treatment!...............................................!31!
4.5.3!
Maintaining!the!Randomization!Codes!and!Breaking!the!Study!Blind!...................!31!
5!
Investigational&Product&......................................................................................&33!
5.1!
SER)287&.................................................................................................................&33!
5.1.1!
Donor!Screening!.....................................................................................................!33!
5.1.2!
SERN287!Manufacturing!..........................................................................................!33!
5.2!
Over)encapsulated&(OE)&Vancomycin&HCl&125&mg&Capsules,&Hard&Gelatin&Capsules&
(“Vancomycin”)&.................................................................................................................&33!
5.2.1!
Vancomycin!HCl!Procurement,!OverNencapsulation,!Packaging!and!Storage!........!33!
5.3!
SER)287&Placebo&Capsules&.....................................................................................&34!
5.3.1!
SERN287!Placebo!Manufacturing!............................................................................!34!


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  12 of 75                                                  10 Oct 2016  
5.4!
Vancomycin&HCl&Placebo&Capsules&(“Vancomycin&Placebo”)&..................................&34!
5.4.1!
Vancomycin!HCl!Placebo!Manufacturing!and!Storage!...........................................!34!
5.5!
Storage&.................................................................................................................&34!
5.5.1!
SERN287!and!SERN287!Placebo!Storage!...................................................................!34!
5.6!
Drug&Accountability&..............................................................................................&35!
5.7!
Prior&and&Concomitant&Medications&......................................................................&36!
6!
Variables&and&Methods&of&Assessment&...............................................................&38!
6.1!
Microbiome&Alterations&and&Engraftment&Primary&Endpoints&...............................&38!
6.1.1!
Microbiome!Alterations!..........................................................................................!38!
6.1.2!
Clinical!Response,!Complete!Remission,!and!Endoscopic!Improvement!...............!38!
6.1.3!
Biomarkers!..............................................................................................................!38!
6.2!
Safety&Variables&....................................................................................................&39!
6.2.1!
The!Safety!Endpoints!..............................................................................................!39!
6.2.2!
Adverse!Events!.......................................................................................................!39!
6.2.3!
Laboratory!Variables!...............................................................................................!43!
6.2.4!
Stool!Samples!.........................................................................................................!45!
6.2.5!
Biopsy!Samples!.......................................................................................................!45!
6.2.6!
Vital&Signs!...............................................................................................................!45!
6.2.7!
Electrocardiograms!.................................................................................................!45!
6.2.8!
Physical!Examinations!.............................................................................................!45!
6.3!
Demographics&and&Baseline&Characteristics&...........................................................&46!
6.3.1!
Subject!Demography!..............................................................................................!46!
6.3.2!
Disease!History!.......................................................................................................!46!
6.3.3!
Baseline!Characteristics!..........................................................................................!46!
6.3.4!
Medical!History!.......................................................................................................!46!
6.3.5!
Prior!and!Concomitant!Medications!.......................................................................!46!
7!
Study&Conduct&...................................................................................................&47!
7.1!
Schedule&of&Events&................................................................................................&47!
7.2!
Procedures&by&Visit&...............................................................................................&52!
7.2.1!
Screening!Day!N17!to!Day!N1!(Visit!1)!......................................................................!52!
7.2.2!
Screening!Visit!2!Day!N17!to!Day!N1!(Visit!2)!............................................................!52!
7.2.3!
Pretreatment!Period!Day!1!(Visit!3)!........................................................................!53!
7.2.4!
Treatment!Period!Day!8!±!1!(Visit!4)!.......................................................................!53!
7.2.5!
Treatment!Period!Day!11!(as!close!to!scheduled!day!as!possible)!.........................!54!
7.2.6!
Treatment!Period!Day!15!±!1!(Visit!5)!.....................................................................!54!
7.2.7!
Treatment!Period!Day!18!(as!close!to!scheduled!day!as!possible)!.........................!54!
7.2.8!
Treatment!Period!Day!22!±!1!(Visit!6)!.....................................................................!54!
7.2.9!
Treatment!Period!Day!29!±!1!(Visit!7)!.....................................................................!55!
7.2.10!
Treatment!Period!Day!36!±!1!(Visit!8)!................................................................!55!
7.2.11!
Treatment!Period!Day!43!±!1!(Visit!9)!................................................................!55!
7.2.12!
Treatment!Period!Day!50!±!1!(Visit!10)!..............................................................!55!
7.2.13!
Treatment!Period!Day!57!±!1!(Visit!11)!..............................................................!56!
7.2.14!
FollowNup!Period!Day!64!±!3!(Visit!12)/Early!Termination!.................................!56!
7.2.15!
FollowNup!Period!Day!71!±!2!(Phone!Call)!..........................................................!57!
7.2.16!
FollowNup!Period!Day!78!±!2!(Phone!Call)!..........................................................!57!
7.2.17!
FollowNup!Period!Day!85!±!2!(Phone!Call)!..........................................................!57!
7.2.18!
FollowNup!Period!Day!92!±!1!(Visit!13)!...............................................................!57!


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7.2.19!
Early!Termination!Visit!.......................................................................................!57!
7.2.20!
FollowNup!Period!Day!246!±!3!(Phone!Call)!........................................................!57!
8!
Statistical&Methods&............................................................................................&59!
8.1!
Study&Subjects&......................................................................................................&59!
8.1.1!
Disposition!of!Subjects!...........................................................................................!59!
8.1.2!
Protocol!Deviations!................................................................................................!59!
8.1.3!
Analysis!Sets!...........................................................................................................!59!
8.2!
Endpoints&for&Analysis&...........................................................................................&60!
8.2.1!
Endpoints!and!Analysis!for!Primary!Objectives!......................................................!60!
8.2.2!
Endpoints!and!Analysis!for!Secondary!Objectives!..................................................!60!
8.2.3!
Exploratory!Endpoints!............................................................................................!60!
8.3!
General&Considerations&.........................................................................................&61!
8.3.1!
Statistical!Methods!.................................................................................................!61!
8.3.2!
Statistical!Significance!............................................................................................!61!
8.3.3!
Missing!or!Spurious!Data!........................................................................................!61!
8.4!
Safety&Analyses&.....................................................................................................&62!
8.4.1!
Adverse!Events!.......................................................................................................!62!
8.4.2!
Clinical!Laboratory!Tests!.........................................................................................!62!
8.4.3!
Vital!Signs!...............................................................................................................!62!
8.4.4!
Physical!Examination!Findings!................................................................................!62!
8.4.5!
Pharmacokinetic!Analyses!......................................................................................!62!
8.5!
Gastrointestinal&Tract&Microbiome&........................................................................&62!
8.6!
Interim&Analyses&...................................................................................................&63!
8.7!
Determination&of&Sample&Size&...............................................................................&63!
9!
ADMINISTRATIVE&REQUIREMENTS&.....................................................................&64!
9.1!
Good&Clinical&Practice&............................................................................................&64!
9.2!
Ethical&Considerations&...........................................................................................&64!
9.3!
Subject&Information&and&Informed&Consent&...........................................................&64!
9.4!
Subject&Confidentiality&..........................................................................................&65!
9.5!
Protocol&Compliance&.............................................................................................&65!
9.6!
Future&Use&of&Stored&Specimens&............................................................................&65!
9.7!
Study&Monitoring&..................................................................................................&65!
9.8!
Data&and&Safety&Monitoring&Committee&................................................................&66!
9.9!
Case&Report&Forms&and&Study&Records&..................................................................&66!
9.10!
Study&Completion&.................................................................................................&67!
10! Reference&List&....................................................................................................&68!
Appendices&...............................................................................................................&72!
 
Tables in Text 
Table 1: Doses, Route, and Schedule of Study Drug Administration ........................35!
Table 2: Laboratory Assessments ...............................................................................44!
Table 3: Schedule of Events .......................................................................................48!
 
 
 


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List of Abbreviations 
 
Abx 
Antibiotic 
AE 
AESI 
Adverse event 
Adverse Event of Special Interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ANOVA 
Analysis of variance 
5-ASA 
Aminosalicylate 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical [Classification System] 
BP 
Blood pressure 
Bpm 
Beats per minute 
CDI 
Clostridium difficile infection 
CFR 
Code of Federal Regulations 
Cm 
Centimeter 
CMV 
Cytomegalovirus 
CS 
Clinically significant 
Cx 
Culture 
D 
Day 
DNA 
Deoxyribonucleic acid 
DRL 
Drug Reference List 
DSMC 
Data and Safety Monitoring Committee 
DSS 
Dextran sodium sulfate 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
CRP 
C-reactive protein 


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EDC 
Electronic data capture 
ESR 
Erythrocyte sedimentation rate 
FMT 
Fecal microbiota transplantation 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
GI 
Gastrointestinal 
HDPE 
High density polyethylene 
HR 
Heart rate 
IBD 
Inflammatory bowel disease 
ICF 
Informed consent form 
IEC 
Independent Ethics Committee 
ICH 
International Conference on Harmonization 
IMP 
Investigational medical product 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat; intention-to-treat 
IVR 
Interactive voice response 
IxRS 
Interactive web/voice response system 
Kg 
Kilogram 
LFT 
Liver function test 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MH 
Medical history 
mL 
Milliliter 
mmHg 
Millimeters of mercury 
MMX 
Multi-matrix system 
NCS 
Not clinically significant 
NSAID 
Non-steroidal anti-inflammatory 
OE 
Overencapsulated 
OTU 
Operational taxonomic unit 
Pbo 
Placebo 


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PBS 
Phosphate buffered saline 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 
PE 
Physical examination 
PI 
Principal Investigator 
PT 
Preferred term 
qid 
Four times a day 
rDNA 
Recombinant deoxyribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCFU 
Spore Colony Forming Unit 
SD 
Standard deviation 
SID 
Subject identification 
SOC 
System organ class 
SPF 
Specific Pathogen Free 
SporQ 
Spore Equivalents, a dosing unit measured by dipicolinic acid content 
TEAE 
Treatment-emergent adverse event 
TMMS 
Total modified Mayo score 
TNBS 
2,4,6-Trinitrobenzenesulfonic acid 
Tregs 
Regulatory T cells 
UC 
Ulcerative colitis 
ULN 
Upper limit of normal 
US 
United States 
Wk 
Week 
WHO 
World Health Organization 
WOCBP 
Women of child bearing potential 
 
 


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1!
INTRODUCTION 
Ulcerative colitis (UC) is a relapsing-remitting chronic inflammatory disorder affecting 
the mucosal surface of the colon, leading to episodes of bloody diarrhea, urgency and 
mucosal inflammation.(Danese and Fiocchi, 2011)  As the disease mostly affects young 
and middle-aged individuals, the disease leads to decreased quality of life in those 
affected by the condition, high morbidity and significant economic burden accounting for 
nearly four billion health care dollars annually.(Ghosh and Mitchell, 2007; Kappelman et 
al., 2008; Rubin et al., 2014; Theede et al., 2015)  Current medical therapies remain 
imperfect for the treatment of UC with the focus of drug development on suppressing the 
immune system rather than reducing the triggers of immune activation.  As 
immunosuppressive agents increase the risk of infectious and oncologic complications, 
alternative mechanisms of action to decrease immune activation, remain attractive 
therapeutic goals for UC.  
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) Studies suggest that 
the intestinal microbiome of UC patients is characterized by a decrease in microbial 
diversity and richness, with a lower prevalence of organisms within 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)   
Given the dysbiosis seen in UC patients, studies have explored the use of fecal microbial 
transplantation (FMT) to treat UC.  Two randomized, double-blind, placebo-controlled 
studies suggest a clinical response in mild-to-moderate UC patients by repopulating the 
intestinal microbial flora via FMT with that of a healthy donor (Moayyedi et al., 2015; 
Rossen et al., 2015). There was increased microbial diversity and greater similarity to 
donor microbiota profile noted in subjects with a clinical response to FMT in both 
studies suggesting that changes in the microbiome due to FMT were responsible for this 
clinical response.  This study will explore microbial therapeutic interventions and the 
impact on the disease course in UC.  The study hypothesis is that SER-287, enriched in 
spore-forming organisms that are diminished in active UC, can induce remission in mild-
to-moderate ulcerative colitis.   
SER-287 (Eubacterial Spores, Purified Suspension, Encapsulated) is an ecology of 
bacterial spores enriched from fecal donations obtained from healthy, screened donors. 
Bacterial spores are enriched by thorough killing of the vegetative microorganisms with 
ethanol, and then purifying and formulating the resulting spore population.  SER-287 is 
delivered as oral capsules for administration to patients.    
SER-287 for this Phase 1b clinical study was manufactured as SER-109 and then became 
SER-287 at the time of clinical labeling. SER-109 was administered in a Phase 1b/2 


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study (SERES-001), and was shown to increase bacterial diversity of the gut microbiota 
as early as 4 days after dosing in adults with recurrent Clostridium difficile infection 
(CDI). Currently there are no differences in the drug products, SER-109 and SER-287.  
Seres anticipates that, pending results from this Phase 1b clinical study, there may be 
future changes in SER-287, with respect to dose, formulation and/or regimen during 
development.!
The patient population targeted for inclusion in this study is adults !18 years of age who 
have mild-to-moderate ulcerative colitis, as defined by a Total Modified Mayo score 
between 4 and 10, inclusive, with a Modified Mayo endoscopic subscore > 1.   
The primary objective of this study is to assess the safety and tolerability of SER-287 in 
patients with active mild-to-moderate ulcerative colitis.  In addition, the study will 
evaluate the microbiome dynamics throughout treatment and assess preliminary efficacy 
data.  
1.1!
Background 
1.1.1! Brief Description of the Indication and Existing Practices  
The annual incidence rate of UC in Western countries is roughly 9.8/100,000 person-
years with increasing incidence observed in developing countries.(Grinspan and 
Kornbluth, 2015) Approximately 50% of patients experience proctosigmoiditis, 30% 
have left-sided disease, and 20% have pancolitis. (Kothari et al., 2015) Overall, 
approximately 50% develop more extensive disease over the first 5 years of disease. 
There is currently no cure for UC.  Therefore, the therapeutic goal is to alleviate and 
control symptoms (induction of remission) and to promote mucosal healing but also to 
prevent disease recurrence (maintenance of remission). 
Current medical therapies for UC include sulfasalazine, aminosalicylates (5-ASAs), 
steroids, immunomodulators (azathioprine and 6-mercaptopurine), anti-TNF agents 
(infliximab, adalimumab, golimumab), anti-integrin agents (vedolizumab), and 
calcineurin inhibitors (cyclosporine and tacrolimus).(Grinspan and Kornbluth, 2015)  As 
the majority of these medications are immunosuppressant agents targeted for moderate-
to-severe disease, there remains an unmet need for safer agents with novel mechanisms 
of action, especially for patients with mild-to-moderate UC who experience frequent 
flares on aminosalicylates or as an alternative to aminosalicylate therapy in those 
intolerant to this class of medication.  As alterations in the intestinal microbiome have 
been identified in UC and preliminary evidence suggests that microbial interventions can 
affect clinical outcomes, the study will assess whether an ecology of bacterial spores 
devoid of vegetative organisms in SER-287 can correct the dysbiosis in UC, increase 
microbial diversity and lead to clinical response in UC patients with active mild-to-
moderate disease.   
 


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1.1.2! Rationale for the Development of the Compound, and Reasons why the 
Investigational Product is Applicable for this Disease 
The intestinal microbiome is comprised of four principle bacterial phyla: Bacteroidetes, 
Firmicutes, Actinobacteria and Proteobacteria.  In healthy subjects, the intestinal 
microbiome is mainly composed of Bacteroidetes and Firmicutes.(Human Microbiome 
Project Consortium, 2012)  Studies have shown that subjects with inflammatory bowel 
disease, including UC, have a decrease in bacterial diversity and alterations in the 
intestinal microbiota compared to healthy subjects.(Baumgart et al., 2007; Frank et al., 
2007; Gevers et al., 2014; 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; Sokol et al., 2008; Varela et al., 2013; Walujkar et al., 2014; Willing et al., 
2010)   
The dysbiosis described in UC is characterized by lower microbial diversity and species 
richness, a greater prevalence of organisms within the phylum, Proteobacteria, and a 
lower prevalence of commensal bacteria within the phylum, Firmicutes.  (Frank et al., 
2007; Lepage et al., 2011; Machiels et al., 2014; Michail et al., 2012; Ott et al., 2004; 
Rajilić-Stojanović et al., 2013; Varela et al., 2013; Walujkar et al., 2014) In particular, 
Firmicutes within the Clostridiales order are poorly represented in active UC subjects 
than in age and sex-matched healthy controls with an inverse correlation between disease 
activity and presence of these organisms.(Michail et al., 2012)  This study will test the 
hypothesis that administering bacterial spores comprised of predominantly Clostridial 
commensals within SER-287 to UC patients can help correct the dysbiosis and improve 
clinical outcomes.      
1.1.3! Pharmacological Concept for the Treatment 
Given the dysbiosis seen in UC patients, studies have explored the use of fecal microbial 
transplantation to treat UC. (Angelberger et al., 2013; Colman and Rubin, 2014; Kump et 
al., 2013; Kunde et al., 2013; Moayyedi et al., 2015; Rossen et al., 2015)  Fecal microbial 
transplantation (FMT) is the transfer of stool from a healthy donor to a recipient.  FMT 
has already demonstrated efficacy in preventing recurrent Clostridium difficile infection 
(CDI) with response corresponding to shifts of the recipient’s flora towards that of the 
donor’s and increasing microbial diversity in the recipient’s microbiome. (van Nood et 
al., 2013; Youngster et al., 2014a, 2014b)  
Most recently, two randomized controlled trials have evaluated the role of FMT in UC.  
One study administered FMT via enema weekly over 6 weeks (treatment group) versus 
water enemas (control group) to 75 patients with mild-to-moderate UC with the primary 
endpoint of clinical remission achieved in 24% of patients in the treatment group and 5% 
in the control group (p=0.03).(Moayyedi et al., 2015) Clinical remission was defined as a 
Mayo score < 3 with an endoscopic subscore of 0 at week 7.  In a second study, donor 
FMT (treatment group) or autologous FMT (control group) was administered twice (3 
weeks apart) via nasoduodenal tube to 50 UC patients with mild-to-moderate ulcerative 
colitis. (Rossen et al., 2015) After 12 weeks, while there was no significant difference in 
clinical remission between groups, there was a trend towards response in the treatment 
group (30.4% versus 20% control group, p=0.51) and there was increased microbial 


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diversity noted in responders of both groups with responders in the treatment group 
developing a similar microbiota profile to the donor.  Given these findings of treatment 
response to FMT in UC patients, this study will explore further if supplementing the 
microbiome of UC patients with select spore-forming organisms in SER-287, that are 
underrepresented in subjects with active ulcerative colitis, could alter the microbiome of 
the recipient and lead to improved clinical outcomes. 
1.1.4! Name and Description of Investigational Product 
SER-287 (Purified Eubacterial Spores, Encapsulated) is an ecology of bacterial spores 
enriched from fecal donations obtained from healthy, screened donors, representing 
approximately 50 commensal bacteria in spore form. The bacterial spores are enriched by 
thorough killing of the vegetative microorganisms, then fractionating the resulting spore 
population away from the inactive components and formulating and encapsulating the 
spores for oral delivery.  SER-287 for the proposed Phase 1b clinical study will be 
manufactured as SER-109. Currently, there are no differences between SER-109 and 
SER-287. Seres anticipates that, pending results from the Phase 1b clinical study, there 
may be future changes in SER-287, with respect to dose, formulation and/or regimen 
during development. 
1.1.5! Summary of Findings from Non-Clinical Studies with Potential Clinical 
Significance  
Recent evidence has identified dysbiosis of the intestinal microbiome as a contributing 
factor to the pathology in UC. Preclinical evidence in mice supports that, more 
specifically, the spore-forming fraction of both murine and human fecal microbiota is 
sufficient to drive protection against experimental colitis, in part via the induction of 
regulatory T cells (Tregs) in the colon (Atarashi et al., 2011, 2013).  
In light of these data, efficacy of a research preparation of SER-287, comprised 
predominantly of Clostridial spore-forming organisms, was evaluated in pilot studies 
using mouse models of colitis [2,4,6-trinitrobenzenesulfonic acid (TNBS) and dextran 
sodium sulfate (DSS)]. In these experimental models of colitis, antibiotic pre-treatment 
with SER-287 (Abx + SER-287) improved clinical outcomes in the DSS model (Further 
details can be found in the Investigator's Brochure). These data support the hypothesis 
that SER-287, in combination with antibiotic pre-treatment, may improve symptoms of 
ulcerative colitis in man. 
1.1.6! Summary of Findings from Previous Clinical Studies  
SERES-101 will be the first study investigating the use of SER-287 in ulcerative colitis.  
At this time, there are no differences between SER-109 and SER-287 but SERES 
anticipates future changes in the dose, frequency and formulation of SER-287 in UC.  
Data from a SER-109 clinical study (SERES-001) in prevention of recurrent Clostridium 
difficile infection (CDI) provides data on SER-109 safety and post-treatment microbiome 
dynamics. SERES-001 has been completed and two additional clinical studies are 
ongoing: 


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•! A Phase 1/2 Study (SERES-001: A Study of Modified Fecal Microbiota 
Transplant [SER-109] Delivered via Oral Administration for the Treatment of 
Recurrent Clostridium difficile) - completed 
•! A Phase 2 Study (SERES-004 ECOSPOR: A Randomized, Double-Blind,  
Placebo-Controlled, Parallel-Group Study of SER-109 to Prevent Recurrent  
Clostridium difficile Infection) - ongoing 
•! An Extension Study to the Phase 2 Study (SERES-005 ECOSPOR II: An Open- 
Labeled Extension of Studies SERES-004/SERES-007 Evaluating SER-109 in  
Patients with Recurrent Clostridium difficile Infection) – ongoing 
Further details can be found in the Investigator's Brochure. 
SERES-001 was an open-label, single arm, descending-dose study that evaluated the 
safety and efficacy of SER-109 in prevention of recurrent CDI in adult patients with a 
history of recurrent CDI episodes, a condition in which the microbiome is characterized 
as a low diversity state. Thirty patients were enrolled following a therapeutic response to 
standard of care CDI antibiotics. The primary endpoint of absence of diarrhea with a 
positive C. difficile test up to 8 weeks following dosing was achieved in 26 (87%) 
patients.  Furthermore, evaluation of the microbiome pre- and post-treatment showed 
SER-109 increased bacterial diversity of the intestinal microbiota as early as 4 days after 
dosing. SER-109 in SERES-001 was safe and tolerable with no deaths. Seven SAEs were 
reported in 4 subjects, none considered related to SER-109.   
Similar to CDI, UC is characterized by a decrease in microbial diversity and richness, 
with a lower prevalence of spore-forming organisms within the phylum, Firmicutes. The 
results from the SERES-001 study in recurrent CDI support exploration of the efficacy of 
SER-287 in increasing bacterial diversity of the intestinal microbiota in UC patients. The 
study population in SERES-001 was older (mean age of 62 years) with frequent co-
morbid illnesses than what is anticipated for the UC population.  Therefore, we anticipate 
a high safety profile in the UC population.  However, as the population will be different 
for this Phase 1b study (SERES-101) than for SERES-001, SERES-101 will evaluate the 
safety, tolerability and microbiome dynamics of SER-287 in UC patients.  
SERES-101 is a Phase 1b multicenter, randomized, double-blind, placebo-controlled 
multiple dose study designed to evaluate the safety and tolerability of SER-287 and to 
evaluate the microbiome alterations and pharmacodynamics associated with two dosing 
regimens of SER-287 in adult subjects with mild-to-moderate UC. Subjects will be 
randomized to one of 4 study arms:  A) Pre-treatment of placebo, followed by weekly 
dosing of SER-287 for 8 weeks, B) Pre-treatment of placebo, followed by daily dosing of 
placebo for 8 weeks. C) Pre-treatment of vancomycin, followed by daily dosing of SER-
287 for 8 weeks, D) Pre-treatment of vancomycin, followed by weekly dosing of SER-
287 for 8 weeks. From screening to last follow-up, the study duration will be between 
35-37 weeks.  


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1.2!
Rationale 
SER-287 (Purified Eubacterial Spores, Encapsulated) is an ecology of bacterial spores 
enriched from fecal donations obtained from healthy, screened donors, representing 
approximately 50 commensal bacteria in spore form.  As UC is characterized by a 
decrease in microbial diversity and richness, with a lower prevalence of spore-forming 
organisms within the phylum, Firmicutes, and preliminary evidence suggests that 
microbial interventions can affect clinical outcomes in UC, the study will examine 
whether SER-287 can correct the dysbiosis in UC, increase microbial diversity and lead 
to clinical response in UC patients with mild-to-moderate disease.   
1.2.1! Rationale for Regimen  
The inflammatory milieu in UC impacts the microbial composition with animal and 
human studies showing a greater representation of Enterobacteriaceae with a relative 
depletion of Clostridial organisms. This dysbiosis is seen in patients with recurrent CDI 
and can be reversed after FMT. While the dysbiosis in Clostridium difficile is mainly 
induced by infection, toxin production and repeated antibiotic usage, the dysbiosis in UC 
is more complex with host factors and alterations in microbial-host interactions likely 
contributing to the witnessed microbial changes.  
This study will evaluate whether repeated dosing can alter the microbial community in 
UC, encourage engraftment and, ultimately, decrease mucosal inflammation.  This study 
will test the weekly dosing strategy that was evaluated in the study by Moayyedi et al. 
and will also evaluate a daily dosing strategy.(Moayyedi et al., 2015) Given that the aim 
of the study is to induce remission in patients with active mild-to-moderate 
inflammation, this study will evaluate a higher frequency of dosing from weekly to daily 
dosing of SER-287 to provide consistent and maximal exposure to SER-287 treatment 
during a period of active inflammation. 
1.2.2! Rationale for dose  
The dose selected in this study is supported by the safety and effectiveness of this dose, 
[1 x 108 Spore Equivalents (SporQs)], administered in the SER-109 Phase 1b/2 study for 
recurrent CDI. The trial explored a range of doses from 3.4"107 to 2.3"1010 SporQs.  The 
doses evaluated were safe with no deaths in the study and no concerning trends in 
laboratory values, vital signs or physical examination findings. The SAEs reported were 
deemed by the investigators to not be related to SER-109.  
The dose selected gives a 230-fold margin to the highest dose tested in SERES-001 and a 
3-fold margin to the lowest dose shown to be effective in SERES-001. Although the 
study population for SERES-001 is not the same study population targeted for the current 
study, the study population in SERES-001 is older (mean age of 62 years) with frequent 
co-morbid illnesses than the general UC population.  
1.2.3! Rationale for Antibiotic Pre-Treatment 
Disease states, such as CDI and UC, are characterized by intestinal dysbiosis and a 
decrease in microbial diversity. Antibiotic treatment prior to administration of a 
repopulating ecology of spores (SER-287) may allow for engraftment of the spores 
administered.  Data described in the DSS animal colitis models with SER-287 


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demonstrate a trend toward improvement by the addition of antibiotics prior to SER-287 
administration (see Investigator’s Brochure).  
Data from the SERES-001 study in prevention of recurrent CDI showed engraftment of 
bacteria from SER-109 as early as 4 days following SER-109 dosing. All the subjects in 
this study were pre-treated with antibiotics prior to SER-109 dosing, supporting, 
although not proving, that antibiotic pre-treatment may enhance engraftment. This study 
will assess whether vancomycin improves engraftment and clinical outcomes through a 
comparison of outcomes in arms with and without vancomycin pre-treatment. 
1.2.4! Rationale for Endpoints  
Efficacy endpoints will be measured incorporating an accepted clinical and endoscopic 
disease activity index in UC, the Total modified Mayo score, with an 8-week treatment 
period to evaluate induction of remission for UC in keeping with FDA regulatory 
guidance. The study will also evaluate endoscopic disease activity before and after 
treatment via central reading.  Clinical disease activity throughout the study will be 
monitored via the partial Mayo score, which is the Mayo Score without the endoscopic 
subscore.   Definitions of disease activity are defined by prior studies for the mild-to-
moderate UC population.(Lichtenstein et al., 2015; Moayyedi et al., 2015; Sandborn et 
al., 2015)  
This study is designed to also evaluate microbiome changes in this Phase 1b study. 
Engraftment is defined as the outgrowth of bacteria that comprise the SER-287 ecology 
in a patient’s gastrointestinal tract post-treatment.  This study will evaluate the 
engraftment of SER-287 bacterial isolates in each treatment arm and determine the 
overall change in composition of the microbiome both by total number of unique types of 
bacteria (ie, α-diversity) and by microbial composition (ie, β-diversity).  The dysbiosis 
described in IBD is characterized by lower microbial diversity and species richness, a 
greater prevalence of pro-inflammatory pathobionts, mainly described within the 
phylum, Proteobacteria, and a lower prevalence of commensal bacteria within the 
phylum, Firmicutes, of which the Clostridial organisms within SER-287 belong.  


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Protocol # SERES-101 
CONFIDENTIAL 
 
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2!
STUDY OBJECTIVES 
2.1!
Primary Objectives 
•! To evaluate the safety and tolerability of SER-287 vs. placebo in adult subjects !18 
years of age with mild-to-moderate ulcerative colitis 
•! To compare the baseline composition of the intestinal microbiome to the post-
baseline composition after initiation of SER-287 or placebo  
•! To determine the engraftment of SER-287 bacteria into the intestinal microbial 
community in each of the SER-287 arms compared to the placebo arm 
2.2!
Secondary Objectives 
•! To determine the proportion of subjects in each of the treatment arms who, at 8 
weeks post initiation of treatment, achieve a clinical response, complete remission, 
and endoscopic improvement 
•! To assess changes in serum and fecal biomarkers from baseline throughout treatment 
 
2.3 Exploratory Objectives 
•! To compare the changes in exploratory biomarkers from mucosal biopsies and stool 
samples in each of the treatment arms from baseline throughout treatment.  
•! To determine the complement of metabolic pathways from stool in each of the 
treatment arms from baseline throughout treatment. 
 
 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  25 of 75                                                  10 Oct 2016  
3!
OVERALL DESIGN AND PLAN OF THE STUDY 
3.1!
Overview 
This is a Phase 1b multicenter, randomized, double-blind, placebo-controlled multiple 
dose study designed to evaluate the safety and tolerability of SER-287 and to evaluate the 
microbiome alterations and pharmacodynamics associated with two dosing regimens of 
SER-287 in adult subjects with mild-to-moderate UC. Subjects will be randomized to 
one of 4 study arms: A) Pre-treatment of placebo, followed by weekly dosing of SER-
287 for 8 weeks; B) Pre-treatment of placebo, followed by daily dosing of placebo for 8 
weeks; C) Pre-treatment of vancomycin, followed by daily dosing of SER-287 for 8 
weeks; D) Pre-treatment of vancomycin, followed by weekly dosing of SER-287 for 8 
weeks.  
 
The study is broken down into 5 study periods:  Screening (Day-17 to Day-1), Pre-
treatment, (Day 1 to Day 7), 8-Week Treatment Period (Day 8-63), a 4-Week Short 
Term Safety Follow-up Period (Day 64-92) and a Long Term Safety Follow-up Day 93 -
246).  Approximately 55 adult subjects with mild-to-moderate ulcerative colitis will be 
enrolled.   
 
Screening includes 2 screening visits.  At the first Screening Visit, (Visit 1), subjects 
will be checked for inclusion/exclusion criteria, and medical history and demographic 
data will be collected.  At the second Screening Visit, (Visit 2) eligible subjects will 
undergo a lower endoscopy (flexible sigmoidoscopy or colonoscopy) and biopsy within 
17 days from the Screening visit and prior to Study Day 1.  Subjects will be on a clear 
liquid diet 1 day before the lower endoscopy (flexible sigmoidoscopy or colonoscopy). 
On the day of the procedure, the subject will administer a bowel prep at the PI discretion 
(e.g., 2 Fleets enemas) and fast for 6 hours before the procedure.   
  
Endoscopy images will be obtained during each endoscopy and will be sent for 
independent central reading and determination of the modified Mayo endoscopic 
subscore. A detailed image review charter from the central reading laboratory will 
outline the endoscopic procedures, video recordings, and equipment to be used for video 
capture and transmission of endoscopic recordings. For each subject, video recording of 
the entire endoscopic procedure will be performed using a storage medium provided by 
the sponsor or designee. The endoscopic recordings will be read centrally in a blinded 
manner by a qualified gastroenterologist according to the image review charter. The 
modified Mayo score used for clinical endpoints in the trial will use the modified Mayo 
endoscopy subscore determined by the central reader. 
! 
The Total modified Mayo score is a composite score.  Only the modified Mayo 
endoscopic subscore is determined by central reader and provided to the clinical site.  If 
the partial Mayo score changes from Visit 1 to Visit 2, the Visit 2 score should be used in 
computing the Total modified Mayo score at Baseline and when assessing the subject for 
the safety stopping rules. Subjects who meet the inclusion criteria (Total modified Mayo 
score of 4 to 10, inclusive and modified Mayo endoscopic subscore of > 1, with evidence 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  26 of 75                                                  10 Oct 2016  
of mucosal lesions), will be randomized using an interactive web/voice response system 
(IxRS) to 1 of 4 treatment groups on Study Day 1 and initiate the pre-treatment regimen. 
 
During the Pre-Treatment period (Day 1 to Day 7) oral vancomycin 125 mg four times 
a day (qid) or matching placebo will be administered for 6 days.  
 
During the 8-Week Treatment Period, all subjects will come to the clinic weekly for 
drug dispensing and asked about adverse events (AEs), change in medications and the 
partial Mayo score assessment (scores should reflect the 24-hour period prior to 
reporting.  The endoscopy procedure day or preparation day should not be included).  All 
subjects will have a lower endoscopy (flexible sigmoidoscopy or colonoscopy) at Visit 
12/Early Termination +/- 3 days to evaluate endoscopic disease activity. Subjects will be 
on a clear liquid diet the day before the lower endoscopy (flexible sigmoidoscopy or 
colonoscopy). On the day of the procedure, the subject will self-administer a bowel prep 
per the PI instructions (e.g., 2 Fleets enemas) and fast for 6 hours before the procedure.   
All subjects will have an in-clinic visit at Visit 12/Early Termination +/- 3 days. 
 
Subjects will then enter the Short Term Safety Follow-up Period in which subjects will 
be contacted by phone on Days 71, 78, 85 +/- 2 days. Subjects will be asked about 
adverse events (AEs), concomitant medications and will complete disease activity 
assessment which includes stool frequency and rectal bleeding, two subscores from the 
total modified Mayo score.  All subjects will have an in-clinic safety visit at Visit 13 +/- 
2 days.  
 
Subjects will then enter the Long Term Safety Follow-up Period in which subjects will 
be contacted by phone on Days 246 +/- 3 days. Following Visit 13 through Day 246/ET 
only SAEs and concomitant medications associated with SAEs will be collected. 
 
To ensure safe study conduct during the Phase 1b study, an independent, unblinded, 
external Data and Safety Monitoring Committee (DSMC) will be established to perform 
safety evaluations on an ongoing basis. A DSMC charter will be developed and will 
detail the review of the safety data.  
3.2!
Criteria for Evaluation of the Study 
The evaluation of the safety data will be performed by comparison of the safety 
endpoints across the treatment arms.  The following safety endpoints will be assessed for 
the comparison: 
•! Incidence of adverse events 
•! Incidence of adverse events of special interest 
•! Laboratory evaluation results 
•! Vital sign measurements 
•! Physical examination findings 
 


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Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  27 of 75                                                  10 Oct 2016  
The evaluation of the efficacy data will be performed by comparison of the efficacy 
endpoints across the treatment arms.  The following efficacy endpoints will be assessed 
across treatment arms at various time points between Visit 1 and Visit 13: 
•! Composition of the intestinal microbiome  
•! Engraftment of SER-287 bacteria in all treatment arms 
•! Clinical response defined as:  
o! A decrease of ≥3 points in Total modified Mayo score (TMMS) from 
baseline, along with EITHER a decrease of >1 point in rectal bleeding 
subscore or absolute rectal bleeding subscore of 0 or 1 
•! Complete remission defined as: 
o! A Total modified Mayo score <2 and an endoscopic subscore 0 with no 
erythema, no blood and no evidence of inflammation  
•! Endoscopic improvement, defined as a decrease in endoscopic subscore > 1 
•! Serum biomarker [C-reactive protein (CRP)]  
•! Fecal biomarker (fecal calprotectin) levels 
 
The following exploratory endpoints may also be evaluated across the treatment arms at 
various time points between Visit 1 and Visit 13: 
•! Stool, and blood metabolic pathways 
•! Serum cytokine profile 
•! Mucosal microbiome  
•! Mucosal transcriptomic profile  
•! Mucosal Histopathology, including CMV Immunohistology stains  
•! Microbial Culture Endpoints: 
o! Candida titer and diversity 
 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  28 of 75                                                  10 Oct 2016  
4!
STUDY POPULATION 
The study population will consist of adult !18 years of age with mild-to-moderate 
ulcerative colitis. Subjects must be able to provide written consent and meet all the 
inclusion criteria and none of the exclusion criteria. 
4.1!
Inclusion Criteria 
To be eligible for enrollment, a subject must meet all of the following criteria before 
undergoing any study-related procedures: 
1.! Signed informed consent 
2.! Male or female ≥18 years of age 
3.! Ulcerative colitis diagnosed by routine clinical, radiographic, endoscopic and 
pathologic criteria (preferably confirmed by colonoscopy and pathology records 
within last 2 years or if unavailable, will need approval by medical monitor)  
4.! Active mild-moderate UC as determined by lower endoscopy (flexible 
sigmoidoscopy or colonoscopy) within approximately 3 days of randomization to 
study 
a.! Total Modified Mayo score of 4 to 10, inclusive  
b.! Modified Mayo endoscopic subscore of > 1, with evidence of mucosal 
lesions 
c.! At least 15 cm of disease from anal verge 
5.! If female, subject is non-lactating, and is either:  
a.! Not of childbearing potential, defined as postmenopausal for at least 1 
year or surgically sterile due to bilateral tubal ligation, bilateral 
oophorectomy, or hysterectomy  
b.! Of childbearing potential and is practicing at least 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 1 of the above methods for the duration of the study  
6.! If male and partner is of childbearing potential, subject agrees to practice at least 
one highly effective method of birth control for the duration of the study  
4.2!
Exclusion Criteria 
A subject will not be enrolled if the subject meets any of the following criteria: 
1.! Fever > 38.3°C 
2.! Known or suspected toxic megacolon and/or known small bowel ileus 
3.! Known history of Crohn’s disease 
4.! Subjects with serum albumin <2.5 g/dL at baseline 
5.! CMV polymerase chain reaction (PCR) positive from blood plasma at screening 
6.! Known stool tests positive for ova and/or parasites or stool culture within the 
30 days before enrollment 
7.! Subjects on cyclosporine or triple immunosuppression, Triple 
immunosuppression will include any three of the following classes of drugs taken 
in combination: steroids (i.e., prednisone/budesonide/budesonide MMX#), 


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Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  29 of 75                                                  10 Oct 2016  
immunosuppressant (i.e., methotrexate/azathioprine/6-mercaptopurine), and/or 
other immunosuppressant (i.e., tacrolimus, cellcept). 
8.! Biologic medication (infliximab/ adalimumab/ golimumab/ 
certolizumab/vedolizumab/ustekinumab/natalizumab) use within 3 months prior 
to screening 
9.! Known active malignancy except for basal cell skin cancer, squamous cell skin 
cancer  
10.!Subjects with previous colectomy, ostomy, J-pouch, or previous intestinal surgery 
(excluding cholecystectomy, appendectomy) 
11.!Subjects with known history of celiac disease or gluten enteropathy 
12.!Subjects with Clostridium difficile positive stool performed by the Central lab at 
Screening Visit  
13.!Antibiotic use within the prior 1 month before randomization  
14.!Expected to receive antibiotics within 8 weeks of signing the Informed Consent 
Form (ICF) (i.e., for planned/anticipated procedure)  
15.!Received an investigational drug within 1 month before study entry 
16.!Received an investigational antibody or vaccine within 3 months before study 
entry 
17.!Previously enrolled in a SER-109/SER-287 study 
18.!Received an FMT within the last 6 months 
19.!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.! Subjects with decompensated liver cirrhosis (Child-Pugh Class B or C) or 
uncontrolled liver disease 
b.! Prior history of bone marrow transplant  
c.! Known Hypogammaglobulinemia  
d.! Known severe immunodeficiency 
e.! Underlying liver function test (LFT) [screening alanine aminotransferase 
(ALT) or aspartate aminotransferase (AST)] abnormalities greater than 2x 
upper limit of normal (ULN) 
f.! Absolute neutrophil count (ANC) <500 
20.!Subjects with anatomic or medical contraindications to lower endoscopy (flexible 
sigmoidoscopy or colonoscopy), including but not necessarily limited to toxic 
megacolon, gastrointestinal (GI) 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) 
21.!Unable to stop steroid enemas or suppositories or mesalamine enemas or 
suppositories before screening visit 
22.!Unable to stop opiate treatment unless on a stable dose and no increase in dose 
planned for the duration of the study 
23.!Unable to stop probiotics before screening visit 
24.!Concurrent intensive induction chemotherapy, radiotherapy, or biologic treatment 
for active malignancy (subjects on maintenance chemotherapy may only be 
enrolled after consultation with medical monitor) 


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Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  30 of 75                                                  10 Oct 2016  
25.!Unable to comply with the protocol requirements  
26.!Any condition that, in the opinion of the investigator, might interfere with study 
objectives 
27.!Known allergy or intolerance to oral vancomycin 
28.!Known active intravenous drug or alcohol abuse or use of other drugs of abuse 
4.3!
Subject Withdrawal and Replacement 
Subjects should continue to be followed for safety assessments through 24 weeks after 
treatment, even after being discontinued from study medication.  However, a patient may 
withdraw from the study at any time for any reason, without any consequence.  
 
Subjects may be required to withdraw from study after discussion with the Sponsor and/or 
Investigator for the following reasons: 
•! Pregnancy (see Section 6.2.2.4); 
•! Adverse event(s); 
•! Met at least one of the safety halting rules (see Section 6.2.2.1) 
•! At the discretion of the Investigator 
•! Protocol violation 
•! Non-compliance 
 
In all cases, the reason(s) for withdrawal will be recorded on the electronic data capture 
(EDC) system. If a subject is prematurely withdrawn from the study drug for any reason 
before Visit 12, the Investigator must make every effort to perform the evaluations 
described for Follow Up Visit 12. 
If a subject withdraws consent and still agrees to undergo a final examination, this will 
be documented on the EDC system and the Investigator’s copy of the ICF, which will be 
countersigned and dated by the subject.  
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, 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). 
Subjects who discontinue from the study after randomization may be replaced.  
4.4!
Planned Sample Size and Number of Study Centers 
Approximately 55 subjects will be enrolled at approximately 20 sites in the United States 
(US).  


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Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  31 of 75                                                  10 Oct 2016  
4.5!
Subject Identification and Randomization 
4.5.1! Subject Identification 
All screened subjects will be assigned a unique subject identification (SID) number that 
will be used through screening, pre-treatment and treatment periods, and safety follow-up 
period.  
4.5.2! Methods of Assigning Patients 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 Visit 3 (Day 1) after all screening procedures 
have been performed and eligibility for the study confirmed. Subjects will be randomized 
via interactive voice/web response system (IxRS) to one of 4 study arms: A) Pre-
treatment of placebo, followed by weekly dosing of SER-287 for 8 weeks; B) Pre-
treatment of placebo, followed by daily dosing of placebo for 8 weeks; C) Pre-treatment 
of vancomycin, followed by daily dosing of SER-287 for 8 weeks; D) Pre-treatment of 
vancomycin, followed by weekly dosing of SER-287 for 8 weeks.  
 
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, subjects, the investigators and other study site personnel, 
and clinical staff will remain blinded to the treatment assignment. The medical monitor, 
study site monitors, and other sponsor representatives involved in the clinical aspects of 
study conduct also will remain blinded to the treatment assignment.  
4.5.3! 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 sponsor 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 


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Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  32 of 75                                                  10 Oct 2016  
regulatory reporting purposes.  
 
If the blind is broken, the date, time, and reason must be recorded in the patient’s EDC 
system, and any associated AE 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 (Visit 1 
through Visit 13) data is declared complete and final, the study blind codes will be 
broken. 
 


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Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
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5!
INVESTIGATIONAL PRODUCT 
5.1!
SER-287 
5.1.1! Donor Screening 
Donors undergo a general health examination including GI medical history, familial GI 
medical history, clinical chemistry, hematology with complete blood count, urinalysis, 
and blood and fecal viral and bacterial pathogen testing before donating stool. The donor 
must successfully complete the physical screening and laboratory tests after the donation 
period before the material can be released for manufacturing. A description of donor 
screening procedures is provided in the Investigator’s Brochure.  
5.1.2! SER-287 Manufacturing 
SER-287 is manufactured as SER-109 using current Good Manufacturing Practice -
compliant processing steps, and is subsequently released using assays for purity, potency, 
and identity. The manufacturing process inactivates non-spore forms of bacteria, fungi, 
and other potential components (parasites and some viruses), substantially reduces the 
amount of undigested food and inactivated vegetative biomass via successive filtration 
steps, and formulates the drug substance in 92% glycerol and approximately 8% saline 
solution (0.9% of sodium chloride), containing less than about 30 mg of non-spore 
solids.  The drug substance is filled into capsules, and then over-encapsulated. For each 
unit-dose bottle, four capsules (1×108 SporQs) are packaged in an HDPE container, 
induction sealed with foil and closed with child resistant closures. At the time of labeling 
for investigational use the drug product becomes SER-287. SER-287 is odorless and 
tasteless as prescribed. If chewed or if capsule integrity is compromised, SER-287 has a 
sweet taste. 
Study drug will be packaged by Catalent Pharma Solutions according to all local legal 
requirements. Study drug will be labeled in accordance with applicable regulatory 
requirements. 
5.2!
Over-encapsulated (OE) Vancomycin HCl 125 mg Capsules, Hard Gelatin 
Capsules (“Vancomycin”) 
5.2.1! Vancomycin HCl Procurement, Over-encapsulation, Packaging and Storage 
Commercially available Vancomycin HCl 125 mg Capsules, USP, in 20-capsule blister 
packs are de-blistered and over encapsulated in size 00 Swedish Orange Capsules with 
microcrystalline cellulose backfill.  Capsules are filled into 40 mL white high density 
polyethylene (HDPE) bottles, induction sealed with a foil seal and closed with child 
resistant closures.  Each bottle is filled with 24 capsules.  Bottles are stored at ambient 
temperature.     


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Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  34 of 75                                                  10 Oct 2016  
5.3!
SER-287 Placebo Capsules 
5.3.1! SER-287 Placebo Manufacturing 
Placebo will be identical to the Investigational Product SER-287 but will not contain 
product spores or non-spore solids. Placebo will consist of 92% glycerol and 
approximately 8% saline solution (0.9% of sodium chloride).  The SER-287 Placebo will 
be provided in a single-dose container of 4 white, size 00 capsules in a foil-sealed, 
opaque, 40 mL HDPE bottle with child resistant closures. At the time of labeling for 
investigational use the placebo becomes SER-287 placebo.  The SER-287 placebo is 
odorless and tasteless as prescribed. If chewed or if capsule integrity is compromised, 
SER-287 placebo has a sweet taste. 
5.4!
Vancomycin HCl Placebo Capsules (“Vancomycin Placebo”) 
5.4.1! Vancomycin HCl Placebo Manufacturing and Storage 
Vancomycin HCl placebo is manufactured in size 00 Swedish Orange Capsules.  
Capsules are filled with microcrystalline cellulose and filled into 40 mL white HDPE 
bottles.  Bottles are induction sealed with a foil seal and closed with child resistant 
closures.  Each bottle is filled with 24 capsules.  Bottles are stored at ambient 
temperature. 
5.5!
Storage 
5.5.1! SER-287 and SER-287 Placebo Storage 
SER-287 or placebo bottles are assembled into weekly kits and stored at or below -15°C 
at the distribution depot. Kits are shipped to the clinical site on dry ice.  Kits are stored at 
or below -15°C at the clinical site until dispensed to the subject.  Subjects are instructed 
to store kits at home in the refrigerator (2°C-8°C).  For more information on storage, 
refer to the Study Manual. 
The doses, route, and schedule of study drug administration are shown in Table 1, below:  
 
 
 
 
 
 
 
 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  35 of 75                                                  10 Oct 2016  
Table 1: Doses, Route, and Schedule of Study Drug Administration 
Group 
Pre-treatment: Vanco or Pbo 
  Treatment Period:  SER-287 or Pbo 
Vanco 
or Pbo 
Regimen 
Admin 
Duration 
  
SER-287 
or Pbo 
Regimen 
Admin 
Duration 
A 
Pbo 
Pbo 
One 
capsule 
four 
times 
daily 
orally 
6 days 
  
SER-287 
+ Pbo 
SER-287 
Weekly 
(1x108 
SporQs) 
+Pbo 
6d/wk 
Four 
capsules 
once daily 
orally 
8 wks 
B 
Pbo 
Pbo 
One 
capsule 
four 
times 
daily 
orally  
6 days 
  
Pbo 
Placebo 
Daily 
Four 
capsules 
once daily 
orally 
8 wks  
C 
Vanco 
Vanco 
125 mg 
qid 
One 
capsule 
four 
times 
daily 
orally 
6 days 
  
SER-287  
SER-287 
Daily 
(1x108 
SporQs)   
Four 
capsules 
once daily 
orally 
8 wks 
D 
Vanco 
Vanco 
125 mg 
qid 
One 
capsule 
four 
times 
daily 
orally 
6 days 
  
SER-287 
+ Pbo 
SER-287 
Weekly 
(1x108 
SporQs) 
+Pbo 
6d/wk   
Four 
capsules 
once daily 
orally 
8 wks 
d = day; Pbo = placebo; qid = Four times a day; wk = week; admin= administration;  
vanco=vancomycin; SporQs= spore equivalents 
 
After the primary study period (Visit 1 to Visit 13) data is declared complete and final, the 
overall randomization code will be broken only for reporting purposes. The record of 
randomization will include study arm assignment and also the association of treatment kit 
number with donor group.  
5.6!
Drug Accountability 
The Investigator is responsible for maintaining accurate study drug accountability 
records throughout the study. 
 
Vancomycin or Vancomycin placebo are provided in sealed bottles containing 24 
capsules.  The seal on a given bottle should be punctured at the time of subject 
randomization to perform drug accountability at the capsule level. Each bottle should be 
stored unopened and intact until dispensed to the subject.  
 
SER-287 or SER-287 placebo are provided in sealed bottles containing four capsules. 
The seal on a given bottle should only be removed at the time of administration. Each 
bottle should be stored unopened and intact until time-of-use. Drug accountability at the 


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Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  36 of 75                                                  10 Oct 2016  
clinical site should be done both at the kit level and at the individual unit-dose bottle 
level.  
5.7!
Prior and Concomitant Medications 
Any medication the subject takes through Visit 13 other than the study drug (vancomycin 
and SER-287), including herbal and other non-traditional remedies, is considered a 
concomitant medication.  Following Visit 13 through Day 246/ET only concomitant 
medications associated with SAEs will be collected.  All concomitant medications must 
be recorded in the EDC system. The following information must be recorded in the EDC 
system for each concomitant medication: generic name (or trade name if generic is not 
known), route of administration, start date, stop date, dosage, and indication. Any 
changes in the dosage or regimen of a concomitant medication must be recorded in the 
EDC system. 
 
At Screening, subjects will be asked about all current and prior IBD medications they 
have taken and in addition all medications taken during the last 6 months (non-IBD 
related)  At each subsequent study visit, subjects will be asked what concomitant 
medications they are currently taking. 
 
Permitted concomitant medications include: 
•! Oral aminosalicylates (Aminosalicylates taken for at least 6 weeks, with a stable 
dose for > 2 weeks prior to screening)  
•! Immunomodulator: 6-Mercaptopurine, Azathioprine, Methotrexate (Stable dose 
for > 12 weeks prior to screening) 
•! Prednisone < 15 mg (Stable dose for > 2 weeks prior to screening) 
•! Budesonide < 6 mg (Stable dose for > 2 weeks prior to screening 
•! Budesonide MMX# < 9 mg (Stable dose for > 2 weeks prior to screening) 
•! Opiate treatment (stable dose) 
•! Short term opiate use is permitted 
•! Short term use of non-steroidals/NSAIDS, is permitted 
•! Low dose aspirin (81mg) is permitted for long-term use 
 
Subjects who are receiving any of the above permitted concomitant medications at the 
time of study entry must keep their dosage stable throughout the study, unless 
investigator judgment requires it to be increased, reduced or discontinued for safety 
concerns or medical necessity.  If there is a change in dosage, the subject would then be 
discontinued from the study.   
 
 
 
 
 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  37 of 75                                                  10 Oct 2016  
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 agent administration. 
•! Probiotics  
•! Loperamide, diphenoxylate/atropine, or bile-salt sequestrant (cholestyramine, 
colesevelam) 
•! Cyclosporine or triple immunosuppression 
•! Biologic medication (infliximab/ adalimumab/ golimumab/ certolizumab/ 
vedolizumab/ ustekinumab/ natalizumab) 
 


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Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  38 of 75                                                  10 Oct 2016  
6!
VARIABLES AND METHODS OF ASSESSMENT 
6.1!
Microbiome Alterations and Engraftment Primary Endpoints 
6.1.1! Microbiome Alterations 
Stool samples will be analyzed to characterize changes in the microbiome and associated 
functional metabolic changes in the gastrointestinal tract at various time points between 
Visit 1 and Visit 13.  
 
Composition of the intestinal microbiome 
Composition of the intestinal microbiome will be assessed at time points between Visit 1 
and Visit 13. 
 
Engraftment of SER-287 bacteria 
Engraftment is defined as the outgrowth of bacteria that comprise the SER-287 spore 
ecology in a subject’s gastrointestinal tract post-treatment. Engraftment of SER-287 
bacteria will be assessed at time points between Visit 4 and 13. 
  
Secondary Endpoints 
6.1.2! Clinical Response, Complete Remission, and Endoscopic Improvement 
Partial Mayo score, which is the Mayo Score without the endoscopic subscore, will be 
assessed at each visit and the Total modified Mayo score (TMMS) will be assessed at 
baseline and at Visit 12 (or early termination) 
Clinical response is defined as:  
$! A decrease of ≥3 points in TMMS from baseline, along with EITHER a decrease 
of >1 point in rectal bleeding subscore OR absolute rectal bleeding subscore of 0 
or 1 
Complete remission is defined as: 
$! A TMMS <2 and an endoscopic subscore of 0 with no erythema, no blood and no 
evidence of inflammation  
Endoscopic improvement is defined as: 
$! a decrease in the modified Mayo endoscopic subscore > 1  
6.1.3! Biomarkers 
The following biomarkers will be evaluated at time points between Visit 1 and Visit 13.  
•! Serum biomarkers (CRP)  
•! Fecal biomarkers (fecal calprotectin) levels  
 
 
 


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Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
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6.1.4 Exploratory Endpoints 
The following exploratory endpoints may be evaluated. Please refer to schedule of 
assessments for times collected.  
•! Stool and blood metabolic pathways  
•! Serum cytokine profile 
•! Mucosal transcriptomic profile  
•! Mucosal microbiome  
•! Mucosal Histopathology, including CMV Immunohistology stains  
•! Microbial Culture Endpoints: 
o! Candida titer and diversity 
6.2!
Safety Variables 
Safety evaluations include medical history, assessment of AEs, clinical laboratory tests 
(chemistry, hematology and urinalysis), physical examination, vital signs, and 
electrocardiograms (ECGs).  
6.2.1! The Safety Endpoints 
•! Incidence of adverse events 
•! Incidence of adverse events of special interest 
•! Laboratory evaluation results 
•! Vital sign measurements 
•! Physical examination findings 
6.2.2! Adverse Events 
An adverse event (AE) 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 or not it is considered to be related to the study drug. 
 
A serious adverse event (SAE) 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 in-patient 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). 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  40 of 75                                                  10 Oct 2016  
•! 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. 
•! Is an important medical event. An important medical event is an event that may not 
result in death, be life-threatening, or require hospitalization but may be considered 
an SAE when, based upon appropriate medical judgment, it may jeopardize the 
subject and may require medical or surgical intervention to prevent 1 of the outcomes 
listed in the definitions for SAEs. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias, convulsions that do not result in in-patient hospitalization, and the 
development of drug dependency or drug abuse. 
 
An adverse event of special interest (AESI) (serious or non-serious) is one of scientific 
and medical concern specific to the product or program, for which ongoing monitoring 
and rapid communication by the investigator to the sponsor is appropriate. 
 
In this protocol, a UC flare, as defined in Section 6.2.2.1 below, has been designated as 
an AESI and as such will be reported and followed in the same manner as a SAE during 
the course of the study.    
 
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 1 of the criteria 
above will not be reported as AEs. Repeating a test because of an abnormal result, in the 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  41 of 75                                                  10 Oct 2016  
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 
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. 
 
All AEs, SAEs and AESIs will be collected from Informed Consent up to Visit 13.  
Following Visit 13 through Day 246, only SAEs will be collected.  All AEs, including 
SAEs and AESIs, will be monitored until resolution or determined by the Investigator to 
be due to a subject’s stable or chronic condition or intercurrent illness. 
The Investigator is responsible for: 
•! Informing the sponsor in the event that a patient or a subject’s partner becomes 
pregnant during the study. A “Pregnancy Report Form” will be generated and the 
pregnancy will be captured in the safety database and will be followed through to the 
outcome. 
•! Evaluating subject safety including assessment of AEs for seriousness, severity, and 
causality. 
Informing the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) of 
AEs as required and SAEs as per IRB/IEC guidelines. 
6.2.2.1! Safety Halting Rules 
 
To ensure subject safety, individual (as listed below) and study-wide (as detailed in the 
DSMC charter) halting rules will be implemented. 
 
Individual halting rules include: 
•! UC flare, defined by: 1) an increase by 2 points from screening of partial Mayo score 
at two contiguous visits after SER-287/placebo initiation (if the partial Mayo score 
changes from Visit 1 to Visit 2, the Visit 2 score should be used in computing the 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  42 of 75                                                  10 Oct 2016  
partial Mayo score at Baseline for the individual halting rules), AND 2) worsening 
clinical status warranting change in UC treatment as determined by principal 
investigator. 
•! Any SAE that is serious, related to study drug, and unexpected, which when referred 
to the DSMC the recommendation is to withdraw the subject from the study. 
If a subject meets the criteria above for at least one of the individual halting rules, he/ she 
will be discontinued from the study. 
6.2.2.2! Reporting Serious Adverse Events 
The Investigator must report any SAEs and AESIs to the PAREXEL Medical Services 
Safety Contact within 24 hours of becoming aware of the event by completing and 
transmitting the Serious Adverse Event report form by fax or email to the PAREXEL 
Safety Contact noted below. If questions arise regarding the reporting procedures or the 
specifics of the reporting event or the site needs to report the event by phone, the 
investigator may call the Safety Contact listed below. A phone report will need to be 
followed by faxing or emailing the written SAE report form within the next 24 hours.  
 
The Sponsor (or Sponsor’s designated agent) will review each SAE report in detail and 
will evaluate the expectedness according to the reference document (Investigator 
Brochure or Summary of Product Characteristics). Based on the Investigator and 
Sponsor’s assessment of the event, a decision will be made concerning the need for 
expedited reporting to regulatory authorities. 
SERIOUS ADVERSE EVENT/ADVERSE EVENTS OF SPECIAL INTEREST 
REPORTING INSTRUCTIONS 
PAREXEL International Corporation 
North America Medical Services 
Telephone Number: +1-781-434-5010 
Fax Number: +1-781-434-5957 
 
Email: NorthAmerica_Medical@PAREXEL.com 
Fax the SAE/AESI report form and any supporting documentation to the PAREXEL 
Medical Services Safety Team within 24 hours of becoming aware of the event. 
The SAE/AESI report form should be completed in its entirety as much as possible. If 
only a partial SAE report is available, preliminary information will be documented on the 
SAE/AESI Report Form and transmitted to the PAREXEL Safety contact within 24 
hours of site awareness. The minimum information required for an initial report is: 
•! Name of person sending the report (i.e., name, address of Investigator); 
•! Subject identification (screening/randomization number, initials, NOT subject name); 
•! Protocol number; 
•! Description of SAE/AESI; 
•! Causality assessment, if possible. 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  43 of 75                                                  10 Oct 2016  
When additional relevant information is available, the SAE/AESI report form will be 
updated with the new information and submitted within 24 hours of site awareness of this 
new information. The event must be documented in the eCRF. 
6.2.2.3! Follow-up of Adverse Events 
All AEs experienced by a subject, irrespective of the suspected causality, will be 
monitored until the AE has resolved, any abnormal laboratory values have returned to 
baseline or stabilized at a level acceptable to the Investigator and Medical Monitor, until 
there is a satisfactory explanation for the changes observed, until the subject is lost to 
follow-up, until it is unlikely that any additional information can be obtained, or until the 
subject has died. 
6.2.2.4! Pregnancy 
The Sponsor has a responsibility to monitor the outcome of pregnancies where there has 
been maternal exposure to the study drug.  
Pregnancy alone is not regarded as an AE unless there is a suspicion that the study drug 
may have interfered with the effectiveness of a contraceptive medication. 
Elective abortions without complications should not be handled as AEs, unless they were 
therapeutic abortions (see below). Hospitalization for normal delivery of a healthy 
newborn should not be considered a SAE. 
All pregnancies must be reported by the Investigator to PAREXEL/Sponsor on the initial 
pregnancy report form within 24 hours after becoming aware of the pregnancy. The 
Investigator must follow up and document the course and the outcome of all pregnancies 
even if the subject was discontinued from the study or if the study has finished. 
All outcomes of pregnancy must be reported by the Investigator to PAREXEL/Sponsor 
on the pregnancy outcome report form within 24 hours after he or she has gained 
knowledge of the normal delivery or elective abortion. 
Any SAE that occurs during pregnancy (including SAEs occurring after last 
administration of study drug) must be recorded on the SAE report form (e.g., maternal 
serious complications, spontaneous or therapeutic abortion, ectopic pregnancy, stillbirth, 
neonatal death, congenital anomaly, or birth defect) and reported within 24 hours in 
accordance with the procedure for reporting SAEs 
If a female partner of a male study subject who has been exposed to the study drug 
becomes pregnant, the pregnancy and outcome of pregnancy should be monitored. 
In the event of pregnancy, the pregnancy should be followed until the outcome of the 
pregnancy is determined. 
6.2.3! Laboratory Variables 
Laboratory assessments will be performed by a central laboratory, as identified in the 
List of Study Personnel. 
Blood samples will be taken using standard venipuncture techniques. A laboratory 
manual will be provided by the central laboratory. This laboratory manual will contain 
detailed instructions for collection, storage, and shipment of samples (e.g., what kind of 
tubes, what kind of sample preparation, mailing addresses, etc.).   


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  44 of 75                                                  10 Oct 2016  
The following laboratory variables (Table 2) will be determined in accordance with the 
Schedule of Events (Table 3).  
 
Table 2: Laboratory Assessments 
Hematology: 
erythrocytes 
mean corpuscular volume (MCV) 
mean corpuscular hemoglobin (MCH) 
neutrophils 
eosinophils 
basophils 
lymphocytes 
monocytes 
platelets 
leukocytes 
hemoglobin 
hematocrit 
Urinalysis1: pH 
protein 
glucose 
ketone 
bilirubin 
blood 
nitrite 
leukocyte esterase 
Clinical 
chemistry: 
creatinine 
glucose 
triglycerides 
urea 
uric acid 
cholesterol 
albumin 
Liver 
enzymes: 
ALP 
AST 
ALT 
GGT 
direct and indirect 
bilirubin 
total bilirubin 
Electrolytes: 
sodium 
potassium 
 
 
Pregnancy test2: In women with childbearing potential only 
ALP = alkaline phosphatase; ALT =  alanine aminotransaminase; AST = aspartate aminotransferase; CBC = 
complete blood count; GGT = γ-glutamyl transferase; RBC =  red blood cells; WBC = white blood cells. 
1 Urinalysis will be performed by dipstick.  If nitrates or leukocytes are positive, a microscopic 
examination will be performed by the central laboratory. 
2 A serum pregnancy test will be done at Screening.  Urine pregnancy tests will be done at Visit 3 (Day 1), 
Visit 12 (Day 64 ± 3) and at Visit 13 (Day 92 ± 1).  
 
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 or not the value is 
of clinical significance and should be recorded as an AE.  Actual laboratory results will 
not be captured on the EDC system. However, if any laboratory results meeting the 
reporting requirements for an AE, the event term (e.g., elevated transaminase) will be 
recorded on the EDC system as an AE or SAE, as applicable. 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  45 of 75                                                  10 Oct 2016  
6.2.4! Stool Samples 
Stool samples will be collected by the subjects and brought to the clinic at Visit 1, Visit 
4, Day 11, Visit 5, Day 18, Visit 6, Visit 12 and Visit 13 or the Early Termination Visit 
(if applicable), and any Unscheduled Visit. 
6.2.5! Biopsy Samples  
A total of 4 biopsies will be obtained between 15 and 30 cm of the colon both at Visit 2 
and at Visit 12.  One biopsy sample will be placed in formalin and 3 biopsies will be 
placed in RNALater.  At the clinical site, samples will be processed and then shipped to 
the central laboratory according to procedures defined in the Laboratory Manual.   
6.2.6 Vital Signs 
The following vital signs will be assessed in accordance with the Schedule of Events 
(Table 2): 
•! Blood pressure (BP; systolic and diastolic; mmHg); 
•! Heart rate (HR; beats per minute); 
•! Oral body temperature (°C); 
•! Respiration rate (breaths per minute). 
•! Height (taken at Screening only) 
•! Weight 
The Investigator or designee will indicate whether or not a value is of clinical 
significance and should be recorded as an AE.   
6.2.7! Electrocardiograms 
Standard 12-lead ECGs will be performed in accordance with the Schedule of Events 
(Table 2). 
Standard safety 12-lead ECGs (single reading) will be performed at Day 8 (before 
dosing), and at Follow-Up on Day 92 as shown in Table 2, the Schedule of Events. 
All ECGs will be evaluated by a qualified physician or delegate for the presence of 
abnormalities.  The Investigator or designee will indicate whether or not a value is of 
clinical significance and should be recorded as an AE.  The ECG data will be collected 
as: Normal; Abnormal, Not Clinically Significant; and Abnormal, Clinically Significant.  
6.2.8! Physical Examinations 
Physical examinations will be performed in accordance with the Schedule of Events 
(Table 2).   
The physical examination includes an assessment of general appearance and evaluation 
of the following: Head/Eyes/Ears/Nose/Throat; Neck; Lungs and Heart; Abdomen; 
Extremities; Neurological; Other. 
Abnormal clinically significant findings will be reported as medical history or AEs as 
determined by Investigator. 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  46 of 75                                                  10 Oct 2016  
6.3!
Demographics and Baseline Characteristics 
Demographics and Baseline Characteristics consist of those variables that are assessed 
only at screening/baseline. 
6.3.1! 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). 
6.3.2! Disease History 
For disease history the following will be documented: 
•! Date of first diagnosis; 
•! Montreal classification 
6.3.3! Baseline Characteristics 
•! General medical history 
•! General surgical history 
•! Smoking history 
6.3.4! Medical History 
For the documentation of the medical history, any previous and concomitant diseases 
before screening will be documented. The medical history will be obtained by 
interviewing the subject or by inspecting his/her medical records. 
6.3.5! Prior and Concomitant Medications 
Prior and concomitant medication will be documented as described in Section 5.7.  Prior 
and concomitant medications will be coded using the WHO Drug Dictionary. 
 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  47 of 75                                                  10 Oct 2016  
7!
STUDY CONDUCT 
7.1!
Schedule of Events 
The study consists of a Screening Visit (Days -17 to -1), a Screening Visit for lower 
endoscopy (flexible sigmoidoscopy or colonoscopy) (at least 3 days before Day 1), a 
pretreatment period (Days 1 to 7), a treatment period (Days 8 to 63), and Short Term 
Safety Follow-up (Day 64 to 92) and a Long Term Safety Follow-up (Day 93-246).  The 
maximal study duration for an individual subject will be 260 days. 
The Schedule of Events is presented in Table 3.  


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  48 of 75                                                  10 Oct 2016  
Table 3: Schedule of Events 
 
VISIT NAME
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Visit 12/ET (j)
Phone calls
Visit 13
Phone call
Day 11(d)
Day 18(d)
Visit/Phone Call
Pre-Treatment Drug 
Dosing
X (c)
Study Drug Dosing 
X(c)
Informed consent
X
Inclusion/ Exclusion 
Criteria
X
X
Central Reading 
Results
X (o)
X
Medical history
X
Randomization
X
Demographic data
X
Physical Ex
X
X
X
X
X
X
Vital signs (a)
X
X
X
X
X
X
ECG
X (b)
X
Bowel Prep (i)
X
X
Lower Endoscopy
X
X
Overnight Fast 
(required for 
endoscopy; when 
possible for other 
visits)
X (k)
X
X 
X 
X 
X (k)
X 
Blood Testing
Hematology
X (g)
X (b)
X(b)
X
X
Clinical chemistry
X (g)
X(b)
X(b)
X
X
CMV PCR (l)
X (g)
Pregnancy test 
(WOCBP)
X (g)
Blood for biomedical 
research
X (b)
X
Blood for 
metabolomics
X (h)
X (b)
X
X
X
X
Blood for CRP
X
X (b)
X
X
X
X
Serum Cytokine
X (h)
X
Visit
Visit
Visit
Visit
Visit
Phone call
Visit
Phone call
Visit
VISIT DAY
Visit for 
sigmoidoscopy(f
)
Visit
Visit
Stool sample
Visit
Stool sample
Visit
Visit
Screening with  lower 
endoscopy (flexible 
sigmoidoscopy or colonoscopy) 
(Day -17 to Day -1 )
Treatment Period (Day 8-Day 63)
Safety Follow Up Period (Day 64-246) 
Day 8 +/- 1d
Day 1
Day 15 +/-1d
Day 22+/-1d
Day 29 +/-1d
Day 36 +/-1d
Day 43  +/-1d
Day 50 +/-1d
Day 57+/-1d
Day 64+/-3d
Weekly on 
Days 71, 78, 
85+/-2d
Day 92+/-2d
Day 246 +/-3d
Pre-Treatment 
Period (Day 1-7)
 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  49 of 75                                                  10 Oct 2016  
 
 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  50 of 75                                                  10 Oct 2016  
Table 3: Schedule of Events (continued) 
 
VISIT NAME
Visit 1
Visit 2
Visit 3
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Visit 12/ET (j)
Phone calls
Visit 13
Phone call
Day 246 +/-3d
Day 11(d)
Day 18(d)
Urine Testing
Urine Pregnancy
X
X 
X
Urinalysis (e)
X
X (b)
X
X
Stool Testing
Stool for 
Microbiome
X (h)
X (b)
X
X
X
X
X
Stool for Microbial 
Culture
X (h) 
X (b)
X
X
X
X
 X
Stool for 
Metabolomics
X (h) 
X(b)
X
X
X
X
Stool for cdiff
X (g)
Stool for Fecal 
calprotectin
X (h) 
X (b)
X
X
X
Biopsies
Mucosal 
Transcriptomics (2 
samples)
X
X
Mucosal Microbiome 
(1sample)      
X
X
Histopathology with 
CMV Stain (1 
sample)
X
X
Visit
Visit
Phone call
Visit
Phone call
Visit
Visit
Visit
Visit
X
Screening with  lower endoscopy 
(flexible sigmoidoscopy or 
colonoscopy) (Day -17 to Day -1 )
Pre-Treatment 
Period (Day 1-7)
Treatment Period (Day 8-Day 63)
Safety Follow Up Period (Day 64-246) 
Short Term Safety Follow-up (Day 64 to 92 ) and a Long Term Safety 
Follow-up (Day 93-246). 
Day 64+/-3d
Weekly on 
Days 71, 78, 
85+/-2d
Day 92+/-2d
Visit 4
Visit 5
VISIT DAY
Day 1
Day 8 +/- 1d
Day 15 +/-1d
Day 22+/-1d
Day 29 +/-1d
Day 36 +/-1d
Day 43  +/-1d
Day 50 +/-1d
Day 57+/-1d
Visit/Phone Call
Visit
Visit for  lower 
endoscopy 
(flexible 
sigmoidoscopy 
or 
Visit
Visit
Stool sample
Visit
Stool sample
Visit
X
 
 
 


Seres Therapeutics, Inc 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  51 of 75                                                  10 Oct 2016  
Table 3: Schedule of Events (continued) 
 
VISIT NAME
Visit 1
Visit 2
Visit 3
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Visit 12/ET (j)
Phone calls
Visit 13
Phone call
Day 246 +/-3d
Day 11(d)
Day 18(d)
Study Drug 
Dispensation
Dispense pre-trtmt 
drug
X
Return pre-trmt 
drug
X
Dispense study drug 
( q )
X
X
X
X
X
X
X
Return study drug
X
X
X
X
X
X
X
Other
Diet Inventory
X
X
X
X
Partial Mayo score
X
X
X
X
X
X
X
X
X
X
X
X 
X
X
Safety Follow Up Period (Day 64-246) 
X
Visit
X
X
Treatment Period (Day 8-Day 63)
Visit
Visit
Visit
Visit
Visit
Concomitant 
medications (n)
BP = blood pressure; cdiff = Clostridium difficile ; CMV = cytomegalovirus; Cx = Culture; d = day; CRP = C-reactive protein; ECG = electrocardiogram; ET = early termination; EX = exam; Flex = flexible; HR = heart rate; PCR = polymerase chain reaction; prep = preparation; RR = respiration rate; 
Sig = sigmoidoscopy; Wk = week; WOCBP = women of childbearing potential.
Notes:  (a) Height on screening only; BP, RR, HR, Temp and weight at all vital signs assessments; (b) Prior to dosing; (c) 1st dose observe 1 hr post-dosing; (d) As close to scheduled day as possible ; (e) Urinalysis will be performed by dipstick; If nitrates or leukocytes are positive, a microscopic 
examination will be performed by the central laboratory (f) Must be performed at least 3 days before Day 1; (g) Sample needs to be obtained and results reviewed prior to  lower endoscopy (flexible sigmoidoscopy or colonoscopy) ; (h) Obtain sample and hold.  Only samples from subjects that are 
randomized will be analyzed; (i) Clear liquid diet day before procedure with bowel prep at PI discretion (e.g. two Fleets enemas 1.5 hours before procedure); (j) Subjects who terminate pr ior to Visit 12 will have a lower endoscopy (flexible sigmoidoscopy or colonoscopy) at the Early Termination visit; 
(k) Beginning the night before the lower endoscopy (flexible sigmoidoscopy or colonoscopy); (l) Quantitative CMV testing on plasma; (n) Concomitant medications will be recorded from Week 12 through Day 246 only if they are associated with an AE; (o) Prior to randomization; (p) Following Visit 
13 throughDay 246/ET only SAEs, and concomitant medications associated with SAEs will be collected;  (q) Instruct subject to take study drug at the same time each day when possible
X
Total modified Mayo 
score
X
Adverse event 
reporting (p)
Visit/Phone Call
Visit
Visit for 
sigmoidoscopy(f
)
Visit
Visit
Stool sample
Visit
Stool sample
Visit
Phone call
Visit
Phone call
Short Term Safety Follow-up (Day 64 to 92 ) and a Long Term Safety 
Follow-up (Day 93-246). 
Visit 4
Visit 5
VISIT DAY
Day 1
Day 8 +/- 1d
Day 15 +/-1d
Day 22+/-1d
Day 29 +/-1d
Day 36 +/-1d
Day 43  +/-1d
Day 50 +/-1d
Day 57+/-1d
Day 64+/-3d
Weekly on 
Days 71, 78, 
85+/-2d
Day 92+/-2d
Screening with  lower 
endoscopy (flexible 
sigmoidoscopy or colonoscopy) 
(Day -17 to Day -1 )
Pre-Treatment 
Period (Day 1-7)


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  52 of 75                                                  10 Oct 2016  
7.2!
Procedures by Visit 
Visits should occur within ± 1 day of the scheduled visit. All times should be recorded 
using the 24-hour clock (e.g., 23:20, not 11:20 pm). 
7.2.1! Screening Day -17 to Day -1 (Visit 1) 
•! Obtain written informed consent for study; 
•! Verify conformance with inclusion/exclusion entry criteria; 
•! Record medical history; 
•! Record Demographics; 
•! Begin Adverse event monitoring; 
•! Record prior/concomitant medication history; 
•! Perform physical exam; 
•! Assess vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
temperature); 
•! Obtain weight and height 
•! Blood sampling for hematology, clinical chemistry, C-reactive protein (CRP); 
•! Urinalysis; 
•! Blood sampling for quantitative cytomegalovirus (CMV) polymerase chain reaction 
(PCR) testing on plasma; 
•! Blood sampling for metabolomics, serum cytokines 
•! Blood sampling for pregnancy test for women of childbearing potential (WOCBP); 
•! Stool sampling for Clostridium difficile, microbiome, microbial culture, 
metabolomics, fecal calprotectin; 
•! Obtain Partial Mayo score; scores should reflect the prior 24 hours 
•! Obtain diet inventory; 
7.2.2! Screening Visit 2 Day -17 to Day -1 (Visit 2) 
•! Verify conformance with inclusion/exclusion entry criteria; 
•! Confirm subject has had no liquids 6 hours prior to lower endoscopy (flexible 
sigmoidoscopy or colonoscopy); 
•! Confirm subject performed bowel preparation at PI discretion (e.g., two Fleets 
enemas 1.5 hours before procedure); 
•! Perform lower endoscopy (flexible sigmoidoscopy or colonoscopy); 
•! Obtain biopsy for mucosal transcriptomics (2 samples); 
•! Obtain biopsy for histopathology with CMV stain (1 sample); 
•! Obtain biopsy for mucosal microbiome (1 sample); 
•! Obtain Partial Mayo score; scores should reflect the 24-hour period before initiation 
of bowel preparation. 


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  53 of 75                                                  10 Oct 2016  
o! Partial Mayo score at Screening Visit 2 should be used when calculating 
the Total modified Mayo score to determine subject eligibility. 
•! Obtain Total modified Mayo score; 
•! Continue adverse event monitoring; 
•! Record concomitant medications. 
7.2.3! Pretreatment Period Day 1 (Visit 3) 
•! Perform central review of results prior to randomization; 
•! Confirm eligibility with Medical Monitor pre-randomization 
•! Perform randomization; 
•! Begin pre-treatment drug dosing (observe subject 1 hour post-dosing) 
•! Perform physical exam; 
•! Assess vital signs (systolic and diastolic blood pressure, respiratory rate, 
temperature); 
•! Obtain weight; 
•! Blood sampling pre-dose for hematology, clinical chemistry; 
•! Blood sampling pre-dose for biomedical research; 
•! Obtain urine sample for pregnancy testing; 
•! Dispense pre-treatment drug; 
•! Obtain Partial Mayo score; scores should reflect the prior 24 hours 
•! Continue adverse event monitoring; 
•! Record concomitant medications. 
7.2.4! Treatment Period Day 8 ± 1 (Visit 4) 
•! Pre-dosing 
o! Return any remaining pre-treatment drug and all bottles dispensed; 
o! Begin treatment period drug dosing (observe subject 1 hour post-dosing); 
o! Blood sampling pre-dose for hematology, clinical chemistry, C-reactive 
protein (CRP); 
o! Perform 12-lead ECG; 
o! Blood sampling pre-dose for metabolomics; 
o! Urinalysis; 
o! Stool sampling pre-dose for microbiome, microbial culture, 
metabolomics, fecal calprotectin; 
•! Dosing 
o! Dispense study drug; 
o! Obtain diet inventory; 
o! Obtain Partial Mayo score; 
o! Continue adverse event monitoring; 


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  54 of 75                                                  10 Oct 2016  
o! Record concomitant medications. 
7.2.5! Treatment Period Day 11 (as close to scheduled day as possible) 
•! Study drug dosing; 
•! Stool sampling for microbiome, microbial culture; 
•! Continue adverse event monitoring; 
•! Record concomitant medications. 
7.2.6! Treatment Period Day 15 ± 1 (Visit 5) 
•! Return study drug; 
•! Dispense study drug 
•! Study drug dosing; 
•! Stool sampling for microbiome, microbial culture; 
•! Obtain Partial Mayo score; scores should reflect the prior 24 hours 
•! Continue adverse event monitoring; 
•! Record concomitant medications; 
•! Remind subject to begin overnight fast where possible the night prior to Visit 6. 
7.2.7! Treatment Period Day 18 (as close to scheduled day as possible) 
•! Study drug dosing; 
•! Stool sampling for microbiome, microbial culture; 
•! Continue adverse event monitoring; 
•! Record concomitant medications. 
7.2.8! Treatment Period Day 22 ± 1 (Visit 6) 
•! Return all unused study drug and any bottles dispensed; 
•! Dispense study drug; 
•! Study drug dosing; 
•! Perform physical exam; 
•! Blood sampling for C-reactive protein (CRP); 
•! Blood sampling for metabolomics; 
•! Assess vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
temperature); 
•! Obtain weight; 
•! Stool sampling for microbiome, microbial culture, metabolomics, fecal calprotectin; 
•! Obtain diet inventory; 
•! Obtain Partial Mayo score; scores should reflect the prior 24 hours 
•! Continue adverse event monitoring; 
•! Record concomitant medications. 


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  55 of 75                                                  10 Oct 2016  
7.2.9! Treatment Period Day 29 ± 1 (Visit 7) 
•! Return all unused study drug and any bottles dispensed; 
•! Dispense study drug; 
•! Study drug dosing; 
•! Obtain Partial Mayo score; scores should reflect the prior 24 hours 
•! Continue adverse event monitoring; 
•! Record concomitant medications. 
•! Remind subject to begin overnight fast where possible the night prior to Visit 8; 
7.2.10! Treatment Period Day 36 ± 1 (Visit 8) 
•! Return all unused study drug and any bottles dispensed; 
•! Dispense study drug; 
•! Study drug dosing; 
•! Perform physical exam; 
•! Blood sampling for hematology, clinical chemistry, C-reactive protein (CRP); 
•! Blood sampling for metabolomics; 
•! Assess vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
temperature); 
•! Obtain weight; 
•! Urinalysis; 
•! Obtain Partial Mayo score; scores should reflect the prior 24 hours 
•! Continue adverse event monitoring; 
•! Record concomitant medications. 
7.2.11! Treatment Period Day 43 ± 1 (Visit 9) 
•! Return all unused study drug and any bottles dispensed; 
•! Dispense study drug; 
•! Study drug dosing; 
•! Obtain Partial Mayo score; 
•! Continue adverse event monitoring; 
•! Record concomitant medications. 
7.2.12! Treatment Period Day 50 ± 1 (Visit 10) 
•! Return all unused study drug and any bottles dispensed; 
•! Dispense study drug; 
•! Study drug dosing; 
•! Obtain Partial Mayo score; scores should reflect the prior 24 hours 
•! Continue adverse event monitoring; 


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  56 of 75                                                  10 Oct 2016  
•! Record concomitant medications. 
7.2.13! Treatment Period Day 57 ± 1 (Visit 11) 
•! Return all unused study drug and any bottles dispensed; 
•! Dispense study drug; 
•! Study drug dosing; 
•! Obtain Partial Mayo score; scores should reflect the prior 24 hours 
•! Continue adverse event monitoring; 
•! Record concomitant medications; 
•! Remind subject to begin overnight fast the night prior to the lower endoscopy 
(flexible sigmoidoscopy or colonoscopy). 
7.2.14! Follow-up Period Day 64 ± 3 (Visit 12)/Early Termination 
•! Return all unused study drug and any bottles dispensed; 
•! Perform physical exam; 
•! Assess vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
temperature); 
•! Obtain weight; 
•! Confirm subject has had no liquids 6 hours prior to lower endoscopy (flexible 
sigmoidoscopy or colonoscopy); 
•! Confirm subject has performed bowel preparation at PI discretion (e.g. two Fleets 
enemas 1.5 hours before procedure); 
•! Perform lower endoscopy (flexible sigmoidoscopy or colonoscopy); 
•! Blood sampling for hematology, clinical chemistry, C-reactive protein (CRP); 
•! Urinalysis; 
•! Blood sampling for metabolomics, serum cytokines; 
•! Blood sampling for biomedical research; 
•! Obtain urine sample for pregnancy testing; 
•! Obtain biopsy for mucosal transcriptomics (2 samples); 
•! Obtain biopsy for histopathology with CMV stain (1 sample); 
•! Obtain biopsy for mucosal microbiome (1 sample); 
•! Stool sampling for microbiome, microbial culture, metabolomics, fecal calprotectin; 
•! Obtain diet inventory; 
•! Obtain Partial Mayo score; scores should reflect the 24-hour period before initiation 
of bowel preparation. 
•! Obtain Total modified Mayo score; 
•! Continue adverse event monitoring; 
•! Record concomitant medications; 
•! Remind subject to begin overnight fast where possible the night prior to Visit 13. 


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  57 of 75                                                  10 Oct 2016  
7.2.15! Follow-up Period Day 71 ± 2 (Phone Call)  
•! Obtain Partial Mayo score; Physician Rating of Disease Activity not collected  
•! Continue adverse event monitoring; 
•! Record concomitant medications. 
7.2.16! Follow-up Period Day 78 ± 2 (Phone Call)  
•! Obtain Partial Mayo score; Physician Rating of Disease Activity not collected  
•! Continue adverse event monitoring; 
•! Record concomitant medications. 
7.2.17! Follow-up Period Day 85 ± 2 (Phone Call)  
•! Obtain Partial Mayo score; Physician Rating of Disease Activity not collected 
•! Continue adverse event monitoring; 
•! Record concomitant medications. 
7.2.18! Follow-up Period Day 92 ± 1 (Visit 13)  
•! Perform physical exam; 
•! Assess vital signs (systolic and diastolic blood pressure, respiratory rate, 
temperature); 
•! Obtain weight; 
•! Perform 12-lead ECG; 
•! Blood sampling for C-reactive protein (CRP); 
•! Blood sampling for metabolomics; 
•! Obtain urine sample for pregnancy testing; 
•! Stool sampling for microbiome, microbial culture, metabolomics, fecal calprotectin; 
•! Obtain Partial Mayo score; scores should reflect the prior 24 hours 
•! Continue adverse event monitoring; 
•! Record concomitant medications. 
7.2.19! Early Termination Visit 
Subjects who discontinue early from the study before Visit 12 should, where possible, 
have an Early Termination visit. This visit should take place as soon as possible after the 
subject stops taking study drug. The observations and procedures scheduled for the 
Follow-Up Visit 12, including a urine pregnancy test, should be performed at the Early 
Termination visit. 
 
For subjects who terminate between Visit 12 and 13, the observations and procedures 
scheduled for the Follow-Up Visit 13 should be performed.   
7.2.20! Follow-up Period Day 246 ± 3 (Phone Call)  
•! Obtain Partial Mayo score; Physician Rating of Disease Activity not collected 


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  58 of 75                                                  10 Oct 2016  
•! Continue adverse event monitoring; 
•! Record concomitant medications. 
 


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  59 of 75                                                  10 Oct 2016  
8!
STATISTICAL METHODS 
This study has a primary study period (from Visit 1 through Visit 13) followed by a long 
term safety follow-up period to Day 246.  The primary study period will be conducted as 
a double-blind study.  The final database for the primary study period will remain 
blinded until all data collected through Visit 13 has been entered, cleaned and declared 
complete and final.  The CSR will be finalized after results from the primary study period 
are complete; all available data post-Visit 13 pertaining to mortality will be provided.  
Results of the long term safety period (through Day 246) will be presented in a separate 
report. 
 
Before the primary study period data is declared complete and final, a statistical analysis 
plan (SAP) will be issued as a separate document, providing detailed methods for the 
analyses outlined below.  Any deviations from the planned analyses will be described 
and justified in the final integrated clinical study report. 
8.1!
Study Subjects 
8.1.1! Disposition of Subjects 
The number and percentage of subjects entering and completing the clinical study will be 
presented, by treatment group. 
8.1.2! Protocol Deviations 
Protocol deviations will be listed by subject. 
8.1.3! Analysis Sets 
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 were randomly assigned.  All safety analyses 
will be conducted based on the Safety Population. 
Intent-to-Treat Analysis Population: The Intent-to-Treat (ITT) Population will consist of 
all subjects who were randomly assigned, including 
those who were not exposed to any study drug, and 
will be analyzed based on the treatment to which 
they were randomly assigned.   
Modified Intent-to-Treat Population: The modified Intent-to-Treat (mITT) Population 
will consist of all randomized patients with baseline 
and at least one post-baseline stool sample, 
including those who were not exposed to any study 
drug, and will be analyzed based on the treatment to 
which they were randomized.   
All clinical response analyses will be conducted in the ITT population and in the mITT 
population as sensitivity analyses. 


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  60 of 75                                                  10 Oct 2016  
All microbiome alterations analyses will be conducted in the mITT population. 
8.2!
Endpoints for Analysis 
8.2.1! Endpoints and Analysis for Primary Objectives 
The primary endpoint for assessment of safety and tolerability will be AEs, classified to 
body system and preferred term as well as severity and causality. Other safety and 
tolerability endpoints are AESIs, laboratory evaluation results, vital sign measurements 
and physical examination findings. Safety endpoint will be summarized by treatment 
group and also for the pooled SER-287 treatments (A, C and D). The assessment of 
safety will be based on descriptive summaries of SER-287 treatment groups and the 
placebo treatment group. 
 
Composition of the microbiome at Visit 1, Visit 4, Visit 5, Visit 6, Visit 12, Visit 13, or 
at early termination will be measured in terms of both the total number of unique types of 
bacteria (i.e., α-diversity) and the microbial composition (i.e., β-diversity). Engraftment 
is defined as the germination and outgrowth of bacteria that comprise the SER-287 spore 
ecology in a subject’s gastrointestinal tract post-treatment. Engraftment will be assessed 
at time points between Visit 4 and Visit 13. 
 
Differences between changes in the microbiome across the various treatment arms will 
be evaluated using both non-parametric tests for α-diversity and multivariate analysis of 
variances of dissimilarity matrices for β-diversity. Dissimilarity will be defined by using 
the unweighted Unifrac dissimilarity metric, which evaluates changes in the overall 
phylogenetic composition between two samples; this method is widely used in the study 
of microbial communities and represents a balanced approach with minimal bias to the 
presence of low- and high-abundance bacteria.  
 
Additional measures of dissimilarity that are routinely used in the analysis of microbiome 
data sets will be further evaluated. 
8.2.2! Endpoints and Analysis for Secondary Objectives 
Efficacy response endpoints comprise clinical response, complete remission and 
endoscopic improvement. The primary time point for analysis is Visit 12. Estimates of 
the risk difference and confidence interval will be reported for treatment groups A, C and 
D separately compared to placebo. 
Serum biomarkers (CRP) and fecal biomarkers (fecal calprotectin) at Visit 1, Visit 4, 
Visit 6, Visit 12 and Visit 13 will be assessed using descriptive summary tables and 
treatment mean [+/- standard deviation (SD)] profile plots (response versus timepoint). 
8.2.3! Exploratory Endpoints 
All time points of exploratory endpoint will be listed and presented in descriptive 
summary tables. 
•! Stool and blood metabolic pathways 


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  61 of 75                                                  10 Oct 2016  
•! Serum cytokine profile 
•! Mucosal transcriptomic profile 
•! Mucosal microbiome  
•! Mucosal Histopathology, including cytomegalovirus (CMV) Immunohistology 
stains 
•! Microbial Culture Endpoints: 
o! Candida titer and diversity 
8.3!
General Considerations 
8.3.1! Statistical Methods 
All safety and tolerability, intestinal microbiome, clinical efficacy, and biomarker data 
will be listed and presented in descriptive summaries by study arm, visit and time point. 
At a minimum, continuous data will be summarized by study arm using descriptive 
statistics (number, mean, SD minimum, median and maximum).  Categorical data will be 
summarized by study arm using frequency tables (number and percentage). 
Selected clinical response and biomarker data will be presented in treatment mean (+/-
SD) profile plots.   
8.3.2! Statistical Significance 
Statistical significance tests, if reported, will be two-sided and will be presented as 
relative measures of the strength of association to study arm for comparison among study 
endpoints.  All reported confidence intervals will be 95%, two-sided.  P-values and/or 
confidence intervals generated for this study are not intended to be conclusive, but 
provided for guidance only.  
In general, inferential analysis will be based on pairwise comparisons, A, C and D 
separately compared to placebo (B) and also the comparisons A versus D and C versus 
D. For continuous data these comparisons will be assessed using confidence intervals 
estimated using one-way analysis of variance (ANOVA) models fit to the separate results 
of each visit. For binary data these comparisons will be assessed by analysis of two-by-
two tables and calculation the risk difference and confidence interval. Additional details 
of the statistical analysis will be addressed in a statistical analysis plan, finalized prior to 
the time the primary study period (Visit 1 to Visit 13) data is declared complete and final 
and study unblinding. 
8.3.3! Missing or Spurious Data 
Any AE with incomplete date or time will be evaluated conservatively in the 
classification of treatment emergent AE.  Any apparently spurious data will be verified.  
No verified data will be excluded from summaries or analysis. 
 
Several missing imputation methods, such as worst case analyses, observed case analyses 
and last observation carried forward, will be applied to analyze the clinical efficacy 
endpoints. 


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  62 of 75                                                  10 Oct 2016  
8.4!
Safety Analyses 
8.4.1! Adverse Events 
Adverse events will be coded by using the Medical Dictionary for Regulatory Activities 
(MedDRA). Summary tables of treatment-emergent adverse events (TEAEs) by 
treatment group will be provided. A TEAE is any AE that newly appeared, increased in 
frequency, or worsened in severity after initiation of study drug. A listing of all AEs, 
including those occurring before the start of study drug, will be provided. The percentage 
of subjects with TEAEs will be tabulated by system organ class (SOC) and preferred 
term (PT) for each treatment group. The incidence of TEAEs based on the number of 
days the subjects in each treatment group were on study drug (per subject on therapy 
day) will also be presented by system organ class and preferred term for each treatment 
group by severity, and by relationship to treatment. Tables of any TEAEs leading to 
study drug discontinuation, AESIs and SAEs will also be provided.  
8.4.2! 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. 
8.4.3! 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. 
8.4.4! Physical Examination Findings 
Abnormal clinically significant physical examination (PE) finding will be reported as 
medical history (MH) or as an AE.  
8.4.5! Pharmacokinetic Analyses  
Not applicable 
8.5!
Gastrointestinal Tract Microbiome 
The gastrointestinal (GI) microbiome of subjects will be characterized by using at 
minimum recombinant deoxyribonucleic acid (rDNA) 16S V4 genomic data sets 
generated from stool collected at the time points defined above for the various endpoints.  
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 an operational taxonomic unit (OTU) and 


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  63 of 75                                                  10 Oct 2016  
phylogenetic clade (clade) and, further, to define the relative proportion of each OTU and 
clade to all other OTUs and clades in a given sample.  
Changes in the composition of the microbiome will be measured and analyzed as 
described in Section 8.2.1. 
8.6!
Interim Analyses 
No interim analysis is planned for this study. 
8.7!
Determination of Sample Size 
No formal sample size calculation was performed.  A sample size of approximately 55 
subjects, with 15 subjects randomized to each of the active arms (Treatment Groups A, C 
and D) and 10 subjects in the placebo arm (Treatment Group B) is considered sufficient 
to evaluate the safety, microbiome alterations, clinical response and exploratory 
objectives of the study.  All comparisons performed in this study will be descriptive in 
nature. P-values and/or confidence intervals generated for this study are not intended to 
be conclusive, but are provided for guidance only. 
 


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  64 of 75                                                  10 Oct 2016  
9!
ADMINISTRATIVE REQUIREMENTS  
9.1!
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. 
9.2!
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, 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. 
9.3!
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. 
 


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  65 of 75                                                  10 Oct 2016  
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. 
9.4!
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. 
9.5!
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. 
9.6!
Future Use of Stored Specimens 
The sponsor may conduct future biomedical research on specimens (including blood and 
feces) 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. 
9.7!
Study Monitoring 
Regular monitoring is defined in ICH Guidance for Industry E6 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, Good Clinical Practice (GCP), and the 
applicable regulatory requirement(s).” The purpose of monitoring is to verify that: 
•! Rights and well-being of the human subjects are protected. 


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  66 of 75                                                  10 Oct 2016  
•! 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. 
9.8!
Data and Safety Monitoring Committee 
To supplement the routine study monitoring outlined in this protocol, an external DSMC 
will monitor the safety data from this study. The members of the DSMC will not be 
involved with the study (i.e., they are not study investigators) and must have no 
competing interests that could affect their roles with respect to the study. The DSMC will 
include 2 clinicians experienced in Gastroenterology and a statistician. The DSMC will 
make recommendations to ensure both patient safety and the continued ethical integrity 
of the study. Specific details regarding the responsibilities and requirements for 
documentation will be described in a separate charter that is reviewed and approved by 
the DSMC.  
9.9!
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 is 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.  
 


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  67 of 75                                                  10 Oct 2016  
In addition to capturing the user identification as part of the audit trail for all data entry, 
the eCRF allows for application of electronic signatures. The Investigator or designated 
subInvestigator, 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. 
9.10! 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 the End-of-Study Visit at Week 13 and the final phone call on Day 246 
•! 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) 
 


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  68 of 75                                                  10 Oct 2016  
10! REFERENCE LIST 
Angelberger, S., Reinisch, W., Makristathis, A., Lichtenberger, C., Dejaco, C., Papay, P., 
Novacek, G., Trauner, M., Loy, A., and Berry, D. (2013). Temporal Bacterial 
Community Dynamics Vary Among Ulcerative Colitis Patients After Fecal Microbiota 
Transplantation. Am. J. Gastroenterol. 
Atarashi, K., Tanoue, T., Shima, T., Imaoka, A., Kuwahara, T., Momose, Y., Cheng, G., 
Yamasaki, S., Saito, T., Ohba, Y., et al. (2011). Induction of colonic regulatory T cells by 
indigenous Clostridium species. Science 331, 337–341. 
Atarashi, K., Tanoue, T., Oshima, K., Suda, W., Nagano, Y., Nishikawa, H., Fukuda, S., 
Saito, T., Narushima, S., Hase, K., et al. (2013). Treg induction by a rationally selected 
mixture of Clostridia strains from the human microbiota. Nature 500, 232–236. 
Baumgart, M., Dogan, B., Rishniw, M., Weitzman, G., Bosworth, B., Yantiss, R., Orsi, 
R.H., Wiedmann, M., McDonough, P., Kim, S.G., et al. (2007). Culture independent 
analysis of ileal mucosa reveals a selective increase in invasive Escherichia coli of novel 
phylogeny relative to depletion of Clostridiales in Crohn’s disease involving the ileum. 
ISME J. 1, 403–418. 
Biedermann, L., Zeitz, J., Mwinyi, J., Sutter-Minder, E., Rehman, A., Ott, S.J., Steurer-
Stey, C., Frei, A., Frei, P., Scharl, M., et al. (2013). Smoking cessation induces profound 
changes in the composition of the intestinal microbiota in humans. PloS One 8, e59260. 
Biedermann, L., Brülisauer, K., Zeitz, J., Frei, P., Scharl, M., Vavricka, S.R., Fried, M., 
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. 
Colman, R.J., and Rubin, D.T. (2014). Fecal microbiota transplantation as therapy for 
inflammatory bowel disease: A systematic review and meta-analysis. J. Crohns Colitis 8, 
1569–1581. 
Danese, S., and Fiocchi, C. (2011). Ulcerative colitis. N. Engl. J. Med. 365, 1713–1725. 
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, 
13780–13785. 
Gevers, D., Kugathasan, S., Denson, L.A., Vázquez-Baeza, Y., Van Treuren, W., Ren, 
B., Schwager, E., Knights, D., Song, S.J., Yassour, M., et al. (2014). The treatment-naive 
microbiome in new-onset Crohn’s disease. Cell Host Microbe 15, 382–392. 
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 
(EFCCA) patient survey. J. Crohns Colitis 1, 10–20. 


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  69 of 75                                                  10 Oct 2016  
Grinspan, A., and Kornbluth, A. (2015). Positioning Therapy for Ulcerative Colitis. Curr. 
Gastroenterol. Rep. 17, 29. 
Human Microbiome Project Consortium (2012). Structure, function and diversity of the 
healthy human microbiome. Nature 486, 207–214. 
Kappelman, M.D., Rifas-Shiman, S.L., Porter, C.Q., Ollendorf, D.A., Sandler, R.S., 
Galanko, J.A., and Finkelstein, J.A. (2008). Direct health care costs of Crohn’s disease 
and ulcerative colitis in US children and adults. Gastroenterology 135, 1907–1913. 
Kothari, M., Mudireddy, P., and Swaminath, A. (2015). Patient considerations in the 
management of ulcerative colitis – role of vedolizumab. Ther. Clin. Risk Manag. 11, 
1235–1242. 
Kump, P.K., Gröchenig, H.-P., Lackner, S., Trajanoski, S., Reicht, G., Hoffmann, K.M., 
Deutschmann, A., Wenzl, H.H., Petritsch, W., Krejs, G.J., et al. (2013). Alteration of 
intestinal dysbiosis by fecal microbiota transplantation does not induce remission in 
patients with chronic active ulcerative colitis. Inflamm. Bowel Dis. 19, 2155–2165. 
Kunde, S., Pham, A., Bonczyk, S., Crumb, T., Duba, M., Conrad, H., Jr, Cloney, D., and 
Kugathasan, S. (2013). Safety, tolerability, and clinical response after fecal 
transplantation in children and young adults with ulcerative colitis. J. Pediatr. 
Gastroenterol. Nutr. 56, 597–601. 
Leone, V., Chang, E.B., and Devkota, S. (2013). Diet, microbes, and host genetics: the 
perfect storm in inflammatory bowel diseases. J. Gastroenterol. 48, 315–321. 
Lepage, P., Häsler, R., Spehlmann, M.E., Rehman, A., Zvirbliene, A., Begun, A., Ott, S., 
Kupcinskas, L., Doré, J., Raedler, A., et al. (2011). Twin study indicates loss of 
interaction between microbiota and mucosa of patients with ulcerative colitis. 
Gastroenterology 141, 227–236. 
Lichtenstein, G.R., Travis, S., Danese, S., D’Haens, G., Moro, L., Jones, R., Huang, M., 
Ballard, E.D., Bagin, R., Hardiman, Y., et al. (2015). Budesonide MMX for the Induction 
of Remission of Mild to Moderate Ulcerative Colitis: A Pooled Safety Analysis. J. 
Crohns Colitis 9, 738–746. 
Machiels, K., Joossens, M., Sabino, J., De Preter, V., Arijs, I., Eeckhaut, V., Ballet, V., 
Claes, K., Van Immerseel, F., Verbeke, K., et al. (2014). A decrease of the butyrate-
producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis 
in patients with ulcerative colitis. Gut 63, 1275–1283. 
Michail, S., Durbin, M., Turner, D., Griffiths, A.M., Mack, D.R., Hyams, J., Leleiko, N., 
Kenche, H., Stolfi, A., and Wine, E. (2012). Alterations in the gut microbiome of 
children with severe ulcerative colitis. Inflamm. Bowel Dis. 18, 1799–1808. 
Moayyedi, P., Surette, M.G., Kim, P.T., Libertucci, J., Wolfe, M., Onischi, C., 
Armstrong, D., Marshall, J.K., Kassam, Z., Reinisch, W., et al. (2015). Fecal Microbiota 


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  70 of 75                                                  10 Oct 2016  
Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a 
Randomized Controlled Trial. Gastroenterology 149, 102–109.e6. 
Morgan, X.C., Tickle, T.L., Sokol, H., Gevers, D., Devaney, K.L., Ward, D.V., Reyes, 
J.A., Shah, S.A., LeLeiko, N., Snapper, S.B., et al. (2012). Dysfunction of the intestinal 
microbiome in inflammatory bowel disease and treatment. Genome Biol. 13, R79. 
van Nood, E., Vrieze, A., Nieuwdorp, M., Fuentes, S., Zoetendal, E.G., de Vos, W.M., 
Visser, C.E., Kuijper, E.J., Bartelsman, J.F.W.M., Tijssen, J.G.P., et al. (2013). Duodenal 
infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368, 407–
415. 
Ott, S.J., Musfeldt, M., Wenderoth, D.F., Hampe, J., Brant, O., Fölsch, U.R., Timmis, 
K.N., and Schreiber, S. (2004). Reduction in diversity of the colonic mucosa associated 
bacterial microflora in patients with active inflammatory bowel disease. Gut 53, 685–
693. 
Papa, E., Docktor, M., Smillie, C., Weber, S., Preheim, S.P., Gevers, D., Giannoukos, G., 
Ciulla, D., Tabbaa, D., Ingram, J., et al. (2012). Non-Invasive Mapping of the 
Gastrointestinal Microbiota Identifies Children with Inflammatory Bowel Disease. PLoS 
ONE 7, e39242. 
Rajilić-Stojanović, M., Shanahan, F., Guarner, F., and de Vos, W.M. (2013). 
Phylogenetic Analysis of Dysbiosis in Ulcerative Colitis During Remission. Inflamm. 
Bowel Dis. 19, 481–488. 
Rossen, N.G., Fuentes, S., van der Spek, M.J., Tijssen, J.G., Hartman, J.H.A., Duflou, A., 
Löwenberg, M., van den Brink, G.R., Mathus-Vliegen, E.M.H., de Vos, W.M., et al. 
(2015). Findings From a Randomized Controlled Trial of Fecal Transplantation for 
Patients With Ulcerative Colitis. Gastroenterology 149, 110–118.e4. 
Rubin, D.T., Mody, R., Davis, K.L., and Wang, C.-C. (2014). Real-world assessment of 
therapy changes, suboptimal treatment and associated costs in patients with ulcerative 
colitis or Crohn’s disease. Aliment. Pharmacol. Ther. 39, 1143–1155. 
Sandborn, W.J., Danese, S., D’Haens, G., Moro, L., Jones, R., Bagin, R., Huang, M., 
David Ballard, E., Masure, J., and Travis, S. (2015). Induction of clinical and 
colonoscopic remission of mild-to-moderate ulcerative colitis with budesonide MMX 
9 mg: pooled analysis of two phase 3 studies. Aliment. Pharmacol. Ther. 41, 409–418. 
Sartor, R.B. (2008). Microbial influences in inflammatory bowel diseases. 
Gastroenterology 134, 577–594. 
Scherl, E.J. (2009). Safety and efficacy of a new 3.3 g b.i.d. tablet formulation in patients 
with mild-to-moderately-active ulcerative colitis: a multicenter, randomized, double-
blind, placebo-controlled study. Am. J. Gastroenterol. 104, 1452–1459. 


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  71 of 75                                                  10 Oct 2016  
Sokol, H., Pigneur, B., Watterlot, L., Lakhdari, O., Bermúdez-Humarán, L.G., 
Gratadoux, J.-J., Blugeon, S., Bridonneau, C., Furet, J.-P., Corthier, G., et al. (2008). 
Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by 
gut microbiota analysis of Crohn disease patients. Proc. Natl. Acad. Sci. 105, 16731–
16736. 
Sutherland, L., Marin, F., and Greer, S. 5-Aminosalicylic acid enema in the treatment of 
distal ulcerative colitis, proctosigmoiditis and proctitis. 
Theede, K., Kiszka-Kanowitz, M., Nordgaard-Lassen, I., and Mertz Nielsen, A. (2015). 
The Impact of Endoscopic Inflammation and Mucosal Healing on Health-related Quality 
of Life in Ulcerative Colitis Patients. J. Crohns Colitis 9, 625–632. 
Varela, E., Manichanh, C., Gallart, M., Torrejón, A., Borruel, N., Casellas, F., Guarner, 
F., and Antolin, M. (2013). Colonisation by Faecalibacterium prausnitzii and 
maintenance of clinical remission in patients with ulcerative colitis. Aliment. Pharmacol. 
Ther. 38, 151–161. 
Walujkar, S.A., Dhotre, D.P., Marathe, N.P., Lawate, P.S., Bharadwaj, R.S., and 
Shouche, Y.S. (2014). Characterization of bacterial community shift in human Ulcerative 
Colitis patients revealed by Illumina based 16S rRNA gene amplicon sequencing. Gut 
Pathog. 6, 22. 
Willing, B.P., Dicksved, J., Halfvarson, J., Andersson, A.F., Lucio, M., Zheng, Z., 
Järnerot, G., Tysk, C., Jansson, J.K., and Engstrand, L. (2010). A pyrosequencing study 
in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel 
disease phenotypes. Gastroenterology 139, 1844–1854. 
Wu, G.D., Bushmanc, F.D., and Lewis, J.D. (2013). Diet, the human gut microbiota, and 
IBD. Anaerobe 24, 117–120. 
Xavier, R.J., and Podolsky, D.K. (2007). Unravelling the pathogenesis of inflammatory 
bowel disease. Nature 448, 427–434. 
Youngster, I., Sauk, J., Pindar, C., Wilson, R.G., Kaplan, J.L., Smith, M.B., Alm, E.J., 
Gevers, D., Russell, G.H., and Hohmann, E.L. (2014a). Fecal Microbiota Transplant for 
Relapsing Clostridium difficile Infection Using a Frozen Inoculum From Unrelated 
Donors: A Randomized, Open-Label, Controlled Pilot Study. Clin. Infect. Dis. 
Youngster, I., Russell, G.H., Pindar, C., Ziv-Baran, T., Sauk, J., and Hohmann, E.L. 
(2014b). Oral, capsulized, frozen fecal microbiota transplantation for relapsing 
Clostridium difficile infection. JAMA 312, 1772–1778. 
 
 


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  72 of 75                                                  10 Oct 2016  
APPENDICES 
Appendix 1: Total Modified Mayo Score  
 
Stool Frequency  
0= Normal  
1= 1-2 stools/day more than normal  
2= 3-4 stools/day more than normal  
3= >4 stools/day more than normal 
 
Rectal Bleeding 
0= None 
1= Visible blood with stool less than half the time 
2= Visible blood with stool half of the time or more 
3= Passing blood alone 
 
Mucosal Appearance at Endoscopya  
0= Normal 
1= Mild disease (erythema, decreased vascular pattern)  
2= Moderate disease (marked erythema, absent vascular pattern, friability, erosions)  
3= Severe disease (spontaneous bleeding, ulcerations)  
 
Physician Rating of Disease Activity  
0= Normal 
1= Mild 
2= Moderate 
3= Severe 
a: The mucosal appearance at endoscopy is not included in the partial Mayo score  
  
 
 
 
 
 
 
Sutherland LR, Marin F, Greer S et al. 5-Aminosalicylic acid enema in the treatment of distal ulcerative 
colitis, proctosigmoiditis and proctitis. Gastroenterology 1987; 92: 1894-8. 
Sandborn WJ, Kamm MA, Lichtenstein GR, Lyne A, Butler T, Joseph RE. MMX Multi-Matrix System 
mesalazine for the induction of remission in patients with mild-to-moderate ulcerative colitis: a combined 
analysis of two randomized, double-blind, placebo-controlled trials. Aliment Pharmacol Ther  26 2007: 
205-215.   


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  73 of 75                                                  10 Oct 2016  
Appendix 2: Diet Inventory 
 
 
Did you eat or drink the 
following products in the 
last 7 days? 
If yes, how recently? 
 
*please 
choose 
only 
one 
response per category, from 
this column 
Example:  
Vegetables (salad, tomatoes, onions, greens, 
carrots, peppers, green beans, etc.) 
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
● Within 24 hrs, 1 to 2 times 
○ Within 24 hrs, 3 or more 
times
Tea or coffee no sugar and no sugar 
replacement 
 
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
○ Within 24 hrs, 1 to 2 times  
○ Within 24 hrs, 3 or more 
times
Soft drinks, tea or coffee with sugar (corn 
syrup, maple syrup, cane sugar, etc.) 
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
○ Within 24 hrs, 1 to 2 times  
○ Within 24 hrs, 3 or more 
times
Diet soft drinks, tea or coffee with sugar 
substitute (Stevia, Equal, Splenda, etc.) 
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
○ Within 24 hrs, 1 to 2 times  
○ Within 24 hrs, 3 or more 
times
Fruit juice (orange, apple, cranberry, prune, etc.) 
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
○ Within 24 hrs, 1 to 2 times  
○ Within 24 hrs, 3 or more 
times
Water 
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
○ Within 24 hrs, 1 to 2 times  
○ Within 24 hrs, 3 or more 
times
Alcohol (beer, brandy, spirits, hard liquor, wine, 
aperitif, etc.) 
 
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
○ Within 24 hrs, 1 to 2 times  
○ Within 24 hrs, 3 or more 
times
Yogurt or other foods containing active 
bacterial cultures (kefir, sauerkraut, etc.) 
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
○ Within 24 hrs, 1 to 2 times  
○ Within 24 hrs, 3 or more 
times
Dairy (milk, cream, ice cream, cheese, cream 
cheese) 
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
○ Within 24 hrs, 1 to 2 times  
○ Within 24 hrs, 3 or more 
times
Probiotic (other than yogurt) 
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
○ Within 24 hrs, 1 to 2 times  
○ Within 24 hrs, 3 or more 
times
 
 


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  74 of 75                                                  10 Oct 2016  
Fruits (no juice) (Apples, raisins, bananas, 
oranges, strawberries, blueberries, etc. (frozen or 
fresh) 
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
○ Within 24 hrs, 1 to 2 times  
○ Within 24 hrs, 3 or more 
times
Vegetables (salad, tomatoes, onions, greens, 
carrots, peppers, green beans, etc.) 
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
○ Within 24 hrs, 1 to 2 times  
○ Within 24 hrs, 3 or more 
times
Beans (tofu, soy, soy burgers, lentils, Mexican 
beans, lima beans, etc.) 
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
○ Within 24 hrs, 1 to 2 times  
○ Within 24 hrs, 3 or more 
times
Whole grains (wheat, oats, brown rice, rye, 
quinoa, wheat bread, wheat pasta, etc.) 
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
○ Within 24 hrs, 1 to 2 times  
○ Within 24 hrs, 3 or more 
times
Starch (white rice, bread, pizza, potatoes, yam, 
cereals, pancakes, etc.)  
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
○ Within 24 hrs, 1 to 2 times  
○ Within 24 hrs, 3 or more 
times
Eggs 
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
○ Within 24 hrs, 1 to 2 times  
○ Within 24 hrs, 3 or more 
times
Processed meat (other red meat and other white 
meat such as lunch meat, ham, salami, bologna, 
sausage, kielbasa, hotdog, bacon, etc.) 
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
○ Within 24 hrs, 1 to 2 times  
○ Within 24 hrs, 3 or more 
times
Red meat (beef, hamburger, pork, lamb) 
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
○ Within 24 hrs, 1 to 2 times  
○ Within 24 hrs, 3 or more 
times
White meat (chicken, turkey, etc.) 
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
○ Within 24 hrs, 1 to 2 times  
○ Within 24 hrs, 3 or more 
times
Shellfish (shrimp, lobster scallops, etc.) 
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
○ Within 24 hrs, 1 to 2 times  
○ Within 24 hrs, 3 or more 
times
Fish (fish nuggets, breaded fish, fish cakes, 
salmon, tuna, etc.) 
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
○ Within 24 hrs, 1 to 2 times  
○ Within 24 hrs, 3 or more 
times
Sweets (pies, jam, chocolate, cake, cookies, etc.) 
○ No, I did not consume 
these products in the last 7 
days 
○ Within the past 4 to 7 days 
○ Within the past 2 to 3 days 
○ Within 24 hrs, 1 to 2 times  
○ Within 24 hrs, 3 or more 
times
Integrative HMP (iHMP Research Network Consortium. The Integrative Human Microbiome Project: 
Dynamic Analysis of Microbiome-Host omics profiles during periods of human health and disease. Cell Host 
Microbe. 2014; 16(3): 276-89.  


Sponsor Name 
Clinical Study Protocol 
Protocol # SERES-101 
CONFIDENTIAL 
 
Amendment 3                                                                  75 of 75                                                  10 Oct 2016  
 
Appendix 3: Montreal Classification of Extent of Ulcerative Colitis 
 
E1: Ulcerative Proctitis – Involvement limited to the rectum (proximal extent of 
inflammation is distal to the rectosimgoid junction  
 
E2: Left-sided UC (distal UC)—Involvement limited to a portion of the colorectum distal 
to the splenic flexure  
 
E3: Extensive UC (pancolitis)—Involvement extends proximal to the splenic flexure  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal Classification of Inflammatory Bowel 
Disease: Controversies, Consensus, and Implications.  Gut 2006; 55:749-53.  

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
SERES-101 
 
A Multiple Dose Study to Evaluate the Safety, Tolerability and Microbiome Dynamics of SER-
287 in Subjects with Mild-to-Moderate Ulcerative Colitis 
 
 
 
 
Version:  Final 2.0  
 
Date: 21 August 2017 


PAREXEL International 
Statistical Analysis Plan 
Seres Therapeutics, Inc. 
SERES-101 
 
 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
 
Final 2.0 
Related to:  SOP-EP.BS-WW-002 
Page 2 of 47 
21 Aug 2017 
 
REVISION HISTORY 
Final SAP 1.0:  
 
11 Apr 2017 
SAP Amendment Final 2.0 
21 Aug 2017 
 


PAREXEL International 
Statistical Analysis Plan 
Seres Therapeutics, Inc. 
SERES-101 
 
 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
 
Final 2.0 
Related to:  SOP-EP.BS-WW-002 
Page 3 of 47 
21 Aug 2017 
 
CHANGES FROM THE FINAL SAP VERSION 1.0, 11 APRIL 2017 
 
Section 2.2, Secondary Objective 
Changed the endpoint from “complete” remission to “clinical” remission. 
 
Section 6.4, Breaking the Study Blind at the End of the Short-term Safety Follow-up Period 
Added language for an independent and unblinded team including a clinical data programmer, 
biostatistician, and statistical programmer to produce unblinded study results after all subjects 
complete Visit 13, Day 92.  This is referred to as “Efficacy” analysis.  A complete CSR will be 
written based on these results. 
 
Section 7.1.1.1, Demographic and Baseline Variables 
Removed variables for “Active UC disease (Histopathology)” and “Active UC disease (Mucosal 
appearance)”  
 
Section 7.1.3.1, Secondary Endpoints 
Defined “clinical remission” as “TMMS ≤ 2 and an endoscopic subscore of 0 or 1.” 
 
Section 7.1.4, Exploratory Endpoints 
Removed histological remission endpoint (Geboes score ≤ 2B.0) and Mucosal Histopathology 
Robarts Histopathologic Index (RHI) endpoint. 
 
Section 7.3.6.3 Demographic Variables 
 
Remove Active UC at Baseline. 
 
Section 7.3.7.2, Clinical Efficacy Response   
Updated to reflect changes to endpoints. 
 
 
 


Seres Therapeutics, Inc. 
PAREXEL International 
Statistical Analysis Plan 
SERES-IOI 
SIGNATURE PAGE- SERES THERAPEUTICS, INC. 
Declaration 
The undersigned has/have reviewed and agree to the statistical analyses and procedures of this 
clinical study, as presented in this document. 
Jeff Zhao, Ph.D. 
Director, Biostatistics 
Executive Vice President and Chief Medical Officer 
\-
TP-EP.BS-WW-001-05 
Eftective date: 29 Jul I 5 
Related to: SOP-EP.BS-WW-002 
Page 4 of47 
Date (DD Mmm YY) 
ct6 ;)..()/1 
Date (DD Mmm YY) 
Final 2.0 
21 Aug2017 
t 
I 
t 
' 
I 
1 


Seres Therapeutics, Inc. 
PAREXEL International 
Statistical Analysis Plan 
SIGNATURE PAGE - PAREXEL 
Declaration 
SERES-I OI 
The undersigned agree to the statistical analyses and procedures of this clinical study. 
If this document has been signed electronically, signature(s) and date(s) are present at the end of 
the document: 
Document prepared and approved by: 
Principal Biostatistician 
TP-EP.BS-WW-001-05 
Effective date: 29 Jul 15 
Related to: SOP-EP.BS-WW-002 
Page 5 of 47 
Date (DD Mmm YY) 
Final 2.0 
2 1 A ug 201 7 


PAREXEL International 
Statistical Analysis Plan 
Seres Therapeutics, Inc. 
SERES-101 
 
 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
 
Final 2.0 
Related to:  SOP-EP.BS-WW-002 
Page 6 of 47 
21 Aug 2017 
 
TABLE OF CONTENTS 
REVISION HISTORY.................................................................................................................... 2 
CHANGES FROM THE FINAL SAP VERSION 1.0, 11 APRIL 2017........................................ 3 
SIGNATURE PAGE - SERES THERAPEUTICS, INC. ............................................................... 4 
SIGNATURE PAGE - PAREXEL ................................................................................................. 5 
TABLE OF CONTENTS ................................................................................................................ 6 
ABBREVIATION AND ACRONYM LIST FROM PROTOCOL ............................................... 8 
1. 
STATISTICAL ANALYSIS PLAN ................................................................................ 10 
2. 
STUDY OBJECTIVES ................................................................................................... 11 
2.1 
Primary Objectives ............................................................................................. 11 
2.2 
Secondary Objectives ......................................................................................... 11 
2.3 
Exploratory Objectives ....................................................................................... 11 
3. 
STUDY DESIGN ............................................................................................................ 12 
4. 
STUDY POPULATION .................................................................................................. 14 
5. 
STATISTICAL BASIS FOR SAMPLE SIZE ................................................................. 15 
6. 
SUBJECT IDENTIFICATION AND RANDOMIZATION ........................................... 16 
6.1 
Subject Identification.......................................................................................... 16 
6.2 
Methods of Assigning Patients to Study Treatment ........................................... 16 
6.3 
Maintaining the Randomization Codes and Breaking the Study Blind .............. 16 
6.4 
Breaking the Study Blind at the End of the Short-term Safety Follow-up 
Period .................................................................................................................. 17 
6.5 
Subject Replacement .......................................................................................... 17 
7. 
STATISTICAL ANALYSIS CONVENTIONS .............................................................. 19 
7.1 
Analysis Variables .............................................................................................. 19 
7.1.1 
Study Subjects ................................................................................................ 19 
7.1.1.1 
Demographic and Baseline Variables ............................................. 19 
7.1.1.2 
General Medical and Surgical History ............................................ 20 
7.1.1.3 
Prior and Concomitant Medications ................................................ 20 
7.1.1.4 
Diet Inventory.................................................................................. 20 
7.1.2 
Microbiome Alterations and Engraftment Primary Endpoints ....................... 20 
7.1.3 
Secondary Endpoints ...................................................................................... 21 
7.1.3.1 
Clinical Response, Clinical Remission, and Endoscopic 
Improvement ................................................................................... 21 
7.1.3.2 
Biomarkers ...................................................................................... 22 
7.1.4 
Exploratory Endpoints .................................................................................... 22 
7.1.5 
Safety Variables .............................................................................................. 23 
7.1.5.1 
Adverse Events ................................................................................ 23 
7.1.5.2 
Clinical Laboratory Tests ................................................................ 23 


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7.1.5.3 
Vital Signs ....................................................................................... 24 
7.1.5.4 
Electrocardiograms .......................................................................... 24 
7.1.5.5 
Physical Examination ...................................................................... 24 
7.2 
Analysis Populations .......................................................................................... 25 
7.2.1 
Safety Population ............................................................................................ 25 
7.2.2 
Intent-to-Treat (ITT) Population ..................................................................... 25 
7.2.3 
Sensitivity Analysis Population – 1 (without replacement) ............................ 25 
7.2.4 
Sensitivity Analysis Population – 2 (with replacements only) ....................... 25 
7.3 
Statistical Analysis Methods .............................................................................. 25 
7.3.1 
Listings and Descriptive Statistics .................................................................. 25 
7.3.2 
Statistical Analysis and Significance Level .................................................... 26 
7.3.3 
Software .......................................................................................................... 26 
7.3.4 
Missing or Spurious Data ............................................................................... 26 
7.3.5 
Interim Analysis and Safety Halting Rules ..................................................... 28 
7.3.6 
Study Subjects ................................................................................................ 28 
7.3.6.1 
Disposition of Subjects .................................................................... 28 
7.3.6.2 
Protocol Deviations ......................................................................... 28 
7.3.6.3 
Demographic Data ........................................................................... 29 
7.3.6.4 
Medical and Surgical History .......................................................... 29 
7.3.6.5 
Prior and Concomitant Medication ................................................. 29 
7.3.6.6 
Diet Inventory Log .......................................................................... 30 
7.3.6.7 
Exposure to the Investigational Medicinal Product ......................... 30 
7.3.7 
Endpoints for Analysis.................................................................................... 30 
7.3.7.1 
Microbiome Alterations and Engraftment Primary Endpoints ........ 30 
7.3.7.2 
Clinical Efficacy Response ............................................................. 30 
7.3.7.3 
Serum Biomarkers ........................................................................... 31 
7.3.7.4 
Fecal Biomarkers ............................................................................. 31 
7.3.7.5 
Exploratory Endpoints ..................................................................... 32 
7.3.8 
Safety Analysis ............................................................................................... 33 
7.3.8.1 
Adverse Events ................................................................................ 33 
7.3.8.2 
Clinical Safety Laboratory Tests (Chemistry, Hematology, 
Liver and Urinalysis) ....................................................................... 34 
7.3.8.3 
Vital Signs ....................................................................................... 35 
7.3.8.4 
Twelve-Lead Electrocardiogram ..................................................... 35 
8. 
CHANGE FROM PROTOCOL ...................................................................................... 36 
9. 
REFERENCES ................................................................................................................ 37 
10. 
TABLES AND LISTINGS TO BE INCLUDED IN SECTION 14 OF THE 
CLINICAL STUDY REPORT ........................................................................................ 38 
11. 
FIGURES TO BE INCLUDED IN SECTION 14 OF THE CLINICAL STUDY 
REPORT .......................................................................................................................... 43 
12. 
LISTINGS TO BE INCLUDED IN SECTION 16 OF THE CLINICAL STUDY 
REPORT .......................................................................................................................... 44 
13. 
DOCUMENTATION OF STATISTICAL METHODS ................................................. 47 
 
 


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ABBREVIATION AND ACRONYM LIST FROM PROTOCOL 
Abbreviation / Acronym 
Definition / Expansion 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ATC 
Anatomical therapeutic chemical 
BLQ 
Below the lower limit of quantification 
BMI 
Body Mass Index 
Bpm 
Beats per minute 
CI 
Confidence interval 
CMV 
Cytomegalovirus 
CRP 
C-reactive protein 
CSP 
Clinical Study Protocol 
CS 
Clinically significant 
CSR 
Clinical study report 
CV 
Coefficient of variation 
DBP 
Diastolic blood pressure 
DSMC 
Data safety monitoring committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ET 
Early termination 
GGT 
Gamma-glutamyl transpeptidase 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
IBD 
Inflammatory bowel disease 
ITT 
Intent to treat 
IxRS 
Interactive voice/web response system 
LFT 
Liver function test 
MCH 
Mean corpuscular hemoglobin 


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Abbreviation / Acronym 
Definition / Expansion 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent to treat 
NCS 
Not clinically significant 
NK 
Not known 
PCR 
Polymerase chain reaction 
RHI 
Robarts Histopathologic Index 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation or single dose 
SE 
Standard error of the mean 
SI 
Standard international  
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TMMS 
Total modified Mayo score 
UC 
Ulcerative Colitis 
ULN 
Upper limit of normal 
WHO-DDE 
World Health Organization - Drug Dictionary Enhanced 
 
 


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1. 
STATISTICAL ANALYSIS PLAN 
The Statistical Analysis Plan (SAP) details the statistical methodology to be used in analyzing 
safety and clinical efficacy study data and outlines the statistical programming specifications for 
the 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 Study Protocol (CSP).  This SAP addresses planned analysis and presentation of safety 
and clinical efficacy to be conducted by PAREXEL as described in the protocol, and as collected 
in the source data.  The planned analysis of microbiome alterations is described in a separate 
document. 
The analyses described are based on the final CSP Amendment 3, dated 10 Oct 2016 and on the 
Blank CRF Casebook (Study Published Date: 08-Jun-2016 08:43 GMT). 
The SAP 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). 


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2. 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
• To evaluate the safety and tolerability of SER-287 vs. placebo in adult subjects ≥18 years of 
age with mild-to-moderate ulcerative colitis 
• To compare the baseline composition of the intestinal microbiome to the post-baseline 
composition after initiation of SER-287 or placebo 
• To determine the engraftment of SER-287 bacteria into the intestinal microbial community in 
each of the SER-287 arms compared to the placebo arm 
2.2 
Secondary Objectives 
• To determine the proportion of subjects in each of the treatment arms who, at 8 weeks post 
initiation of treatment, achieve a clinical response, clinical remission, and endoscopic 
improvement 
• To assess changes in serum and fecal biomarkers from baseline throughout treatment 
2.3 
Exploratory Objectives 
• To compare the changes in exploratory biomarkers from mucosal biopsies and stool samples 
in each of the treatment arms from baseline throughout treatment. 
• To determine the complement of metabolic pathways from stool in each of the treatment 
arms from baseline throughout treatment. 


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3. 
STUDY DESIGN 
This is a Phase 1b multicenter, randomized, double-blind, placebo-controlled multiple dose study 
designed to evaluate the safety and tolerability of SER-287 and to evaluate the microbiome 
alterations and pharmacodynamics associated with two dosing regimens of SER-287 in adult 
subjects with mild-to-moderate ulcerative colitis (UC). Subjects will be randomized to one of 4 
study arms:  
A) Pre-treatment of placebo, followed by once weekly dosing of SER- 287 for 8 weeks;  
B) Pre-treatment of placebo, followed by once daily dosing of placebo for 8 weeks;  
C) Pre-treatment of vancomycin, followed by once daily dosing of SER-287 for 8 weeks;  
D) Pre-treatment of vancomycin, followed by once weekly dosing of SER-287 for 
8 weeks. 
The doses, route, and schedule of study drug administration are shown below: 
Group 
Pre-­treatment: Vanco or Pbo 
Treatment Period:  SER--‐287 or Pbo 
Vanco or 
Pbo 
Regimen 
Admin 
Duration  SER-­287 
or Pbo 
Regimen 
Admin 
Duration 
A 
Pbo 
Pbo 
One capsule 
four times 
daily orally 
6 days 
SER-
287 + 
Pbo 
SER-287 Weekly 
(1x108 SporQs) +Pbo 
6d/wk 
Four capsules 
once daily 
orally 
8 wks 
B 
Pbo 
Pbo 
One capsule 
four times 
daily orally 
6 days 
Pbo 
Placebo Daily 
Four capsules 
once daily 
orally 
8 wks 
C 
Vanco 
Vanco 
125 mg 
qid 
One capsule 
four times 
daily orally 
6 days 
SER-
287 
SER-287 Daily 
(1x108 SporQs) 
Four capsules 
once daily 
orally 
8 wks 
D 
Vanco 
Vanco 
125 mg 
qid 
One capsule 
four times 
daily orally 
6 days 
SER- 
287 + 
Pbo 
SER-287 Weekly 
 (1x108 SporQs)+Pbo 
6d/wk 
Four capsules 
once daily 
orally 
8 wks 
The study has 5 study periods: Screening (Day-14 to Day-1), Pre-treatment, Treatment, a 
4-Week Short Term Safety Follow-up and a Long Term Safety Follow-up.  The Schedule of 
Events is presented in Table 3 of the CSP. 
The Pre-Treatment Period (Day 1 to Day 7) includes administration of either oral vancomycin 
125 mg four times a day for 6 days or matching placebo. 
The Treatment Period (8 weeks, Day 8-63) includes administration of 4 capsules taken orally 
once a day of SER-287 or placebo according to the treatment group to which they have been 


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assigned: SER-287 once daily, SER-287 once weekly with matching placebo on other days, or 
placebo daily. 


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4. 
STUDY POPULATION 
The study population will consist of adult subjects with active mild-to-moderate ulcerative 
colitis. 
Detailed lists of inclusion and exclusion criteria are shown in Sections 4.1 and 4.2 of the CSP. 


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5. 
STATISTICAL BASIS FOR SAMPLE SIZE 
No formal sample size calculation was performed. A sample size of approximately 55 subjects 
with 15 subjects randomized to each of the active arms (Treatment Groups A, C and D) and 
10 subjects in the placebo arm (Treatment Group B) is considered sufficient to evaluate the 
safety, microbiome alterations, clinical response and exploratory objectives of the study. 


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6. 
SUBJECT IDENTIFICATION AND RANDOMIZATION 
6.1 
Subject Identification 
All screened subjects will be assigned a unique subject identification (SID) number that will be 
used through screening, pre-treatment and treatment periods and safety follow-up period. 
6.2 
Methods of Assigning Patients 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 Visit 3 (Day 1) after all screening procedures have been 
performed and eligibility for the study confirmed. Subjects will be randomized via interactive 
voice/web response system (IxRS) to one of 4 study arms: A) Pre- treatment of placebo, 
followed by weekly dosing of SER-287 for 8 weeks; B) Pre- treatment of placebo, followed by 
daily dosing of placebo for 8 weeks; C) Pre-treatment of vancomycin, followed by daily dosing 
of SER-287 for 8 weeks; D) Pre-treatment of vancomycin, followed by weekly dosing of SER-
287 for 8 weeks. The randomization scheme was also designed to facilitate balance across the 3 
donor lots manufactured for SER-287. 
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. 
During the double-blind period, subjects, the investigators, other study site personnel and clinical 
staff will remain blinded to the treatment assignment. The medical monitor, study site monitors, 
and other sponsor representatives involved in the clinical aspects of study conduct also will 
remain blinded to the treatment assignment. 
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 sponsor personnel who require knowledge of 


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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.  
A record of any unblinding event will be captured in the database including information of who 
made the unblinding decision (sponsor, medical monitor, investigator, other), reason, date, time 
and unblinded personnel names and roles. 
6.4 
Breaking the Study Blind at the End of the Short-term Safety Follow-up 
Period 
The primary study period will be conducted as a double-blind study. The database will remain 
blinded until all data collected through Visit 13 (Day 92 ± 2days) have been entered, cleaned and 
declared complete and final.  After finalization, an “efficacy” database lock will occur.  An 
independent, unblinded team, comprised of a clinical data programmer, biostatistician, and 
statistical programmer, will access the randomization codes, merge the codes into the SDTM 
datasets, and produce the complete set of analysis datasets, tables, figures, and listings for the 
CSR.  Only data from pre-study up to and including Visit 13/Day 92 will be included in the CSR 
with the exception of deaths.  All available data on deaths reported at the time the CSR is being 
written, regardless of timepoint in the study, will be reported.   
The blinded study team will not be involved in any unblinded analyses and will not have access 
to the data nor the results until all subjects have completed the study at Day 246 or discontinued 
from the study. 
Study subjects will continue to be monitored through Day 246. Results of the long-term safety 
period (through Day 246) will be presented in a separate report.   
6.5 
Subject Replacement 
Subjects who meet the following criteria may be replaced.  
• Subject withdrew from treatment before Study Day 48 (less than 6-week treatment); or 
• Subject didn’t have the post-treatment endoscopy procedure performed; 


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A treatment-specific replacement method will be implemented, i.e. replacement subjects will be 
randomized to receive the treatment to which discontinued subjects were randomized.  Only the 
first 55 enrolled subjects are eligible to be replaced. The number of subjects who can be replaced 
will depend on the drug availability. 
 
 


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7. 
STATISTICAL ANALYSIS CONVENTIONS 
7.1 
Analysis Variables 
7.1.1 
Study Subjects 
7.1.1.1 
Demographic and Baseline Variables 
The following demographic and anthropometric information will be recorded: 
• Date of informed consent 
• Age at screening (years) 
• Sex 
• Height (cm) at screening 
• Body weight (kg), predose on Day 1 
• Body mass index (BMI) kg/m2 
• 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) 
• Ulcerative colitis disease history: date of first diagnosis 
Time since original UC diagnosis will be calculated from date of first diagnosis to date of 
informed consent (months) 
• Type of UC: Montreal classification 
• Smoking history (never, current or former with start and end years) 
• Modified Mayo score (rectal bleeding, stool frequency, endoscopic score, physician’s rating 
and Total) 
• Severity of UC (Mild/Moderate) 
o Mild UC is defined as the total modified Mayo score at Baseline (Visit 2)  of 4, 5 
or 6 
o Moderate UC is defined as the total modified Mayo score at Baseline (Visit 2)  of 
7, 8, 9 or 10 


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• Current UC treatment (Yes/No) 
Subjects with any ongoing oral medications for the UC indication(s) will be considered as 
Yes.  Subjects taking multiple UC concomitant medications will be counted in each 
concomitant medication category: 
o Oral 5-ASA 
o Immunomodulator 
o Steroid 
o Other. 
7.1.1.2 
General Medical and Surgical History 
The medical history will include the question whether subject has any vancomycin allergy and 
will also collect records of any medical/surgical history apart from IBD. Medical history items 
include medical condition or event, year of diagnosis, outcome (resolved or ongoing) and 
whether the patient is currently being treated for the condition. Medical history will be collected 
during screening and medical condition terms will be coded using MedDRA 18.1. 
7.1.1.3 
Prior and Concomitant Medications 
At Screening, subjects will be asked what medications they have taken during the last 6 months. 
Prior and concomitant medication other than the study drug (vancomycin and SER-287), 
including herbal and other non-traditional remedies will be documented from screening through 
Visit 13. Medications used to treat inflammatory bowel disease (IBD) will be flagged and also 
medications used to treat an AE. Prior and concomitant medications will be coded using the 
WHO Drug Dictionary (WHO-DDE, September 1st 2015). 
7.1.1.4 
Diet Inventory 
Diet inventory log (CSP Appendix 2) responses will be collected at Screening Visit 1, treatment 
period Visit 6 (Day 22) and follow-up Visit 12 (Day 64) or early term (ET). 
7.1.2 
Microbiome Alterations and Engraftment Primary Endpoints 
The record of stool samples collected at Visit 1, Visit 4, Visit 5, Visit 6, Visit 12 and Visit 13 or 
the Early Termination Visit (if applicable), and any Unscheduled Visit will include record of 
date and time produced, refrigerated (Yes/No), status (frozen, ambient or cooled) and 
Clostridium difficile result.  


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Genomic sequence results for assessment of microbiome alterations, composition of the 
intestinal microbiome and engraftment of SER-287 bacteria will be presented in a separate 
report.  
Presentation and analysis of these endpoints/results will be discussed in a separate SAP and are 
not part of the work order with PAREXEL. 
7.1.3 
Secondary Endpoints 
7.1.3.1 
Clinical Response, Clinical Remission, and Endoscopic Improvement 
The total modified Mayo score (TMMS, CSP Appendix 1) is a composite score, including the 
modified Mayo endoscopic subscore, the patient report outcome (stool frequency and rectal 
bleeding) as well as physician’s rating. Only the modified Mayo endoscopic subscore is 
determined by the central reader and provided to the clinical site. 
Total modified Mayo score items scored on a 4 point scale from 0 = none or normal to 3 = most 
severe symptom category are stool frequency, rectal bleeding, mucosal appearance at endoscopy 
and physician rating of disease activity. 
Partial Mayo score, which is the TMMS without the endoscopic subscore, will be assessed at 
each visit and the TMMS will be assessed at baseline (Visit 2) and at Visit 12 (or early 
termination).  The primary efficacy analysis time point is Visit 12, after 8-week treatment period. 
Baseline scores for the TMMS and for the partial Mayo are calculated using the Screening Visit 
2 assessments. If the partial Mayo score changes from Visit 1 to Visit 2, the Visit 2 score should 
be used in computing the TMMS at Baseline and when assessing the subject for the safety 
stopping rules. 
Clinical response is defined as: 
•  A decrease of ≥3 points in TMMS from baseline, along with EITHER a decrease of ≥1 point 
in rectal bleeding subscore OR absolute rectal bleeding subscore of 0 or 1 
Clinical remission is defined as: 
•  A TMMS ≤2 and an endoscopic subscore of 0 or 1 
Endoscopic improvement is defined as: 
• a decrease in the endoscopic subscore ≥1 


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Details of each flexible sigmoidoscopy procedure will be recorded to the electronic case report 
form (eCRF) including date and time, verify preparation and sample collection: biopsy samples 
for mucosal transcriptomics, mucosal microbiome sample, histopathology with cytomegalovirus 
(CMV) stain sample, video for central reading. 
7.1.3.2 
Biomarkers 
The following biomarkers will be evaluated at Visit 1, Visit 4, Visit 6, Visit 8 (CRP only), 
Visit 12 and Visit 13: 
• Serum biomarkers (C-reactive protein, CRP) 
• Fecal biomarkers (fecal calprotectin) levels 
7.1.4 
Exploratory Endpoints 
The following exploratory endpoints may be evaluated: 
• Stool and blood metabolic pathways 
•  Serum cytokine profile 
• Mucosal microbiome 
• Mucosal transcriptomic profile 
•  Mucosal Histopathology, including CMV Immunohistology stains 
•  Microbial Culture Endpoints: Candida titer and diversity 
One exploratory endpoint is included in this SAP and will be analyzed by PAREXEL; other 
exploratory endpoints will be discussed and presented in a separate SAP and are not part of the 
work order with PAREXEL.  
• Microbial Culture Endpoints:  
o Candida albicans titer 
Candida albicans will be analyzed first for the samples from the first 28 subjects at Visit 1, 4 and 
12.  All the samples collected in other visits for the first 28 subjects, and all the samples for the 
rest of subjects may be analyzed based on the observations from the analysis results of the first 
28 subjects at Visit 1, 4 and 12. 
o Candida species titer 


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Analyses for Candida species may be conducted in the same manner as described above in 
Candida albicans. 
7.1.5 
Safety Variables 
Safety evaluations include assessment of AEs, clinical laboratory tests (chemistry, hematology, 
liver function and urinalysis), physical examination, vital signs and electrocardiograms (ECGs). 
7.1.5.1 
Adverse Events 
Adverse events including local and systemic reactions not considered medically serious, will be 
recorded from screening through Visit 13.  Serious adverse events will be recorded from 
screening through Day 246. 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA, 
version 18.1). 
A treatment-emergent adverse event (TEAE) is defined as an AE that begins or that worsens in 
severity after at least one dose of the study drug (including pre-treatment) has been administered. 
Incidence of TEAE will be summarized by number of subjects and by therapy day. For each 
subject completing therapy, the total therapy days will be calculated including both the pre-
treatment and treatment periods as the end date of treatment minus start date of pre-treatment 
therapy plus one (1). For each subject who is discontinued from treatment, total therapy days will 
be calculated up to the day when therapy was discontinued.  
Any AEs with incomplete start and end dates/times will be treated as follows: 
• Adverse events with unknown start and/or end times (but where the date is known) will be 
imputed with a time of 00:00 h for the tabulations but will be shown as NK:NK in the listings 
(where NK = Not Known). 
• Adverse events with completely unknown start dates will be considered as treatment-
emergent for the tabulations and will be shown as NK in the listings. 
7.1.5.2 
Clinical Laboratory Tests 
The following safety laboratory parameters will be measured: 


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• Hematology: erythrocytes, mean corpuscular volume (MCV), mean corpuscular hemoglobin 
(MCH), neutrophils, eosinophils, basophils, lymphocytes, monocytes, platelets, leukocytes, 
hemoglobin and hematocrit  
• Chemistry: creatinine, glucose, triglycerides, urea, uric acid, cholesterol, albumin, sodium 
and potassium 
• Liver enzymes: alkaline phosphatase (ALP) aspartate aminotransferase (AST),  alanine 
aminotransaminase (ALT), γ-glutamyl transferase (GGT), direct and indirect bilirubin, total 
bilirubin 
• Urinalysis: pH, protein, glucose, ketone, bilirubin, blood, nitrite and leukocyte esterase. If 
nitrates or leukocytes are positive, a microscopic examination will be performed.  
• Pregnancy test, serum and urine, for women of childbearing potential (WOCBP) 
7.1.5.3 
Vital Signs 
The following vital signs measurements will be obtained: 
• Systolic blood pressure (SBP) [mmHg] 
• Diastolic blood pressure (DBP) [mmHg] 
• Heart rate (bpm) 
• Body temperature (oral) [°C] 
• Respiratory rate (breaths per minute) 
• Weight (kg) 
7.1.5.4 
Electrocardiograms  
Standard safety 12-lead ECGs (single reading) will be performed at Day 8 (before dosing), and at 
Follow-Up on Day 92 and will be recorded to the eCRF as: Normal; Abnormal, Not Clinically 
Significant (NCS); and Abnormal, Clinically Significant (CS). 
7.1.5.5 
Physical Examination 
Physical examinations will be performed in accordance with the Schedule of Events CSP 
Table 3.  Abnormal findings determined by the Investigator to be clinically significant will be 
reported as medical history if observed prior to randomization to study drug (including pre-
treatment therapy), or AEs if observed post-randomization during the study period. 


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7.2 
Analysis Populations 
7.2.1 
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 were randomly assigned.  
All safety analyses including descriptive summaries will be conducted based on the Safety 
Population. 
7.2.2 
Intent-to-Treat (ITT) Population 
The Intent-to-Treat (ITT) Population will consist of all subjects who were randomly assigned, 
including those who were not exposed to any study drug, and will be analyzed based on the 
treatment to which they were randomized. 
All clinical efficacy analyses will be conducted in the ITT population. 
Subject listings will be provided for the ITT population. 
7.2.3 
Sensitivity Analysis Population – 1 (without replacement) 
The Sensitivity Analysis Population – 1 will consist of all randomized subjects, excluding any 
additional subjects randomized to replace withdrawn subjects as described in Section 6.5.  
Subjects will be analyzed based on the treatment to which they were randomized.  
7.2.4 
Sensitivity Analysis Population – 2 (with replacements only) 
The Sensitivity Analysis Population – 2 will consist of all randomized subjects, excluding any 
withdrawn subjects who were replaced as described in Section 6.5. Subjects will be analyzed 
based on the treatment to which they were randomized.  
7.3 
Statistical Analysis Methods 
7.3.1 
Listings and Descriptive Statistics 
All original and derived parameters as well as population characteristics will be listed and 
described using summary statistics. Frequency counts (number of subjects [n] and percentages) 
will be made for each qualitative variable. Descriptive statistics (n, mean, standard deviation 


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[SD], median, minimum and maximum) will be calculated for each quantitative variable (unless 
otherwise stated). All listings will include repeated and unscheduled measurements. 
Selected clinical response data will be presented in treatment mean (+/- SD) profile plots. 
The following rules will apply to any repeated measurements: 
• If the repeated measurement occurs prior to the first dose of study drug then the last obtained 
value of any repeated measurement will be used in the descriptive statistics. 
• If the repeated measurement occurs after the first dose of study drug then the first value 
observed of any repeated measurements will be used in the descriptive statistics. 
7.3.2 
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 study arm for comparison among study endpoints. All 
reported confidence intervals (CIs) will be 95%, two-sided. There will be no adjustment of 
p-values or CIs for multiple comparisons. P-values and/or CIs generated for this study are not 
intended to be conclusive, but provided for guidance only. 
In general, inferential analysis will be based on pairwise comparisons, A, C and D separately 
compared to placebo (B), and the comparisons A versus D and C versus D.  If there is no trend in 
the differences between A and D, and C and D, then A, C and D will be pooled together versus 
B.  For continuous data these comparisons will be assessed using CIs estimated by one-way 
analysis of variance (ANOVA) models fit to the separate results of each visit. For binary data 
these comparison will be assessed by analysis of two-by- two tables (using Fisher’s exact test) 
and calculation of the risk difference, odds ratio and their corresponding asymptotic CIs.   
7.3.3 
Software 
All statistical analyses will be performed using SAS® Version 9.3 or later.  
7.3.4 
Missing or Spurious Data 
Any AE with incomplete date or time will be evaluated conservatively in the classification of 
treatment emergent AE.  
The following imputation methods will be performed on the secondary and exploratory clinical 
endpoints, as specified in the succeeding sections on endpoint analyses below: 


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• Last Observation Carried Forward (LOCF) will be performed on the ITT population.  
Baseline values will not be carried forward. 
•  Observed Case analyses will be performed on the ITT population, the Sensitivity Analysis 
Population – 1 and the Sensitivity Analysis Population – 2.   
•  Worst Case analyses will be performed on the ITT population, the Sensitivity Analysis 
Population – 1 and the Sensitivity Analysis Population – 2.     
The specifications are as follows: 
 
Observed Case 
Worst Case 
Early Termination (ET) 
The data observed at ET visit 
will be used in the analysis; if 
the clinical endpoint is missing 
or non-calculable, the subject 
will not be included in the 
analysis. 
All randomized subjects will 
be included in the analysis 
and ET subjects whose 
endpoints are collected prior 
to study Day 48, or missing, 
or non-calculable will be 
considered as having the 
worst outcome for the 
clinical endpoints. 
Treatment Failure 
A subject who is 
considered as treatment 
failure is defined per PIs’ 
decisions, this includes 
subjects who need the 
addition of UC 
medications for UC flares 
during study treatment 
period (from Visit 4 to 
Visit 12) 
If the clinical endpoint(s) for a 
subject is available and 
calculable, the subject will be 
included in the analysis and the 
observed values for those 
endpoints will be used. 
If the endpoint(s) is missing or 
non-calculable, the subject will 
not be included in the analysis. 
All randomized subjects will 
be included and the subjects 
who are considered as 
treatment failure will be 
considered as having the 
worst outcome for the 
clinical endpoints. 
 
No other missing data will be imputed. Any apparently spurious data will be verified. No 
verified data will be excluded from summaries or analysis.  


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7.3.5 
Interim Analysis and Safety Halting Rules 
No interim analysis for efficacy is planned for this study. 
An independent, unblinded, external Data and Safety Monitoring Committee (DSMC) has been 
established to perform safety evaluations on an ongoing basis. A DSMC charter, which has been 
reviewed and approved by the DSMC members, details the review of the safety data. The DSMC 
will make recommendations to ensure both patient safety and the continued ethical integrity of 
the study. Specific details regarding the responsibilities and requirements for documentation are 
described in the DSMC charter. 
To ensure subject safety, individual (CSP Section 6.2.2.1) and study-wide (as detailed in the 
DSMC charter) safety halting rules will be implemented. 
7.3.6 
Study Subjects 
7.3.6.1 
Disposition of Subjects 
The number and percentage of subjects entering and completing the clinical study will be listed 
for all randomized subjects and summarized overall and by treatment group for the ITT 
Population. The coded information of each subject discontinued (adverse event, lost to follow up, 
at the discretion of the investigator, protocol violation, noncompliance, withdrawal by subject, 
pregnancy, met individual halting rule: UC Flare, met individual halting rule: SUSAR and Other) 
will be listed and summarized. Detail will be included in the listing of subjects discontinued due 
to the following reasons: at the discretion of the investigator, protocol violation or other. The AE 
numbers will be reported for subjects discontinued for AE. 
A record of Study Visits completed will be listed and summarized by treatment for the ITT 
Population. 
7.3.6.2 
Protocol Deviations 
All protocol deviations, including those recorded by the Investigator or identified by data 
validation checks and will be recorded to a deviation log. All protocol deviations will be 
discussed between PAREXEL (Medical Monitory, Data Manager and Biostatistician) and also 
the Sponsor during the clean file meeting before database lock. 
Protocol deviations will be listed and any unblinding event record will be listed for the ITT 
population. Assignment to analysis populations will be presented for each subject.  


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7.3.6.3 
Demographic Data 
The following demographic data and baseline data will be listed: age, sex, height, weight, BMI, 
ethnic origin, race, date of first UC diagnosis and time since UC diagnosis, UC Montreal 
classification, severity of UC, smoking history, ongoing UC treatment, medical history 
vancomycin allergy.  
Summary tables by treatment and overall for these demographic and baseline data will be 
presented for the Safety Population and the ITT Population.  
7.3.6.4 
Medical and Surgical History 
Medical and surgical history will be listed.  The listing will include reported term, MedDRA 
preferred term and system organ class, the year of diagnosis or procedure, outcome (ongoing or 
resolved) and, if ongoing, is the patient currently being treated (yes or no). The medical history 
vancomycin allergy item will be listed and summarized with demographic data. 
7.3.6.5 
Prior and Concomitant Medication 
All prior and concomitant medications will be listed.  The listing will include generic name, 
WHO-DDE preferred term, start date (and calculated study day if start date is complete), 
ongoing or discontinued date (and calculated study day if discontinued date is complete), 
indication, route of administration, dose and dose unit, frequency and flags of medication to treat 
UC, medication to treat AE and prohibited medications.  
Separate listings, sorted by treatment, subject, WHO-DDE preferred term and start date will be 
presented of all prior and all concomitant medications for the UC indication.  For each UC 
concomitant medication, the medication category (if available), start date and end date/ongoing 
will be listed and indicated if it is a stable UC background therapy during 8-week treatment 
period as defined in protocol.  (Note that changing UC background therapy during 8-week 
treatment period is considered as a major protocol deviation.)  Any changes in UC background 
therapy will be flagged. 
All prior medications will be summarized by WHO-DDE preferred term and treatment for the 
ITT Population. Prior medications with UC indication will be summarized separately by WHO-
DDE preferred term and treatment. Concomitant medications will be summarized by WHO-DDE 
preferred term, treatment and study phase (pretreatment or treatment) for the ITT Population. 
Separate summaries will be presented of prohibited concomitant medications, all permitted UC 


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concomitant medications and of prohibited concomitant medications or dose changes to 
permitted UC concomitant medications for the ITT Population. This summary table will be the 
basis for sensitivity analyses on the clinical endpoints. 
7.3.6.6 
Diet Inventory Log 
Diet inventory log responses will be presented in a listing. 
7.3.6.7 
Exposure to the Investigational Medicinal Product 
The record of actual treatment or dose received including drug dispensed and returned will be 
presented in a listing for the ITT population and summarized by treatment for each period (pre-
treatment and treatment) in the Safety population. Any subject who was not randomized but 
received a dose of study medication, or received incorrect treatment, will be flagged in the listing 
and identified in a table footnote. 
7.3.7 
Endpoints for Analysis 
7.3.7.1 
Microbiome Alterations and Engraftment Primary Endpoints 
Genomic sequence results of the stool samples and assessment of microbiome alterations, 
composition of the intestinal microbiome and engraftment of SER-287 bacteria will be presented 
in a separate report beyond the scope of work conducted by PAREXEL. These data will not be 
considered in this SAP. The clinical record of stool samples collected will be listed. 
7.3.7.2 
Clinical Efficacy Response 
All TMMS item scores with associated calculations of clinical response, clinical remission, and 
endoscopic improvement will be listed. All partial Mayo item scores with the Partial Mayo Score 
(sum) and score change from baseline will be listed by visit. The record of flexible 
sigmoidoscopy procedures will be listed separately.  The Geboes score based on biopsy collected 
at Baseline and post-treatment visit will be listed.  
Descriptive summaries by treatment will be presented for clinical response, clinical remission, 
and endoscopic improvement at Visit 12/ Early Termination visit for the ITT population, 
Sensitivity Analysis population – 1 and Sensitivity Analysis population – 2. Each endpoint will 
be calculated using the Observed Case and Worst Case methods for imputation of missing data 
(Section 7.3.4).  


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Efficacy response endpoints comprise clinical response, clinical remission, and endoscopic 
improvement. The primary time point for analysis is Visit 12. Estimates of the Visit 12 
difference of rate (active treatment - placebo), 95% CI and statistical significance will be 
reported for treatment groups A, C and D separately compared to placebo B (A vs. B; C vs. B: D 
vs. B), A and D pooled together compared to placebo (A+D vs. B), A, C and D pooled together 
compared to placebo (A+C+D vs. B) and for A and C separately compared to D (A vs. D; C vs. 
D) for the ITT population, observed cases and worst case method, the Sensitivity Analysis 
Population – 1 and the Sensitivity Analysis Population – 2. Corresponding calculations of the 
odds ratio and relative risk will be also presented in those tables. 
The following SAS® code will be applied for each comparison (two-by-two table) to estimate 
exact 95% CI for the clinical response (CLINRESP) rate in each treatment and asymptotic 95% 
CI for the risk difference and odds ratio: 
proc freq; 
table TRT* CLINRESP /nopercent nocol alpha=0.05 chisq riskdiff relrisk exact;  
ods  select CrossTabFreqs RiskDiffCol2 RelativeRisks; 
run; 
quit; 
Other efficacy endpoints will be analyzed using similar SAS code. 
7.3.7.3 
Serum Biomarkers 
Serum biomarkers (CRP) observed values and change from baseline at each visit will be listed 
and summarized by treatment and visit.  Mean (+/- SD) profile plots (response versus time point 
by treatment) of observed and change from baseline will be presented for the ITT population. 
The summary table and figures will use both observed case and LOCF imputation for missing 
values. 
7.3.7.4 
Fecal Biomarkers 
Fecal biomarkers (fecal calprotectin) observed values and change from baseline at each visit will 
be listed and summarized by treatment and visit. Mean [+/ SD] profile plots (response versus 
timepoint by treatment) of observed and change from baseline will be presented for the ITT 
population. The summary table and figures will use both observed case and LOCF imputation for 
missing values. 


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7.3.7.5 
Exploratory Endpoints 
Results of the following exploratory endpoints collected at Baseline and post-baseline visits will 
be listed and presented in descriptive summary tables. 
Serum cytokine profiles observed and change from baseline values will be listed and 
summarized for the ITT population. The summary table will use both observed case and LOCF 
imputation for missing values. 
Mucosal Histopathology with CMV stain Geboes scores will be listed and summarized by 
treatment and visit for the ITT population. A summary table will include Geboes score frequency 
tabulated (number and percentage or subjects) at baseline and the post-baseline visits by 
treatment group for the ITT population.   
Descriptive statistics for the titers of Candida albicans isolated at Visit 1, Visit 4 and Visit 12 
will be presented by treatment group for the ITT population.  The fold change from baseline 
(Visit 1) to each post-baseline visit, and the fold change from Visit 4 to each following visit will 
be also summarized by treatment group.  Only subjects with evaluable samples at baseline/Visit 
4 and the specified post-baseline/following visit will be included in the analysis of the fold 
change from baseline/Visit 4 at that visit.   
In addition, the preceding summary tables summarizing titers and fold change from baseline of 
Candida albicans will be provided for the subset of subjects with a positive titer (>=50 CFU/g) at 
baseline (Visit 1), Visit 4 or Visit 12 by treatment group in the ITT population.  A similar 
summary table will be provided for the subset of subjects with a positive titer (>=50 CFU/g) at 
Visit 4 or Visit 12 by treatment group in the ITT population. 
Any titer at Baseline or Visit 4 (when calculating change from Visit 4) that has a value of  “<50 
Colony forming unit (CFU)/g” recorded will be given a value of 49 in the analyses, as the 
imputation method for the calculation of the fold change from Baseline, or change from Visit 4. 
A plot presenting the average fold change from baseline of Candida albicans for subjects with at 
least 1 positive post-baseline titer by visit and treatment group will be generated for the ITT 
population.  A similar plot presenting the average fold change from Visit 4 will be generated for 
subjects with at least 1 positive titer at Visit 12 in the ITT population.  In the plot, the Y-axis will 
be the average fold change from baseline and the X-axis will present the visit time points for 
Visit 1, Visit 4 and Visit 12. 


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The analyses planned for Candida albicans may be repeated for Candida species. 
As majority of stool samples are handled as refrigerated samples, all the frozen samples will not 
be used for any of these analyses. 
7.3.8 
Safety Analysis 
The analysis of the safety variables will be based on the Safety Population. 
Safety endpoint will be summarized by treatment group and also for the pooled SER-287 
treatments (A, C and D). The assessment of safety will be based on descriptive summaries of 
SER-287 treatment groups and the placebo treatment group. 
7.3.8.1 
Adverse Events 
All AEs from screening to Day 92, and all SAEs from screening to Day 246 will be collected and 
listed, including those occurring before the start of study drug. Separate listings will be presented 
for AEs leading to death, SAEs, AEs of special interest (AESI) and AEs leading to study drug 
discontinuation. The following information will be included in the listings: reported (verbatim) 
term, MedDRA preferred term, system organ class, start date, end date or ongoing, serious, 
AESI, action taken (drug withdrawn, dose not changed, not applicable), relationship to study 
drug (not related, possibly related, related), outcome (fatal, not recovered/ not resolved, 
recovered/ resolved), severity (mild, moderate, severe) and treatment given (yes, no). 
The following additional information will be presented for SAEs: results in death, requires or 
prolongs hospitalization, results in persistent or significant disability/incapacity, is life 
threatening, is associated with congenital anomaly or birth defect. 
An overall TEAE summary by treatment will include number and percentage of subjects with 
event counts for SAE, AESI, severe AE, related and possibly related AE, AE leading to 
discontinuation of study drug and AE leading to death. The number and percentage of subjects 
with event counts of TEAEs will be tabulated by system organ class (SOC) and preferred term 
(PT) for each treatment group. The incidence of TEAEs based on the number of days the 
subjects in each treatment group were on study drug (per subject on therapy day) will also be 
presented by system organ class and preferred term for each treatment group. For calculation of 
incidence per subject, each type of event will be counted at most once per subject. For 
calculation of incidence per subject on therapy days all adverse events will be counted.  


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The subject incidence and incidence per subject therapy day will also be summarized by severity 
and by relationship to treatment.  
7.3.8.2 
Clinical Safety Laboratory Tests (Chemistry, Hematology, Liver and 
Urinalysis) 
Clinical safety laboratory tests will be reported in standard international (SI) units.   
All scheduled and unscheduled laboratory results will be presented for each subject, sorted by 
category, subject, test and sample time for hematology observed and change from baseline, 
chemistry tests observed and change from baseline, liver function tests observed and change 
from baseline and urinalysis observed values with change from baseline reported for quantitative 
assessments. Flags will be attached to values outside of the laboratory’s reference limits along 
with the Investigator’s assessment of NCS or CS. Listings will include change from baseline, 
where baseline is the latest scheduled or repeat assessment obtained on Day 1 prior to pre-
treatment dosing.   
A separate listing of all subjects with any abnormal hematology results will be presented, 
grouped by test category and ordered by test, subject and sample time.  All results, both normal 
and abnormal, for the subject at the other sample times for this hematology test will also be 
included in this listing.  A similar listing will be created for all abnormal chemistry and liver 
function test results. The liver function tests ALT, AST, total bilirubin and ALP will be assessed 
for signs of hepatic impairment and liver injury. These tests will be reported for each scheduled 
or unscheduled laboratory assessment that had ALT > 3xULN, AST > 3xULN, or total 
bilirubin ≥ 2xULN. Laboratory results and other laboratory tests for these subjects will be 
reviewed and evaluated relative to Hy’s law (Reference 2): 
1. a subject having 3-fold or greater elevations above the ULN of ALT or AST  
2. the subject also having total bilirubin >2xULN 
3. the subject does not show elevated serum ALP (ALP < 2xULN) 
Quantitative hematology, chemistry and liver test observed values and changes from baseline 
will be summarized descriptively (n, mean, SD, median, minimum, maximum) by treatment and 
visit. Quantitative urinalysis tests will also be presented in a summary table.  
The record of serum and urine pregnancy tests will listed. 


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The record of biopsy sample collected will be listed. 
7.3.8.3 
Vital Signs 
Individual data listings of vital signs (observed and change from baseline) will be presented for 
each subject. Baseline is the assessment taken on Day 1 of the pre-treatment period or the latest 
unscheduled assessment taken predose of the pre-treatment study drug. Descriptive statistics (n, 
mean, SD, median, minimum, maximum) of the vital signs observed and change from baseline 
will be presented by treatment group for all scheduled study visits. Baseline is the latest 
scheduled or unscheduled assessment prior to the first dose of study drug in the pre-treatment 
period. 
7.3.8.4 
Twelve-Lead Electrocardiogram 
The record of ECG, date, time and overall interpretation will be listed and the overall 
interpretation summarized by treatment and visit. 
 
 


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8. 
CHANGE FROM PROTOCOL 
In Protocol Amendment 3, 10 Oct 2016 
In SAP Amendment 
The Modified Intent-to-Treat (mITT) 
population will consist of all randomized 
patients with baseline and at least one post-
baseline stool sample, who were exposed to 
any amount of study drug, and will be analyzed 
based on the treatment to which they were 
randomized (pages 8, 59).  
Deleted: 
mITT 
Complete remission defined as: 
A Total Modified Mayo Score ≤ 2 and an 
endoscopic subscore 0 with no erythema, no 
blood and no evidence of inflammation. (pages 
4, 27, 38),  
Deleted: 
Complete remission 
 
Added: 
Clinical remission defined as: 
A Total Modified Mayo Score ≤ 2 and an 
endoscopic subscore 0 or 1 
 
 
 
 
 
 
 
 
 
 


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9. 
REFERENCES 
1. SAS® Version 9.3 of the SAS System for Personal Computers. Copyright © 2002-2003. SAS 
Institute Inc. SAS and all other SAS Institute Inc. product or service names are registered 
trademarks or trademarks of SAS Institute Inc., Cary, NC, USA. 
2. Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation. Food 
and Drug Administration Web site. http://www.fda.gov. Accessed September 15, 2016. 
 
 


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10. 
TABLES AND LISTINGS TO BE INCLUDED IN SECTION 14 OF 
THE CLINICAL STUDY REPORT 
Subject Disposition 
Table 14.1.1 
Subject Disposition by Treatment (Intent to Treat Population) 
Table 14.1.2 
Study Visits Completed by Treatment (Intent to Treat Population) 
Baseline and Demographic Data 
Table 14.1.3.1 
Subject Demographics and Baseline Variables (Safety Population)  
Table 14.1.3.2.1 
Subject Demographics and Baseline Variables (Intent to Treat Population) 
Table 14.1.3.2.2 
Subject Demographics and Baseline Variables (Sensitivity Analysis 
Population – 1) 
Table 14.1.3.2.3 
Subject Demographics and Baseline Variables (Sensitivity Analysis 
Population – 2) 
Table 14.1.4.1.1 
All Prior Medications (Intent to Treat Population)  
Table 14.1.4.1.2 
Prior Medications for Ulcerative Colitis (Intent to Treat Population) 
Table 14.1.4.2.1 
All Prior and Concomitant Medications (Intent to Treat Population)  
Table 14.1.4.2.2 
All Prior and Concomitant Medications for UC (Intent to Treat Population) 
Table 14.1.4.3.1 
All Concomitant Medications (Intent to Treat Population)  
Table 14.1.4.3.2 
All Concomitant Medications for UC (Intent to Treat Population) 
Table 14.1.4.4 
All Post-treatment Medications (Intent to Treat Population)  
Table 14.1.4.5.1 
Record of Prohibited Concomitant Medications for UC Indications Taken 
During the Study Treatment Period  (Intent to Treat Population) 
Table 14.1.4.5.2 
Record of Prohibited Concomitant Medications for non-UC Indications 
(Intent to Treat Population) 


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Table 14.1.4.5.3 
Record of Dose Changes During the Study Treatment Period to Permitted 
Prior and Concomitant Medications for Ulcerative Colitis (Intent to Treat 
Population) 
Table 14.1.4.6 
Record of All Permitted Concomitant Medications for Ulcerative Colitis 
Taken During the Study Treatment Period  (Intent to Treat Population) 
Study Drug Exposure 
Table 14.2.1 
Study Drug Compliance Rate by Treatment  (Safety Population) 
Endpoints for Analysis 
Table 14.2.2.1 
Clinical Response, Clinical Remission, and Endoscopic Improvement by 
Treatment (Intent to Treat Population, Observed Case) 
Table 14.2.2.2 
Clinical Response, Clinical Remission, and Endoscopic Improvement by 
Treatment (Intent to Treat Population, Worst Case) 
Table 14.2.2.3 
Clinical Response, Clinical Remission, and Endoscopic Improvement by 
Treatment (Sensitivity Analysis Population – 1, Observed Case) 
Table 14.2.2.4 
Clinical Response, Clinical Remission, and Endoscopic Improvement by 
Treatment (Sensitivity Analysis Population – 1, Worst Case) 
Table 14.2.2.5 
Clinical Response, Clinical Remission, and Endoscopic Improvement by 
Treatment (Sensitivity Analysis Population – 2, Observed Case) 
Table 14.2.2.6 
Clinical Response, Clinical Remission, and Endoscopic Improvement by 
Treatment (Sensitivity Analysis Population – 2, Worst Case) 
Table 14.2.3.1.1 
Serum C-reactive Protein (CRP) Observed and Change from Baseline by 
Treatment and Visit (Intent to Treat Population) 
Table 14.2.3.1.2 
Serum C-reactive Protein (CRP) Observed and Change from Baseline by 
Treatment and Visit (Intent to Treat Population, LOCF) 
Table 14.2.3.2.1 
Fecal Calprotectin Observed and Change from Baseline by Treatment and 
Visit (Intent to Treat Population) 


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Table 14.2.3.2.2 
Fecal Calprotectin Observed and Change from Baseline by Treatment and 
Visit (Intent to Treat Population, LOCF) 
Table 14.2.3.3 
Serum Cytokine Profile Observed Values and Change from Baseline by 
Treatment and Visit (Intent to Treat Population) 
Table 14.2.3.4.1 
Mucosal Histopathology with Cytomegalovirus (CMV) Stain Geboes 
Scores Summary by Treatment and Visit (Intent to Treat Population) 
Table 14.2.3.4.2 
Mucosal Histopathology with CMV Stain Geboes Scores Shift from 
Baseline to Day 64 by Treatment (Intent to Treat Population) 
Table 14.2.4.1.1 
Titers of Candida albicans Observed Values and Fold Change from 
Baseline by Treatment and Visit (Intent to Treat Population) 
Table 14.2.4.1.2 
Titers of Candida albicans Observed Values and Fold Change from Visit 4 
by Treatment and Visit (Intent to Treat Population) 
Table 14.2.4.1.3 
Titers of Candida albicans Observed Values and Fold Change from 
Baseline by Treatment and Visit (Intent to Treat Population, Positive Titer 
at Baseline) 
Table 14.2.4.1.4 
Titers of Candida albicans Observed Values and Fold Change from Visit 4 
by Treatment and Visit (Intent to Treat Population, Positive Titer at Visit 
4) 
Table 14.2.4.2.1 
Titers of Candida species Observed Values and Fold Change from Baseline 
by Treatment and Visit (Intent to Treat Population) 
Table 14.2.4.2.2 
Titers of Candida species Observed Values and Fold Change from Visit 4 
by Treatment and Visit (Intent to Treat Population) 
Table 14.2.4.2.3 
Titers of Candida species Observed Values and Fold Change from Baseline 
by Treatment and Visit (Intent to Treat Population, Positive Titer at 
Baseline) 
Table 14.2.4.2.4 
Titers of Candida species Observed Values and Fold Change from Visit 4 
by Treatment and Visit (Intent to Treat Population, Positive Titer at Visit 
4) 


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Safety Data 
 
Table 14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events by Treatment 
(Safety Population) 
Table 14.3.1.2.1 
Treatment-Emergent Adverse Events Incidence by Subject by Treatment, 
System Organ Class and Preferred Term (Safety Population) 
Table 14.3.1.2.2 
Treatment-Emergent Adverse Events Incidence by Subject Therapy Day by 
Treatment, System Organ Class and Preferred Term (Safety Population) 
Table 14.3.1.3.1 
Treatment-Emergent Adverse Events Incidence by Subject by Treatment, 
System Organ Class, Preferred Term and Severity (Safety Population) 
Table 14.3.1.3.2 
Treatment-Emergent Adverse Events Incidence by Subject Therapy Day by 
Treatment, System Organ Class, Preferred Term and Severity (Safety 
Population) 
Table 14.3.1.4.1 
Treatment-Emergent Adverse Events Incidence by Subject by Treatment, 
System Organ Class, Preferred Term and Causality (Safety Population) 
Table 14.3.1.4.2 
Treatment-Emergent Adverse Events Incidence by Subject Therapy Day by 
Treatment, System Organ Class, Preferred Term and Causality (Safety 
Population) 
Listing 14.3.2.1 
Subject Listing of Adverse Events Leading to Death (Safety Population) 
Listing 14.3.2.2 
Subject Listing of Serious Adverse Events (Safety Population) 
Listing 14.3.2.3 
Subject Listing of Adverse Events of Special Interest (Safety Population) 
Listing 14.3.2.4 
Subject Listing of Adverse Events Leading to Study Drug Discontinuation 
(Safety Population) 
Listing 14.3.4.1 
Abnormal Hematology Laboratory Test Values (Safety Population) 
Listing 14.3.4.2 
Abnormal Chemistry Laboratory Test Values (Safety Population) 
Listing 14.3.4.3 
Abnormal Liver Function Test Values (Safety Population) 
Listing 14.3.4.4 
Liver Safety Monitoring Assessments Listed by Subject Time Point and 


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Test (Safety Population) 
Table 14.3.5.1.1 
Hematology Observed and Change from Baseline Summary by Treatment 
and Visit (Safety Population) 
Table 14.3.5.1.2 
Chemistry Tests Observed and Change from Baseline Summary by 
Treatment and Visit (Safety Population) 
Table 14.3.5.1.3 
Liver Function Tests Observed and Change from Baseline Summary by 
Treatment and Visit (Safety Population) 
Table 14.3.5.1.4 
Urinalysis Quantitative Tests Observed and Change from Baseline 
Summary by Treatment and Visit (Safety Population) 
Table 14.3.6.1 
Vital Signs Observed Values and Change from Baseline by Treatment and 
Visit (Safety Population) 
Table 14.3.6.2 
Electrocardiogram Overall Interpretation by Treatment and Visit (Safety 
Population) 
 
 
 


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11. 
FIGURES TO BE INCLUDED IN SECTION 14 OF THE CLINICAL 
STUDY REPORT  
Figure 14.2.1.1 
Serum C-reactive Protein (unit) Mean (+/- Standard Deviation) Profiles 
versus Study Day (Intent to Treat Population) 
Figure 14.2.1.2 
Serum C-reactive Protein (unit) Change from Baseline Mean (+/- Standard 
Deviation) Profiles versus Study Day (Modified Intent to Treat Population) 
Figure 14.2.2.1 
Fecal Calprotectin (unit) Mean (+/- Standard Deviation) Profiles versus 
Study Day (Intent to Treat Population) 
Figure 14.2.2.2 
Fecal Calprotectin (unit) Change from Baseline Mean (+/- Standard 
Deviation) Profiles versus Study Day (Modified Intent to Treat Population) 


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12. 
LISTINGS TO BE INCLUDED IN SECTION 16 OF THE CLINICAL 
STUDY REPORT 
Subject Disposition 
Listing 16.2.1.1 
Subject Disposition and Informed Consent (All Randomized Subjects) 
Listing 16.2.1.2 
Study Visits Completed (Intent to Treat Population) 
Listing 16.2.2.1 
Protocol Deviations (Intent to Treat Population) 
Listing 16.2.2.2 
Subject Unblinding Events (Intent to Treat Population) 
Listing 16.2.3 
Assignment to Analysis Populations (Intent to Treat Population) 
Baseline and Demographic Data 
Listing 16.2.4.1.1 
Subject Demographics and Baseline Characteristics Subject History 
(Intent to Treat Population) 
Listing 16.2.4.1.2 
Subject Demographics and Baseline Characteristics – UC History (Intent 
to Treat Population) 
Listing 16.2.4.2 
Medical and Surgical History (Intent to Treat Population) 
Concomitant Medication and Diet 
Listing 16.2.4.3.1.1 
Prior Medication for Ulcerative Colitis Indication (Intent to Treat 
Population) 
Listing 16.2.4.3.1.2 
Prior Medications for Non-Ulcerative Colitis Indication (Intent to Treat 
Population) 
Listing 16.2.4.3.2.1 
Prior and Concomitant Medication for Ulcerative Colitis Indication 
(Intent to Treat Population) 
Listing 16.2.4.3.2.2 
Prior and Concomitant Medication for Non-Ulcerative Colitis Indication 
(Intent to Treat Population) 
Listing 16.2.4.3.3.1 
Concomitant Medication for Ulcerative Colitis Indication (Intent to Treat 
Population) 


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Listing 16.2.4.3.3.2 
Concomitant Medication for Non-Ulcerative Colitis Indication (Intent to 
Treat Population) 
Listing 16.2.4.3.4 
Post-treatment Medication (Intent to Treat Population) 
Listing 16.2.4.3.5.1 
Prior and Concomitant Permitted Medication for Ulcerative Colitis 
Indication (Intent to Treat Population) 
Listing 16.2.4.3.5.2 
Prior and Concomitant Prohibited Medications for Ulcerative Colitis 
(Intent to Treat Population) 
Listing 16.2.4.3.5.3 
Prohibited Concomitant Medications (Intent to Treat Population) 
Listing 16.2.4.6 
Diet Inventory Log (Intent to Treat Population) 
Study Drug Exposure 
Listing 16.2.5 
Pre-treatment and Treatment Period Drug Dispensed and Returned (Safety 
Population) 
Endpoints for Analysis 
Listing 16.2.6.1.1 
Total Modified Mayo Score (TMMS) and Clinical Efficacy Endpoints 
(Intent to Treat Population) 
Listing 16.2.6.1.2 
Partial Mayo Score and Change from Baseline (Visit 2) by Visit (Intent to 
Treat Population) 
Listing 16.2.6.1.3 
Endoscopy Procedure (Intent to Treat Population) 
Listing 16.2.6.2 
Serum C-reactive Protein Observed and Change from Baseline (Intent to 
Treat Population) 
Listing 16.2.6.3 
Fecal Calprotectin Observed and Change from Baseline (Intent to Treat 
Population) 
Listing 16.2.6.4 
Serum Cytokine Profile, Observed and Change from Baseline (Intent to 
Treat Population)  
Listing 16.2.6.5 
Mucosal Histopathology with CMV Stain Geboes Scores (Intent to Treat 
Population) 


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Listing 16.2.6.6 
Stool Sample Collection (Intent to Treat Population) 
Listing 16.2.6.7 
Candida Albicans, Observed Value by Treatment by Visit (Intent to Treat 
Population) 
Listing 16.2.6.8 
Candida Species, Observed Value by Treatment by Visit (Intent to Treat 
Population) 
Safety Variables 
Listing 16.2.7 
All Adverse Events and Pre-Treatment Adverse Events (Safety 
Population) 
Listing 16.2.8.1 
Hematology Observed Values and Change from Baseline (Safety 
Population) 
Listing 16.2.8.2 
Chemistry Observed Values and Change from Baseline (Safety 
Population) 
Listing 16.2.8.3 
Liver Function Tests Observed Values and Change from Baseline (Safety 
Population) 
Listing 16.2.8.4 
Urinalysis Observed Values and Change from Baseline (Safety 
Population) 
Listing 16.2.8.5 
Pregnancy Tests (Safety Population)  
Listing 16.2.9.1 
Vital Signs Observed Values and Change from Baseline (Safety 
Population) 
Listing 16.2.9.2 
Electrocardiogram Assessments (Safety Population) 
 
 


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13. 
DOCUMENTATION OF STATISTICAL METHODS 
Appendix 16.1.9.2.1 Statistical Analysis of Study Endpoints