ECOSPOR IV: An Open-Label Extension of Study SERES-012 and Open-Label Program for Evaluating SER-109 in Subjects With Recurrent Clostridioides Difficile Infection (RCDI)
Phase: PHASE3
Conditions: Clostridioides Difficile Infection
Sponsor: Seres Therapeutics, Inc.

Seres Therapeutics, Inc. 
Protocol: SERES-013
CONFIDENTIAL
Amendment 8 Date:  16 February 2021 
Page 1 of 80
CLINICAL STUDY PROTOCOL
SER-109 
(Eubacterial Spores, Purified Suspension, Encapsulated) 
SERES-013: ECOSPOR IV: AN OPEN-LABEL EXTENSION OF STUDY
SERES-012 AND OPEN-LABEL PROGRAM FOR EVALUATING SER-109 IN 
ADULT SUBJECTS WITH RECURRENT CLOSTRIDIOIDES DIFFICILE
INFECTION (RCDI) 

Seres Therapeutics, Inc.  
 
Protocol: SERES-013 
CONFIDENTIAL 
Amendment 8 Date:  16 February 2021  
 
Page 4 of 80 
 
INVESTIGATOR’S AGREEMENT 
 
 
I have read the SERES-013 Protocol Amendment 8, dated 16 February 2021, and agree to conduct 
the study as outlined. I agree to maintain the confidentiality of all information received or 
developed in connection with this protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 

Seres Therapeutics, Inc.  
 
Protocol: SERES-013 
CONFIDENTIAL 
Amendment 8 Date:  16 February 2021  
 
Page 5 of 80 
 
STUDY CONTACTS 
 
Sponsor Responsible Medical Officer 
 
 
 
 
 
 
 
CRO Medical Monitor 
  
 
 
 
 

Seres Therapeutics, Inc.  
 
Protocol: SERES-013 
CONFIDENTIAL 
Amendment 8 Date:  16 February 2021  
 
Page 6 of 80 
 
1. 
PROTOCOL SYNOPSIS 
SPONSOR NAME: Seres Therapeutics, Inc.  
ACTIVE INGREDIENT: SER-109 (Eubacterial Spores, Purified Suspension, Encapsulated) 
PROTOCOL TITLE: ECOSPOR IV: An Open-Label Extension of Study SERES-012 and Open-Label 
Program for Evaluating SER-109 in Adult Subjects with Recurrent Clostridioides  difficile Infection (RCDI) 
STUDY CENTERS: Approximately 140 study centers in North America  
PLANNED STUDY PERIOD:  
Estimated date first patient enrolled: 4Q2017 
Estimated date last patient completed: 2Q2022 
CLINICAL PHASE: 3 
DEFINITIONS:  
For this study, CDI recurrence during the study is defined by the following criteria: 
x 
Positive Clostridioides difficile test on a stool sample determined by a toxin assay  
x 
3 unformed bowel movements per day over 2 consecutive days and the requirement that patients 
must continue to have diarrhea until antibiotic treatment is initiated 
x 
Assessment by the investigator (based on clinical assessment) that the patient’s condition warrants 
antibiotic treatment 
OBJECTIVES: 
Subjects who are participating in the open-label extension of Study SERES-012 (Cohort 1) have the following 
objectives.   
Primary Efficacy Objective 
x 
To evaluate SER-109 in the reduction of CDI recurrence rate and increase in sustained clinical 
response rate determined by a toxin assay, up to 8 weeks after initiation of treatment 
Secondary Efficacy Objectives 
x 
To evaluate SER-109 in the reduction of CDI recurrence rates, determined using a PCR algorithm 
(see Laboratory Manual) up to 8 weeks after initiation of treatment 
x 
To evaluate the time to CDI recurrence, determined by a toxin assay, after initiation of a treatment 
regimen of SER-109  
x 
To evaluate the time to CDI recurrence, determined using a PCR algorithm, after initiation of a 
treatment regimen of SER-109 
x 
To evaluate the proportion of subjects experiencing CDI recurrence, determined by a toxin assay, 
up to 4, 12, and 24 weeks after initiation of a treatment regimen of SER-109  
x 
To evaluate the proportion of subjects experiencing CDI recurrence, determined using a PCR 
algorithm, up to 4, 12, and 24 weeks after initiation of a treatment regimen of SER-109  
Primary Safety Objective 
x 
To evaluate the safety and tolerability of SER-109 in adult subjects with recurrent CDI 
Exploratory Objectives 
x 
To evaluate changes in the composition of the gut microbiome from Baseline up to 1, 2, 8, and 24 
weeks after initiation of a treatment regimen of SER-109 

Seres Therapeutics, Inc.  
 
Protocol: SERES-013 
CONFIDENTIAL 
Amendment 8 Date:  16 February 2021  
 
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x 
To evaluate changes in the fecal metabolome from Baseline up to 1, 2, and 8 weeks after initiation 
of a treatment regimen of SER-109 
x 
To determine the incidence of mortality from all causes up to 8 and 24 weeks after initiation of a 
treatment regimen of SER-109  
x 
To determine the incidence of hospitalizations for recurrent CDI up to 8 and 24 weeks after initiation 
of a treatment regimen of SER-109 
x 
To determine the incidence of all hospitalizations up to 8 and 24 weeks after initiation of a treatment 
regimen of SER-109 
x 
To determine, for subjects who are hospitalized, the total length of stay (days) of hospitalization, 
including days in the intensive care unit, up to 8 and 24 weeks after initiation of a treatment regimen 
of SER-109 
x 
To assess health outcomes, including Health Related Quality of Life (HRQOL), by using the 
EuroQol 5 Dimensions 5 Level (EQ-5D-5L) and the HRQOL survey for CDI (CDiff32) up to 24 
and 8 weeks after initiation of a treatment regimen of SER-109, respectively 
After the last subject rolls over from SERES-012 (Cohort 1), SERES-013 will commence enrollment of Cohort 
2, the Open-Label population. The objectives for Cohort 2 are the following: 
Primary safety objective 
x 
To evaluate the safety and tolerability of SER-109 in adult subjects with recurrent CDI 
Efficacy objectives 
x 
To evaluate SER-109 in the reduction of CDI recurrence rates and increase in sustained clinical 
response rates, determined by a toxin assay, up to 8 and 12 weeks after initiation of treatment 
No Secondary efficacy objectives 
Exploratory objectives 
x 
To evaluate changes in the composition of the gut microbiome from Baseline to 1 week after 
initiation of a treatment regimen of SER-109  
x 
To evaluate changes in the fecal metabolome from Baseline to 1 week after initiation of a treatment 
regimen of SER-109 
x 
To determine the incidence of mortality from all causes up to 8 and 24 weeks after initiation of a 
treatment regimen of SER-109  
x 
To determine the incidence of hospitalizations for recurrent CDI up to 8 and 24 weeks after initiation 
of a treatment regimen of SER-109 
x 
To determine the incidence of all hospitalizations up to 8 and 24 weeks after initiation of a treatment 
regimen of SER-109 
x 
To determine, for subjects who are hospitalized, the total length of stay (days) of hospitalization, 
including days in the intensive care unit, up to 8 and 24 weeks after initiation of a treatment regimen 
of SER-109 

Seres Therapeutics, Inc.  
 
Protocol: SERES-013 
CONFIDENTIAL 
Amendment 8 Date:  16 February 2021  
 
Page 8 of 80 
 
x 
To assess the EuroQol 5 Dimensions 5 Level (EQ-5D-5L) Visual Analog Scale at Screening and at 
Week 8 
x 
To assess a Bowel Cleanse Patient Satisfaction Survey Measure at Week 8 on using a Bowel Cleanse 
Patient Satisfaction Survey Measure on a bowel cleanse administered prior to SER-109  
STUDY DESIGN: 
ECOSPOR IV; Cohort 1 is an open-label extension of Study SERES-012. This study is designed to evaluate the 
safety, tolerability, and efficacy of a SER-109 treatment regimen in adult subjects 18 years of age or older with 
recurrent Clostridioides. difficile infection (RCDI), who received a SER-109 or placebo treatment regimen in 
Study SERES-012. 
Approximately 30 eligible subjects with recurrent CDI disease from Study SERES-012 are expected to enroll in 
Cohort 1. 
Subjects who had a per-protocol recurrence of CDI within 8 weeks of receipt of a SER109 or placebo treatment 
regimen in Study SERES-012 and who have responded to CDI SOC antibiotic therapy defined as 10 to 21 days 
of treatment with vancomycin [125 mg QID] or fidaxomicin [200 mg BID] will be eligible to enroll in Study 
SERES-013, and will receive a SER-109 treatment regimen. A SER-109 treatment regimen is 
 
 administered orally in 4 capsules once daily for 3 consecutive days.  
Subjects being considered for SERES-013 will start screening for 013 at the Recurrence Visit of Study SERES-
012.  Subjects with a confirmed recurrence of CDI will receive 10 to 21 days of treatment with vancomycin [125 
mg QID] or fidaxomicin [200 mg BID]. On Day -1, within 3 days of completion of SOC antibiotic treatment for 
their CDI, subjects will undergo a bowel cleanse followed by overnight fasting prior to scheduled randomization 
on Day 1. 
  
Laboratory values or procedures obtained during the screening window and from the central laboratory of Study 
SERES-012 (e.g. Recurrence Visit) do not need to be repeated at the Screening Visit for SERES-013. The 
SERES-012 Recurrence Visit may be used for the SERES-013 Screening Visit. However, if the SERES-012 
Recurrence Visit occurred outside the SERES-013 screening window (Day -24 to Day -2), the required screening 
procedures for SERES-013 must be repeated within the screening window.  
 
Subjects will come to the clinic after an overnight fast on the morning of Day 1 to receive a single dose of oral 
SER-109 
 in 4 capsules and have all safety evaluations performed. On Day 1, subjects will be 
dispensed a 2-day supply of SER-109 
 in 4 capsules with instructions for home-administration of 
a single daily dose in the morning before breakfast on Day 2 and Day 3. Subjects will be contacted by phone on 
Day 2 and Day 3 to confirm they have taken study drug before breakfast and to inquire about their general health. 
If subjects have not taken study drug when contacted, they will be reminded to do so as soon as possible. From 
Day 1 to Week 8, all subjects will be contacted by phone by study site personnel weekly, with the exception of a 
home or in-clinic visit at Week 2 and an in-clinic visit at Week 8, and queried for adverse events (AEs) and 
diarrheal symptoms. After Week 8, all subjects will be contacted by phone by study site personnel every 4 weeks 
(i.e., Weeks 12, 16, 20, and 24) and queried for serious adverse events [SAEs] and adverse events of special 
interest [AESIs]). Health-related quality of life and health outcomes will be assessed throughout the study via the 
CDI-specific, Cdiff32 Health Related Quality of Life (HRQoL) and EuroQol 5 Dimension 5 Level (EQ-5D-5L) 
questionnaires. 
To document episodes of diarrhea, subjects will complete a diarrhea log (see Investigator Site File) to include 
days with diarrhea as well as no diarrhea,IGLDUUKHDOV\PSWRPVUHFXU3 unformed stools per day over 2 
consecutive days) between scheduled visits, subjects will be instructed to contact the investigator and return to 
the clinic for a C. difficile stool toxin test and clinical evaluation for recurrence of CDI (Recurrence Visit). 
Subjects who have a confirmed CDI recurrence should continue to be followed for safety assessments through 
Week 24. Favorable clinical outcome (or Sustained clinical response) in this study will be determined by the 
absence of CDI recurrence up to 8 weeks after initiation of the SER-109 treatment regimen. CDI recurrence is 
GHILQHGDV3 unformed stools per day over 2 consecutive days and the requirement that subjects must continue 
to have diarrhea until antibiotic treatment is initiated, with a positive C. difficile toxin assay on a stool sample and 
a decision by the investigator (based on clinical assessment), that antibiotic treatment is needed. To inform subject 
(
)
(
)

Seres Therapeutics, Inc.  
 
Protocol: SERES-013 
CONFIDENTIAL 
Amendment 8 Date:  16 February 2021  
 
Page 9 of 80 
 
care, a C. difficile stool test may be performed locally at the study site. Stool samples collected for suspected CDI 
recurrence will also be processed and shipped to a central laboratory for C. difficile stool testing (see Laboratory 
Manual). The subject should not initiate antibiotics for suspected CDI prior to providing a stool sample for the 
central laboratory stool testing. Data from the C. difficile toxin test (either EIA or CCNA), performed at the central 
laboratory, will be used for the primary endpoint analysis. The central laboratory results will be communicated to 
the investigator and the decision to treat with antibiotics will be based upon the investigator’s assessment. 
The schedule of assessments and procedures is provided in Table 1. 
 
The Open-Label cohort (Cohort 2) will commence after the last subject from SERES-012 rolls over into SERES-
013.    The primary objective in Cohort 2 is to describe safety and tolerability of SER-109 in subjects 18 years of 
age or older with at least a first recurrence of CDI. Approximately -200 subjects are expected to be enrolled in 
Cohort 2  
In Cohort 2, subjects with symptoms suggestive of RCDI may submit a stool sample for CDI toxin or PCR 
testing at a Clinical Laboratory Improvement Amendment (CLIA)- certified local laboratory or the central 
laboratory with a prescreening  or screening consent.  Stool samples submitted to the central lab for pre-screening 
and screening will be tested using a PCR . test.   All subjects who are confirmed to have toxin  or PCR positive 
CDI at prescreening will undergo all Screening Visit assessments after providing signed informed consent. 
Subjects with one or more recurrences of CDI (including the current episode) who have responded to CDI 
antibiotic therapy defined as 10 to 42 days of treatment with vancomycin or 10 to 25 days of fidaxomicin [200 
mg] will be potentially eligible to enroll in Study SERES-013 to receive a SER-109 treatment regimen.  A SER-
109 treatment regimen is 
 administered orally in 4 capsules once daily 
for 3 consecutive days. During the screening window (Day -24 to Day -2), after informed consent is obtained, 
subjects will be assessed for eligibility and undergo physical examination. Vital signs and laboratory specimens 
will be obtained. At screening, subjects will complete a EuroQol 5 Dimension 5 Level (EQ-5D-5L) Visual 
Analog Scale. 
On Day -1, within 3 days of completion of antibiotic treatment for their CDI, subjects will undergo a bowel 
cleanse with magnesium citrate, or GoLytely if they have renal impairment, prior to scheduled allocation on 
Day 1.  
Subjects will come to the clinic on the morning of Day 1 to receive a single dose of oral SER-109 
 
in 4 capsules. On Day 1, subjects will be dispensed a 2-day supply of SER-109 
 in 4 capsules with 
instructions for home-administration of a single daily dose in the morning on Day 2 and Day 3. Subjects will be 
contacted by phone on Day 2 and Day 3 to confirm they have taken study drug and to inquire about their general 
health. If subjects have not taken study drug when contacted, they will be reminded to do so as soon as possible. 
From Day 1 to Week 8, all subjects will be contacted by phone by study site personnel weekly, with the exception 
of a home or in-clinic visit at Week 8,and queried for adverse events (AEs) and diarrheal symptoms. At the Week 
8 visit, subjects will complete the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Visual Analog Scale and the Bowel 
Cleanse Patient Satisfaction Survey Measure.  After Week 8, all subjects will be contacted by phone by study site 
personnel every 4 weeks (i.e., Weeks 12, 16, 20, and 24) and queried for serious adverse events [SAEs] and 
adverse events of special interest [AESIs]) and diarrheal symptoms. ,IGLDUUKHDOV\PSWRPVUHFXUXQIRUPHG
stools per day over 2 consecutive days), subjects will be instructed to contact the investigator and have an in-
home or clinic visit for a C. difficile stool toxin test and clinical evaluation for recurrence of CDI (Recurrence 
Visit). 
Subjects who have a confirmed CDI recurrence should continue to be followed for safety assessments through 
Week 24. Favorable clinical outcome (or Sustained clinical response) in this study will be determined by the 
absence of CDI recurrence up to 8 and 12 weeks after initiation of the SER-109 treatment regimen. CDI recurrence 
LVGHILQHGDVXQIRUPHGVWRROVSHUGD\RYHUFRQVHFXWLYHGD\VDQGWKHUHTXLUHPHQWWKDWVXEMHFWVPXVWFRQWLQXH
to have diarrhea until antibiotic treatment is initiated, with a positive C. difficile toxin assay on a stool sample and 
a decision by the investigator (based on clinical assessment), that antibiotic treatment is needed. Stool samples 
collected for suspected CDI recurrence will be processed and shipped to a central laboratory for C. difficile stool 
testing (see Laboratory Manual). The subject should not initiate antibiotics for suspected CDI prior to providing 
a stool sample for the central laboratory stool testing. Data from the C. difficile toxin test (either EIA or CCNA), 
performed at the central laboratory, will be used for the primary efficacy endpoint. The central laboratory results 
will be communicated to the investigator and the decision to treat with antibiotics will be based upon the 
investigator’s assessment. 
)
)
 (
 (

Seres Therapeutics, Inc.  
 
Protocol: SERES-013 
CONFIDENTIAL 
Amendment 8 Date:  16 February 2021  
 
Page 10 of 80 
 
 
The schedule of assessments and procedures for Cohort 2 is provided in Table 2. 
 
PLANNED NUMBER OF SUBJECTS: 
Approximately 30 adults who experienced recurrent C. difficile by Week 8 in Study SERES-012 will make up 
Cohort 1. Approximately 200 subjects will be enrolled in Cohort 2 for a total of 230 subjects across Cohorts 1 
and 2. 
PRIMARY DIAGNOSIS: Recurrent CDI 
INCLUSION CRITERIA: 
To be eligible for enrollment, a subject must meet all the following criteria before undergoing any study 
related- procedures: 
For Cohort 1: 
1. Previously enrolled in Study SERES-012 and experienced a CDI recurrence within 8 weeks after receipt 
of a treatment regimen of SER-109 or placebo in Study SERES-012 
2. Signed informed consent prior to initiation of any study-specific procedure or treatment. The subject, or 
their legally authorized representative, must be willing to provide written informed consent and 
understand the potential risks and benefits from study enrollment and treatment. 
3. The CDI recurrence in Study SERES012 must have met the protocol definition of: 
a. 
3 unformed stools per day for 2 consecutive days 
b. A positive C. difficile stool toxin assay  
c. 
The requirement of CDI SOC antibiotic therapy defined as 10 to 21 days of treatment with 
vancomycin [125 mg QID] or fidaxomicin [200 mg BID].  
d.    An adequate clinical response following SOC antibiotic therapy, defined as (<3 unformed stools in 
24 hours) for 2 or more consecutive days before initiation of study drug on Day 1. 
4. If female, subject is nonlactating, 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. 
5. If male, and partner is of childbearing potential, subject agrees to practice at least 1 highly effective 
method of birth control for the duration of the study. 
For Cohort 2 
1. Signed informed consent prior to initiation of any study-specific procedure or treatment. The subject, or 
their legally authorized representative, must be willing to provide written informed consent and 
understand the potential risks and benefits from study enrollment and treatment. 
2. HSLVRGHVRI&',LQFOXVLYHRIWKHFXUUHQWHSLVRGHZLWKestimated total number of prior episodes 
3. The CDI recurrence must have met the protocol definition of: 
a. 
 unformed stools per day for 2 consecutive days 
b. A positive C. difficile stool toxin assay or PCR test (either local or central laboratory)  
c. 
The requirement of CDI antibiotic therapy defined as 10 to 42 days of treatment with vancomycin 
or 10 to 25 days with fidaxomicin [200 mg]. It is acceptable if subject was started on metronidazole, 
switched to vancomycin or fidaxomicin and is treated for a minimum of 10 days of vancomycin or 
fidaxomicin with a total treatment duration of up to a maximum of 42 days for switch to vancomycin 
or 25 days for switch to fidaxomicin. 
d. An adequate clinical response following antibiotic therapy, defined as (<3 unformed stools in 
24 hours) for 2 or more consecutive days before initiation of study drug on Day 1. 
e. 
The requirement that the subject can be dosed with study drug within 4 days of antibiotic 
completion 
4. Male or Female Subject  18 years of age  

Seres Therapeutics, Inc.  
 
Protocol: SERES-013 
CONFIDENTIAL 
Amendment 8 Date:  16 February 2021  
 
Page 11 of 80 
 
5. If female, subject is nonlactating, 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 1 highly effective 
method of birth control for the duration of the study. 
7. If currently taking probiotics, must be willing to stop at time of consent, for the duration of the study. 
EXCLUSION CRITERIA: 
A subject will not be enrolled if the subject meets any of the following criteria: 
For Cohort 1: 
1. Female subjects who are pregnant, breastfeeding, lactating, or planning to become pregnant during the 
study. 
2. Known or suspected toxic megacolon and/or known small bowel ileus. 
3. Admitted to or expected to be admitted to an intensive care unit for medical reasons (not just boarding). 
Note: nursing homes, rehabilitation, assisted living centers and acute care hospitals are acceptable. 
4. Absolute neutrophil count of <500 cells/mm3 
5. Taking antibacterial therapy other than antibiotics for the most recent episode of CDI during the 
screening period (a single-day antibiotic prophylactic regimen is permitted), or projected to receive 
antibiotics during the 8-week period post-randomization.  
6. Major gastrointestinal surgery (e.g., significant bowel resection or diversion) within 3 months before 
enrollment (this does not include appendectomy or cholecystectomy), or any history of total colectomy 
or bariatric surgery. (bariatric surgery which does not disrupt the gastrointestinal lumen, i.e., restrictive 
procedures such as banding, are permitted). 
7. History of active inflammatory bowel disease (ulcerative colitis, Crohn’s disease, microscopic colitis) 
with diarrhea believed to be caused by active inflammatory bowel disease in the past3 months. 
8. Unable to stop loperamide, diphenoxylate/atropine, or cholestyramine prior to start of study. 
9. Unable to stop opiate treatment unless on a stable dose, including PRN dosing, as of the onset of 
diarrhea and no increase in dose planned for the duration of the study. Note: Short term (One day) 
opiate use is permitted (e.g., for a dental extraction). 
10. Known positive stool cultures for other enteropathogens including, but not limited to, Salmonella, 
Shigella, and Campylobacter within the 30 days before enrollment.  
11. Known stool studies positive for ova and/or parasites within the 30 days before enrollment.  
12. Poor concurrent medical risks with clinically significant co-morbid disease such that, in the opinion of 
the investigator, the subject should not be enrolled. 
13. Received a human monoclonal antibody against C. difficile toxin within 3 months before study entry. 
14. Received an investigational drug or vaccine, or participated in any experimental procedure within 
1 month (3 months for monoclonal antibodies) before study entry. 
15. Any history of immunoglobulin (IgG) replacement therapy within the past 3 months. 
16. Any history of fecal microbiota transplantation (FMT) in the past 3 months. 
17. Known active intravenous drug or alcohol abuse or use of other drugs of abuse. 
18. Concurrent intensive induction chemotherapy, radiotherapy, or biologic treatment for active 
malignancy (subjects on maintenance chemotherapy may only be enrolled after consultation with the 
study medical monitor). 
19. Unable to comply with the protocol requirements, including the ability to take oral drugs; or any 
condition that, in the opinion of the investigator, might interfere with study objectives. 
20. Life expectancy is 24 weeks or less. 
For Cohort 2 (all Cohort 1 exclusion criteria plus number 21 below apply) 
21. Previously enrolled in a Seres Therapeutics clinical study. An exception is made for subjects who 
screened in SERES-012 who did not receive SER-109 and did not previously roll-over to SERES-013.  

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Protocol: SERES-013 
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Amendment 8 Date:  16 February 2021  
 
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x 
Change in the composition of the gut microbiome from Baseline up to 1, 2, 8, and 24 weeks after 
initiation of treatment 
x 
Change in the fecal metabolome from Baseline up to 1, 2, and 8 weeks after initiation of treatment 
x 
Incidence of mortality from all causes up to 8 and 24 weeks after initiation of treatment  
x 
Incidence of hospitalizations for recurrent CDI up to 8 and 24 weeks after initiation of treatment 
x 
Incidence of all hospitalizations up to 8 and 24 weeks after initiation of treatment  
x 
Total length of stay (days) of hospitalization, including days in the intensive care unit, up to 8 and 
24 weeks after treatment initiation (for subjects hospitalized) 
x 
Changes from Baseline in Health-Related Quality of Life (HRQoL) and health outcomes as assessed 
by the EQ-5D-5L up to Week 24, and assessed by the Cdiff32 HRQoL from  up to Week 8, or at an 
ET or Recurrence visit prior to Week 8, after initiation of treatment  
Safety Endpoints 
x 
Incidence of AEs 
x 
Laboratory evaluation results 
x 
Vital sign measurements  
x 
Physical examination findings 
 
Study Endpoints for Cohort 2 
Primary Safety Endpoints 
x 
Incidence of AEs 
x 
Laboratory evaluation results 
x 
Vital sign measurements 
x 
Physical examination findings 
Efficacy Endpoint 
x 
Recurrence of CDI and sustained clinical response as determined by a toxin assay up to 8 and 12 
weeks after initiation of treatment  
x 
There are no secondary endpoints 
Exploratory Endpoints 
x 
Change in the composition of the gut microbiome from Baseline up to 1 week after initiation of 
treatment in a subgroup of subjects 
x 
Change in the fecal metabolome from Baseline up to 1 week after initiation of treatment in a 
subgroup subjects 
x 
Incidence of mortality from all causes up to 8 and 24 weeks after initiation of treatment  
x 
Incidence of hospitalizations for recurrent CDI up to 8 and 24 weeks after initiation of treatment 

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Protocol: SERES-013 
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Amendment 8 Date:  16 February 2021  
 
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x 
Incidence of all hospitalizations up to 8 and 24 weeks after initiation of treatment  
x 
Total length of stay (days) of hospitalization, including days in the intensive care unit, up to 8 and 
24 weeks after treatment initiation (for subjects hospitalized) 
x 
Change in EQ-5D-5L visual analog score from Screening to Week 8 visit after initiation of treatment 
x 
Assess Bowel Cleanse Patient Satisfaction Survey Measure at Week 8  
Analysis of Primary Efficacy Endpoint:  
In Cohort 1, the primary efficacy outcome is the recurrence of CDI determined by a toxin assay through Week 8 
after receipt of a SER-109 treatment regimen in the ITT Population. Subjects will be categorized as having 
favorable (sustained clinical response) (no CDI recurrence) or unfavorable outcomes (had CDI recurrence). Rules 
for imputing CDI recurrence status for subjects with missing data will be provided in the Statistical Analysis Plan 
(SAP).   
The number and percentage of subjects defined as having favorable and unfavorable outcomes will be reported 
with exact 95% confidence intervals (CIs) for subjects who were randomized to SER-109 and placebo in 
SERES-012 separately, as well as both groups combined. The CIs will be derived using the Clopper-Pearson 
exact method. 
In Cohort 2, the efficacy outcome is the recurrence of CDI determined by a toxin assay through Week 8 and 12  
after receipt of a SER-109 treatment regimen in the ITT Population. Subjects will be categorized as having 
favorable (sustained clinical response) (no CDI recurrence) or unfavorable outcomes (had CDI recurrence). Rules 
for imputing CDI recurrence status for subjects with missing data will be provided in the Statistical Analysis Plan 
(SAP).   
The number and percentage of subjects defined as having favorable and unfavorable outcomes will be reported 
with exact 95% confidence intervals (CIs) derived using the Clopper-Pearson exact method. 

 
Seres Therapeutics, Inc.  
 
 
 
 
 
Protocol SERES-013 
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Amendment 8 Date:16 February 2021 
 
 
 
 
 
 
 
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h The stool sample collected on Day -1 should be collected prior to the bowel cleanse and may be brought to the study site for the Day 1 visit. The stool samples 
collected on Week 8 (in clinic visit) may be collected at home prior to the visit and brought to the study site. If the subject is unable to bring the sample to the 
study site at any other visit, a courier may be arranged to pick up the sample at the subject's home and bring it to the study site.  
i Administer if prior to Week 8 visit. 
j  As necessary for safety of subject, study visits including Week 2, Week 8, Unscheduled, and Early Termination, may be conducted remotely at subject’s home, 
with qualified nurse or site personnel who will be appropriately documented on the site’s delegation log to perform these Remote Study Visits and associated 
procedures (Modification due to COVID-19 pandemic). If a nurse or site personnel cannot perform the visits, a telephone call or a video conference (Zoom, 
Skype, FaceTime, etc.) should be conducted in place of the Week 2, Week 8, Unscheduled, and Recurrence / Early Termination visits and must be documented in 
the source. Any required procedures not performed during a remote visit at the subject’s home will be documented as a protocol deviation by site staff. 
k When visits are conducted over the phone, transcription of the EQ-5D-5L may be performed over the phone by site staff. The discussion with the subject must 
be documented in source files. (Modification due to COVID-19 pandemic). 

 
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Amendment 8 Date:16 February 2021 
 
 
 
 
 
 
 
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 Abbreviations: Abx=antibiotics; AE=adverse event; C.diff=Clostridioides difficile; ET=early termination; FBMR=future biomedical research; HRQoL=Health-
Related Quality of Life; IxRS=interactive voice and web response system; ; TC=telephone call; WOCBP=women of childbearing potential 
a Subjects with a confirmed CDI recurrence after Week 8 should continue to be followed for safety assessments through Week 24. 
b Phone call:  Confirm termination of antibiotics on day of last scheduled antibiotic dose and review instructions for Day -1 activities including collection of a stool 
sample before beginning the magnesium citrate or GoLytely (polyethylene glycol electrolyte solution) bowel cleanse. All subject should be reminded to collect 
a stool sample collected at Day -1 will be returned to the clinic on Day 1  
c Subjects should be called on Day 2 and Day 3 to confirm they have taken study drug and to inquire about their general health 
d Blood pressure, pulse, respiratory rate, and body temperature  
e To be assessed immediately before and approximately 30 minutes after study drug dosing 
f To be assessed prior to study drug dosing 
g If termination visit precedes 8 weeks, safety laboratory tests and EQ-5D-5L Visual Analog Scale and Bowel Cleanse Patient Satisfaction Survey Measure will 
be obtained at this visit 
h For all visits performed remotely by a telephone contact, a standardized script will be used to ask about the subject’s general health, AEs, concomitant 
medications and to perform a diarrhea assessment 
iStool sample will be collected for all subjects at Day -1 and brought to the clinic at the Day 1 visit.   In a subgroup of subjects who consent, a stool specimen 
obtained at Week 1 may be couriered or brought in to the study site 
j If a nurse or site personnel cannot perform the visits, a telephone call or a video conference (Zoom, Skype, FaceTime, etc.) should be conducted in place of the 
Week 8, Unscheduled, and Recurrence / Early Termination visits and must be documented in the source. Any required procedures not performed during a remote 
visit at the subject’s home will be documented as a protocol deviation by site staff. 
kSubjects may sign a pre-screening consent to obtain stool specimen for toxin or PCR assay at Local or Central Laboratory. Prescreening may be repeated but 
requires a separate consent and a new subject number. Note that Central Laboratory will only perform PCR test on qualifying CDI  
 
 
 

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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
PROTOCOL SYNOPSIS .............................................................................................6 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............24 
3. 
LIST OF ACRONYMS, ABBREVIATIONS, AND DEFINITIONS OF 
TERMS .......................................................................................................................28 
4. 
INTRODUCTION ......................................................................................................30 
4.1. 
Summary of Clinical Efficacy and Safety ..................................................................31 
4.2. 
Rationale .....................................................................................................................35 
4.2.1. 
Rationale for Dose and Treatment Regimen ..............................................................36 
4.2.2. 
Rationale for Endpoints and C. difficile Diagnostic Criteria ......................................36 
5. 
STUDY OVERVIEW .................................................................................................38 
5.1. 
Trial Conduct ..............................................................................................................38 
6. 
STUDY OBJECTIVES ..............................................................................................42 
6.1. 
Primary Efficacy Objective ........................................................................................42 
6.2. 
Secondary Efficacy Objectives ...................................................................................42 
6.3. 
Primary Safety Objective ............................................................................................42 
6.4. 
Exploratory Efficacy Objectives .................................................................................42 
6.5. 
Primary Safety Objective ............................................................................................43 
6.6. 
Efficacy Objectives .....................................................................................................43 
6.7. 
Exploratory Objectives ...............................................................................................43 
7. 
STUDY ENROLLMENT AND WITHDRAWAL ....................................................44 
7.1. 
Inclusion Criteria ........................................................................................................44 
7.2. 
Exclusion Criteria .......................................................................................................45 
7.3. 
Subject Monitoring and Withdrawal ..........................................................................47 
7.3.1. 
Reasons for Withdrawal .............................................................................................47 
7.3.2. 
Handling of Withdrawals and Discontinuations of Treatment ...................................47 
7.3.3. 
Lost to Follow-up .......................................................................................................47 
7.3.4. 
Termination of Study ..................................................................................................47 
8. 
INVESTIGATIONAL PRODUCT ............................................................................47 
8.1. 
SER-109 ......................................................................................................................47 

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8.1.1. 
Donor Screening .........................................................................................................47 
8.1.2. 
Manufacturing and Storage .........................................................................................48 
8.2. 
SER-109 Kit Storage and Handling ............................................................................48 
8.3. 
Compliance .................................................................................................................48 
8.4. 
Method of Assigning Patients to Study Treatment .....................................................48 
8.5. 
Maintaining the Randomization Codes and Breaking the Study Blind ......................48 
8.6. 
Concomitant Medications ...........................................................................................49 
8.6.1. 
Prohibited Concomitant Medications and Procedures ................................................49 
8.7. 
Criteria for Confirmed  Clostridioides difficile Recurrence 
Post-Randomization ....................................................................................................49 
9. 
STUDY PROCEDURES ............................................................................................50 
9.1. 
Duration of Participation ............................................................................................50 
9.2. 
Medical History ..........................................................................................................50 
9.3. 
Physical Examination .................................................................................................50 
9.4. 
Body Weight ...............................................................................................................50 
9.5. 
Vital Signs ..................................................................................................................50 
9.6. 
Laboratory Assessments .............................................................................................51 
9.6.1. 
Hematology and blood chemistry ...............................................................................51 
9.6.2. 
Urinalysis ....................................................................................................................51 
9.6.3. 
Pregnancy Testing ......................................................................................................51 
9.7. 
Stool Sample Collection and Analysis .......................................................................52 
9.8. 
Biological Specimen Collection for Future Biomedical Research .............................52 
9.9. 
Monitoring of Diarrheal Symptoms and General Health ...........................................53 
9.10. 
Health Outcome Assessment ......................................................................................53 
9.11. 
Quality of Life Assessment ........................................................................................53 
9.12. 
Clinical Response Evaluation .....................................................................................54 
10. 
STUDY SCHEDULE .................................................................................................54 
10.1. 
Screening Period .........................................................................................................55 
10.1.1. 
Clinic Visit (Day -24 to Day -2) .................................................................................55 
10.1.2. 
Pre-treatment Preparation Phone Call Visit (Day -4 to -2) .........................................57 
10.1.3. 
Pre-treatment Preparation Phone Call Visit (Day -1) .................................................57 
10.2. 
Efficacy Period ...........................................................................................................58 
10.2.1. 
Clinic Visit (Day 1) ....................................................................................................58 

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10.2.1.1. 
Before Administering Study Drug (Pre-dose) ............................................................58 
10.2.1.2. 
Administering Study Drug ..........................................................................................59 
10.2.1.3. 
After Administering Study Drug (Post-dose): ............................................................59 
10.2.2. 
Phone Call Visit (Day 2) .............................................................................................59 
10.2.3. 
Phone Call Visit (Day 3) .............................................................................................60 
10.2.4. 
Phone Call Visit (Week 1) ..........................................................................................60 
10.2.5. 
Clinic or Home Visit (Week 2) ...................................................................................61 
10.2.6. 
Phone Call Visits (Weeks 3-7) ...................................................................................61 
10.2.7. 
End of Efficacy Period Clinic Visit (Week 8) ............................................................62 
10.3. 
Follow-up Period ........................................................................................................62 
10.3.1. 
Phone Call Visits (Every 4 Weeks) ............................................................................62 
10.3.2. 
Phone Call Visit - Study Completion (Week 24) .......................................................63 
10.3.3. 
Recurrence and Early Termination (ET) Visits ..........................................................63 
11. 
ASSESSMENT OF SAFETY AND ADVERSE EVENT REPORTING ..................65 
11.1. 
Serious Adverse Event Reporting ...............................................................................68 
12. 
STATISTICAL METHODS .......................................................................................69 
12.1. 
STUDY ENDPOINTS ................................................................................................69 
12.1.1. 
Primary Efficacy Endpoint .........................................................................................69 
12.1.2. 
Secondary Efficacy Endpoints ....................................................................................69 
12.1.3. 
Exploratory Efficacy Endpoints .................................................................................69 
12.1.4. 
Safety Endpoints .........................................................................................................70 
12.2. 
Analysis Populations ..................................................................................................70 
12.3. 
Determination of Sample Size ....................................................................................71 
12.4. 
General Statistical Considerations ..............................................................................71 
12.5. 
Subject Population and Baseline Characteristics ........................................................71 
12.6. 
Study Drug Exposure ..................................................................................................71 
12.7. 
Efficacy Analysis ........................................................................................................71 
12.7.1. 
Primary Efficacy Analysis ..........................................................................................71 
12.7.2. 
Sensitivity Analysis for the Primary Efficacy Endpoint .............................................72 
12.7.3. 
Secondary Efficacy Analysis (applies to Cohort 1 only) ............................................73 
12.8. 
Exploratory Analysis ..................................................................................................73 
12.9. 
Safety Analysis ...........................................................................................................73 
12.10. 
Handling of Missing Data ...........................................................................................74 

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13. 
ADMINISTRATIVE REQUIREMENTS ..................................................................75 
13.1. 
Good Clinical Practice ................................................................................................75 
13.2. 
Trial Governance and Oversight .................................................................................75 
13.3. 
Ethical Considerations ................................................................................................75 
13.4. 
Subject Information and Informed Consent ...............................................................76 
13.5. 
Subject Confidentiality ...............................................................................................76 
13.6. 
Protocol Compliance ..................................................................................................76 
13.7. 
Future Use of Stored Specimens .................................................................................76 
13.8. 
Study Monitoring ........................................................................................................76 
13.9. 
Case Report Forms and Study Records ......................................................................77 
13.10. 
Study Completion .......................................................................................................78 
14. 
LIST OF REFERENCES ............................................................................................79 
 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments and Procedures for Cohort 1 ..............................................15 
Table 2: 
Schedule of Assessments and Procedures for Cohort 2 ..............................................20 
 

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3. 
LIST OF ACRONYMS, ABBREVIATIONS, AND DEFINITIONS 
OF TERMS 
 
AE 
Adverse Event 
Abx 
Antibiotics 
AESI 
Adverse Event of Special Interest 
BMI 
Body Mass Index 
CCNA 
Cell Cytotoxicity Neutralization Assay  
CDI 
Clostridioides difficile infection 
C. difficile or C. diff Clostridioides difficile 
Cdiff32 HRQoL 
Clostridium difficile (CDiff32) Health-Related Quality of Life Survey 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CLIA 
Clinical Laboratory Improvement Amendment 
CMH 
Cochran-Mantel-Haenszel 
DSMC 
Data Safety Monitoring Committee 
eCRF 
electronic Case Report Form 
EAIR 
exposure-adjusted incidence rates 
EIA 
Enzyme immunoassay 
ET 
Early Termination 
EQ-5D-5L 
EuroQol 5 Dimensions 5 Level 
FDA 
Food and Drug Administration 
FMT 
Fecal microbiota transplantation 
GCP 
Good Clinical Practice  
GMP 
Good Manufacturing Practice 
GDH 
Glutamate dehydrogenase 
GI 
Gastrointestinal 
HRQoL 
Health-Related Quality of Life 
IBS 
Irritable Bowel Syndrome 
ICF 
Informed Consent Form  
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 

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IRB 
Institutional Review Board 
ISC 
Independent Statistical Center 
ITT 
Intent-to-Treat 
IxRS 
Interactive voice and web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified Intent-to-Treat 
NAAT 
Nucleic acid amplification testing 
OTU 
Operational taxonomic unit 
PCR 
Polymerase Chain Reaction 
PP 
Per-Protocol 
RCDI 
Recurrent Clostridioides difficile infection 
RR 
Relative risk 
SAE 
Serious adverse event 
SAER 
Serious adverse event report  
SAP 
Statistical Analysis Plan 
 
 
SOC 
Standard of care 
 
 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
WOCBP 
Women of childbearing potential 
 
 
 

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4. 
INTRODUCTION  
Clostridioides difficile is a sporeforming Gram-positive anaerobe present throughout the 
environment and, in low amounts, can be a component of the gut flora of a healthy individual. 
Clostridioides difficile infection (CDI) usually develops in patients with a history of antibiotic use 
that depletes the normal gut flora, enabling C. difficile to colonize and proliferate within the colon, 
elaborating virulent toxins A and B. These toxins invade epithelial cells disrupting their 
cytoskeleton, resulting in damage to the epithelial barrier and promoting mucosal inflammation. 
The clinical manifestations of CDI vary broadly, ranging from nuisance diarrhea lasting a few 
days, to more pronounced disease with severe colonic inflammation that can develop into 
pseudomembranous colitis with associated systemic toxicity requiring lifesaving colectomy. 
With ever increasing use of antibiotics, particularly in the aging populations in hospitals and in 
nursing homes, the incidence of C. difficile -associated disease has been increasing such that 
C. difficile is the leading cause of nosocomial infection in the United States (US). The Centers for 
Disease Control and Prevention estimate that C. difficile causes diarrhea linked to approximately 
29,000 American deaths each year (Lessa et al, 2015). In Canada, there are approximately 37,900 
CDI episodes each year (2012); 7980 (21%) of these are relapses (Levy, 2015). In the European 
Union (EU), the number of reported cases of CDI has also increased in recent years, and is 
estimated to affect 172,000 patients per year. 
Clostridioides difficile spores can survive for months in hospitals and long term care facilities 
where they can cause repeated CDI episodes. Virtually all antibiotics have been implicated in 
association with CDI. The mechanistic link to antibiotic use is based on the finding that a healthy 
microbial ecology resists pathogen colonization by competing for nutrients and resources in the 
gut (Theriot et al, 2014; Weingarden- et al, 2014). Antibiotic use disrupts the microbiota and 
liberates nutrients that enable colonization by C. difficile (Ng et al, 2013).  
The incidence of recurrent CDI has paralleled the increased incidence of primary infection. CDI 
recurs in approximately 25% of patients after antibiotic treatment for first time disease (Bakken et 
al, 2011; Depestel and Aronoff, 2013; Surawicz- et al, 2013). After the first recurrent episode, 
patients are at an even higher risk for subsequent CDI, estimated to be > 60% after the second or 
subsequent episode (Higa and Kelly, 2013). There are few proven, approved therapeutic options 
for significantly reducing CDI recurrence in patients with recurrent CDI. Some patients are treated 
with antibiotics indefinitely to avoid persistent diarrhea and other sequelae of CDI. 
SER-109 is an Ecobiotic drug being developed for the treatment of adults with recurrent CDI. 
SER-109 is an ecology of bacteria in spore form, enriched from stool donations obtained from 
healthy, screened donors. The bacterial spores are enriched by thorough killing of the vegetative 
microorganisms, then fractionating the resulting spore population away from inactive components 
and formulating and encapsulating the spores for oral delivery. SER-109 is administered to 
subjects after completion of a course of antibiotic therapy for recurrent CDI.  
SER-109 has been shown to prevent CDI and to treat C. difficile relapse in nonclinical studies in 
mice and hamsters (see Investigator’s Brochure for more information). Clinical experience with 
SER-109 includes four studies: 1) a completed open-label, two-part study in 30 subjects with a 
history of 3 or more occurrences of CDI (SERES-001); 2) a completed double-blind, placebo-
controlled, parallel-group study in adults with recurrent CDI (SERES-004); 3) a completed 
expanded access for intermediate-size patient populations and open-label extension of study 

)

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and 12/15 (80.0%) subjects randomized to receive placebo. Overall, of the 42 subjects who met 
the primary endpoint of CDI recurrence by Week 8, 35 subjects discontinued the study due to their 
CDI recurrence prior to Week 8. Of the 35 subjects who discontinued the study due to a CDI 
recurrence prior to Week 8, 34 enrolled in the open-label extension study SERES-005. 
In Study SERES-004, a total of 66 of the 89 subjects randomized (74.2%), 46 of the 60 (76.7%) 
subjects who received SER-109 and 20 of the 29 (69.0%) subjects who received placebo, 
experienced at least 1 TEAE. Fifteen of the 89 (16.9%) subjects, 11 of the 60 (18.3%) subjects 
who received SER-109 and 4 of the 29 (13.8%) subjects who received placebo, experienced at 
least 1 TEAE that was considered by the investigators to be drug-related. Like Study SERES-001, 
the most commonly reported SOC was GI disorders (55% in the SER-109 group and 44.8% in the 
Placebo group). The most commonly reSRUWHGLQFLGHQFHSUHIHUUHGWHUPV in the GI SOC 
reported in subjects who received SER-109 were diarrhea, abdominal pain, flatulence, nausea, and 
constipation. The majority of TEAEs were mild or moderate in severity. Six of the 60 (10%) 
subjects who received SER-109 experienced an event that has been reported as severe. Twelve of 
the 89 (10.1%) subjects enrolled (9 subjects who received SER-109 [15%] and 3 subjects who 
received placebo [10.3%] have experienced a total of 43 treatment-emergent SAEs, none of which 
were considered to be drug-related by the investigator. One subject had an SAE (metastatic non-
small cell lung cancer) that was fatal and led to study withdrawal.  
SERES-005 began as an open-label extension study of SERES-004 conducted in the U.S, offered 
to subjects who received an investigational product in SERES-004, but recurred prior to 8-weeks 
post-treatment. In April 2016, the study was amended to include expanded access to an 
intermediate-size patient population of adults, 18 years of age or older with recurrent CDI, for 
whom there is no comparable or alternative therapy. Seventy-two subjects, 34 who enrolled from 
Study SERES-004 and 38 who enrolled under expanded access met the eligibility criteria for the 
study. The primary efficacy objective was to evaluate CDI recurrence rates in adults up to 8 weeks 
post-treatment with SER-109. The primary safety objective was to evaluate the safety and 
tolerability of SER-109 in adults with recurrent CDI.  
Overall, CDI recurrence was observed within 8 weeks post-treatment in 38.9% (28/72) of subjects, 
including 52.4% (11/21) in the SERES-004 SER-109 group, 15.4% (2/13) in the SERES-004 
Placebo group, and 39.5% (15/38) in the Expanded Access group. Among the 58 subjects treated 
with vancomycin followed by SER-109, CDI recurrence within 8 weeks post-treatment was 
observed in 41.4% (24/58). Among the 13 subjects treated with fidaxomicin followed by SER-
109, CDI recurrence was observed within 8 weeks post-treatment in 30.8% (4/13) of subjects. 
$PRQJVXEMHFWV\HDUVROG&',RFFXUUHGLQVXEMHFWVDQGLQWKRVH\HDUV
old, CDI occurred 12/28 subjects (42.9%).  Hospitalizations overall occurred in 9 (12.5%), 10 
(13.9%), and 12 (16.7%) subjects by 8, 12, and 24 weeks, respectively. All four (5.6%) 
hospitalizations for CDI occurred within the first 8 weeks. 
Overall, 55 (76.4%) subjects had 241 TEAEs. Seven (7) subjects had 11 study-drug related or 
possibly related AEs.  Eleven subjects experienced 21 SAEs. There was a tendency for more 
VXEMHFWVZLWK6$(VLQWKRVH\HDUVROGWKDQWKRVH\HDUVROG, 20.5% vs. 7.1%, respectively. 
None were drug-UHODWHGRUSRVVLEO\UHODWHG(LJKWVXEMHFWVDOO\HDUVROGKDGVHYHUH7($(V
)RXUVXEMHFWVDOO\HDUVold had TEAEs leading to study withdrawal. The most frequently 
affected system organ class (SOC) was gastrointestinal (GI) accounting for 52.8% of events with 
preferred terms diarrhea, abdominal pain, constipation, nausea, flatulence, vomiting followed by 

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Infections and infestations (36.1%) with preferred terms urinary tract infection, nasopharyngitis, 
and cellulitis. Overall, most events were of mild or moderate intensity: 33.3% of subjects had 
TEAEs that were mild in intensity, 31.9% subjects had at least TEAE of moderate intensity. 
Related events mainly affected the GI SOC. 
Eleven subjects had 21 SAEs leading to three of four deaths and study discontinuation. One subject 
had 8 SAEs: diastolic congestive heart failure, myocardial infarction, left face zoster shingles, 
severe sepsis and septic shock, cerebrovascular accident, pneumonia and aspiration pneumonia. 
Myocardial infarction, cerebrovascular accident and aspiration pneumonia were fatal. One subject 
had inflammatory diarrhea and sepsis that was fatal. One subject had dehydration and 
cerebrovascular accident that was fatal. One subject had C. difficile colitis that was fatal. All SAEs 
were not considered related to study drug. 
Of the other SAEs, 3 were severe including diarrhea related to C. difficile, recurrent syncope, and 
CDI recurrence, and 4 were moderate in intensity including lumbar compression fracture, diarrhea, 
hyperkalemia and exacerbation of end-stage renal disease, and pancolitis. These SAEs and fatality 
rates are consistent with those expected in the study population with multiple comorbidities. 
SERES-012 was a stratified, randomized, double-blind placebo-controlled Phase 3 study, that 
enrolled subjects with recurrent CDI defined as 2 or more recurrences of CDI in the previous 12 
months. Subjects were stratified by age (<\HDUV 65 years) and antibiotic treatment of the 
qualifying CDI (vancomycin; fidaxomicin), and were randomized in a 1:1 ratio to SER-109 
administered as 4 capsules (
) for 3 consecutive days or identical appearing placebo 
after administration of a bowel cleanse on completion of antibiotics. The primary objective was to 
demonstrate the superiority of SER-109 vs. placebo in reducing recurrences by eight weeks, as 
determinHGE\V\PSWRPVXQIRUPHGERZHOPRYHPHQWVIRUGD\V and by using toxin detection 
by EIA, reflexing to CCNA. Investigator assessment that the subject required treatment must also 
have been met. 
This is a summary from the interim analysis dataset. The majority of the 182 subjects were female 
(n = 109; 59.9%). Most of them were white (n = 170; 93.4%). The mean age was 65.5 years and 
VXEMHFWVZHUH\HDUVRIDJH There were more females in the SER-109 group 
62/90 (68.9%) vs. 47/92 (51.1%) and there were fewer subjects with a second recurrence in the 
SER-109 group (56.7%) vs. placebo group (64.1%). Other demographic and baseline 
characteristics were similar between the two groups. 
The study met the primary endpoint of reducing the relative risk of CDI recurrence by toxin assay 
up to 8 weeks following dosing in the ITT population. Overall, recurrence of CDI up to 8 weeks 
post-treatment was observed in 48 of 182 (26.4%) subjects of all subjects enrolled. Ten (10) of the 
90 (11.1 %) subjects randomized to receive SER-109, and 38 of the 92 (41.3%) subjects 
randomized to receive placebo experienced a CDI recurrence prior to Week 8. The relative risk of 
CDI recurrence in the SER-109 versus placebo arm up to Week 8 was 0.27 (95% CI: 0.15 to 0.51) 
and the absolute difference in recurrence rates was 30.2%. Sustained clinical response was 
observed in 80 of 90 (88.9%) SER-109 subjects and 54 of 92 (58.7%) placebo subjects. 
With regard to age < 65 years, recurrence was observed by Week 8 in 2/40 (5.0%) subjects 
randomized to receive SER-109 and 13/40 (32.5%) subjects randomized to receive placebo 
(relative risk of CDI recurrence in the SER-109 versus placebo arm up to Week 8 was 0.15 [95% 
&,WR@)RUDJH\HDUVUHFXUUHQFHZDVREVHUYHGE\:HHN 8 in 8/50 (16.0%) subjects 

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randomized to receive SER-109 and 25/52 (48.1%) subjects randomized to receive placebo 
(relative risk of CDI recurrence in the SER-109 versus placebo arm up to Week 8 was 0.33 [95% 
CI: 0.17 to 0.67]). With regard to the prior antibiotic vancomycin regimen, recurrence was 
observed by Week 8 in 9/65 (13.8%) subjects randomized to receive SER-109 and 27/68 (39.7%) 
subjects randomized to receive placebo (relative risk of CDI recurrence in the SER-109 versus 
placebo arm up to Week 8 was 0.35 [95% CI: 0.18 to 0.68]). For the prior antibiotic fidaxomicin 
regimen, recurrence was observed by Week 8 in 1/25 (4.0%) subjects randomized to receive SER-
109 and 11/24 (45.8%) subjects randomized to receive placebo (relative risk of CDI recurrence in 
the SER-109 versus placebo arm up to Week 8 was 0.09 [95% CI: 0.01 to 0.63]). 
 Overall, 168 of the 182 subjects (92.3%) experienced at least 1 TEAE. Eighty-four (84) of the 90 
(93.3%) subjects who received SER-109 experienced a total of 529 TEAEs, and 84 of the 92 
(91.3%) subjects who received placebo experienced a total of 598 TEAEs. Overall, 94 of the 182 
(51.6%) subjects experienced a total of 452 TEAEs that were considered by the Investigator to be 
related or possibly related to study drug – 51.1% in the SER-019 group and 52.2% in the placebo 
group. Fifteen (15) of the 90 (16.7%) subjects who received SER-109 experienced a total of 26 
treatment-emergent SAEs and 19 of the 92 (20.7%) subjects who received placebo experienced a 
total of 32 treatment-emergent SAEs. Four (4) of the 90 (4.4%) subjects who received SER-109 
experienced a total of 4 treatment-emergent adverse events of special interest ( for example, blood 
stream infection, meningitis, abscess) (AESI) and 3 of the 92 (3.3%) subjects who received placebo 
experienced a total of 3 treatment-emergent AESIs. None of these SAEs or AESIs were considered 
related to investigational product by the Investigator.  Three deaths were outcomes of SAEs, all in 
the SER-109 group, consisting of worsening glioblastoma, atrial fibrillation and sepsis, and 
subdural hematoma after a fall.  
7KHPRVWFRPPRQO\UHSRUWHGLQFLGHQFHSUHIHUUHGWHUPVLQERWKWUHDWPHQWJURXSVZHUH
flatulence, abdominal distension, abdominal pain, constipation, diarrhea, nausea, fatigue, chills, 
DQGGHFUHDVHGDSSHWLWH,QDGGLWLRQWKHFRPPRQO\UHSRUWHGLQFLGHQFHSUHIHUUHGWHUPVZHUH
urinary tract infection in subjects who received SER-109; and vomiting and C. difficile colitis in 
subjects who received placebo. A larger number of some GI AEs in the placebo group may be 
because of the higher rate of recurrences in that group, Overall, the safety profile was similar 
between SER-109 and placebo recipients.  
Thus, clinical experience to date suggests that SER-109 is well-tolerated with an acceptable safety  
profile. Overall, there have been no drug-related treatment-emergent SAEs and the majority of 
related TEAEs have been mild or moderate in severity and most commonly associated with the 
gastrointestinal tract. Additional information regarding clinical experience with SER-109 can be 
found in the Investigator’s Brochure. 
Although safety data with SER-109 has been relatively consistent across studies, efficacy data in 
the placebo-controlled Study SERES-004 was inconsistent with results from the open-label Study 
SERES-001. There are a number of factors that may explain why the primary endpoint of reducing 
the relative risk of CDI recurrence at up to 8-weeks was not achieved in Study SERES-004. First, 
the diagnostic test for entry may not have differentiated subjects with active CDI disease from 
those with C. difficile carriage. This would have led to enrolling subjects who may have been 
experiencing post-CDI irritable bowel syndrome (IBS)-like symptoms but, were only colonized 
by C. difficile and did not have an active infection. These subjects may not have been distributed 
equally between the treatment arms. Additionally, the diagnostic test for recurrences which 

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primarily used polymerase chain reaction testing (PCR), also known as nucleic acid amplification 
testing (NAAT), which could have overestimated recurrences during the trial.  Finally, although 
analysis of the microbiome identified that SER-109 in SERES-004 was biologically active, the 
dose administered in Phase 2 may not have been optimal for efficacy (see rationale below).  Both 
changing the dose and definition of recurrence in SERES-012 likely led to a more robust and well-
controlled trial, with statistically significant and clinically meaningful improvement observed. 
4.2. 
Rationale  
There are few proven, approved therapeutic options for significantly reducing CDI recurrence in 
patients with recurrent CDI.   
This study is being conducted primarily to gather safety and tolerability data as well as efficacy 
from subjects exposed to SER-109 at the dose used in SERES-012. In addition to subjects rolling 
over from SERES-012 (Cohort 1), subjects with first recurrence or more will be eligible for Cohort 
2. There are no data to suggest differences in safety profile in subjects with at least one recurrence 
versus those with at least two recurrences. In a Phase 3b/4 study that described safety in groups 
with 0, 1, or 2 recurrences, there were no differences when comparing an extended pulsed course 
of fidaxomicin with vancomycin (Cornely 2019). 
 
Extended FID 
Vancomycin 
Number 
randomized 
181 
181 
Number 
preceding 
CDI episodes 
0 
1 
2 
0 
1 
2 
N in group 
141 
26 
10 
140 
29 
10 
N with AEs 
(%) 
94 (67) 
19 (73) 
8 (80) 
101 (72) 
18 (62) 
9 (90) 
N with SAEs 
(%) 
58 (41) 
7 (27) 
3 (30) 
61 (44) 
11 (38) 
5 (50) 
N with deaths 
(%) 
25 (18) 
1 (4) 
2 (20) 
32 (23) 
3 (10) 
1 (10) 
 
The majority of subjects enrolled in the trial were having their first occurrence of CDI.  Those with 
first and second recurrence make up a small proportion of subjects.  However, there does not 
appear to be an increased AE, SAE, or death rate going from first occurrence to second and third 
occurrences.  These data support inclusion of first recurrence (second occurrence) subjects in the 
larger safety population.  Enrollment of patients with first CDI recurrence will allow participating 
centers to present the protocol to a higher number of subjects, who previously did not qualify.  
The reason to require toxin testing in the pivotal efficacy study was to ensure exclusion of carriers 
which could potentially be imbalanced across treatment arms.  However, this significantly limited 
availability of treatment to a population in whom toxin testing was available.  Inclusion criteria 
have been broadened to allow evaluation of safety and tolerability in subjects who may receive 
SER-109 where toxin testing using EIA is not available, but who meet the diagnostic criteria based 
on clinical indicators and a positive PCR test for C. difficile. In the IDSA treatment guidelines, 
diagnosis of C. difficile infection using PCR alone is acceptable in patients who meet clinical 
diagnostic criteria (McDonald 2018). Subjects who have been treated with longer duration and 

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dose of vancomycin or duration of fidaxomicin will also be enrolled given changes in standard-of-
care durations of antibiotics towards prolonged and tapering courses (McDonald 2018, Cornely 
2019). Broadening eligibility to subjects with C. difficile infection who do not have access to toxin 
EIA testing or who have received longer courses of antibiotics prior to study participation better 
reflect ‘real world’ management of CDI patients.  Subjects previously screened in SERES-012 
who did not receive SER-109 and had not previously rolled over to SERES-013 will also be 
eligible. 
4.2.1. 
Rationale for Dose and Treatment Regimen 
In this study, subjects will receive a dose of SER109 (
) 
per day for 3 consecutive days. The dose and treatment regimen was the one used in SERES-012. 
In Study SERES-001, subjects received doses of SER-109 ranging from 
 
 given over one or two days. Analysis of changes in the subject microbiome 
demonstrates that spore forming species richness in the subjects' GI tract at 1 week was positively 
correlated with SER-109 dose. Importantly, of subjects who recurred in SERES-004, about 50% 
of recurrences in both placebo and SER109 arms happened by Day 10 and 75% by Day 20, starting 
as early as Day 3. In SERES-004, the engraftment of SER-109 spore-forming bacteria in treated 
subjects’ gastrointestinal tracts was less robust and less rapid as compared to that observed in 
SERES-001, although it was significantly greater than the changes in placebo-treated 
subjects. Engraftment improved at later time points, but due to early recurrences, the SER-109-
induced microbiome change in SERES-004 may have been too late from a therapeutic 
perspective. In addition, it was generally observed that commensal spore-forming species richness 
at 1-week post dosing is correlated with better clinical outcome. In aggregate, these observations 
are central to the design of the proposed regimen that provides a higher daily dose (
) 
repeated daily over 3 days following the completion of antibiotics as compared to dosing in 
SERES-004. Due to the fact that recurrence happens early, the slower SER-109-induced 
microbiome changes in SERES-004 suggest that the 
 was likely below 
the required amount to achieve a therapeutic response. To account for variations in antibiotic 
washout, and to provide dosing prior to the earliest observed recurrences, three (3) doses will be 
administered on Days 1-3 following antibiotic cessation. We have chosen a three-fold higher dose 
level based on the 
, as an amount commensurate with engraftment 
richness to the degree correlating with protection against recurrence. 
4.2.2. 
Rationale for Endpoints and C. difficile Diagnostic Criteria  
The introduction of molecular tests, which are more sensitive and detect microbial DNA to the C. 
difficile toxin gene instead of toxin, has led to greater detection of Clostridioides difficile but detect 
C. difficile bacteria regardless of toxin production. This phenomenon has called into question 
whether a positive PCR or NAAT result reflects clinical disease or represents C. difficile 
colonization (Polange et al, 2015).  
Thus, in SERES-004, the diagnostic test for entry may not have differentiated subjects with active 
CDI disease from those with C. difficile carriage. This would lead to enrolling subjects who may 
be experiencing a post-CDI irritable bowel syndrome (IBS) if colonized by C. difficile. IBS 
following CDI is reported to occur in up to 25% of CDI patients (Wadhwa et al, 2016). This would 

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have decreased the power of the study to differentiate the treatment arms as those subjects without 
a true diagnosis of RCDI are less likely to recur. 
Since PCR diagnostics in SERES-004 may have led to misclassification of subjects with diarrhea 
and C. difficile colonization as recurrence, the primary efficacy endpoint in this study is the 
recurrence of CDI in subjects who receive SER-109 or placebo using a C. difficile toxin positive 
diagnostic (not toxin gene-based) up to 8 weeks after initiation of treatment. Unlike the PCR 
diagnostic for C. difficile, the toxin-based tests, such as enzyme immunoassay (EIA) for toxin A 
and B or the cell cytotoxicity neutralization assay (CCNA) detects the presence of C. difficile toxin 
LQIHFDOVDPSOHV7KXVUHFXUUHQFHLVGHILQHGDV unformed stools per day for 2 consecutive days 
with a positive C. difficile test on a stool sample determined by a toxin assay, and assessment by 
the investigator that the clinical condition of the subject warrants antibiotic treatment.  

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5. 
STUDY OVERVIEW 
ECOSPOR IV – Cohort 1 is an open-label extension of Study SERES-012. This study is designed 
to evaluate the safety, tolerability, and efficacy of a treatment regimen SER-109 in adult subjects 
18 years of age or older with recurrent Clostridioides difficile infection (RCDI), who received a 
treatment regimen of SER-109 or placebo in Study SERES-012. In Cohort 2 of ECOSPOR IV, the 
primary study objective is to examine safety and tolerability in a cohort of subjects receiving SER-
109 at the dose used in SERES-012.  
This study will be conducted at approximately 140 study centers in the North America. For  Cohort 
1, subjects who had a per-protocol recurrence of CDI within 8 weeks of receipt of a treatment 
regimen of SER 109 or placebo in Study SERES-012, and who have responded to 10 to 21 days 
of standard-of-care (SOC) antibiotic treatment for CDI (i.e. vancomycin [125 mg QID] and/or 
fidaxomicin [200 mg BID]) will be eligible to enroll and receive a treatment regimen of SER-109 
in Study SERES-013. A treatment regimen of SER-109 is administered orally as 
 
 in 4 capsules once daily for 3 consecutive days. Approximately 30 
eligible subjects with recurrent CDI disease from Study SERES-012 are expected to enroll in 
Cohort 1. Approximately 200 subjects will be enrolled through the Open-Label program in Cohort 
2For Cohort 2, subjects with one or more recurrences of CDI (including the current episode) who 
have responded to CDI antibiotic therapy defined as 10 to 42 days of treatment with vancomycin 
[125 mg QID] or 10 – 25 days of fidaxomicin [200 mg BID] will be potentially eligible to enroll 
in Study SERES-013 to receive a SER-109 treatment regimen. 
The study duration is approximately 27 weeks, including a ~3-week Screening Period, an 8-week 
Efficacy Period, and a 16-week Follow-up Period from initiation of treatment on Day 1. Subjects 
treated with prolonged or tapering doses of antibiotics after prescreening confirmation of CDI will 
be screened during the 3-week screening period (Day -24 to Day -2) 
In Cohort 1, favorable clinical outcome, or sustained clinical response, will be determined by the 
absence of CDI recurrence up to 8  weeks after initiation of treatment of study drug, with CDI 
UHFXUUHQFH GHILQHG DV  3 unformed stools per day over 2 consecutive days with a positive 
C. difficile test on a stool sample determined by a toxin assay and a decision by the investigator 
(based on clinical assessment) that antibiotic treatment is needed. Data from the C. difficile toxin 
assay (either enzyme immunoassay [EIA] or cell cytotoxicity neutralization assay [CCNA]), 
performed at the central laboratory, will be used for the primary endpoint analysis. The central 
laboratory results will be communicated to the investigator and the decision to treat with antibiotics 
will be based upon the investigator’s assessment. 
In Cohort 2, favorable clinical outcome, or sustained clinical response, will be determined by the 
absence of CDI recurrence up to 8 or 12 weeks after initiation of treatment of study drug, with CDI 
recurrence defined in the same manner as for Cohort 1. 
5.1. 
Trial Conduct 
For Cohort 1, screening will begin at the Recurrence Visit of Study SERES-012. Eligible subjects, 
or their legally authorized representative, will provide informed consent and undergo all baseline 
evaluations at the Screening Visit. Assessments performed at the Recurrence Visit of Study 
SERES-012 do not need to be repeated, if performed within the SERES-013 screening window 
(Day -24 to Day -2) and from the central laboratory of study SERES-012.  

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For Cohort 2, subjects with symptoms suggestive of RCDI may submit a stool sample for CDI 
toxin or PCR testing at a Clinical Laboratory Improvement Amendment (CLIA)- certified local 
laboratory or the central laboratory with a prescreening or screening consent. The central 
laboratory will only be performing PCR testing on qualifying CDI. All subjects who are confirmed 
to be toxin or PCR positive at prescreening will undergo all Screening Visit assessments after 
providing signed informed consent.  Subjects who were previously test negative who have a new 
episode may repeat pre-screening or screening using a new consent and study number. 
Cohort 1 subjects will receive 10 to 21 days of treatment with vancomycin [125 mg QID] or 
fidaxomicin [200 mg BID]. On Day 1, within 3 days of completion of SOC antibiotic treatment 
for their CDI, subjects will undergo a bowel cleanse by consuming 10 oz. (~300 mL) of oral 
magnesium citrate followed by overnight fasting. Subjects with impaired kidney function who are 
unable to take magnesium citrate will take 250 mL of GoLytely (polyethylene glycol electrolyte 
solution).  
Subjects will come to the clinic after an overnight fast on Day 1 to receive a dose of oral SER-109 
(
) in 4 capsules and have all safety evaluations performed. On Day 1, subjects will be 
dispensed a 2-day supply of SER-109 (
) in 4 capsules with instructions for at-home 
administration of a single daily dose in the morning before breakfast on Day 2 and Day 3. Subjects 
will be contacted by phone on Day 2 and Day 3 to confirm they have taken study drug in the 
morning before breakfast and to inquire about their general health. If subjects have not taken study 
drug when contacted, they will be reminded to do so as soon as possible. From Day 1 to Week 8, 
all subjects will be contacted by phone by study site personnel weekly, with the exception of a 
home or in-clinic visit at Week 2 and an in-clinic visit at Week 8, and queried for adverse events 
(AEs) and diarrheal symptoms. After Week 8, all subjects will be contacted by phone by study site 
personnel every 4 weeks (i.e., Weeks 12, 16, 20, and 24) and queried for serious adverse events 
[SAEs] and adverse events of special interest [AESIs]). Health-related quality of life and health 
outcomes will be assessed throughout the study via the CDI-specific, Cdiff32 Health Related 
Quality of Life (HRQoL) and EuroQol 5 Dimension 5 Level (EQ-5D-5L) questionnaires. 
All AEs, SAEs/AESIs, and concomitant medications will be collected from initiation of study drug 
administration up to Week 8. From Week 8 up to Week 24, all SAEs/AESIs and SAE/AESI-related 
data, and any antibiotic medication and its corresponding indication will be collected. 
To document episodes of diarrhea, subjects will complete a daily diarrhea log (see Investigator 
Site File) to include days with diarrhea as well as no diarrhea. ,IGLDUUKHDOV\PSWRPVUHFXU
unformed stools per day over 2 consecutive days) between scheduled visits, subjects will be 
instructed to contact the investigator and return to the clinic for a C. difficile stool toxin test and 
clinical evaluation for recurrence of CDI (Recurrence Visit). 
Subjects who have a confirmed CDI recurrence should continue to be followed for safety 
assessments through Week 24. Favorable clinical outcome in this study will be determined by the 
absence of CDI recurrence up to 8 weeks after initiation of the SER-109 treatment regimen. 
Sustained clinical response is favorable clinical outcome. &', UHFXUUHQFH LV GHILQHG DV 
unformed stools per day over 2 consecutive days and the requirement that subjects must continue 
to have diarrhea until antibiotic treatment is initiated, with a positive C. difficile toxin assay on a 
stool sample and a decision by the investigator (based on clinical assessment), that antibiotic 
treatment is needed. To inform subject care, a C. difficile stool test may be performed locally at 
the study site. Stool samples collected for suspected CDI recurrence will also be processed and 

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CDI prior to providing a stool sample for the central laboratory stool testing. Data from the C. 
difficile toxin test (either EIA or CCNA), performed at the central laboratory, will be used for the 
primary endpoint analysis. The central laboratory results will be communicated to the investigator 
and the decision to treat with antibiotics will be based upon the investigator’s assessment. 
The schedule of assessments and procedures is provided in Table 2. 

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6. 
STUDY OBJECTIVES 
The study objectives remain the same for Cohort 1.  
6.1. 
Primary Efficacy Objective 
x To evaluate SER-109 in the reduction of CDI recurrence rates and increased sustained 
clinical response rate, determined by a toxin assay, up to 8 weeks after initiation of 
treatment 
6.2. 
Secondary Efficacy Objectives 
x To evaluate SER-109 in the reduction of CDI recurrence rates, determined using a PCR 
algorithm (see Laboratory Manual) up to 8 weeks after initiation of treatment 
x To evaluate the time to CDI recurrence, determined by a toxin assay, after initiation of 
a treatment regimen of SER-109  
x To evaluate the time to CDI recurrence, determined using a PCR algorithm, after 
initiation of a treatment regimen of SER-109 
x To evaluate the proportion of subjects experiencing CDI recurrence, determined by a 
toxin assay, up to 4, 12, and 24 weeks after initiation of a treatment regimen of SER-
109  
x To evaluate the proportion of subjects experiencing CDI recurrence, determined using 
a PCR algorithm, up to 4, 12, and 24 weeks after initiation of a treatment regimen of 
SER-109  
 
6.3. 
Primary Safety Objective 
x To evaluate the safety and tolerability of SER-109 in adult subjects with recurrent CDI 
6.4. 
Exploratory Efficacy Objectives 
x To evaluate changes in the composition of the gut microbiome from Baseline up to 1, 
2, 8, and 24 weeks after initiation of a treatment regimen of SER-109 
x To evaluate changes in the fecal metabolome from Baseline up to 1, 2, and 8 weeks 
after initiation of a treatment regimen of SER-109 
x To determine the incidence of mortality from all causes up to 8 and 24 weeks after 
initiation of a treatment regimen of SER-109  
x To determine the incidence of hospitalizations for recurrent CDI up to 8 and 24 weeks 
after initiation of a treatment regimen of SER-109 
x To determine the incidence of all hospitalizations up to 8 and 24 weeks after initiation 
of a treatment regimen of SER-109 

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x To determine, for subjects who are hospitalized, the total length of stay (days) of 
hospitalization, including days in the intensive care unit, up to 8 and 24 weeks after 
initiation of a treatment regimen of SER-109 
x To assess health outcomes, including Health Related Quality of Life (HRQOL), by 
using the EuroQol 5 Dimensions 5 Level (EQ-5D-5L) and the HRQOL survey for CDI 
(CDiff32) up to 24 and 8 weeks after initiation of a treatment regimen of SER-109, 
respectively 
For Cohort 2, the primary objectives are safety and tolerability. 
6.5. 
Primary Safety Objective 
x To evaluate the safety and tolerability of SER-109 in adult subjects with recurrent CDI 
6.6. 
Efficacy Objectives 
x To evaluate SER-109 in the reduction of CDI recurrence rates and increase in 
sustained clinical response rates, determined by a toxin assay, up to 8 and 12 weeks 
after initiation of treatment 
6.7. 
Exploratory Objectives 
x To evaluate changes in the composition of the gut microbiome from Baseline to 1 week 
after initiation of a treatment regimen of SER-109 
x To evaluate changes in the fecal metabolome from Baseline to 1 week after initiation 
of treatment 
x To determine the incidence of mortality from all causes up to 8 and 24 weeks after 
initiation of a treatment regimen of SER-109  
x To determine the incidence of hospitalizations for recurrent CDI up to 8 and 24 weeks 
after initiation of a treatment regimen of SER-109 
x To determine the incidence of all hospitalizations up to 8 and 24 weeks after initiation 
of a treatment regimen of SER-109 
x To determine, for subjects who are hospitalized, the total length of stay (days) of 
hospitalization, including days in the intensive care unit, up to 8 and 24 weeks after 
initiation of a treatment regimen of SER-109 
x To assess the EuroQol 5 Dimensions 5 Level (EQ-5D-5L) Visual Analog Scale at 
Screening and at 8 weeks    
x To assess patient satisfaction with a bowel cleanse administered prior to SER-109, a 
Bowel Cleanse Patient Satisfaction Survey Measure at 8 weeks 

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7. 
STUDY ENROLLMENT AND WITHDRAWAL 
7.1. 
Inclusion Criteria 
To be eligible for enrollment, a subject must meet all the following criteria before undergoing any 
study related- procedures: 
For Cohort 1: 
1. Previously enrolled in Study SERES-012 and experienced a CDI recurrence within 
8 weeks after receipt of a treatment regimen of SER-109 or placebo in Study SERES-012.  
2. Signed informed consent prior to initiation of any study-specific procedure or treatment. 
The subject, or their legally authorized representative, must be willing to provide written 
informed consent and understand the potential risks and benefits from study enrollment 
and treatment. 
3. The CDI recurrence in Study SERES-012 must have met the protocol definition of: 
a.  unformed stools per day for 2 consecutive days 
b. A positive C. difficile stool toxin assay  
c. The requirement of CDI SOC antibiotic therapy (defined as 10 to 21 days of 
treatment with vancomycin [125 mg QID] or fidaxomicin [200 mg] mg BID).  
d. An adequate clinical response following SOC antibiotic therapy, defined as (<3 
unformed stools in 24 hours) for 2 or more consecutive days before initiation of study 
drug on Day 1.  
4. 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. 
5. If male, and partner is of childbearing potential, subject agrees to practice at least 
1 highly effective method of birth control for the duration of the study. 
For Cohort 2: 
1. Signed informed consent prior to initiation of any study-specific procedure or treatment. 
The subject, or their legally authorized representative, must be willing to provide written 
informed consent and understand the potential risks and benefits from study enrollment 
and treatment.  
2. HSLVRGHVRI&',LQFOXVLYHRIWKHFXUUHQWHSLVRGHZLWK.estimated total number of prior 
episodes 
3. The CDI recurrence must have met the protocol definition of:  
a.  unformed stools per day for 2 consecutive days 

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b. A positive C. difficile stool toxin or PCR assay (either local or central laboratory).  
c. The requirement of CDI antibiotic therapy (defined as 10 to  42 days of treatment 
with vancomycin or 10 to 25 days with fidaxomicin [200 mg]. It is acceptable if 
subject was started on metronidazole, switched to vancomycin or fidaxomicin and 
is treated for a minimum of 10 days of vancomycin or fidaxomicin with a total 
treatment duration of up to a maximum of - 42 days for vancomycin or 25 days for 
fidaxomicin.  
d. An adequate clinical response following antibiotic therapy, defined as <3 unformed 
stools in 24 hours) for 2 or more consecutive days before initiation of study drug 
on Day 1.  
e. The requirement that the subject can be dosed with study drug within 4 days of 
antibiotic completion. 
4. 0DOHRUIHPDOHVXEMHFW 18 years of age. 
5. If female, subject is non-lactating, and is either: 
a. Not of childbearing potential, defined as post-menopausal 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 1 highly 
effective method of birth control for the duration of the study. 
7. If currently taking probiotics, must be willing to stop at time of consent, for the duration 
of the study. 
7.2. 
Exclusion Criteria 
Cohort 1 
A subject will not be enrolled if the subject meets any of the following criteria: 
1. Female subjects who are pregnant, breastfeeding, lactating, or planning to become pregnant 
during the study. 
2. Known or suspected toxic megacolon and/or known small bowel ileus. 
3. Admitted to or expected to be admitted to an intensive care unit for medical reasons (not 
just boarding). Note: nursing homes, rehabilitation, assisted living centers and acute care 
hospitals are acceptable. 
4. Absolute neutrophil count of <500 cells/mm3 
5. Taking antibacterial therapy other than antibiotics for the most recent episode of CDI 
during the screening period (a single day antibiotic prophylactic regimen is permitted), or 
projected to receive antibiotics during the 8-week period post-randomization.  

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6. Major gastrointestinal surgery (e.g., significant bowel resection or diversion) within 
3 months before enrollment (this does not include appendectomy or cholecystectomy), or 
any history of total colectomy or bariatric surgery. (Bariatric surgery which does not 
disrupt the gastrointestinal lumen, i.e., restrictive procedures such as banding, are 
permitted). 
7. History of active inflammatory bowel disease (ulcerative colitis, Crohn’s disease, 
microscopic colitis) with diarrhea believed to be caused by active inflammatory bowel 
disease in the past 3 months. 
8. Unable to stop loperamide, diphenoxylate/atropine, or cholestyramine prior to enrollment. 
9. Unable to stop opiate treatment unless on a stable dose, including PRN dosing, as of the 
onset of diarrhea and no increase in dose planned for the duration of the study. Note: Short 
term (1 day) opiate use is permitted (e.g., for a dental extraction). 
10. Known positive stool cultures for other enteropathogens including, but not limited to, 
Salmonella, Shigella, and Campylobacter within the 30 days before enrollment.  
11. Known stool studies positive for ova and/or parasites within the 30 days before enrollment 
12. Poor concurrent medical risks with clinically significant comorbid disease such that, in the 
opinion of the investigator, the subject should not be enrolled. 
13. Received a human monoclonal antibody against C. difficile toxin within 3 months before 
study entry. 
14. Received an investigational drug or vaccine, or participated in any experimental procedure 
within 1 month (3 months for monoclonal antibodies) before study entry. 
15. Any history of immunoglobulin (IgG) replacement therapy within the past 3 months. 
16. Any history of fecal microbiota transplantation (FMT) within the past 3 months. 
17. Known active intravenous drug or alcohol abuse or use of other drugs of abuse. 
18. Concurrent intensive induction chemotherapy, radiotherapy, or biologic treatment for 
active malignancy (subjects on maintenance chemotherapy may only be enrolled after 
consultation with the study medical monitor). 
19. Unable to comply with the protocol requirements, including the ability to take oral drugs; 
or any condition that, in the opinion of the investigator, might interfere with study 
objectives  
20. Life expectancy is 24 weeks or less  
For Cohort 2 , all Cohort 1 exclusion criteria plus number 21, below, apply. 
21. Previously enrolled in a Seres Therapeutics clinical study An exception is made for 
subjects who screened in SERES-012 who did not receive SER-109 and did not 
previously roll-over to SERES-013. 
 

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7.3. 
Subject Monitoring and Withdrawal 
7.3.1. 
Reasons for Withdrawal 
Subjects should continue to be followed for safety assessments up to 24 weeks after treatment, 
even after a CDI recurrence. However, a subject may withdraw from the study at any time for any 
reason, without any consequence. In addition, a subject may be withdrawn from the study for 
reasons including the following: 
x AE (typically an SAE) 
x Subject choice (withdrawal of consent by subject or their legally authorized 
representative; investigator will attempt to ascertain reason) 
x Protocol violation/non-compliance 
7.3.2. 
Handling of Withdrawals and Discontinuations of Treatment 
The primary reason for withdrawal from the study will be recorded in an electronic case report 
form (eCRF). Subjects who voluntarily withdraw, or who are withdrawn from the study will be 
encouraged to complete the Early Termination Visit. The Early Termination Visit procedures are 
listed in Section 10.3.3. Although subjects are free to withdraw at any time, subjects will be 
encouraged to remain in the study for follow-up safety evaluation. 
Those subjects who withdraw from the study will be referred to a physician for follow-up care. 
7.3.3. 
Lost to Follow-up 
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 contact the subject and document subject 
outcome, (i.e., 3 documented contact attempts via phone calls, e-mail, etc., on separate occasions 
will be made to locate or contact the subject, and/or to determine health status). 
7.3.4. 
Termination of Study 
Although the sponsor has every intention of completing the study, the sponsor may terminate the 
study at any time for clinical or administrative reasons. 
8. 
INVESTIGATIONAL PRODUCT 
8.1. 
SER-109 
SER-109 is an ecology of bacterial spores enriched from stool donations obtained from healthy, 
screened donors. SER-109 is formulated as an oral capsule for administration to patients following 
cessation of antibiotic therapy. 
8.1.1. 
Donor Screening 
Donors undergo a general health examination including gastrointestinal (GI) medical history, 
familial GI medical history, blood chemistry, hematology with complete blood count, urinalysis, 

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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. 
8.1.2. 
Manufacturing and Storage 
SER-109 is manufactured using current Good Manufacturing Practice (GMP).  Stool raw material 
is sourced from donors who are screened for health history, physical status, and a panel of pathogen 
tests; materials from a single donor are pooled to make a manufacturing lot.  The manufacturing 
process inactivates non-spore forms of live bacteria and fungi, and potential parasites and viruses, 
and substantially reduces the amount of undigested food and inactivated non-spore components 
via successive separation steps.  The purified material is then concentrated to enable oral capsule 
formulation, stored frozen, and quality control tested until formulation. 
8.2. 
SER-109 Kit Storage and Handling 
The investigational product (SER-109) will be provided as a per subject kit to include 3 bottles 
containing four size 00 capsules (
) in an opaque, 40 mL high density polyethylene 
container sealed with foil. 
SER-109 is odorless and tasteless as prescribed. If chewed or if capsule integrity is compromised, 
SER-109 has a sweet taste. 
Instructions for shipment, storage, accountability, reconciliation, and destruction of study drug are 
provided in the Pharmacy Manual. 
8.3. 
Compliance 
Subjects will be instructed to return all unused medication and all used packaging materials to the 
clinic at the Week 8 visit. Subject compliance to study drug will be checked by the investigator or 
their designee(s) and documented in the CRFs (e.g., tablet count). Subjects will be instructed to 
take all study drug doses in the morning after an overnight fast (nothing by mouth except for small 
DPRXQWVRIZDWHURIKRXUV6XEMHFWVZLOOEHDVNHGWRUHPDLQIDVWLng for up to 60 minutes 
following dosing. In Cohort 2, fasting is not required.   
8.4. 
Method of Assigning Patients to Study Treatment 
This is an open-label study. All subjects who qualify for dosing will receive single daily doses of 
SER-109 (
) in 4 capsules administered over 3 consecutive days.  
The interactive voice and web response system (IxRS) will assign appropriate bottles of 
SER-109 that will be available at the site for all subjects on their Day 1 study visit. Subjects who 
discontinue this study or who have previously received SER-109 in this study will not be 
permitted to re-enter. Similarly, SER-109 dispensed to a subject may not be re-used, even if the 
bottle(s) are returned unopened.  
8.5. 
Maintaining the Randomization Codes and Breaking the Study Blind 
Not applicable. This study is not randomized or blinded.  

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8.6. 
Concomitant Medications 
8.6.1. 
Prohibited Concomitant Medications and Procedures 
The following therapies are prohibited for the duration of the study unless there has been a 
confirmed recurrence. 
x Probiotics 
x Loperamide 
x Diphenoxylate/atropine 
x Cholestyramine  
x Opiate treatment unless on a stable dose. Note: Short term (one day) opiate use is 
permitted (e.g., for a dental extraction). 
x Oral metronidazole, oral fidaxomicin and oral vancomycin except for treatment of 
suspected or confirmed CDI recurrence.  
x Fecal Microbiota Transplant (FMT) prior to recurrence in the study 
8.7. 
Criteria 
for 
Confirmed 
Clostridioides 
difficile 
Recurrence 
Post-Randomization 
Cohort 1 subjects suspected of having CDI will be asked to contact the investigator and return to 
the clinic for a C. difficile stool toxin test and evaluation for recurrence of CDI (Recurrence Visit) 
(see Section 10.3.3). For both Cohort 1 and Cohort 2 subjects, during the COVID-19 pandemic 
home visits will be allowed in place of clinic visits. subjects suspected of having CDI will be asked 
to contact the investigator and return to the clinic or have a home visit for a C. difficile stool toxin 
test to be sent to the central laboratory and evaluation for recurrence of CDI (Recurrence Visit). If 
the subject is seen in a home visit, the investigator will determine treatment based on the clinical 
evaluation and stool test result. 
The home visit will remain an option for a clinic visit during follow-up visits after enrollment for 
Cohort 2. 
Subjects must fulfill the following criteria: 
1.  unformed stools per day over 2 consecutive days 
2. Diarrhea as defined here should continue up until the day antibiotics to treat CDI are 
initiated. A positive C. difficile test on a stool sample determined by a toxin assay 
 A C. difficile stool test will be performed at the central laboratory. This result will 
be used for the primary endpoint analysis. The central laboratory results will be 
communicated to the investigator. 
3. Assessment by the investigator that the clinical condition of the subject warrants treatment 

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9. 
STUDY PROCEDURES 
For Cohort 1, the schedule of assessments and procedures is presented in Table 1. For Cohort 2, 
the schedule of assessments and procedures is presented in Table 2.  
9.1. 
Duration of Participation 
The duration of study participation is up to approximately 27 weeks, consisting of a Screening 
Period lasting up to ~3 weeks, an 8-week Efficacy Period, and a 16-week Follow-Up Period from 
initiation of study drug on Day 1. 
9.2. 
Medical History 
At the time of Screening, subjects’ medical history will be updated with particular attention to the 
most recent CDI history. The antibiotic regimen, including dose and duration after the most recent 
CDI recurrence, will be documented.  Subjects must demonstrate an adequate clinical response to 
the antibiotic regimen to treat the most recent CDI recurrence defined as (<3 unformed stools in 
24 hours) for 2 or more consecutive days before study drug dosing. 
9.3. 
Physical Examination 
For cohort 1, a physical examination will be conducted by a physician at the timepoints indicated 
in Table 1. A focused history and physical will be conducted at Week 8 and at the Early 
Termination Visit or any Recurrence Visit to the study site, if applicable. 
For Cohort 2 subjects, a physical examination will be performed by the principal investigator or 
delegated qualified individual at screening. A focused history and physical by delegated qualified 
individual will be performed at Day 1, Week 8, any recurrence visit, and the Early Termination 
Visit if it occurs before Week 8. 
9.4. 
Body Weight 
For Cohort 1, body weight will be obtained at all in-clinic visits according to the schedule in 
Table 1. 
For Cohort 2, Body Weight will be obtained at the Screening Visit according to the schedule in 
Table 2.  
9.5. 
Vital Signs 
For Cohort 1, vital sign assessments including systolic and diastolic blood pressure, pulse, 
respiratory rate, and oral body temperature measurements will be obtained at the visits indicated 
in Table 1. Vital sign assessments on Day 1 should be obtained immediately before and 
approximately 30 minutes after dosing. 
For Cohort 2, Vital Sign assessments including systolic and diastolic blood pressure, pulse, 
respiratory rate, and oral temperature measurements will be obtained at the clinic or home visits. 

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9.6. 
Laboratory Assessments 
All hematology and blood chemistry laboratory tests will be performed by the central laboratory. 
The laboratory facilities for analysis of clinical laboratory samples obtained under this protocol 
will have adequate licensure and accreditation. Urine pregnancy tests will be performed at the 
sites. Details of sample handling, specific tests performed, and methodology will be provided in 
the Laboratory Manual.  
9.6.1. 
Hematology and blood chemistry 
For Cohort 1, blood samples for hematology and blood chemistry will be obtained according to 
the schedule in Table 1. Blood samples for hematology and blood chemistry obtained on Day 1 
(pre-dose) will be used to determine baseline data. 
The central laboratory will flag subjects if they have all of the following abnormal laboratory 
results: 
x $ODQLQHDPLQRWUDQVIHUDVH$/7[XSSHUOLPLWRIQRUPDO8/1 
x Aspartate DPLQRWUDQVIHUDVH$67[8/1 
x Total bilirubin > 2 x ULN 
x Alkaline phosphatase < 2 x ULN 
These subjects meet the conditions of a Hy’s Law case, and should be reported in the same manner 
as an SAE (see Section 11.1). 
For Cohort 2, blood samples for hematology and blood chemistry will be obtained on the Screening 
Visit, which will be used to determine baseline data. A second and final sample will be obtained 
at the 8 week visit or the Early Termination Visit (if before 8 weeks). 
Subjects who do not have an absolute neutrophil count (ANC) result from the Screening visit must 
have a local or central laboratory result to ensure study eligibility before the first dose of SER-109 
is administered. 
9.6.2. 
Urinalysis 
For Cohort 1, urine dipstick testing will be performed at the study site according to the schedule 
in Table 1. If results for nitrates or leukocytes are positive, the urine sample may be sent to the 
central laboratory for analysis at the discretion of the investigator. 
For Cohort 2, urine dipstick testing will no longer be performed. (Table 2) 
9.6.3. 
Pregnancy Testing 
For Cohort 1, women of childbearing potential (WOCBP) will have urine pregnancy tests 
according to the schedule in Table 1. 
For Cohort 2, Women of childbearing potential (WOCBP) will have urine pregnancy tests at the 
Screening Visit and at the 8 week visit or the Early Termination Visit (if before 8 weeks) according 
to the schedule in Table 12. 

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9.7. 
Stool Sample Collection and Analysis 
Cohort 1, subjects will be asked to collect stool at home or in the clinic according to the schedule 
in Table 1. The sample collected on Day -1 may be brought to the study site for the Day 1 Visit. If 
the subject is unable to bring the stool sample to the study site for any visit, arrangements may be 
made to pick up the sample at the subject’s home and bring it to the study site or may ship directly 
to the central laboratory (i.e., home visit by nurse or courier). Samples brought to the study site 
will be processed and then shipped to a central laboratory according to procedures defined in the 
Laboratory Manual. Stool collection kits will be provided to the subjects by the study sites. 
Microbiome and metabolomics testing may be performed on some or all stool samples collected 
on Day -1 (prior to administering the bowel cleanse), at Week 1, Week 2, Week 8, Week 24 (for 
microbiome testing only), and at the Early Termination Visit or any Recurrence Visit to the study 
site, if applicable.  
If recurrent CDI is suspected, to inform subject care, a C. difficile test can be performed by a CLIA-
certified local laboratory using an FDA-approved test in order to inform subject treatment. Stool 
samples collected for suspected CDI recurrence must also be processed and shipped to a central 
laboratory for C. difficile stool testing (see Laboratory Manual for details of C. difficile testing 
performed at the central laboratory). The subject should not initiate antibiotics for suspected CDI 
prior to providing a stool sample for the central laboratory stool testing. Data from the C. difficile 
toxin assay (either enzyme immunoassay [EIA] or cell cytotoxicity neutralization assay [CCNA]), 
performed at the central laboratory, will be used for the primary endpoint analysis. The central 
laboratory results will be communicated to the investigator and the decision to treat with antibiotics 
will be based upon their assessment. 
For Cohort 2, subjects will be asked to collect stool prior to the bowel cleanse on Day -1.  The 
sample collected on Day -1 may be brought to the study site for the Day 1 Visit.  A subgroup of 
subjects who consent will collect a stool specimen at Week 1 and will make arrangements to return 
it to the clinic or ship directly to the central laboratory.  Microbiome and metabolomics testing 
may be performed on some or all stool samples collected on Day -1 (prior to administering the 
bowel cleanse), and at Week 1.   
The subjects will be instructed to call the study site if diarrhea develops. If recurrent CDI is 
suspected, stool sample must be collected and shipped to central laboratory for C. difficile stool 
testing (see Laboratory Manual for details of C. difficile testing performed at the central 
laboratory). The subject should not initiate antibiotics for suspected CDI prior to providing a stool 
sample for the central laboratory stool testing. Data from the C. difficile toxin assay (either enzyme 
immunoassay [EIA] or cell cytotoxicity neutralization assay [CCNA]), will be used for the primary 
endpoint analysis. The central laboratory result will be communicated to the investigator and the 
decision to treat with antibiotics will be based upon their assessment. 
 
9.8. 
Biological Specimen Collection for Future Biomedical Research 
The sponsor may conduct future biomedical research on specimens (including serum and stool) 
routinely and specifically collected during this clinical study for potential commercial use by Seres 
Therapeutics, Inc. and specimens may be stored for up to 10 years.  

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9.9. 
Monitoring of Diarrheal Symptoms and General Health 
Cohort 1 subjects will be instructed to complete a daily diarrhea log (see Investigator Site File) 
every day whether or not they experience diarrhea. At all scheduled telephone calls and study site 
visits, subjects will be queried regarding general well-being; AEs; diarrheal symptoms, including 
the day, frequency, and quality of bowel movements described as diarrhea; and concomitant 
medications according to a standardized questionnaire. Any subject suspected of having an episode 
RI&',SHUSURWRFROGHILQLWLRQXQIRUPHGVWRROVSHUGD\ODVWLQJFRQVHFXWLYHGD\VZLOOEH
asked to come in for an in-clinic visit, where possible, for a C. difficile stool toxin test and 
evaluation for recurrence of CDI (see Section 10.3.3).  
Cohort 2: at all scheduled telephone calls and clinic or home visits, subjects will be queried 
regarding general health; AEs; diarrheal symptoms, including the day, frequency, and quality of 
bowel movements described as diarrhea; and concomitant medications according to a standardized 
questionnairH$Q\VXEMHFWVXVSHFWHGRIKDYLQJDQHSLVRGHRI&',SHUSURWRFROGHILQLWLRQ
XQIRUPHGVWRROVSHUGD\ODVWLQJFRQVHFXWLYHGD\VZLOOEHDVNHG to arrange for an in-clinic or 
home visit for a C. difficile stool toxin test (to be sent to central laboratory) and evaluation for 
recurrence of CDI.  
9.10. 
Health Outcome Assessment 
Information such as mortality from any cause, hospitalizations, and hospital length of stay (in 
days), including days in the intensive care unit, will be collected as part of the health outcomes 
assessment throughout this study.  
9.11. 
Quality of Life Assessment 
The EQ-5D-5L is a standardized measure of health status. The CDiff32 HRQoL is a newly 
developed and validated health-related quality of life questionnaire specific to patients with CDI 
(Garey et al, 2016). For Cohort 1 only, administer the EQ-5D-5L and Cdiff32 HRQoL at the time 
points indicated in the Schedule of Assessments (Table 1).  
For Cohort 2, the EQ-5D-5L visual analog scale will be completed using a paper questionnaire at 
Screening and Week 8.  In addition, subjects will be asked to complete a Bowel Cleanse Patient 
Satisfaction Survey Measure at Week 8 on the bowel cleanse procedure administered prior to 
SER-109. This survey is modified from one that has previously been validated in subjects 
undergoing colonoscopy (Hatoun 2016). This questionnaire has been minimally modified as 
shown below. 
 
 
Original for Colonoscopy 
Prep 
SER-109 
Responses 
1 
How easy or difficult was it to 
consume the study drug? 
How easy or difficult was it to 
consume the bowel cleanse? 
Very easy 
Easy 
Tolerable 
Difficult 
Very difficult 
2 
Were you able to consume the 
entire preparation as 
instructed? 
Were you able to consume the 
entire bowel cleanse as instructed? 
Yes 
No 

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3 
Please describe your overall 
experience of the study 
preparation: 
Please describe your overall 
experience of the bowel cleanse: 
Excellent 
Goodc 
Fair 
Poor 
Bad 
4 
The taste of this study 
preparation was: 
The taste of this bowel cleanse was: Excellent 
Good 
Tolerable 
Poor 
Bad 
5 
Would you ask your doctor 
for this preparation again if 
you needed another 
colonoscopy in the future? 
Would you take this bowel cleanse 
again if you needed to take the 
study drug, SER-109, in the future? 
Yes 
No 
6 
Would you refuse the same 
preparation again if it were to 
be prescribed to you in the 
future? 
Would you refuse the bowel 
cleanse again if it were to be 
prescribed to you in the future? 
Yes 
No 
9.12. 
Clinical Response Evaluation 
Recurrence of CDI will be determined by the investigator based on the following definition: 
x A CDI episode is defined as  unformed stools per day over 2 consecutive days with 
a positive C. difficile stool test on a stool sample determined by a toxin assay and a 
decision by the investigator, based on clinical assessment, that antibiotic treatment is 
needed. 
If subjects experience diarrhea symptoms XQIRUPHGVWRROVSHUGD\IRUFRQVHFXWLYHGD\V or 
suspect a CDI episode, they should contact the investigator immediately (including on weekends) 
to arrange a Recurrence Visit for clinical evaluation and a C. difficile stool toxin test (central 
laboratory). The subject should not initiate antibiotic treatment for suspected CDI until instructed 
to do so by the investigator. 
10. 
STUDY SCHEDULE 
The Schedule of Assessments and Procedures is presented in Table 1 and Table 2. Study days are 
relative to the oral administration of the first dose of study drug on Day 1. Assessments will be 
performed and noted in each subject’s chart or record. In Cohort 1, as necessary for safety of 
subject, study visits including  Week 2, Week 8, Unscheduled, and Early Termination, may be 
conducted at subject’s home, with qualified nurse or site personnel who will be appropriately 
documented on the site’s delegation log to perform these Remote Study Visits and associated 
procedures.  If a nurse or site personnel cannot perform the visits, a telephone call or a video 
conference (Zoom, Skype, FaceTime, etc.) should be conducted in place of the Week 2, Week 8, 
Unscheduled, and Recurrence / Early Termination visits and must be documented in the source.  
Any required procedures not performed during a remote visit at the subject’s home will be 
documented as a protocol deviation by site staff. The option of additional home visits was added 

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to maintain follow-up when subjects were not able to be seen in the clinic for planned study visits 
due to COVID-19. 
In Cohort 2, the Week 8, early termination, and recurrence visits may all be conducted at home or 
in the clinic. If a nurse or site personnel cannot perform the visits due to COVID-19, a telephone 
call or a video conference (Zoom, Skype, FaceTime, etc.) should be conducted in place of the visits 
and must be documented in the source.  Any required procedures not performed during a remote 
visit at the subject’s home will be documented as a protocol deviation by site staff. 
 
10.1. 
Screening Period  
For Cohort 2, subjects with symptoms suggestive of RCDI may submit a stool sample for CDI 
toxin or PCR testing at a Clinical Laboratory Improvement Amendment (CLIA)- certified local 
laboratory or the central laboratory with a prescreening or screening consent. Stool samples 
submitted to the central lab for screening will be tested via PCR. ..Subjects who were previously 
test negative who have a new episode may repeat pre-screening or screening using a new consent 
and study number.  
10.1.1. 
Clinic Visit (Day -24 to Day -2) 
For Cohort 1, screening for this study begins at the Recurrence Visit of Study SERES-012. 
Assessments performed at the Recurrence Visit in Study SERES-012 do not need to be repeated if 
performed within the SERES-013 screening window (Day -24 to Day -2) and from the central 
laboratory of study SERES-012. Cohort 2 subjects will undergo all screening procedures and 
assessments, with the exception of urine dipstick.   
x After a full explanation of the study protocol, have each subject or their legally 
authorized representative sign an informed consent form (ICF) before performing any 
study-related activity (including Screening activities).  
x Subjects will receive 10 to 21 days of treatment with vancomycin [125 mg QID] or 
fidaxomicin [200 mg BID]. For Cohort 2, subjects will receive 10 to 42 days of 
vancomycin or 10 to 25 days of fidaxomicin (200 mg). On Day -1, within 3 days of 
completion of antibiotic treatment for their CDI, subjects will undergo a bowel cleanse 
by consuming 10 oz. (~300 mL) of oral magnesium citrate followed by overnight 
fasting in Cohort 1 only. Cohort 2 will not require fasting after bowel cleanse. Subjects 
with impaired kidney function who are unable to take magnesium citrate will take 250 
mL of GoLytely (polyethylene glycol electrolyte solution). 
x Assess each patient to ensure all inclusion criteria are met and no exclusion criteria are 
met.  
x Update medical history. Ensure documentation of most recent CDI episode to include 
dates, test results, duration, and antibiotic treatment received.  
x Perform a physical examination including vital sign measurements (blood pressure, 
pulse, respiratory rate, and body temperature), and weight.  

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x For Cohort 2 only, subjects will complete EuroQol 5 Dimension 5 Level (EQ-5D-5L) 
Visual Analog Scale using a paper questionnaire 
x Provide stool collection kits. 
x Collect blood and urine samples and ship to the central laboratory for evaluation of: 
 Blood chemistry 
 Hematology 
 Urine dipstick performed at the study site; if positive for nitrates and/or leukocytes, 
sample may be sent to central laboratory for analysis at the investigator’s discretion 
(Cohort 1 only) 
 Urine pregnancy test, if applicable 
Note: Laboratory values obtained during the screening window and from the central 
laboratory of Study SERES-012 (e.g., SERES-012 Week 8 visit) do not need to be 
repeated at the Screening Visit.  The SERES-012 Recurrence Visit assessments 
may be used for the SERES-013 Screening Visit. However, if the Recurrence Visit 
occurred outside the SERES-013 screening window (Day -24 to Day -2), the 
required screening procedures for 013 must be repeated within the screening 
window (Refer to Table 1: Schedule of Assessments and Procedures). 
x Obtain information regarding prior medication use within the 8 weeks before 
anticipated enrollment as well as concomitant medications. Note:  For Cohort 1, 
Comprehensive prior medication and concomitant medicine information from SERES-
012 study can be used for this purpose.  
x Ensure documentation of recent antibiotic or immunosuppressive medication use that 
may affect eligibility in the study.  
x Assess AEs for Cohort 1 only.  
x Register subject in IWRS.  
x Instruct subjects that, should they enroll in the study, they will need to meet the 
following requirements:  
 Probiotic use is prohibited during the study.  
 If currently experiencing an active CDI: 
 On Day -4 to Day -2, subject should take their last dose of antibiotic 
treatment for their CDI.  
 On Day -1, before beginning the magnesium citrate or GoLytely 
(polyethylene glycol electrolyte solution) bowel preparation, they should 
collect a stool sample.  
 Subjects are to contact the investigator immediately (including on weekends) if they 
experience diarrheal symptoms or suspect a CDI episode to arrange a Recurrence 
Visit (see Section 10.3.3) for clinical evaluation and a C. difficile stool toxin testing 
at the Central Laboratory. Advise subjects that antibiotic treatment should be 

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initiated only after a positive C. difficile test, and clinical assessment by the 
investigator. 
10.1.2. 
Pre-treatment Preparation Phone Call Visit (Day -4 to -2) 
Contact subject by phone to: 
x Perform diarrhea assessment to ensure that subject’s diarrhea has been controlled (< 3 
unformed stools per day for 2 consecutive days). 
x Assess AEs for Cohort 1 only. 
x Review concomitant medications. 
x Remind subject to not take antibiotics beyond Day -2. 
x For both cohorts, remind subject to collect a stool sample at Day -1.   For those required 
to administer a bowel cleanse, instruct the subject to collect the sample before 
beginning the magnesium citrate or GoLytely (polyethylene glycol electrolyte solution) 
bowel cleanse on Day -1. 
10.1.3. 
Pre-treatment Preparation Phone Call Visit (Day -1) 
Contact subject by phone to: 
x Ensure all inclusion criteria continue to be met and no exclusion criteria are met, 
including that subject’s CDI has responded to antibiotics without diarrhea over the 
previous 2 days (< 3 unformed stools per day). 
x Ensure subject has discontinued antibiotics to control CDI symptoms, and has had their 
last dose of antibiotic on any day from Day- 4 to Day -2. 
 Remind subject to collect a stool sample.  Instruct the subject to collect the 
sample before beginning the magnesium citrate or GoLytely bowel cleanse. 
 Ensure subject consumes a 10 oz (~300 mL) bottle of magnesium citrate (or, for 
subjects with impaired renal function, 250 mL of GoLytely and is prepared to fast 
overnight (no food RUGULQNRWKHUWKDQVPDOODPRXQWVRIZDWHUIRU8 hours) 
before anticipated receipt of study drug. 
x Assess AEs. 
x Review concomitant medications. 
x Remind subject to bring their Day -1 stool sample collected at home to the study site 
on Day 1 to be processed for shipment to the central laboratory. 
x Remind subjects in Cohort 1 to bring their SERES-012 electronic diary device to the 
site at their Day 1 visit so it can be collected and a SERES-013 device can be dispensed.  
An electronic diary will not be used for subjects in Cohort 2. 

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10.2. 
Efficacy Period 
10.2.1. 
Clinic Visit (Day 1) 
10.2.1.1. Before Administering Study Drug (Pre-dose) 
Both Cohort 1 and 2 
x Assess subject to ensure all inclusion criteria are met and no exclusion criteria are met.  
Ensure that subject’s CDI has responded to antibiotics without diarrhea for the previous 
2 days (< 3 unformed stools per day).  
x Review concomitant medications and update information regarding prior medication 
use. Confirm that subject took their last dose of antibiotic treatment for their CDI on 
any day from Day -4 to Day -2. 
x Ensure subject consumed a 10 oz (~300 mL) bottle of magnesium citrate or 250 mL of 
GoLytely on Day -1. 
x Obtain stool sample from subject’s Day -1 at home collection and process, store, and 
ship per Laboratory Manual. 
x Perform a focused history and physical exam. including vital sign measurements (i.e., 
blood pressure, pulse, respiratory rate, and body temperature 
x Urine Pregnancy test, if applicable 
x Access the IxRS to obtain the bottle number of SER-109 
x Provide stool collection kit  
For Cohort 1, 
x Ensure subject is undergoing a fast (no food or drink other than small amounts of water) 
IRUKRXUVEHIRUHDQWLFLSDWHGUHFHLSWRIVWXG\GUXJ Collect blood and urine samples 
for the following laboratory tests:  
 Blood chemistry 
 Hematology 
 Serum for future biomedical research 
 Urine dipstick performed at the study site; if positive for nitrates and/or leukocytes, 
the sample may be sent to central laboratory for analysis at the discretion of the 
investigator 
x Assess AEs. 
x Administer the EQ-5D-5L and CDiff32 questionnaires. 
x Collect SERES-012 diarrhea diary device and dispense SERES-013 device with 
instructions to continue completing the diary daily through week 24. 
For Cohort 2 subjects: 
x Subjects will not have to undergo a fast prior to study dose 

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x For subgroup of subjects who consent in Cohort 2, remind subjects to courier or bring 
their Week 1 stool specimen to the clinic. Provide stool collection kit to these subjects. 
10.2.1.2. Administering Study Drug  
On Day 1, administer 4 study drug capsules orally with at least 8 oz of water (capsules are to be 
swallowed, not chewed). 
10.2.1.3. After Administering Study Drug (Post-dose): 
x ObseUYHVXEMHFWLQWKHFOLQLFIRU60 minutes. 
x Assess vital sign measurements (i.e., blood pressure, pulse, respiratory rate, and oral 
body temperature) approximately 30 minutes after dosing. 
x Assess AEs. 
x Provide subject with stool collection kits. 
x Provide specific instructions and a reminder card on reporting and follow-up of 
symptoms including diarrhea and abdominal discomfort, collection of samples, 
reporting of any concerns, and, in particular, notification of the investigator of the 
occurrence of diarrhea. 
x Ensure subject continues to fast for a total of 1 hour after dosing (post-dose).(Cohort 1 
only; no fasting required in Cohort 2) 
x Dispense a 2-day supply of study drug to subjects with instructions for proper storage 
and home-administration on Day 2 and Day 3. 
x Release subject from the clinic upon authorization by the investigator. 
x Review instructions with subject for recording episodes of diarrhea (See Investigator 
Site Manual). 
x Investigators should manage subjects’ expectations, they may have diarrhea early-on 
after receiving drug in the study. 
10.2.2. 
Phone Call Visit (Day 2) 
Contact subject by phone to:  
x For cohort 1, confirm administration of 2nd dose (4 capsules) of study drug in the 
morning before breakfast For cohort 2, confirm administration of 2nd dose (4 capsules) 
of study drug in the morning. If subject has not yet taken study drug, remind subject to 
take study drug as soon as possible. 
x Inquire about general health. 
x Perform diarrhea assessment: 
 Remind subjects they may have diarrhea early-on after receiving drug in the study. 
 Remind subjects to complete the diarrhea log/device (see Investigator Site 
File).(Cohort 1 only) 

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x Assess AEs. 
x Review concomitant medications. 
10.2.3. 
Phone Call Visit (Day 3) 
Contact subject by phone to: 
x Confirm administration of 3rd dose (4 capsules) of study drug in the morning before 
breakfast (fasting for Cohort 1 only).For Cohort 2, confirm administration of 2nd dose 
(4 capsules) of study drug in the morning. If subject has not yet taken study drug, 
remind subject to take study drug as soon as possible. 
x Inquire about general health. 
x Perform diarrhea assessment: 
 Remind subjects they may have diarrhea early-on after receiving drug in the study. 
 Remind subjects to complete the diarrhea log/device (see Investigator Site 
File).(Cohort 1 only) 
x Assess AEs. 
x Review concomitant medications. 
For Cohort 1,  
x Remind subject to bring their Week 1 stool sample collected at home to the study site 
to be processed for shipment to the central laboratory or make arrangements for a 
courier for delivery to the study site.   
For Cohort 2 
x A subgroup of subjects who consent will collect a stool specimen at Week 1 and will 
make arrangements to return it to the clinic or ship directly to the central laboratory.    
10.2.4. 
Phone Call Visit (Week 1) 
Contact subject by phone at Week 1 (± 2 days). 
x Perform diarrhea assessment: 
 If subject has a suspected episode of CDI, obtain information regarding the day, 
frequency, and quality of bowel movements during diarrheal episodes. 
 If subject reports episode(s) of diarrhea ( 3 unformed stools per day) lasting 2 or 
more consecutive days, obtain stool sample. Complete Recurrence Visit 
assessments (see Section 10.3.3).  
x Assess AEs. 
x Review concomitant medications. 
For Cohort 1, 
x The CDiff32 questionnaire will be administered. 

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x Remind subject to bring their Week 1 stool sample collected at home to the study site 
to be processed for shipment to the central laboratory or make arrangements for a 
courier for delivery to the study site.   
For subgroup of subjects who consent in Cohort 2, remind subjects to courier their Week 1 stool 
sample collected at home to the study site to be processed for shipment to the central laboratory. 
10.2.5. 
Clinic or Home Visit (Week 2)  
For Cohort 1, arrange for a home visit or an in-clinic visit at Week 2 (± 2 days) to: 
x Perform diarrhea assessment: 
 If subject has a suspected episode of CDI, obtain information regarding the day, 
frequency, and quality of bowel movements during diarrheal episodes. 
 If subject reports episode(s) of diarrhea ( 3 unformed stools per day) lasting 2 or 
more consecutive days, obtain stool sample. Complete Recurrence Visit 
assessments (see Section 10.3.3).  
x Assess AEs. 
x Review concomitant medications.  
x Collect a serum sample and a stool sample (if ICF for FBMR obtained) 
10.2.6. 
Phone Call Visits (Weeks 3-7)  
For Cohort 1, contact subject by phone at Weeks 3-7 (± 2 days). 
x Perform diarrhea assessment: 
 If subject has a suspected episode of CDI, obtain information regarding the day, 
frequency, and quality of bowel movements during diarrheal episodes. 
 If subject reports episode(s) of diarrhea ( 3 unformed stools per day) lasting 2 or 
more consecutive days, arrange a Recurrence Visit (see Section 10.3.3).  
 Advise subject to continue diarrhea log, and collect stool sample for the Recurrence 
Visit. 
 Advise subject to not initiate antibiotic treatment for CDI until advised to do so by 
the study investigator. 
x Assess AEs. 
x Review concomitant medications. 
x Remind subject to bring their Week 8 stool sample collected at home to the study site 
to be processed for shipment to the central laboratory. 
For Cohort 2, Phone call visits will take place from Week 1-7 
x For all phone call visits, a standardized script will be used to inquire about general 
health, AEs, concomitant medications and to perform a diarrhea assessment. There will 
be no stool collection for Week 8 

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10.2.7. 
End of Efficacy Period Clinic Visit (Week 8) 
Subjects will be seen in the clinic at the study site or at a home visit at Week 8 (± 2 days). The 
home visit option for Cohort 1 is only during COVID-19 period, but for Cohort 2 is option 
throughout study. 
x Obtain stool sample from subject’s Week 8 at home collection and process, store, and 
ship per Laboratory Manual (Cohort 1 only). 
x Perform diarrhea assessment: 
 If subject has a suspected episode of CDI, obtain information regarding the day, 
frequency, and quality of bowel movements during diarrheal episodes. 
 If subject reports episode(s) of diarrhea ( 3 unformed stools per day) lasting 2 or 
more consecutive days, obtain stool sample. Complete Recurrence Visit 
assessments (see Section 10.3.3).  
x Assess AEs. 
x Review concomitant medications. 
x Perform a focused history and physical exam. 
x Collect blood and urine samples for the following laboratory tests:  
 Blood chemistry 
 Hematology 
 Urine pregnancy test, if applicable 
x The EQ-5D-5L and CDiff32 questionnaires will be administered. (for Cohort 1 only) 
x The EQ-5D-5L VAS using a paper questionnaire (for Cohort 2 only)  
x Bowel Cleanse Patient Satisfaction Survey Measure using a paper questionnaire (for 
Cohort 2 only)  
x Provide subject with stool collection kits as necessary. 
x Perform Drug Accountability 
10.3. 
Follow-up Period 
10.3.1. 
Phone Call Visits (Every 4 Weeks) 
Contact subject by phone at Weeks 12, 16 and 20 (± 3 days) to: 
x Perform diarrhea assessment: 
 If subject has a suspected episode of CDI, obtain information regarding the day, 
frequency, and quality of bowel movements during diarrheal episodes. 
 If subject reports episode(s) of diarrhea ( 3 unformed stools per day) lasting 2 or 
more consecutive days, arrange a Recurrence Visit (For Cohort 1) (see 
Section 10.3.3)  

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 Advise subject to continue diarrhea log, and collect stool sample for the Recurrence 
Visit  
 Advise subject not to initiate antibiotic treatment for CDI until advised to do so by 
the study investigator. 
x Assess AEs. 
x Review concomitant medications. 
x Remind subject to bring their Week 24 stool sample collected at home to the study site 
to be processed for shipment to the central laboratory or make arrangements for a 
courier for delivery to the study site (For Cohort 1). 
10.3.2. 
Phone Call Visit - Study Completion (Week 24) 
Contact subject by phone at Week 24 (± 3 days) to: 
x Perform diarrhea assessment: 
 If subject has a suspected episode of CDI, obtain information regarding the day, 
frequency, and quality of bowel movements during diarrheal episodes. 
 If subject reports episode(s) of diarrhea ( 3 unformed stools per day) lasting 2 or 
more consecutive days, obtain stool sample. Complete Recurrence Visit 
assessments (see Section 10.3.3).  
x Assess AEs. 
x Review concomitant medications.  
x The EQ-5D-5L questionnaire will be administered. (to be completed in Cohort 1 only) 
x Remind subject to bring their Week 24 stool sample collected at home to the study site 
to be processed for shipment to the central laboratory or make arrangements for a 
courier for delivery to the study site (Cohort 1 only) 
x Remind subject to either send their diarrhea device to the study site with the courier or 
bring it with them when they drop off their Week 24 stool sample. (Cohort 1 only) 
10.3.3. 
Recurrence and Early Termination (ET) Visits 
For Cohort 1, any subject suspected of having an episode of CDI per protocol definition  
unformed stools per day over 2 consecutive days) will be asked to contact the investigator and 
return to the clinic or have a home visit for a C. difficile stool test and evaluation for recurrence of 
CDI. Additionally, all subjects will be seen in the clinic or have a home visit if the subject 
withdraws early from the study, whenever possible. These home visits are permitted only during 
COVID-19. 
Perform the following assessments and procedures: 
x Obtain stool sample from subject’s at-home collection and process, store, and ship 
sample per Laboratory Manual. 
x Perform diarrhea assessment: 

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 If subject has a suspected episode of CDI that has not already been reported, obtain 
information regarding the day, frequency, and quality of bowel movements during 
diarrhea episodes. 
 If subject reports episode(s) of diarrhea ( 3 unformed stools per day) lasting 2 or 
more consecutive days, obtain stool sample. To inform subject care, a C. difficile 
test on unformed stool may be performed locally at the study site (see Laboratory 
Manual); ship stool to the central laboratory for C. difficile stool testing (see 
Laboratory Manual). The subject should not initiate antibiotics for CDI prior to 
providing a stool sample for the central laboratory stool testing. 
 If the C. difficile test on a stool sample determined by a toxin assay is positive and 
the investigator determines that antibiotic treatment is appropriate per protocol 
guidelines (see Section 8.7), prescribe standard of care antibiotic regimen to control 
CDI.  
 Advise subject to continue diarrhea log up until the day of initiation of antibiotic 
treatment for their CDI.  
x Assess AEs. 
x Review concomitant medications. 
x Perform a focused history and physical exam. 
x Collect blood and urine samples for the following laboratory tests:  
 Blood chemistry 
 Hematology 
 Serum for future biomedical research 
 Urine pregnancy test, if applicable 
x The EQ-5D-5L and CDiff32 questionnaires will be administered. (*Note: the CDiff32 
questionnaire should only be completed for an ET or Recurrence Visit prior to Week 
8). 
 
For Cohort 2, any subject suspected of having an episode of CDI per protocol definition  
unformed stools per day over 2 consecutive days) will be asked to contact the investigator and 
return to the clinic or have a home visit for a C. difficile stool test and evaluation for recurrence of 
CDI. Additionally, all subjects will be seen at home or in the clinic if the subject withdraws early 
from the study, whenever possible. 
x Perform diarrhea assessment: 
 If subject has a suspected episode of CDI that has not already been reported, 
obtain information regarding the day, frequency, and quality of bowel movements 
during diarrhea episodes. 
 If subject rHSRUWVHSLVRGHVRIGLDUUKHD unformed stools per day) lasting 2 or 
more consecutive days, obtain stool sample to ship to the central laboratory for C. 

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difficile stool testing (see Laboratory Manual). The subject should not initiate 
antibiotics for CDI prior to providing a stool sample for the central laboratory 
stool testing. 
 If the C. difficile test on a stool sample determined by a toxin assay is positive and 
the investigator determines that antibiotic treatment is appropriate per protocol 
guidelines (see Section 8.7), prescribe standard of care antibiotic regimen to 
control CDI.  
x Assess AEs 
x Review concomitant medications. 
x Perform a focused history and physical exam 
x If termination visit precedes 8 weeks, safety laboratory tests, EQ-5D-5L VAS, and 
Bowel Cleanse Patient Satisfaction Survey Measure will be performed using a paper 
questionnaire  
11. 
ASSESSMENT OF SAFETY AND ADVERSE EVENT REPORTING 
All AEs, SAEs/AESIs, and concomitant medications will be collected from the time of initiation 
of study drug up to Week 8. From Week 8 up to Week 24, all SAEs/AESIs and SAE/AESI-related 
data, and any antibiotic medication and its corresponding indication will be collected.  
The investigator is responsible for: 
x Informing the sponsor in the event that a subject 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. 
x Instructing subjects in the self-reporting of selected AEs including diarrhea and 
abdominal discomfort. 
x Evaluating subject safety including assessment of AEs for seriousness, severity, and 
causality. 
x Informing the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
of AEs as required and SAEs as per IRB/IEC guidelines. 
For the purpose of this study, an 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 related to the study drug. 
An SAE is any AE regardless of causality that: 
x Results in death. 

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x Is life threatening. Life threatening means that the subject was at immediate risk of 
death from the adverse event as it occurred. This does not include an event that, 
hypothetically had it occurred in a more severe form, it might have caused death.  
x Requires inpatient hospitalization or prolongation of existing hospitalization; hospital 
admissions and/or surgical operations scheduled to occur during the study period, but 
planned before study entry are not considered AEs if the illness or disease existed 
before the subject was enrolled in the study, provided that it did not worsen in any 
unexpected manner during the study (e.g., surgery performed earlier than planned). 
x Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a subject’s ability to conduct normal life functions. 
x Is associated with a congenital anomaly/birth defect. 
x 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, may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in 
the definition of an SAE. 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 inpatient 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, an invasive infection (e.g., bacteremia, abscess, meningitis) is designated as an 
AESI, and as such, will be reported and followed in the same manner as an SAE during the course 
of the study. 
All AEs, including SAEs and AESIs, will be graded for severity by using common terminology 
criteria for adverse events' (Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
Publish Date: May 28, 2009 with the exception of diarrhea.  Criteria for diarrhea severity will be 
as follows:   
x mild: 3-4 unformed bowel movements per day 
x moderate: 5-6 unformed bowel movements per day 
x VHYHUHXQIRUPHGERZHOPRYHPHQWVSHUGD\ 
 
In general, the severity of AEs can be assessed using following guidelines: 
Severity 
Description 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living* 

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 Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living 
(ADL)** 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. **Self-care ADL refer to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not bedridden. 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: 
x Is associated with accompanying symptoms; 
x Requires additional diagnostic testing or medical/surgical intervention; 
x Leads to a concomitant drug treatment or any change in a concomitant medication or 
therapy; 
x Is considered an AE by the investigator. 
Laboratory results that fall outside the reference range and do not meet one of the criteria above 
will not be reported as AEs. Repeating a test because of an abnormal result, in the absence of the 
above conditions, does not constitute an 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: 
x 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 
x 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. Additionally, serious criteria will be collected for all SAEs. 
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. 
With regards to events of diarrhea, diarrhea that meets the protocol definition of CDI recurrence 
XQIRUPHd stools per day over 2 or more consecutive days and the requirement that subjects 
must continue to have diarrhea until antibiotic treatment is initiated, a positive C. difficile test on 

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a stool sample determined by a toxin assay, and assessment by the investigator that treatment is 
required) should NOT be entered as an AE. Events of diarrhea that are not associated with CDI 
recurrence (e.g., due to food poisoning or flu), should be reported as an AE (e.g., Diarrhea [Not 
CDI related]). Other symptoms associated with CDI recurrence, e.g. abdominal pain, abdominal 
distension, should be reported as adverse events. 
When CDI recurrence is deemed serious due to hospitalization, CDI recurrence should be included 
as an SAE term and recorded as the reason for hospitalization in the Hospitalization CRF page. 
11.1. 
Serious Adverse Event Reporting 
The sponsor has requirements for expedited reporting of SAEs meeting specific criteria to 
worldwide regulatory authorities. Therefore, the sponsor (or sponsor’s designee) must be notified 
immediately regarding any SAE that occurs after administration of the study drug. 
All SAEs must be reported to the medical monitor within 24 hours of knowledge of the event at 
the study site. Refer to the Investigator Site File for detailed instructions. 
The study site will transmit an SAE report (SAER) to the sponsor or sponsor’s designee by 
facsimile or email. The study site will be provided with SAER forms wherein the following 
information is requested: 
x Subject identification, investigator name, and study site number 
x SAE information: event term, onset date, severity, and causal relationship to study drug 
x The outcomes attributable to the event (i.e. serious criteria) (e.g., death, life threatening, 
inpatient hospitalization, prolongation of existing hospitalization, a congenital 
anomaly, a persistent or significant disability or incapacity, or other important medical 
event) 
x A summary of relevant test results, pertinent laboratory data, and any other relevant 
medical history 
x The date of study drug administration 
x Whether or not the study drug was discontinued 
x Supplemental information, which may include the following hospital records: 
laboratory results, radiology reports, progress notes, admission and emergency room 
notes, holding and observation notes, discharge summaries, autopsy reports, and death 
certificates 
In addition, relevant eCRF pages should be appended to communicate relevant study drug and 
subject outcome information. 
The SAER should be faxed or emailed within 24 hours with as much of the above information as 
available at the time. The following minimum information is required for an initial SAE report: 
subject identification, reporting source (i.e., Site Name and Site Number), and an event or 
outcome. Supplemental information may be transmitted by using a follow-up report and should 
not delay the initial report. The sponsor may contact the study site to solicit additional information 
or follow-up on the event. 

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The investigator must take all therapeutic measures necessary for resolution of the SAE. Any 
medications or procedures necessary for treatment of the SAE must be recorded in the appropriate 
pages of the subject’s eCRF. 
12. 
STATISTICAL METHODS 
12.1. 
STUDY ENDPOINTS  
12.1.1. 
Primary Efficacy Endpoint  
For Cohort 1, recurrence of CDI or sustained clinical response as determined by a toxin assay up 
to 8 weeks after initiation of treatment is the primary efficacy endpoint. A recurrence is defined as 
 unformed stools per day for 2 consecutive days and the requirement that subjects must continue 
to have diarrhea until antibiotic treatment is initiated, with a positive C. difficile test on a stool 
sample determined by a toxin assay, and assessment by the investigator that the clinical condition 
of the subject warrants antibiotic treatment. 
For Cohort 2, recurrence of CDI or sustained clinical response as determined by a toxin assay up 
to 8 and 12 weeks after initiation of treatment are the efficacy endpoints. 
12.1.2. 
Secondary Efficacy Endpoints 
For Cohort 1, secondary efficacy endpoints are the following: 
x Recurrence of CDI as determined by PCR algorithm up to 8 weeks after initiation of 
treatment  
x Time to recurrence of CDI from initiation of treatment as determined by a toxin assay  
x Time to recurrence of CDI from initiation of treatment as determined by PCR algorithm 
x Recurrence of CDI, as determined by a toxin assay, up to 4, 12 and 24 weeks after 
initiation of treatment 
x Recurrence of CDI, as determined by a PCR algorithm, up to 4, 12 and 24 weeks after 
initiation of treatment 
For Cohort 2, secondary efficacy endpoints are not being sought. 
12.1.3. 
Exploratory Efficacy Endpoints 
For Cohort 1, exploratory endpoints are the following: 
x Change in the composition of the gut microbiome from Baseline up to 1, 2, 8, and 24 
weeks after initiation of treatment 
x Change in the fecal metabolome from Baseline up to 1, 2, and 8 weeks after initiation 
of treatment 
x Incidence of mortality from all causes up to 8 and 24 weeks after initiation of treatment  
x Incidence of hospitalizations for recurrent CDI up to 8 and 24 weeks after initiation of 
treatment 

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x Incidence of all hospitalizations up to 8 and 24 weeks after initiation of treatment  
x Total length of stay (days) of hospitalization, including days in the intensive care unit, 
up to 24 weeks after treatment initiation (for subjects hospitalized) 
x Changes from Baseline in Health-Related Quality of Life (HRQoL) and health 
outcomes as assessed by the EQ-5D-5L from Day 1 through Weeks 8 and 24, and 
assessed by the Cdiff32 HRQoL from Day 1 to Week 1 and Week 8, or at an ET or 
Recurrence visit prior to Week 8, after initiation of treatment  
For Cohort 2, exploratory endpoints are the following: 
x Change in the composition of the gut microbiome from Baseline up to 1 week after 
initiation of treatment in a subgroup of up to approximately 50 subjects 
x Change in the fecal metabolome from Baseline up to 1 week after initiation of treatment 
in a subgroup of up to approximately 50 subjects. 
x Incidence of mortality from all causes up to 8 and 24 weeks after initiation of treatment  
x Incidence of hospitalizations for recurrent CDI up to 8 and 24 weeks after initiation of 
treatment 
x Incidence of all hospitalizations up to 8 and 24 weeks after initiation of treatment  
x Total length of stay (days) of hospitalization, including days in the intensive care unit, 
up to 24 weeks after treatment initiation (for subjects hospitalized) 
x Change in EQ-5D-5L visual analog score from Screening to Week 8 visit after initiation 
of treatment 
x Assess Bowel Cleanse Patient Satisfaction Survey Measure at Week 8  
12.1.4. 
Safety Endpoints 
Safety endpoints are the following: 
x Incidence of AEs 
x Laboratory evaluation results 
x Vital sign measurements 
x Physical examination findings 
12.2. 
Analysis Populations 
Three analysis populations will be defined: 
x Intent-to-Treat (ITT) Analysis Population. The ITT Population will consist of all 
enrolled subjects. 
x Modified Intent-to-Treat (mITT) Analysis Population. The mITT Population will be 
composed of all enrolled subjects who received any amount of SER-109, whose CDI 
was clinically controlled by antibiotic treatment before receiving SER-109, and who 
have at least 1 post-baseline evaluation.  

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x Safety Population. The Safety Population will consist of all enrolled subjects who 
received any amount of SER-109. All safety analyses will be conducted based on the 
Safety Population. 
12.3. 
Determination of Sample Size 
Approximately 30 subjects are anticipated to enroll from SERES-012 (Cohort 1). The recurrence 
rates prior to 8 weeks after initiation of study drug assumed in SERES-012 are 16% in SER109 
and 36% in placebo. However, it is expected that only a fraction of subjects who recur in SERES-
012 prior to 8 weeks will roll-over to this study, since a follow-up of 8 weeks from start of study 
drug in earlier protocol versions of SERES-012 (up through and including Amendment 5) was 
required before rolling over to SERES-013, regardless of when the CDI recurrence occurred in 
SERES-012. Additionally, 200 subjects with RCDI may enroll in the Open-Label program (Cohort 
2) into SERES-013. Approximately 230 subjects total will be assessed for safety and tolerability, 
and efficacy. 
12.4. 
General Statistical Considerations 
Descriptive statistics, including the numbers and percentages for dichotomous or categorical 
variables, and the numbers, means, standard deviations, medians, minimums, and maximums for 
continuous variables will be provided. Listings of individual subject data will be produced.  
All summary tables will be presented based on the following groups: For Cohort 1, 1) Subjects 
who were randomized to SER-109 in SERES-012, 2) Subjects who were randomized to placebo 
in SERES-012, 3) Overall (groups 1 and 2 combined).  For Safety and Tolerability and Primary 
Efficacy, summary tables will include an additional fourth group consisting of Cohort 2 . The 
safety summary will be presented combining all subjects (pooling cohort 1 and cohort 2). 
A comprehensive statistical analysis plan (SAP) will be submitted to regulatory authorities. 
12.5. 
Subject Population and Baseline Characteristics 
Enrollment, protocol deviations, and discontinuations from the study will be summarized by group 
for the ITT Population. Demographics (e.g., age, race, ethnicity, sex), baseline characteristics 
(e.g., weight,), medical history, and other baseline characteristics will be summarized by group for 
the Safety, ITT and mITT Populations. 
12.6. 
Study Drug Exposure 
SER-109 exposure will be summarized as the total number of capsules taken with counts and 
percentages of subjects by group. The summary will be presented for the Safety, ITT, and mITT 
Populations.  
12.7. 
Efficacy Analysis 
12.7.1. 
Primary Efficacy Analysis 
For Cohort 1, the primary efficacy endpoint is the recurrence of CDI up to Week 8 in the ITT 
Population. Subjects will be categorized as having favorable (no CDI recurrence or sustained 
clinical response) or unfavorable outcomes (had CDI recurrence). The number and percentage of 

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subjects defined as having favorable (sustained clinical response) and unfavorable (had CDI 
recurrence) outcomes will be reported with exact 95% confidence intervals (CIs) for each group. 
The CIs will be derived using the Clopper-Pearson exact method (Clopper and Pearson, 1934). 
Subjects who are lost to follow-up, terminated the trial early, or died without a recorded recurrence 
of CDI before Week 8 will be defined as having an unfavorable outcome for the primary analysis. 
Subjects who miss any contact with the site (phone calls or the Week 2 visit) before Week 8 but 
ZKRGRQRWUHSRUWRUPRUHFRQVHFXWLYHGD\VZLWK 3 unformed stools at the subsequent contact 
will be defined as having a favorable outcome (or sustained clinical response) for the primary 
analysis. Additional rules for imputing CDI recurrence status for subjects with at least one 
component of the CDI recurrence endpoint criteria missing will be provided in the SAP.  
For Cohort 2. the efficacy endpoint is the recurrence of CDI up to Week 8 or 12 in the ITT 
Population. Subjects will be categorized as having favorable (no CDI recurrence or sustained 
clinical response) or unfavorable outcomes (had CDI recurrence). The number and percentage of 
subjects defined as having favorable (sustained clinical response) and unfavorable (had CDI 
recurrence) outcomes will be reported with exact 95% confidence intervals (CIs) for each group. 
The CIs will be derived using the Clopper-Pearson exact method (Clopper and Pearson, 1934). For 
the Week 8 analysis, subjects who are lost to follow-up, terminated the trial early, or died without 
a recorded recurrence of CDI before Week 8 will be defined as having an unfavorable outcome for 
the efficacy analysis. Subjects who miss any contact with the site (phone calls or the Week 2 visit) 
before Week 8 EXWZKRGRQRWUHSRUWRUPRUHFRQVHFXWLYHGD\VZLWK 3 unformed stools at the 
subsequent contact will be defined as having a favorable outcome (or sustained clinical response) 
for the analysis.  For the Week 12 analysis, subjects who are lost to follow-up, terminated the trial 
early, or died without a recorded recurrence of CDI before Week 12 will be defined as having an 
unfavorable outcome for the efficacy analysis. Subjects who miss any contact with the site (phone 
calls or the Week 2 visit) before Week 12 but who do not report 2 or more consecutive days with 
 3 unformed stools at the subsequent contact will be defined as having a favorable outcome (or 
sustained clinical response) for the analysis.  Additional rules for imputing CDI recurrence status 
for subjects with at least one component of the CDI recurrence endpoint criteria missing will be 
provided in the SAP. 
12.7.2. 
Sensitivity Analysis for the Primary Efficacy Endpoint 
Sensitivity analyses of the primary efficacy endpoint as described in Section 12.7.1 will also be 
conducted as follows:  
x For Cohort 1, all subjects who are lost to follow-up, terminated the study prematurely, 
or died without having a CDI recurrence by Week 8, will be considered to have a 
favorable outcome (sustained clinical response). Subjects who missed any contact with 
the site before Week 8 (phone calls or the Week 2 visit) but who do not report 2 or 
PRUHFRQVHFXWLYHGD\VZLWK 3 unformed stools at the subsequent contact will continue 
to be defined as having a favorable outcome (sustained clinical response) for this 
analysis, which will be conducted in the ITT Population  
x For Cohort 2, all subjects who are lost to follow-up, terminated the study prematurely, 
or died without having a CDI recurrence by Week 8 or 12, will be considered to have 
a favorable outcome (sustained clinical response) in the two analyses. 
The primary efficacy outcome will also be analyzed for the mITT Population.  

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12.7.3. 
Secondary Efficacy Analysis (applies to Cohort 1 only) 
Time to recurrence of CDI will be summarized by group for the ITT and mITT Populations using 
the median, 25th and 75th percentiles from a Kaplan Meier- analysis. The 95% CI for the median 
will also be provided. Subjects who complete the follow-up period and do not experience a CDI 
recurrence by the end of the follow-up period will be censored on the date of last contact. Subjects 
who are lost to follow-up or who terminated the study prematurely before experiencing a CDI 
recurrence will be censored in the analysis on the date of last contact. Subjects who die before 
having a CDI recurrence will be censored on the date of death. Subjects who were assessed to have 
a CDI recurrence due to missing or incomplete data for one or more of the 3 components of CDI 
recurrence will not be counted as an event, but censored on their last date of contact. Subjects who 
were not dosed will have their time to recurrence measured from their enrollment date. 
12.8. 
Exploratory Analysis 
The exploratory endpoints will be summarized descriptively for the mITT populations. Mean, 
median, standard deviation, maximum and minimum will be presented for continuous variable. 
Count, Percentage and total will be presented for categorical variables. More details of the 
exploratory efficacy endpoints will be specified in the SAP. 
12.9. 
Safety Analysis 
All safety analyses will be conducted in the Safety Population.  All safety summary tables will be 
presented for the following groups: 1) Cohort 1 2) Cohort 2 3) all subjects pooling Cohorts 1 and 
2.  Any additional analyses will be detailed in the SAP. 
Adverse events will be coded by using the Medical Dictionary for Regulatory Activities 
(MedDRA). Summary tables of TEAEs will be provided. A TEAE is any AE that newly appeared, 
increased in frequency, or worsened in severity after initiation of SER-109. A listing of all AEs, 
including those occurring before the start of study drug, will be provided. The percentage of 
patients with TEAEs will be tabulated by system organ class and preferred term on Day 10, Week 
2, Week 8 and Week 24. The incidence of TEAEs by system organ class and preferred term, by 
severity, and by relationship to treatment on Day 10, Week 2, Week 8 and Week 24 will also be 
presented. Tables of any TEAE leading to SER-109 discontinuation and SAEs will also be 
provided.   
An additional analysis will determine the incidence of TEAEs based on the number of days the 
patients were followed before receiving antibiotics for treatment of recurrent CDI. The incidence 
of TEAEs per patient for days before receiving antibiotics will be tabulated by system organ class 
and preferred term, and by severity and relationship to treatment.   
Descriptive statistics of the laboratory parameters and vital sign measurements will be presented 
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. Laboratory parameters 
will be defined, as within or outside normal limits, and shift tables from baseline to each 
postbaseline visit will be provided.   

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12.10. 
Handling of Missing Data 
Every effort will be made to collect all data at specified times, according to the schedule of study 
events. 
For the primary endpoint in Cohort 1, subjects who are lost-to-follow-up, terminated from the 
study prematurely, or died without a CDI recurrence before 8 weeks after treatment are defined as 
having an unfavorable outcome for the primary analysis. Subjects who miss any contact with the 
site before Week 8 (phone calls or Week 2 visit) but who do not report 2 or more consecutive days 
ZLWK 3 unformed stools at the subsequent telephone contact or by Week 8 will be defined as 
having a favorable outcome for the primary analysis. If the Week 8 visit is missed, a subject will 
be considered as having an unfavorable outcome for the primary analysis if he reports 2 or more 
FRQVHFXWLYHGD\VZLWK 3 unformed stools at the next unmissed telephone contact or visit. If any 
of the 3 components of the CDI recurrence criteria is missing, and the non-missing components 
meet the CDI recurrence criteria, then an unfavorable outcome for the primary analysis is imputed. 
However, if some of the 3 components of the CDI recurrence criteria are missing, and at least 1 of 
the non-missing components does not meet the CDI recurrence criteria, then a favorable outcome 
for the primary analysis is imputed. The imputed recurrence status for subjects who have at least 
one component of the CDI recurrence endpoint criteria missing will be detailed in the SAP. 
For the efficacy endpoints determined at 2 timepoints in Cohort 2, subjects who are lost-to-follow-
up, terminated from the study prematurely, or died without a CDI recurrence before 8 (or 12) 
weeks after treatment are defined as having an unfavorable outcome for the primary analysis. 
Subjects who miss any contact with the site before Week 8 (or 12) (phone calls) but who do not 
UHSRUWRUPRUHFRQVHFXWLYHGD\VZLWK 3 unformed stools at the subsequent telephone contact or 
by Week 8 (or 12) will be defined as having a favorable outcome for the primary analysis. If the 
Week 8 (or 12) visit is missed, a subject will be considered as having an unfavorable outcome for 
the primary analysis if he repoUWVRUPRUHFRQVHFXWLYHGD\VZLWK 3 unformed stools at the next 
unmissed telephone contact or visit. If any of the 3 components of the CDI recurrence criteria is 
missing, and the non-missing components meet the CDI recurrence criteria, then an unfavorable 
outcome for the primary analysis is imputed. 
Missing data for the time to CDI recurrence analyses will be handled with censoring by the Kaplan-
Meier method. Subjects who complete the study and do not experience a CDI recurrence by the 
end of the follow-up period will be censored on the date of last contact. Subjects who are lost to 
follow-up or who terminate the trial prematurely before experiencing a CDI recurrence will be 
censored on the date of last contact. Subjects who die before experiencing a CDI recurrence will 
be censored on their date of death. Subjects who were assessed to have a CDI recurrence due to 
missing or incomplete data for one or more of the 3 components of CDI recurrence will not be 
counted as an event, but censored on their last date of contact. Sensitivity analyses of the time to 
recurrence endpoint will be provided in the SAP. 
No other imputations for missing data will be made (except as detailed in the SAP for missing 
dates and times). 

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13. 
ADMINISTRATIVE REQUIREMENTS 
13.1. 
Good Clinical Practice 
This study will be conducted in accordance with the International Conference on Harmonisation 
(ICH) guidelines for Good Clinical Practice (GCP) and the appropriate regulatory requirements. 
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. 
x The principal investigator has the overall responsibility for the conduct and 
administration of the study at the study site and for contacts with the sponsor, the 
IRB/IEC, and local authorities. 
x The principal investigator is responsible for ensuring the privacy, health, and welfare 
of the subjects during and after the clinical study.  
x 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. 
x 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. 
x 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. 
13.2. 
Trial Governance and Oversight 
This study was developed in collaboration with a Clinical Advisory Committee, which comprises 
both sponsor-employed and independent scientific experts who provide input on study design, 
interpretation of study results, and subsequent peer reviewed scientific publications. 
13.3. 
Ethical Considerations 
This 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. 

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13.4. 
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 or their legally 
authorized representative (LAR) in accordance with local practice and regulations. 
For Cohort 2, a prescreen consent will be available for testing the stool for C. difficile toxin or 
PCR assay either at the local or central laboratory.  The central laboratory will test with the PCR 
assay for eligibility. 
The background of the proposed study, procedures, and benefits and risks of the study must be 
explained to the subject or LAR. The subject or LAR must be given sufficient time to consider 
whether to participate in the study. 
A copy of the ICF, signed and dated by the subject or LAR, must be given to the subject or LAR. 
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. 
13.5. 
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 a regulatory authority 
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. 
13.6. 
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. Study sites that fail to comply may be terminated. 
13.7. 
Future Use of Stored Specimens 
The sponsor may, where permitted by local regulations, conduct future biomedical research on 
specimens (including serum, and stool) routinely and specifically collected during this clinical 
study for potential commercial use by Seres Therapeutics, Inc., and specimens may be stored for 
up to 10 years.  
13.8. 
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 

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operating procedures, GCP, and the applicable regulatory requirement(s).” The purpose of 
monitoring is to verify that: 
x The rights and well-being of the human subjects are protected. 
x The reported study data are accurate, complete, and verifiable from source documents. 
x 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 study 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. 
13.9. 
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 study 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 study site (including the electronic audit trail) will be maintained 
or made available at the study 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.  
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 sub--investigator, 
after review of the data in the eCRF, will confirm the validity of each subject’s data by electronic 
signature. This electronic signature will be certified as outlined in 21 CFR Part 11. 
The sponsor will retain the original eCRF data and audit trail. An electronic or certified paper copy 
of all completed eCRF data, including query resolution correspondence, will be provided to the 
investigator at the end of the study. 

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13.10. 
Study Completion 
The sponsor requires the following data and materials to be submitted before a study can be 
considered complete or terminated: 
x Laboratory findings, clinical data, and all special test results from the time of informed 
consent through the End of Study Visit at Week 24 
x Electronic CRFs properly completed by appropriate study personnel and signed and 
dated by the investigator 
x Complete study drug accountability records  
x Copies of IRB/IEC approval and notification of the original protocol and of any 
protocol amendments, if appropriate 
x A summary of the study prepared by the investigator (an IRB/IEC summary letter is 
acceptable) 

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14. 
LIST OF REFERENCES 
Anderson MJ, Walsh DCI. PERMANOVA, ANOSIM, and the Mantel test in the face of 
heterogeneous dispersions: what null hypothesis are you testing? Ecol Monogr. 2013;83(4):557 
74. 
Bakken JS, Borody T, Brandt LJ, Brill JV, Demarco DC, Franzos MA, et al; Fecal Microbiota 
Transplantation Workgroup. Treating Clostridium difficile infection with fecal microbiota 
transplantation. Clin Gastroenterol Hepatol. 2011 Dec;9(12):1044 9.  
Centers for Disease Control and Prevention. Clostridium difficile infection. Available from: 
http://www.cdc.gov/hai/organisms/cdiff/Cdiff_infect.html. Accessed 2015 Mar 01. 
Chao A. Nonparametric estimation of the number of classes in a population. Scand J Statist. 
1984;11(4):265 70. 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika 1934; Vol. 26 (4): 404-13. 
Colwell RK, Coddington JA. Estimating terrestrial biodiversity through extrapolation. Philos 
Trans R Soc Lond B Biol Sci. 1994 Jul 29;345(1311):101 18. 
Cornely AO, Vehreschild MJGT, Adomakoh N, Georgopali A, Karas A, Kazeem G. Guery B. 
Extended pulsed fidaxomicin versus vancomycin for C. difficile infection: EXTEND study 
subgroup analysis.   Eur J Clin Microbiol and Inf Dis 2019; 38: 1187-94 
Depestel DD, Aronoff DM. Epidemiology of Clostridium difficile infection. J Pharm Pract. 2013 
Oct;26(5):464 75.  
Farrington CP, Manning G. Test statistics and sample size formulae for comparative binomial 
trials with null hypothesis of non-zero risk difference or non-unity relative risk. Statistics In 
Medicine. 1990 May;1447-1454. 
Garey KW, Aitken SL, Gschwind L, Goddu S, Xie Y, Duff C, et al. Development and validation 
of a Clostridium difficile health-related quality-of-life questionnaire. J Clin Gastroenterol. 2016 
Sep;50(8):631-7. 
Hatoum HT, Lin SJ, Joseph RE, Dabdal DN. Validation of a patient satisfactions scale in patients 
undergoing bowel preparation prior to colonoscopy. Patient. 2016;9:27-34. 
Higa JT, Kelly CP. New drugs and strategies for management of Clostridium difficile colitis. J 
Intensive Care Med. 2013 Feb 7;29(4):190 9. 
Hughes JB, Hellmann JJ, Ricketts TH, Bohannan BJ. Counting the uncountable: statistical 
approaches to estimating microbial diversity. Appl Environ Microbiol. 2001 Oct;67(10):4399 406. 
Lessa FC, Mu Y, Bamberg WM, Beldavs ZG, Dumyati GK, Dunn JR, et al. Burden of Clostridium 
difficile infection in the United States. N Engl J Med. 2015 Feb 26;372(9):825 34. 
Levy A. et. al. (2015) Incidence and Costs of Clostridium difficile Infections in Canada, OFID, 1-
10. 
McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, et al. Clinical practice 
guidelines for Clostridium difficile infection in adults and children: 2017 Update by the Infectious 

Seres Therapeutics, Inc.  
 
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Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America 
(SHEA). Clin Infect Dis 2018;66:e1-e48. 
National Cancer Institute, Common Terminology Criteria for Adverse Events v4.0, NCI, NIH, 
DHHS. May 29, 2009, NIH publication # 09-7473 
Ng KM, Ferreyra JA, Higginbottom SK, Lynch JB, Kashyap PC, Gopinath S, et al. Microbiota 
liberated host sugars facilitate post antibiotic expansion of enteric pathogens. Nature. 2013 Oct 
3:502(7469):96 9.  
Polange, CM, Gyorke CE, Kennedy MA, Leslie JL, Chin DL, Wang S, et al. Overdiagnosis of 
Clostridium difficile infection in the molecular test era. JAMA Intern Med. 2015 
Nov;175(11):1792-801. 
Surawicz CM, Brandt LJ, Binion DG, Ananthakrishnan AN, Curry SR, Gilligan PH, et al. 
Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J 
Gastroenterol. 2013 Apr;108(4):478 98. 
Theriot CM, Koenigsknecht MJ, Carlson PE Jr, Hatton GE, Nelson AM, Li B, et al. Antibiotic 
induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium 
difficile infection. Nat Commun. 2014;5:3114. 
Wadhwa A, Al Nahhas MF, Dierkhising RA, Patel R, et al. High risk of post-infectious irritable 
bowel syndrome in patients with Clostridium difficile infection. Aliment Pharmacol Ther. 2016 
Jul 22. doi: 10.1111/apt.13737. 
Weingarden AR, Chen C, Bobr A, Yao D, Lu Y, Nelson VM, et al. Microbiota transplantation 
restores normal fecal bile acid composition in recurrent Clostridium difficile infection. Am J 
Physiol Gastrointest Liver Physiol. 2014 Feb 15;306(4):G310 9.