Clinical trial NCT03005379
Conditions: Clostridium Difficile Infection
Keywords: FMT recurrent c. difficile infectious disease intestine clinical trial gastrointestinal prevention randomized diarrhea fecal microbiota therapy
Sponsor: VA Office of Research and Development
Start date: 2018-11-15; Completion date: 2023-01-31
Enrollment: 153 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether Fecal Microbiota Therapy (FMT) is effective vs. placebo in the prevention of C. difficile infection recurrence.

Detailed description:
Clostridium difficile infection (CDI) is one of the most common nosocomial infections and is increasingly seen in non-hospitalized patients. Although more than 90% of patients have symptom resolution with a course of standard antimicrobial therapy, subsequent recurrence rates range from 15-30% (after the first CDI episode) to 40-50% (after the second and subsequent episodes). Fecal microbiota transplantation (FMT) has shown promise as an adjunct to standard antimicrobial therapy, reducing recurrence among FMT recipients to 15%.

The primary study goal is to assess the efficacy of FMT for the prevention of subsequent recurrent CDI, when administered after successful treatment of recurrent CDI with standard antimicrobial therapy. Secondary goals are to evaluate, the efficacy of FMT in terms of CDI severity, duration, the safety of FMT, and in the event of a positive study result, establish a mechanism for providing FMT within the VA system.

This study will enroll 390 participants. Participants will be randomized (1:1 ratio) to FMT or placebo, stratified by number of prior recurrent CDI episodes (1 versus \>1). They will be assessed for symptoms of CDI, other study outcomes and any treatment-related adverse events at 2, 14, 28, 42, and 56 days, and month 3, 4, 5 and 6 after administration of the study treatment.

The primary outcome is recurrent CDI (definite or possible) or death within 56 days of randomization.

Definite recurrence is defined as any of the following: The new onset of more than three loose or watery stools in 24 hours for two consecutive days, not explained by another diagnosis; Other clinical symptoms including ileus, toxic megacolon, or colectomy; plus laboratory confirmation of C. difficile from a stool specimen by toxin Enzyme Immunoassays (EIA) test. Possible recurrence is defined as the same clinical manifestations as above, but without laboratory confirmation of C. difficile (stool test not sent, negative EIA toxin test result, or uninterpretable result).

Arms: arm 1: Fecal Microbiota Therapy (FMT) arm 2: Placebo
Interventions: intervention 1: Fecal Microbiota Therapy (FMT) intervention 2: Placebo
Intervention descriptions: intervention 1: Oral capsule-delivered FMT intervention 2: Oral capsule-delivered placebo

Protocol documents:
ICF_002.pdf: 
Official Title: CSP 2004, Microbiota or Placebo After Antimicrobial Therapy for Recurrent C. Difficile at 
Home (MATCH)  
NCT Number: NCT03005379 
Document Type: Informed Consent Form 
Document Date: 05/23/2022 


I
1930271777 
7 
L 
Department of Veterans Affairs 
IRB #: 
4713-B 
Date: [I] / [I] / I I I I I (mmldd/yyyy) 
VA RESEARCH CONSENT FORM 
(Page 1 of 11)
Participant ID: I I I I I I 
Title of Study: MATCH: Microbiota or placebo after Antimicrobial Therapy for recurrent C. difficile at Home 
Principal Investigator: Andrew Reinink MD 
V AMC: Minneapolis - 618
Principal Investigators for Multisite Study: Aasma Shaukat, MD MPH, and Dimitri Drekonja, MD MS
IN-PERSON CONSENT FORM 
INTRODUCTION 
It is important that you read and understand the following explanation of the proposed research 
study before you agree to participate. This consent form describes: 
• The purpose,
• The description of the study,
• The benefits,
• The risks and/or discomforts,
• Steps taken to decrease or eliminate the risks, discomforts, or possible pain,
• Any other treatments that may be available, and
• Confidentiality and use of research results.
This consent form may contain words you do not understand. Please ask the study doctor 
or the study staff to explain any words or information that are not clear to you. 
PURPOSE OF THE STUDY 
You are being asked to voluntarily participate in a research study because you have justcompleted 
treatment for an episode of Clostridioides difficile infection that recurred after at least 
one previous episode. This study is being done to find out whether fecal microbiota 
transplantation (also known as a "stool transplant" or "fecal transplant"), is an effective treatment 
to prevent future episodes of Clostridioides difficile infection, when it is given after a course of 
antibiotics as the initial treatment. In this study, you will be randomized (like the flip of a coin) to 
receive fecal transplant or placebo after having a favorable response to a standard course of 
antibiotic treatment. Placebo treatment will appear identical to fecal transplant, but contains no 
fecal material or other medicine. 
Patients are thought to be at risk for Clostridioides difficile infection when the normal communities 
of microbes (the microbiota) that live in the colon (large intestine) are disrupted, which is usually 
due to antibiotic use. A normal or healthy microbiota is made up of hundreds of different types 
of bacteria, containing trillions of individual bacteria. This healthy micro biota is believed to be a 
barrier for disease-causing bacteria like Clostridioides difficile to enter the colon and cause disease. 
An unhealthy, or disrupted, micro biota is one where the diversity and number of bacteria is 
decreased, making it easier for Clostridium difficile to enter and cause disease. Patients who have 
just completed treatment for an episode of Clostridioides difficile infection have a very disrupted 
Printed name and last 4 of SS# (If addressograph 
label is used, please mask all other information) 
I I I I I 
VA Form 10-1086
Version date 4/19/2022 
Effective date of consent form as indicated by 
provided MV ARCS IRB approval stamp. 
los,2312022 
I 
June 1990 
MV ARCS form revised October 2015 
Minneapolis VA Health Care System IRB (Institutional Review 
Board) 
Effective Date: 
May 23, 2022 





















Prot_000.pdf: 
 
    VA Cooperative Studies Program #2004 
     
Microbiota or Placebo after Antimicrobial Therapy  
for Recurrent C. difficile at Home 
 
 
 
 
 
Protocol 
Version 3.4 
May 2, 2022 
 
 
Principal Investigators: Dimitri Drekonja, MD, MS   
Aasma Shaukat, MD, MPH 
Biostatisticians: 
Jane Zhang, Ph.D. 
 
 
 
 
 
 
 
PRIVILEGED AND CONFIDENTIAL 
 
Not For Distribution Beyond the 
Official Committee Function and Use 


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Protocol Chronology 
 
Protocol Version # / Amendment # 
Date of Protocol / Amendment 
CSSEC Protocol 
10/28/15 
V1.1 (After CSSEC) 
8/25/16 
V1.2 (Interim Draft) 
7/18/17 
V2.0 (Interim Draft) 
4/27/18 
V3.0 (Kick-off Version) 
9/6/18 
V3.1 (Update due to FDA Safety Memo) 
7/16/19 
V3.2 (Update for processing consent and randomization 
with VVC)   
7/16/2020 
V3.3 (Exclusion criteria change, AE/SAE clarification, 
update to ICF COVID language. 
10/15/2021 
V3.4 (Update for use of DocuSign as a method of 
signing Informed Consent form, update the modification 
of sample size, reduction in power, drop out rate, and 
enrollment  time) 
5/2/2022 
 
 
 


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CSP #2004, MATCH, Protocol Version 3.4 
 
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TABLE OF CONTENTS 
LETTERS OF SUBMITTAL......................................................................................................................I 
EXECUTIVE SUMMARY/ABSTRACT ................................................................................................ XI 
PLANNING COMMITTEE .................................................................................................................. XV 
I. 
INTRODUCTION AND BACKGROUND ..................................................................................... 1 
 BACKGROUND ..................................................................................................................................................... 1 
 FECAL MICROBIOTA THERAPY (FMT) ....................................................................................................................... 2 
 STUDY RATIONALE ................................................................................................................................................ 3 
 SUMMARY OF STUDY GOALS .................................................................................................................................. 3 
II. 
STUDY OBJECTIVES AND HYPOTHESES ............................................................................... 5 
 PRIMARY OBJECTIVE ............................................................................................................................................. 5 
 SECONDARY OBJECTIVES ........................................................................................................................................ 5 
 SAFETY OBJECTIVES .............................................................................................................................................. 6 
 EXPLORATORY ANALYSES ....................................................................................................................................... 6 
III. 
SUMMARY OF STUDY DESIGN .................................................................................................. 7 
A. OVERVIEW .......................................................................................................................................................... 7 
B. STUDY POPULATION AND RATIONALE ....................................................................................................................... 9 
C. INCLUSION CRITERIA ........................................................................................................................................... 11 
D. EXCLUSION CRITERIA ........................................................................................................................................... 12 
E. TREATMENTS AND RATIONALE .............................................................................................................................. 12 
F. OUTCOME MEASURES AND RATIONALE .................................................................................................................. 13 
G. SAMPLE SIZE ..................................................................................................................................................... 15 
H. DATA COLLECTION AND FOLLOW-UP ...................................................................................................................... 16 
I. ALTERNATE DESIGN CONSIDERATIONS .................................................................................................................... 18 
IV. 
IMPORTANCE TO THE VETERANS ADMINISTRATION ................................................... 21 
V. 
STUDY POPULATION ................................................................................................................. 23 
A. INCLUSION CRITERIA ........................................................................................................................................... 23 
B. EXCLUSION CRITERIA ........................................................................................................................................... 23 
C. INCLUSION OF WOMEN AND MINORITIES ................................................................................................................ 27 
VI. 
HUMAN RIGHTS ISSUES AND INFORMED CONSENT PROCEDURES .......................... 29 
A. RISKS AND BENEFITS ........................................................................................................................................... 29 
B. INFORMED CONSENT PROCESS .............................................................................................................................. 30 
C. WITHDRAWAL ................................................................................................................................................... 31 
VII. OUTCOME MEASURES AND RATIONALE ............................................................................ 33 
A. PRIMARY OUTCOME ........................................................................................................................................... 33 
B. SECONDARY OUTCOMES ...................................................................................................................................... 35 
C. SAFETY OUTCOMES ............................................................................................................................................ 38 
D. OUTCOME MEASUREMENTS IN EXPLORATORY ANALYSES ........................................................................................... 39 
VIII. BASELINE ASSESSMENTS AND PROCEDURES ................................................................... 41 
A. RECRUITMENT AND SCREENING ............................................................................................................................. 41 
B. BASELINE DATA COLLECTION ................................................................................................................................ 43 
C. TREATMENT ADMINISTRATION .............................................................................................................................. 44 
D. STOOL SPECIMENS .............................................................................................................................................. 44 


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IX. 
STRATIFICATION AND RANDOMIZATION.......................................................................... 47 
A. STRATIFICATION OF RANDOMIZATION ..................................................................................................................... 47 
B. RANDOMIZATION PROCEDURE .............................................................................................................................. 47 
C. BLINDING.......................................................................................................................................................... 47 
X. 
TREATMENT REGIMENS .......................................................................................................... 49 
A. OVERVIEW ........................................................................................................................................................ 49 
B. FECAL MICROBIOTA TREATMENT (FMT)................................................................................................................. 52 
XI. 
FOLLOW-UP .................................................................................................................................. 55 
A. TIME TABLE ....................................................................................................................................................... 55 
B. FOLLOW-UP PROCEDURES .................................................................................................................................... 56 
C. STUDY WITHDRAWAL AND CROSSOVER .................................................................................................................. 57 
D. STUDY TERMINATION AND CLOSEOUT .................................................................................................................... 57 
XII. BIOSTATISTICAL CONSIDERATIONS ................................................................................... 59 
A. HYPOTHESIZED EVENT RATES, TREATMENT EFFECT SIZE, AND SAMPLE SIZE ................................................................... 59 
B. DURATION OF STUDY/FEASIBILITY/NUMBER OF PARTICIPATING SITES .......................................................................... 63 
C. INTERIM MONITORING AND ANALYSIS .................................................................................................................... 64 
D. FINAL STATISTICAL ANALYSIS OF THE DATA .............................................................................................................. 65 
XIII. FEASIBILITY ................................................................................................................................. 71 
A. ESTIMATING THE PATIENT POPULATION .................................................................................................................. 71 
B. CENTRALIZED AND REGIONAL ENROLLMENT AND FOLLOW-UP ..................................................................................... 73 
C. A PILOT STUDY TO TEST RECRUITMENT PROCESS ...................................................................................................... 74 
XIV. ADVERSE EVENT ASSESSMENT AND REPORTING ........................................................... 77 
A. DEFINITIONS ...................................................................................................................................................... 77 
B. REPORTING OF AES AND SAES IN CSP #2004 ......................................................................................................... 78 
C. ROLE OF THE SITE INVESTIGATOR IN EVENT MONITORING .......................................................................................... 79 
D. AE AND SAE MONITORING AND REPORTING ........................................................................................................... 79 
XV. STUDY MONITORING AND QUALITY CONTROL .............................................................. 81 
A. PROCEDURES OVERVIEW ..................................................................................................................................... 81 
B. MONITORING BODIES AND CSP MONITORING ......................................................................................................... 81 
C. MONITORING PARTICIPANT INTAKE........................................................................................................................ 84 
D. MONITORING MEDICAL CENTER (SITE) PERFORMANCE.............................................................................................. 85 
E. MONITORING PARTICIPANT SAFETY ....................................................................................................................... 85 
F. MINIMIZING ATTRITION ....................................................................................................................................... 85 
XVI. DATA MANAGEMENT PROCEDURES .................................................................................... 87 
A. DATA COLLECTION METHODS ............................................................................................................................... 87 
B. DATA QUALITY CONTROL ..................................................................................................................................... 88 
C. ELECTRONIC STUDY FILE ...................................................................................................................................... 89 
D. QUALITY CONTROL OF THE PROCESS ...................................................................................................................... 90 
E. DATA SECURITY .................................................................................................................................................. 90 
F. DATA SHARING .................................................................................................................................................. 92 
XVII. 
GOOD CLINICAL PRACTICES .......................................................................................... 95 
A. ROLE OF GOOD CLINICAL PRACTICES ...................................................................................................................... 95 
B. SUMMARY OF MONITORING AND AUDITING PLANS................................................................................................... 95 


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PUBLICATIONS ..................................................................................................................... 97 
A. PUBLICATION POLICY .......................................................................................................................................... 97 
B. PLANNED PUBLICATIONS ...................................................................................................................................... 98 
XIX. REFERENCES ................................................................................................................................ 99 
 
 
 


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Letters Of Submittal       
 
Principal Proponents 
 
DEPARTMENT OF VETERANS AFFAIRS 
Minneapolis VA Healthcare System 
One Veterans Drive 
Minneapolis, MN 55417 
 
 
October 28, 2015 
 
Grant Huang, M.P.H., Ph.D. 
Acting Director,  
VA Cooperative Studies Program (121-D) 
810 Vermont Avenue, NW 
Washington, DC 20420 
 
Dear Dr. Huang: 
 
We are submitting a proposal for the VA Cooperative Studies Program #2004: Microbiota vs.   
Antimicrobial Therapy for recurrent C. difficile at Home for review by the Cooperative Studies Scientific 
Evaluation Committee. The proposal assesses the efficacy of fecal microbiota transplantation (FMT) for 
the prevention of subsequent recurrent Clostridium difficile infection (CDI), when administered after 
successful treatment of recurrent CDI with standard antimicrobial therapy.  
 
Clostridium difficile infection is a common nosocomial infection, and is increasingly seen in non-
hospitalized patients. Although more than 90% of patients have symptom resolution with standard 
antimicrobial therapy, subsequent recurrence rates range from 15-30% (after the first CDI episode) to 40-
50% (after two or more episodes).  Fecal microbiota transplantation has shown promise as an adjunct to 
standard antimicrobial therapy, reducing recurrence to 15%. Recent administration of FMT via oral 
capsule provides an opportunity to deliver FMT via a non-invasive and convenient method. With the high 
burden of recurrent CDI in the Veterans Health Administration, considerable interest in FMT exists from 
both providers and patients. Current availability of FMT is site-dependent, with some VA facilities 
performing the procedure, others referring patients to community-based providers, and others having no 
mechanism of providing FMT. Furthermore, the lack of strong evidence for the efficacy of CDI treatment 
has led to regulatory uncertainty, with the Food and Drug Administration requiring an Investigational 
New Drug application (IND) for research involving FMT, but exercising “enforcement discretion” 
regarding the IND requirement for treatment of CDI with FMT. 
 
 


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This study is important to both our Veterans and the public. After numerous meetings and discussions, we 
believe that our protocol is ready for review by the CSSEC. 
Thank you for your consideration. 
 
 
Sincerely yours, 
  
 
 
 
 
 
 
 
Dimitri Maximilian Drekonja, M.D., M.S. 
 
             Aasma Shaukat, M.D. M.P.H 
Staff Physician,  
 
 
 
 
             GI Section Chief,  
Minneapolis VA Medical Center 
 
 
             Minneapolis VA Medical Center 
Assistant Professor of Medicine,  
 
 
             Associate Professor of Medicine 
University of Minnesota 
 
 
                          University of Minnesota 
Minneapolis, MN  55417 
 
 
 
             Minneapolis, MN 55417 
 
 


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Executive Summary/Abstract       
Background:  
 
Clostridium difficile infection (CDI) is one of the most common nosocomial infections and is 
increasingly seen in non-hospitalized patients. Although more than 90% of patients have symptom 
resolution with a course of standard antimicrobial therapy, subsequent recurrence rates range from 15-
30% (after the first CDI episode) to 40-50% (after the second and subsequent episodes).  Fecal microbiota 
transplantation (FMT) has shown promise as an adjunct to standard antimicrobial therapy, reducing 
recurrence among FMT recipients to 15%. The recent successful administration of FMT via oral capsule 
provides an opportunity to deliver FMT via a non-invasive and convenient method, which also allows for 
effective blinding. With the VA having a high burden of recurrent CDI, there has been considerable 
interest in FMT from both providers and patients. The availability of FMT is site-dependent, with some 
VA facilities performing the procedure, others referring patients to community-based providers, and 
others having no mechanism of providing FMT. Furthermore, the lack of strong evidence for the efficacy 
of CDI treatment has led to regulatory uncertainty, with the Food and Drug Administration requiring an 
Investigational New Drug application (IND) for research involving FMT, but exercising “enforcement 
discretion” regarding the IND requirement for treatment of CDI with FMT. 
 
Objectives:  
 
The primary study goal is to assess the efficacy of FMT for the prevention of subsequent 
recurrent CDI, when administered after successful treatment of recurrent CDI with standard antimicrobial 
therapy. Secondary goals are to evaluate the safety of FMT, and in the event of a positive study result, 
establish a mechanism for providing FMT within the VA system. 
 
Research Plan:  
 
This study will enroll 318 participants who have: 1) One or more episodes recurrent CDI (defined 
as > 3 loose/watery stools/24h for 2 consecutive days with CDI treatment, and not explained by another 
diagnosis PLUS laboratory confirmation of C. difficile; or ileus, or toxic megacolon PLUS laboratory 
confirmation of C. difficile, occurring within 90 days of a prior CDI episode), 2) Resolution or 
improvement of symptoms from most recent CDI episode, defined as no longer meeting the clinical 
definition for CDI for a 48 hour period during treatment, including not meeting the definition again after 
an initial improvement, 3) Within the enrollment window: from 2 days after completion of antimicrobial 
therapy for CDI (to allow for a washout period) to 14 days after completion of therapy or 30 days after the 


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onset of CDI whichever is the later, 4) Age ≥ 18 years, 5) Enrolled in a VHA facility, and 6) Able and 
willing to provide informed consent. 
 
 
Subjects will be excluded if they have/are: 1) Unlikely to swallow capsules, 2) Pregnancy, 
planning to be pregnant, or breastfeeding, 3) Receipt of cytotoxic chemotherapy or immune globulin, or 
confirmed neutropenia (absolute neutrophil count of < 1,000 cells/mL) within the past 3 months, 4) 
Inflammatory bowel disease or other chronic diarrheal disease/fecal incontinence predating CDI, 5) 
Ongoing antibiotic use, 6) Prior FMT, 7) Life expectancy of < 8 weeks, 8) Anaphylactic food allergy, 9) 
Active enrollment in another research study on antibiotics, probiotics, or FMT without investigators 
approval, 10) Presence of an ileostomy or colostomy, 11) HIV with CD4 count < 200 cells/µL in prior 3 
months, 12) Bone marrow/peripheral blood stem cell transplant in the past year, 13) Decompensated 
cirrhosis, or 14) Unlikely to follow study protocol.  
 
 
Participants will be randomized (1:1 ratio) to FMT or placebo, stratified by number of prior 
recurrent CDI episodes (1 versus >1).  They will be assessed for symptoms of CDI, other study outcomes, 
and any treatment-related adverse events at 2, 14, 28, 42, and 56 days, and month 3, 4, 5 and 6 after 
administration of the study treatment.  
 
 
The primary outcome is recurrent CDI (definite or possible) or death within 56 days of 
randomization. Definite recurrence is defined as: new onset of more than 3 loose or watery stools in 24 
hours for 2 consecutive days not explained by another diagnosis, with laboratory confirmation of C. 
difficile by enzyme-linked immunoassay (EIA) toxin test from a stool specimen; or ileus, toxic 
megacolon, or colectomy with laboratory confirmation. 
 
Possible recurrence is defined identically as above but WITHOUT laboratory confirmation of C. difficile 
(not tested or negative test). 
 
 
We postulate that FMT will result in a 15% absolute reduction in the recurrence rate of CDI (20% 
versus 35%). Using a Chi-square test with a 2-sided test of significance, α = 0.05, a sample size of 318 
participants will be required to test the primary hypothesis with 85% power, adjusted for 1% losses. The 
planned study duration is 6.5 years with 6 years for subject accrual and 6 months follow-up.  
 


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In order to maximize the number of potentially eligible participants and to make participation 
available to the largest number of Veterans, the study design is based on central enrollment, follow-up, 
and coordination.  
 
 


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Planning Committee 
 
Dimitri Drekonja, M.D., MS.  
Study Co-Chair  
 
 
 
Minneapolis VA Healthcare System 
 
 
One Veterans Drive 
 
 
 
 
Minneapolis, MN 55417 
Dimitri.Drekonja@va.gov 
Peter Guarino, MPH, PhD. 
 
SCHARP Director 
 
 
 
 
Vaccine and Infectious Disease Division 
Fred Hutchinson Cancer Research Center 
1100 Fairview Avenue 
Seattle, WA 98109 
Pguarino@scharp.org 
 
Aasma Shaukat, M.D., MPH.  
Study Co-Chair  
 
 
 
Minneapolis VA Healthcare System 
 
 
One Veterans Drive 
 
 
 
 
Minneapolis, MN 55417 
Aasma.Shaukat@va.gov 
 
Gary R. Johnson, MS.  
 
 
 
Acting Director, WH-CSPCC (151A) 
 
VA Connecticut Healthcare System 
 
 
950 Campbell Avenue 
West Haven, CT 06516 
Gary.Johnson4@va.gov 
 
Frank Lederle, M.D. 
(deceased) 
 
 
Minneapolis VA Healthcare System 
 
 
One Veterans Drive 
Minneapolis, MN 55417 
 
Anne H. Davis-Karim, Pharm.D. 
 
 
Clinical Research Pharmacist 
 
 
 
CSPCRPCC 
 
 
 
 
2401 Centre Avenue SE  
Albuquerque, NM 87106 
 
 
 
Anne.Davis-Karim@va.gov 
 
John Concato, M.D. 
 
 
 
 
Director, CERC 
 
 
 
VA Connecticut Healthcare System 
 
 
950 Campbell Avenue 
West Haven, CT 06516 
John.Concato@va.gov 
 
Tassos Kyriakides, Ph.D. 
 
 
 
Study Biostatistician, CSPCC (151A) 
 
VA Connecticut Healthcare System 
 
 
950 Campbell Avenue 
West Haven, CT 06516 
Tassos.Kyriakides@va.gov 
 
Jason Dominitz, M.D. 
National Program Director for Gastroenterology 
VA Puget Sound Healthcare System Seattle 
1660 S. Columbian Way 
Seattle, WA 98108 
Jason.Dominitz@va.gov 
Jane H. Zhang, Ph.D. 
 
 
 
 
Study Biostatistician, CSPCC (151A) 
 
VA Connecticut Healthcare System 
 
 
950 Campbell Avenue 
West Haven, CT 06516 
Jane.Zhang@va.gov 
 
 
Dale Gerding, M.D. 
Chief, Medical Service  
 
 
VA Chicago Health Care System 
 
333 E. Huron 
Chicago, IL 60611 
Dale.Gerding2@va.gov 
 
 
 
 


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I. 
Introduction and Background 
 Background 
 
Clostridium difficile infection (CDI) has transformed over the past 15 years from a relatively rare 
cause of antibiotic-associated diarrhea to the leading cause of infectious diarrhea in hospitalized patients, 
rivaling methicillin-resistant Staphylococcus aureus (MRSA) as the leading cause of all nosocomial 
infections (1, 2). The impetus for this transformation was the emergence of an epidemic strain of C. difficile 
in the early 2000s (3), variously designated as the North American pulsed-field type 1 (NAP1), BI, and 
027 by pulsed-field gel electrophoresis, restriction endonuclease analysis, and PCR-ribotyping, 
respectively. Emergence of this strain led to an increase in the incidence and severity of CDI, in addition 
to an increase in the mortality rate (3). Nationwide estimates of CDI exceed 450,000, resulting in 29,000 
deaths and over $4 billion in healthcare costs (1, 2, 4). This increase in CDI has been even more striking in 
the Veterans Affairs (VA) Healthcare System, with rates of CDI exceeding those from non-VA facilities 
by 2-to-3 fold (5). Risk factors for CDI include increasing age, hospitalization, multiple medical 
comorbidities, proton-pump inhibitor use, and antimicrobial use; all of which are common in the VA 
population. 
 
 
Currently, C. difficile is one of three organisms to be assigned the top threat level of “urgent” by 
the US Centers for Disease Control and Prevention in its first Antimicrobial Resistance Threat Report, 
released in 2013 (6). In contrast to the other 2 organisms receiving this designation, the inclusion of C. 
difficile was not based on limited treatment options due to antimicrobial resistance, but rather because of 
the high incidence rate of recurrent disease after successful treatment of CDI. Unfortunately, despite 
recurrence being the major challenge in treating CDI, treatment options are poorly studied, with few 
randomized controlled trials (RCTs) available to help inform clinicians and policy-makers. 
 
 
Treatment guidelines (7) suggest that either vancomycin or fidaxomicin can be used for the 
treatment of the initial episode of CDI, based on recent studies suggesting that vancomycin is preferred 
over metronidazole for the initial episode of CDI of any severity (8), and that fidaxomicin is non-inferior 
to vancomycin (9, 10). Unfortunately, although initial clinical cure is achieved in >90% of patients with 
each of these drugs, recurrent CDI (variously defined as an episode of CDI that occurs 8 weeks or less 
after a previous episode (11), or within 90 days of a previous episode (9, 12), provided that symptoms from 
the earlier episode resolved) occurs in 15-30% of cases (8, 9, 13). Patients with a first recurrence have a 40% 


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risk of a second recurrence, after which the risk of subsequent recurrences exceeds 50%, leading to 
malnutrition, repeat clinic visits and hospitalizations, and decreased quality of life (14).  
 
 
The optimal treatment of recurrent CDI is unknown. Guidelines from the Infectious Diseases 
Society of America suggest that for the first recurrence, either vancomycin in a tapered and/or pulsed 
dose strategy or fidaxomicin should be used, and that further episodes can be treated with a variety of 
strategies, including tapered vancomycin or fecal microbiota transplantation (FMT) (7). Similarly, 
guidelines from the European Society of Clinical Microbiology and Infectious Diseases suggest 
vancomycin or fidaxomicin use for the first recurrence and FMT for multiple recurrences (15), and the 
American College of Gastroenterology recommends metronidazole or vancomycin in a pulsed regimen 
for the 1st and 2nd recurrence, with consideration of FMT after 3 recurrences (16). The supporting evidence 
for these recommendations is of low quality, being largely guided by case series data and expert opinion. 
Comparing fidaxomicin, vancomycin, and tapered vancomycin for the treatment of recurrent CDI is the 
subject of CSP #596, which will provide guidance as to the optimal antimicrobial treatment for recurrent 
CDI. However, the role of FMT in the treatment of recurrent CDI is currently unknown. 
 
 
 Fecal Microbiota Therapy (FMT)  
 
The use of FMT was first reported in the medical literature in 1958, when it was used to treat 
post-antibiotic pseudo-membranous colitis in 4 patients (17). Since then, numerous case series have been 
published, with most reporting success rates in excess of 80%. FMT, also known as a “stool transplant,” 
is thought to prevent recurrent CDI via rapid restoration of the normal diverse colonic microbiota by 
delivering a large inoculum of typical organisms, as opposed to allowing the gradual repopulation of the 
colonic microbiota through normal dietary and environmental exposure (18). Delivery of FMT has been 
performed via enema, colonoscopy, nasogastric tube, and most recently, via oral capsule (19). In 2013, a 
small unblinded trial of FMT vs. 2 vancomycin-based control groups was published (20), reporting a 
success rate of 81% among the 16 patients randomized to FMT, vs. 23% and 31% in the 2 control groups. 
A recent systematic review identified a total of 520 patients with recurrent CDI treated with FMT, from 
21 case series and 2 RCTs (21). Although the overall rate of symptom resolution without recurrence was 
85%, the majority of included studies were case series, and only 1 of the 2 RCTs had a non-FMT control 
group (20).  
 
 
At the time of submitting this protocol, a 3rd randomized control trial has been presented in 
abstract form. This trial of FMT vs. placebo (both delivered via colonoscopy) showed similar success 


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rates. Specifically, FMT success was 20/22 (91%), vs. 15/24 (63%) for placebo (Oral presentation, Dr. 
Colleen Kelly, American College of Gastroenterology Annual Scientific Meeting, October 2015). 
Notably, in many of the studies it was unclear as to whether the FMT was administered as part of the 
initial treatment of CDI, or rather as an adjunct to standard treatment given to prevent subsequent 
recurrence. Accordingly, there is a need for an adequately-powered RCT designed to evaluate the efficacy 
of FMT for the prevention of recurrent CDI when compared to standard antimicrobial therapy. 
 
 Study Rationale 
 
With more than 90% of patients having resolution of symptoms with a course of standard 
antimicrobial therapy, but then having recurrence rates ranging from 15-30% (after the first CDI episode) 
to 40-50% (after the second and subsequent episodes), adjunctive treatments to prevent recurrence after 
initial symptom resolution are needed. The recent successful administration of FMT via oral capsule (19) 
provides an opportunity to deliver FMT via a non-invasive and convenient method, which also allows the 
possibility of effective blinding. With the VA having a high burden of recurrent CDI, there has been 
considerable interest in FMT from both providers and patients. Currently the availability of FMT is site-
dependent, with some VA facilities performing the procedure, others referring patients to community-
based providers, and others having no mechanism of providing FMT. Furthermore, the lack of strong 
evidence for the efficacy of CDI treatment has led to regulatory uncertainty, with the Food and Drug 
Administration requiring an Investigational New Drug application (IND) for research involving FMT, but 
exercising “enforcement discretion” regarding the IND requirement for treatment of CDI with FMT. 
 
 
With the high burden of CDI in the VA, the high recurrence rates, and the uncertainty regarding 
both how to treat recurrent CDI and the efficacy of FMT, a definitive RCT of FMT for the prevention of 
recurrent CDI is needed. A trial of capsule-administered FMT vs. placebo, both administered after 
successful initial treatment of recurrent CDI with standard antimicrobial therapy, for the prevention of 
subsequent recurrent CDI is hereby proposed. 
 
 Summary of Study Goals 
 
 
The primary study goal is to assess the efficacy of FMT for the prevention of subsequent 
recurrent CDI, when administered after successful treatment of recurrent CDI with standard antimicrobial 
therapy. Secondary goals are to evaluate the safety of FMT, and in the event of a positive study result, 
establish a mechanism for providing FMT within the VA system. 


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II. 
Study Objectives and Hypotheses 
 Primary Objective 
 
The proposed study’s primary objective is to compare the incidence of recurrent CDI (definite or 
possible) or death within 56 days of randomization among participants receiving FMT vs. those receiving 
placebo capsules, after both groups have been successfully treated with one course of standard 
antimicrobial therapy.   
 
 
Definite CDI recurrence is defined as: New onset of more than 3 loose or watery stools in 24 
hours for 2 consecutive days with laboratory confirmation of C. difficile positive EIA toxin test from a 
stool specimen and absence of another diagnosis; or ileus, toxic megacolon, or colectomy with laboratory 
confirmation. 
 
 
Possible recurrence is defined identically as above but WITHOUT laboratory confirmation of C. 
difficile (no specimen, not tested or negative test). 
 
 
Our primary hypothesis is that Veterans receiving FMT after standard antimicrobial therapy will 
have reduced rates of recurrent CDI compared to those receiving placebo after standard antimicrobial 
therapy. 
 
 Secondary Objectives 
 
 
Secondary objectives include treatment comparisons between FMT and placebo of occurrences of 
components of definite or possible CDI and other manifestations of CDI: 
 
i. 
The incidence of recurrent CDI (definite or possible) or death within 6 months of 
randomization; 
ii. 
The incidence of definite recurrent CDI within 56 days after randomization; 
iii. 
The incidence of possible recurrent CDI within 56 days after randomization; 
iv. 
The incidence of diarrhea that is negative for C. difficile by laboratory testing within 56 
days after randomization; 
v. 
Abdominal pain; 
vi. 
Urgency; 


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vii. 
Fecal incontinence;  
viii. 
The number of CDI recurrences within 6 months after randomization; and 
ix. 
Self-reported quality of life within 56 days after randomization. 
 
 Safety Objectives 
 
We will monitor the incidence, severity, and relatedness of serious adverse events and 
complications within 6 months to evaluate the safety of FMT. In the six months following study 
treatment, we will review electronic medical records and communicate with subjects via telephone to 
evaluate for possible transmission of infectious agents or development of new conditions theoretically 
linked to alterations in gut microbiota. 
 
 Exploratory Analyses 
 
 
The following exploratory analyses are proposed: 
i. 
Characterization and comparison of the colonic microbiome, before and after 
FMT/placebo administration; 
ii. 
Comparison of the post-FMT colonic microbiome to the donor microbiome; and 
iii. 
Comparison of the post-FMT microbiome of individuals who experience recurrence vs.  
the microbiome of those not experiencing recurrence at baseline, day 14, and day 56. 
 
 
 


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III. 
Summary of Study Design 
A. Overview 
 
This is a randomized, double-blind, placebo-controlled trial of capsule-delivered FMT for the 
prevention of recurrent CDI, administered after successful initial treatment of recurrent CDI with standard 
antimicrobial therapy. Initial treatment of the recurrent CDI episode will be at the discretion of the local 
provider, which currently could include metronidazole, vancomycin, or fidaxomicin. Patients will be 
contacted by Study Coordinators who will utilize direct referrals, reports of positive microbiology tests 
for C. difficile, diagnostic codes, and prescriptions to identify patients with recurrent CDI and obtain 
permission to contact the patient from the treating or primary care provider. Patients with CDI who have 
completed a standard course of antimicrobial treatment and exhibit a favorable response to treatment, who 
express interest in enrolling, and meet inclusion criteria will be scheduled for a visit with a Study 
Coordinator (SC). The SC will travel to the patient’s location to enroll the patient and administer the 
study treatment. After obtaining informed consent and enrolling the patient, the patient will take the 
randomly assigned treatment capsules (FMT or placebo) under direct supervision of the Study 
Coordinator.  
 
 
Following capsule administration, follow-up will be done via scheduled calls from either an 
automated Integrated Voice Response System (IVRS) or from study personnel, with ad-hoc contact 
triggered by either patients reporting symptoms or study personnel noting clinical manifestations of 
recurrence in the medical record, which will be monitored on a regular basis. The primary endpoint, first 
incidence of recurrent CDI (definite or possible) or death, will be assessed within 56 days of 
randomization. Safety outcomes and applicable secondary outcomes will be assessed until 6 months after 
randomization. 
 
 
 


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Figure 1. Study overview 
 


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B. Study Population and Rationale 
 
Historically, FMT has been administered to patients with multiple recurrences of CDI. In part, 
this may have been due to the need for a procedure of some sort, with enema being the least-invasive 
method of administration, followed by nasogastric tube and colonoscopic administration. Aesthetic 
concerns were often invoked, with the assumption that FMT would not be acceptable to patients who 
would otherwise be treated with another round of antimicrobials. However, as FMT has become more 
common, it has been used for patients having their first recurrence of CDI (19, 20). In the RCT comparing 
FMT to two vancomycin-based control groups, the number of recurrences per patient were not reported, 
but it is clear from the range of prior episodes that there was at least one patient with a first recurrence in 
each treatment group (20). In the case series describing FMT administered via capsule, 1 of 20 patients 
treated had just a single recurrence of CDI (19). Patient surveys indicate that the majority of patients are 
willing to undergo FMT, particularly if recommended by their provider (22). In deciding which patients to 
include in this trial (1st, 2nd, or ≥ 3 episodes of recurrent CDI), consideration was given to the following:  
 
(i) Possible benefit of treatment: The large effect size observed in the case series and the 
published RCTs is notable, especially for a condition where each subsequent episode of 
recurrence leads to an increased risk of still further recurrences. If FMT is shown to be as 
effective as suggested in these preliminary studies, reserving it for patients who are further 
advanced into the cycle of multiple recurrences may be counterproductive. Since FMT can now 
be administered via capsule, the possible harms of FMT are decreased, whereas the potential 
benefit remains great. 
 
(ii) Acceptability: Patients with a first episode of recurrent CDI have been included in recent 
studies of FMT, demonstrating that at least some patients are willing to undergo this novel 
therapy without having gone through repeated episodes of recurrent CDI. The published 
experience with FMT suggests that patients tolerate the procedure very well, although having 
already undergone FMT, this is a unique population. In a survey of patients without CDI, 94% of 
respondents indicated that they would undergo FMT if recommended by their physician, although 
the acceptance rate may be artificially inflated by a high rate of non-responders (52%) (22). The 
non-responders might be more likely to not be as accepting of FMT. Indeed, in an in-person 
survey of hospitalized patients with CDI who had a higher response rate of 81%, acceptance of 
FMT to treat their current CDI was lower (59%). However, a majority of patients (53%) indicated 


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that they would participate in a study of FMT vs. standard antimicrobial therapy, if such a study 
were available (23). 
 
(iii) Published experience with FMT: Most reported cases of recurrent CDI treated with FMT are 
in patients with multiple recurrences. However, recent studies of FMT have included patients 
experiencing their first recurrence of CDI. This suggests that both patients and providers are 
viewing FMT as a therapy that needs not be reserved for the patient with multiple episodes of 
recurrence. 
 
(iv) Biological plausibility: The pathogenesis of CDI begins with the elimination of the usual 
fecal microbiota, which normally confers some degree of colonization resistance to pathogens 
such as C. difficile. Microbiologic analysis of the diversity of the fecal microbiota shows that the 
diversity is markedly decreased after just one recurrence of CDI, such that it is not readily 
distinguishable from that of patients with multiple episodes of recurrence (24). Accordingly, the 
benefits of restoring the microbiota via FMT may be as beneficial after one episode of 
recurrence as after multiple episodes.  
  
(v) Adequate number of cases: Enrolling patients with a single episode of recurrent CDI 
increases the number of potentially eligible patients available for recruitment. This is illustrated 
in Table 1, which details the outcome of 100 patients, starting with an initial episode of CDI, and 
then continuing on to list the number expected to have subsequent recurrences, based on the 
number of patients at risk and the percentage expected to recur at each episode of recurrence. 
 
Table 1. Number of patients expected to experience a first, second, and third recurrence, 
based on 100 patients with an initial CDI episode. 
Episode of CDI 
Number of patients expected 
per episode 
Percent expected to recur 
Initial episode 
100 
25% 
1st recurrence 
25 
40% 
2nd recurrence 
10 
50% 
3rd recurrence 
5 
   > 50% 
Restricting enrollment to two or more recurrences results in a more than 50% reduction in potentially eligible patients (25 vs. 10); 
such a restriction will impact recruitment efforts. 


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(vi) Ability to detect a treatment effect: Enrolling patients at the first episode of recurrent CDI 
does affect the ability to detect a treatment effect, since those with a first recurrence are expected 
to have a smaller risk of subsequent recurrences than those having multiple recurrences. 
Accordingly, this decreases the overall number of subsequent recurrences, which affects the 
necessary sample size needed to detect a clinically significant treatment effect. This is further 
explored in the biostatistical section of the protocol (Section XII). 
 
 
In summary, after considering the possible benefit of treatment, acceptability, published 
experience with FMT, biological plausibility, adequate number of cases, and ability to detect a treatment 
effect, enrollment of patients with a first recurrence of CDI is scientifically justifiable and provides an 
increased pool of potential study participants. Although it is anticipated that patients with multiple 
recurrences are more likely to enroll than patients with a first recurrence, capsule administration of FMT 
is the most appealing route of FMT delivery (22), and may help boost enrollment among those with a first 
recurrence. 
 
 
C. Inclusion Criteria 
 
In order to maximize the clinical relevance of this trial, inclusion/exclusion criteria were designed 
to be as inclusive as possible. The rationale for the proposed exclusion criteria are discussed below. The 
study’s inclusion criteria are: 
1) One or more episodes recurrent CDI (defined as > 3 loose/watery stools/24h for 2 
consecutive days with CDI treatment, and not explained by another diagnosis PLUS 
laboratory confirmation of C. difficile; or ileus, or toxic megacolon PLUS laboratory 
confirmation of C. difficile, occurring within 90 days of a prior CDI episode with similar 
symptoms and laboratory confirmation); 
2)  Resolution or improvement of symptoms from most recent CDI episode, defined as no 
longer meeting the clinical definition for CDI for a 48 hour period during treatment, 
including not meeting the definition again after an initial improvement;  
3)  Within the enrollment window: 2 days after completion of antimicrobial therapy for CDI 
(to allow for a washout period) to 14 days after completion of therapy or 30 days after the 
onset of CDI whichever is later; 
4)  Age ≥ 18 years; 
5)  Enrolled in a VHA facility; and 
6) Able and willing to provide informed consent. 


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D. Exclusion Criteria 
 
The exclusion criteria are: 
1)  Unlikely to swallow capsules; 
2)  Pregnancy, planning to be pregnant, or breastfeeding; 
3)  Receipt of cytotoxic chemotherapy, intravenous or subcutaneous immune globulin, or 
confirmed neutropenia (absolute neutrophil count of < 1,000 cells/µL) within the past 3 
months;  
4)  Inflammatory bowel disease or other chronic diarrheal disease/fecal incontinence 
predating CDI; 
5)  Ongoing antibiotic use other than those for the current episode of CDI; 
6)  Prior FMT; 
7)  Life expectancy of < 8 weeks; 
8)  Anaphylactic food allergy; 
9)  Active enrollment in another research study on antibiotics, probiotics, or FMT without 
investigators approval; 
10)  Presence of an ileostomy or colostomy; 
11)  HIV with CD4 count < 200 cells/µL in prior 3 months; 
12)  Decompensated cirrhosis; 
13)  Bone marrow/peripheral blood stem cell transplant in the past year;  
14) Receipt of bezlotoxumab during the most recent episode of CDI; 
15) Unlikely to follow study protocol. 
 
E. Treatments and Rationale 
 
Under the study protocol, individuals in both treatment arms will be randomized in a 1:1 ratio to 
received blinded FMT or placebo after initial treatment with antimicrobials has resulted in symptom 
improvement or resolution, which occurs in >90% of CDI episodes. The objective of FMT is to decrease 
the risk of subsequent recurrence of CDI, not treatment of CDI symptoms. As such, it can be considered 
as an adjunct to standard antimicrobial therapy. 
 
 
A complete description of the treatment regiments is given in Section X.  


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F. Outcome Measures and Rationale 
1. 
Primary Outcome 
 
The primary outcome for this trial was selected to reflect the circumstances that currently lead 
clinicians and patients to consider FMT, and to provide a result that is clinically relevant. Since the great 
majority of patients referred for FMT are undertaking the procedure to reduce the risk of subsequent 
recurrent CDI, the primary outcome was chosen to provide a clear answer regarding the efficacy of FMT 
in preventing recurrent CDI.  
 
 
The primary outcome is recurrent CDI (definite or possible) or death within 56 days of 
randomization.  
 
 
Definite recurrence is defined as any of the following: 
• 
The new onset of more than three loose or watery stools in 24 hours for two consecutive 
days, not explained by another diagnosis; 
• 
Other clinical symptoms including ileus, toxic megacolon, or colectomy;  
 
PLUS  
• 
Laboratory confirmation of C. difficile from a stool specimen by EIA toxin test. 
 
 
Possible recurrence is defined as the same clinical manifestations as above, but WITHOUT 
laboratory confirmation of C. difficile (stool test not sent, negative EIA toxin test result, or uninterpretable 
result).  
2. 
Secondary Outcomes 
i) 
The incidence of recurrent CDI (definite or possible) or death within 6 months of 
randomization; 
ii) 
Definite recurrent CDI within 56 days, as defined above; 
iii) 
Possible recurrent CDI within 56 days, as defined above; 
iv) 
Death within 56 days since randomization; 
v) 
Episode of diarrhea that is negative for C. difficile by EIA toxin test and PCR within 56 
days  
 
This is similar to a possible recurrent CDI episode, but includes only episodes of 
diarrhea that test negative for C. difficile by EIA toxin test and PCR, not episodes 
that are not tested or are uninterpretable; 


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vi) 
Episode of diarrhea that is negative for C. difficile by EIA toxin testing but positive by 
PCR within 56 days  
 
This is similar to possible recurrent CDI, but includes only episodes of diarrhea 
that test negative for C. difficile by EIA toxin test, not episodes that are not tested 
or are uninterpretable; 
vii) Abdominal pain for all possible CDI cases; 
viii) Urgency for all possible CDI cases; 
ix) 
Fecal incontinence for all possible CDI cases; 
x) 
Number of CDI recurrences within 6 months 
The number of CDI recurrences within 6 months for a patient is the count of 
separate CDI recurrences from randomization to 6 months after randomization; 
and 
xi) 
Quality of life at day 56 
We will use a brief assessment of both overall and gastrointestinal health status, 
using a previously validated instrument. 
3. 
Safety Outcomes 
 
Because of the limited information regarding long-term safety of FMT, safety outcomes will be 
collected until 6 months after FMT/placebo randomization. Monitoring and reporting of AEs and SAEs 
are further described in Section XIV. 
 
Safety outcomes to be collected include: 
i) 
Serious adverse events, with a focus on SAEs involving hospitalization (new or 
prolonged), and all-cause mortality;  
ii) 
Adverse events which may be related to FMT treatment.  This includes adverse events 
which Site Investigators consider related/possibly related to the study treatment and all 
adverse events which occur within 14 days of study treatment (since an aggregate 
analysis of events temporally linked to treatment could show a causal relationship when 
compared to placebo); 
iii) 
Infectious transmissions which are plausibly linked to FMT treatment; and 
iv) 
Development of new conditions theoretically linked to alterations in gut microbiota.  
 


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4. 
Outcome Measurements in Exploratory Analyses 
 
We believe that evaluating microbiome is important, particularly in the context of this large trial 
incorporating a placebo control. Prior work demonstrating similarity between the post-transplant 
microbiome and the donor microbiome suggests that “engraftment” of the donor microbiome is important 
for clinical success. However, since these data come from uncontrolled series, this hypothesis has not 
been rigorously tested. The microbiome component can give us valuable insight in the event the study has 
positive or negative results.  If a clear correlation between recurrent CDI and failure to engraft is 
demonstrated, this would clarify the mechanism whereby FMT confers its benefit. Conversely, if subjects 
with engraftment of the donor microbiome recur at a similar rate as do those without engraftment, this 
would suggest that other factors may be contributing to recurrence.  
 
A stool sample for the assessment of the colonic microbiome will be obtained at the time of 
randomization, at 14 days after randomization, and 56 days after administration of FMT/placebo. The first 
sample will be transported to the central laboratory performing the microbiome characterization by the 
Study Coordinator, whereas the second sample and last sample will be mailed to the same laboratory by 
the participant via a pre-paid mailer. 
 
 
Shannon index (diversity) and the abundance-based coverage estimate (ACE) (richness) will be 
the outcome measurements to evaluate microbiome. 
 
The following exploratory analyses are proposed: 
i. 
Characterization and comparison of the colonic microbiome of individuals with CDI 
randomized to FMT and placebo, before and after FMT/placebo administration; 
ii. Comparison of the post-FMT colonic microbiome of individuals randomized to FMT and 
placebo to the donor microbiome; and 
iii. Comparison of the post-FMT microbiome of individuals that experience a recurrence to 
the microbiome of those not experiencing recurrence. 
 
G. Sample Size 
 
The target sample size will be 318 participants. We anticipate the rate of recurrent CDI following 
standard antimicrobial therapy is 35%; the study is powered to detect a clinically significant absolute 
difference of 15%. This difference is chosen based on the non-invasive nature of the intervention, as well 
as favorable safety data from the > 500 cases of FMT reported in the literature. Using the 318 participants 


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and above assumptions, there will be 85% power to detect a 15% absolute difference (20% vs. 35%) with 
a two-sided significant threshold of 0.05, and a 1% drop-out rate. Complete details of the sample size 
calculation are described in Section XII. 
 
H. Data Collection and Follow-up 
 
Baseline data will be collected at the time of enrollment, which occurs when the patient signs the 
informed consent form in the presence of a Study Coordinator (SC). The SC will have reviewed the 
patient’s medical record as part of the screening process, and been in telephone contact to verify interest 
in participation, assess inclusion/exclusion criteria, and resolution/improvement of CDI symptoms while 
on standard antimicrobial therapy. However, baseline data will only be recorded after enrollment. As part 
of the baseline data, a quality of life questionnaire will be administered (25), assessing overall and 
gastrointestinal quality of life.  
 
 
At the time of capsule administration, participants will be asked to provide an optional stool 
sample for characterization of the microbiome. Participants will be provided with: a diary to record 
symptoms and details of their bowel patterns in case they develop diarrhea, a copy of the Bristol stool 
chart to help them characterize their stool in a consistent fashion, and stool collection/mailing kits. The 
mailing kits will be used to collect stool samples in the event of new diarrhea occurring after the study 
visit, including collection of a sample for characterization of the colonic microbiome at day 14 and at 
approximately day 56. Additionally, participants will be provided with a pamphlet describing the study, 
instructions on what to do in the event of recurrent diarrhea or other symptoms of CDI, a study participant 
card to inform healthcare providers about their participation, and contact information for the Study 
Coordinator. Following capsule administration, the remainder of the study activities will occur via 
scheduled telephone calls. 
 
 
Participants will be assessed for symptoms of CDI and adverse events with a call from study 
personnel at days 2, 14, and 56 after capsule administration. The day 56 (8 week) call will be used to 
assess the primary endpoint, confirmed or possible recurrent CDI, as well as the secondary endpoints, 
including the quality-of-life questionnaire. Interspersed amid these calls will be bi-weekly calls (on day 
28 and 42) from an automated system or study personnel that will prompt participants to answer questions 
regarding any new diarrhea, abdominal pain, new antibiotic use, AE/SAE, or concerns that they are 
experiencing an onset of CDI. Affirmative answers will be followed up by a call from the Study 
Coordinator, who will ask further details regarding the positive response. Participants experiencing new 


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diarrhea, in addition to seeking clinical care at their local facility, will be further contacted by the Study 
Coordinator, collect a stool sample using a collection kit provided by the SC, and mail in a pre-paid 
mailer to the central laboratory, where it will be tested for C. difficile toxin B by PCR and for existing 
toxin by EIA. For the purposes of differentiating confirmed vs. possible CDI recurrence, we will use the 
EIA toxin test. 
 
 
After randomization, from week 8 to month 6, the automated calls or study initiated contacts will 
decrease in frequency to once a month, with the same triggers for a follow-up call from a Study 
Coordinator. At month 6 a final call by the SC will occur to assess any new symptoms of recurrent CDI, 
serious adverse events and possibly related non-serious adverse events, and any other reported symptoms. 
A schematic of the study timeline for an individual participant is displayed in Table 2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 2. Study Timeline 
Time 
Initial 
episode of 
CDI 
Recurrent 
CDI within 
90 days of 
the initial 
one 
Washout 
2-14 days 
after 
antibiotic 
treatment 
Day 0  
Officially in 
the study 
Day 1-56 
Day 57-
180 
Patient events 
Acute 
CDI 
episode 
Recurrent 
CDI 
episode 
Antibiotic 
washout 
Receive study 
treatment 
FMT or 
placebo  
-Monitor 
symptoms 
-Report new 
diarrhea, 
AE/SAE 
-Monitor 
symptoms 
-Report 
new 
diarrhea, 
AE/SAE 
Study activities 
-Note 
episode  
-Monitor 
for 
recurrence 
in next 90 
days 
-Note 
episode 
-Assess 
eligibility 
-Ask 
provider to 
ask patient 
if can 
contact 
-Assess 
interest 
-Schedule 
study visit 
-Ensure 
still 
without 
symptoms 
-Verify 
interest in 
study 
-Travel to 
patient 
-Verify 
eligibility 
-Obtain 
consent 
-Randomize 
-Administer 
capsules 
-Collect stool 
sample 
(optional) 
-QoL 
assessment 
 
-Scheduled 
calls days 2, 
14, 28, 56 
-Stool sample 
day 14, day 56 
(optional) and 
when a 
possible CDI 
occurs 
(mailed) 
-QoL 
assessment at 
day 56 
-Monthly 
calls 
-Study 
complete 
at day 180 
*Note that these pre-enrollment days overlap, as some patients will receive longer-duration treatment for their episode of 
recurrent CDI, or a longer washout period based on ability to schedule a study visit. 
 
I. Alternate Design Considerations 
 
Adding a second route of FMT delivery was considered, with the possibility of using 2 
randomizations (first randomizing to 1 of 2 routes of delivery, then randomizing to FMT vs. placebo). 
This would allow an overall comparison of FMT (via any route) vs. placebo, and a second comparison of 
FMT by route of delivery. The increased sample size, cost, and complexity of this approach were deemed 
to be prohibitive, and this approach was discarded. An uncontrolled observational study was considered to 
be largely confirmatory, since the numerous published case series provide similar data. Furthermore, the 
consensus of the Planning Committee members was that a higher-quality study was needed to help 


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definitively answer the question of whether FMT should be widely offered within the VA system, and if 
so, how it could be delivered in a safe and accessible manner. 
 
 


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IV. 
Importance to the Veterans Administration 
During the past decade, the incidence rate of CDI has increased dramatically in North America 
and Europe, with a corresponding increase in disease severity (3, 26, 27). A recent publication based on 
surveillance from multiple US sites indicates that the number of yearly CDI cases in the US exceeds 
450,000 (2). Increases have occurred in all age groups, but the elderly have been disproportionally 
affected. Mortality attributable to CDI has also increased dramatically, with recent estimates from the 
CDC of 29,000 deaths annually in the US (2). These marked changes in the CDI incidence and mortality 
have coincided with the emergence and spread of an epidemic strain of C. difficile variously designated as 
BI/NAP1/027 by different typing methods (3). Currently, C. difficile is the most prevalent cause of 
healthcare-associated enteric infections in the US, rivaling MRSA as the leading cause of all nosocomial 
infections (1). 
 
CDI has been a particularly important problem in VA hospitals since the risk factors for CDI are 
common in Veteran patients, i.e. elderly, with multiple medical comorbidities, prolonged hospital stays, 
and frequently exposed to antibiotics. CDI trends in VA hospitals have mirrored or exceeded those seen 
in non-VA hospitals. The incidence of CDI among Veterans has recently been reported, based on 
systematic surveillance by Multidrug-resistant Organism prevention coordinators at each VA facility (5).  
From October 2010 through June 2012, there were a total of nearly 10,000 CDI cases recorded, with 0.66 
cases per 100 admissions (5). Viewed as rates of hospital-onset, healthcare facility associated CDI (the 
most common classification of CDI), VA rates were 9.3/10,000 patient days. This compares to a reported 
incidence of 6.4 to 7.9 cases/10,000 patient-days in non-VA hospitals and nursing homes in 2006 (28), and 
2.8 cases/10,000 patient-days in a national survey of community hospitals (1). Prior studies suggest that 
1% of all patients hospitalized in the VA were diagnosed with CDI (29). According to VA administrative 
data sources, there were approximately 624,858 hospitalizations in VA facilities in FY 2012, meaning 
that a 1% incidence of CDI resulted in 6,249 cases among inpatients alone. With VA-based studies 
reporting recurrence rates of 22-30%, this translates to estimated 1,375 – 1,875 cases of recurrent CDI 
annually. These estimates are consistent with FY 2012 data regarding CDI diagnoses (available in the 
inpatient and outpatient treatment files), which report 6,046 cases of CDI and 1,517 cases of recurrent 
CDI. When outpatient CDI diagnoses were included, the total number of initial CDI cases rose from 
6,046 to 8,878.  
 


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The economic burden of recurrent CDI is substantial, with estimates ranging from $4,000 to 
$10,000 per episode. Application of this range to the approximately 1,500 annual cases of recurrent CDI 
in hospitalized Veterans yields an estimated total annual cost for recurrent CDI of $6 million to $15 
million. As demonstrated by the nearly 3,000 outpatient CDI diagnoses in the VA FY 2012 data, CDI has 
increasingly been reported in non-hospitalized patients, implying that studies of hospitalized patients 
likely underestimate the financial burden of CDI in the VA. Finally, CDI is also associated with 
substantial mortality. CDI-attributable mortality rose to 48 per 1 million person years in 2006-7, a 5-fold 
increase from 1999-2000 (30). A more recent publication estimates the US CDI annual mortality at 29,000 
(2). 
 
Recurrent CDI is perhaps the most challenging dilemma facing VA clinicians who treat this 
disease. Although effective treatments are available for CDI, 15 to 30% of patients who respond to initial 
courses of treatment develop recurrent CDI, usually within 1-4 weeks of completing treatment with either 
vancomycin or metronidazole (14). The risk of recurrent CDI is even greater in patients who have already 
had one or more recurrences, and many patients develop repeated episodes that may continue to occur 
over a period of months or years. The GI Field Advisory Committee receives numerous inquiries every 
month about stool transplants for Veterans with recurrent CDI (personal communication, Jason 
Dominitz). Currently there are no VHA guidelines for FMT. Treatment of recurrent CDI is a priority 
research area for the VA and there is already one CSP study (CSP #596) underway comparing three 
antimicrobial regimens for the treatment of recurrent CDI. However, a study to determine whether FMT 
adds clinical benefit when administered after standard antimicrobial therapy is urgently needed. 
 
 
 
 
 
 


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V. 
Study Population 
A. Inclusion Criteria 
 
In order to maximize the clinical relevance of this trial, inclusion/exclusion criteria were designed 
to be as inclusive as possible. The rationale for the proposed exclusion criteria are discussed below. The 
study’s inclusion criteria are: 
1) One or more episodes recurrent CDI (defined as > 3 loose/watery stools/24h for 2 
consecutive days with CDI treatment, and not explained by another diagnosis PLUS 
laboratory confirmation of C. difficile; or ileus or toxic megacolon PLUS laboratory 
confirmation of C. difficile, occurring within 90 days of a prior CDI episode with 
similar symptoms and laboratory confirmation); 
2) Resolution or improvement of symptoms from most recent CDI episode, defined as no 
longer meeting the clinical definition for CDI for a 48 hour period during 
antimicrobial treatment, including not meeting the definition again after an initial 
improvement; 
 
3)  Within the enrollment window: 2 days after completion of antimicrobial therapy for 
CDI (to allow for a washout period) to 14 days after completion of therapy or 30 days 
after the onset of CDI whichever is later; 
4) Age ≥ 18 years; 
5) Enrolled in a VHA facility; and 
6) Able and willing to provide informed consent. 
 
 
B. Exclusion Criteria 
 
The exclusion criteria are: 
 
1) Unlikely to swallow capsules; 
 
2) Pregnancy, planning to be pregnant, or breastfeeding; 
3) Receipt of cytotoxic chemotherapy, intravenous or subcutaneous immune globulin, or 
confirmed neutropenia (absolute neutrophil count of < 1,000 cells/µL) within the past 
3 months;  
4) Inflammatory bowel disease or other chronic diarrheal disease/fecal incontinence 
predating CDI; 


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5) Ongoing antibiotic use other than for treatment current CDI episode or long-term 
antibiotic use; 
6) Prior FMT; 
7) Life expectancy of < 8 weeks; 
8) Anaphylactic food allergy; 
9) Active enrollment in another research study on antibiotics, probiotics, or FMT without 
investigators approval; 
10) Presence of an ileostomy or colostomy; 
11) HIV with CD4 count < 200 cells/µL in prior 3 months; 
12) Bone marrow/peripheral blood stem cell transplant in the past year; 
13) Decompensated cirrhosis;  
14) Receipt of bezlotoxumab during the most recent episode of CDI; 
15) Unlikely to follow study protocol. 
 
 
Rationale for each exclusion criterion 
 
Unlikely to swallow capsules: 
 
With FMT delivery via capsule, the ability to safely swallow capsules is a basic requirement. In 
previous studies where FMT was delivered in capsule-form, the size of the capsules was “00”- which is 
approximately the size of a large multivitamin pill; capsules are expected to be the same size in this study. 
All patients, including an 11 year old, were able to swallow the capsules without difficulty (19). Patients 
needing liquid formulations of medications or those having medications administered through a feeding 
tube would be considered ineligible due to a higher risk of aspiration or airway obstruction. 
 
Pregnancy: 
 
Data supporting FMT safety during pregnancy is not available. Based on the absence of such data 
and the heightened safety concerns when dealing with a vulnerable population, pregnancy is an exclusion 
criterion. Women of child-bearing potential (those who are not permanently sterilized or post-menopausal 
for at least 12 mos.) will undergo a urine pregnancy test on the day of FMT/Placebo prior to enrollment. 
Women who are breastfeeding are excluded for similar heightened safety concerns regarding the effects 
on the infant. 
 
 
 


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Specific immune-compromising states: 
 
The immune-compromising conditions that preclude study participation are based on a case series 
of immune-compromised patients, who reported a favorable response to FMT with few adverse events 
(31). This study included patients with the Acquired Immune Deficiency Syndrome, solid organ 
transplants, oncologic conditions, immunosuppressive therapy for inflammatory bowel disease, and 
others. Cytotoxic immunotherapy is an exclusion criterion because it induces significant disruption of the 
intestinal mucosa, increasing the risk of bacterial translocation and subsequent sepsis. Similarly, 
neutrophils are the main defense against bacterial translocation, and thus a known deficiency in this 
defense is an exclusion criterion. Patients with a recent history of low ANC (<1,000 cells/µL) will be 
retested before enrollment in the study. Immune globulin therapy is an exclusion based on anecdotal 
reports of using immune globulin to treat CDI, and because patients with common-variable immune 
deficiency (a common reason for immune globulin therapy) often have diarrhea as a manifestation of their 
underlying disease. Advanced HIV (defined as CD4 count <200), bone marrow/peripheral stem cell 
transplant recipients, and those with decompensated cirrhosis will also be excluded based on theoretical 
increased risk of infectious complications. 
 
Inflammatory bowel disease or other chronic diarrheal disease/fecal incontinence predating CDI: 
 
Since diarrhea will result in meeting the study’s primary outcome, it is critical that patients 
experiencing chronic diarrhea or fecal incontinence are not included, as a continuation of this chronic 
condition will result in treatment failure. However, if the diarrhea and incontinence symptoms have 
developed only after the patient had a CDI episode, the patient should not be excluded, as this is precisely 
the type of chronic morbidity that FMT is purported to improve. 
 
Long-term antibiotic use or use of antibiotic other than for treatment of CDI or prior FMT: 
 
Since the mechanism of FMT for the prevention of CDI is the restoration of the normal fecal 
microbiome, continued use of antibiotics, or concurrent use of an antibiotic other than that for current 
CDI episode (which disrupt the microbiome) will likely lead to treatment failure, and as such is an 
exclusion criterion.  Failure of a prior FMT is also an exclusion criterion since such patients would be 
expected to have a higher failure rate after a subsequent FMT. 
 
Life expectancy of < 8 weeks: 
 
Although it is recognized that physician estimates of life expectancy may be inaccurate, patients 
who are unlikely to survive until the 8 week primary outcome assessment will not be eligible for 
enrollment. 


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Anaphylactic food allergy: 
 
Although anaphylaxis due to food antigens present in donor stool has not been reported. We have 
opted to exclude patients with documented anaphylaxis to food since we cannot guarantee that the donor 
stool will be free of the particular antigen. This is not anticipated to be a common occurrence. 
 
Active enrollment in another research study on antibiotics, probiotics, or FMT without investigators 
approval:  
 
Use of antibiotics or probiotics may affect the CDI recurrence rate, and as such, participation in 
such studies and CSP #2004 will not be allowed. A notable exception to this is that patients who 
experience recurrent CDI while in CSP #596 (fidaxomicin vs. vancomycin vs. tapered vancomycin) will 
be offered enrollment in the proposed study. The co-chair of CSP #596 is a member of the CSP #2004 
planning committee, and has indicated that once study participants have met the primary endpoint 
(recurrent CDI) in that trial, there is no objection to them enrolling in the proposed study. Patients with 
recurrence after a prior FMT will be excluded as they will have already received the study intervention, 
and still recurred. Thus, they are likely to reflect a subgroup of patients at extreme risk of recurrence. 
 
Presence of an ileostomy or colostomy: 
 
Although CDI has been reported in patients with surgical removal of the colon and a resulting 
ileostomy or colostomy, this is a rare scenario. The normal flora of the colon has been reasonably well 
characterized, whereas the flora of the distal small bowel in patients with an ileostomy or colostomy is 
unknown. It is also difficult to assess the ostomy output for study inclusion and end points. Whether they 
would derive the same benefit from administration of FMT is uncertain; and due to the difficulty of 
assessing eligibility and outcomes, such patients will be excluded. 
 
Unlikely to follow study protocol: 
 
If a patient is deemed unable to follow the study protocol after screening by the Study 
Coordinators (SC) or Site Investigators (SIs), the patient will be excluded. This allows SCs (in 
conjunction with the SIs) flexibility in dealing with more unusual circumstances that may preclude 
successful participation, but which are not anticipated ahead of time. Each such exclusion will be 
discussed with the SI, and a reason will be recorded. Possible reasons include: inability to consistently 
reach patient via telephone, documented history of medical non-compliance, unwillingness to meet with 
SCs, inability to identify another individual who will know the patient’s whereabouts. Patients who are 
currently inpatient at a VA facility will also be considered unable to follow study protocol since VA 
regulations would not permit study drug to be administered under those circumstances. At the discretion 


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of the SC and SI, this may also include individuals enrolled in another interventional trial which may 
interfere with the ability to participate in MATCH. 
 
 
Bezlotoxumab is a relatively new drug indicated for prevention of CDI recurrence which is used 
rarely in the VA (13 times in FY21 per VA PBM). While its use is uncommon, including a drug approved 
for the same indication as we are studying could decrease recurrence rates and potentially introduce bias. 
Thus, use of this medication will be added as a study exclusion criterion. 
 
C. Inclusion of Women and Minorities 
 
Because female Veterans comprise such a small proportion of the VA population (approximately 
5%), the study recruitment team will make a special effort to recruit female Veterans. No special 
recruitment effort of minorities is planned because they are well represented among the VA population. 
Demographics, including race/ethnicity and gender, will be monitored in randomized as well as excluded 
patients. No patient will be excluded on the basis of gender or race. 
 
 
 
 
 


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VI. 
Human Rights Issues and Informed Consent Procedures  
A. Risks and Benefits 
 
The risks of FMT have thus far been largely procedural, including an episode of aspiration that 
was attributed to the sedation used for colonoscopic administration of FMT, and peritonitis that 
occurred after administering FMT via an indwelling gastric tube (32). A patient who was given FMT via 
colonoscopy for recurrent CDI experienced diverticulitis with symptoms beginning a few hours after 
the treatment; it was unclear whether the event was due to the FMT treatment itself or whether it 
resulted from the colonoscopy (33). Infectious complications have been rare and mostly mild; a single 
case of norovirus was reported shortly after FMT in one patient, but this occurred in the setting of a 
healthcare worker who cared for the patient also having an acute norovirus-like illness (34). An episode 
of zoster was also reported post-FMT; the relatedness of the 2 events is unknown (35). Serious systemic 
infections have also been rarely reported. The FDA noted two cases, one fatal, of invasive infections 
with extended-spectrum beta-lactamase (ESBL)-producing E. coli in two immunocompromised adults. 
(54) The fecal microbiota transplant  used to treat these individuals came from a single donor and was 
not tested for ESBL organisms prior to use. Following notification of this issue on June 13, 2019, the 
manufacturer of the study drug (University of Minnesota) began testing all donor stool for multi-drug 
resistant organisms (MDROs) as required by the FDA, in addition to continuing donor screening to 
exclude potential donors at high risk of MDRO colonization. Testing was also performed to rule out 
common MDROs in all lots of study drug taken by participants in CSP #2004.  
 
 
Other possible complications relate to the possible role of the fecal microbiome in autoimmune 
disease and metabolism. A patient with quiescent inflammatory bowel disease was reported to have a 
flare of his disease after FMT; again, it is uncertain as to whether this was related to the CDI, the FMT, or 
coincidental (36). A case of excessive weight gain post-FMT was recently reported in a patient who 
received stool from an obese donor (37). Two cases of peripheral neuropathy after FMT have also been 
reported in the literature. A relationship with FMT has been posited but is uncertain (38).  
 
 
These risks will be clearly presented in the informed consent form, and patients will have ample 
opportunity to ask questions in the time between the first contact with the study team and enrollment 
(expected to be 7-28 days).  
 


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The possible benefits of FMT are: a decreased risk of recurrent CDI, avoidance of prolonged 
courses of antimicrobials and healthcare visits, and improved quality of life. The informed consent 
process will review the preliminary efficacy data for FMT and standard antimicrobial therapy, and present 
this information using simple and straightforward language. 
 
B. Informed Consent Process  
 
The informed consent process will be initiated as soon as a potentially eligible patient indicates 
interest in participation. A waiver of informed consent will be sought for recruiting purposes only, which 
will allow the Study Coordinators (SCs) to identify and review the medical records of patients with 
recurrent CDI. Once the SCs establish that the patient is willing to be called about the study (which will 
be facilitated by communicating with the treating provider or other responsible provider), the patient will 
be contacted and information about the study will be provided. If the patient remains interested and meets 
eligibility criteria, an informed consent form and information about the study will be mailed to the patient 
to ensure that there is sufficient time to review the information prior to enrollment. In the event that time 
does not permit mailing the material for the patient to review, study staff may review the material via  
telephone. Prior to enrollment, the SC will call the potential participant to go over study materials and 
informed consent and answer any questions.   
 
 
The study’s informed consent can be signed either by wet signature or electronic/digital signature. 
When an electronic document with a digital signature is used for the documentation of consent, this study 
will use the DocuSign platform which is 21 CFR, Part 11 complaint to obtain the required signatures. A 
script to be used with DocuSign will be included in the Study’s Operations Manual. 
 
 
The SC will also confirm that the potential participant is willing to proceed with the visit, 
including the need to drink only clear liquids for 4 hours prior to the study visit and for 2 hours after 
swallowing the study treatment. At enrollment, the SC(s) will review the informed consent form with the 
participant, answer any questions, ensure eligibility criteria are met, and obtain the participant’s signature 
on the informed consent form. As indicated by the inclusion criteria, only participants capable of 
providing informed consent will be enrolled (i.e., informed consent from a surrogate decision maker will 
not be considered). 
 
 
With the emergence of the novel coronavirus that causes COVID-19, the possibility of 
transmission of COVID-19 through travel or fact-to-face meeting needs to be considered. There may be 


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some condition when travel or face-to-face meeting is not feasible. Due to COVID-19 or for other 
reasons, the study may process consent with the VA Video Connect (VVC). VVC is an approved VA 
Mobile app which meets VA mobile application compliance/data security control requirements 
(encryption in transit, etc.) and secure software security standards.  VVC is based on the use of the mobile 
application used within Telehealth.  Potential participants will need a device with access to this VA 
Mobile app. After confirming a potential participant is willing to process consent through VVC, two 
copies of ICFs will be mailed to the participant and a VVC meeting will be scheduled.  
 
 
During the VVC call, SC explains the consent form line by line to the participant and answers all 
questions. Participant signs two sets of consent forms while meeting with and /or SC over VVC. Veteran 
keeps one copy of the ICF for reference until the signed forms are received. Participant mails one signed 
consent back to Minneapolis.  After SC receives the signed consent, the consent process with VVC is 
completed and randomization visit via VVC will be arranged. 
 
 
 
Given the use of VA Video Connect (VVC) to effect remote participant consent and 
randomization, there could be a time lag between the day of signing of the informed consent 
form (ICF) to the day of randomization/administration of study medication. If this time lag is 
more than 60 days, a re-consent is required.  
 
C. Withdrawal 
 
After randomization, study participation consists of recording symptoms, reporting them via the 
scheduled and as-needed phone calls, submitting a stool sample in the event of an episode of diarrhea, and 
submitting an optional day 14 and day 56 stool samples for microbiota characterization. Accordingly, 
attempts to minimize withdrawal will be made by discussing, prior to enrollment, the importance of 
participating in the study. Participants will be asked to provide several means of contacting them, 
including a home phone, cell phone, mailing address, and the contact information of a person who would 
be able to reach them. If participants opt to withdraw from the study and not participate in further 
symptom reporting, two types of withdrawal will be available to the participant: 
1) No active follow-up, but allow study staff to assess for outcomes such as recurrent CDI 
and mortality via electronic record review; or 
2) Complete withdrawal, with no active or electronic follow-up beyond the time of 
withdrawal.  


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Participants opting for complete withdrawal prior to the primary outcome 
assessment will have their status at the time of withdrawal carried forward for the 
primary outcome assessment (recurrent CDI or no recurrent CDI). 
 


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VII. 
Outcome Measures and Rationale 
A. Primary Outcome 
 
The primary outcome for this trial was selected to reflect the circumstances that currently lead 
clinicians and patients to consider FMT, and to provide a result that is clinically relevant. Since the great 
majority of patients referred for FMT are undertaking the procedure to reduce the risk of subsequent 
recurrent CDI, the primary outcome was chosen to provide a clear answer regarding the efficacy of FMT 
in preventing recurrent CDI.  
 
 
The primary outcome is recurrent CDI (definite or possible) or death within 56 days of 
randomization.  
 
 
Definite recurrence is defined as any of the following: 
-the new onset of more than three loose or watery stools in 24 hours for two consecutive days not 
explained by another diagnosis 
-other clinical symptoms including ileus, toxic megacolon, and colectomy 
PLUS  
-laboratory confirmation of C. difficile from a stool specimen by toxin testing. 
 
 
Possible recurrence is defined as the same clinical manifestations as above, but WITHOUT 
laboratory confirmation of C. difficile (stool test not sent, negative result for EIA toxin test, or 
uninterpretable result). Site Investigators (SIs) will be asked to review cases where it is unclear to the 
Study Coordinator as to whether the outcome has been met; SIs will also evaluate the relatedness of the 
intervention to any reported adverse events (AEs) or serious adverse events (SAEs). 
 
 
Using recurrent CDI as the primary outcome reflects the reality that preventing recurrence drives 
most patients to consider and providers to offer FMT. In reviewing the literature on FMT, many studies 
report resolution of CDI symptoms and recurrent CDI as outcomes, administered after a course of 
antimicrobial therapy, and many specifically state that FMT was administered after patients became 
“asymptomatic” or had “a reduction of symptoms” (21). Preventing recurrence (vs. treatment of an active 
episode of CDI) also comports with how recent reviews recommend utilizing FMT, and with our clinical 
experience in referring patients to undergo FMT. Accordingly, the prevention of recurrent CDI among 


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patients who have had a favorable response to standard antimicrobial therapy is the appropriate primary 
outcome for this trial. 
 
 
The definition of recurrent CDI (both definite and possible) reflects the importance of symptoms 
in diagnosing and managing recurrent CDI. It also highlights an area of uncertainty which any study of 
recurrent CDI encounters, namely that not every episode of diarrhea occurring after a prior episode of 
CDI is recurrent CDI, regardless of stool test results and response to empiric treatment. Discussing this 
difficulty requires some baseline definitions: Recurrent CDI is defined as an episode of CDI occurring 
within 56 days of a prior CDI episode (11), presuming the symptoms from the prior episode resolved. The 
definition for CDI includes symptoms (typically diarrhea, but rarely ileus, toxic megacolon, or 
colectomy), plus a stool laboratory test indicating presence of C. difficile, its toxins, or the genetic 
elements encoding the toxins. Unfortunately, studies have demonstrated that asymptomatic patients with a 
recent episode of CDI test positive for a prolonged time post-infection, regardless of test used (39, 40). 
Accordingly, guidelines for CDI discourage using a microbiological test-of-cure, but rather recommend 
symptom assessment.  
 
 
For this trial, universal stool testing for any subject experiencing diarrhea during follow-up will 
be attempted. This will be accomplished by the Study Coordinator educating the participant, both at 
enrollment and during subsequent contacts, stressing the need to be evaluated for recurrent CDI should 
diarrhea or other CDI symptoms recur. Subjects will also be provided with a home collection kit with a 
postage-paid package whereby they can submit a stool sample to a central laboratory for C. difficile 
testing by EIA and PCR, which will be useful in the event that their local provider opts to empirically 
treat for CDI without laboratory confirmation, and provides consistent testing with the same testing 
method. Subjects with symptoms plus a positive EIA toxin stool test (from either the central or a local 
laboratory) will be classified as definite recurrent CDI. Subjects with symptoms not explained by another 
diagnosis but without laboratory confirmation (negative or no testing) or with laboratory confirmation 
other than EIA toxin will be classified as possible recurrent CDI. Definite and possible cases will be 
combined as recurrent CDI for the purposes of the primary outcome. Finally, death will also be 
considered as meeting the primary outcome, since death eliminates the possibility of recurrent CDI. 
 
Justification of the primary end point assessment at day 56: 
 
Using day 56 as the primary endpoint for recurrence (vs. a longer period) was carefully 
considered. Assessing the primary outcome at day 56 is important from the scientific, clinical, and 
regulatory standpoint. Clinically, recurrence generally occurs within 7 to 14 days after cessation of 


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antimicrobial therapy. However, non-CDI diarrheal illness is very common in the population (0.72 
episodes/person-year). The combination of the main manifestation of CDI (diarrhea) being non-specific 
and common, plus a test that can remain persistently positive regardless of symptoms, makes it difficult to 
distinguish recurrent CDI from diarrhea caused by either another pathogen or non-infectious diarrhea, 
including a post-infectious motility disorder. There is currently no standardized approach to 
differentiating recurrent CDI from diarrhea of another cause.  Since any episode of diarrhea could count 
as an outcome for recurrent CDI in our study, we would be at risk of counting many episodes of non-CDI 
diarrhea as our endpoint beyond 56 days.  
 
 
From the regulatory perspective, recurrence at 56 days meets the FDA standards, as seen in the 
recent approval process of fidaxomicin. Day 56 endpoint also allows comparison with other pivotal 
studies evaluating therapies for recurrent CDI. Prior clinical trials evaluating FMT for recurrent CDI have 
used time from treatment to endpoint of 56 days (Youngster 2014; Kelly 2015) and 70 days (Van Nood) 
respectively, while the recently funded CSP #596 is using day 59 as its endpoint. In this study, the 
primary endpoint assessment is at day 56 from randomization and day from 58-90 from end of treatment 
for prior episode. Using the same definition allows for comparison across trials, and provides clinicians 
with a uniform outcome to assess when selecting treatment.   
 
 
From the study design perspective, using a 6 month endpoint would have the following 
challenges: drop outs and loss of follow-up, dilution of endpoint with non-CDI related GI symptoms or 
other etiologies of diarrhea and difficulty in power and sample size calculations since recurrence rates are 
largely unknown at 6 months. In summary, we chose to apply 56 days as the primary endpoint and use 
recurrence at 6 months as secondary endpoint in order to reduce complexity to the study.  
 
B. Secondary Outcomes 
 
We realize that the durability of response after FMT is unknown, and is an important question. 
Therefore, we propose to collect recurrence of CDI or death at 6 months as the first secondary endpoint 
and other secondary endpoints. 
 
i) Recurrent CDI (definite or possible) or death within 6 months of randomization;  
ii) Definite recurrent CDI within 56 days, as defined above; 
iii)  Possible recurrent CDI within 56 days, as defined above; 
iv)  Death within 56 days; 


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v)  Episode of diarrhea that is negative for C. difficile by EIA toxin testing and PCR within 56 
days 
This is same as a possible recurrent CDI, but includes only episodes of diarrhea 
that test negative for C. difficile by EIA and PCR, not episodes that are not tested 
or are uninterpretable; 
vi) Episode of diarrhea that is negative for C. difficile by EIA toxin testing but positive by PCR 
within 56 days  
 
This is similar to a possible recurrent CDI, but includes only episodes of diarrhea 
that test negative for C. difficile by EIA toxin testing, not episodes that are not 
tested or are uninterpretable; 
vii)  Abdominal pain among all possible CDI cases; 
viii) Urgency among all possible CDI cases; 
 ix)  Fecal incontinence among all possible CDI cases; 
x)  Number of CDI recurrences within 6 months 
The number of CDI recurrences within 6 months for a patient is the count of 
separate CDI recurrences from randomization to 6 months after randomization; 
and 
xi)  Quality of life at day 56 
We will use a brief assessment of both overall and gastrointestinal health status, 
using a previously validated instrument. 
 
 
Secondary outcomes include the individual components of the primary outcome (definite 
recurrence, possible recurrence, and death), as well as PCR negative diarrhea, EIA toxin negative 
diarrhea, number of CDI recurrences, and self-reported quality of life. Additionally, an assessment for 
non-diarrheal manifestations of CDI such as abdominal pain, urgency, and fecal incontinence will be 
performed. A brief assessment of both overall and gastrointestinal health status, using a previously 
validated instrument, will be performed (25). 
 
 
Because abdominal pain is common and has a wide variety of causes beyond CDI, the assessment 
of abdominal pain will be standardized in the operations manual. In brief, assessment will begin with 
asking participants about any abdominal pain during the assessed time period, whether any pain present is 
new or worsened since the study intervention, their rating of the severity on a standardized pain scale of 0 
to 10, and whether they sought medical care for the pain. If medical care was sought, records regarding 


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that care will be requested by study personnel, and the pain will be placed into 3 distinct categories by 
Study Coordinators and SIs:  
 
1) Abdominal pain with non-CDI cause (e.g., documented renal calculus or appendicitis); 
2) Abdominal pain without clear non-CDI cause; or  
3) Abdominal pain occurring in conjunction with criteria meeting primary endpoint (e.g., 
diarrhea, ileus, toxic megacolon). 
 
 
Urgency will be assessed based on a modified 0 to 3 scale addressing frequency, intensity, and 
impact on social performance, with 0 representing normal control, 1 representing occasional feelings of 
urgent need for defecation, 2 representing frequent feelings of urgent need for defecation with sudden 
need for a toilet interfering with social functions, and 3 being inability to control defecation. 
  
 
Fecal incontinence will be assessed via two questions based on modification of several scales: 1). 
Have you had new or worsening symptoms of unintentionally passing liquids or solids from your rectum 
more than once per week for at least two weeks; and 2). Have you required use of pads or had to alter 
your lifestyle based on these or similar symptoms? If either is answered affirmatively, the definition of 
fecal incontinence will be met. 
 
 
The inclusion of PCR negative diarrhea and EIA toxin negative diarrhea as separate entities is to 
assess the proportion of possible recurrent CDI or subjects with recurrent CDI that tests negative for CDI 
using different testing methods, and whether this proportion is affected by FMT. The use of a direct EIA 
test for preformed toxin was selected based on FDA input, and recent data suggesting that PCR may be an 
overly-sensitive test, detecting C. difficile genetic material that is of little clinical relevance.(41)  
Additionally, this also accounts for all possible combinations of symptoms plus CDI test status (Table 3). 
 
 
 
 
 
 
 
 


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Table 3. Possible combinations of symptoms and test status and subsequent outcome 
classification 
CDI symptom 
status* 
CDI test status** 
Primary outcome (definite or 
possible recurrent CDI) 
Absent 
Negative 
Not met 
Absent 
Positive (if ordered off protocol) 
Not met 
Present 
Positive toxin test (regardless of PCR test) 
Met (definite recurrent CDI) 
Present 
Negative toxin and negative PCR test 
Met (possible recurrent CDI) 
Present 
Negative toxin and positive PCR test 
Met (possible recurrent CDI) 
Present 
Toxin testing not performed but positive PCR 
test 
Met (possible recurrent CDI) 
Present 
Not sent or no conclusive test result for both 
toxin test and PCR 
Met (possible recurrent CDI) 
* CDI symptoms include: diarrhea, toxic megacolon, ileus, and not explained by other diagnosis  
**In the case of discordant results for a given episode between two sources, such as outside, local or central laboratories, any 
positive test for toxin by EIA will be used for outcome classification. 
 
C. Safety Outcomes 
 
Because of the limited information regarding long-term safety of FMT, safety outcomes will be 
collected until 6 months after FMT/placebo randomization. Monitoring and reporting of AEs and SAEs 
are further described in Section XIV. 
 
Safety outcomes to be collected include: 
 
i) Serious adverse events, with a focus on SAEs involving hospitalization (new or 
prolonged), and all-cause mortality;  
ii) Adverse events which may be related to FMT treatment.  This includes adverse events 
which Site Investigators consider related/possibly related to the study treatment and all 
adverse events which occur within 14 days of study treatment (since an aggregate 
analysis of events temporally linked to treatment could show a causal relationship when 
compared to placebo); 
iii) Infectious transmissions which are plausibly linked to FMT treatment; and  
iv) Development of new conditions theoretically linked to alterations in gut microbiota.  


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D. Outcome Measurements in Exploratory Analyses 
 
An optional stool sample for the assessment of the colonic microbiome will be obtained at the 
time of randomization, at day 14, and at 56 days after administration of FMT/placebo. The first sample 
will be sent to the designated storage facility by the Study Coordinator, whereas subsequent samples will 
be mailed to the same facility by the participant via a pre-paid mailer. 
 
 
Shannon index (diversity) and the abundance-based coverage estimate (ACE) (richness) will be 
the outcome measurements to evaluate microbiome. 
 
 
The following exploratory analyses are proposed: 
i. 
Characterization and comparison of the colonic microbiome of individuals with CDI 
randomized to FMT and placebo, before and after FMT/placebo administration; 
ii. Comparison of the post-FMT colonic microbiome of individuals randomized to FMT and 
placebo to the donor microbiome; 
iii. Comparison of the post-FMT microbiome of individuals that experience a recurrence (at 
day 14 and at day 56) to the microbiome of those not experiencing recurrence (at day 56);  
iv. Comparison of the number of CDI episode within six months after randomization 
between two treatment arms.  
The number of CDI episodes within 6 months for a patient is the count of 
separate CDI episode from randomization to day 180 after randomization. 
 
 
FMT is a promising therapy for recurrent CDI, with high level of public interest and demand, 
which has outpaced the scientific evidence. However, there is paucity of data on the mechanistic and 
translational aspect of how FMT may work. Prior work demonstrating similarity between the post-
transplant microbiome and the donor microbiome suggests that “engraftment” of the donor microbiome is 
important for clinical success. However, since these data come from uncontrolled series, this hypothesis 
has not been rigorously tested. Advances in DNA sequencing technologies have created a new field of 
research, called metagenomics, allowing comprehensive examination of microbial communities. The 
current study provides a unique opportunity to characterize the gut microbiota and make meaningful 
comparisons between microbial composition of individuals pre-post FMT vs. placebo, and between donor 
and recipient, regardless of whether the study has positive or negative results.  If a clear correlation 
between recurrent CDI and failure to engraft is demonstrated, this would clarify the mechanism whereby 
FMT confers its benefit. Conversely, if subjects with engraftment of the donor microbiome recur at a 


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similar rate as do those without engraftment, this would suggest that other factors may be contributing to 
recurrence. Collecting samples is not a barrier to enrollment, since participants can opt out of this portion 
of the study and these comparisons would allow us to confirm the hypothesis that recurrent CDI is 
associated with reduced diversity and compositional changes in the fecal microbiota, and characterize 
post-FMT microbiota profiles that may serve as a benchmark for future studies. 
 
 
The development of mechanistic models for microbial engraftment and clinical course is of great 
interest to the international scientific community. At the federal level, the NIH Human Microbiome 
Project is one example of similar efforts designed to take advantage of large scale, high through ‘omics’ 
analyses to study the microbiome in human health. Adding these exploratory aims pose minimum burden 
on the study and enable us to contribute to the ongoing efforts to understand the human microbiome. 
 
 
 
 
 


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VIII. 
Baseline Assessments and Procedures 
A. Recruitment and Screening 
 
A relatively novel method of enrollment will be used in this study, with central Study 
Coordinators identifying eligible patients in the entire VA system. The identification of eligible patients 
will be accomplished using multiple strategies, as outlined below, which include electronic case finding 
and direct referrals from clinical providers.  
 
 
Our main strategy for recruitment is through electronic case finding of all new diagnoses of CDI 
across the VA using Corporate Data Warehouse (CDW) support through VA Informatics and Computing 
Infrastructure (VINCI), which is updated daily. An incident case of CDI will be identified through 
electronic monitoring of orders for C. difficile testing, lab results, diagnostic codes for outpatient and 
inpatient visits, and prescriptions. A pilot screening study has been completed at the Minneapolis VA 
Healthcare System using the above case-finding system, which was developed with support from the 
Centers for Chronic Diseases and Outcomes Research at the Minneapolis VA. Once the system has been 
successfully refined, it will be transitioned to an automated system. The Study Coordinators will screen 
cases found through this automated system, and will then utilize the patient’s electronic medical record to 
assess for inclusion/exclusion criteria using national Computerized Patient Record System (CPRS) access 
via Compensation and Pension Records Interchange (CAPRI).  
 
 
If the patient appears eligible at initial screening, a Study Coordinator (SC) will contact the 
patient’s provider and ask the provider or a member of their care team to obtain permission for the SC to 
initiate contact via telephone. If the patient agrees to be contacted, the SC will contact the patient, provide 
information about the study and, if the patient is interested in participating, mail an informed consent 
form for the patient to review. At this time, study personnel will make travel arrangements to meet the 
potential participant at their home for enrollment and treatment administration, which will take place 2-14 
days after stopping standard antimicrobial therapy. Study personnel will review the medical records for 
any indications that a home visit places the visiting Study Coordinator at a safety risk, utilizing methods 
that VA homecare providers routinely use prior to all new homecare visits. If there is a concern for safety, 
two SCs will travel to that individual’s residence. Based on the experience of the Minneapolis VA Health 
Care System Homecare services, which provided approximately 8,500 homecare visits over the past 12 
months, this is extremely unlikely. In their experience providing healthcare to diverse patient groups in 


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numerous urban and rural areas of Minnesota and Wisconsin, there have been no incidents where home 
healthcare was not feasible. 
 
 
Prior to committing to travel, the Study Coordinator (SC) will contact the potential participant to 
verify that they have completed their standard antimicrobial therapy, that they are still planning on 
enrolling, and that they have met the criteria of having resolved/improved symptoms of CDI (3 or fewer 
stools per day for at least 2 days, without subsequent worsening, and no other manifestations of CDI such 
as ileus or toxic megacolon). If all these conditions are met, a Study Coordinator will arrange travel to the 
potential participant’s home at a mutually agreed-upon date and time, with the randomly allocated 
treatment detailed in the randomization scheme. Once at the participant’s home, the SC will review the 
study information with the participant, answer any remaining questions, obtain written informed consent, 
and then proceed with data collection and treatment administration.  
 
 
With the emergence of the novel coronavirus that causes COVID-19, the possibility of 
transmission of COVID-19 through travel or face-to-face meeting needs to be considered. For safety or 
other reasons, the study may conduct consent and randomization remotely using VVC. After a potential 
participant signs a consent with VVC, a second VVC will be scheduled for administration of study 
therapy. Prior to the 2nd VVC, the Study Coordinator (SC) will mail the study therapy to the participant 
along with other study supplies. During the 2nd VVC, the SC will confirm that they are still planning on 
enrolling and that they have met the criteria of having resolved/improved symptoms of CDI (3 or fewer 
stools per day for at least 2 days, without subsequent worsening, and no other manifestations of CDI such 
as ileus or toxic megacolon). If all these conditions are met, proceed with data collection and instruct the 
participant take the study therapy, instruct them collect study specimen, and show them how to collect, 
package and handle future study specimen. The SC will encourage family/friend to be available if they 
are part of the veteran’s household. The second VVC meeting should last an hour after swallowing study 
medication to make sure patient is tolerating study medication. 
 
 
To ensure safety during the VVC the following steps will be taken: 
a) We will be screening very carefully for swallowing difficulty, both on chart review and on 
participant interviews and exclude anyone with any current or past history of swallowing 
difficulties 
b) We will recommend that a second person be present with the participant at the time of 
swallowing pills. We will be flexible at timing the visit when a second person may be available 
 


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In case of a choking emergency, we will use the standard 1-911 feature built into VVC for 
emergency services. Currently this is available for all VVC visits, and dials the local emergency service 
listed in the medical record for the participant. At the beginning of the visit, we will clarify this 
information with the participant. 
 
 
A second recruitment strategy is that patients identified through the central electronic case finding 
described above will be sent a letter of invitation with information about the study. Interested individuals 
that contact the study team will be screened by Study Coordinators for eligibility. Those individuals that 
do not respond (an opt-out number will be provided for those NOT wishing to be contacted) will be 
contacted by the SCs after 1 week to provide information about the study and invite them to participate. 
Patients that are contacted outside the window of recruitment will be tracked separately and encouraged 
to contact the study team if future CDI episodes occur. 
 
 
A third recruitment strategy will be to disseminate information about the trial to VHA Infectious 
Disease (ID) and Gastrointestinal (GI) physicians. The bulk of recurrent CDI patients are seen by either 
ID or GI providers in the VHA. Dr. Shaukat is a member of the GI field advisory committee, and has 
access to the VHA Gastroenterologists email list. Similarly, Dr. Drekonja has access to the VHA ID 
providers email list. Both physicians already receive regular inquires by colleagues about FMT for CDI 
treatment.  
 
 
A fourth recruitment strategy would be to screen and enroll individuals that are not eligible to 
participate in CSP #596. Additional details are provided in Section XII B. 
 
 
A final strategy will be to disseminate information about the study to Veterans through 
advertisement on newsletters, flyers in the VA Medical Centers, and contacting community Veteran 
groups.  
B. Baseline Data Collection 
 
 
The following baseline data will be collected at the time of enrollment:  
 
1) Demographics (gender, age, race, ethnic status, marital status, education level, service 
history, height, weight); 
2) Contact information for participant and two (2) additional contacts; 
3) Past medical history 


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a) Surgical history 
 
b) Medical history 
c) Prior CDI history (number of prior episodes and dates, previous treatments, 
concomitant non-CDI antibiotic use during current CDI episode) 
d) Medication use (prescription, over-the-counter, supplements, including 
probiotics) 
e) Laboratory results from the time of the most recent CDI diagnosis, if available 
(including complete blood count, serum creatinine, and albumin); and 
4)  Gastrointestinal Quality of Life Index (QoLI). 
 
 
C. Treatment Administration 
 
The assigned treatment will be administered to the participant by the Study Coordinator traveling 
to conduct the study visit, who will observe the participant ingest the FMT capsules. The capsules will be 
administered after 4 hours of clear liquids only, to ensure an empty stomach. No acid-suppressive 
medications are needed, and the participant can drink clear liquids to help facilitate in swallowing the 
capsules. After treatment administration, participants will be asked to ingest only clear liquids for 2 hours, 
and refrain from lying supine to minimize any chance of reflux. Details of capsule administration will be 
based on the manufacturer’s recommendation based on past clinical use, but is currently planned for a 
total of 5 capsules. 
 
 
After the participant has successfully ingested the capsules, the Study Coordinator will ensure 
that the participant has all the study supplies, knows how and when to contact the study team, and 
completes the in-person study procedures. Within a week of enrollment, the participant will be entered in 
the local CPRS (Minneapolis or a regional site) where study enrollment and other notes will be posted. 
The participant’s primary/referring provider will be notified of the participant’s enrollment in the study, 
and where to find the research notes in their medical record. The remainder of the study follow-up will be 
completed via telephone, as described in Section III.H. 
 
D. Stool Specimens 
Two types of stool testing will be collected during study participation: (i) testing at the time of a 
new diarrhea episode, and (ii) optional collection for characterization of the colonic microbiota after 
randomization, before study drug administration, at day 14, and at the end of the study (day 56).  


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The testing of diarrheal stools will be done by EIA toxin test and by PCR detection of the toxin B 
gene. Based on emerging data that PCR testing may lead to over-diagnosis, the EIA toxin test will be the 
test used to differentiate definite vs. possible CDI. Both will be performed at a central study laboratory. 
Samples will be collected by the participant using collection kits that are routinely used for home stool 
collection, and sent to the central laboratory in pre-paid mailers. Both the collection kit and the mailer 
will be provided by the Study Coordinator (SC) at the time of enrollment. 
 
 
The optional collection of stool for characterization of the microbiota will be done at the time of 
enrollment, at day 14 and at day 56. These samples will be stored at a central location until microbiome 
sequencing is performed to characterize the diversity and relative abundance of bacterial species. 
Collection will be done at the day of randomization, prior to administration of study drug and by the 
participant, with guidance from the SC, at day 14, and at day 56. The participant will be asked to provide 
a stool sample using the collection kit that the Study Coordinator will provide; the participant will then 
obtain a stool sample using a collection kit. If this cannot be performed by the participant, the participant 
can opt to have the SC assist in collection, or forego the stool collection step but still participate in all 
other study procedures. 
 
 


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IX. 
Stratification and Randomization 
A. Stratification of Randomization 
 
All eligible participants will be randomized in a 1:1 ratio to the two treatment arms, FMT or 
placebo. Randomization will be stratified by regional site, and within regional sites by number of 
previous recurrences (1 vs. 2 or more). Randomization will be performed by an automated randomization 
system located at the study web site using a computer generated randomization scheme produced by the 
West Haven Cooperative Studies Program Coordinating Center (WH-CSPCC).   
 
 
Stratification on the basis of previous recurrences (1 vs. 2 or more) is necessary for several 
reasons.  Since the recurrent CDI rate among patients with one recurrence is lower than those with two or 
more recurrences (Table 1), stratification on previous recurrences will permit a balanced distribution of 
the number of prior recurrence between two treatment arms, and then maintain the statistical power to 
detect the designed treatment effect. Additionally, the stratification provides an opportunity to evaluate 
any potential different treatment effects between patients with one previous recurrence and patients with 
more than one recurrence.   
 
B. Randomization Procedure 
 
Prior to traveling to a potential participant, the Study Coordinator (SC) will log in to the study 
web site, obtain the next available study treatment serial number for that coming enrollment/ 
randomization, obtain the study treatment identified by the serial number, and travel to the potential 
participant with the assigned treatment. Following enrollment, the participant will swallow the assigned 
treatment capsules under direct observation of the SC, which will complete administration of the study 
treatment. After an enrollment trip, the SC will log in to the randomization web site again and provide 
feedback about the success of the randomization. Detailed instructions are documented in the Operations 
Manual. 
 
C. Blinding 
 
The study subjects, personnel, Study Co-Chairs’ office, and the team members (except 
Biostatisticians at the WH-CSPCC and the clinical research pharmacist in Albuquerque, NM) will be 
blinded to the treatment assignment. Placebo treatment will consist of identical-appearing placebo 


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capsules using inert filler materials. The capsules used are opaque, making the FMT and placebo capsules 
indistinguishable to external inspection. The bottles in which the study medication will be provided will 
also be opaque and will remain sealed until the time the treatment is administered to the participant. The 
Study Coordinators will observe the participant during administration, ensuring that the capsules are not 
opened or otherwise manipulated in an effort to unblind the treatment. 


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X. 
Treatment Regimens  
A. Overview 
 
Under the study protocol, FMT or placebo will be administered after initial treatment with 
antimicrobials has resulted in symptom improvement or resolution, which occurs in >90% of CDI 
episodes. The objective of FMT is to decrease the risk of subsequent recurrence of CDI, not treatment of 
CDI symptoms. As such, it can be considered as an adjunct to standard antimicrobial therapy. Recurrence 
of CDI has been variably defined in the literature, and in recent trials has anywhere from 56 to 90 days 
after the initial CDI episode. The various times between the initial and recurrent episodes of CDI in key 
studies are presented in Table 4. 
 
 


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Table 4. Time between prior and current CDI episodes and time from treatment until 
primary outcome assessment, for various studies. 
Study 
author, year (description) 
Time between prior 
and current CDI 
episodes 
Time from 
treatment to 
primary outcome 
assessment 
Comments 
Youngster 2014 
(encapsulated FMT series) 
Not defined 
56 days 
Time also not defined 
in online appendix 
Van Nood, 2013 (NEJM 
FMT trial) 
56-70 days after 
cessation of 
antibiotic therapy 
70 days 
Time between episodes 
from prior methods 
paper 
Cornely 2012 
(Clin Inf Disease, 
Fidaxomicin vs. vancomycin 
for recurrent CDI) 
3 months 
28 days 
Not clear if 3 months 
from diagnosis or end 
of therapy 
Louie 2011 
(NEJM Fidaxomicin vs. 
vancomycin trial) 
3 months 
28 days 
Not clear if 3 months 
from diagnosis or end 
of therapy 
Johnson 2007 
(Rifaximin for recurrent 
CDI) 
Not stated 
Not stated 
 
Pepin 2006 
(Metronidazole vs. 
vancomycin for recurrent 
CDI) 
60 days  
60 days 
Both from time of 
diagnosis 
McFarland 2002  
(Vancomycin taper for 
recurrent CDI) 
1 year 
2 months 
 
Surawicz 2000 
(Vancomycin vs. 
metronidazole for recurrent 
CDI) 
1 year 
2 months 
 
CSP 596 
(Vancomycin vs. 
vancomycin taper vs. 
fidaxomicin) 
56 days 
59 days 
28 days after 
vancomycin taper; 49 
days after vancomycin 
and fidaxomicin 
standard therapy 
 


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Initial treatment of the recurrent CDI episode 
 
The optimal treatment of recurrent CDI is unknown. Guidelines from the Infectious Diseases 
Society of America suggest that for the first recurrence, either vancomycin in a tapered and/or pulsed 
dose strategy or fidaxomicin should be used, and that further episodes can be treated with a variety of 
approaches, including FMT (7). Similarly, guidelines from the European Society of Clinical Microbiology 
and Infectious Diseases suggest vancomycin or fidaxomicin for the first recurrence, and FMT for multiple 
recurrences (15), and the American College of Gastroenterology recommends metronidazole or 
vancomycin in a pulsed regimen for the first and second recurrence, with consideration of FMT after 3 
recurrences (16). The supporting evidence for these recommendations is of low quality, being largely 
guided by case series data and expert opinion.  
 
 
For this trial, the choice of standard antimicrobial therapy will be at the discretion of the treating 
provider. Prior guidelines suggested metronidazole or vancomycin for the treatment of recurrent CDI, 
although vancomycin use has been increasing (42), and will likely continue to increase based on updated 
guidelines and a recent study demonstrating significantly improved initial cure rates vs. metronidazole (8), 
although recurrence rates are statistically not different between the two drugs. Fidaxomicin has been 
newly recommended as standard therapy for recurrent CDI by the updated Infectious Diseases Society of 
America guidelines , and was already suggested by European guidelines. Currently, its use in the VA is 
restricted to patients with three or more recurrences; however, future use may change pending the updated 
guidelines and formulary decisions. 
 
 
The decision to enroll patients after any standard antimicrobial therapy vs. dictating a specific 
agent was carefully considered. Few RCTs of recurrent CDI are available to guide drug selection, and 
those that are available have not identified an agent as being clearly superior (12, 43) to others. One study 
combined a subgroup of patients with recurrent CDI from two trials comparing vancomycin to 
fidaxomicin, which showed a reduction in recurrence with the use of fidaxomicin (20% vs. 36%: P = 
.045) (12). However, this finding requires confirmation, which is a goal of CSP #596 (standard dose 
vancomycin vs. tapered vancomycin vs. fidaxomicin). In the absence of data demonstrating a clear benefit 
for one agent, mandating use of a certain drug for the initial treatment of CDI is not justifiable. 
Furthermore, this imposes an artificial scenario, which in turn could render study findings out of sync 
with real-world practice. Requiring treatment with a specific drug would also limit the available patient 
pool, since antibiotic treatment may be initiated prior to any consideration of entry into the study.  


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Finally, dictating use of one drug raises the risk of serious problems should that agent be withdrawn from 
the market or found to be inferior to another agent during the trial. Accordingly, initial treatment will be 
allowed to utilize any standard antimicrobial that is recommended for recurrent CDI by a major clinical 
guideline (Infectious Diseases Society of America, American College of Gastroenterology, or European 
Society of Clinical Microbiology and Infectious Diseases); currently such guidelines include 
metronidazole, vancomycin, rifaximin, or fidaxomicin (7, 15, 16). If a new agent is released and approved for 
use during the trial, demonstration of non-inferiority or superiority to a guideline-recommended agent 
would allow classification as a standard antimicrobial treatment. 
 
 
In order to be eligible to enroll and be randomized in the trial, patients must demonstrate 
symptom improvement or resolution, irrespective of which standard antimicrobial treatment they have 
been prescribed. Symptom improvement or resolution is defined as no longer meeting the clinical 
definition of acute CDI for a consecutive 48 hour period during treatment, and not again meeting the 
definition after an initial improvement. The clinical criteria for CDI are more than three loose or watery 
stools/24 hours, or other uncommon manifestations such as ileus, or toxic megacolon. Thus, to be eligible 
for study enrollment, patients will need to have three or fewer non-watery stools/24 hours and be without 
any of the more rare but severe manifestations of CDI for a 48 hour period, and not have subsequent 
worsening of symptoms. Window for enrollment will be from 2 days after completion of antimicrobial 
therapy for CDI (to allow for a washout period) to 14 days after completion of therapy or 30 days after the 
onset of CDI whichever is later, with optimal goal of enrollment between days 2 and 7 after antimicrobial 
therapy. 
 
B. Fecal Microbiota Treatment (FMT) 
 
Key issues regarding FMT include the source and route of delivery. Summary information is 
included below; for more information, please refer to the Investigator’s Brochure/Drug Information 
report. 
 
1. 
Source: 
 
Published studies have used locally-procured stool from either related or anonymous donors, 
while others have utilized a group of dedicated donors for their FMT program. Using a central pool of 
donors has several advantages over identifying a new donor for each patient undergoing FMT. These 
include eliminating the need to identify a suitable donor for each new patient, reducing the number of 
donors undergoing the cost and process of extensive stool and serological testing prior to stool donation, 


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and thus reducing the risk of a false-negative test exposing a recipient to a possible infectious 
complication. Additionally, utilizing a stable and clearly defined cohort of donors will allow for stringent 
quality control and inspection of the donation and preparation process. The option of creating a system of 
donor identification, screening, and testing, as well as the development of the capacity to process the stool 
into a form suitable for administration were considered. However, there are several institutions with 
already-established programs and capacity, and it would be much more time and cost-effective to partner 
with one of these programs to provide the donor material and processing capacity needed for this trial. 
 
 
In collaboration with the Albuquerque Cooperative Studies Program Clinical Research Pharmacy 
Coordinating Center (CSPCRPCC), a list of essential criteria for such a partner were developed:  (i) an 
existing or pending Investigational New Drug (IND) application and/or Biologic Master File (BMF) for 
the FMT product, (ii) a published protocol for donor screening, testing, and material preparation, (iii) 
safety record, (iv) efficacy record, and (v) the ability to provide capsules manufactured under cGMP 
conditions. Additional desirable features include preliminary efficacy data for FMT delivered via capsule 
form, dose standardization, and ease of handling (i.e., no need for freezer storage and ease of transport).  
 
2. 
Route of delivery: 
 
The original letter-of-intent for this study had proposed to use an enema rather than colonoscopy 
or naso-jejunal tube delivery, which at the time were the three routes of delivery with published case 
series. This was based on the principal that an enema is less invasive and easier to blind vs. colonoscopy 
and naso-jejunal tube. However, a recent publication of a small case series demonstrating that FMT could 
be delivered orally led to a renewed consideration of this approach. Capsule-delivered FMT offers a 
further improvement in tolerability, ease of administration, and ease of blinding when compared to 
alternate routes considered: enema, naso-duodenal or naso-jejunal, or colonoscopy administration. It also 
eliminates the need for more advanced care such as radiology services to verify naso-jejunal tube 
placement, or an endoscopist to perform the colonoscopy. 
 
 
Efficacy of FMT via enema, colonoscopy, or naso-jejunal tube is similar, with no significant 
differences in prevention of recurrence (albeit with few studies that directly compared methods) (44, 45). 
Aggregated success rates for FMT via enema, colonoscopy, and naso-jejunal administration are 78%, 
90%, and 77%, respectively (21). A study of 116 patients randomized to FMT via colonoscopy versus 
frozen capsule found that both treatments prevented recurrence in 96.2% of treated patients (19, 45). 
Mechanistically, delivery via capsule is analogous to delivery via naso-jejunal tube, especially since the 


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capsules used typically dissolve after 2-3 hours, by which time they are expected to have entered the 
small intestine. With initial efficacy data comparable to that seen with other routes of delivery, and the 
much more favorable profile regarding tolerability, logistics, and safety, FMT via capsule is believed to 
be the best delivery modality for this trial.   
 
3. 
Dose:  
 
The optimal dose for FMT is unknown. Significant variability has been noted between different 
publications, both regarding the initial amount of stool used, the various volumes of diluents used, and the 
use of centrifugation to concentrate the stool organisms. The dose used for the recent case series of FMT 
via capsule was chosen arbitrarily (personal communication, Ilan Youngster). The FMT dose used in this 
study will be based on the dose recommended for the specific product when used in clinical care.  
Detailed information about the dose and number of capsules each patient will consume will be provided 
in the Operations Manual.  
 
 
In summary, Veteran patients who have received standard antimicrobial therapy for CDI as 
prescribed by their treating clinician, have resolution of CDI or have maintained improvement of 
symptoms, and who consent to participate in the study, will receive FMT or placebo via oral 
administration of FMT or placebo capsules. 
 
 
 
 


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XI. 
Follow-up  
A. Time Table 
 
The study time-table for study activities and data collection is laid out below (Table 5): 
 
Table 5. Study activities and data collection 
Time 
Prior 
to 
Rand. 
Rand.  Day 0 
48 
hours 
Week 
2 
Weeks 
4, 6 
Weeks 
8 
Subject 
contact 
the 
study 
Month 
3, 4, 5 
Month 
6 
Form1 
/screening log 
X 
 
 
 
 
 
 
 
 
Coordinator visit 
 
X 
 
 
 
 
 
 
 
Coordinator call 
 
 
X 
X 
 
X 
 
 
X 
AVRS 
call/Coordinator 
call (Form 17) 
 
 
 
 
X 
 
  
X 
 
Stool sample 
(optional) 
 
X 
 
X 
 
X 
 
 
 
Forms 2-8 
(Baseline) 
 
X 
 
 
 
 
 
 
 
Form 10/11 
(Safety follow-
up) 
 
 
X 
X 
 
 
 
 
 
Form 12/13 
(Evaluation) 
 
 
 
 
X 
 
 
X 
Form 18 (Exit) 
 
 
 
 
 
 
 
 
X 
Form 
14/15(AE/SAE) 
 
@ 
@ 
@ 
@ 
@ 
@ 
@ 
@ 
Form 16 
Unscheduled 
Contact 
 
 
@ 
@ 
@ 
 
@ 
@ 
 
Form 9 (CDI 
Evaluation) & 
diagnosis stool 
sample 
 
 
@ 
@ 
@ 
@ 
@ 
 
 
Form 7 (QoL) 
 
X 
 
 
 
X 
 
 
 
@ Fill out an AE or SAE form when an AE or SAE occurs or study team becomes aware of event (see Section XIV); fill out a 
form 9 when a potential episode of recurrent CDI is notified.   
 
 
Overall, this is a short-duration study, with patients becoming potentially eligible by having an 
episode of recurrent CDI, responding to standard antimicrobial treatment, enrolling, and being 
randomized to FMT vs. placebo capsules. Follow-up lasts for 6 months, after which study participation is 
completed. 


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B. Follow-up Procedures 
 
 
Study follow-up will be done by telephone, using a combination of scheduled calls by an 
automated system, triggered calls based on responses to the automated calls, and scheduled calls from 
Study Coordinators (SCs).  
 
 
Participants will be assessed for symptoms of CDI and any treatment-related adverse events with 
a call from study personnel at days 2, 14, and 56 after capsule administration. The day 56 (8 week) call 
will be used to assess the primary endpoint, confirmed or possible recurrent CDI, as well as the secondary 
endpoints, including the quality-of-life questionnaire. Interspersed amid these in-person calls will be bi-
weekly calls (on day 28 and 42) from an automated system or study personal that will prompt participants 
to answer general questions regarding any new diarrhea, abdominal pain, new antibiotic use, or concerns 
that they are experiencing a recurrence of CDI. Affirmative answers will be followed up by a call from 
the SC, who will ask further details regarding the positive response. Participants experiencing new 
diarrhea, in addition to seeking clinical care at their local facility, will be instructed to contact the study 
coordinator, collect a stool sample using a collection kit provided by the SC, and mail in a pre-paid mailer 
to the central laboratory, where it will be tested for C. difficile toxin by EIA, and the presence of the toxin 
B gene by PCR. If an automated system call fails to reach a participant within a six day time window, a 
SC will follow-up with the participant with at least three phone contacts and carefully document these 
attempts. Study Coordinators will continue to assess for study endpoints via medical record review, even 
in the unlikely event where no phone contact can be made.  
 
 
After randomization, from week 8 to month 6, the automated calls or study personal contact will 
decrease in frequency to once a month, with the same triggers for a follow-up call from a Study 
Coordinator. At month 6 a final call by the SC will occur to assess any new symptoms of recurrent CDI, 
serious adverse events, hospitalization, and any other reported symptoms. A schematic of the study 
timeline for an individual participant is displayed above (Table 5). 
 
 
Symptoms of recurrent CDI will be managed clinically by the local providers, with results 
monitored remotely by SCs. Participants will be asked to collect and mail a stool specimen to the central 
laboratory for C. difficile testing if they experience symptoms of recurrence.  
 


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C. Study Withdrawal and Crossover 
 
We hope to limit study withdrawal by carefully educating potential participants regarding study 
expectations and procedures prior to enrollment. Furthermore, the fact that follow-up is via telephone 
should limit the demands on a participant’s time and expenses. Cross-over is not planned in this study; 
FMT will not be provided to those experiencing recurrence. Patients experiencing recurrence will be 
asked whether they have undergone FMT outside of the study protocol, and if so, to provide details 
regarding administration (route, setting, supervision, etc.). 
 
D. Study Termination and Closeout  
 
At the 6 month follow-up visit, participation in the trial is concluded. A note indicating study 
completion will be placed into the Computerized Patient Record System (CPRS), and the provider(s) 
caring for the participant will be notified. 
 
 
 
 


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XII. 
Biostatistical Considerations 
A. Hypothesized Event Rates, Treatment Effect Size, and Sample Size 
1. 
Effect size 
 
Sample size calculations were initiated with a determination of what improvement in the rate of 
recurrence would be sufficiently large to be considered clinically significant. For a high-risk procedure, 
the benefit must be substantial enough to outweigh the potential risks. In the case of FMT, approximately 
500 cases have been reported in the medical literature, with few reports of harm (21). Those that were 
reported were largely related to the route of delivery—including a fatal aspiration event associated with 
colonoscopy, and peritonitis associated with administration of FMT via an indwelling gastric tube. Since 
the protocol proposal is FMT administration via capsules, which confers substantially less risk, it is 
appropriate to consider a 15%-20% reduction in recurrent CDI rates as clinically significant. An absolute 
improvement (reduction) of 15% was selected as the threshold for clinical significance, meaning that if 
the placebo group had a recurrence rate of 35%, the FMT group would have a rate of 20% to be 
considered a clinically significant difference.  
 
2. 
Expected Recurrence Rate after Standard Antimicrobial Therapy 
 
Recurrence rates for CDI after antimicrobial treatment are well-described for the initial episode; 
unfortunately, subsequent rates of recurrence are less well known. Data regarding subsequent rates of 
recurrence derive from a few RCTs that included subjects with a previous episode of CDI, and several 
observational studies. Two RCTs comparing fidaxomicin to vancomycin for the treatment of CDI have 
been reported (9, 10), each containing a subgroup of patients with a prior episode of CDI (the rest 
experiencing their first episode). A subsequent publication assessed the difference in recurrence by 
treatment arm in those with prior CDI (12). The overall recurrence rate for those with prior CDI was 27% 
(36% vancomycin vs. 20% fidaxomicin: P = .045). Another trial compared high-dose vancomycin vs. 
low-dose vancomycin vs. metronidazole for the treatment of recurrent CDI, each with the addition of a 
probiotic (Saccharomyces boulardii) vs. placebo (43). In this study, the overall recurrence rate was 45%. 
Among the six different treatment arms, in five treatment arms recurrence rates were between 45% and 
51%; the combination of S. boulardii and high-dose vancomycin had a recurrence rate of 17% (3/18). 
Finally, in the trial of FMT vs. two vancomycin-based control groups, the combined recurrence rate in the 
vancomycin groups was 73% (19/26) (20).  


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Observational data regarding subsequent recurrence after treatment of recurrent CDI is variable, 
both in terms of results and the population studied. In contrast to the RCTs which predominantly studied 
patients being treated for their first episode of recurrence, many of the observational studies report on 
patients with multiple episodes of recurrence. Reporting and publication bias is a significant concern, 
since successful experiences may be more likely to be submitted and accepted for publication. Those 
caveats aside, there is still valuable information regarding recurrence rates to be gained from this 
literature. An older case series describes no recurrence (after a mean of 6 months follow-up) among 22 
patients treated with vancomycin using a tapered/pulsed dosing strategy (46), whereas another study 
evaluating tapered or pulsed dose vancomycin reported a 38% recurrence rate (10/26) (47). Finally, a small 
case series described successful treatment without recurrence in 7 of 8 patients using vancomycin 
followed by a course of rifaximin (48). Details of these studies are summarized in Table 6.    
 
Table 6. Studies reporting antimicrobial treatment of recurrent CDI and 
subsequentrecurrence rates 
Study 
Study type 
N 
Population 
Treatment 
Recurrence 
rate 
Cornely 
2012 (12) 
RCT 
128 
Patients with 1st 
recurrence of 
CDI 
Vancomycin or 
fidaxomicin 
27% 
Surawicz 
2000 (43) 
RCT 
170 
Patients with 1st 
recurrence of 
CDI 
High-dose 
vancomycin, low-dose-
vancomycin, or 
metronidazole, all with 
S. boulardii vs. 
placebo 
45% 
van Nood 
2013(20) 
RCT 
26 
Patients with 
recurrent CDI 
(1-9 episodes) 
Vancomycin or 
vancomycin plus 
bowel lavage 
73% 
Pepin 2006 
(49) 
Retrospective 
cohort 
463 
Patients with 1st 
recurrence of 
CDI 
Vancomycin or 
metronidazole 
33% 
McFarland 
2002 (47) 
Retrospective 
cohort 
26 
Patients with 
recurrent CDI 
(1-14 episodes) 
Vancomycin 
taper/pulsed dose 
38% 
Tedesco 
1985 (46) 
Case series 
22 
Patients with 
multiple 
relapses 
Vancomycin 
taper/pulsed dose 
0% 


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Johnson  
2007 (48) 
Case series 
8 
Patients with 
recurrent CDI 
(4-8 episodes) 
Vancomycin followed 
by rifaximin 
13% 
 
 
The three largest studies report recurrence rates of 27%, 33%, and 45%. All of these included 
only patients with a first recurrence of CDI; subsequent recurrence rates are typically higher. Importantly, 
the placebo arm of the recently presented RCT (Kelly, oral presentation) had a recurrence rate of 37%, 
although the precision of this estimate is limited by the sample size of 24. Accordingly, we believe that 
35% is a conservative estimate for an expected recurrence rate after treatment with standard 
antimicrobial therapy. If enrolled patients have a history of multiple recurrences, the recurrence rate is 
likely to be in the 40%-50% range (14). 
 
 
Expected recurrence rates after FMT have recently been systematically reviewed and 
summarized. The overall recurrence rate, including case series and RCTs of all FMT delivery methods, is 
15% (21). The single published series regarding capsule delivery of FMT reported a recurrence rate of 30% 
(6/20) (19), with another series (presented in abstract form only) reporting no recurrences in 29 patients 
(Abstract 89. Fecal microbiome transplantation (FMT) via oral fecal microbial capsules for recurrent 
Clostridium difficile infection (rCDI) Session: Oral Abstract Session: New Considerations in C. difficile 
Prevention and Treatment/ October 2, 2013, IDWeek, San Francisco). Given the overall recurrence rate 
for FMT of 15%, the data from the published study of capsule-delivered FMT indicating a recurrence rate 
of 30%, and taking into account the unpublished study, we believe that anticipating a 20% recurrence 
rate after standard antimicrobial therapy followed by FMT is appropriate. 
  
3. 
Sample size of the primary outcome 
 
Accordingly, sample size was estimated using the following assumptions: 
 
1) Recurrence rate of standard antimicrobial therapy followed by placebo of 35%; 
2) Recurrence rate of standard antimicrobial therapy followed by FMT of 20%; 
3) Two-sided significance level of 0.05; and 
4) Overall drop-out rate of 1%. 
 
 
Using the method described in Fleiss (50) for comparing two proportions, a total sample size of 318 
provides 85% power to find an absolute difference of 15% in the recurrence rate with the addition of FMT 
to standard antimicrobial therapy for recurrent CDI. 


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Table 7.  Sample Size Estimation Table  
Recurrent CDI or All-Cause Mortality by Day 56 
Power 
Placebo 
 (Control Arm) 
FMT 
 (Experimental Arm) 
Absolute 
Reduction 
0.80 
0.85 
0.90 
45% 
35% 
10% 
758 
866 
1014 
 
30% 
15% 
327 
374 
436 
 
25% 
20% 
177 
202 
236 
40% 
30% 
10% 
717 
820 
961 
 
25% 
15% 
305 
349 
408 
 
20% 
20% 
164 
181 
218 
35% 
23% 
12% 
450 
515 
602 
 
20% 
15% 
276 
318 
372 
 
17% 
18% 
186 
212 
247 
30% 
22% 
8% 
950 
1086 
1270 
 
15% 
15% 
243 
277 
323 
 
12% 
18% 
159 
182 
212 
 
 
Using the assumption in the above target sample size of 318, the following scenarios were 
considered as sensitivity power analyses: 
• 
If the recruitment rate is less than anticipated, the study will still maintain 82% power to detect an 
absolute reduction of 15% with a sample size of 300 (83% of the target sample size).  
• 
If the control group event rate was 30%, lower than anticipated, the study would still maintain 
90% power to detect an absolute reduction of 14%. 
• 
If the effect size is smaller than hypothesized, the study would still maintain 75% power to detect 
an absolute reduction of 13% while the control event rate maintains as 35%. 
 
 
In summary, the anticipated rate of recurrent CDI following standard antimicrobial therapy is 
35% (see Table 6); the study is powered to detect a clinically significant difference of 15%. As previously 
discussed, this difference is chosen based on the non-invasive nature of the intervention, as well as 
favorable safety data from the > 500 cases of FMT reported in the literature. The rate of recurrence will 
be affected by the mixture of patients enrolling; if most enroll after their first recurrence, the rate of 
subsequent recurrence may be slightly lower, whereas if most enroll after multiple recurrences, 35% is 
likely an underestimate. Using the above assumptions, the previously specified 85% power with a two-
sided significant threshold of 0.05, and a 1% drop-out rate, the total sample size is 318 participants. 


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B. Duration of Study/Feasibility/Number of Participating Sites 
 
It is estimated (see Section XII about the feasibility details) that there will be approximately 1,600 
unique Veterans eligible for the trial overall in a year, per inclusion criteria. Additionally, we have 
calculated that 44% of cases/patients are from the top 26 sites in terms of recurrent CDI cases, where CSP 
#596 will recruit from. These 704 patients will not be eligible for enrollment in CSP #2004 initially, 
because enrolling from those sites would decrease eligible subjects for CSP #596, adversely affecting that 
study. However, those ineligible for or experiencing recurrences in CSP #596 will be offered participation 
in our study, a situation which we hope to encourage by maintaining a strong collaboration between the 
chairs of CSP #596 and #2004. The anticipated recurrence rate in CSP #596 is 47%; accordingly, 
approximately 330 patients initially in CSP #596 may be offered enrollment in CSP #2004. 
 
 
 
In the spring of 2021, the study fell behind in recruitment. The MATCH study Executive 
Committee believe the following four reasons caused the recruitment to fall below target:  
 
• 
There was a three-month initial delay in recruitment until the study therapy became available.  
• 
 In July 2019, the FDA placed a clinical hold on all FMT studies while it was investigating a 
serious adverse event (death) caused by a multi-drug resistant organism (MDRO) infection, 
acquired through a fecal microbiota transplant (note: this event was not in CSP #2004). 
Enrollment was reopened 1.5 months later, after CSP #2004 provided satisfactory measures to 
mitigate the MDRO infection risk.  
• 
 As a result of the COVID-19 pandemic, study recruitment was put on hold for five months 
(March 18, 2020 – August 28, 2020) to minimize exposure risk for potential participants and 
research personnel.  
• 
Even after the study resumed in August 2020, the ongoing pandemic and associated exposure risk 
have caused patients/potential study participants to be reluctant to seek care and therefore unable 
to provide a stool sample for diagnostic testing. As a result, providers at some VAMCs could not 
order a confirmatory stool test for CDI and instead diagnosed recurrent CDI using clinical criteria 
only. Hence, the study’s database screening algorithm could not identify patients who might have 
been eligible for the study.      
 
  


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Due to the above reasons, the study Executive Committee decided to modify the sample size from 
390 to 318, reduce power from 90% to 85% and increase enrollment time from 3-years to 6-years. Our 
original randomization target and power were calculated based on a 15% absolute reduction in the 
cumulative event rate for the primary endpoint for FMT and placebo.  In the modified sample size 
calculation, assuming a 1% dropout rate, a sample size of 318 participants (159 in each treatment arm) is 
required to detect this difference using a 2-sided test of significance with α= 0.05 and β=0.15 (power of 
85%). 
 
The Study Leadership, with endorsement of the study’s DMC, requested a 36-month extension of 
recruitment. This, in combination with a modified sample size, would maintain a high statistical power (at 
least 85%) to test the primary hypothesis. 
C. Interim Monitoring and Analysis 
 
Interim monitoring will be performed by the WH-CSPCC and will focus on recruitment, baseline 
comparability of treatment groups, protocol adherence, completeness of data, accrual of primary endpoint 
events (i.e., information accrual), safety, and treatment efficacy. The WH-CSPCC will provide interim 
reports to the Data Monitoring Committee (DMC), which will meet for two scheduled interim analyses.  
 
1.  
Efficacy and Futility Analyses 
 
Two interim analyses of the primary outcome (recurrent CDI or death) are planned, after which 
the DMC will decide whether to continue the trial or not. The DMC will have discretion to request 
additional or differently scheduled interim analyses. The first interim analysis will be done when at least 
159 subjects have been enrolled and followed for more than 56 days (50% accrual of primary outcome 
information), and the second when at least 239 subjects have been enrolled and followed for more than 56 
days (75% accrual of primary outcome information). For both interim analyses, a stopping rule with a 
wide boundary such as the Haybittle and Peto method (51, 52) will be used. It is suggested that the 
significance level for the interim analyses will be 0.001 and the two-sided significance level for the final 
analysis will be 0.05. The inflation of the overall type I error will be negligible. At the first interim 
analysis, there will be approximately 80% power to detect an 18.5% absolute reduction in the primary 
outcome relative to the placebo arm (based on a placebo rate of 35%). At the second interim analysis, 
there will be approximately 82% power to detect a 16% absolute reduction in the primary outcome 
relative to the placebo arm (again assuming a 35% primary outcome rate in the placebo arm). 


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At the time of the two interim analyses, a futility analysis will be performed to assess the 
likelihood of eventual success based on the observed data. The conditional power (53) to fulfill the study 
will be provided to the DMC as either an exact value of power or through a Yes/No question. If the 
conditional power is low, the DMC may recommend stopping the study or continuing with an adjustment 
to the sample size and extension of the trial. Definite recurrent CDI, a secondary endpoint, is as important 
as possible recurrent CDI, which is a symptom-based component of the primary endpoint. Accordingly, 
we will process the futility analysis to both primary endpoint as well as definite recurrent CDI, one of the 
key secondary endpoints. 
 
2.  
Interim Safety Monitoring 
 
Safety will be monitored by the WH-CSPCC, the CSPCRPCC, and the Study Co-Chairs' Office 
throughout the study. Safety reports will be submitted to the DMC approximately every 6 months after 
enrollment begins, or more frequently, if requested by the DMC. For reports to the DMC closed session, 
serious adverse events (SAEs) will be summarized by treatment groups and relatedness to the assigned 
interventions. The proportion of participants experiencing an SAE in each treatment group will be 
calculated and analyzed using the chi-square test or Fisher’s exact test, as appropriate. In the event that 
SAEs or mortality are noted to be excessive in either study arm, the DMC may consider recommending 
that the trial be stopped or that the protocol be modified.  
 
D. Final Statistical Analysis of the Data 
 
All primary analyses will be according to the principle of intent-to-treat; i.e., subjects will be 
analyzed according to their original treatment assignment regardless of protocol adherence. 
1. 
Baseline Comparability 
 
In order to assess the adequacy of randomization, the baseline characteristics to be compared and 
summarized include: age, gender, ethnicity, medical comorbidities, and number of prior CDI episodes 
experienced. The distribution of baseline patient characteristics between groups will be evaluated using 
descriptive statistics. A priori baseline variables which will be used for covariate adjustment include age, 
gender, number of prior CDI episodes, and immunodeficiency.  


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2. 
Analysis of Primary Outcome Measure 
 
The primary outcome (recurrent CDI or death within 56 days) will be compared between the 
FMT arm and the placebo arm, using a p-value of 0.05 (two-sided). A generalized linear model will be 
used for the analysis since it is appropriate for a binary endpoint and can be adjusted for covariates and 
tested for interactions. Based on the study, design treatment arm, as well as a previous recurrence of CDI 
(1 vs. =>2) will be considered as fixed effects, and the status of having a recurrence of CDI or death will 
serve as the outcome. The number of primary outcomes as well as the percentage of primary outcomes 
will be summarized by treatment. The odds ratio of having a primary outcome in terms of FMT treatment 
to the placebo with 95% confidence interval will also be provided.  The primary hypothesis will be tested 
by the above generalized linear model with treatment adjusted for study design. Treatment by number of 
prior CDI episodes interactions will be examined in exploratory analyses. A p-value of 0.05 will be used 
for all sub-group analyses of the primary outcome. 
 
 
As another exploratory analysis of the primary outcome, we will test the treatment effect adjusted 
for study design as well as a set of pre-specified baseline covariates to examine their influence on the 
treatment comparison. Treatment by covariate interactions will be examined for the following baseline 
covariates: gender, age, number of prior CDI episodes, and immunosuppression. A p-value of 0.05 will be 
used for all sub-group analyses of the primary outcome. 
 
 
Survival status on participants who cannot be contacted by day 56 will be obtained using the VA 
Beneficiary Identification and Records Locator System (BIRLS), the National Center for Health 
Statistics’ National Death Index database, and the Social Security Administration’s Death Master File. 
Participants who completely withdraw from the study will have their last assessment (recurrent CDI or 
not) carried forward, whereas those partially withdrawing (i.e., allowing medical record review) will have 
their CDI status updated based on information in the medical record.  
3. 
Analysis of Secondary Outcomes  
The first secondary outcome (recurrent CDI or death within 6 months) will be summarized by 
incidence between the FMT arm and the placebo arm.  Treatment group comparisons will be based on 
generalized linear model.  The odds ratio of having a recurrent CDI or death within 6 months in terms of 
FMT treatment to the placebo tested and the estimator with 95% confidence interval will also be 
provided. Kaplan-Meier survival curves, adjusted for censoring due to loss to follow-up, will also be used 
to evaluate treatment effects for 6-month recurrent CDI. The Cox proportional hazards model will also be 


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used to test the effect of treatment adjusted for the study design. The proportional hazard assumption will 
be tested using log (log) plots with visual examination, in order to assure the validity of this analysis. If 
the assumption is not valid, appropriate adjustments will be made, such as adding time by covariate 
interaction terms or use of stratification. 
 
 
Analyses of secondary outcomes (definite recurrent CDI, possible recurrent CDI, death, urgency, 
fecal incontinence, diarrhea that is negative for C. difficile by PCR, number of CDI recurrences within 6 
months, and quality of life at day 56) between treatment groups will be assessed using a p-value of 0.05, 
without adjusting for multiple comparisons. 
 
 
The same method of analysis that was applied for primary outcomes will be used for the 
secondary outcomes of: definite or possible recurrent CDI by 6 month, definite recurrent CDI by day 56, 
possible recurrent CDI by day 56, death by day 56.  
 
 
The secondary endpoints of abdominal pain, urgency, fecal incontinence, and diarrhea that is 
negative for C. difficile by PCR are among the secondary analyses.  They will be performed among both 
possible recurrent CDI cases as well as definite recurrent CDI cases. Similar method of analysis that was 
applied to the primary outcome will be used for these secondary endpoints.  
 
The number of definite or possible CDI recurrences by 6 months will be summarized as mean 
with standard deviation by treatment group and be analyzed by an ANOVA model. We will also 
categorize them into three levels of discrete ordinal measurement – none, one, and more than one. A 
generalized linear model with a cumulative logit link function will be used to investigate the effects of 
treatment on a number of CDI recurrences. Otherwise, a weighted-least-squares analysis will be used to 
assess the mean score of number of CDI recurrences for each treatment arm. As for the primary outcome, 
treatment comparisons will be adjusted for both the study design and the pre-specified set of baseline 
covariates. 
 
Kaplan-Meier survival curves, adjusted for censoring due to loss to follow-up, will be used to 
evaluate treatment effects for 6-month all-cause mortality. Treatment group comparisons will be based on 
the log-rank test.  The Cox proportional hazards model will also be used to test the effect of treatment 
adjusted for the study design. The proportional hazard assumption will be tested using log (log) plots with 
visual examination, in order to assure the validity of this analysis. If the assumption is not valid, 


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appropriate adjustments will be made, such as adding time by covariate interaction terms or use of 
stratification. 
 
Quality of life (a continuous measurement) differences between the two treatment arms will be 
analyzed using a linear model. Since some of the censoring, such as death, may be informative, we will 
conduct the analyses both with and without adjusting for the possibility of informative censoring. First, 
the analysis will be done on the observed quality of life, regardless of whether the censoring is 
informative or not. Then, we will assign a lower score to those missing due to death and analyze the data 
adjusted for the informative censoring as a sensitivity analysis. 
4. 
Analysis of Safety Outcomes  
Kaplan-Meier survival curves, adjusted for censoring due to loss to follow-up, will be used to 
evaluate treatment effects for 6-month all-cause mortality. Treatment group comparisons will be based on 
the log-rank test.  The Cox proportional hazards model will also be used to test the effect of treatment 
adjusted for the study design. The proportional hazard assumption will be tested using log (log) plots with 
visual examination, in order to assure the validity of this analysis. If the assumption is not valid, 
appropriate adjustments will be made, such as adding time by covariate interaction terms or use of 
stratification. 
 
The number of SAEs and proportion of participants experiencing an SAE up to six months in 
each treatment group will be summarized by treatment arm, and MedDRA System Organ Class. The same 
summary will be done on all protocol specified AEs.  
5. 
Analysis of Exploratory Outcomes  
 
The Shannon index (diversity) and the abundance-based coverage estimate (ACE) (richness) will 
be used as endpoints to perform the following exploratory analyses in order to evaluating the microbiome 
of patients pre- and post-treatment: 
 
i. 
Characterization and comparison of the colonic microbiome of individuals with CDI 
randomized to FMT and placebo, before and after FMT/placebo administration; 
ii. Comparison of the post-FMT colonic microbiome of individuals randomized to FMT and 
placebo to the donor microbiome; and 


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iii. Comparison of the post-FMT microbiome of individuals that experience a recurrence to the 
microbiome of those not experiencing recurrence. 
 
 
Using collected stool samples, we will extract DNA, quantify and amplify microbial communities, 
and use 16S rRNA gene profiling using V5 + V6 hypervariable regions sequencing on the Illumina MiSeq 
platform to characterize the microbial community structure.  Taxonomic classification will be performed 
against the version 14 data release from the Ribosomal Database Project. Specifically, we will be 
quantifying microbial diversity using two validated indices to characterize microbial diversity and richness 
with the Shannon index (diversity) and the abundance-based coverage estimate (ACE) (richness) 
respectively. These two indices are calculated to assess parametric and non-parametric diversity. The 
Shannon index is scored between 0 and 7 while the ACE ranges from 0 to 8000.  
 
 
Student t-test (paired and unpaired), Pearson and Spearman correlations will be used to compare 
scores pre-post FMT and donor-recipient. Our hypothesis is that post- FMT samples will show increased 
diversity and richness compared to pre-FMT, and that post-FMT changes will resembles the microbiota 
composition of donor specimens, and that post-FMT changes will be sustained over 6 months. 
 
 
Prior estimates from the literature suggest that the mean Shannon index for pre and post FMT will 
be 1.68+0.75 and 3.37 +0.46 respectively. Assuming half the study participants agree to provide an 
additional sample for characterization of stool microbiome (n=200) we would have >95% power to estimate 
differences pre and post FMT.  
 
 
Additional analyses may include: differences in beta diversity (community composition) using 
analysis of similarity (ANOSIM), other diversity indices [number of operational taxonomic unit (OTU) 
sequences (S obs), sequencing coverage estimation, UniFrac analysis, ANOSIM analysis, principal 
coordinate analysis (PCoA), Mantel tests, Kruskal – Wallis analysis, and analysis of molecular variance 
(AMOVA) will be performed.  
 
 


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XIII. 
Feasibility 
A. Estimating the Patient Population 
 
An assessment of study participant availability was performed by searching national VA data 
from the Cooperate Data Warehouse (CDW) to identify recurrent CDI episodes in fiscal year 2014. We 
queried the laboratory test name file to identify all diagnostic tests associated with CDI. These included 
nucleic acid amplification tests (NAAT), EIA toxin test, or other tests (glutamate dehydrogenase [GDH] 
plus NAAT, GDH plus toxin A/B EIA, cell culture cytotoxin assay, or anaerobic toxigenic culture).   
 
 
A total of 108,664 CDI test result records were extracted from patients identified in the last 2 
quarters of fiscal year 2013 through fiscal year 2014, of which 15.6% (n = 16,952) of tests were positive 
using data from the CDW laboratory chemistry data domain. We applied a definition of recurrent CDI 
episode as follows: the number of days from a previous positive CDI lab result to the current positive lab 
result was more than or equal to 10 and less than or equal to 90 days. We identified a total of 11,242 
positive CDI results in fiscal year 2014 on 8,726 unique Veteran patients. Of these, 1,370 (15.7%) had a 
laboratory-confirmed episode of recurrent CDI. In addition to the laboratory confirmed cases, we 
identified 1,476 (16.9%) cases of recurrent CDI based on inpatient or outpatient diagnoses (but without 
laboratory confirmation in CDW data).  
 
 
A pilot study at the Minneapolis VA was performed to determine what percentage of these cases 
lacking lab confirmation have lab confirmation documented in the electronic medical record (either by a 
non-VA laboratory result, or a VA result not captured by our search of CDW data). The table below 
displays the laboratory confirmed cases of recurrent CDI, and the cases lacking laboratory confirmation. 
 
 


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Table 8. Cases of recurrent Clostridium difficile infection (CDI) identified using VA data 
from Corporate Data Warehouse, including laboratory-confirmed cases and cases lacking 
laboratory confirmation. 
 
Number of individuals 
Unique Veterans with laboratory confirmed CDI 
in year 2014  
8,726 
Unique Veterans with laboratory confirmed 
recurrent CDI in year 2014 
1,370 (15.7%) 
Unique Veterans with a recurrent CDI diagnosis 
WITHOUT laboratory confirmation in year 2014 
1,476 (16.9%) 
 
CSP #596, Optimal Treatment for Recurrent Clostridium difficile Infection (CDI), is another 
ongoing, randomization study in 26 VA sites. The patient population of CSP #596 is also recurrent CDI 
patients. The primary objective of CSP #596 is to determine whether 1) standard fidaxomicin treatment 
and 2) standard vancomycin treatment followed by taper and pulse vancomycin treatment are superior to 
standard vancomycin treatment alone for sustained clinical response at day 59 for all treatments, for 
participants with either their first or second recurrence of CDI. This study, CSP #2004, is mainly 
enrolling from sites that were not selected by CSP #596, although subjects not eligible for or experiencing 
recurrence in CSP #596 are eligible to enroll in CSP #2004. Accordingly, we assume that CSP #596 will 
be recruiting from most of the top 26 sites in terms of recurrent CDI cases, although as discussed above, 
the anticipated 47% recurrence rate in CSP #596 may result in approximately 330 patients who may be 
offered participation in CSP #2004. This is particularly important as these patients have already 
demonstrated a willingness to enroll in a CDI clinical trial and participate in the research process. 
 
Using this data it is estimated that there will be approximately 1,600 unique Veterans eligible for 
the trial in a year (assuming that ~15% of the approximately 1,500 patients with a CDI diagnosis but no 
lab confirmation in CDW will have laboratory confirmation from a non-VA laboratory or from a VA 
laboratory not captured by CDW). Additionally, we have calculated that 44% of the cases are from the 
top 26 sites in terms of recurrent CDI cases, where CSP #596 will recruit from. Considering the 97 sites 
that are not involved in CSP #596, there will be approximately 896 unique Veterans eligible for the CSP 
#2004 study.  It is anticipated that a total of 130 potential participants would have to be enrolled per year 
(14.5% of eligible) in order to accrue 390 participants in 3 years.  
 


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In summary, we plan a 3-year recruitment to enroll a total 390 participants (130/year) with an 
annual enrollment rate of 14.5% among eligible participants.  In the Fall 2021, the study was approved to 
modify a total 3-year recruitment into a total 6-year recruitment to enroll a total 318 participants 
(60/year). 
 
B. Centralized and Regional Enrollment and Follow-up 
The study is expected to complete enrollment of at least 318 participants in 6 years, with a 
minimum of 56 days of follow-up for study outcomes for all randomized participants. The study design is 
based on conducting the trial with VA-system-wide central enrollment, central follow-up and 
coordination, as described in section A of Section VIII. Running the study centrally includes centralized 
screening, recruitment, and follow-up for participants’ safety as well as outcome data collection. Central 
enrollment is selected for two main reasons: 
 
a. Feasibility: The estimated 1,600 eligible patients (per year) are distributed among 120+ VA sites. 
In order to reach the target of 60 participants per year, all non-CSP #596 sites would have to 
participate. Given the small number of cases at any given facility (15-25/year), the resources, 
time and effort required for a traditional participating-site design would not be practical. In order 
to maximize efficiency in enrolling eligible participants central enrollment is a pragmatic and 
resource effective approach.  
 
b. Patient centered approach: Central enrollment provides the opportunity to reach geographically 
diverse patients across all VA facilities nationally, without restriction of site and status of the 
facility. A critical design factor is the timing between episodes of CDI, initiation of treatment and 
window available for enrollment. A central enrollment strategy would allow identification of 
recurrent cases in real-time, and being able to reach the patient in a timely manner. This also 
avoids the burden and inconvenience for the patient to come to a VA facility.  
 
In addition, participants’ safety records such as SAEs will be reported by SCs and SIs using 
CDW data and medical record review. This allows for morbidity and mortality events to be captured in a 
uniform and comprehensive fashion compared to a usual trial setting.  
 
In summary, centralized recruitment and follow-up is necessary for the purpose of conducting 
CSP #2004 efficiently. The centralized recruitment in this trial will be done ethically with protection of 


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the patients’ rights and privacy. Patients’ safety will be monitored through patient contacts and medical 
record review as would be done in a traditional participating-site trial setting. This approach allows for 
collection of high quality study data, similar to a standard design. Prior CSP studies (such as CSP#566) 
have also used this strategy successfully.  
 
C. A Pilot Study to Test Recruitment Process  
 
To assess feasibility and test the proposed enrollment methods, a pilot study was conducted at the 
Minneapolis VA Medical Center. A list of 100 CDI cases within VISN 23 in the last year was obtained 
based on the following criteria: ICD-9 diagnosis OR Positive PCR (the lab test used currently at this 
facility) and treatment for CDI for index and prior episode. These criteria are different from what we plan 
to use in the trial, because we wanted to assess the specificity of our search algorithm for finding a 
positive PCR, i.e.  for charts where only an ICD-9 is found, and how many may have a PCR that our 
search was missing.  
 
 
We were able to review charts for 69 patients (31 were not viewable with our current level of 
authorization; a request for CAPRI access to view these records is pending). Among the 69 viewable 
records, 31 were identified as having an ICD-9 code for CDI but no PCR result. Of these 31 charts, there 
were no cases where chart review identified a positive PCR that was missed by electronic screening 
(100% specificity). Of the remaining 38 records, 10 were not eligible per study criteria (main reasons 
were patient comorbidity such as terminal cancer, inflammatory bowel disease or dementia, and living in 
a nursing home). Of the 28 that were eligible, we were not able to reach the primary care physician (PCP) 
or treating provider in 4 cases (no listed phone numbers or incorrect numbers, or did not return phone 
calls or emails in a week). Of the 24 patients whose PCP’s we were able to reach, 100% reported having 
heard about FMT as a therapy for preventing recurrent CDI.  Most PCPs were reached successfully within 
one working day. Twenty-three of the 24 (95%) said they would be happy to contact their patient about 
the study and call us back. Two PCPs gave us additional patient names that would be potentially eligible.  
A summary is provided in Table 9.  
 
 
 
 
 
 


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Table 9. Summary of Pilot Study at the Minneapolis VA Medical Center 
List of potentially eligible in VISN 23 
100 
Patients charts we had access to 
69 
Chart with +PCR (that would be study eligible) 
38 
Eligible to enroll by study criteria 
28 (74% of the 38) 
Unable to contact PCP  
4(14% of the 28) 
Contacted PCP 
24 
Average time to make contact 
8 hours (many same day) 
PCP aware of FMT as an option 
24 (100% of all contacted PCP) 
PCP agreed to call patient and call us back 
23 (95% of all contacted PCP) 
 
 
An additional 10 patients with a recent positive PCR (within 2 weeks) were subsequently used to 
assess the timing and logistics of contacting patients who had been recently diagnosed and treated for 
recurrent CDI; 2 such patients were identified. In both cases the provider was contacted, was willing to 
contact the patient, and was able to do so on the same day. Both patients agreed to be contacted and 
discuss the details of their recent CDI episode. Both had substantially improved on their current CDI 
therapy, such that they would meet CSP #2004 eligibility criteria.  Both met eligibility criteria with at 
least 7 days of antimicrobial therapy remaining (7 and 13 days, respectively). Thus, if we were currently 
enrolling, the Study Coordinators would have at least 9 days to organize travel and administer the study 
intervention, assuming a 2-day washout period after completing antimicrobial therapy. Since the allowed 
washout period is 2-7 days, the time period available to arrange travel would be 9-14 days and 15-20 
days, respectively. 
 
 
Limitations: Since most of the providers contacted were in Minneapolis or the surrounding area, 
the rate of potential participation may be higher than in the actual study.  
 


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XIV. 
Adverse Event Assessment and Reporting 
A. Definitions 
 
Adverse events and SAEs will be collected according to the ICH Guideline for Clinical Safety 
Data Management (ICH-E2A) and CSP Global SOP 3.6 definitions. 
1. 
Adverse Event (AE) 
 
An AE is any untoward physical or psychological occurrence in a human participating in 
research. An AE can be any unfavorable and unintended event, including an abnormal laboratory 
finding, symptom, or disease associated with the research or the use of a medical investigational 
test article. An AE does not necessarily have to have a causal relationship with the research. (see 
VHA Handbook 1058.01, 21 CFR 312.32 and CSP Global SOP 3.6) 
2. 
Serious Adverse Events (SAEs) 
 
An SAE is an adverse event (as defined above) that, in the view of either the Site Investigator or 
sponsor: 
• 
Results in death; 
• 
Is a life-threatening experience; 
• 
Requires inpatient hospitalization (≥24 hours) or prolongation of existing hospitalization; 
• 
Results in persistent or significant disability or incapacity; 
• 
Results in a congenital anomaly/birth defect; or 
• 
Any other condition that, based upon medical judgment, may jeopardize the participant and 
require medical, surgical, behavioral, social or other intervention to prevent one of the above 
outcomes. 
3. 
Relatedness 
 
Relatedness involves an assessment of the degree of causality (attributability) between the study 
intervention and the event. The assessment of relatedness provided by the Site Investigator is part of the 
information used by the sponsor to determine if the adverse event presents a patient safety concern or 
requires regulatory reporting. Pursuant to CSP Global SOP 3.6, an AE or SAE is deemed to be 
attributable to the use of a study drug/device if “there is a reasonable possibility that the experience may 
have been caused by the drug/device or by participation in the trial.” Thus, all adverse events with a 
reasonable causal relationship to the investigational treatment should be considered “possibly related” or 


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“related.” A definite relationship does not need to be established, but there should be some evidence to 
suggest a causal relationship between the investigational treatment and the adverse event (21 CFR 
312.32).  
4. 
Unanticipated or unexpected  
 
VHA policy (handbooks 1200.05 and 1058.01), state that “unanticipated and unexpected refer to 
an event or problem in human research that is new or greater than previously known in terms of nature, 
severity, or frequency, given the procedures described in protocol-related documents and the characteristics 
of the study population.” Thus, whether an event is anticipated or unanticipated is determined based on pre-
specified characteristics of the study population and treatment. In addition to study outcomes including 
recurrent CDI and certain complications thereof, events which are expected in this study are diarrhea, 
abdominal pain, vomiting and nausea. Other symptoms or diagnoses not listed here may also be judged 
expected on the basis of published information on this population and study treatment. 
5. 
Severity 
 
 
NIH Division of AIDS grading scale (see the appendix in the Operations Manual) for both solicited 
and non-solicited adverse events will be used to classify the severity of adverse events and serious adverse 
events. 
   
B. Reporting of AEs and SAEs in CSP #2004 
 
The following adverse events will be collected and reported to the sponsor on study forms: 
• 
All serious adverse events, beginning at randomization/administration of study medication 
(defined as the opening of the study drug bottle) and continuing until the six-month visit;    
• 
All adverse events which are believed to be related or possibly related to the study treatment 
continuing until the six month visit; and  
• 
All adverse events regardless of seriousness or relatedness for the first 14 days after study 
treatment.  
 
 
Site staff will assess participants for AE/SAEs during all follow up visits/phone calls using open-
ended questions concerning any new symptoms or side effects. All participants will be monitored for 
adverse events from the time of randomization/ administration of study medication to the study exit time 
(typically at 6 months after study treatment). The SI will evaluate whether each AE or SAE is potentially 
related or unrelated to the study intervention; an adjudication committee will also be utilized in 


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ambiguous cases. The SI should also continue with follow-up assessments through monthly contact until 
resolution of the adverse event is achieved, or the adverse event is stabilized with no further change 
expected. 
 
C. Role of the Site Investigator in Event Monitoring 
 
The Site Investigators as well as Study Co-Chairs will be responsible for the following adverse 
medical event reporting requirements: 
• 
Reviewing the accuracy and completeness of all adverse events reported; 
• 
Complying with study policies as well as IRB policies for reporting adverse events, serious 
adverse events, and unanticipated problems involving risks to participants or others;  
• 
Reporting to CSP all SAEs within 72 hours of becoming aware of the event; 
• 
Reporting to the IRB safety issues reported to the site by the Sponsor; and 
• 
Closely monitoring research subjects for any new AEs and SAEs. 
D. AE and SAE Monitoring and Reporting 
 
AEs and SAEs will be monitored at the study sites throughout the period of the study, beginning 
at randomization/ administration of study medication and continuing through end-of-study for each 
participant.  The study will report all SAEs and those non-serious AEs determined to be possibly related, 
or related to the intervention or study.  Reportable AEs will be collected and recorded on the appropriate 
case report form.  All SAEs, including both those related to the study intervention and those not related to 
the study intervention will be collected and recorded on the appropriate case report form.  
 
All SAEs require expedited reporting.  An SAE case report form will be completed and submitted 
via the data capture system within 72 hours of the Site Investigator/ Study Coordinator initially becoming 
aware of the event.  The Study Pharmacist at CSPCPRCC will be responsible for evaluating all SAEs for 
participant safety concerns in a timely manner.   
 
SAEs that suggest evidence of a causal relationship between one of the study interventions and 
the adverse medical event and which are unexpected will be reviewed by the Study Leadership Team (i.e., 
Study Chairpersons, Study Biostatistician, Study Project Manager, and the Study Pharmacist) prior to 
notifying VA Central Office whenever feasible.  


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The CSP #2004 Biostatistician(s) and the Clinical Research Pharmacist will tabulate and 
summarize all AEs and SAEs for the DMC on a schedule set by the DMC, but no less than annually. The 
DMC will also determine when the committee should be unblinded to treatment assignment in reviewing 
AE/SAE data. The DMC will advise the CSP Director whether the study should continue or be stopped 
for safety reasons. Any SAE which is assessed as at least possible related to FMT and any suspected or 
proven transmission of infection from the FMT product to a participant will be reported to the DMC 
within 7 calendar days. FDA safety reporting will adhere to the FDA’s Guidance for Industry and 
Investigators: Safety Reporting Requirements for INDs and BA/BE studies. 
E. Authorization to Break the Blind  
Under unusual circumstances, chiefly related to participant safety, unblinding may be necessary. 
This is usually done after consultation with the Study Co-Chairs (Dimitri Drekonja, MD or Aasma 
Shaukat, MD). If Drs. Drekonja and Shaukat are unavailable, the CSPCRPCC Clinical Research 
Pharmacist (Annie Davis-Karim or another Clinical Research Pharmacist) or the Study Biostatistician 
(Jane Zhang) should be contacted.  
 
If knowledge of treatment assignment is required to treat an emergency, the treating physician may 
contact the CSPCRPCC through the 24-hour emergency call service at (505) 248-3203 to obtain study drug 
assignment information. The CSPCRPCC will notify the Study Co-Chair’s Office and the WH-CSPCC by 
telephone as soon as possible after an unblinding has occurred. 
 
 


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XV. 
Study Monitoring and Quality Control  
A. Procedures Overview  
 
The VA Cooperative Studies Program establishes overall policies and procedures that are applied 
to all VA cooperative studies through the Study Co-Chairs’ office at the Minneapolis VA Healthcare 
System, and the WH-CSPCC. The Cooperative Studies Scientific Evaluation Committee (CSSEC) 
reviews the scientific merit of all new cooperative study proposals. The CSSEC is composed of both VA 
and non-VA clinical research scientists and biostatisticians. The organizational and administrative 
structure of this cooperative study is similar to others in the Cooperative Studies Program and includes 
the components described below. 
B. Monitoring Bodies and CSP Monitoring 
 
The Executive Committee is chaired by the Study Co-Chairs and consists of the Study 
Biostatisticians, Study Research Pharmacist, selected participating investigators, and expert consultants.  
The Executive Committee is concerned with overall study management and is the decision-making body 
for the operational aspects of the study. The Executive Committee monitors the performance of 
participating medical centers and the quality of data collected, and plans and oversees the publication and 
presentation of all data from the study.  The Executive Committee must grant permission before any study 
data may be used for presentation or publication. This committee will hold conference calls on a monthly 
basis to review the study progress, and meet every 12 months to review blinded study data and decide 
upon any study changes. 
 
 
The WH-CSPCC and the Study Co-Chairs will administer the trial, oversee its organization, and 
perform the day-to-day scientific and administrative coordination of the study. This includes development 
of the protocol, operations manual, and case report forms; ensuring appropriate support for the 
participating centers; scheduling meetings and conference calls; responding to site queries about the 
protocol; conducting site visits; preparing interim and final progress reports; and archiving study data. 
Participant accrual and data quality are monitored closely to ensure that the study is progressing 
satisfactorily. 
 
The Minneapolis VA Health Care System IRB will serve as the oversight body for the protection 
of human subjects. Any additional sites (two are planned) will also submit the protocol to their IRB of 
record for the oversight of the research activities at those sites.  


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The Albuquerque CSPCRPCC will be responsible for acquiring, storing, and providing study 
medication to the Study Coordinators who will oversee treatment administration. Additionally, the 
CSPCRPCC will be responsible for monitoring the safety of trial participants through the review, 
assessment, and communication of adverse events (AEs) and SAEs reported by study personnel. The 
CSPCRPCC will maintain ongoing communication with the Study Co-Chairs, the Executive Committee, 
the WH-CSPCC, and CSP Central Office. The CSPCRPCC will serve as liaison to the Food and Drug 
Administration (FDA), including filing and maintaining the Investigational New Drug application (IND) 
and reporting certain SAEs as required by Federal regulations. In conjunction with the WH-CSPCC, the 
CSPCRPCC will prepare safety data reports for various committees including the DMC, IRB, Executive 
Committee, and the study group.  
 
The DMC will provide interim reviews of the study's ongoing progress. The DMC is composed 
of clinical and statistical members with expertise in clinical trials and/or the study subject area. These 
experts are not participants in the trial and have not participated in the planning of the protocol.  The 
Study Co-Chairs, Study Biostatisticians, Clinical Research Pharmacist, and the Director of the WH-
CSPCC are ex officio (liaison, non-voting) members of the DMC. The DMC will meet at least annually to 
review the progress of the study and monitor participant intake, outcomes, adverse events, serious adverse 
events, and other issues related to participant safety.  The DMC’s primary responsibilities will be to 
review safety and the progress of the study and to decide whether or not the study should continue. To 
help the DMC make its assessment, the Study Co-Chairs and Study Biostatisticians will provide the DMC 
with appropriate monitoring data before each meeting. The DMC makes recommendations to the 
Director, VA CSR&D about whether the study should continue or be stopped.   
 
A member of the Human Rights Committee (HRC) at the WH-CSPCC may conduct a site visit to 
at least one participating center during the course of the study to determine if participants’ rights and 
safety are being properly protected. The HRC member may interview study participants during the site 
visit. 
 
The Outcome Adjudication Committee will consist of 3 members nominated by the Executive 
Committee and chosen for their clinical and technical expertise. Since recurrent CDI is a clinical 
diagnosis, and motility disorders can cause symptoms similar to recurrent CDI, committee members will 
review all cases of possible recurrent CDI. In conjunction with the Study Co-Chairs, they will establish a 
standard adjudication procedure to categorize all possible recurrences, and whether they meet the primary 
endpoint of definite or possible CDI. 


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There will be two affiliated sites for CSP #2004, selected to facilitate Study Coordinator travel 
throughout the United States. The Site Investigator (SI) at each center is responsible for the conduct of the 
study at the center. The SI is expected to attend all annual Study Group meetings, as well as to hire and 
supervise local study personnel. By agreeing to participate in the study, the affiliated site delegates 
responsibility for global monitoring of the ongoing study to the DMC, HRC, and CSPCRPCC. However, 
the IRB of the medical center will have oversight of the research activities conducted at each affiliated 
site. 
 
The Study Group will consist of the Study Co-Chairs, CSP staff (Biostatisticians, Project 
Manager, Clinical Research Pharmacist, and others), Site Investigators, and Study Coordinators. The 
Study Co-Chairs will lead the Study Group, which typically meets monthly by teleconference and once 
per year in a face-to-face meeting to discuss the progress of the study, any problems encountered, and any 
suggestions for improving the study.  
 
The CSP Site Monitoring, Auditing, and Resource Team (SMART), located at the CSPCRPCC in 
Albuquerque, will monitor the trial for compliance with Good Clinical Practices. GCP monitors from 
SMART will visit participating sites shortly after sites randomize their first few participants and yearly 
thereafter to monitor investigator regulatory compliance, protocol adherence, and overall research 
practices. Additional monitoring visits may be conducted as deemed necessary by study leadership or 
SMART.  SMART will provide an orientation to GCP at the study kick-off meeting and provide GCP 
tools to enhance compliance.   
 
The SMART reviewer examines participant study files, including source documents held 
electronically, in clinic files and participants’ official VA medical records and reviews regulatory 
essential documents, such as IRB correspondence.  Areas of particular concern are informed consent 
issues, protocol adherence, safety monitoring, IRB reviews and approvals, regulatory documents, 
participant records, drug accountability, site operations, and investigator involvement in the trial. 
Monitoring may include but is not limited to the informed consent process, data validation, source 
verification, and safety reporting. Additionally, SMART will conduct periodic routine audits throughout 
the course of the study and for-cause audits of participating sites only as requested by study leadership or 
CSPCO.  Audits can be announced or unannounced.  
 


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In addition to SMART visits, WH-CSPCC, the Executive Committee, and the DMC will monitor 
protocol adherence centrally through periodic reports, data queries and SC/SI conference calls.  
Additional, site-specific monitoring may be conducted if triggered by study performance metrics. 
 
 
The site is required to document protocol breaches and any medical center with repeated protocol 
violations is reported to the Executive Committee and the Director, VA CSR&D.  If a Site Investigator 
feels that adherence to the protocol will be detrimental to a particular participant’s health or well-being, 
the interest of the participant must take precedence.   
C. Monitoring Participant Intake  
 
The Study’s Executive Committee, Study Co-Chairs, and the Study Biostatisticians will monitor 
the intake rate and operational aspects of the study.  The target enrollment for the study is 318Veterans. If 
recruitment is not proceeding at an appropriate rate, the Study Co-Chairs and the Study Biostatisticians 
will scrutinize the reasons for participant exclusions and other barriers to recruitment.  Based on this 
information, the Executive Committee may choose, with the approval of the Director, VA CSR&D, to 
make modifications to the inclusion/exclusion criteria, or extend the recruitment period and/or to extend 
the total length of the study.  
 
Medical centers will only be allowed to continue in the study if adequate participant intake is 
maintained. The target recruitment for the study is 5 participants per month. Because there is usually a 
ramp-up in recruitment early on, if the Minneapolis site does not enroll at least 32 participants during the 
first six months after being fully staffed, or 65 participants within the first year, it will be considered for 
probation or reduction in funding.  If the Minneapolis site does fall behind in enrollment as described 
above, we will consider opening one or two regional sites. For all regional sites, the expected enrollment 
is 4 participants per month. A site that does not enroll at least 12 participants during the first six months, 
or 24 participants within the first year, will be considered for probation or reduction in funding. If a site is 
placed on probation, the Study Co-Chairs and Study Biostatistician will confer with the site personnel 
and, if necessary, visit the site to help improve the rate of recruitment. If there is no improvement in 
accrual after the probation period, the site may be subject to reduced funding or possible termination as a 
study site. The Executive Committee only takes actions leading to discontinuation of a site with the 
concurrence of the Director, VA CSR&D.  If a site is terminated from the trial, resources are reallocated 
to other sites or used to start up a backup site.  


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D. Monitoring Medical Center (Site) Performance 
 
Strict adherence to the protocol is expected of all centers, and is monitored by the DMC, the 
Executive Committee and the Study Group.  Data quality and the completeness of data retrieval are 
closely monitored on an ongoing basis by the WH-CSPCC.  The Study Biostatistician presents interim 
monitoring reports, overall and by site, to the Executive Committee and the DMC that include the 
following types of information: recruitment of participants, characteristics of the population, 
completeness of data retrieval, and data quality.  If an item is identified as an outlier in terms of data 
quality, a site conference call or site visit is initiated to assess the reasons that problems are occurring and 
how they can be corrected.   
E. Monitoring Participant Safety 
 
The Study Co-Chairs and/or Site Investigators are responsible for following AE reporting 
requirements. These responsibilities include: 1) reviewing the accuracy and completeness of all AEs 
reported, 2) compliance with CSP, IRB, and local policies for reporting AEs and/or SAEs, and 3) closely 
monitoring research participants for any new AEs or SAEs.  Study participants are monitored remotely 
using a combination of in-person and automated telephone calls, and via periodic monitoring of the 
medical record during the 6 month follow-up period. Participants will also be asked to contact study 
personnel regarding all SAEs and any non-serious AEs which occur within 14 days of or are potentially 
related to study treatment.  
F. Minimizing Attrition 
 
As a primary way to minimize withdrawal from the study, study personnel provide thorough pre-
enrollment education for all prospective participants about the study objectives and procedures in order to 
assess and confirm the participants’ commitment to and feasibility for long-term follow-up.  Study 
personnel also provide ongoing education and feedback during the study to reinforce the participants’ 
commitment to long-term follow-up. If participants do opt to withdraw, partial (allowing medical record 
review) or full withdrawal will be discussed. 
 
To compensate participants for the time and effort required to conduct follow-up calls, 
compensation will be provided using the following schedule: $100 at enrollment, $50 at day 56, and $100 
at 6 months (study completion). All follow-up will be conducted centrally, via telephone, minimizing 
participant burden.  All participants will be compensated for the completion of 1st study visit regardless of 


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whether they continued in the study.   A relatively modest payment was selected to minimize the risk of 
financial coercion.  
 
 


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XVI. 
Data Management Procedures 
A. Data Collection Methods 
1. 
Data Capture 
 
Data for CSP #2004 will be managed by the West Haven Cooperative Studies Program 
Coordinating Center (WH-CSPCC) and will utilize several technologies to manage data collection. The 
first is iDatafax, a web-based Electronic Data Capture (eDC) system supports both faxing and eDC 
components for data collection. The system uses a data entry component eDC and intelligent character 
recognition (ICR) for faxes. The iDataFax application also provides a data management structure where 
source documents associated with CRFs can be maintained for each participant within the Participant 
Study folder. All the CRFs (1, 2, 4 - 18) utilize iDataFax version 2016 eDC application. 
 
The second is Teleform, a paper-based forms processing application utilizing optical character 
recognition (OCR) for verifying Case Report Forms (CRFs). Teleform version 11.2 design capabilities 
are used for the development of Case Report Forms (CRFs) as well as used for capturing personal health 
information (PHI) data (Informed Consent, HIPAA, Participant Contact Information-Form 3).  Teleform 
application will be used for data capture of (PHI) which will be faxed to the WH-CSPCC fax server as 
soon as it is completed. Once the CRFs are received at the WH-CSPCC, they will be processed through 
the Teleform reader and verifier software where a Research Associate will review the CRFs for 
consistency and completeness. CRFs processed by way of Teleform verifier will be exported to an image 
file folder, and the extracted data items will be exported to a comma delimited file in a data capture 
folder, both on a secure WH-CSPCC file server. All changes or corrections to data entered on paper CRFs 
will be dated and initialed by site personnel on the original CRF and the associated data edit sheet if 
applicable. 
 
All CRFs (not containing PHI) will either be entered into eDC component or faxed to iDataFax 
system. When data is entered into the eDC and saved, the system records the information into the study 
database. Through iDataFax, paper CRFs can also be faxed from study personnel. The faxed information 
will be delivered to the WH-CSPCC as data images directly into a folder system where the images are 
stored as fax files. Once the faxed CRF is received at the WH-CSPCC, the data image created by the 
iDataFax software is verified with the data recorded on the CRF and is saved into the study database. 


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 iDataFax will store, display, and be used to manage CRF data collected via paper as well as data 
collected via eDC. iDataFax will be set up to provide direct feedback on the completeness and accuracy 
of data as it is being entered. Range checks for all data fields will identify invalid and extreme outlier 
values. Missing data or data values that exceed the range checks will be flagged when the data is entered 
into the system. If the data are corrected and the value appears within the acceptable range, then the error 
flag will disappear. Other integrity checks will be conducted to identify form completion errors and 
logically inconsistent data values within forms or between forms. Most of these checks will be 
programmed into the iDataFax system to automatically fire when data is entered, but others will be added 
manually into the system by the study programmer at the WH-CSPCC. If data are not corrected prior to 
CRF submission, the flag will turn into an automatic data query and will remain outstanding until 
addressed by personnel and/or the study team. Queries should be handled promptly with careful attention 
given to resolving all outstanding outlier, missing, or inconsistent data values. Reasons for any 
temporarily or permanently missing data should be noted in the appropriate query reply field. 
 
CRF data collection within iDatafax application will be saved on a server in CSP Palo Alto 
center. Databases on this server are considered the official database of record and should maintain tight 
access control. Accessing the system requires a VA intranet connection and a browser; the eDC system is 
accessible via each site’s study sub-site on SharePoint. The CRF data will be exported from iDatafax 
server in Palo Alto to SQL database server located in Martinsburg, VA. The data stored within the SQL 
database is parsed into SQL views. The WH-CSPCC will be able to access each CRF data within the SQL 
database by way of SQL view. Data will be extracted from the views and transferred into SAS datasets 
downloaded to WH-CSPCC’s UNIX server as the final study database. 
 
Data summaries will be prepared by the WH-CSPCC and forwarded to the Study Co-Chairs and 
site personnel on a monthly basis. For monitoring purposes, reports of site performance in recruitment, 
treatment compliance, follow-up, and risk based monitoring (RBM) tables will be generated monthly. 
B. Data Quality Control 
 
During study start-up, the CRFs will be field-tested using eDC data enter, data capture and fax-
based system.  Communication between WH-CSPCC, CSPCRPCC, the Study sites, and the central 
database will be tested.   


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On a weekly basis, or more frequently, programmers at WH-CSPCC will transfer the cumulative 
data in the central database to SAS datasets on the WH-CSPCC UNIX server. SAS programs will be run 
to generate reports that summarize the accumulated study data and data exceptions. These notices may 
request further completion, correction, or verification of specific data items.  A computerized record will 
be kept of the number and types of errors to ensure a high level of data integrity.  Interim progress reports 
of cumulative errors and overall data quality will be sent to the Site Investigators, the Executive 
Committee, and the DMC. Unresolved data queries will be included in the datasets that will be used in 
interim reports.  However, every effort will be made to resolve all outstanding Data Correction Forms 
(DCFs) prior to a DMC report. 
 
Data files on the central study database containing the accumulated participant information will 
be examined for completeness and consistency at regular intervals. Tested and validated computer 
programs will check newly entered forms for missing or out-of-range values.  Computer-generated 
notices will be mailed to participating investigators requesting completion of forms and follow-up on 
DCFs for correction or verification of specific data items. A computerized record of the types of errors 
will be kept in order to ensure a high level of data integrity. 
 
At periodic intervals, a cumulative record of errors and data quality progress reports will be sent 
to Site Investigators and the Study Co-Chairs. Data edits and removal of duplicate records will be applied 
to the data files on a regular basis, and cleaned (final) files through the time of the most recent running of 
data edits will be created. These final files will be used to run monitoring reports on a regular basis. The 
progress of data collection will be monitored with computerized data form inventory programs that will 
produce a profile of all forms expected and received for each study participant. Missing-form reports will 
be generated and sent to the sites periodically during the enrollment phase of the study. 
 
Data quality will be monitored on an ongoing basis by the WH-CSPCC.  The Study 
Biostatistician will present interim monitoring reports to the Executive Committee at least monthly and to 
the DMC at least annually. Interim reports will include recruitment of participants, characteristics of the 
population, completeness of data retrieval, and data quality.   
C. Electronic Study File 
 
CSP has established a Clinical Trials Management System (CTMS). This system is hosted on a 
server at a secure VA regional data facility and is based in a MS SharePoint platform. An MS SharePoint 


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site or similar CTMS will be used for maintaining an electronic version of the Central Study File for this 
study. Participating medical centers will be able to access current and past versions of the Study Protocol, 
Operations Manual, Operations Memoranda and other work instructions, CRFs, and other study-related 
documentation, as well as meeting announcements, conference call notices, and study newsletters using 
the CTMS.   
D. Quality Control of the Process 
 
The Study Co-Chairs and the WH-CSPCC will prepare an Operations Manual that will be 
provided to the Site Investigators as a guide to the operation and management of the study as well as a 
technical reference manual. A training session will be held at the study kick-off meeting for all study 
personnel in order to: (1) assure uniformity in participant management and data collection procedures, 
and (2) train the personnel in study procedures and criteria. 
 
Study procedures will be reinforced by the use of regular conference calls, particularly in the first 
few months of the study. All study personnel will attend group meetings during the enrollment period 
when study procedures again will be discussed in detail.  The Study Co-Chairs’ Office and the WH-
CSPCC study personnel will be available to clarify study procedures by telephone, fax and e-mail. 
 
If the Executive Committee determines that a procedure must be changed, the participating sites 
will be informed by conference call and an operations memo, and an updated section of the Operations 
Manual pertinent to the changed procedure will be provided to all sites. 
E. Data Security 
 
CSP has a commitment to maintaining data security and patient privacy. Standard practices and 
policies as part of the responsible conduct of clinical research studies are implemented and reviewed 
periodically. CSP Center Directors are responsible for ensuring that all CSP Data Security Policies are 
enforced within their Centers. All study data collected will be handled, maintained and stored according 
to CSP standard practices and policies. This includes but is not limited to the following:   
• 
Protected Health Information (PHI) as defined by HIPAA will not be used for any purpose that is 
not related to the activities of this study 
• 
Records are identified only by a participant identification number  
➢ Patient identification numbers are not derived from or related to information about an 
individual 


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➢ All electronic PHIs are stored on secure servers and may not be moved to a PC or other 
external device 
➢ Paper CRFs, if any, are stored in locked file cabinets and rooms 
• 
When necessary, PHI may be transported between secure servers. PHI must be encrypted and 
password protected while being transferred using a FIPS 140-2 certified program.  Any 
removable storage device used to transfer PHI (e.g., hard-copy printouts, data tapes, encrypted 
CDs, encrypted USB drives, etc.) should either be destroyed after transfer is complete or given to 
the Data Security Administrator to be secured in a secure, fireproof safe. A trackable mail system 
must be used for the physical data transfers 
• 
Data from studies are utilized at WH-CSPCC and are not removed from the Center  
• 
No PHI may be sent via MS Outlook or Exchange unless the message is secured utilizing 
encryption and VA-authorized security protocol 
• 
Documents sent for medical evaluation purposes (e.g., endpoint adjudication) are sent via 
trackable express mail or password protected email. Personal information is redacted by the 
VAMC or WH-CSPCC if not determined to be necessary for completing the evaluation 
• 
Only VA-owned equipment or equipment configured to VA security standards is permitted to 
directly connect to the CSP networks in accordance with VA Directive 6504   
• 
Training, reminders, and signed data security statements are used to ensure CSP personnel 
understand VA policies 
• 
Sharing of CSP study data outside of CSP requires the approval of the Director, CSR&D, and 
data use agreements.  In addition, sharing of data outside of the VA requires local ISO, PO, and 
ACOS-R approvals. 
 
Any data capture system used for data collection in this study will be fully compliant with US 
Federal regulations regarding electronic web-based data capture systems established by the FDA under 21 
CFR 11.  Data entered directly into the central database provides the official clinical record for data 
collection. Source documentation is handled in the same manner as a paper based system. All paper-based 
records will be kept under lock and key.  
 
The electronic data capture system will utilize state-of-the-art technologies that meet or exceed 
the current VA standards for transport in order to protect the data during transmission. In brief, electronic 
systems will employ secure socket layer technology and FIPS 140-2 compliant encryption algorithms to 
ensure that data is not vulnerable during transport. Hard copy data will be sent via a traceable mail system 
(i.e., UPS), via a courier, or via secure fax. 


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Access to the study data will be afforded the same level of security as all forms of VA protected 
and/or highly sensitive information. Access is heavily restricted to individuals with CSP approval to 
access the data. Individuals must be properly credentialed research staff and must be compliant with VA 
security trainings (i.e., Research Data Security, HIPAA and VA Privacy Training, Cyber-Security, and 
Good Clinical Practices).  In addition, research data will be stored on VA secure servers with restricted 
permissions for copying and exporting data. Only properly approved Coordinating Center personnel will 
have the ability to copy and export data. These individuals have received training on the local SOPs 
governing their permissions and will not access or export data without written approval from the 
Coordinating Center Director. Furthermore, the permissions of the electronic systems are structured such 
that individual sites can only see the data for their study participants, and they cannot see or access the 
data for another clinical site or for another participant. 
 
Backup copies of the database will be transferred to the WH-CSPCC behind the VA firewall on a 
frequent basis depending on the study need.  These backup copies will be transferred and stored across 
secure connections according to VA regulations and WH-CSPCC operating procedures. Periodic off-site 
back-ups will be made as part of a comprehensive disaster recovery plan. 
F. Data Sharing 
 
Upon final analyses of the stated objectives in this proposal, the study plans to submit results for 
publication in scientific peer-reviewed journals and provide summary results on clinicaltrials.gov. After 
acceptance of the primary and other stated analyses by a journal, CSP will make these publication(s) 
available via the National Library of Medicine’s PubMed Central within a year of the date of publication. 
 
 
Digital data underlying primary scientific publications from this study will be held as part of a 
data sharing resource maintained by the Cooperative Studies Program (CSP). Study data held for this 
purpose may include data, data content, format, and organization. The data may contain but are not 
limited to individually identifiable information, other protected health information, and study codes. The 
data may be available to the public and other VA and non-VA researchers under certain conditions and 
consistent with the informed consent and CSP policy which prioritize protecting subjects’ privacy and 
confidentiality to the fullest extent possible. A detailed plan for data sharing will be developed in 
accordance with current technology, infrastructure, best practices, and policies and procedures in place at 
the time of oversight committee reviews (e.g. Privacy Board, IRB, Information Security and IT 
standards). The plan will include how data will be discovered, retrieved, and analyzed, managed and will 


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note the materials that are available in machine readable formats. This plan may be revised to ensure 
consistency with VA, including CSP policies and standards for overall management and sharing. 
 
 


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XVII. 
Good Clinical Practices 
A. Role of Good Clinical Practices  
This trial will be conducted in compliance with Good Clinical Practice (GCP) regulations. The 
intent of these regulations is to safeguard particpants’ welfare and assure the validity of data resulting 
from the clinical research. The VA Cooperative Studies Program will assist Site Investigators (SIs) in 
complying with GCP requirements through its Site Monitoring, Auditing, and Resource Team (SMART) 
based in Albuquerque, NM. SMART serves as the Quality Assurance arm of CSP for GCP compliance. 
Study site personnel will receive GCP orientation at the study organizational meeting. SMART will 
provide training, manuals and materials to assist study personnel in organizing study files, and will be 
available throughout the trial to advise and assist SIs regarding GCP issues.  
B. Summary of Monitoring and Auditing Plans 
Monitoring Visits 
➢ Initiation visits at each site soon after sites randomize their first few participants. 
➢ Yearly routine monitoring visits to each site. 
➢ Final monitoring visit to each site during the last year of the study. 
➢ Additional monitoring visits may be conducted as deemed necessary by study 
leadership or SMART 
Audits  
➢ Routine audits – independent site visits to one or more sites per year as determined 
by SMART. 
➢ For-cause audits – independent audit of a site as requested by study leadership or 
CSPCO.   
➢ Audits may be scheduled or unannounced. 
 
 
 


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XVIII. Publications 
A. Publication Policy 
 
According to the policy of the Cooperative Studies Program, outcome data will not be revealed to 
the Study Co-Chairs or Site Investigators until data collection is completed and the study database is 
locked.  This policy safeguards against possible biases affecting the data collection. 
 
All presentations and publications from this study will follow CSP policy as stated in the CSP 
Guidelines.  The presentation or publication of any or all data collected by Site Investigators on 
participants of CSP #2004 is under the direct control of the Executive Committee.  No individual Site 
Investigator has the right to perform analyses, make interpretations, make public presentations, or seek 
publication of any or all of the data without the approval of the Executive Committee. This is true 
whether the publication or presentation is concerned with the results of the principal undertaking or is 
associated with the study in some other way. 
 
The Executive Committee has the authority to establish one or more publication committees 
(usually comprised of subgroups of Site Investigators and some members of the Executive Committee) 
for the purpose of producing manuscripts for presentation and publication.  A presentation or publication, 
formulated by the Executive Committee or its authorized representatives, should be circulated to all 
members of the Executive Committee for review, comments, and suggestions prior to submission of the 
manuscript to the presenting or publishing body. 
 
All publications must give proper recognition to the Department of Veterans Affairs Cooperative 
Studies Program and should list or reference all principal and Site Investigators in the study.  Any 
manuscript, abstract, or letter to the editor submitted for publication or presentation must be sent to the 
CSP Director for approval prior to submission for publication. Primary manuscripts will also be presented 
to the members of the study’s DMC for information purposes.   
 
 


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B. Planned Publications 
 
An intended plan of the main publications is given below: 
Table 10. Intended study publication plan 
Manuscript 
Projected time of submission 
Study design and baseline patient 
characteristics 
6 months after enrollment is completed 
Primary efficacy analysis 
6-12 months after end of study 
Secondary and exploratory outcomes, 
including safety outcomes 
12-18 months after end of study 
 
 
 
 


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35. 
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Alang N, Kelly CR. Weight gain after fecal microbiota transplantation. Open Forum Infect Dis. 
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Important Safety Alert Regarding Use of Fecal Microbiota for Transplantation and Risk of Serious 
Adverse Reactions Due to Transmission of Multi-Drug Resistant Organisms.  Reported 6/13/19 by 
the US Food and Drug Administration.  https://www.fda.gov/vaccines-blood-biologics/safety-
availability-biologics/important-safety-alert-regarding-use-fecal-microbiota-transplantation-and-
risk-serious-adverse 


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SAP_001.pdf: 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   VA Cooperative Studies Program #2004 
     
Microbiota or Placebo After Antimicrobial Therapy  
for Recurrent C. difficile at Home 
(MATCH) 
 
Statistics Analysis Plan 
Version 1.2 
December 4, 2019 
 
 


 
 
 
 
 


1. 
Introduction ............................................................................................................................. 1 
 
Overview ......................................................................................................................... 1 
1.1.1 
Overview of Statistical Analysis Plan........................................................................ 1 
1.1.2 
Background of the CSP #2004 Study ........................................................................ 1 
1.2 
Study Objectives and Hypothesis ................................................................................... 1 
1.2.1 
Primary Objective ...................................................................................................... 1 
1.2.2 
Secondary Objectives................................................................................................. 2 
1.2.3 
Safety Objectives ....................................................................................................... 3 
1.2.4 
Exploratory Analyses ................................................................................................. 3 
1.3 
Outcome Measurement ................................................................................................... 3 
1.3.1 
Primary Outcome ....................................................................................................... 3 
1.3.2 
Secondary Outcomes ................................................................................................. 4 
1.3.3 
Safety Outcomes ........................................................................................................ 5 
1.3.4 
Outcome Measurements in Exploratory Analyses ..................................................... 6 
1.4 
Patient Characteristics ..................................................................................................... 7 
1.4.1 
Screened Population................................................................................................... 7 
1.4.2 
Enrolled/Randomized Participants............................................................................. 7 
2. 
Statistical Approaches ............................................................................................................. 9 
 
Study Design Summary .................................................................................................. 9 
2.1.1 
Effect Size .................................................................................................................. 9 
2.1.2 
Expected Recurrence Rate after Standard Antimicrobial Therapy ............................ 9 
2.1.3 
Sample Size of the Primary Outcome ...................................................................... 12 
2.2 
 Interim Monitoring and Analysis ................................................................................. 14 
2.2.1  Overview .................................................................................................................. 14 
2.2.2  Monitoring Recruitment........................................................................................... 14 
2.2.3  Monitoring Safety .................................................................................................... 14 
2.2.4  Monitoring Efficacy Outcomes ................................................................................ 15 
2.2.5 
Monitoring Protocol Adherence .............................................................................. 16 
2.2.6 
Sample Size Re-estimation ...................................................................................... 16 
3. 
Final Statistical Analysis....................................................................................................... 17 
3.1.1 
Overview .................................................................................................................. 17 
3.1.2 
Baseline Comparability ............................................................................................ 17 
3.1.3 
Analysis of Primary Outcome Measure ................................................................... 17 
3.2 
Analysis of Secondary Outcomes ................................................................................. 19 


3.2.1 
Recurrence of CDI or death within 6 months .......................................................... 19 
3.2.2 
Definite Recurrent CDI, Possible Recurrent CDI, Diarrhea with Negative CDI .... 19 
3.2.3 
Death within 56 Days............................................................................................... 19 
3.2.4 
Death within 6 Months............................................................................................. 20 
3.2.5 
Urgency, Fecal Incontinence, and Abdominal Pain................................................. 20 
3.2.6 
Number of Definite or Possible CDI Recurrences by 6 Months ............................. 20 
3.3 
Analysis of Safety Outcomes ........................................................................................ 21 
3.3.1 
Serious Adverse Events (SAE) ................................................................................ 21 
3.3.2 
Adverse Events (AE) ............................................................................................... 22 
3.3.3 
Analysis of Exploratory Outcomes .......................................................................... 22 
4. 
Ground Rules and Data Handling Conventions .................................................................... 23 
4.1 
Baseline Definitions or Conventions ............................................................................ 23 
4.2 
Handling of Missing Data ............................................................................................. 24 
4.3 
Description of Protocol Deviations ............................................................................... 25 
4.4 
Datasets/Programs/Variables ........................................................................................ 25 
4.5 
Analysis Datasets .......................................................................................................... 25 
4.6 
Programming Specifications and Software ................................................................... 26 
4.7 
Validation of Statistical Programs ................................................................................ 26 
 


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1. 
Introduction 
     Overview 
1.1.1 
Overview of Statistical Analysis Plan 
This Statistical Analysis Plan (SAP) is intended to be a comprehensive and detailed description 
of the strategy, rationale, and statistical techniques that will be used in the monitoring and 
analysis of the data collected in this study. 
1.1.2 
Background of the CSP #2004 Study 
Clostridium difficile infection (CDI) is one of the most common nosocomial infections and is 
increasingly seen in non-hospitalized patients. Although more than 90% of patients have 
symptom resolution with a course of standard antimicrobial therapy, subsequent recurrence rates 
range from 15-30% (after the first CDI episode) to 40-50% (after the second and subsequent 
episodes).  Fecal microbiota transplantation (FMT) has shown promise as an adjunct to standard 
antimicrobial therapy, reducing recurrence among FMT recipients to 15%. The recent successful 
administration of FMT via oral capsule provides an opportunity to deliver FMT via a non-
invasive and convenient method, which also allows for effective blinding. With the VA having a 
high burden of recurrent CDI, there has been considerable interest in FMT from both providers 
and patients. The availability of FMT is site-dependent, with some VA facilities performing the 
procedure, others referring patients to community-based providers, and others having no 
mechanism of providing FMT. Furthermore, the lack of strong evidence for the efficacy of CDI 
treatment has led to regulatory uncertainty, with the Food and Drug Administration requiring an 
Investigational New Drug application (IND) for research involving FMT, but exercising 
“enforcement discretion” regarding the IND requirement for treatment of CDI with FMT. 
 
1.2    Study Objectives and Hypothesis 
1.2.1 
Primary Objective 
The study’s primary objective is to compare the incidence of recurrent (definite or possible) CDI 
following prior successful treatment with one course of standard antimicrobial therapy) or death 


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within 56 days of randomization, among participants receiving FMT vs. those receiving placebo 
capsules.   
 
Definite CDI recurrence is defined as: new onset of more than 3 loose or watery stools in 24 
hours for 2 consecutive days not explained by another diagnosis, with laboratory confirmation of 
C. difficile from a stool specimen by EIA toxin test.  
 
Possible recurrence is defined identically as above but WITHOUT laboratory confirmation of C. 
difficile (no specimen, not tested or negative test). 
 
To operate the definition:  
Possible CDI recurrence is defined as CDI symptoms present (a Form 9 is filled) + 
Adjudicated as “Yes, CDI recurrence” regardless of lab results. 
 
Definite CDI recurrence is defined as CDI symptoms present (a Form 9 is filled, with a 
“Yes” answer for item B.1, B.2 or B.3 in Form 9) + Toxin positive regardless of 
adjudication results. 
 
Our primary hypothesis is that Veterans receiving FMT after standard antimicrobial therapy will 
have reduced rates of CDI recurrence compared to those receiving placebo. 
1.2.2 
Secondary Objectives  
Secondary objectives include FMT vs. placebo comparisons of occurrences of components of 
definite or possible CDI and other manifestations of CDI: 
 
i. The incidence of CDI recurrence (definite or possible) or death within 6 months 
of randomization; 
ii. The incidence of definite CDI recurrence within 56 days after randomization; 
iii. The incidence of possible CDI recurrence within 56 days after randomization; 
iv. Death within 56 days; 
v. Episodes of diarrhea that is negative for C. difficile by EIA toxin test and PCR within 56 
days after randomization; 
vi. Episodes of diarrhea that is negative for C. difficile by EIA toxin testing but positive by 
PCR within 56 days 


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December 4, 2019 
vii. Abdominal pain which is related to the onset of diarrhea among those possible 
recurrent CDI episodes; 
viii. Urgency among those possible recurrent CDI; 
ix. Fecal incontinence among those possible recurrent CDI; 
x. The number of CDI recurrences (definite or possible) within 56 days post 
randomization; 
xi. The number of CDI recurrences (definite or possible) within 6 months post 
randomization; and 
xii. Self-reported quality of life within 56 days post randomization. 
 
1.2.3 
Safety Objectives 
We will monitor the incidence, severity, and relatedness of serious adverse events and 
complications within 6 months to evaluate the safety of FMT. In the six months following study 
treatment, we will review electronic medical records and communicate with subjects via 
telephone to evaluate for possible transmission of infectious agents or development of new 
conditions theoretically linked to alterations in gut microbiota. 
1.2.4 
Exploratory Analyses  
The following exploratory analyses are proposed: 
i. Characterization and comparison of the colonic microbiome, before and after 
FMT/placebo administration; 
ii. Comparison of the post-FMT colonic microbiome to the donor microbiome; 
iii. Comparison of the post-FMT microbiome of individuals who experience; and 
recurrence vs.  the microbiome of those not experiencing recurrence. 
 
1.3    Outcome Measurement 
1.3.1 
Primary Outcome 
The primary outcome for this trial was selected to reflect the circumstances that currently lead 
clinicians and patients to consider FMT, and to provide a result that is clinically relevant. Since 


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the great majority of patients referred for FMT are undertaking the procedure to reduce the risk 
of subsequent CDI recurrence, the primary outcome was chosen to clearly assess the efficacy of 
FMT in preventing CDI recurrence.  
 
The primary outcome is definite or possible CDI recurrence, or death within 56 days of 
randomization.  
 
Definite recurrence is defined as any of the following: 
• The new onset of more than three loose or watery stools in 24 hours for two 
consecutive days not explained by another diagnosis. 
• Other clinical symptoms including ileus, toxic megacolon, or colectomy. 
 
PLUS  
• Laboratory confirmation of C. difficile from a stool specimen by EIA toxin test. 
 
Possible recurrence is defined using the same clinical manifestations as above, but WITHOUT 
laboratory confirmation of C. difficile (stool test not sent, negative result, or uninterpretable 
result).  
 
To operate the definition:  
Possible CDI recurrence is defined as CDI symptoms present (a Form 9 is filled) + 
Adjudicated as “Yes, CDI recurrence” regardless of lab results. 
 
Definite CDI recurrence is defined as CDI symptoms present (a Form 9 is filled, with a 
“Yes” answer for item B.1, B.2 or B.3 in Form 9) + Toxin positive regardless of 
adjudication results. 
 
1.3.2 
Secondary Outcomes 
i. 
The incidence of CDI recurrence (definite or possible) or death within 6 months 
of randomization; 
ii. 
The incidence of definite CDI recurrence within 56 days after randomization; 
iii. 
The incidence of possible CDI recurrence within 56 days after randomization; 
iv. 
Death within 56 days since randomization; 


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December 4, 2019 
v. 
Episodes of diarrhea that is negative for C. difficile by EIA toxin test and PCR 
within 56 days after randomization; 
vi. 
Episodes of diarrhea that is negative for C. difficile by EIA toxin testing but 
positive by PCR within 56 days 
vii. 
Abdominal pain which is related with the onset of diarrhea among those possible 
CDI recurrent cases; 
viii. 
Urgency among those possible CDI recurrent cases; 
ix. 
Fecal incontinence among those possible recurrent CDI; 
x. 
The number of CDI recurrences (definite or possible) within 56 days post 
randomization; 
xi. 
Number of CDI recurrences (definite or possible) within 6 months: 
• The number of CDI recurrences within 6 months for a patient is the count 
of separate CDI recurrences from randomization to 6 months after 
randomization; and 
xii. 
Quality of life at day 56: 
• We will use a brief assessment of both overall and gastrointestinal health 
status, using a previously validated instrument (see study protocol). 
1.3.3 
Safety Outcomes 
Because of the limited information regarding long-term safety of FMT, safety outcomes will be 
collected until 6 months after FMT/placebo is administrated.  
 
Safety outcomes to be collected include: 
i. 
Serious adverse events, with a focus on SAEs involving hospitalization (new or 
prolonged); 
ii. 
Adverse events which may be related to FMT treatment.  This includes adverse 
events which Site Investigators consider related/possibly related to the study 
treatment, diarrhea, fever, abdominal pain and all other adverse events which 
occur within 14 days of study treatment (since an aggregate analysis of events 
temporally linked to treatment could show a causal relationship when compared 
to placebo); 


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December 4, 2019 
iii. 
Infectious transmissions which are plausibly linked to FMT therapy; and  
iv. 
Development of new conditions potentially linked to alterations in gut microbiota.  
1.3.4 
Outcome Measurements in Exploratory Analyses 
 
We believe that evaluating the gut microbiome is important, particularly in the context of this 
large trial incorporating a placebo control. Prior work demonstrating similarity between the post-
transplant microbiome and the donor microbiome suggests that “engraftment” of the donor 
microbiome is important for clinical success. However, since these data come from uncontrolled 
studies, this hypothesis has not been rigorously tested. The microbiome component can give us 
valuable insight into the mechanism of the resulting effect.  If a clear correlation between 
recurrent CDI and failure to engraft is demonstrated, this would clarify the mechanism whereby 
FMT confers its benefit. Conversely, if subjects with engraftment of the donor microbiome recur 
at a similar rate as do those without engraftment, this would suggest that other factors may be 
contributing to recurrence.  
 
A stool sample for the assessment of the colonic microbiome will be obtained at the time of 
randomization and 56 days after administration of FMT/Placebo. The first sample will be 
transported to the central laboratory performing the microbiome characterization by the Study 
Coordinator, whereas the second sample will be mailed to the same laboratory by the subject via 
a pre-paid mailer. 
 
Shannon index (diversity) and the abundance-based coverage estimate (ACE) (richness) will be 
the outcome measurements to evaluate microbiome. 
 
The following exploratory analyses are proposed: 
i. Characterization and comparison of the colonic microbiome of individuals with 
CDI randomized to FMT and placebo, before and after FMT/placebo 
administration; 
ii. Comparison of the post-FMT colonic microbiome of individuals randomized to 
FMT and placebo to the donor microbiome; and 


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December 4, 2019 
iii. Comparison of the post-FMT microbiome of individuals that experience a 
recurrence to the microbiome of those not experiencing recurrence. 
 
1.4   Patient Characteristics 
1.4.1 
Screened Population 
A relatively novel method of enrollment will be used in this study, with central Study 
Coordinators identifying eligible participants in the entire VA system. The identification of 
eligible participants will be accomplished using multiple strategies, as outlined below, which 
include electronic case finding and direct referrals from clinical providers.  
Our main strategy for recruitment is through electronic case finding of all new diagnoses of CDI 
across the VA using Corporate Data Warehouse (CDW) support through VA Informatics and 
Computing Infrastructure (VINCI), which is updated daily. An incident case of CDI will be 
identified through electronic monitoring of orders for C. difficile testing, lab results, diagnostic 
codes for outpatient and inpatient visits, and prescriptions. The system has been successfully 
refined and is transition to an automated system. It is planned to run weekly or bi-weekly.  The 
Study Coordinators will screen cases found through this automated system, and will then utilize 
the patient’s electronic medical record to assess for inclusion/exclusion criteria using national 
Computerized Patient Record System (CPRS) access via Compensation and Pension Records 
Interchange (CAPRI).  
 
If the patient appears eligible at initial screening, a Study Coordinator (SC) will contact the 
patient’s provider and ask the provider or a member of their care team to obtain permission for 
the SC to initiate contact via telephone. If the patient agrees to be contacted, the SC will contact 
the patient, provide information about the study and, if the patient is interested in participating, 
mail an informed consent form for the patient to review.  
1.4.2 
Enrolled/Randomized Participants 
Participants qualified to be randomized within CSP #2004 must meet all eligibility criteria. The 
Inclusion and Exclusion criteria are detailed in the Study Protocol and Operations Manual and 
are summarized as follows (Table 1). 


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Table 1. Study Flowchart 
 
 


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2. 
Statistical Approaches 
 
Study Design Summary 
2.1.1 
Effect Size 
Sample size calculations were initiated with a determination of what improvement in the rate of 
recurrence would be sufficiently large to be considered clinically significant. For a high-risk 
procedure, the benefit must be substantial enough to outweigh the potential risks. In the case of 
FMT, approximately 500 cases have been reported in the medical literature, with few reports of 
harm. Those that were reported were largely related to the route of delivery - including a fatal 
aspiration event associated with colonoscopy, and peritonitis associated with administration of 
FMT via an indwelling gastric tube. Since the protocol proposal is FMT administration via 
capsules, which confers substantially lower risk, it is appropriate to consider a 15%-20% 
reduction in the CDI recurrence rate as clinically significant. An absolute improvement 
(reduction) of 15% was selected as the threshold for clinical significance, meaning that if the 
placebo group had a recurrence rate of 35%, the FMT group would have to achieve a rate of 20% 
for the difference in rates to be considered clinically significant.  
2.1.2 
Expected Recurrence Rate after Standard Antimicrobial Therapy 
CDI recurrence rates after antimicrobial treatment are well-described for the initial episode; 
unfortunately, subsequent rates of recurrence are less well known. Data regarding subsequent 
rates of recurrence derive from a few RCTs that included subjects with a previous episode of 
CDI, and several observational studies. Two RCTs comparing fidaxomicin to vancomycin for the 
treatment of CDI have been reported, each containing a subgroup of patients with a prior episode 
of CDI (the rest experiencing their first episode). A subsequent publication assessed the 
difference in recurrence by treatment arm in those with prior CDI. The overall recurrence rate for 
those with prior CDI was 27% (36% vancomycin vs. 20% fidaxomicin: P = .045). Another trial 
compared high-dose vancomycin vs. low-dose vancomycin vs. metronidazole for the treatment 
of recurrent CDI, each with the addition of a probiotic (Saccharomyces boulardii) vs. placebo. In 
this study, the overall recurrence rate was 45%. Among the six different treatment arms, five 
treatment arms had recurrence rates between 45% and 51%; the combination of S. boulardii and 
high-dose vancomycin had a recurrence rate of 17% (3/18). Finally, in the trial of FMT vs. two 


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December 4, 2019 
vancomycin-based control groups, the combined recurrence rate in the vancomycin groups was 
73% (19/26).  
 
Data from observational studies on subsequent recurrence after treatment of recurrent CDI is 
variable, both in terms of results and the population studied. In contrast to the RCTs which 
predominantly studied patients being treated for their first episode of recurrence, many of the 
observational studies reported on patients with multiple episodes of recurrence. Reporting and 
publication bias is a significant concern, since successful experiences may be more likely to be 
submitted and accepted for publication. Those caveats aside, there is still valuable information 
regarding recurrence rates to be gained from this literature. An older case series describes no 
recurrence (after a mean of 6 months follow-up) among 22 patients treated with vancomycin 
using a tapered/pulsed dosing strategy, whereas another study evaluating tapered or pulsed dose 
vancomycin reported a 38% recurrence rate (10/26). Finally, a small case series described 
successful treatment without recurrence in 7 of 8 patients using vancomycin followed by a 
course of rifaximin. Details of these studies are summarized in Table 2. 
 
 
 


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December 4, 2019 
Table 2. Studies reporting antimicrobial treatment of recurrent CDI and subsequent 
recurrence rates 
Study 
Study type 
N 
Population 
Treatment 
Recurrence 
rate 
Cornely 
2012 
RCT 
128 
Patients with 
1st recurrence 
of CDI 
Vancomycin or 
fidaxomicin 
27% 
Surawicz 
2000  
RCT 
170 
Patients with 
1st recurrence 
of CDI 
High-dose 
vancomycin, low-
dose-vancomycin, or 
metronidazole, all 
with S. boulardii vs. 
placebo 
45% 
van Nood 
2013 
RCT 
26 
Patients with 
recurrent CDI 
(1-9 episodes) 
Vancomycin or 
vancomycin plus 
bowel lavage 
73% 
Pepin 2006  Retrospective 
cohort 
463 
Patients with 
1st recurrence 
of CDI 
Vancomycin or 
metronidazole 
33% 
McFarland 
2002  
Retrospective 
cohort 
26 
Patients with 
recurrent CDI 
(1-14 
episodes) 
Vancomycin 
taper/pulsed dose 
38% 
Tedesco 
1985  
Case series 
22 
Patients with 
multiple 
relapses 
Vancomycin 
taper/pulsed dose 
0% 
Johnson  
2007  
Case series 
8 
Patients with 
recurrent CDI 
(4-8 episodes) 
Vancomycin 
followed by 
rifaximin 
13% 
 
The three largest studies report recurrence rates of 27%, 33%, and 45%. All of these included 
only patients with a first recurrence of CDI; subsequent recurrence rates are typically higher. 
Importantly, the placebo arm of the recently presented RCT (Kelly, oral presentation) had a 
recurrence rate of 37%, although the precision of this estimate is limited by the sample size of 
24. Accordingly, we believe that 35% is a conservative estimate for an expected recurrence 
rate after treatment with standard antimicrobial therapy. If enrolled participants have a 
history of multiple recurrences, the recurrence rate is likely to be in the 40%-50% range. 


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December 4, 2019 
Expected recurrence rates after FMT have recently been systematically reviewed and 
summarized. The overall recurrence rate, including case series and RCTs of all FMT delivery 
methods, is 15%. The single published series regarding capsule delivery of FMT reported a 
recurrence rate of 30% (6/20), with another series (presented in abstract form only) reporting no 
recurrences in 29 patients (Abstract 89. Fecal microbiome transplantation (FMT) via oral fecal 
microbial capsules for recurrent Clostridium difficile infection (rCDI) Session: Oral Abstract 
Session: New Considerations in C. difficile Prevention and Treatment/ October 2, 2013, IDWeek, 
San Francisco). Given the overall recurrence rate for FMT of 15%, the data from the published 
study of capsule-delivered FMT indicating a recurrence rate of 30%, and taking into account the 
unpublished study, we believe that anticipating a 20% recurrence rate after standard 
antimicrobial therapy followed by FMT is appropriate. 
2.1.3 
Sample Size of the Primary Outcome 
Accordingly, sample size was estimated using the following assumptions: 
1) Recurrence rate of standard antimicrobial therapy followed by placebo of 35% 
2) Recurrence rate of standard antimicrobial therapy followed by FMT of 20% 
3) Two-sided significance level of 0.05 
4) Overall drop-out rate of 5%. 
 
Using the method described in Fleiss for comparing two proportions, a total sample size of 390 
provides 90% power to find an absolute difference of 15% in the recurrence rate with the 
addition of FMT to standard antimicrobial therapy for recurrent CDI. 
 
 
 


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Table 3.  Sample Size Estimation Table  
Recurrent CDI or All-Cause Mortality by Day 56 
Power 
Placebo 
 (Control Arm) 
FMT 
 (Experimental Arm) 
Absolute 
Reduction 
0.80 
0.85 
0.90 
45% 
35% 
10% 
792 
905 
1059 
 
30% 
15% 
343 
392 
457 
 
25% 
20% 
187 
213 
248 
40% 
30% 
10% 
749 
857 
1004 
 
25% 
15% 
320 
366 
427 
 
20% 
20% 
173 
191 
229 
35% 
23% 
12% 
471 
539 
629 
 
20% 
15% 
290 
333 
390 
 
17% 
18% 
196 
223 
259 
30% 
22% 
8% 
992 
1134 
1326 
 
15% 
15% 
255 
291 
339 
 
12% 
18% 
168 
192 
223 
 
Using the assumption in Table 3 above of a target sample size of 390, the following scenarios 
were considered as sensitivity power analyses: 
• If the recruitment rate is lower than anticipated, the study will still maintain 82% power 
to detect an absolute reduction of 15% with a sample size of 300 (77% of the target 
sample size).  
• If the control group event rate was lower than anticipated (30%), the study would 
maintain 90% power to detect an absolute reduction of 14%. 
• If the effect size is smaller than hypothesized, the study would still maintain 80% power 
to detect an absolute reduction of 13% while the control event rate maintains as 35%. 
 
In summary, the anticipated rate of recurrent CDI following standard antimicrobial therapy is 
35%; the study is powered to detect a clinically significant difference of 15%. As previously 
discussed, this difference is chosen based on the non-invasive nature of the intervention, as well 
as favorable safety data from the > 500 cases of FMT reported in the literature. The rate of 
recurrence will be affected by the mixture of patients enrolling; if most enroll after their first 
recurrence, the rate of subsequent recurrence may be slightly lower, whereas if most enroll after 
multiple recurrences, 35% is likely an underestimate. Using the above assumptions, the 


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December 4, 2019 
previously specified 90% power with a two-sided significant threshold of 0.05, and a 5% drop-
out rate, the total sample size is 390 participants. 
 
2.2  Interim Monitoring and Analysis 
2.2.1  
Overview 
Interim monitoring will be performed by the West Haven Cooperative Studies Program 
Coordinating Center (WH-CSPCC) and will focus on recruitment, baseline comparability of 
treatment groups, protocol adherence, completeness of data, accrual of primary endpoint events 
(i.e., information accrual), safety, and treatment efficacy. The WH CSPCC will provide the basis 
for reporting to the Data Monitoring Committee (DMC) as well as the interim reports to the 
DMC, which will meet for two scheduled interim analyses.  
2.2.2  
Monitoring Recruitment 
The WH-CSPCC will monitor the recruitment process to assure early recognition of lower than 
anticipated performance and to identify reasons for inadequate performance for the trial. To 
assist in this process, the WH-CSPCC will produce weekly data monitoring reports (Appendix 
Tables 1-8) to include number of screening forms completed, reasons for non-matriculation into 
the study, number of informed consent documents signed, and number of randomizations, overall 
and by month. The same reports will be made available to the DMC at each of its meetings.  
Predicted total patient accrual for the full study will be extrapolated from the accumulated data. 
2.2.3  
Monitoring Safety 
Trial safety will be monitored by Site Investigators, WH-CSPCC and the CSPCRPCC, 
throughout the study. Safety reports will be submitted to the DMC approximately every 6 
months after enrollment begins, or more frequently, if requested by the DMC. For reports 
included in the DMC closed session, serious adverse events will be summarized by treatment 
group, and relatedness to the assigned interventions.  
 
Site Investigators will review and evaluate adverse events, their relatedness and severity without 
un-blinding study group assignment. The relatedness between an adverse event and study 


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December 4, 2019 
therapy will be assessed in terms of reasonable attribution to the study intervention (No, 
Possibly, Yes). The severity of adverse events will be classified in terms of general AE 
descriptions including diarrhea, abdominal pain, nausea, vomiting which doesn’t fit SAE criteria 
and SAEs. Among the SAEs, the severity will be reported and monitored in term of serious 
reasons (Death, Life-threatening, Hospitalization or Prolongation of Hospitalization, Significant 
disability/incapacity Congenital anomaly/Birth Defect or Other condition) as well as SAE 
outcome (ongoing, resolved, resolved with sequelae and fatal). 
 
For SAE that are reported as at least possibly related to study therapy or any suspected or proven 
transmission of infection from possible FMT product, the CSPCRCC and WH-CSPCC will 
communicate with the DMC for further discussion and recommendation. If it is necessary, the 
therapy assignment can be unblinded.  
   
In general, the proportion of participants experiencing an AE as well as the AE incidence rate in 
each treatment arm will be calculated. The same data will be generated for SAE. If the DMC 
finds the proportion or incidence rate of AEs/SAEs unacceptably higher in one treatment group 
compared to another, it may consider recommending that either the trial be stopped, or the 
protocol be modified. 
2.2.4  
Monitoring Efficacy Outcomes  
Two interim analyses of the primary outcome (recurrent CDI or death) are planned, after which 
the DMC will decide whether to recommend the trial to continue. The DMC will have discretion 
to request additional or differently scheduled interim analyses. The first interim analysis will be 
done when at least 195 subjects have been enrolled and followed for more than 56 days (50% 
accrual of primary outcome information), and the second when at least 292 subjects have been 
enrolled and followed for more than 56 days (75% accrual of primary outcome information). For 
both interim analyses, a stopping rule with a wide boundary such as the Haybittle and Peto 
method will be used. It is suggested that the significance level for the interim analyses will be 
0.001 and the two-sided significance level for the final analysis will be 0.05. The inflation of the 
overall type I error will be negligible. At the first interim analysis, there will be approximately 
82% power to detect an 18.5% absolute reduction in the primary outcome relative to the placebo 


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December 4, 2019 
arm (based on a placebo rate of 35%). At the second interim analysis, there will be 
approximately 85% power to detect a 16% absolute reduction in the primary outcome relative to 
the placebo arm (again assuming a 35% primary outcome rate in the placebo arm). 
At the time of the two interim analyses, a futility analysis will be performed to assess the 
likelihood of eventual success based on the observed data. The conditional power to fulfill the 
study will be provided to the DMC. If the conditional power is low, such as less than 10% per 
observed trend, then the DMC may recommend stopping the study. In both interim analyses 
especially the second one, if the conditional power is between 60% to 80% with a more than 5% 
treatment effect, then the DMC may recommend continuing with an adjustment to the sample 
size and extension of the trial.  
In addition to these futility analyses for the primary endpoint, the observed laboratory confirmed 
event rate is monitored from the initiation of the trial and compared with the primary event rate. 
When considering the futility analyses, the DMC may also consider the laboratory confirmed 
evidence of futility (i.e., secondary outcomes) and would reserve the option of recommending 
early termination of the trial for futility or continuing with a possible adjustment to sample size.  
2.2.5 
Monitoring Protocol Adherence 
Protocol adherence will be monitored to assure early identification of poor performance in the trial. 
Periodic reports will be provided to the Executive Committee and to the DMC at each of its 
meetings. Specific parameters to be monitored include: 
• Randomization of ineligible participants 
• Treatment allocation errors 
• Failure to complete required follow-up assessments on time 
• Loss and withdrawal rates 
2.2.6 
Sample Size Re-estimation  
In CSP #2004, the sample size assumptions regarding the control group event rate, the effect size 
and dropout rate will be re-evaluated at two interim analysis time to determine whether the 
estimated sample size is sufficient. If necessary, the sample size will be re-estimated based on 
the accumulated data under the condition that the observed treatment is above 5% and 


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December 4, 2019 
conditional power based on observed trend is above 60%. This information will be presented to 
the DMC who will make a recommendation to the WH-CSPCC on whether the sample size for 
the trial should be amended to achieve the study objectives.      
3. 
Final Statistical Analysis 
3.1.1 
Overview 
All primary analyses will be according to the principle of intent-to-treat; i.e., subjects will be 
analyzed according to their original treatment assignment regardless of protocol adherence. 
3.1.2 
Baseline Comparability 
In order to assess the adequacy of randomization, the baseline characteristics to be compared and 
summarized include: age, birth sex, race, ethnicity, marital status, education, military service 
history, surgical history, medical history including diabetes, coronary artery disease, chronic 
liver disease, chronic kidney disease, hematologic cancer, solid-organ cancer, systemic 
antibiotics, solid organ or bone marrow transplant, and number of prior CDI episodes 
experienced, nursing home status and usage of probiotic supplements in the past 12 months. The 
baseline laboratory information includes serum creatinine, serum albumin, WBC, HGB, and 
platelet count. The distribution of baseline patient characteristics between groups will be 
evaluated using descriptive statistics. A priori baseline variables which will be used for covariate 
adjustment include age, sex, number of prior CDI episodes, and immunodeficiency.  
3.1.3 
Analysis of Primary Outcome Measure 
The primary outcome (recurrent CDI or death within 56 days) will be summarized in terms of 
incidence rate with 95% confidence interval by treatment arm. Absolute treatment difference 
with 95% confidence interval will also be summarized. A generalized linear model will be used 
to make treatment comparisons since it is appropriate for a binary endpoint and can be adjusted 
for covariates and tested for interactions. Based on the study design, treatment arm, as well as a 
previous recurrence of CDI (1 vs. ≥ 2) will be considered as fixed effects, and the status of 
having a recurrence of CDI or death will serve as the outcome. The odds ratio of having a 
primary outcome in terms of FMT treatment to the placebo with 95% confidence interval will 


Statistics Analysis Plan v.1.2 
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December 4, 2019 
also be provided.  The primary hypothesis will be tested by the above generalized linear model 
with treatment adjusted for study group assignment. Treatment by number of prior CDI episodes 
interactions will be examined in exploratory analyses. A p-value of 0.05 will be used for all 
interaction tests and sub-group analyses of the primary outcome. 
 
As an exploratory analysis of the primary outcome, we will test the treatment effect adjusted for 
study design as well as a set of pre-specified baseline covariates to examine their influence on 
the treatment comparison. Treatment by covariate interactions will be examined for the 
following baseline covariates: gender, race (white vs. other), age, number of prior CDI episodes, 
and immunosuppression status. A p-value of 0.05 will be used for all interaction tests and sub-
group analyses of the primary outcome. 
 
Another exploratory analysis, Kaplan-Meier survival curves, adjusted for censoring due to loss to 
follow-up, will also be used to evaluate treatment effects for time to first recurrent CDI within 
56-days. A log-rank test will be used to test the effect of treatment. 
 
Chi-square test in the difference of primary incidence rate will also be processed as an 
exploratory analysis. 
 
Participants who cannot be contacted by day 56 will have their CDI status updated based on 
information in the medical record. Participants who completely withdraw from the study will 
have their last assessment (recurrent CDI or not) carried forward, whereas those partially 
withdrawing (i.e., allowing medical record review) will have their CDI status updated based on 
information in the medical record. Participants who do not withdraw from the study but are lost 
to follow-up will have their CDI status updated based on information in their medical record. In 
the meantime, the study team will contact that participant’s previous treating physicians and 
primary care physicians for information about possible recurrent CDI. Survival status on patients 
who cannot be contacted by day 56 will be obtained using the VA Beneficiary Identification and 
Records Locator System (BIRLS), the National Center for Health Statistics’ National Death 
Index database and the Social Security Administration’s Death Master File. With the above 
follow-up process, we will include every randomized participant for the final analysis of primary 


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December 4, 2019 
endpoint. In the meantime, a sensitivity analysis will be performed on the primary endpoint by 
assuming those participants who cannot be contacted by day 56 as having a recurrent CDI.  
 
3.2 Analysis of Secondary Outcomes  
3.2.1 
Recurrence of CDI or death within 6 months 
The first secondary outcome (recurrent CDI or death within 6 months) will be summarized using 
incidence with 95% confidence interval (FMT vs placebo arm).  Treatment group comparisons 
will be based on generalized linear model.  The odds ratio (FMT vs placebo) of having a 
recurrent CDI or death within 6 months (95% confidence interval) will be provided. Kaplan-
Meier survival curves, adjusted for censoring due to loss to follow-up, will also be used to 
evaluate treatment effects for time to first recurrent CDI within 6-months. The Cox proportional 
hazards model will also be used to test the effect of treatment adjusted for the study design. The 
proportional hazard assumption will be tested by visual examination of log (log) plots, to assure 
the validity of this analysis. If the assumption is not valid, appropriate adjustments will be made, 
such as adding time by covariate interaction terms or use of stratification. 
 
Missing data due to early withdrawal or loss to follow-up will be handled in the same way as for 
primary outcome analysis. 
3.2.2 
Definite Recurrent CDI, Possible Recurrent CDI, Diarrhea with Negative CDI 
Secondary outcomes such as definite recurrent CDI, possible recurrent CDI and diarrhea with 
negative CDI will be summarized and analyzed the same way as the primary endpoint. Each of 
these endpoints is designed to address one unique research question. Between treatment group 
analysis will be carried out using an alpha-level of 0.05, without adjusting for multiple 
comparisons for each endpoint. 
 
possiblePossible3.2.3 
Death within 56 Days 
Death within 56 days will be summarized using incidence rate (95% confidence interval) by 
treatment. This study outcome will be analyzed the same way as the primary outcome. 


Statistics Analysis Plan v.1.2 
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December 4, 2019 
3.2.4 
Death within 6 Months 
Death within 6 months will be summarized using incidence rate (95% confidence interval) by 
treatment. Kaplan-Meier survival curves, adjusted for censoring due to loss to follow-up, will be 
used to evaluate the treatment effects for 6-month all-cause mortality. Treatment group 
comparisons will be carried out using the log-rank test.  The Cox proportional hazards model 
will also be used to test the effect of treatment adjusted for study treatment assignment. The 
proportional hazard assumption will be tested by visual examination of log (log) plots, to assure 
the validity of this analysis. If the assumption is not valid, appropriate adjustments will be made, 
such as adding time by covariate interaction terms or use of stratification. 
3.2.5 
Urgency, Fecal Incontinence, and Abdominal Pain  
Urgency, fecal incontinence, abdominal pain, severity of abdominal pain, and number of 
episodes of abdominal pain will be summarized using descriptive statistics by treatment arm. 
Chi-square test will be applied to all categorical endpoints to test treatment effect.  ANOVA as 
well as Log-rank test will be applied on severity of abdominal pain to test the treatment effect. 
 
The summaries and tests described above will be compiled for CDI cases. Similar reports will be 
generated for possible recurrent CDI cases, definite recurrent CDI and PCR negative cases 
separately.   
 
The summary will be done for diarrhea that is negative for C. difficile by PCR, number of CDI 
recurrences within 6 months, and quality of life at day 56; between treatment groups will be 
carried out using an alpha-level of 0.05, without adjusting for multiple comparisons. 
3.2.6 
Number of Definite or Possible CDI Recurrences by 6 Months 
The number of definite CDI recurrences by 6 months will be summarized using mean (standard 
deviation) by treatment group and analyzed using an ANOVA model. This variable will also be 
categorized into three levels of discrete ordinal measurement – none, one, and more than one. A 
generalized linear model with a cumulative logit link function will be used to investigate the 
effects of treatment on the number of CDI recurrences. Otherwise, a weighted-least-squares 
analysis will be used to assess the mean score of number of CDI recurrences for each treatment 


Statistics Analysis Plan v.1.2 
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December 4, 2019 
arm. As for the primary outcome, treatment comparisons will be adjusted for both the study arm 
assignment and the pre-specified set of baseline covariates. 
 
Similar analyses will be used for the number of possible CDI recurrences by 6 months. 
 
In terms of counting episodes of recurrent CDI, two episodes within 8 days of onset time will be 
treated as a single episode.  
 
3.2.7 
Quality of life at day 56 
Quality of life, Gastrointestinal Quality of Life Index, (a continuous measurement) will be 
summarized by visit time (baseline or 8-week) and treatment arm. The differences between the 
two treatment arms at week 8 will be analyzed using a linear model. Since some of the 
censoring, such as death, may be informative, analyses both with and without adjusting for the 
possibility of informative censoring will be conducted. First, the analysis will be done on the 
observed quality of life, regardless of whether the censoring is informative or not. Then, a lower 
score will be given to those missing due to death and the data adjusted for the informative 
censoring as a sensitivity analysis. 
 
3.3 Analysis of Safety Outcomes  
3.3.1 
Serious Adverse Events (SAE) 
All randomized participants will be included in the SAE analyses. 
 
The number of SAEs and proportion of participants experiencing an SAE up to six months will 
be summarized by treatment arm, MedDRA System Organ Class and Preferred Terms. The 
treatment comparison of SAE incidence (total number of SAE during the entire study time) will 
be made using a Poisson regression model where total actual follow-up time will serve as the 
exposure variable. The treatment comparison in incidence of subject having SAE will be made 
using a Chi-square test. SAE criteria, SAE outcome and attribution to the study intervention, 
severity, and SAE leading to discontinuation from the study will be tabulated by treatment arm. 
 


Statistics Analysis Plan v.1.2 
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December 4, 2019 
SAEs occurring in the first 48 hours or 14 days after randomization will be summarized and 
analyzed in a similar way as described above. 
3.3.2 
Adverse Events (AE) 
In this study, the following specific AEs occurring at day 2 and day 14 are collected: diarrhea, 
abdominal pain, vomiting, nausea, fever, bloating, gas/flatulence, belching, fatigue, constipation 
and anorexia. Their severity and ongoing status are also collected. For each AE, the total number 
of AE and the proportion of participants experiencing that AE at day 2 and day 14 will be 
summarized by treatment arm. The severity and current status will be summarized in terms of 
count and proportion by treatment. All treatment comparisons will be made using a Chi-square 
test. For each AE event, only participants providing a valid answer will be included in the 
summary and analysis.  
 
Other reported AEs will be summarized and analyzed in a similar way as the study SAEs. 
3.3.3 
Analysis of Exploratory Outcomes  
The Shannon index (diversity) and the abundance-based coverage estimate (ACE) (richness) will 
be used as endpoints in the following exploratory analyses that aim at evaluating the microbiome 
of patients pre- and post-treatment: 
i. 
Characterization and comparison of the colonic microbiome of individuals with 
CDI randomized to FMT and placebo, before and after FMT/placebo 
administration; 
ii. 
Comparison of the post-FMT colonic microbiome of individuals randomized to 
FMT and placebo to the donor microbiome; and 
iii. 
Comparison of the post-FMT microbiome of individuals that experience a 
recurrence to the microbiome of those not experiencing recurrence. 
Collected stool samples will be used to extract DNA, quantify and amplify microbial 
communities, and use 16S rRNA gene profiling using V5 + V6 hypervariable regions sequencing 
on the Illumina MiSeq platform to characterize the microbial community structure.  Taxonomic 
classification will be performed using Version 14 data release from the Ribosomal Database 
Project. Specifically, we will be quantifying microbial diversity using two validated indices to 


Statistics Analysis Plan v.1.2 
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December 4, 2019 
characterize microbial diversity and richness with the Shannon index (diversity) and the 
abundance-based coverage estimate (ACE) (richness) respectively. These two indices are 
calculated to assess parametric and non-parametric diversity. The Shannon index is scored 
between 0 and 7 while the ACE ranges from 0 to 8000.  
 
Student t-test (paired and unpaired), Pearson and Spearman correlations will be used to assess 
and compare pre- and post FMT, and donor-recipient scores. Our hypothesis is that post- FMT 
samples will show increased diversity and richness compared to pre-FMT; that post-FMT 
changes will resemble the microbiota composition of donor specimens; and that post-FMT 
changes will be sustained over 6 months. 
 
Prior estimates from the literature suggest that the mean Shannon index for pre- and post FMT 
will be 1.68+0.75 and 3.37 +0.46 respectively. Assuming half the study participants agree to 
provide an additional sample for characterization of stool microbiome (n=200) we would have 
>95% power to estimate assess pre- and post FMT differences.  
 
Additional analyses may include: differences in microbiota diversity (community composition) 
using analysis of similarity (ANOSIM), other diversity indices (number of operational taxonomic 
unit (OTU) sequences (S obs), sequencing coverage estimation, UniFrac analysis, ANOSIM 
analysis, principal coordinate analysis (PCoA), Mantel tests, Kruskal – Wallis analysis), and 
analysis of molecular variance (AMOVA) will be performed.  
 
4. 
Ground Rules and Data Handling Conventions 
4.1 Baseline Definitions or Conventions 
Baseline will be defined as the last assessment taken prior to or at the randomization and the 
assignment of study treatment. These assessments are usually captured in the participant’s 
subject’s electronic medical record or updated during the randomization visit.  
 


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December 4, 2019 
4.2 Handling of Missing Data  
For data summaries, descriptive statistics will be calculated using available data.  The number of 
missing data values will be reported for major data items and presented by reporting the number 
of values that were available and/or the number of missing responses. Missing data can occur 
through loss to follow-up, or missed contact, etc.  
For recurrent CDI incident data at day 56, participants who cannot be contacted by day 56 will 
have their CDI status updated based on information found in the medical record. Participants 
who completely withdraw from the study will have their last assessment (recurrent CDI or not) 
carried forward, whereas those partially withdrawing (i.e., allowing medical record review) will 
have their CDI status updated based on information in the medical record. In this way there 
should be no missing data for incidence of recurrent CDI at day 56, which is the CDI portion of 
the primary study endpoint as the primary analysis. In the meantime, a sensitivity analysis will 
be performed on the primary endpoint by assuming those participants who cannot be contacted 
by day 56 as having a recurrent CDI.  
For the survival outcome, no missing data is expected since we perform a time to event analysis.   
Quality of life will be measured at two different time points, day 1 and day 56. A longitudinal 
linear model will be used for the analysis. For this analysis, missing data due to death can be 
handled through imputation method. Missing due to loss of follow-up other than death will be 
treated as missing. 
For safety data such as SAE, the study team will periodically check the participant’s VA 
electronic medical record through CPRS or CDW to capture all VA hospitalization records and 
report those related SAEs. If a non-VA hospitalization is recorded in CPRS or CDW, it will also 
be reported with the available information. A similar process will be used for AEs. The number 
of missing SAE or AE data is expected to be minimal because of the utilization of the electronic 
medical record. All safety data will be summarized and analyzed using reported valid data. 
 


Statistics Analysis Plan v.1.2 
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December 4, 2019 
4.3 Description of Protocol Deviations  
The frequency of protocol deviations will be tabulated by protocol deviation category and 
treatment group.  The number and category of protocol deviations will also be summarized by 
protocol violation type and site.  
 
4.4 Datasets/Programs/Variables  
Raw Datasets:   Raw datasets will be created for each study case report form (Forms 1-7, 9-17).  
CRFs are transmitted to WH-CSPCC via iDataFax and will be processed through internal and 
external data checking, validating, and quality control procedures. Each CRF is then exported to 
our local server as a CSV file.  CSV files will be read by SAS programs to create SAS datasets 
for each CRF.  The iDataFax data management tools are used to create and manage the updating 
and checking of these datasets.   
 
4.5 Analysis Datasets   
Programs will be developed to create analysis datasets that will facilitate production of tables and 
figures for interim reports and final analyses. These files include:  
• 
Screening Activities  
 
 
 
Screening.sas7bdat 
• 
Demographic, Baseline and Participant Status  
Demo.sas7bdat 
• 
All participant Follow-up  
 
 
 
FollowUp.sas7bdat 
• 
Evaluation CDI 
 
 
 
 
EvaluationCDI.sas7bdat 
• 
Efficacy  
 
 
 
 
 
Efficacy.sas7bdat 
• 
Safety  (AE/SAE) 
 
 
 
 
Safety.sas7bdat 
DEMO:  Demographic, Baseline Data and Participant Status dataset – One record per enrolled 
participant.  Includes screening data (Form 2), baseline data, QoL (at baseline only) (Forms 4 – 
7), randomization (Randomization Assignment), and termination data (Form 17 Exit) for all 
randomized patients.  Value added fields include all survival times, study time, and others. 
FOLLOW-UP:  Data collected at regular follow-up contact – One record per regular follow-up 
contact for each randomized participant, therefore creating multiple records per randomized 
participant.  Follow-up data includes Forms 10-16.   


Statistics Analysis Plan v.1.2 
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December 4, 2019 
EVALUATION CDI:  Data collected in Form 9. Value added fields include indications of 
primary endpoint, possible recurrent CDI, definite recurrent CDI, possible CDI with negative lab 
result. consolidated death within 56 days, and consolidated death within 180 days  
EFFICACY: Demo Data and Evaluation CDI data – One record per enrolled participant.  It 
merges demographic data with CDI evaluation data and includes the value-added fields such as 
primary endpoint, possible recurrent CDI, definite recurrent CDI, possible CDI with negative lab 
result, consolidated death within 56 days, and consolidated death within 180 days. Primary and 
secondary endpoints and baseline information are included for major efficacy analyses. 
SAFETY:  Adverse Event dataset that includes all reported adverse events and serious adverse 
events.   There is one record per adverse event record including the initial report and all follow-
ups.  Value added fields include MedDRA coding terms.  
 
4.6 Programming Specifications and Software  
Programming for data summaries and analyses will be primarily performed using SAS v9.3 or 
v9.4 on the UNIX AIX platform.  Programming specifications and documentation will be 
completed according to the study data management plan and WH-CSPCC work instructions. 
 
4.7 Validation of Statistical Programs  
This study may adapt programs which have been validated for use in other studies at WH-
CSPCC. If so, program validation may include review of the result and testing of the adapted 
program using study data. New statistical programs will be drafted, tested, and validated by a 
biostatistician or a programmer before use. 
 


Statistics Analysis Plan v.1.2 
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December 4, 2019 
Appendix 
CSP #2004 MATCH 
 
Table of Contents 
 
Table 1. 
Number of Participants Screened, Enrolled and Randomized by Month  
Table 2. 
Number of Participants Screened, Eligible and Randomized by Site 
Figure 1. 
Cumulative Number of Patients Randomized by Month 
Table 3. 
Summary of Screening and Reasons for Participants Not Being Eligible 
Table 4. 
Distribution of Randomized Patients by Site and Stratification 
Table 5 
Participants Study Status 
Table 6.  
Completeness of Expected Follow-up Forms by Site 
Table 7.  
Summary of Data Queries by Form Pack and Site 
Table 8.  
Summary of Protocol Deviation 
Table 9. 
Baseline Demographic Characteristics by Treatment 
Table 10. 
Baseline Laboratory Assessments by Treatment 
Table 11.  
Baseline Physical Examination 
Table 12. 
Baseline Medical History 
Table 13:  
Summary of Study Specific Adverse Events by Treatment 
Table 14:  
Summary Serious Adverse Events Reasons by Treatment 
Table 15:    
Summary of MedDRA Coding of Serious Adverse Events by Treatment 
Table 16:  
Summary Other Adverse Events Reasons by Treatment 
Table 17:   
Recurrent CDI or Death within 56 Days by Treatment Assigned 
 
Table 17A: 
 Recurrent CDI or Death within 6 Months by Treatment Assigned 
Table 18:  
Number of Recurrent CDIs within 56 days by Treatment Assigned 


Statistics Analysis Plan v.1.2 
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December 4, 2019 
Table 18A:   Number of Recurrent CDIs within 6 Months by Treatment Assigned 
Table 19A:  
CDI Evaluation among Definite CDIs within 56 Days by Treatment 
Assigned  
Table 19B:  
CDI Evaluation among Possible CDIs within 56 Days by Treatment 
Assigned  
Table 19C:  
CDI Evaluation among Possible CDIs but not Definite CDI within 56 
Days by Treatment Assigned  
Table 19D:  
CDI Evaluation among Potential CDIs but not Possible CDI within 56 
Days by Treatment Assigned  
Table 20:  
Summary of Gastrointestinal QoL Score (GQoL) by Time Point and 
Treatment Assigned 
Table 21:  
Summary of Colonic Microbiome by Time Point and Treatment Assigned 
 
 
 


Statistics Analysis Plan v.1.2 
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December 4, 2019 
CSP #2004  
Table 1: Number of Potential Participants Screened, Eligible, and Randomized by Month 
 
 
 
 
 
 
CSP #2004 
Table 2: Cumulative Number of Patients Screened, Eligible and Randomized by Site 
 
 
 
 
 
 
 
 
 
 
Month 
No. 
Screened 
No. 
Eligible 
No. 
Randomized 
Cumulative 
No. Screened 
Cumulative 
No. Eligible 
Cumulative 
No. 
Randomized 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
… 
 
 
 
 
 
 
36 
 
 
 
 
 
 
Site 
Cumulative 
No. Screened 
Cumulative 
No. Eligible 
Cumulative No. 
Randomized 
Minneapolis 
 
 
 


Statistics Analysis Plan v.1.2 
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December 4, 2019 
CSP #2004  
Figure 1: Cumulative Number of Patients Randomized  
 
 
 
 
 
 
 
 
 
 
0
50
100
150
200
250
300
350
400
450
0
10
20
30
40
Number of Randomization
Month
Cumulative Number of Patients Randomized by 
Month
Expected Number of
Randomization


Statistics Analysis Plan v.1.2 
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December 4, 2019 
CSP #2004  
Table 3: Summary of Screening and Reasons for Not Eligible  
 
Reason for Not Eligible 
Number 
Percent 
INCLUSION CRITERIA 
 
 
Current episode of CDI being treated with standard antimicrobial 
treatment 
 
 
Prior episode of CDI within 90 days before the onset of the current CDI 
 
 
Age >= 18 years 
 
 
Willing and able to provide informed consent  
 
 
EXCLUSION CRITERIA :  
 
 
Inability to swallow capsules 
 
 
Pregnant or planning to become pregnant 
 
 
Receipt of cytotoxic chemotherapy, immune globulin, or confirmed 
neutropenia (absolute neutrophil count of < 1,000 cells/mL), within the 
past 3 months 
 
 
Inflammatory bowel disease or other chronic diarrheal disease/fecal 
incontinence predating CDI 
 
 
 Ongoing antibiotic use 
 
 
 Prior FMT 
 
 
 Life expectancy of < 8 weeks 
 
 
 Anaphylactic food allergy 
 
 
Active enrollment in another research study on antibiotics, probiotics, 
or FMT without investigators approval 
 
 
 Inability to follow study protocol 
 
 
 
 
 


Statistics Analysis Plan v.1.2 
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December 4, 2019 
CSP #2004  
Table 4:  Distribution of Randomized Patients by Site and Stratification 
 
Site 
Randomization 
Stratification 
Treatment 1 
Treatment 2 
N 
% 
 
 
Minneapolis 
Overall 
 
 
 
 
 
1st recurrent CDI 
 
 
 
 
 
>1 recurrent CDI 
 
 
 
 
 
 
CSP #2004  
Table 5:  Subject Study Status 
Site 
Description 
Treatment 1 
Treatment 2 
N 
% 
 
 
Minneapolis 
No. of Randomized 
 
 
 
 
 
 
 
 
 
 
 
Being followed 
 
 
 
 
 
Exit from study 
 
 
 
 
 
     Completed 
6-mo 
follow-up 
 
 
 
 
 
     Death 
 
 
 
 
 
     Lost to follow-up 
 
 
 
 
 
     Withdrew 
 
 
 
 
 
     Other 
 
 
 
 
 
 
CSP#2004 
Table 6:  Completeness of Expected Follow-up Forms by Site 
Visits 
Treatment 1 
Treatment 2 
Total 
Expected 
Completed 
(%) 
Expected 
Completed 
(%) 
Expected 
Completed 
(%) 
Baseline 
 
 
 
 
 
 
Day 2 
 
 
 
 
 
 
Week 2 
 
 
 
 
 
 
Week 8 
 
 
 
 
 
 
6 Months 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistics Analysis Plan v.1.2 
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December 4, 2019 
 CSP #2004 
 
         Table 7:  Summary of Data Queries by Form Pack and Site 
Form 
Site 1 
Site 2 
Site 3 
Total 
Queries 
Unresolved 
Queries 
 (%) 
Total 
Queries  
Unresolved 
Queries 
 (%) 
Total 
Queries  
Unresolved 
Queries 
 (%) 
Form 1 
 
 
 
 
 
 
Form 2 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CSP #2004  
Table 8: Summary of Protocol Deviations by Treatment 
Deviation Type 
Treatment 1 
Treatment 2 
N 
% 
N 
% 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistics Analysis Plan v.1.2 
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December 4, 2019 
CSP #2004 
Table 9:  Baseline Demographic Characteristics by Treatment Assigned 
Characteristic 
Treatment 1 
Treatment 2 
Total 
N 
% 
N 
% 
N 
% 
Mean Age (SD) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gender 
 
 
 
 
 
 
Male 
 
 
 
 
 
 
Female 
 
 
 
 
 
 
 
 
 
 
 
 
 
Race 
 
 
 
 
 
 
  White 
 
 
 
 
 
 
   Black or African-American or 
Negro 
 
 
 
 
 
 
   American Indian or Alaskan 
Native 
 
 
 
 
 
 
Asian Indian 
 
 
 
 
 
 
Chinese 
 
 
 
 
 
 
Japanese 
 
 
 
 
 
 
   Filipino 
 
 
 
 
 
 
Korean 
 
 
 
 
 
 
Vietnamese 
 
 
 
 
 
 
   Other Asian 
 
 
 
 
 
 
Native Hawaiian 
 
 
 
 
 
 
Guamanian or Chamorro 
 
 
 
 
 
 
Samoan 
 
 
 
 
 
 
Other Pacific Islander 
 
 
 
 
 
 
   Other 
 
 
 
 
 
 
Refused to Answer 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ethnicity 
 
 
 
 
 
 
Not Hispanic 
 
 
 
 
 
 
Mexican, Mexican 
American, Chicano 
 
 
 
 
 
 
Puerto Rican 
 
 
 
 
 
 
Cuban 
 
 
 
 
 
 
Other Spanish, Hispanic or 
Latino 
 
 
 
 
 
 
Refused to Answer 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hight (cm) 
 
 
 
 
 
 
Weight (kg) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Education 
 
 
 
 
 
 
    < High School Diploma 
 
 
 
 
 
 
    High School diploma 
 
 
 
 
 
 


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December 4, 2019 
    Technical Certificate 
 
 
 
 
 
 
    Associate Degree 
 
 
 
 
 
 
    Bachelor’s Degree 
 
 
 
 
 
 
    Master’s Degree 
 
 
 
 
 
 
    Ph.D. or Professional Dr 
 
 
 
 
 
 
 
 
CSP #2004 
Table 10: Baseline Laboratory Assessments 
Assessments 
Treatment 1 
Treatment 2 
Total 
Mean (SD)  
N 
Mean (SD)  
N 
Mean (SD)  
N 
Serum Albumin 
 
 
 
 
 
 
Serum Creatinine 
 
 
 
 
 
 
WBC 
 
 
 
 
 
 
Hemoglobin 
 
 
 
 
 
 
Hematocrit 
 
 
 
 
 
 
Platelet count 
 
 
 
 
 
 
 
CSP #2004 
Table 11: Baseline Physical Examination 
Assessments 
Treatment 1 
Treatment 2 
Total 
N 
Mean (SD) 
Or % 
N 
Mean (SD) 
Or % 
N 
Mean (SD) 
Or % 
Weight (lbs.) 
 
 
 
 
 
 
Height (inches) 
 
 
 
 
 
 
SBP (mmHg) 
 
 
 
 
 
 
DBP (mmHg) 
 
 
 
 
 
 
Heart Rate (beats/min) 
 
 
 
 
 
 
Respiration (breaths/min) 
 
 
 
 
 
 


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December 4, 2019 
CSP #2004 
Table 12: Baseline Medical History 
Assessments 
Treatment 1 
Treatment 2 
Total 
N 
Mean 
(SD) 
Or % 
 
N 
Mean 
(SD) 
Or % 
 
N 
Mean (SD) 
Or % 
 
Surgical History 
 
 
 
 
 
 
     Appendectomy 
 
 
 
 
 
 
     Gastric Bypass or Banding 
 
 
 
 
 
 
Resection of Small Bowel or Colon 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
 
 
 
 
 
Diabetes 
 
 
 
 
 
 
Coronary artery disease 
 
 
 
 
 
 
Chromic liver disease 
 
 
 
 
 
 
Chronic kidney disease 
 
 
 
 
 
 
Hematologic cancer 
 
 
 
 
 
 
Solid-organ cancer 
 
 
 
 
 
 
Systemic antibiotics in last 6 months 
 
 
 
 
 
 
Others 
 
 
 
 
 
 
 
 
 
 
 
 
 
Resident in Nursing Home 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of prior episode of CDI 
 
 
 
 
 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
>4 
 
 
 
 
 
 
 
 
 
 
 
 
 
Use of probiotics in the past 12 months 
 
 
 
 
 
 
Lactobacillus species 
 
 
 
 
 
 
Saccharomyces species 
 
 
 
 
 
 
Multiple agents 
 
 
 
 
 
 
Other probiotics 
 
 
 
 
 
 
 
 


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December 4, 2019 
CSP #2004 
Table 13: Summary of Study Specific Adverse Events by Treatment at 48 Hours 
Event 
Description 
Treatment 1 
Treatment 2 
Total 
p-value 
 
 Event 
Count 
N (%) 
 Event 
Count 
N (%) 
 Event 
Count 
N (%) 
 
 
Count 
of 
form 
received 
 
 
 
 
 
 
 
Diarrhea 
No. event 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdominal 
pain 
No. event 
 
 
 
 
 
 
 
 
Severity: Mild 
 
 
 
 
 
 
 
 
                Moderate 
 
 
 
 
 
 
 
 
                Severe 
 
 
 
 
 
 
 
 
Ongoing (yes) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vomiting 
No. event 
 
 
 
 
 
 
 
 
Severity: Mild 
 
 
 
 
 
 
 
 
                Moderate 
 
 
 
 
 
 
 
 
                Severe 
 
 
 
 
 
 
 
 
Ongoing (yes) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nausea 
No. event 
 
 
 
 
 
 
 
 
Severity: Mild 
 
 
 
 
 
 
 
 
                Moderate 
 
 
 
 
 
 
 
 
                Severe 
 
 
 
 
 
 
 
 
Ongoing (yes) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bloating 
No. event 
 
 
 
 
 
 
 
 
Severity: Mild 
 
 
 
 
 
 
 
 
                Moderate 
 
 
 
 
 
 
 
 
                Severe 
 
 
 
 
 
 
 
 
Ongoing (yes) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gas/Flatulence 
No. event 
 
 
 
 
 
 
 
 
Severity: Mild 
 
 
 
 
 
 
 
 
                Moderate 
 
 
 
 
 
 
 
 
                Severe 
 
 
 
 
 
 
 
 
Ongoing (yes) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Belching 
No. event 
 
 
 
 
 
 
 
 
Severity: Mild 
 
 
 
 
 
 
 
 
                Moderate 
 
 
 
 
 
 
 
 
                Severe 
 
 
 
 
 
 
 
 
Ongoing (yes) 
 
 
 
 
 
 
 


Statistics Analysis Plan v.1.2 
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December 4, 2019 
 
 
 
 
 
 
 
 
 
 
 
Fatigue 
No. event 
 
 
 
 
 
 
 
 
Severity: Mild 
 
 
 
 
 
 
 
 
                Moderate 
 
 
 
 
 
 
 
 
                Severe 
 
 
 
 
 
 
 
 
Ongoing (yes) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Constipation 
No. event 
 
 
 
 
 
 
 
 
Severity: Mild 
 
 
 
 
 
 
 
 
                Moderate 
 
 
 
 
 
 
 
 
                Severe 
 
 
 
 
 
 
 
 
Ongoing (yes) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anorexia 
No. event 
 
 
 
 
 
 
 
 
Severity: Mild 
 
 
 
 
 
 
 
 
                Moderate 
 
 
 
 
 
 
 
 
                Severe 
 
 
 
 
 
 
 
 
Ongoing (yes) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fever 
No. event 
 
 
 
 
 
 
 
 
Mean temperature 
 
 
 
 
 
 
 
 
STD  
 
 
 
 
 
 
 


Statistics Analysis Plan v.1.2 
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December 4, 2019 
CSP #2004  
Table 14: Summary Serious Adverse Events Reasons by Treatment 
  
Treatment 1 
Treatment 2 
All 
  
N (%) 
N (%) 
N (%) 
No. of Randomized Participants 
67 
  
70 
137 
  
  
    
    
    
No. Serious Adverse Events after 
Randomization/Implantation 
10 (14.9) 
7 (10.0) 
17 (12.4) 
 
  
  
  
 
  
  
  
SAE Criteria 
    
    
    
Death 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Life-threatening 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Congenital 
Anomaly/Birth 
Defect 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Hospitalization/Prolongation of 
Hospitalization 
9 (90.0) 
6 (85.7) 
15 (88.2) 
Disability - Incapacity 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Other Event Considered Serious 
by LSI 
1 (10.0) 
2 (28.6) 
3 (17.6) 
  
    
    
    
SAE 
Attribution 
to 
the 
study 
intervention 
    
    
    
Not Attributed 
9 (90.0) 
6 (85.7) 
15 (88.2) 
Possibly Attributed 
1 (10.0) 
1 (14.3) 
2 (11.8) 
Yes, Attributed 
0 (0.0) 
0 (0.0) 
0 (0.0) 
  
    
    
    
SAE Outcome 
    
    
    
Death 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Life-threatening 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Severe 
10 (100.0) 
5 (71.4) 
15 (88.2) 
Moderate 
0 (0.0) 
2 (28.6) 
2 (11.8) 
Mild 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Unknown 
0 (0.0) 
0 (0.0) 
0 (0.0) 
 
  
  
  
SAE cause discontinuation from the 
study 
    
    
    
Yes 
0 (0.0) 
0 (0.0) 
0 (0.0) 
No 
0 (0.0) 
0 (0.0) 
0 (0.0) 
 
  
  
  
 
 
 
 
 
 
 
* More than one SAE Criteria can be checked per SAE.  Therefore, percentages do not sum up to 100%. 
   Data is arbitrary for explain the table set up only.  
 


Statistics Analysis Plan v.1.2 
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December 4, 2019 
CSP #2004  
Table 15:   Summary of MedDRA Coding of Serious Adverse Events by Treatment 
  
Treatment 1 
Treatment 2 
All 
  
  
N 
  
  
N 
  
  
N 
  
No. of Randomized 
Participants 
  
67 
  
  
70 
  
  
137 
  
Total Subject-Year In Study 
  
100.9 
  
  
108.7 
  
  
209.6 
  
No. Serious Adverse Events 
after Randomization 
  
161 
240.3 
  
153 
218.6 
  
314 
229.2 
No. Subjects with SAEs 
after Randomization 
  
41 
61.2 
  
38 
54.3 
  
79 
57.7 
  
    
    
    
  
  
  
SYSTEM ORGAN 
CLASS/Preferred Term 
No. of 
SAEs 
No. of 
Subjs 
% of 
Subjs 
No. of 
SAEs 
No. of 
Subjs 
% of 
Subjs 
No. of 
SAEs 
No. of 
Subjs 
% of 
Subjs 
  
  
  
  
  
  
  
  
  
  
BLOOD AND 
LYMPHATIC SYSTEM 
DISORDERS 
1 
1 
1.5% 
2 
2 
2.9% 
3 
3 
2.2% 
Autoimmune haemolytic 
anaemia 
0 
0 
0.0% 
1 
1 
1.4% 
1 
1 
0.7% 
Haemorrhagic anaemia 
1 
1 
1.5% 
0 
0 
0.0% 
1 
1 
0.7% 
Normochromic normocytic 
anaemia 
0 
0 
0.0% 
1 
1 
1.4% 
1 
1 
0.7% 
  
  
  
  
  
  
  
  
  
  
CARDIAC DISORDERS 
67 
28 
41.8% 
49 
23 
32.9% 
116 
51 
37.2% 
Cardiac failure congestive 
32 
20 
29.9% 
36 
20 
28.6% 
68 
40 
29.2% 
Atrial fibrillation 
10 
8 
11.9% 
2 
2 
2.9% 
12 
10 
7.3% 
Acute myocardial infarction 
7 
5 
7.5% 
1 
1 
1.4% 
8 
6 
4.4% 
Myocardial infarction 
4 
4 
6.0% 
1 
1 
1.4% 
5 
5 
3.6% 
Cardiomyopathy 
3 
3 
4.5% 
0 
0 
0.0% 
3 
3 
2.2% 
Cardiac arrest 
1 
1 
1.5% 
1 
1 
1.4% 
2 
2 
1.5% 
Coronary artery disease 
2 
2 
3.0% 
0 
0 
0.0% 
2 
2 
1.5% 
Ventricular fibrillation 
1 
1 
1.5% 
1 
1 
1.4% 
2 
2 
1.5% 
Acute left ventricular failure 
0 
0 
0.0% 
1 
1 
1.4% 
1 
1 
0.7% 
Angina pectoris 
0 
0 
0.0% 
1 
1 
1.4% 
1 
1 
0.7% 
Angina unstable 
1 
1 
1.5% 
0 
0 
0.0% 
1 
1 
0.7% 
Atrioventricular block 
complete 
1 
1 
1.5% 
0 
0 
0.0% 
1 
1 
0.7% 
Bradycardia 
0 
0 
0.0% 
1 
1 
1.4% 
1 
1 
0.7% 
Cardiac failure 
0 
0 
0.0% 
1 
1 
1.4% 
1 
1 
0.7% 
Cardiac failure acute 
0 
0 
0.0% 
1 
1 
1.4% 
1 
1 
0.7% 
Congestive cardiomyopathy 
1 
1 
1.5% 
0 
0 
0.0% 
1 
1 
0.7% 
Coronary artery occlusion 
1 
1 
1.5% 
0 
0 
0.0% 
1 
1 
0.7% 
Mitral valve incompetence 
1 
1 
1.5% 
0 
0 
0.0% 
1 
1 
0.7% 
Pulseless electrical activity 
0 
0 
0.0% 
1 
1 
1.4% 
1 
1 
0.7% 
  
  
  
  
  
  
  
  
  
  


Statistics Analysis Plan v.1.2 
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December 4, 2019 
CONGENITAL, 
FAMILIAL AND 
GENETIC DISORDERS 
0 
0 
0.0% 
1 
1 
1.4% 
1 
1 
0.7% 
Haemorrhagic arteriovenous 
malformation 
0 
0 
0.0% 
1 
1 
1.4% 
1 
1 
0.7% 
  
  
  
  
  
  
  
  
  
  
EAR AND LABYRINTH 
DISORDERS 
1 
1 
1.5% 
0 
0 
0.0% 
1 
1 
0.7% 
Vertigo 
1 
1 
1.5% 
0 
0 
0.0% 
1 
1 
0.7% 
 
Data is arbitrary for explain the table set up only.  
 
 
CSP #2004  
Table 16: Summary Other Adverse Events Reasons by Treatment  
Event 
Treatment 1 
Treatment 2 
Total 
 
 
 
 
 
 
No. Subject Enrolled 
 
 
 
 
 
 
Subject-year of follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
No. AEs 
 
 
 
 
 
 
No. Subject with AE 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Attribution to Study Therapy 
 
 
 
 
 
 
   Not Attributed 
 
 
 
 
 
 
   Possibly Attributed 
 
 
 
 
 
 
   Yes, Attributed 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severity of AE 
 
 
 
 
 
 
   Mild 
 
 
 
 
 
 
   Moderate 
 
 
 
 
 
 
   Severe 
 
 
 
 
 
 
   Life-threatening 
 
 
 
 
 
 
   Death 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE still ongoing 
 
 
 
 
 
 
   No 
 
 
 
 
 
 
   Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cause discontinuation from the study 
 
 
 
 
 
 
   No 
 
 
 
 
 
 
   Yes 
 
 
 
 
 
 


Statistics Analysis Plan v.1.2 
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December 4, 2019 
CSP #2004 
Table 17:  Summary of Potential Recurrent CDI within 56 Days by Treatment Assigned 
 
Description 
Treatment 1 
Treatment 2 
 
Overall 
n 
N* 
% 
n 
N* 
% 
n 
N* 
% 
No. of Randomization 
 
 
 
 
 
 
 
 
 
No. of potential 
recurrent CDI (Form 
9) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No. of Possible 
recurrent CDI 
 
 
 
 
 
 
 
 
 
No. of Cases with 
Toxin+ 
 
 
 
 
 
 
 
 
 
No. of Possible CDI or 
Cases with Toxin+ 
 
 
 
 
 
 
 
 
 
No. of Cases with 
PCR+ 
 
 
 
 
 
 
 
 
 
No. of Cases with 
Toxin - & PCR +  
 
 
 
 
 
 
 
 
 
No. of Cases with 
Toxin - & PCR - 
 
 
 
 
 
 
 
 
 
 
*N is number of form 9. 
 
 


Statistics Analysis Plan v.1.2 
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December 4, 2019 
CSP #2004 
Table 17A:  Recurrent CDI or Death within 56 Days by Treatment Assigned 
 
Primary Outcome (No. 
recurrent CDI of Death) 
Treatment 1 
Treatment 2 
Odds Ratio 
(95% CI) 
p-vale to test 
odds ratio =1 
R/N 
% 
R/N 
%  
 
 
No. of Randomization 
 
 
 
 
 
 
No. of recurrent CDI 
(definite or possible) or 
Death 
 
 
 
 
 
 
 
 
 
 
 
 
 
No. of definite recurrent 
CDI 
 
 
 
 
 
 
 
 
 
 
 
 
 
No. of Death 
 
 
 
 
 
 
 
 
 
 
 
 
 
No. of possible recurrent 
CDI 
 
 
 
 
 
 
 
 
Table 17B:  Recurrent CDI or Death within 6 Months by Treatment Assigned 
Same lay out as table 17. 
 


Statistics Analysis Plan v.1.2 
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December 4, 2019 
CSP #2004 
Table 18:  Number of Recurrent CDIs within 56 days by Treatment Assigned 
 
Number of recurrent 
CDI 
Treatment 1 
Treatment 2 
Odds Ratio (95% 
CI) 
p-vale to test odds 
ratio =1 
R/N 
% 
R/N 
%  
 
 
No. of Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
Definite CDI 
 
 
 
 
 
 
    0 
 
 
 
 
 
 
    1 
 
 
 
 
 
 
   Above 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Possible CDI 
 
 
 
 
 
 
    0 
 
 
 
 
 
 
    1 
 
 
 
 
 
 
   Above 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Possible or Definite CDI 
 
 
 
 
 
 
    0 
 
 
 
 
 
 
    1 
 
 
 
 
 
 
   Above 1 
 
 
 
 
 
 
 
 
Table 18A:  Number of Recurrent CDIs within 6 Months by Treatment Assigned 
 
 


Statistics Analysis Plan v.1.2 
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December 4, 2019 
CSP #2004  
Table 19A:  CDI Evaluation among Definite CDIs within 56 Days by Treatment Assigned 
Description 
Treatment 1 
Treatment 2 
Total 
 
No 
Yes 
N/A 
No 
Yes 
N/A 
No 
Yes 
N/A 
 
 
 
 
 
 
 
 
 
 
No. of Randomization 
 
 
 
 
 
 
 
 
 
No. of Subs with definite CDI  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Symptoms 
 
 
 
 
 
 
 
 
 
    >3 loose stools per 24h for days 
 
 
 
 
 
 
 
 
 
    Ileus 
 
 
 
 
 
 
 
 
 
    Toxin megacolon 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stool Specimen Collected 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urgency 
 
 
 
 
 
 
 
 
 
   Occasional urgency 
 
 
 
 
 
 
 
 
 
   Frequent urgency 
 
 
 
 
 
 
 
 
 
   Inability to control defecation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unintentional passing of stool  
 
 
 
 
 
 
 
 
 
Use pads or altered lifestyle 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdominal pain 
 
 
 
 
 
 
 
 
 
  New pain or worsening 
 
 
 
 
 
 
 
 
 
  Pain scale (mean, std) 
 
 
 
 
 
 
 
 
 
  No. of episode pain/day (mean, std) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical office visit  
 
 
 
 
 
 
 
 
 
Cause of abdominal pain 
 
 
 
 
 
 
 
 
 
    With non-CDI cause 
 
 
 
 
 
 
 
 
 
    Without clear non-CDI cause 
 
 
 
 
 
 
 
 
 
    With criteria meeting primary endpoint 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antibiotic use since randomization 
 
 
 
 
 
 
 
 
 
 
Table 19B:  CDI Evaluation among Possible CDIs within 56 Days by Treatment Assigned  
Table 19C:  CDI Evaluation among Possible CDIs but not definite CDI within 56 Days by Treatment 
Assigned  
 
 


Statistics Analysis Plan v.1.2 
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December 4, 2019 
CSP #2004  
Table 20: Summary of Gastrointestinal QoL Score (GQoL) by Time Point and Treatment 
Assigned 
GQoL Score 
Treatment 1 
Treatment 2 
Difference of 
Treatment 1 – 
Treatment2  
p-value 
N 
Mean (SD) 
N 
Mean (SD) 
 
 
Baseline 
 
 
 
 
 
 
6 Months 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CSP #2004  
Table 21: Summary of Colonic Microbiome by Time Point and Treatment Assigned 
 
Treatment 1 
Treatment 2 
Difference of 
Treatment 1 – 
Treatment2  
p-value 
N 
Mean (SD) 
N 
Mean (SD) 
 
 
Baseline time 
 
 
 
 
 
 
 Colonic microbiome 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 Months 
 
 
 
 
 
 
 Colonic microbiome 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistics Analysis Plan v.1.2 
47 
December 4, 2019 
CSP #2004  
Table 22A: Summary of Form 9 cases with clinical symptoms as B.1 (>3 loose/watery stools 
per 24 h for 2 consecutive days) 
  
PCR + 
PCR -  
PCR N/A 
Total 
Toxin + 
  
  
  
  
Toxin - 
  
  
  
  
Toxin N/A 
  
  
  
  
Total 
  
  
  
  
 
Table 22B: Summary of Form 9 cases with any of the three clinical symptoms (>3 
loose/watery stools per 24 h for 2 consecutive days, or ileus, or toxic megacolon) 
 
  
PCR + 
PCR -  
PCR N/A 
Total 
Toxin + 
  
  
  
  
Toxin - 
  
  
  
  
Toxin N/A 
  
  
  
  
Total