Randomized Double Blind Controlled Trial for the Treatment of Nucleic Acid Amplification Test (NAAT)+/Toxin Enzyme Immunoassay (EIA)- Clostridium Difficile in the Hematology Oncology Population
Phase: PHASE2
Conditions: Clostridium Difficile Infection, Hematologic Diseases, Bone Marrow Transplant, Oncologic Disorders
Sponsor: Medical College of Wisconsin

 
 
 
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CLINICAL STUDY PROTOCOL 
 
 
 
Protocol Title 
 
Randomized double blind placebo controlled trial for the treatment of NAAT(+)/toxin  
EIA(-) Clostridium difficile in the hematology oncology population  
 
Clinical Trials.gov Number 
 
NCT03030248 
 
 
 
Principal Investigator 
 
L. Silvia Munoz-Price, MD, PhD 
 
 
 
Original Protocol V1.5 March 20, 2018 
 
Current Version: V 4.0 November 7, 2019  
 
 
 
 
 
 
 
Proprietary and Confidential 
The information in this document is considered privileged and confidential, and may not 
be disclosed to others except to the extent necessary to obtain Institutional Review 
Board approval and informed consent, or as required by federal and state laws. Persons 
to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed. 
 
 
 

 
 
 
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Principal Investigator: 
L. Silvia Munoz-Price, MD, PhD 
Enterprise Epidemiologist 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-0752 
414-805-0748 
305-733-5113 
smunozprice@mcw.edu 
 
Sub-Investigator: 
Parameswaran Hari, MD 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-4600 
 
Collaborator: 
Sol Aldrete, MD 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-9237 
 
Collaborator: 
Saurabh Chhabra, MD 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-4600 
 
Collaborator: 
Daniel Stein, MD 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-955-6845 
 
Biostatistician: 
Sergey Tarima 
Medical College of Wisconsin 
8701 Watertown Plank Rd. 
Milwaukee, WI 53226 
414-456-5605 
 
 
 
 
Pharmacist (blinded): 
Sara Revolinski, PharmD 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
Phone: 414-955-2873 
Cell: 262-327-5504 
 
Pharmacist (unblinded): 
Kristin Busse 
Investigational Drug Pharmacy 
Froedtert Hospital 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-3145  
 
Clinical Research Manager - Hematology: 
Paulette Jacobs, BS, MS, CCRP 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
Office: 414-805-4594 
Pager: 414-318-1703 
 
Laboratory Contact: 
Taylor Park 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
Cell:  612-562-0087 
Office:  414-955-0344 
Pager:  414-314-0308 
 
Matt Faron, Ph.D (weekend coverage) 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
Cell: 815-302-3111 
Office: 414-805-6967 
 
 
 
Investigational Agent:  Vancomycin 
 
 
Funding Sponsor: 
MCW Cancer Center 
 

 
 
 
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REVISION HISTORY 
Revision history is presented in chronological order so that the information pertaining to the 
most current version of the protocol is presented last in this section. 
Original protocol: Version 1.1, Version Date 07/28/17 
Original protocol: Version 1.2, Version date 09/11/17 
Original protocol: Version 1.3, Version date 10/26/17 
Original protocol: Version 1.4, Version date 11/20/17 
Original protocol: Version 1.5, Version date 03/20/18 
Amended protocol: Version 2.0, Version date 11/09/18 
Amended protocol: Version 3.0, Version date 01/15/19 
Amended protocol: Version 4.0, Version date 11/07/19 

 
 
 
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PROTOCOL SUMMARY 
Title 
Randomized double blind placebo controlled trial for the treatment 
of NAAT(+)/toxin EIA(-) Clostridium difficile in the hematology 
oncology population 
IND Sponsor 
Not applicable 
Principal Investigator 
Luisa Silvia Munoz-Price, MD, PhD 
Study Sites 
Froedtert Hospital Cancer Center (CC) & Center For Advanced Care 
(CFAC) 
Clinical Trial Phase 
Pilot 
Study Disease 
Clostridium difficile infection (CDI) 
Inclusion Criteria 
Patients must meet all inclusion criteria to be eligible to participate 
in the study. 
• 
Patients must be at least 18 years of age at time of consent. 
• 
Presence of loose stools triggered clinical C. difficile NAAT/toxin 
EIA testing. 
• 
Having both C. difficile NAAT (+) and C. difficile toxin EIA (-). 
• 
Patient admitted in a hematology-oncology unit which for the 
purposes of this study will be defined as 7-CFAC, 8-CFAC, and 
9-CFAC (when applicable).  
• 
Patients must be willing to keep a study supplied drug diary. 
Exclusion Criteria 
Patients must NOT meet any exclusion criteria to be eligible to 
participate in the study. 
• 
Presence of sepsis. Sepsis will be defined as a Sequential 
[Sepsis-related] Organ Failure Assessment (SOFA) score of 2 
points or more as per 2016 definitions.1  
• 
Patient is only boarding in hematology-oncology units and would 
have not otherwise been admitted to these units. 
• 
Inability to take oral medications. 
• 
Unwillingness or inability to provide written informed consent. 
• 
Patient has a documented allergy to vancomycin. 
• 
Patient has a documented life expectancy shorter than 
treatment course (14 days). 
• 
Patient is unwilling or unable to collect stool samples in the 
outpatient setting after discharge. 
• 
Diagnosis of C. difficile colitis [NAAT(+) and toxin EIA(+)] in the 
preceding 3 months from enrollment. 

 
 
 
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• 
Received oral vancomycin during their current hospitalization, 
excluding empiric treatment given while pending C. difficile 
NAAT/toxin EIA results. Intravenous vancomycin is not an 
exclusion criterion.  
• 
Women known to be pregnant or lactating during the study. 
Study Rationale 
Clostridium difficile infection (CDI) is considered the most frequent 
healthcare associated infection in the US, causing almost half a 
million cases per year with an estimated annual cost of 4.8 billion 
dollars.  Despite the existence of a few treatment options against 
CDI, yearly attributable deaths are estimated at 29,300 in the US. 
From April 2014 to April 2016, Froedtert Health reported 899 CDIs. 
In our institution, we perform 300 hematopoietic stem cell 
transplants (HSCT) a year and our hematology oncology inpatient 
units have our highest CDI rates. 
Primary Objectives 
To characterize the impact of oral vancomycin on C. difficile and 
VRE loads after end of treatment compared to a placebo group. 
Secondary Objectives 
To determine the effect of oral vancomycin on structural and 
functional microbiome changes after end of treatment compared to 
a placebo group. 
 
To characterize the impact of oral vancomycin against a placebo 
group on the daily frequency of loose stools by the end of treatment. 
Endpoints 
C. difficile loads, VRE loads, microbiome structure and function, 
number of stools per day. 
Study Design 
This is a randomized double-blind controlled trial of vancomycin 
against placebo for the treatment of NAAT(+)/EIA(-) in hematology 
oncology patients. 
Study Agent 
Vancomycin capsules against placebo capsules 
Number of Subjects 
30 (15 per arm) 
Subject Participation 
Duration 
Patients may continue study treatment for approximately 14-15 days 
from the time of study entry. 
Duration of Follow up 
90 days from the time of study entry 
Estimated Time to 
Complete Enrollment: 
Approximately 36 months 
Statistical 
Methodology: 
The primary outcomes of this randomized double-blind controlled 
intervention trial will be change in C. difficile between day 1 and day 
14 and change in C. difficile between day 14 and day 28. Thirty 
patients will be randomized to either 14 days of vancomycin or 
placebo capsules. Subjects enrolled will be consecutive hematology 

 
 
 
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oncology inpatients with a C. difficile NAAT(+) and a toxin EIA(-). 
Block randomization will be used to assign patients to the treatment 
or placebo arms. Randomized assignments will be placed in sealed 
envelopes which will only be handled by the research pharmacist. 
Clinical providers, research team, and patients will remain blinded 
to allocation. Study related stool collections will be obtained on days 
1, 7, 14, 21, and 28 (+/- 2 days) [Day 1=first day study drug was 
administered]. Patients will be followed for 90 days starting on day 
1.  Patients unable to take at least one dose of study treatment will 
be removed from analysis and replaced. All statistical analyses will 
be performed by Dr. Sergey Tarima.  
Safety Assessments 
Oral vancomycin has very limited systemic absorption. The most 
common side effects associated with this oral drug include nausea, 
abdominal pain, vomiting, hypokalemia, diarrhea, and hypokalemia. 
 
Patients will be followed for a total of 90 days after the first day of 
study drug administration or until death, whichever occurs first. 
Patients removed from the study treatment for unacceptable SAEs 
will be followed until resolution or stabilization of the adverse event. 
SAEs will be followed until completion.  
 
If a patient is unable to take oral medications, then vancomycin may 
be held for up to 7 days until patient is able to tolerate oral 
medicines. If vancomycin is held for more than 7 days, the patient 
will be removed from treatment but will continue to provide stool 
samples and complete study questionnaires and diaries as required 
per protocol to receive the gift cards. 
 
Given that patients included in this study will all have diarrhea, then 
diarrhea will not be considered an Adverse Event. Special 
consideration for early study withdrawal due to worsening of 
diarrhea will be followed. We will perform dose modifications or 
dosing delays for nausea, vomiting, abdominal pain, renal failure, or 
hypokalemia.  
 
 
 

 
 
 
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SCHEMA 
 
 
 
 

 
 
 
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STUDY CALENDAR 
 
STUDY CALENDAR 
 
Treatment (vancomycin 
vs. placebo12 
Post-antibiotic treatment 
Parameter 
Pre-study 
Baseline4 
Day 
11,4 
Pre-
dose 
Day 7 
+/- 2 
days 
Day 14 
+/- 2 
days 
Day 21 
+/- 2 
days 
Day 28 
+/- 2 
days 
Day 90 
+/- 5 
days 
Informed consent 
X 
 
 
 
 
 
 
Medication History  
X 
 
 
 
 
 
 
Baseline Questionnaire 
X 
 
 
 
 
 
 
WBC, BMP and albumin 
from index admission 
X 
X 
X3 
X3 
 
 
 
Urine pregnancy test7 
X 
 
 
 
 
 
 
Concomitant 
medications10 
X 
X 
X 
X 
X 
 
 
Stool samples2 
X 
X8 
X 
X 
X 
X 
X 
On-study Questionnaire6 
 
X5 
X 
X 
X 
X 
X 
AE/SAE assessment11 
 
X 
X 
X 
X 
 
 
Gift Card Dispensation9 
 
 
 
X 
 
X 
X 
Drug Diary 1 Return 
 
 
 
X 
 
 
 
1 First day of study drug administration (vancomycin or placebo). 
2 All stool samples should be placed in a refrigerator or on ice and given to CTO study staff who 
will submit them to Dr. Munoz-Price’s lab staff (TRBC). 
3 If hospitalized.  
4 Pre-study baseline and Day 1 can be done on the same day. No need to repeat Day 1 
assessments (labs, concomitant medications) if done within one day of the first dose of study 
drug. 
5 Complete only if >one day since the Baseline Questionnaire was completed.  
6 May be conducted in person or via telephone after the patient is discharged.  
7 Only for women of child-bearing potential who have not had a pregnancy test within two weeks 
prior to enrollment.  Prior pregnancy test may be done on serum or urine. 
8 Day 1 samples can be obtained within 48 hrs prior to the first administration of study drug. 
 
9 A $100 gift card will be dispensed when the day 14 sample is received by the study staff and 
again when the day 28 sample is received by study staff.  A $100 gift card will be dispensed 

 
 
 
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when the day 90 sample is received by study staff.  Patients must be compliant with all sample 
collections to be eligible to receive the gift cards.  
10 All concomitant medications will be collected from time of consent until Day 21. The only 
drugs that will be followed until Day 90 are any antibiotics. 
11 AE/SAEs will be followed from consent until Day 21. The only AE that will be followed until 
Day 90 will be a diagnosis of Clostridium difficile which is defined as NAAT + and EIA +. 
12 Patients who stop study drug early will be asked to continue to bring stool samples and 
complete questionnaires and diaries through Day 90.  If patients are compliant with 
requirements, they will still be eligible to receive gift cards for their stool sample collections. 

 
 
 
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TABLE OF CONTENTS 
REVISION HISTORY ................................................................................................................. 3 
PROTOCOL SUMMARY ........................................................................................................... 4 
SCHEMA ................................................................................................................................... 7 
STUDY CALENDAR .................................................................................................................. 8 
TABLE OF CONTENTS ...........................................................................................................10 
LIST OF ABBREVIATIONS ......................................................................................................12 
1 BACKGROUND .....................................................................................................................13 
1.1 STUDY DISEASE ................................................................................................................13 
1.2 INVESTIGATIONAL AGENT(S) ...............................................................................................13 
1.3 SIMILAR ONGOING RANDOMIZED CLINICAL TRIAL...................................................................14 
2 HYPOTHESIS AND OBJECTIVES ........................................................................................14 
2.1 PRIMARY HYPOTHESIS .......................................................................................................14 
2.2 SECONDARY HYPOTHESIS ..................................................................................................15 
2.3 RATIONALE FOR THE OUTCOME MEASURES SELECTION .......................................................15 
3. 
STUDY DESIGN .........................................................................................................16 
3.1 
GENERAL DESCRIPTION ................................................................................................16 
3.2 
PRIMARY ENDPOINT(S) .................................................................................................16 
3.3 
SECONDARY ENDPOINT(S) ............................................................................................16 
3.4 
RANDOMIZATION ...........................................................................................................17 
3.5 
STUDY TIMELINE ...........................................................................................................17 
3.6 
PRIMARY COMPLETION .................................................................................................17 
3.7 
STUDY COMPLETION .....................................................................................................17 
4 
PATIENT SELECTION AND IDENTIFICATION .........................................................18 
4.1 
INCLUSION CRITERIA .....................................................................................................18 
4.2 
EXCLUSION CRITERIA ...................................................................................................18 
4.3 
PATIENT IDENTIFICATION...............................................................................................19 
5 
STUDY ENTRY AND WITHDRAWAL; STUDY PROCEDURES ................................19 
5.1 
STUDY ENTRY PROCEDURES.........................................................................................19 
5.2 
STUDY PROCEDURES DURING TREATMENT.....................................................................20 
6 
TREATMENT PLAN ...................................................................................................22 
6.1 
STUDY DRUG AND PLACEBO ..........................................................................................22 
6.2 
MONITORING SUBJECT COMPLIANCE .............................................................................22 
6.3 
FOLLOW-UP PERIOD .....................................................................................................23 
7 
DOSING DELAYS/DOSE MODIFICATIONS ..............................................................23 
7.1 
MONITORING AND TOXICITY MANAGEMENT .....................................................................25 
8 
ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) .....................25 
8.1 
DEFINING AND REPORTING AN ADVERSE EVENT ..............................................................25 
8.2 
DEFINING AND REPORTING A SERIOUS ADVERSE EVENT (SAE) .......................................26 
8.3 
REPORTING AES/SAES TO THE DATA AND SAFETY MONITORING COMMITTEE .................27 

 
 
 
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8.4 
REPORTING AES/SAES TO MCW COMMITTEE INSTITUTIONAL REVIEW BOARD................27 
8.5 
UNANTICIPATED PROBLEM INVOLVING RISK TO SUBJECT OR OTHER (UPIRSO) ...............27 
8.6 
AE GRADING AND ATTRIBUTION ....................................................................................27 
9 
PHARMACEUTICAL INFORMATION ........................................................................28 
9.1 
VANCOMYCIN [VANCOCIN® (VANCOMYCIN HYDROCHLORIDE, USP) CAPSULES] ..........28 
9.2 
PLACEBO CAPSULES .....................................................................................................30 
10 
STATISTICAL CONSIDERATIONS ...........................................................................31 
10.1 
STUDY ENDPOINTS .......................................................................................................31 
10.2 
STUDY DESIGN .............................................................................................................32 
10.3 
STRATIFICATION FACTORS ............................................................................................32 
10.4 
SAMPLE SIZE AND POWER ESTIMATE .............................................................................33 
10.5 
REPLACEMENT POLICY .................................................................................................33 
10.6 
ACCRUAL ESTIMATES....................................................................................................33 
10.7 
INTERIM ANALYSES AND STOPPING RULES .....................................................................34 
10.8 
ANALYSES PLANS .........................................................................................................34 
10.9 
EVALUATION OF SAFETY ...............................................................................................35 
11 
DATA AND SAFETY MONITORING PLAN (DSMP) ..................................................35 
11.1 
DATA AND SAFETY MANAGEMENT OVERVIEW ................................................................35 
11.2 
STUDY TEAM ................................................................................................................35 
11.3 
QUALITY ASSURANCE ...................................................................................................36 
11.4 
CLINICAL TRIALS OFFICE ...............................................................................................36 
11.5 
DSMC .........................................................................................................................36 
12 
REGULATORY COMPLIANCE, ETHICS AND STUDY MANAGEMENT ...................37 
12.1 
ETHICAL STANDARD ......................................................................................................37 
12.2 
REGULATORY COMPLIANCE ...........................................................................................37 
12.3 
INSTITUTIONAL REVIEW BOARD .....................................................................................37 
12.4 
INFORMED CONSENT PROCESS .....................................................................................37 
12.5 
SUBJECT CONFIDENTIALITY AND ACCESS TO SOURCE DOCUMENTS/DATA........................38 
12.6 
PROTECTION OF HUMAN SUBJECTS ...............................................................................38 
12.7 
INVESTIGATOR COMPLIANCE .........................................................................................38 
12.8 
ONSITE AUDITS ............................................................................................................38 
13 
DATA HANDLING AND RECORD KEEPING ............................................................39 
13.1 
OVERVIEW ...................................................................................................................39 
13.2 
CASE REPORT FORMS ..................................................................................................39 
13.3 
STUDY RECORD RETENTION .........................................................................................39 
13.4 
PUBLISHING DATA ........................................................................................................39 
REFERENCE LIST ...................................................................................................................40 
APPENDIX 1. SPECIMEN COLLECTION ................................................................................42 
APPENDIX 2. QUESTIONNAIRES ...........................................................................................45 

 
 
 
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LIST OF ABBREVIATIONS 
16S rRNA 
Modality of gene sequencing  
BUN 
blood urea nitrogen 
CCCTO 
Cancer Center Clinical Trials Office 
CDI 
Clostridium difficile infection 
BMP 
Basic metabolic panel 
CRC 
Clinical Research Coordinator 
EIA 
Enzyme immunoassay   
NAAT 
Nucleic acid amplification test 
PCR 
 Polymerase chain reaction 
qPCR 
Quantitative Polymerase chain reaction 
VRE 
vancomycin resistant enterococcus 
WBC 
white blood cell (count) 

 
 
 
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1 BACKGROUND 
1.1 Study Disease  
 
Clostridium difficile infection (CDI) is considered the most frequent healthcare associated 
infection in the US, causing almost half a million cases per year with an estimated annual cost 
of 4.8 billion dollars.2, 3 Despite the existence of a few treatment options against CDI, yearly 
attributable deaths are estimated at 29,300 in the US.2 From April 2014 to April 2016, Froedtert 
Health reported 899 CDIs. In our institution, we perform 300 hematopoietic stem cell transplants 
(HSCT) a year and our hematology oncology inpatient units have our highest CDI rates. Since 
2015 we have cultured the stool of over 1000 hematology oncology patients finding a 
colonization rate of 15%, with two thirds of these patients testing positive for C. difficile upon 
admission. Using this cohort, we determined that the relative risk of developing CDI was 4.9 
times higher if C. difficile colonized (p<0.0001). However, are these episodes of diarrhea a 
manifestation of CDI or are we detecting C. difficile colonization among patients with concurrent 
diarrhea caused by a different etiology?  
 
Clinical diagnosis of CDI is ascertained using a highly sensitive test --nucleic acid amplification 
test (NAAT)--, which is unable to differentiate C. difficile colonization from CDI.4 Patients with 
hematologic malignancies commonly experience diarrhea triggering a C. difficile NAAT test. 
Diarrhea in this population can be caused by many etiologies (e.g. chemotherapy, graft versus 
host disease (GVHD), and antibiotics). Thus, it is difficult to establish CDI in hematology 
oncology patients even if they test C. difficile NAAT(+).5 Additionally, the presentation of CDI in 
this population tends to be mild, reinforcing the suspicion that these cases might constitute 
colonized patients with concomitant diarrhea due to other etiologies.5 More importantly, 
unnecessary antibiotic treatment can be detrimental for hematologic patients by further 
disrupting the structure and function of their already perturbed gut microbiome, and 
subsequently increasing their risk for colonization by other pathogens such as vancomycin 
resistant enterococcus (VRE), GVHD, or bacteremia.6 Moreover, the degree of microbiome 
disruption during HSCT engraftment was recently associated with higher mortality.7 Early 2017 
Froedtert replaced C. difficile NAAT with a two-step test, in which a positive NAAT will reflex to a 
C. difficile toxin enzyme immunoassay (EIA), to determine if clinically significant amounts of 
toxin are being produced. However, NAAT(+), toxin(-) results will create a treatment dilemma, 
especially in immunocompromised populations. This pilot project aims to determine both the 
microbiome and the clinical implications of treating C. difficile toxin(-) patients. We hypothesize 
that antibiotic treatment of C. difficile NAAT(+), toxin(-) patients will increase C. difficile and VRE 
loads after the antibiotic course, will prolong C. difficile carriage status, will worsen the gut 
microbiota structure and function, without a clear clinical improvement in the hematology-
oncology inpatient population.   
 
1.2 Investigational Agent(s)  
 
Oral vancomycin versus placebo 
This study aims to compare the standard antibiotic treatment (oral vancomycin) versus placebo 
(no antibiotics). Oral vancomycin is currently FDA approved for the treatment of NAAT (+) C. 
difficile colitis, regardless of toxin production. However, recent European literature shows that 
treatment of NAAT(+) EIA toxin (-) C. difficile patients might not be necessary.8-10 Furthermore, 
we hypothesize that vancomycin treatment of NAAT(+) EIA toxin(-) might be deleterious for the 
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Detection of free C. difficile toxin in the stool was the standard of care for the diagnosis of CDI 
from 1983 through 2010. Since then, NAAT became the standard diagnostic test for over 60% 
of US hospitals (National Healthcare Safety Network, unpublished data). However, there is 
growing evidence that symptomatic patients who are NAAT(+), toxin(-) have outcomes similar to 
patients who are NAAT(-), toxin(-); some of these outcomes include 30-day mortality, ICU 
admission, and hospital readmission triggered by C. difficile.8, 11-13 Furthermore, the United 
Kingdom has successfully used a similar two step diagnostic algorithm with a confirmatory toxin 
EIA since 2012.14 
 
The adverse health consequences resulting from antibiotic overtreatment of NAAT(+), toxin(-) 
patients may be particularly important in transplant recipients.15 The usual treatment prescribed 
for CDI at the Froedtert Memorial Lutheran Hospital is oral vancomycin. While this drug has 
excellent activity against C. difficile and commonly suppresses its growth to non-detection, it 
does not eradicate carriage and its use results in marked and prolonged disruption of the lower 
intestinal microbiota.15, 16 Meanwhile, the degree of lower intestinal microbiota disruption at the 
time of HSCT engraftment has been demonstrated to be an independent predictor (controlling 
for other markers of underlying disease) of overall and transplant-related 3-year mortality.17 In 
addition, recent findings suggest that bone marrow suppressive effects of antibiotics, in this 
case potentially unnecessary oral vancomycin (which is not appreciably absorbed), may be 
solely mediated via microbiota disruption.18 All these data supports the notion that antibiotic 
treatment of NAAT(+), toxin(-) C. difficile patients might have significant negative repercussions 
without a clear clinical benefit.  
 
1.3 Similar ongoing randomized clinical trial 
 
A similar randomized clinical trial comparing the effectiveness of vancomycin versus placebo in 
a NAAT+/EIA- is underway at Washington University in St. Louis. This study is funded and 
designed in collaboration with the Centers for Disease Control and Prevention (CDC). Even 
though this CDC funded study is done in the general inpatient population, its protocol was 
recently modified to include hematology oncology patients. The new amendments in our current 
version of the protocol are aimed to mirror the less restrictive exclusion criteria used by 
Washington University and CDC. These include the use of gift cards to increase the compliance 
with stool collections and courier services or pre-paid shipping labels to send stool samples.  
 
2 HYPOTHESIS AND OBJECTIVES 
2.1  Primary Hypothesis 
Treatment of NAAT(+)/EIA(-) patients with oral vancomycin will prolong and increase the C. 
difficile and VRE fecal loads when compared to a placebo group.  
 
Primary Objectives 
To characterize the impact of oral vancomycin on C. difficile and VRE loads after end of 
treatment compared to a placebo group. 
 
2.1.1  
Compare the impact of vancomycin against placebo on the C. difficile load fluctuations 
from day 1 to end-of-treatment (day 14-15) and to day 28. This will be ascertained 
using quantitative PCR. 
 
2.1.2  
Characterize the differential VRE load from day 1 to day 28. This will be ascertained 
using selective solid media. 

 
 
 
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2.1.3  
Establish the long-term persistence of C. difficile by quantitative PCR at day 90. 
 
2.2  Secondary Hypothesis 
Oral vancomycin administered to NAAT(+)/EIA(-) patients will cause a greater disruption of the 
structure and function of the gut microbiome without improving the persistence of diarrhea when 
compared to a placebo group. 
 
Secondary Objectives 
Determine the effect of oral vancomycin on structural and functional microbiome changes after 
end of treatment compared to a placebo group. 
 
2.2.1  
Characterize the impact of oral vancomycin against placebo on structural alterations of 
the microbiome after end of treatment using 16S rRNA sequencing. Structural 
microbiota changes will be defined as 1) Alpha diversity index (Shannon index), 2) 
Abundance of specific phyla and taxa. 
 
2.2.2  
Characterize the impact of oral vancomycin against placebo on functional microbiome 
changes after end of treatment by measuring: 1) Primary and secondary bile acids, 2) 
Amino acids, 3) Sugars, and 4) Lipids. 
 
2.2.3  
Characterize the impact of oral vancomycin against a placebo group on the frequency 
of loose stools by the end of treatment. 
 
2.3  Rationale for the Outcome Measures Selection 
 
The gut microbiome has been shown to play an important role in the protection of individuals 
from the development of C. difficile infection. In previous studies, it has been shown that 
patients experiencing active C. difficile infection show marked shifts in their microbiome: 
reduced overall microbial diversity, reduced abundance of numerous taxa, including the 
Bacteroidetes, Lachnospiraceae, and Ruminococcacae, an increased abundance of members 
of Clostridia, and concomitant shifts in the metabolome of the microbiota. 
 
C. difficile loads: Antibiotics cause perturbations of the gut microbiota that allow C. difficile 
spore germination and vegetative bacterial growth in the colon with subsequent toxin 
production. 19, 20 Therefore, a necessary step for the biological progression of C. difficile is an 
increase of C. difficile fecal loads. Oral vancomycin for CDI treatment has been associated with 
an initial decrease of C. difficile loads followed by a rebound of C. difficile loads 1-2 weeks after 
completion of therapy.21 Our study will expand on this finding by evaluating the C. difficile loads 
by qPCR (not culture) only among NAAT(+) toxin(-) patients.    
 
VRE loads: Oral vancomycin in mice markedly increases their susceptibility to intestinal 
colonization by VRE upon challenge. 22, 23 This effect is believed to occur through microbiota 
perturbation;20however, the longitudinal association between oral vancomycin and higher VRE 
fecal loads is still unknown in humans.22  
 
Microbiome structure: Vancomycin use in mice has been shown to produce marked structural 
microbiota perturbations.22 23However, its effect in humans is still not well characterized.22 We 
hypothesize that oral vancomycin treatment will have a profound disruption on Shannon index 
and specific taxa.  
 

 
 
 
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Microbiome function: Structural microbiota changes impact the metabolic environment of the 
gut.24 Primary and secondary biliary acids, amino acids, lipids and sugars play key roles 
promoting and inhibiting germination, and are associated with outgrowth of vegetative forms and 
development of toxin.24-26 Derangements of these metabolites have major impact on the 
susceptibility of the host to pathogens. 25, 26 
 
Frequency of stools:  A recent observational study also showed that NAAT(+)/ toxin(-) and 
NAAT(-) groups had similar duration of diarrhea.8 Our study will explore this observation with a 
controlled design. 
 
3. 
STUDY DESIGN 
3.1 
General Description 
 
This pilot study will be a randomized double blind intervention trial for consecutive hematology 
oncology inpatients with a C. difficile NAAT(+) and a toxin EIA(-). After enrollment, patients will 
be randomized to treatment with vancomycin 125 mg capsules by mouth approximately every 4-
6 hours for 14-15 days or to placebo with identical looking capsules for the same length of 
treatment. Block randomization will be used to assign patients to the treatment or placebo arms. 
Randomized assignments will be placed in sealed envelopes which will only be handled by the 
research pharmacist. Clinical providers, research team, and patients will remain blinded to 
allocation. 
 
3.1.1 
Number of Subjects 
We plan to randomize 30 patients (15 to each arm).  
 
3.2 Primary Endpoint(s) 
 
3.2.1 
Endpoint 1: C. difficile fecal loads:  Stool samples collected for diagnosis and days 1, 
7, 14, 21, 28, and 90 will be thawed in batches and one cc aliquot will be extracted 
refreezing the remaining sample at -80 degrees F. One cc aliquot will then be divided 
into 4 sub-samples of equal volume and with the same unique identifier. This identifier 
will be able to chronologically cluster samples by each unique patient. One sample will 
be used for C. difficile qPCR determination and VRE cultures using methods 
previously described in the literature.5, 23 
 
3.3 Secondary Endpoint(s) 
 
3.3.1 
Endpoint 2a: VRE fecal loads: As per 3.2.1. 
 
3.3.2 
Endpoint 2b: Alpha diversity index (Shannon index) Sub-sample of stool from 
diagnosis, days 1, 7, 14, 21, 28 & 90 will be used for 16S rRNA gene sequencing to 
determine the microbiome community structure. 
 
3.3.3 
Endpoint 2c: Abundance of specific phyla and taxa: As per 3.3.2. 
 
3.3.4 
Endpoint 2d: Metabolites: These will include 1) Primary and secondary bile acids, 2) 
Amino acids, 3) Sugars, and 4) Lipids. They will be measured using mass 
spectrometry using stool from diagnosis, days 1, 7, 14, 21, 28 & 90. 
 

 
 
 
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3.3.5 
Endpoint 2e: Frequency of loose stools: this will be obtained using the baseline CRF 
and on study questionnaires on days 1, 7, 14, 21, 28 & 90. 
 
3.4 Randomization 
 
Block randomization (15 patients per block) will be used to assign patients to the treatment or 
placebo arms. Prior to the study onset, 30 randomized assignments will be placed in individually 
sealed envelopes which will only be handled by the research pharmacist. Clinical providers, 
research team, and patients will remain blinded to allocation. If patient substitution is deemed to 
be required, then an additional block randomization and placement of randomized assignments 
in sealed envelopes will be performed.  
 
3.5 Study Timeline 
 
The study will take approximately 4 years to complete from protocol submission to manuscript 
preparation. The majority of the time will be spent enrolling and randomizing patients. Upon 
completion of follow up of all 30 included patients, samples will be sent to our collaborators for 
metabolomics and sequencing. 
 
3.6 Primary Completion 
 
The study is expected to reach primary completion approximately 36 months from the time the 
study opens to accrual. 
 
3.7 Study Completion 
 
The study is expected to reach study completion approximately 42 months from the time the 
study opens to accrual. 
 
 
 

 
 
 
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4 
PATIENT SELECTION AND IDENTIFICATION 
4.1 Inclusion Criteria 
 
Patients must meet all inclusion criteria to be eligible to participate in the study. 
 
4.1.1 
Patients must be at least 18 years of age at time of consent. 
 
4.1.2 
Presence of loose stools triggered clinical C. difficile NAAT/toxin EIA testing. 
 
4.1.3 
Having both C. difficile NAAT (+) and C. difficile toxin EIA (-).  
 
4.1.4 
Patient admitted in a hematology-oncology unit which for the purposes of this study will 
be defined as 7-CFAC,8-CFAC, and 9-CFAC (when applicable).  
 
4.1.5 
Patients must be willing to keep a study supplied drug diary. 
 
4.2 Exclusion Criteria 
 
Patients must NOT meet any exclusion criteria to be eligible to participate in the study. 
 
4.2.1 
Presence of sepsis. Sepsis will be defined as a Sequential [Sepsis-related] Organ 
Failure Assessment (SOFA) score of 2 points or more as per 2016 definitions.1 
 
4.2.2 
Patient is only boarding in hematology-oncology units and would have not otherwise 
been admitted to these units. 
 
4.2.3 
Inability to take oral medications. 
 
4.2.4 
Unwillingness or inability to provide written informed consent. 
 
4.2.5 
Patient has a documented allergy to vancomycin. 
 
4.2.6 
Patient has a documented life expectancy shorter than treatment course (14 days). 
 
4.2.7 
Patient is unwilling or unable to collect stool samples in the outpatient setting after 
discharge. 
 
4.2.8 
Diagnosis of C. difficile colitis [NAAT(+) and toxin EIA(+)] in the preceding 3 months 
from enrollment.  
 
4.2.9 
Received oral vancomycin during their current hospitalization, excluding empiric 
treatment given while pending C. difficile NAAT/toxin EIA results. Intravenous 
vancomycin is not an exclusion criterion.  
 
4.2.10 
Women known to be pregnant or lactating during the study. 
 
 
 

 
 
 
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4.3 Patient Identification 
 
It is preferred that all samples be collected Monday-Friday from 7 am to 5 pm only, with few 
exceptions. All samples, including those collected outside of 7 am to 5 pm, should be kept in the 
study refrigerators located on designated CFAC floors until the CCCTO study staff collects 
them. Please see Appendix 1 for outpatient collections using courier/shipping services. The 
Clinical Research Coordinator (CRC) will de-identify the samples and assign them a unique 
patient number (UPN). These UPNs will be assigned to patients sequentially (CD001, CD002, 
CD003. etc.) as they sign consent. A sub-identifier will be used to identify the time point of the 
sample, see Table 1 below. This will result in every sample having a 5-digit identifier (i.e. 
CD001-03 is the first patient’s Day 7 sample, CD004-01 is the fourth patient’s baseline sample). 
 
Sub-identifier 
Time point 
-01 
Baseline 
-02a 
Day 1a 
-03 
Day 7 (+/- 2 days) 
-04 
Day 14 (+/- 2 days) 
-05 
Day 21 (+/- 2 days) 
-06 
Day 28 (+/- 2 days) 
-07 
Day 90 (+/- 5 days) 
a Day 1 sample may be skipped if < 48 hours has passed since the 
Baseline sample was collected. 
 
5 STUDY ENTRY AND WITHDRAWAL; STUDY PROCEDURES 
5.1 Study Entry Procedures 
 
5.1.1 
Consent and Authorization 
The study-specific assessments are detailed in this section and outlined in the Study 
Calendar. A written, signed informed consent form (ICF) and a Health Insurance 
Portability and Accountability Act (HIPAA) authorization must be obtained before any 
study-specific assessments are initiated. A member of the clinical research staff or 
designee will present the potential subject with the consent and allow the potential 
subject adequate time to read and review the informed consent form. The research 
staff member will then discuss the study and answer questions about time obligations 
and study requirements in detail to the potential subject. Subjects must be able to 
understand the document and provide appropriate informed consent. If the potential 
subject signs the consent, then all appropriate signatures are obtained, and a copy of 
the signed consent is given to the subject. A signed ICF copy will be filed in the 
medical record. The original will be kept on file with the study records.  
 
All patients who are consented will be registered in OnCore®, the MCW Cancer Center 
Clinical Trial Management System. The system is password protected and meets 
HIPAA requirements. 
 
 

 
 
 
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5.1.2 
Pretreatment Period 
 
Screening Assessments 
Screening will be done based on microbiology reports with NAAT(+)/EIA(-) results and 
physical location is 7-CFAC,8-CFAC, or 9-CFAC (when applicable).  
 
If there are any eligibility questions, please contact the Principal Investigator Dr. Silvia 
Munoz-Price, MD, PhD; cell: (305)733-5113 and/or primary coordinator. 
 
The screening procedures and assessments must be completed prior to, or on the 
same day as, the first administration of study drug. This will include:  
 
Medical History review 
 
Baseline Questionnaire 
 
WBC, BMP, and albumin labs 
 
Urine pregnancy test for women of child-bearing potential (unless a serum 
or urine pregnancy test was done within two weeks of enrollment) 
 
Concomitant medications 
 
Collection of stool sample. If a patient is unable to provide a stool sample 
before to treatment onset, then the PI or her physician designee could 
obtain rectal swabs in lieu of a stool sample. The patient and the attending 
physician would need to verbally consent prior to the procurement of the 
rectal swabs.  
 
5.2 Study Procedures during Treatment 
 
Patients must meet eligibility criteria on Day 1 to be treated.  
 
5.2.1 
Study Procedures, Day 1, 7, 14 (if hospitalized, otherwise follow 5.2.2.): 
• 
WBC, BMP, and albumin labs 
• 
Concomitant medications 
• 
Collection of stool sample or rectal swabs if inpatient 
• 
On-Study Questionnaire 
• 
AE/SAE assessment 
 
5.2.2 
Study Procedures, Days 21, 28, 90  
• 
Concomitant medications (only collected through Day 21) 
• 
Collection of stool sample  
• 
On-Study Questionnaire 
• 
AE/SAE assessment (only collected through Day 21) 
 
5.2.3 
Study Diaries 
• 
While inpatient, the nursing staff will log the date, number and type of bowel 
movements per day on the study drug diary supplied by the study staff.  All 
medications will be tracked on the patient’s electronic Medication Administration 
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• 
While outpatient, the patient will complete two study diaries supplied by study staff 
prior to discharge.   
o When applicable, the patient will log the date, time study drug was taken, and 
number and type of bowel movements per day on the Study Drug Diary 1.  
Patient should return the Study Drug Diary 1 with their day 14 sample 
collection. 
o The patient will log all other antibiotics taken from the date of discharge until 
the day 90 sample collection on the Other Antibiotic Diary.  Patient should 
return the Other Antibiotic Diary with their day 90 sample collection. 
 
5.2.4 
Gift Card Remuneration 
• 
Remuneration is as follows (total=$300): 
o $100 at the day 14 sample collection 
o $100 at the day 28 sample collection  
o $100 at the day 90 sample collection  
• 
If a patient withdraws early, remuneration will only be for the portions of the study 
already completed by the patient. 
 
5.2.5 
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue for 
14-15 days or until:  
• 
C. difficile disease progression defined as development of sepsis (as per clinical 
team’s or investigator’s judgment), or the occurrence of any of the following 
conditions after 48-72 hours of first intake of study drug: a). worsening abdominal 
pain or b). worsening of diarrhea or c). new onset of ileus. The presence of any of 
these situations will grant unblinding of the study drug and the subject will be 
offered vancomycin if on placebo.  
• 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the investigator’s or clinical team’s judgment.  
• 
Inter-current illness that prevents further treatment administration. 
• 
Patient decides to withdraw from the study. 
• 
Significant patient noncompliance with protocol. 
• 
Unacceptable adverse event(s) not covered by the first item (C. difficile 
progression). 
 
For any patient randomized AND given at least one dose of the study drug AND who 
must stop study treatment due to adverse outcomes: patients will be followed with 
Study Drug Diary 1, stool collections, and will remain eligible for gift cards for stool 
samples. 
 
For any patient randomized AND given at least one dose of the study drug AND who 
must stop study treatment NOT due to adverse outcomes (i.e. patient decides he/she 
doesn’t want to be part of the study): patient is off the study. No further diaries, stool 
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For any patient randomized AND not given at least one dose of the study drug: patient 
is off the study. No further diaries, stool collections, or gift cards are needed. 
 
5.2.6 
Patient-Initiated Withdrawal:  A patient may decide to withdraw from the study at any 
time. 
 
5.2.7 
Investigator-Initiated Withdrawal:  The Investigator will withdraw a patient whenever 
continued participation is no longer in the patient’s best interests. Reasons for 
withdrawing a patient include, but are not limited to, disease progression (as described 
above in section 5.2.5), the occurrence of an adverse event or a concurrent illness, a 
patient’s noncompliance or simply significant uncertainty on the part of the Investigator 
that continued participation is prudent.  
 
5.2.8 
Withdrawal Documentation Procedure:  The reason for study withdrawal and the date 
the patient was removed from the study must be documented in the medical record. 
 
6 
TREATMENT PLAN 
6.1 Study drug and Placebo 
 
Treatment will be administered on an inpatient basis. Patients being discharged home prior to 
the completion of the 14-15 day regimen should be sent with enough medication to last through 
the completion of the regimen.  
 
Regimen Description 
Study Drug 
Premedication; 
precautions 
Dose 
Route 
Schedule 
Length 
Vancomycin 
None 
One capsule 
(125 mg) q4-6hr 
Oral 
Days 1-14  
14-15* 
days  
Placebo 
None 
One capsule   
q4-6hr 
Oral 
Days 1-14 
*Study drug may be given on day 15 if all 4 doses were not given on day 1. 
 
Probiotics can be given to patients if needed.   
 
6.1.1 
Dietary Restrictions:  None  
 
6.1.2 
Prohibited Medications:  None 
 
6.2 Monitoring Subject Compliance  
 
Study drug will be administered or dispensed only to eligible patients under the supervision of 
the investigator or identified sub-investigator(s). The appropriate study personnel will maintain 
records of study drug receipt and dispensing. Comprehensive instructions will be provided to the 
patient in order to ensure compliance with dosing procedures. 
 

 
 
 
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Outpatients still receiving the study drug will be requested to maintain a Study Drug diary to 
record each dose of medication with the time of self-administration. The Study Drug diary will be 
returned to clinic staff at the completion of study drug (approximately day 14-15).  
 
6.3 Follow-Up Period 
 
Patients will be followed for a total of 90 days after the first day of study drug administration or 
until death, whichever occurs first. After day 90, patients will not be followed, even for survival, 
and will have completed study protocol and procedures. 
 
Patients removed from the study treatment for unacceptable SAEs will be followed until 
resolution or stabilization of the adverse event. SAEs will be followed until completion.  
 
7 
DOSING DELAYS/DOSE MODIFICATIONS  
If a patient is unable to take oral medications, then vancomycin may be held for up to 7 days 
until patient is able to tolerate oral medicines. If vancomycin is held for more than 7 days, the 
patient will be removed from treatment but will continue to provide stool samples and complete 
study questionnaires and diaries as required per protocol to receive the gift cards. 
 
Given that patients included in this study will all have diarrhea, then diarrhea will not be 
considered an Adverse Event. Consideration for early study withdrawal due to worsening of 
diarrhea would need to follow section 5.2.3. 
 
 
 

 
 
 
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Tables for Dosing Delays for Specific Adverse Events 
 
 
Adverse Event:  Nausea/Vomiting  
Grade of 
Event 
Management/Next Dose for Vancomycin/placebo 
≤ Grade 1 
No change in dose 
Grade 2 
 No change in dose 
Grade 3 
Hold* until < Grade 2 
  
Grade 4 
Hold* until < Grade 2 
Recommended management:  antiemetics. 
*Patients requiring a delay of 7 days should go off protocol therapy 
  
 
Adverse Event:  Renal failure1 
Grade of 
Event 
Management/Next Dose for Vancomycin/placebo 
≤ Grade 1 
No change in dose 
Grade 2 
 No change in dose 
Grade 3 
  Hold* until < Grade 2  
Grade 4 
  Hold* until < Grade 2 
1 Only if renal failure is related to study drug. Determination will be 
done by Sara Revolinski, PharmD (in a blinded fashion)  
*Patients requiring a delay of 7 days should go off protocol therapy 
  
 
Adverse Event:  Abdominal Pain 
Grade of 
Event 
Management/Next Dose for Vancomycin/placebo 
≤ Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3 
Hold* until < Grade 2 
  
Grade 4 
 Hold* until < Grade 2 
*Patients requiring a delay of 7 days should go off protocol therapy 
  
 
Adverse Event:  Hypokalemia1 
Grade of 
Event 
Management/Next Dose for Vancomycin/placebo 
≤ Grade 1 
No change in dose 
Grade 2 
No change in dose  
Grade 3 
Hold* until < Grade 2 
  
Grade 4 
 Hold* until < Grade 2 
 
1 Only if hypokalemia is related to study drug. Determination will 
be done by Sara Revolinski, PharmD (in a blinded fashion)  
*Patients requiring a delay of 7 days should go off protocol therapy 
  

 
 
 
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7.1 Monitoring and Toxicity Management 
 
Each patient receiving Vancomycin/placebo will be evaluable for safety. Given to the lack of 
absorption of the drug, the safety parameters will be limited to renal failure or hypokalemia 
coinciding with the study drug, nausea, and vomiting, and spontaneous reports of adverse 
events reported to the investigator by patients. 
 
Both renal failure and hypokalemia are commonly encountered among hospitalized hematology 
oncology patients. Dr. Sara Revolinski (Blinded Pharmacist) will be in charge of making the 
determination of relatedness to the study drug based on temporal association and the lack of 
other nephrotoxic drugs. Dr. Revolinski can be contacted by phone 414-955-2873 or cell 262-
327-5504. 
 
Each patient will be assessed periodically for any toxicity development. Toxicity will be 
assessed according to the NCI CTCAE v4.0. Dose adjustments will be made according to the 
system showing the greatest degree of toxicity. 
 
8 
ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) 
8.1 
Defining and reporting an Adverse Event  
 
Definition. Any clinically relevant deterioration in laboratory assessments or other clinical 
finding is considered an AE.  
 
Reporting source. AEs may be spontaneously reported by the patient and/or in response to an 
open question from study personnel or revealed by observation, physical examination or other 
diagnostic procedures.  
 
Prior to the trial. Planned hospital admissions or surgical procedures for an illness or disease 
that existed before the patient was enrolled in the trial are not to be considered AEs unless the 
condition deteriorated in an unexpected manner during the trial (e.g., surgery was performed 
earlier or later than planned).  
 
Treatment events. For all AEs, the investigator must determine both the intensity of the event 
and the relationship of the event to study drug administration.  
 
Follow-up of Adverse Events. All adverse events will be collected and followed with 
appropriate medical management until the day 21 visit. Patients will be followed until day 90 for 
a diagnosis of C. difficile colitis [NAAT (+) and toxin EIA (+)]. 
 
Signs or symptoms reported as adverse events will be graded and recorded by the investigator, 
according to the CTCAE. When possible, signs and symptoms indicating a common underlying 
pathology should be noted as one comprehensive event.  
 
All adverse events, whether or not unexpected, and whether or not considered to be associated 
with the use of the study drug, will be entered into OnCore®. 
 
 
 
 

 
 
 
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8.2 Defining and reporting a Serious Adverse Event (SAE) 
 
8.2.1 
Definition 
 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
• 
Death. Results in death. 
• 
Life threatening. Is life threatening (refers to an AE in which the patient was at risk 
of death at the time of the event. It does not refer to an event which hypothetically 
might have caused death if it were more severe). 
• 
Hospitalization. Requires inpatient hospitalization or prolongation of an existing 
hospitalization (see clarification in the paragraph below on planned 
hospitalizations). 
• 
Disability/incapacity. Results in persistent or significant disability or incapacity. 
(Disability is defined as a substantial disruption of a person’s ability to conduct 
normal life functions). 
• 
Medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the patient, 
require medical or surgical intervention to prevent one of the outcomes listed 
above, or involves suspected transmission via a medicinal product of an infectious 
agent  
 
Clarification should be made between a serious AE (SAE) and an AE that is 
considered severe in intensity (Grade 3 or 4), because the terms serious and severe 
are NOT synonymous. The general term severe is often used to describe the intensity 
(severity) of a specific event; the event itself, however, may be of relatively minor 
medical significance (such as a Grade 3 headache). This is NOT the same as serious, 
which is based on patient/event outcome or action criteria described above, and is 
usually associated with events that pose a threat to a patient’s life or ability to function. 
A severe AE (Grade 3 or 4) does not necessarily need to be considered serious. For 
example, a white blood cell count of 1000/mm3 to less than 2000 is considered Grade 
3 (severe) but may not be considered serious. Seriousness (not intensity) serves as a 
guide for defining regulatory reporting obligations 
 
8.2.2 
Reporting SAEs 
 
Serious AEs must be reported from the date the participant signs Informed consent 
until the day 21 visit or until they are resolved unless they are clearly determined to be 
due to a patient’s stable or chronic condition or intercurrent illness(es). 
 
For serious AEs, the investigator must determine both the intensity of the event and 
the relationship of the event to study drug administration.  
 
Since this is an investigator-initiated study, the principal investigator, also referred to 
as the sponsor-investigator, is responsible for reporting serious adverse events (SAEs) 
to any regulatory agency and to the sponsor-investigator’s IRB when required.  
 
 

 
 
 
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8.3 Reporting AEs/SAEs to the Data and Safety Monitoring Committee 
 
Review all unexpected grade 3, and all grade 4 and 5 adverse events, as well as any others 
requiring expedited reporting as defined in this protocol. Non-hematological grade 4 and all 
grade 5 events must be reported to the DSMC within 5 calendar days of study staff’s 
knowledge. Hematological grade 4 events can be routine reported. Given that patients included 
in this study will all have diarrhea, then diarrhea will not be considered an adverse event unless 
it worsens (increase in grade). 
 
Report Method:  The study staff will use email to report SAEs to the DSMC. The SAE report 
must include event term(s), serious criteria, and the sponsor-investigator’s or sub-investigator’s 
determination of both the intensity of the event(s) and the relationship of the event(s) to study 
drug administration. Intensity for each SAE, including any lab abnormalities, will be determined 
by using the NCI CTCAE as a guideline whenever possible.  
 
The criteria are available online at http://ctep.cancer.gov/reporting/ctc.html. 
 
8.4 Reporting AEs/SAEs to MCW Committee Institutional Review Board 
 
The study staff must report events to the MCW IRB within five business days of his/her 
awareness of the event if it meets expedited reporting criteria.  
 
8.5 Unanticipated Problem Involving Risk to Subject or Other (UPIRSO) 
 
The investigator and his or her team will follow the Medical College of Wisconsin policies related 
to unanticipated problems involving risks to subjects or others. This information may be found 
on the Human Research Protection Program website.  
 
8.6 
AE Grading and Attribution 
 
8.6.1 
Adverse Event Grading 
 
Grade 
Description 
0 
No AE (or within normal limits). 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2 
Moderate; minimal, local or noninvasive intervention (e.g., packing cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL). 
3 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to AE 
 
 
 
 

 
 
 
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8.2.2 
Adverse Event Attribution 
 
Attribution is an assessment of the relationship between the AE and the medical intervention. 
 
Relationship 
Attribution 
Description 
Unrelated to 
investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related to the intervention 
Unlikely 
The AE is doubtfully related to the intervention 
Related to 
investigational 
agent/intervention 
Possible 
The AE may be related to the intervention 
Probable 
The AE is likely related to the intervention 
Definite 
The AE is clearly related to the intervention 
 
9 PHARMACEUTICAL INFORMATION 
9.1 Vancomycin [VANCOCIN® (vancomycin hydrochloride, USP) CAPSULES] 
 
VANCOCIN CAPSULES are indicated for the treatment of C. difficile-associated diarrhea. 
VANCOCIN CAPSULES are also used for the treatment of enterocolitis caused by 
Staphylococcus aureus (including methicillin-resistant strains). Parenteral administration of 
vancomycin is not effective for the above infections; therefore, VANCOCIN CAPSULES must be 
given orally for these infections. 
 
Orally administered VANCOCIN is not effective for other types of infections. To reduce the 
development of drug-resistant bacteria and maintain the effectiveness of VANCOCIN 
CAPSULES and other antibacterial drugs, VANCOCIN CAPSULES should be used only to treat 
infections that are proven or strongly suspected to be caused by susceptible bacteria. When 
culture and susceptibility information are available, they should be considered in selecting or 
modifying antibacterial therapy. In the absence of such data, local epidemiology and 
susceptibility patterns may contribute to the empiric selection of therapy. 
 
Product Description:  VANCOCIN CAPSULES for oral 
administration contain chromatographically purified vancomycin 
hydrochloride, a tricyclic glycopeptide antibiotic derived from 
Amycolatopsis orientalis (formerly Nocardia orientalis), which has 
the chemical formula C66H75Cl2N9O24•HCl. The molecular 
weight of vancomycin hydrochloride is 1485.73; 500 mg of the 
base is equivalent to 0.34 mmol. 
 
Vancomycin hydrochloride has the structural formula:  
 
The capsules contain vancomycin hydrochloride equivalent to 125 
mg (0.08 mmol) or 250 mg (0.17 mmol) vancomycin. The 
capsules also contain F D & C Blue No. 2, gelatin, iron oxide, 
polyethylene glycol, titanium dioxide, and other inactive 
ingredients. 
 

 
 
 
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Oral vancomycin (vancocin) is available in 125 mg and 250 mg capsules for oral administration. 
VANCOCIN 125 mg CAPSULES have an opaque blue cap and opaque brown body imprinted 
with “3125” on the cap and “VANCOCIN HCL 125 MG” on the body in white ink. 
 
Classification:  Vancomycin is an antibacterial drug 
 
Mechanism of Action:  The bactericidal action of vancomycin against Staphylococcus aureus 
and the vegetative cells of Clostridium difficile results primarily from inhibition of cell-wall 
biosynthesis. In addition, vancomycin alters bacterial-cell-membrane permeability and RNA 
synthesis. 
 
Metabolism:  Vancomycin is poorly absorbed after oral administration. During multiple dosing 
of 250 mg every 8 hours for 7 doses, fecal concentrations of vancomycin in volunteers 
exceeded 100 mg/kg in the majority of samples. No blood concentrations were detected and 
urinary recovery did not exceed 0.76%. In anephric subjects with no inflammatory bowel 
disease who received vancomycin oral solution 2 g for 16 days, blood concentrations of 
vancomycin were less than or equal to 0.66 μg/mL in 2 of 5 subjects. No measurable blood 
concentrations were attained in the other 3 subjects. Following doses of 2 g daily, 
concentrations of drug were >3100 mg/kg in the feces and  
 
Contraindications:  Vancomycin capsules are contraindicated in patients with known 
hypersensitivity to vancomycin. 
 
Side Effects:  Oral vancomycin is not absorbed and overall well tolerated. The main adverse 
reactions associated with this drug were nausea, abdominal pain and hypokalemia.  
 
System/Organ Class 
Adverse Reaction 
Vancocin % (N=260)a 
Gastrointestinal 
Nausea 
17 
Abdominal pain 
15 
Vomiting 
9 
Diarrhea 
9 
Flatulence 
8 
General disorders and 
administration site conditions 
Pyrexia 
9 
Edema, peripheral 
6 
Fatigue 
5 
Infections and infestations 
Urinary tract infection 
8 
Metabolism and nutritional disorders 
Hypokalemia 
13 
Musculoskeletal and connective 
tissue disorders 
Back pain 
6 
Nervous system disorders 
Headache 
7 
a Adverse reaction rates were derived from the incidence of treatment-emergent adverse events. 
 
9.1.1 
Investigational Agent Administration  
 
The study drug will be handled by the Investigational Drug Services staff under the 
direction of the Investigational Pharmacist, Kristen Busse, PharmD. (email: 
IDS.pharmacy@froedtert.com).  

 
 
 
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9.1.2 
Storage Requirements 
 
Capsules need to be stored at controlled room temperature, 59° to 86°F (15° to 30°C). 
 
9.1.3 
Stability 
 
Capsules are stable for 6 months from the date of compounding. 
 
9.1.4 
Route of Administration  
 
Capsules will be taken by mouth. 
 
9.1.5 
Nursing Implications 
 
Vancomycin is excreted in human milk based on information obtained with the 
intravenous administration of vancomycin. However, systemic absorption of 
vancomycin is very low following oral administration of VANCOCIN. It is not known 
whether vancomycin is excreted in human milk, as no studies of vancomycin 
concentration in human milk after oral administration have been done. Caution should 
be exercised when VANCOCIN is administered to a nursing woman. Because of the 
potential for adverse events, a decision should be made whether to discontinue 
nursing or discontinue the drug, taking into account the importance of the drug to the 
mother. 
 
9.1.6 
Agent Supply 
 
The investigational product will be supplied unblinded to the study site’s pharmacy in 
bulk containers from Skywalk Pharmacy, a compounding pharmacy. Vancomycin and 
placebo will be manufactured by Skywalk Pharmacy to be identical in size, shape, 
color, appearance and taste. It will be the responsibility of the study site’s pharmacy to 
maintain the blind once a subject has been randomized.  
 
9.1.7 
Agent Accountability 
 
The Investigational Drug Services Pharmacy staff will manage drug accountability 
records. 
 
9.1.8 
Agent Destruction and Return 
 
Any drug dispensed to the patient but not taken by the patient will be returned to the 
Investigational Drug Services Pharmacy at the end of the treatment period. 
 
At the conclusion of the study, any returned or unused agent will be destroyed 
according to institutional policies. The destruction will be recorded on the Drug 
Accountability Record Form. 
 
9.2 
Placebo Capsules 
 
Product Description:  The placebo capsules will be filled with Microcrystalline Cellulose, an 
inactive ingredient that is allergen free. 

 
 
 
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9.2.1 
Investigational Agent Administration  
 
The study drug will be handled by the Investigational Drug Services staff under the 
direction of the Investigational Pharmacist, Kristen Busse, PharmD. (email: 
IDS.pharmacy@froedtert.com).  
 
9.2.2 
Storage Requirements 
 
Capsules need to be stored at controlled room temperature, 59° to 86°F (15° to 30°C). 
 
9.2.3 
Stability 
 
Capsules are stable for 6 months from the date of compounding. 
 
9.2.4 
Route of Administration  
 
Capsules will be taken by mouth. 
 
9.2.5 
Agent Supply 
 
The investigational product will be supplied unblinded to the study site’s pharmacy in 
bulk containers from Skywalk Pharmacy, a compounding pharmacy. Vancomycin and 
placebo will be manufactured by Skywalk Pharmacy to be identical in size, shape, 
color, appearance and taste. It will be the responsibility of the study site’s pharmacy to 
maintain the blind once a subject has been randomized.  
 
9.2.6 
Agent Accountability 
 
The Investigational Drug Services Pharmacy staff will manage drug accountability 
records. 
 
9.2.7 
Agent Destruction and Return 
 
Any drug dispensed to the patient but not taken by the patient will be returned to the 
Investigational Drug Services Pharmacy at the end of the treatment period. 
 
At the conclusion of the study, any returned or unused agent will be destroyed 
according to institutional policies. The destruction will be recorded on the Drug 
Accountability Record Form. 
 
10 STATISTICAL CONSIDERATIONS 
10.1 Study Endpoints 
 
Primary outcomes: (1) Change in C. difficile between day 1 and day 14, (2) change in C. difficile 
between day 14 and day 28. 
 
Endpoint 1. C. difficile fecal loads.  
 

 
 
 
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Endpoint 2a. VRE fecal loads. 
Endpoints 2b and 2c. Alpha diversity index and abundance of phyla/taxa. 
Endpoint 2d. Fecal levels of primary and secondary bile acids, amino acids, sugars and lipids. 
Endpoint 2e. Frequency of loose stools   
 
Endpoints 1-2a will be measured on stool samples using both culture methods and qPCR. 
Endpoints 2b-2d will be measured from stool samples using 16S rRNA sequencing at the 
MCW’s MCW Genomic Sciences & Precision Medicine Center and mass spectrometry at 
MCW’s Core Lab.  
Endpoint 2e will be measured by both patient questionnaires and diaries.  
 
Stool samples will be thawed in batches and one cc aliquot will be extracted refreezing the 
remaining sample at -80. One cc aliquot will then be divided into 4 sub-samples of equal volume 
and with the same unique identifier. One sample will be used for C. difficile qPCR determination 
and VRE quantification. A sample will undergo DNA extraction, which will be sequenced and 
analyzed using bioinformatics at the MCW Genomic Sciences & Precision Medicine Center.   
 
For metabolomics, 100 mg of thawed stool sample will be mixed with 100 µL of water, 20 µL of 
internal standards, and 800 µL of methanol. Samples will be vortexed for 2 min and then cooled 
in a refrigerator for 30 min. Samples will be spun at 20,000 rcf for 10 min at 4°C. The 
supernatant will be transferred to clean vials and stored at -80°C. The functional microbiome 
characterization will be done using mass spectrometry. 
 
10.2 Study Design 
 
This pilot study will be a randomized double blind intervention trial for consecutive hematology 
oncology inpatients with a C. difficile NAAT(+) and a toxin EIA(-). After enrollment, patients will 
be randomized to treatment with vancomycin 125 mg capsules by mouth approximately every 4-
6 hours for 14-15 days or to placebo with identical looking capsules for the same dosing and 
length of treatment. Block randomization will be used to assign patients to the treatment or 
placebo arms. Randomized assignments will be placed in sealed envelopes which will only be 
handled by the research pharmacist. Clinical providers, research team, and patients will remain 
blinded to allocation.  
 
Study related stool collections will be obtained on days 1, 7, 14, 21, and 28 (+/- 2 days) and on 
day 90 (+/- 5 days) [Day 1=first day study drug was administered] and sent to Dr. Munoz-Price’s 
research laboratory located at the Center for Infectious Diseases Research located in TBRC 
C3693. The transport of each sample to the lab will be coordinated by the CRC and lab staff. 
After testing as stated in this protocol, the remaining stool may be frozen and stored at -80 
degrees F in Dr. Munoz-Price’s research laboratory. Any leftover stool samples may be stored 
for further testing as stated in this protocol. The CRC will collect baseline demographics, all 
medications from enrollment to day 21. If the patient is discharged prior to the completion of 
treatment, the CRC will follow the patient by phone with stool samples dropped off by the patient 
or sent to the site using the designated courier or shipper.  
 
10.3 Stratification Factors 
 
None. 
 
 
 

 
 
 
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10.4 Sample Size and Power Estimate 
 
We anticipate C. difficile fecal loads in the vancomycin group to decrease from day 1 to 14 with 
a subsequent rebound by day 28. Contrary to this, we expect to see stable loads in the placebo 
arm.  
 
As shown on Figure, the standard errors of 
log of C. difficile load [log(C. difficile)] at 
different time points based on 52 patients 
were not higher than 0.2. This means that 
the upper bound for standard deviation of 
log(C. difficile) is approximately 1.44, and the 
standard deviation of change in log(C. 
difficile) is approximately bounded at 2 under 
the assumption of positive correlation 
between C. difficile assessments. With 15 
subjects per groups we will be able to detect 
a difference between the groups of 5.9 units 
on log(C. difficile) scale (POWER = 0.8, 
ALPHA = 0.025).  
 
10.5 Replacement Policy 
 
Patients that are unable to take at least one dose of study drug due to adverse events or 
progression of C. difficile disease or whom withdraw from treatment will be removed from 
primary analysis and replaced. Patients who do take at least one dose of study drug and stop 
study treatment will continue to collect stool samples and study diaries as per protocol unless 
the patient decides to withdraw from the study. Enrollment will continue until there are 15 
patients per group who are included in the primary analysis.  
 
Patients removed from the study treatment for unacceptable AEs will be followed until resolution 
or stabilization of the adverse event. SAEs will be followed until completion. Stool collections, 
Diaries, and gift cards will continue as per protocol.. 
 
10.6 Accrual Estimates 
 
On March 1, 2017, Froedtert Health started performing C. difficile testing using NAAT, and if 
positive reflexing to an EIA. On April 2017, 8CFAC and 7CFAC combined had 8 NAAT(+)/EIA(-) 
cases, and 6 and 3 cases in May and June, respectively (≈5 per month). This would mean that 
in order to screen 60 patients (30 included and 30 excluded) we would need 36 months. Please 
note that there is an expected seasonal decrease of C. difficile infections during the summer.  
 

 
 
 
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10.7 Interim Analyses and Stopping Rules 
 
None 
 
10.8 Analyses Plans 
 
Dr. Sergey Tarima will be in charge of the statistical analyses.  
 
After the preplanned tests for the primary outcomes the secondary outcomes will be 
investigated on exploratory basis. 
 
We plan to enroll 15 patients per group with 1, 14, & 28 day load assessments so that missing 
data will not affect the power properties. Other measurements or at other time points some data 
may be missing but under the assumption of missing at random (MAR) and a correctly chosen 
statistical model, all relevant information is retained for statistical inference. Departures from 
MAR will be investigated with a sensitivity analysis (e.g. tipping-point analysis). 
 
10.8.1 
Primary Analysis (or Analysis of Primary Endpoints) 
 
Endpoint 1: Linear model analysis will be used to compare vancomycin and placebo 
groups. We will test if the pre-to-post treatment changes (changes between the 1st 
FMLH C. difficile utilization and results - by unit 
Units 
with 
NAAT (+)
Reflex C. 
diff tests 
done
NAAT (+) EIA (+)
Reflex C. 
diff tests 
done
NAAT (+) EIA (+)
Reflex C. 
diff tests 
done
NAAT (+)
EIA (+)
3NW       
8
2
0
0
4
2
0
3SW       
14
3
2
17
3
3
10
1
0
4NE       
17
4
2
11
1
1
16
4
1
4NW       
4
1
1
4
2
0
8
2
0
4PV       
7
1
1
13
5
2
0
0
0
4SE       
6
1
1
9
2
2
9
2
0
4SW       
11
1
1
8
2
1
0
0
0
5NW
0
0
0
3
1
1
0
0
0
5SW
0
0
0
5
1
0
0
0
0
5SE       
8
3
0
0
0
0
13
3
0
7CFAC
23
2
1
23
4
2
19
3
1
7NT       
4
1
0
6
2
1
4
1
0
8CFAC
35
8
1
36
6
2
22
3
2
8NT       
10
2
0
14
1
0
13
1
1
9NT       
13
2
0
17
5
2
20
5
0
ER        
36
11
4
30
6
4
19
5
3
MICU
26
2
0
15
2
0
10
2
0
NICU
2
1
0
0
0
0
0
0
0
SICU
0
0
0
7
1
0
1
1
0
APRIL
MAY
JUNE
This table only includes the primary units that have NAAT(+) samples at FMLH. Please note that the sum of B, or E, or H will 
not coincide with the numbers shown in Hospital worksheet. 

 
 
 
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and 14th day samples) differ between the groups controlling for the baseline (at day 1) 
value of C. difficile load. The likelihood ratio test will be used and statistical 
significance will be declared if p-value <2.5%. The post treatment changes (changes in 
C. difficile load between days 14, 21 & 28) will be compared between the groups via 
linear regression model as well, controlling for the baseline and post treatment values 
of C. difficile load. Significance will be declared if p-value < 2.5%. Thus, by the use of 
Bonferroni adjustment, Type I error for the primary analyses will be controlled at 5%. 
Given the behavior of C. difficile loads previously reported by Sethi et al.21 this variable 
will also be analyzed on logarithmic scale. 
 
10.8.2 
Secondary Analysis (or Analysis of Secondary Endpoints) 
 
Secondary analysis will be performed with and without cross-over subjects. If a subject 
changes his/her treatment (cross-over), analysis will be performed on a time-
dependent status of exposure to vancomycin. 
 
For Endpoint 2a, we will use statistical modelling to model overtime dynamics of 
log(VRE) and compare the modelled profiles between the groups.  
 
For Endpoint 2b, 2c, 2d, temporal trends will be investigated and compared between 
the groups using linear mixed models. Both structural and functional microbiome 
changes will be compared using generalized estimating equations with a proper link 
function for different study outcomes. Leave one out cross validation will be used to 
estimate robust standard errors. 
 
For Endpoint 2e, linear trends of stool rates over time will be compared between the 
groups using Poisson regression model with repeated measures. Leave one out cross 
validation will be used to estimate robust standard errors. 
 
10.9 
Evaluation of Safety 
 
Analyses will be performed for all patients having received at least one dose of study 
drug. The study will use the NCI CTCAE v4.0. 
 
11 DATA AND SAFETY MONITORING PLAN (DSMP) 
11.1 Data and Safety Management Overview 
 
The Medical College of Wisconsin (MCW) Data Safety Monitoring Committee (DSMC) and the 
MCW Institutional Review Board (IRB) will approve protocol-specific DSM plans. A local, 
investigator-initiated trial will be required to be continuously monitored by the principal 
investigator of the study with regular safety and progress reports submitted to the DSMC.  
 
The DSMP for this study will involve the following entities: 
 
11.2 Study Team 
 
The study team minimally consists of the principal investigator, the clinical research coordinator, 
regulatory specialist and the study biostatistician. While subjects are on treatment, the principal 
investigator will meet regularly with the research coordinator and the study biostatistician to 

 
 
 
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review study status. This review will include but not be limited to reportable SAEs and UPIRSOs 
and an update of the ongoing study summary that describes study progress in terms of the 
study schema. The appropriateness of further subject enrollment and the specific intervention 
for a next subject enrollment is addressed.  
 
11.3 Quality Assurance  
 
This protocol was classified as intermediate risk and will be reviewed internally by the MCW 
Cancer Center Clinical Trials Office Quality Assurance Staff according to the MCWCC Data and 
Safety Monitoring Plan and current version SOP, 6.5.2 Internal Quality Assurance Reviews. 
 
11.4 Clinical Trials Office 
 
The MCWCC Clinical Trials Office [CTO] provides administrative assistance and support to the 
DSMC.  
 
11.5 DSMC 
 
The Medical College of Wisconsin Cancer Center places the highest priority on ensuring the 
safety of patients participating in clinical trials. Every cancer interventional trial conducted at 
MCW includes a plan for safety and data monitoring. 
 
This study will be reviewed by the Medical College of Wisconsin Cancer Center Data and Safety 
Monitoring Committee (MCWCC DSMC). A summary of the MCWCC DSMC activities are as 
follows:  
• 
Review the clinical trial for data integrity and safety  
• 
Review all unexpected grade 3, and all grade 4 and 5 adverse events, as well as any 
others requiring expedited reporting as defined in this protocol. Non-hematological grade 
4 and all grade 5 events must be reported to the DSMC within 5 calendar days of study 
staff’s knowledge. Hematological grade 4 events can be routine reported. Given that 
patients included in this study will all have diarrhea, then diarrhea will not be considered 
an adverse event unless it worsens (increases in grade). 
• 
Review all DSM reports  
• 
Submit a summary of any recommendations related to study conduct  
• 
Terminate the study if deemed unsafe for patients  
 
A copy of the MCWCC Data and Safety Monitoring Plan and membership roster will be 
maintained in the study research file and updated as membership changes. The committee will 
review reports from the study PI twice annually (or more frequently if needed) and provide 
recommendations on trial continuation, suspension or termination as necessary.  
 
Any available DSMC letters will be submitted to the IRB of record as required. 
 
 

 
 
 
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12 REGULATORY COMPLIANCE, ETHICS AND STUDY 
MANAGEMENT 
12.1 Ethical Standard 
 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements. 
 
12.2 Regulatory Compliance 
 
This study will be conducted in compliance with: 
• 
The protocol. 
• 
Federal regulations, as applicable, including: 21 CFR 50 (Protection of Human 
Subjects/Informed Consent); 21 CFR 56 (Institutional Review Boards) and §312 
(Investigational New Drug Application; and 45 CFR 46 Subparts A (Common Rule), B 
(Pregnant Women, Human Fetuses and Neonates), C (Prisoners), and D (Children), 
GCP/ICH guidelines, and all applicable regulatory requirements. The IRB must comply 
with the regulations in 21 CFR §56 and applicable regulatory requirements. 
 
12.3 Institutional Review Board 
 
The protocol, the proposed informed consent form and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the MCW Institutional Review Board. Prior to obtaining MCW approval, the 
protocol must be approved by the Medical College of Wisconsin Cancer Center Scientific 
Review Committee. The initial protocol and all protocol amendments must be approved by the 
IRB prior to implementation.  
 
12.4 Informed Consent Process 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of this therapy will be provided to the subjects and their families. 
Consent forms describing in detail the study interventions/products, study procedures and risks 
are given to the subject and written documentation of informed consent is required prior to 
starting intervention/administering study product. 
 
Consent forms will be IRB-approved and the subject (and Legally Authorized Representative, if 
necessary) will be asked to read and review the document. Upon reviewing the document, the 
investigator or designee will explain the research study to the subject and answer any questions 
that may arise. In accordance with 46 CR 46.111, the subject will sign and date the informed 
consent document prior to any procedures being done specifically for the study.  
 
A copy of the informed consent document will be given to the subjects for their records. After the 
subject’s visit in which the consent is signed, it is documented in the clinic chart that the consent 
has been signed and that all questions have been answered to the subject’s satisfaction after 
adequate time for review of the consent. It is also documented that a copy of the consent is 
given to the subject. The original consent is kept with the subject’s study file, and a copy of the 

 
 
 
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consent is sent to the OCRICC office, which will then submit to HIM a copy of the signed 
consent to be scanned into EPIC, the legal medical record. 
 
12.5 Subject Confidentiality and Access to Source Documents/Data 
 
Subject confidentiality is strictly held in trust by the sponsor-investigator, participating 
investigators, and any staff. This confidentiality includes the clinical information relating to 
participating subjects, as well as any genetic or biological testing. 
 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor-investigator. 
 
The conditions for maintaining confidentiality of the subjects’ records are required for the life of 
the data. These rules apply equally to any and all MCWCC projects.  
 
12.6 Protection of Human Subjects 
 
12.6.1 
Protection from Unnecessary Harm 
 
Each clinical site is responsible for protecting all subjects involved in human 
experimentation. This is accomplished through the IRB mechanism and the informed 
consent process. The IRB reviews all proposed studies involving human 
experimentation and ensures that the subject’s rights and welfare are protected and 
that the potential benefits and/or the importance of the knowledge to be gained 
outweigh the risks to the individual. The IRB also reviews the informed consent 
document associated with each study in order to ensure that the consent document 
accurately and clearly communicates the nature of the research to be done and its 
associated risks and benefits. 
 
12.6.2 
Protection of Privacy 
 
As noted, patients will be informed of the extent to which their confidential health 
information generated from this study may be used for research purposes. Following 
this discussion, they will be asked to sign informed consent documents. The original 
signed document will become part of the patient’s medical records, and each patient 
will receive a copy of the signed document.  
 
12.7 Investigator Compliance  
 
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB and the appropriate regulatory authority(ies).  
 
12.8 Onsite Audits 
 
Auditing is essential to ensure that research conducted at the Medical College of Wisconsin 
(MCW) Cancer Center is of the highest quality and meets MCW and regulatory agency 
standards.  
 
Regulatory authorities, the IRB and/or sponsor may request access to all source documents, 
data capture records and other study documentation for on-site audit or inspection. Direct 

 
 
 
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access to these documents must be guaranteed by the investigator, who must provide support 
at all times for these activities. 
 
13 DATA HANDLING AND RECORD KEEPING 
13.1 Overview 
 
Every effort is made to uphold the integrity of the project, the research, the institution, and the 
researchers involved. Data collection guidelines and methodologies are carefully developed 
before the research begins. Investigators focus on the following to ensure data integrity:  well-
trained data collectors/recorders to ensure consistency and quality, well-designed data 
collection protocols and ongoing monitoring. In this way, study rigor and validity are maintained. 
Data is protected from physical damage as well as from tampering, loss or theft. This project’s 
data management is a multidisciplinary activity that includes investigators, research 
coordinators and nurses, data mangers, support personnel, biostatisticians and database 
programmers. Quality control will be applied to each stage of data handling to ensure that all 
data are reliable and have been processed correctly.  
 
13.2 Case Report Forms  
 
The principal investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study. Study-
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis. All study data will be entered into OnCore® via standardized 
CRFs, in accordance with the study calendar, using single data entry with a secure access 
account.  
 
All source documentation and data will be available for review/monitoring by the MCWCC 
DSMC and regulatory agencies. 
 
13.3 Study Record Retention 
 
The principal investigator is required to maintain adequate records of the disposition of the drug, 
including dates, quantity and use by subjects, as well as written records of the disposition of the 
drug when the study ends.  
 
In accordance with FDA regulations, the investigator shall retain records for a period of two 
years following the date a marketing application is approved for the drug for the indication for 
which it is being investigated; or, if no application is to be filed or if the application is not 
approved for such indication, until two years after the investigation is discontinued and FDA is 
notified. 
 
13.4 Publishing Data 
 
At least one manuscript will be developed from the experience gathered in this study. Data 
owners will be the PI and co-investigator. Authorship for future publications will include Drs. 
Revolinski, Aldrete, Charlson, in addition to the PI and Co-PI.  
 
 

 
 
 
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REFERENCE LIST 
 
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Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315:801-810. 
 
2.  Centers for Disease Control and Prevention (CDC). Antibiotic Resistance Threats in the 
US 2013. Available at http://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf. 
(accessed 6-30-2016). 
 
3.  Olsen MA, Young-Xu Y, Stwalley D et al. The burden of clostridium difficile infection: 
estimates of the incidence of CDI from U.S. Administrative databases. BMC Infect Dis 
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4.  Lessa FC, Winston LG, McDonald LC. Burden of Clostridium difficile infection in the 
United States. N Engl J Med 2015; 372:2369-2370. 
 
5.  Kinnebrew MA, Lee YJ, Jenq RR et al. Early Clostridium difficile infection during 
allogeneic hematopoietic stem cell transplantation. PLoS One 2014; 9:e90158. 
 
6.  Taur Y, Pamer EG. The intestinal microbiota and susceptibility to infection in 
immunocompromised patients. Curr Opin Infect Dis 2013; 26:332-337. 
 
7.  Shono Y, Docampo MD, Peled JU et al. Increased GVHD-related mortality with broad-
spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human 
patients and mice. Sci Transl Med 2016; 8:339ra71. 
 
8.  Origuen J, Corbella L, Orellana MA et al. Comparison of the clinical course of 
Clostridium difficile infection in GDH-positive, toxin-negative patients diagnosed by PCR 
to those with a positive toxin test. Clin Microbiol Infect 2017. 
 
9.  Dubberke ER, Burnham CA. Diagnosis of Clostridium difficile Infection: Treat the Patient, 
Not the Test. JAMA Intern Med 2015; 175:1801-1802. 
 10.  Davies K, Davis G, Barbut F, Eckert C, Petrosillo N, Wilcox MH. Variability in testing 
policies and impact on reported Clostridium difficile infection rates: results from the pilot 
Longitudinal European Clostridium difficile Infection Diagnosis surveillance study 
(LuCID). Eur J Clin Microbiol Infect Dis 2016; 35:1949-1956. 
 11.  Longtin Y, Trottier S, Brochu G et al. Impact of the type of diagnostic assay on 
Clostridium difficile infection and complication rates in a mandatory reporting program . 
Clin Infect Dis 2013; 56:67-73. 
 12.  Planche TD, Davies KA, Coen PG et al. Differences in outcome according to Clostridium 
difficile testing method: a prospective multicentre diagnostic validation study of C difficile 
infection. Lancet Infect Dis 2013; 13:936-945. 
 13.  Polage CR, Gyorke CE, Kennedy MA et al. Overdiagnosis of Clostridium difficile 
Infection in the Molecular Test Era. JAMA Intern Med 2015; 175:1792-1801. 

 
 
 
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 14.  Crobach MJ, Planche T, Eckert C et al. European Society of Clinical Microbiology and 
Infectious Diseases: update of the diagnostic guidance document for Clostridium difficile 
infection. Clin Microbiol Infect 2016; 22 Suppl 4:S63-S81. 
 15.  Lewis BB, Buffie CG, Carter RA et al. Loss of Microbiota-Mediated Colonization 
Resistance to Clostridium difficile Infection With Oral Vancomycin Compared With 
Metronidazole. J Infect Dis 2015; 212:1656-1665. 
 16.  Abujamel T, Cadnum JL, Jury LA et al. Defining the vulnerable period for re-
establishment of Clostridium difficile colonization after treatment of C. difficile infection 
with oral vancomycin or metronidazole. PLoS One 2013; 8:e76269. 
 17.  Taur Y, Jenq RR, Perales MA et al. The effects of intestinal tract bacterial diversity on 
mortality following allogeneic hematopoietic stem cell transplantation. Blood 2014; 
124:1174-1182. 
 18.  Josefsdottir KS, Baldridge MT, Kadmon CS, King KY. Antibiotics impair murine 
hematopoiesis by depleting intestinal microbiota. Blood 2016. 
 19.  Britton RA, Young VB. Role of the intestinal microbiota in resistance to colonization by 
Clostridium difficile. Gastroenterology 2014; 146:1547-1553. 
 20.  Buffie CG, Pamer EG. Microbiota-mediated colonization resistance against intestinal 
pathogens. Nat Rev Immunol 2013; 13:790-801. 
 21.  Sethi AK, Al-Nassir WN, Nerandzic MM, Bobulsky GS, Donskey CJ. Persistence of skin 
contamination and environmental shedding of Clostridium difficile during and after 
treatment of C. difficile infection. Infect Control Hosp Epidemiol 2010; 31:21-27. 
 22.  Isaac S, Scher JU, Djukovic A et al. Short- and long-term effects of oral vancomycin on 
the human intestinal microbiota. J Antimicrob Chemother 2017; 72:128-136. 
 23.  Deshpande A, Hurless K, Cadnum JL et al. Effect of Fidaxomicin versus Vancomycin on 
Susceptibility to Intestinal Colonization with Vancomycin-Resistant Enterococci and 
Klebsiella pneumoniae in Mice. Antimicrob Agents Chemother 2016; 60:3988-3993. 
 24.  Theriot CM, Young VB. Microbial and metabolic interactions between the gastrointestinal 
tract and Clostridium difficile infection. Gut Microbes 2014; 5:86-95. 
 25.  Theriot CM, Koenigsknecht MJ, Carlson PE, Jr. et al. Antibiotic-induced shifts in the 
mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile 
infection. Nat Commun 2014; 5:3114. 
 26.  Theriot CM, Bowman AA, Young VB. Antibiotic-Induced Alterations of the Gut Microbiota 
Alter Secondary Bile Acid Production and Allow for Clostridium difficile Spore 
Germination and Outgrowth in the Large Intestine. mSphere 2016; 1. 
 
 
 

 
 
 
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APPENDIX 1. SPECIMEN COLLECTION 
Instructions for Stool Specimen Collection and Handeling 
 
Stool collection: 
• 
If Stool Sample is Collected while Patient is Inpatient: 
The nursing staff will utilize the standard inpatient stool collection kit.  CRC will notify the 
nursing staff every day a specimen collection is required. After the specimen is collected, 
the nurse will place the specimen in the study-supplied refrigerator and call/page the CRC 
who will pick up the sample. 
o Rectal Swab Collection 
1. Rectal swabs may be collected from hospitalized patients if they are unable to 
provide a bowel movement within 24 hours of the designated collection time 
point.  (Only stool specimens (not rectal swabs) will be collected from patients 
who have been discharged.) 
2. Instructions for collecting rectal swabs: 
a. Overall goal: obtain 4 swabs in a manner the patient can tolerate. 
b. Can obtain two swabs together/two insertions, or to do each one 
individually/4 insertions. 
c. Insert the swab(s) a few centimeters into the patient’s rectum and turn 
gently. Withdraw the swab carefully. 
d. If the swab does not have stool on it, reinsert the swab slightly further into 
the patient’s rectum and try again. 
e. Rectal swabs will be double bagged and placed in the study-supplied 
refrigerator.  Nurse will call/page the CRC who will pick up the sample. 
However, if the PI is the staff member collecting the rectal swab, the PI will 
take the sample directly to the lab. 
 
*Prior to patient leaving the hospital, CRC will give the patient Stool Sample 
Collection Kit(s), Styrofoam container(s), Shipping supplies, Drug Diaries and 
Instructions (as applicable). 
 
• 
If Stool Sample is Collected while Patient is Outpatient: 
Patients will collect stool sample(s) at home at appropriate time points according to the 
instructions provided.  Samples may be returned to the clinic by either of the following: 
o Patients will call CRC at number provided on instructions to arrange a time to drop 
off samples. Appropriate locations for patients to drop off appropriately packed 
stool samples include (but are not limited to) the Cancer Center lab (2nd floor) or 
the Grace clinic (Cancer Center 4th floor). 
OR 
o If patients do not live nearby and will not be returning to the clinic at a specified 
collection timepoint, a courier or shipping company pre-paid box may be used (i.e. 
USPS, FedEx, etc.).  The CRC will determine which method is appropriate for each 
patient. 
1. For the courier, patients must live within a 1-hour drive from the site.  Patients 
will call CCCTO study staff to arrange a time for the courier service (CS 
Logistics) to pick up the sample(s).  The courier service (CS Logistics) will 

 
 
 
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contact the CCCTO study staff to arrange delivery of the sample(s).   
2. For the shipping company pre-paid box, patients will be provided with the 
proper shipping materials and shipping label. 
 
Specimen Labeling: 
All specimen containers must be labeled with the study name (“C. diff study”), patient study ID#, 
time point (Baseline, D1, D7, etc.), and date/time of specimen collection. 
 
Transporting and Storage Requirements: 
Study staff will pick up stool sample from CFAC unit and store in Cancer Center Clinical Trials 
Office (CCCTO) lab until pick up. Study staff will call and/or page research lab staff as soon as 
sample is received. Research lab staff will pick up samples in the CCCTO lab.  No processing 
will be done in the CCCTO lab. 
 
Study staff will complete a requisition for the samples (see form on next page); A copy of the 
requisition will be retained by the study staff in the research binder. 
 
For inpatient samples, it is preferred that they are collected Monday thru Friday, 7 AM to 5 PM.  
Regardless of collection time, nurses should place the stool samples inside the CFAC study 
refrigerators located in the dirty supply rooms and notify the CCCTO staff. 
 
All samples should be transported to the research lab as soon as possible after collection. 
Samples should be kept in a refrigerator while waiting for transportation to the research lab. 
Samples should be packed and transported according to IATA regulations. Personnel from Dr. 
Silvia Munoz-Price’s lab will pick up the study samples from the CCCTO lab. CRC will 
coordinate sample pick up with the research lab.  
 
 

 
 
 
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Randomized double blind placebo controlled trial for the treatment of 
NAAT(+)/toxin EIA(-) Clostridium difficile in the hematology oncology population 
 
 
“C. diff study” Specimen Requisition Form 
 
 
Patient Information: 
 
Patient Initials: ____________________________ 
 
Patient Study ID #: _________________________ 
 
 
Research Sample Information: 
 
Date of Sample Collection: ________________ Time of Sample Collection: _______________ 
 
 
Study time point (circle one):  
Pre-study Baseline 
Day 1 
Day 7 
 
 
 
Day 14 
Day 21 
Day 28 
Day 90 
 
 
 
Date and Time Lab was Notified of Sample Availability: ______________________________ 
 
Name of Lab Staff Receiving Notification: _________________________________________ 
 
Person Completing Requisition:  ________________________________________________ 
 
Phone Number of Person Completing Requisition: __________________________________ 
 
 
 
Lab Staff Picking Up Research Sample: __________________________________________ 
 
Date and Time of Pick-Up:  ____________________________________________________ 
 
 
 
 
 

 
 
 
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APPENDIX 2. QUESTIONNAIRES 
Randomized double blind placebo controlled trial for the treatment of NAAT(+)/toxin EIA(-) 
Clostridium difficile in the hematology oncology population 
 
Patient study ID # ______________ 
Date Questionnaires completed: ________________ 
Time Questionnaire completed: _________________ 
 
Baseline Questionnaires 
To be asked to patients; responses should be verbal and recorded by study staff. 
Do NOT hand these questionnaires to the patient. 
 
History of C. difficile infection (CDI) 
 
NOTE:  If the medical record clearly documents the presence of CDI in contradiction of the 
patient’s response, then the study case report forms should be completed using the contents 
of the medical record. 
 
1. Have you had a diagnosis of C. difficile infection prior to this 
admission? 
If yes, go to question 2.  
If no, skip to Medical History Questionnaire on next page. 
YES                 NO 
2. Have you had at least two episodes of C. difficile infection 
within the past 2 years? 
YES                 NO 
3. Have you had at least one episode within the past 6 months? 
If yes, go to question 4.  
If no, skip to Medical History Questionnaire on next page. 
YES                 NO 
4. During any of these previous episodes: 
a. 
Were you hospitalized? 
YES      NO      Don’t know 
b. 
Were you in the intensive care unit?   
YES      NO      Don’t know 
c. 
Were you diagnosed by colonoscopy? 
YES      NO      Don’t know 
 
Questionnaire version: 06/20/17 
 

 
 
 
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Randomized double blind placebo controlled trial for the treatment of NAAT(+)/toxin EIA(-) 
Clostridium difficile in the hematology oncology population 
 
Patient study ID # ______________ 
Date Questionnaires completed: ________________ 
Time Questionnaire completed: _________________ 
Selected Medical History 
 
1. Have you had any surgeries in the past 90 days? 
If yes, go to question 2.  
If no, skip to question 3. 
YES                 NO 
2. Have any of those been open abdominal 
surgeries?   
YES                 NO 
3. How many times are you currently having bowel 
movements within a 24-hour period? (circle 
one) 
None      1      2     3     4     5     6     7     
8     9       10       11    more than 11 
4. Regarding your current stool pattern, when did 
the frequency of bowel movements increase or 
change?  
 
5. What is the consistency of the majority of your 
bowel movements within the past 5 days? (Use 
Bristol chart) 
Type 1      Type 2      Type 3      Type 4    
Type 5      Type 6      Type 7 
6. Are you currently having abdominal pain?  
If yes, go to question 2.  
If no, skip to question 3. 
YES                 NO 
7. When did the abdominal pain start?    
Date: __________________ 
8. Currently having nausea? 
YES                 NO 
9. Currently vomiting?   
YES                 NO 
NUTRITIONAL INTAKE:  
10. Type of caloric intake (circle one):  
Normal/solids        Soft 
Liquid        Parenteral/enteral 
11. How much of your meals are you eating?  
<50%        >50%       Can’t tell 
Questionnaire version: 06/20/17 
 
Signature of staff member completing questionnaires: ________________________________   

 
 
 
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Page 47 of 48 
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Randomized double blind placebo controlled trial for the treatment of NAAT(+)/toxin EIA(-) 
Clostridium difficile in the hematology oncology population 
 
Patient study ID # _____________ 
Date Questionnaires completed: ________________ 
 
Expected Time point (D7, 14, 21, 28, or 90): ___________ 
Actual Time point: ___________ 
 
On-Study Questionnaire 
 
To be asked to patients; responses should be verbal and recorded by study staff. 
Do NOT hand these questionnaires to the patient. 
Questionnaires can be done in person or over the phone. 
 
NOTE:  If the medical record clearly contradicts the patient’s response, then the study case 
report forms should be completed using the contents of the medical record. 
1. Since the last questionnaire, the frequency of bowel 
movements has: 
Increased          Decreased 
Remains unchanged 
2. How many times are you currently having bowel 
movements within a 24-hour period? (circle one) 
None      1      2     3     4     5     6     7     8     
9       10       11     more than 11 
3. What is the consistency of the majority of your bowel 
movements within the past 5 days? (Use Bristol chart) 
Type 1      Type 2      Type 3      Type 4      
Type 5      Type 6      Type 7 
4. Since the last questionnaire, have you experienced 
fever (temp >100.3)? 
YES       NO       Not sure 
5. Since the last questionnaire, have you had new onset 
of abdominal pain? 
YES       NO       Not sure 
6. Since the last questionnaire, have you been diagnosed 
with pseudomembranous colitis? 
YES       NO       Not sure 
7. Since the last questionnaire, have you been admitted 
to the hospital?  
If yes, go to question 8.  
If no, skip to question 10. 
YES       NO 
8. If yes, which hospital? 
 
9. If yes, which dates were you admitted? 
 

 
 
 
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Randomized double blind placebo controlled trial for the treatment of NAAT(+)/toxin EIA(-) 
Clostridium difficile in the hematology oncology population 
 
Patient study ID # _____________ 
Date Questionnaires completed: ________________ 
 
Expected Time point (D7, 14, 21, 28, or 90): ___________ 
Actual Time point: ___________ 
 
10. Since the last questionnaire, have you been started on 
any new antibiotics? 
If yes, go to question 11.  
If no, skip to question 12. 
YES       NO       Not sure 
11. If yes, which antibiotic were you started on and when? 
 
12. Since the last questionnaire, have you been started on 
a new chemotherapy agent? 
If yes, go to question 13.  
If no, skip to question 14. 
YES       NO       Not sure 
13. If yes, which chemotherapy were you started on and 
when? 
 
14. Since the last questionnaire, has there been any 
changes in your diet? 
Normal/solids        Soft           Liquid 
15. Since the last questionnaire, have you had any new or 
worsened medical problems? 
 
 
 
Signature of staff member completing questionnaires: ________________________________ 
 
 
 
 
 
 
 
 
Questionnaire version: 11/20/18