Clinical trial NCT03937999
Conditions: Clostridium Difficile
Keywords: clostridium difficile diarrhea
Sponsor: Montefiore Medical Center
Start date: 2019-08-30; Completion date: 2022-05-15
Enrollment: 1 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will examine whether the human monoclonal antibody, bezlotoxumab administered AFTER acute Clostridioides difficile (C.diff) has resolved, but during a period of subsequent antibiotic therapy, will eliminate the high risk of C. diff relapse.

Detailed description:
Clostridioides difficile (C. diff) is a germ (bacteria) that causes life-threatening diarrhea. It is usually a side-effect of taking antibiotics that affect the normal balance of bacteria in the intestines. When the "good bacteria" in the intestine are killed by antibiotics, the C.diff bacteria begin to grow and produce toxins, causing frequent diarrhea and other symptoms such as abdominal pain or tenderness, loss of appetite, low-grade fever, nausea and vomiting. C. diff can be treated by using special antibiotics, but it tends to come back in about 20% of patients. C-diff is problematic because of frequent relapses after apparent cure. The greatest risk factor for relapse is receipt of subsequent antibiotics, in the hospital, shortly after being treated.

Zinplava™(bezlotoxumab) is an FDA approved human monoclonal antibody designed to prevent the recurrence of C.diff.This is not an antibiotic, as it does not kill C. diff, but is an antibody to C. diff toxins, which stops the damage. When Bezlotoxumab is given during a C. diff infection together with antibiotics to kill C. diff, it decreases the risk that C. diff will come back by about one-half. Bezlotoxumab is approved for use when given during a C. diff infection, but it has not been used to prevent C diff in other situations, such as the one being studied in this research.

Arms: arm 1: Single dose of Bezlotoxumab 10mg/kg iv over 60 minutes on Day 0 arm 2: Control group who are eligible as per the inclusion/exclusion criteria to the Bezlotoxumab arm, but not given Bezlotoxumab (Day 0) .
Interventions: intervention 1: Bezlotoxumab
Intervention descriptions: intervention 1: Injection: 1,000 mg/40 mL (25 mg/mL) solution in a single-dose vial.

Protocol documents:
Prot_SAP_000.pdf: 
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Investigator
Investigator
Investigator  Studies
Studies
Studies  Program
Program
Program  (MISP)
(MISP)
(MISP)
Protocol
Protocol
Protocol  Template
Template
Template
Requirements for Submitting a Full Proposal
Section #1 - MISP Protocol Identification
Study Title:
 
A pragmatic trial of secondary prophylaxis with Bezlotoxumab to prevent C. difficile 
relapse among hospitalized adults receiving antibiotics.
                                                                                                                                                             
Request Date:
August 31,2018
Institution Name
Montefiore Medical Center
Investigator 
Contact 
Information:
Full address 
Phone No.
Fax  No.
e-mail address
Paul Riska
111 E 210th Street
Division of Infectious Disease/AIDS Center
Bronx,NY 10467
718-920-6494
Fax 718-231-9187
priska@montefiore.org
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Section #2- Core Protocol
2.1 Objectives & 
Hypotheses 
2.1 Objectives: 
A.
Can monoclonal antibody treatment active against C. difficile toxin B 
(Bezlotoxumab) prevent relapse of CDI (C. difficle infection) among patients 
recently infected with C difficile, with resolved CDI after completing standard C. 
difficile therapy, but receiving subsequent  antibiotics for other infections?
B.
Does stool carriage of C difficile after end of CDI treatment predict relapse? If 
so, are failures of CDI prophylaxis due to reinfection or relapse with the same 
strain?
2.1.1 List the clinical hypotheses. 
A.
Antibody active against C. difficile toxinB (Bezlotoxumab) can prevent 
relapse of C. difficile disease (CDI), when patients recently affected by CDI 
are prescribed antibiotics for other indications.
B.
Failures of CDI prophylaxis, if found, are due to persistent carriage of C. 
difficile, rather than acquisition of a new strain.
2.2 Background & 
Rationale, 
Significance of 
Selected Topic & 
Preliminary Data 
Clostridioides difficile infection (CDI) is the leading hospital-acquired infection in the 
US, affecting nearly 500,000 persons annually, and killing 29,000.  Of concern, 
83,000 patients or ~20% have relapsing disease with an estimated healthcare cost of 
$13,500 – 18,000 per relapse (Lessa, 2015).  Some of these relapses can continue 
to recur whenever treatment is stopped. The main risk factor for CDI relapse after 
resolution of symptoms is further antibiotic exposure (Despande, 2015) as this is 
believed to disrupt the intestinal microbiome favoring regrowth of C difficile.  
Attempts to attenuate the risk of CDI relapse include prolonged use of CDI-active 
therapy, fecal microbiota transplant (FMT) and monoclonal antibodies targeting C. 
difficile toxins.   Retrospective studies by Van wise (2016) and Wong (2015) , 
including nearly 500 patients showed CDI relapse rates in a population of recent CDI 
patients receiving further antibiotics could be reduced from 20-27% to 4-8% with oral 
vancomycin and/or metronidazole.  Another study showed no benefit of oral 
vancomycin prophylaxis after a first episode of CDI (Carignan, 2016).  Fidaxomicin 
may be even better in this regard due to its more selective effect on the microbiome 
leading to fewer relapses after initial treatment (15% relapse with fidaxomicin vs. 
25 % for vancomycin)(Louie,2011; Fidaxomicin Package Insert ). In initial CDI 
therapy where concurrent antibiotics were also used in this trial, Fidaxomicin still 
demonstrated less relapse than oral vanco,17% vs. 26% [Mullane,2011] Finally, 
prophylactic fidaxomicin use prevented C difficile in high risk oncology patients, all of 
whom also received other antibiotics(rate of confirmed  CDI was 4% vs. 10% with  
placebo) (Mullane, 2018). Nonetheless, the recent Infectious Disease Society of 
America statement on CDI (published 3/2018) indicates the following: “There are 
insufficient data at this time to recommend extending the length of anti–C. difficile 
treatment beyond the recommended treatment course or restarting an anti–C. 
difficile agent empirically for patients who require continued antibiotic therapy 
directed against the underlying infection or who require retreatment with antibiotics 
shortly after completion of CDI treatment, respectively (no recommendation)”.  FMT 
has shown promising efficacy in frequent CDI relapsers (Moayyedi, 2017) but is 
cumbersome, there is no FDA-approved regimen, and there are potential long-term 
adverse side effects as the intestinal microbiota has been associated with colon 
cancr, diabetes, obesity, and atopic disorders such as asthma.
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Bezlotoxumab is an FDA-approved monoclonal antibody targeting the pathogenic 
major toxin B of C. difficile, which has been shown in the MODIFY trials to reduce the 
risk of recurrent CDI from 27 to 16% when used concurrently with primary CDI therapy 
(Merck, Zinplava Package Insert, Wilcox,2017). In these pivotal studies, 35-42% of 
subjects (in different treatment groups) had concurrent antibiotics with CDI therapy, and 
~35% continued antibiotics beyond their CDI therapy (Wilcox, appendix, 2017).  The 
efficacy of bezlotoxumab in this high-risk group for relapse has not been specifically 
reported; nonetheless, bezlotoxumab was effective in other high-risk groups including 
older age (>=65), the immunocompromised, and those with more than 1 prior CDI or 
severe CDI.    
While Bezlotoxumab was approved for use during an episode of CDI concurrent with 
standard-of-care CDI-active antibiotics, there is no reason to expect it would not work in 
the high-risk setting proposed here – inpatient subjects with recently treated CDI (within 
the past 90days) receiving subsequent courses of antibiotics for non-CDI indications.   
This cohort of patients at our institution has a 20.8% rate of CDI (Wong, 2015) which is 
increased to 26.7% if age of >=60 is used as a cutoff (unpublished data).  Birch et al 
(2018) showed that within the MODIFY trials, the timing of Bezlotoxumab use relative to 
the start of CDI-active antibiotics ( a 10-14day window) had no bearing on its efficacy; its 
half-life of 19 days means that it provides protection over the course of the 12-week 
observation period after the start of CDI therapy.  This proposal suggests expanding the 
utilization of bezlotoxumab to a 14-90 day (~2-12 weeks) window after initial CDI therapy, 
if and when other antibiotics with a propensity for inducing CDI relapse are utilized. A 
single dose of bezlotoxumab in this setting would not affect the risk for CDI acquisition or 
relapse, but should attenuate the clinical consequences of this occurring by neutralizing 
the pathogenic toxin B, to a similar extent as in the MODIFY trials.   In fact, it may work 
more efficiently as the highest levels of antibody will be available during the highest risk 
period for relapse –concurrently or shortly after use of CDI-inducing antibiotics.
2.3 Study Design
This proposal uses a prospective cohort of CDI patients, 60 years of age and older, 
admitted to 2 sites of 1 Medical Center, and receiving “other” antibiotics, within 14-90 
days of their CDI diagnosis.  
These patients will be identified by a bioinformatics approach, using Clinical Looking 
Glass software developed at our medical center.  All inpatients 60 years old or 
above, with a CDI laboratory diagnosis within 14-90 days of the present date will be 
assessed for use of antibiotics at high-risk for inducing CDI, as well as any 
concurrent C difficile active antibiotics (“prophylaxis”).  
In addition, all new 
admissions to our hospital with a CDI diagnosis within 12 months are flagged for 
infection control purposes, and these patients will also be assessed for qualification 
into the study.  Inclusion criteria are :
1.
CDI within 90 days
2.
Use of high-risk antibiotics for inducing CDI within 72 hrs. of enrolment
3.
No use of CDI active antibiotics within 24 hrs.
4.
Able to sign consent for the study, or have an identified surrogate.
As this is a pragmatic study, reflecting mostly standard medical care, there are few 
exclusion criteria : 
1. Prior CDI episode was felt to be colonization after chart review; 
2. Subject not expected to survive 8 weeks (based on PI impression or chart review, 
considering factors including end-stage cancer, CHF, sepsis with high pressor 
requirement); 
3. Documentation of current diarrhea (3 or more unformed stools per day) at time of 
enrollment, possibly due to CDI. 
4. Receipt of prior fecal microbiota transplant or prior bezlotoxumab.
5. Congestive heart failure, as this diagnosis demonstrated increased mortality in the 
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MODIFY studies with bezlotoxumab vs. placebo (Zinplava Package insert).
Those patients meeting the study inclusion/exclusion criteria will be offered open-
label Bezlotoxumab infusion.  This active intervention arm will have baseline stool 
samples collected for C difficile culture and typing at study entry and upon CDI 
relapse, if any
The comparator groups will be 
1. The historical control group from the Wong study, and 
2. A concurrent observational arm – consisting of those patients otherwise eligible for 
the study, but :
A.
Not consenting to study enrolment, and
B.
Taking no form of CDI prophylaxis (no oral vancomycin, metronidazole or 
fidaxomicin use as defined below).
All cohort members will be subject to standardized chart review for baseline 
parameters at study entry, and structured followup by chart review every 2 
weeks for 8 weeks for CDI relapse (the primary endpoint), tolerability of study 
drug (if administered) , length of hospitalization/ICU stay  or death.   
Use of CDI prophylaxis will be adjudicated to see if it conforms to the standards 
established in the Wong study – prophylaxis used for at least 50% of the duration of 
the concomitant antibiotics course and at least up to 72 hrs before the end of the 
concomitant antibiotics.  Patients receiving any such prophylaxis will be excluded 
from the per-protocol analysis, which will be the primary analysis.   
Secondary 
analysis will also be performed on an intent-to-treat basis, where group assignment 
is determined based on use of prophylaxis at study entry only. 
This design was chosen to parallel that of the retrospective Wong study at our same 
site – to allow comparisons  with  the historical treatment groups in that study.               
2.4 Study Flowchart
.
2.5 Study 
STUDY DESIGN
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Procedures
This prospective cohort study will be conducted using inpatients at the 1044 adult 
medical/surgical-beds on 2 campuses of the Montefiore Medical Center in the Bronx, 
New York.  No work on this study will proceed until it is approved by our local 
Institutional Review Board.
SUBJECT IDENTIFICATION –INCLUSION CRITERIA
All patients with a laboratory diagnosis of CDI initially diagnosed within 3 months of 
screening, who are getting an order placed for inpatient antibiotics will be identified 
by bioinformatics–and will be eligible for study entry.  They will be screened for 
concurrent use of metronidazole, oral vancomycin or fidaxomicin –if present; they will 
be rescreened for inclusion if further antibiotics are given without concurrent 
prophylaxis.   If no prophylaxis is identified, then their providers will be approached to 
consider enrolling the patient into the current active arm for open-label 
Bezlotoxumab.
Inclusion criteria are :
1.
CDI within 90 days
2.
Use of high-risk antibiotics for inducing CDI within 72 hrs of enrolment
3.
No use of CDI active antibiotics within 24 hrs
4.
Able to sign consent for the study, or have an identified surrogate.
EXCLUSION CRITERIA
As this is a pragmatic study, reflecting mostly standard medical care, there are few 
exclusion criteria : 
1. Prior CDI episode was felt to be colonization after chart review(any physician-
identified diarrhea is allowed, but not testing of asymptomatic patients such as test-
of-cure testing or admission screening); 
2. Subject not expected to survive 8 weeks; 
3. Documentation of current diarrhea (3 or more unformed stools per day) at time of 
enrollment, possibly due to CDI. 
4. Receipt of prior fecal microbiota transplant since the last CDI episode, or planned 
at time of screening or prior bezlotoxumab.
5. Congestive heart failure, as this diagnosis demonstrated increased mortality in the 
MODIFY studies with bezlotoxumab vs. placebo (Zinplava Package insert).
CLINICAL DATA COLLECTION
Data on included patients will be collected by medical record review both manually 
and by using Clinical Looking Glass (CLG) software. Clinical data collected consists 
of patient demographics, comorbidities by ICD10 codes, length of hospital stay, 
nursing home residence, all antimicrobial agents received, use of proton pump 
inhibitors or histamine-2 blockers, all prior C. difficile assays, and severity of CDI 
markers on the date of CDI diagnosis – maximum temperature, maximum WBC, 
maximum creatinine, serum albumin –in order to calculate a Zar severity score (Zar, 
2007).  Manual chart reviews will be performed of all antibiotic courses for 8 weeks 
from enrollment and to assess for signs of CDI relapse, including symptoms such as 
abdominal pain or diarrhea as well as physical findings, vital signs, white blood cell, 
microbiologic data including both positive and negative C. difficile assays, and 
radiographic data.  Particular weight will be given to assessment by infectious 
disease specialists, if consultation is performed.
DEFINITIONS
A valid high risk antibiotic course is defined as:
1.
Consisting  of a beta lactam, carbapenem, quinolone, clindamycin, 
macrolide, or polymyxin, AND 
2.
Starting as early as 14days after the index CDI date, avoiding courses that 
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overlap with extended initial CDI treatment regimens, AND.
3.
Encompassing all antibiotics separated by up to 72 hrs linked into the same 
course, AND
4.
Ending with the  first episode of CDI relapse, as all concurrent (started within 
48HR of recurring C. difficile symptoms) and subsequent antibiotic courses 
are excluded from further analysis
 A course with CDI  prophylaxis is defined as:
1.
Having concurrent use of either metronidazole (intravenous or oral) or oral 
vancomycin or fidaxomicin therapy for at least 50-percent of the duration of 
the high risk antibiotic course, AND
2.
Having prophylaxis to within  72 hours of  the last dose of the high-risk 
antibiotic agent; thus an extended high risk antibiotic course may have a  
segment covered by  prophylaxis, but if the last 3 days are no longer 
receiving the potential benefit of prophylaxis, the course is considered to be 
unprophylaxed.
A CDI relapse is defined as:
1.
Attributable to a high risk antibiotic exposure if clinical symptoms and/or 
positive stool assay developed greater than  48-hours after antibiotic 
exposure, AND
2.
Occurring within 8 weeks of completion of the high risk antibiotic course, 
AND
3.
Compatible with clinical evidence suggestive of CDI disease during chart 
review; including a leukocytosis without alternative etiology and responding 
to CDI treatment, new onset of diarrhea, presence of radiographic or if 
relevant autopsy evidence of colitis, and/or repeat positive stool assay with 
appropriate clinical symptoms. If these indicators of CDI were present at the 
time of antibiotic onset, or within 48hrs, this was deemed a recurrence of 
infection NOT attributable to the high risk antibiotic course and was omitted 
from the relapse population.
The beneficial effects of Bezlotoxumab will be considered to last for the entire 8 
week observation period, regardless of the number or timing of antibiotic courses 
within that period.  Analysis of the effects of cumulative exposure to high-risk 
antibiotics or exposure late in this period will be assessed separately.  The effect of 
subsequent CDI-active antibiotics, while excluded within 24 hrs of Bezlotoxumab 
dosing but potentially used within the Bezlotoxumab therapeutic window, will also be 
considered in secondary analyses (intent-to-treat). 
LABORATORY INVESTIGATION
Using a C. difficile toxigenic culture well-established in the laboratory of the PI 
(referenced in Boyanton, 2012), stool will be collected by rectal swab from consented 
subjects in the Bezlotoxumab arm.  If subsequent stool samples are sent to our 
clinical microbiology laboratory for any reason, they are routinely held for 5 days and 
would be available for C difficile toxigenic culture.  Isolated organisms can be 
comparatively typed by the multi-locus variable number tandem repeat methodology 
(Marsh, 2007   ) with great variability in the 3 amplified PCR product sizes. Common 
letters (below) reflect isolates from neighbor pairs (same ward, same week) albeit 
each column is a unique patient. 
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2.6 Study Duration
Estimate of 1 year required to recruit 50 patients (from an estimated 150 eligible) and 
another 6 months to complete the study analysis.  A computer simulation indicates 
there should be 150 eligible subjects in 1 year. Of these, ~50 will be on prophylaxis 
and ~50 will decline participation and will be followed as no prophylaxis controls.
2.7 Statistical 
Analysis and 
Sample Size 
Justification 
The PI and local statistician will be responsible for analyzing the study data.
Variables/Time Points of Interest
The primary outcome variable is relapse of CDI within 8 weeks of study entry. 
Secondary outcomes are relapse of CDI within 4 weeks of study entry (the interval 
with highest protective antibody levels), all-cause mortality, time to relapse and 
duration of hospitalization. 
Baseline variables collected for each subject include :
age, gender, number/dates/treatment of prior CDI episodes,  current PPI use and 
H2-blocker use, Charlson score, immunosuppression, Inflammatory Bowel Disease 
of Irritable Bowel Syndrome, use of cathartics/lactulose, and indication for current 
antibiotics.
Variables related to the past CDI episode include markers of disease severity : WBC, 
fever >100.5oF, creatinine, albumin – to generate a Zar score (Zar,2007)
 
Statistical Methods
The analysis population is the per-protocol population, with 2 major comparator 
groups – those receiving Bezlotoxumab and those with no prophylaxis.  The latter 
will be comprised of 3 subgroups – the control group from the Wong study and 2 
concurrent observation groups- a PASSIVE followup group of subjects undergoing 
chart review , and an ACTIVE followup group of subjects declining study drug but 
agreeing to phone followup at 8 weeks.   All groups will be compared across 
baseline parameters cited above.  Risk factors pre-specified for recurrent CDI 
include age, immunocompromise, and severe CDI will be compared across groups, 
and tested for associations for the major outcomes of CDI relapse and mortality at 4 
weeks and 8 weeks.
In the Wong study, there was a remarkably equal distribution of variables among the 
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antibiotic prophylaxis and no prophylaxis groups.  We similarly expect no imbalance 
between our current study and observation groups in terms of risk factor distribution, 
though self-selection bias will be considered at the interim analysis after 30 
intervention patients are enrolled.  
Categorical variables will be compared using chi-square and Fisher’s Exact analysis 
and continuous variables will be compared using Mann-Whitney analysis, with p 
<0.05 considered to be significant. 
In survival analysis (Kaplan-Meier), time to CDI relapse is defined from the date of 
bezlotoxumab study dosing or study refusal - to the date of relapse and limited by a 
maximum observable window of 8 weeks from the dose of bezlotoxumab. Subjects 
are censored on the date of death, if death occurred within the observable window, 
or at the beginning of a new potential antibiotic prophylaxis course (i.e.. If within the 
8 week observation period there is receipt of metronidazole, oral vancomycin or 
fidaxomicin.) or receipt of fecal microbiota transplant.  A Cox proportional hazards 
model will be used for group comparison when adjusting for covariates.
The survival analysis from the Wong study, demonstrating the benefits of antibiotic 
prophylaxis on preventing relapsed CDI,  is summarized in the following figure:
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For the second objective, rates of CDI relapse will be compared among study 
subjects with or without C. difficile colonization at study entry.   This is an exploratory 
study to inform future studies. It is expected that 20% of subjects will be colonized at 
study entry (based on Sunkesula,2013) –the expected number of these that  relapse 
is unknown, as data is conflicting on whether colonization is protective or predictive 
of relapse. 
Power/Sample Size:
Estimates of group size and expected antibiotic prophylaxis outcomes are derived 
from the Wong and Van Hise studies which have similar or nearly identical design to 
the current proposal, albeit retrospective. In the Wong study, of 248 enrolled 
subjects, 104 received prophylaxis with metronidazole (n=63 total, 19 combined with 
vancomycin) or vancomycin (n=60) , and 144 did not.  In this latter group, 86 were 
>= 60 yrs old of whom 23 relapsed, for a relapse rate of 26.7%.  For the 
bezlotoxumab arm, the expected benefit is between a 43-54% reduction in relapse 
incidence (Gerding, 2018), with the variability based on the number of risk factors for 
CDI relapse in our population – all have at least 1 risk factor : most with age >65 and 
all with concurrent high-risk antibiotics.  The expected CDI relapse rate in the active 
arm is therefore 12.2-15.2%.  Thus 
1.
We need 62 bezlotoxumab subjects (at 12.2% relapse)) to be 80% powered to 
detect a difference in outcomes vs. the no prophylaxis control population (with a 
relapse rate of 26.7%), with a two-tailed alpha=0.05.
2.
We need 103 bezlotoxumab subjects (at 15.2% relapse)) to be 80% powered to 
detect a difference in outcomes vs. the no prophylaxis control population (with a 
relapse rate of 26.7%), with a two-tailed alpha=0.05.
In 1 year, we expect 50 bezlotoxumab subjects and 50 no-prophylaxis controls in the 
prospective cohort.  The numbers of subjects in the no-prophylaxis observational 
arms can be supplemented by retrospective chart reviews incorporating the same 
analysis used in the prospective study, or by merging with the control arm of the 
Wong study.
Given the prospective design, with more data available regarding relapse than in the 
Wong study (wherein outpatient records were not yet electronic) and the fact that 
relapse rates in the control group in the MODIFY studies were 39% in those over 65, 
its possible that more relapses will occur in the no-prophylaxis group than the 26.7% 
expected.  This would lower the numbers needed to show a significant benefit.  An 
interim analysis is planned after 6 months or 30 subjects enrolled, to re-assess 
realistic timelines for achieving significant results from this project.  Notably, this is a 
pilot study which if it meets targets, could potentially be extended by 3 to 6 months to 
achieve statistically significant power.  
Alternatively, if study effects exceed 
expectations, a placebo-controlled design could be considered moving forward- for 
the pilot study, this is precluded by the larger sample size anticipated for such a  
project.
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2.8 Specific Drug 
Supply 
Requirements 
The Bezlotoxumab drug supplies will be open label and provided by MSD.  
The institution’s research pharmacy will require bulk supplies from MSD (one large 
container of 10 courses at 1 time). As bulk supplies are provided by MSD, our 
institution’s pharmacy will be responsible for preparing individual patient doses. A 
description as to how the clinical supplies are to be packaged and labeled for each 
patient will be added to the protocol.
Note: At conclusion of the study or upon drug expiration, the MSD GRS will be 
responsible for issuing a Drug Disposition Letter to the investigator for US based 
studies.  
The investigator will be responsible for the destruction of the supplies at the study 
center pursuant to the ICH/GCP Guidelines, local regulations and the investigator’s 
institutional policies. Clinical supplies will be received by a designated person 
(research pharmacist) at the study site, handled and stored safely and properly, and 
kept in a secured location to which only the investigator and designated assistants 
have access. Clinical supplies are dispensed in accordance with the protocol. The 
investigator is responsible for keeping accurate records of the clinical supplies, the 
amount dispensed to and returned by the patients, and the disposition at the end of 
the study.
2.9 Adverse 
Experience 
Reporting
The study agreement will outline the requirement for adverse experience reporting.  
The Model Study Agreement will be used.  Tolerability of study drug will be assessed 
with longitudinal assessments/chart reviews.  Any adverse events during infusion will 
be recorded and any deaths or serious events leading to prolonged hospitalization or 
readmission (potentially ascribed to the study drug) in the subsequent 30 days will 
be reported to our local IRB and the FDA MedWatch.
All active study subjects will be queried at 1 day, 4 weeks and 8 weeks after 
enrollment  for any change in their health status reflecting potential safety concerns 
related to receipt of study drug.  Though not a primary focus of this research, any 
Serious Adverse Events will be tabulated and reported to the IRB, and Suspected 
Unexpected SAE’s (SUSAR) will be reported to the FDA.
A Safety Officer will be designated (an ID physician who is not  part of the study 
team) to review all SAE’s after 12 and 25 (of 50 planned) subjects have been 
enrolled, and together with a statistician, determine if there are serious safety 
concerns related to the study drug requiring modification or termination of the study 
protocol.
2.10 Itemized Study 
Budget 
A preliminary study budget is provided with the initial proposal submitted to give 
guidance to the MISP Review Committee as to the expected study costs.   A refined 
itemized budget detailing the costs associated with the study will be provided with 
the final protocol or included in the study agreement as Exhibit B.  
2.11 References
Birch T, Golan Y, Rizzardini G, Jensen E, Gabryelski L, Guris D, Dorr MB; (2018) Efficacy of 
bezlotoxumab based on timing of administration relative to start of antibacterial therapy for 
Clostridium difficile infection. J Antimicrob Chemother. 2018 Sep 1;73(9):2524-2528.
Boyanton, Jr,. B L, P Sural, CR. Loomis, C Pesta, L Gonzalez-Krellwitz, B Robinson-Dunn 
and PF Riska. (2012) ,Loop-Mediated Isothermal Amplification Compared to Real-time PCR 
and Enzyme Immunoassay for Toxigenic C. difficile Detection.  Journal of Clinical 
Microbiology, 50(3):640-45
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Carignan A, Poulin S, Martin P, Labbé AC, Valiquette L, Al-Bachari H, Montpetit LP, Pépin 
J.(2016)Efficacy of Secondary Prophylaxis With Vancomycin for Preventing Recurrent 
Clostridium difficile Infections. Am J Gastroenterol. 2016 Dec;111(12):1834-1840.
Deshpande A, Pasupuleti V, Thota P, Pant C, Rolston DD, Hernandez AV, Donskey CJ, 
Fraser TG. (2015) Risk factors for recurrent Clostridium difficile infection: a systematic review 
and meta-analysis.Infect Control Hosp Epidemiol. 2015 Apr;36(4):452-60. 
Gerding DN, Kelly CP, Rahav G, Lee C, Dubberke ER, Kumar PN, Yacyshyn B, Kao D, Eves 
K, Ellison MC, Hanson ME, Guris D, Dorr MB (2018) Bezlotoxumab for Prevention of 
Recurrent Clostridium difficile Infection in Patients at Increased Risk for Recurrence. Clin 
Infect Dis. 2018 Aug 16;67(5):649-656.
Lessa FC, Mu Y, Bamberg WM, Beldavs ZG, Dumyati GK, Dunn JR, Farley MM, Holzbauer 
SM, Meek JI, Phipps EC, Wilson LE, Winston LG, Cohen JA, Limbago BM, 
Fridkin SK, Gerding DN, McDonald LC. (2015) Burden of Clostridium difficile infection in the 
United States.N Engl J Med. 2015 Feb 26;372(9):825-34  
Marsh JW, O'Leary MM, Shutt KA, Sambol SP, Johnson S, Gerding DN, Harrison LH.(2010)
Multilocus variable-number tandem-repeat analysis and multilocus sequence typing reveal 
genetic relationships among Clostridium difficile isolates genotyped by restriction 
endonuclease analysis. J Clin Microbiol. 2010 Feb;48(2):412-8.
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Garey KW, Gould CV, Kelly C, Loo V, Shaklee Sammons J, Sandora TJ, Wilcox MH. (2018) 
Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 
Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare 
Epidemiology of America (SHEA).Clin Infect Dis. (2018 Mar 19);66(7):987-994
Merck Sharp & Dohme Corp. Zinplava (Bezlotoxumab) Prescribing
Information. 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/
2016/761046s000lbl.pdf.
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Clostridium difficile-associated diarrhoea: a systematic review of randomised controlled 
trials.Med J Aust. 2017 Aug 21;207(4):166-172. 
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JA, Pergam SA, Alexander BD, Dubberke ER, Broyde N, Gorbach SL, Sears PS. (2018) A 
Randomized, Placebo-Controlled Trial of Fidaxomicin for Prophylaxis of 
Clostridium difficile Associated Diarrhea in Adults undergoing Hematopoietic Stem Cell 
Transplantation.Clin Infect Dis. 2018 Jun 9. doi: 10.1093/cid/ciy484
Mullane KM, Miller MA, Weiss K, Lentnek A, Golan Y, Sears PS, Shue YK, Louie TJ, Gorbach 
SL. (2011) Efficacy of fidaxomicin versus vancomycin as therapy for Clostridium difficile 
infection in individuals taking concomitant antibiotics for other concurrent infections Clin Infect 
Dis. (2011 Sep);53(5):440-7. .
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Empirical Clostridium difficile Infection(CDI) Therapy Result in False-Negative CDI Diagnostic 
Test Results? Clinical Infectious Diseases 2013;57(4):494–500
                                                                                                                                                         
Van Hise,NW,  Alex M. Bryant, Erin K. Hennessey, Andrew J. Crannage,  Jad A. Khoury, 
and Farrin A. Manian (2016). Efficacy of Oral Vancomycin in  Preventing Recurrent 
Clostridium difficile Infection in Patients Treated With Systemic Antimicrobial Agents Clinical 
Infectious Diseases (2016) ;63(5):651–3  
Wilcox MH, Gerding DN, Poxton IR, Kelly C, Nathan R, Birch T, Cornely OA, Rahav G, Bouza 
E, Lee C, Jenkin G, Jensen W, Kim YS, Yoshida J, Gabryelski L, Pedley A, Eves K, Tipping R, 
IRB NUMBER: 2019-10212
IRB APPROVAL DATE: 06/23/2020
IRB NUMBER: 2019-10212
IRB APPROVAL DATE: 06/23/2020


      MISP Template: Protocol
12
Final Version: 8/13/2010
Guris D, Kartsonis N, Dorr MB; MODIFY I and MODIFY II Investigators. (2017) N Engl J Med. 
(2017 Jan 26); 376(4):305-317 Bezlotoxumab for Prevention of Recurrent 
Clostridium difficile Infection.
Wong,D &  PF Riska ( 2015) “Secondary Prophylaxis in High Risk Patients Reduces the Risk 
of Clostridium difficile Recurrence” , , oral presentation at Interscience Conference on 
Antimicrobial Agents And Chemotherapy, Sept 20,2015 San Diego, CA
Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. (2007) A comparison of vancomycin and 
metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by 
disease severity.Clin Infect Dis. 2007 Aug 1;45(3):302-7.
2.12 Publication 
Plan
One major manuscript is expected from this work within 2 years of study startup –
probably to a journal like Clinical Infectious Disease..  The clinical microbiology data 
maybe part of a separate manuscript. 
Preliminary data may be presented in abstract form at ID Week 2019.

2.13 Curriculum 
Vitae
Attached.
2.13 Protocol 
Submission for 
Investigator-
Initiated Studies 
U.S. protocols should be submitted by US investigators directly or through the Global 
Research Specialist at  www.merckiisp.com  
Non U.S. protocols should be submitted to the MSD office by the investigators.
IRB NUMBER: 2019-10212
IRB APPROVAL DATE: 06/23/2020
IRB NUMBER: 2019-10212
IRB APPROVAL DATE: 06/23/2020