Clinical trial NCT02996487
Conditions: Clostridium Difficile Infection
Sponsor: William Beaumont Hospitals
Start date: 2016-12-19; Completion date: 2023-06-28
Enrollment: 1294 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this study is to evaluate whether using vancomycin orally can prevent CDI in patients who are colonized with C. difficile who are admitted to the hospital and need antibiotics for another infection.

Detailed description:
Screening to Prophylax against CDI (SToP CDI) is a prospective, single-center, double-blinded, randomized, placebo-controlled study of the effectiveness of vancomycin vs. placebo for preventing CDI in patients colonized with toxigenic C. difficile and receiving high-risk antibiotics. The investigators plan to screen 2500 patients to randomize 200.

Consented patients will have a stool sample collected and tested for presence of toxigenic C. difficile by polymerase chain reaction (PCR) test. Patients who test negative will simply be followed for development, severity and outcome of CDI. Patients who test positive (are colonized with C. difficile) will be randomized to one of two arms:

Arm 1: Patients receive 125 mg vancomycin by mouth (PO) every 6 hours as prophylaxis against C. difficile for the duration of their antibiotic treatment +3 days.

Arm 2: Patients receive placebo by mouth (PO) every 6 hours for the duration of their antibiotic treatment +3 days.

Arms: arm 1: Placebo every 6 hours. A placebo will look like the drug being studied, but have no active ingredients, in this case it will be fruit punch with vitamins added to mimic the taste of vancomycin. arm 2: Vancomycin 125 mg by mouth every 6 hours
Interventions: intervention 1: Vancomycin intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_001.pdf: 
1
Version Date 12/17/2019
Research Strategy
1. Significance
1.1 Clostridium difficile-Infection: A Major Health Epidemic
Clostridium difficile-infection (CDI) includes a wide range of illnesses, from uncomplicated diarrhea to 
toxic megacolon and multi-organ dysfunction syndrome necessitating colectomy (1). It is the most common 
cause of infectious nosocomial diarrhea in developed countries, and is now the single most common pathogen 
found among Healthcare-Associated Infections (HAI), accounting for 12% of all HAIs (2). In 2013, the Centers 
for Disease Control and Prevention (CDC) declared CDI one of only three urgent threats which they define as 
immediate public health threats that require urgent and aggressive action (3). The mortality rate from the 
severe forms of CDI is high and rising. The CDC estimated there were 250,000 hospitalizations and 14,000 
deaths related to CDI in the United States in 2007 (12). A more recent CDC study raised the estimates to 
453,000 hospitalizations and 29,000 deaths annually based on 2011 data (4). These two studies are in line 
with data from the Healthcare Cost and Utilization Project, which found that there were 336,600 
hospitalizations and 30,600 deaths annually associated with CDI based on 2009 data (13). Despite these 
already staggeringly high statistics, the incidence and mortality rates from CDI continue to rise (5). The elderly 
are disproportionately affected by CDI. Hospital patients ≥65 have 5-fold higher rates of CDI than patients 45-
64 and 20-fold higher than patients 18-45 years of age (6).
CDI is caused by C. difficile, a spore-forming, anaerobic, gram-positive bacillus that can be found as a 
colonizer in the colon of otherwise healthy adults. Some strains of C. difficile produce toxins (A and B), which 
are directly responsible for the pathogenicity of the organism; strains that do not produce toxins do not cause 
CDI (14, 15). CDI results from proliferation of toxigenic C. difficile that is no longer held in balance by the 
beneficial normal flora of the gut. Antimicrobial therapy that disrupts the normal intestinal flora is the single 
largest risk factor for CDI. Spread of C. difficile occurs via the fecal-oral route, where the organism enters the 
gastrointestinal tract by ingestion of spores from contaminated surfaces (16). Transmission occurs primarily via 
contact with skin contaminated by spores or from a contaminated environment (17, 18). The rising incidence of 
CDI has been attributed to the frequent use of broad-spectrum antibiotics, such as ampicillin, amoxicillin, 
clindamycin, fluoroquinolones, and cephalosporins (7, 8). The current roadblock in the field of CDI is that 
there is no established intervention to significantly reduce the incidence and mortality rates for this disease at 
the level of the individual patients who receive antibiotics. The goal of this study is to prove that 
prophylaxis of high-risk patients is an effective means of preventing CDI.
1.2 Emergence of Hypervirulent C. difficile: Implications on Increased Disease Severity
The hypervirulent, epidemic strain of C. difficile, NAP1/BI/027, is responsible for increased nosocomial 
outbreaks and concomitant morbidity and mortality worldwide (19-21). The NAP1/BI/027 strain is more 
resistant to fluoroquinolones than prior strains (22), and multiple reports cite that this epidemic strain is more 
difficult to treat and eradicate. Furthermore, this strain specifically has a lower susceptibility to metronidazole, 
which had previously been a cornerstone of treatment for C. difficile. The NAP1/BI/027 strain has variations in 
its toxin genes and produces increased levels of toxins A and B, as well as an extra toxin, known as the binary 
toxin, which accounts for its increased pathogenicity (19). This strain of the organism is a cause of worldwide 
outbreaks of CDI, and has been associated with significant increases in incidence, severity, and mortality (6, 
19, 23). When examined at our institution, 60% of CDI was due to the hypervirulent strain of C. difficile, and 
was associated with higher rates of treatment failure and mortality (24).  
1.3 Economic Impact of CDI
The economic burden associated with C. difficile infections is increasing. Current estimates of annual 
costs attributed to CDI vary, but are all higher than one billion dollars per year (12). Each episode of CDI 
increases both direct healthcare cost and length of stay for patients affected (25). With the emergence of the 
hypervirulent epidemic strain, and the associated increase in incidence and severity of CDI, along with more 
refractory and recurrent infections, estimates are that direct healthcare costs related to CDI may double over 
the next several decades. Several published studies have reported estimated annual overall costs of CDI in the 
United States and Europe that range as high as $4.8 billion based purely on hospital admissions (12, 26-29). In 
all of the studies, the investigators stated that their estimates were conservative and likely underestimated the 
total expense of treating CDI. The economic burden of CDI is even more significant as these studies only 
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consider direct healthcare costs and no study to date has attempted to ascertain the economic burden to the 
infected individual in terms of personal expenditures, missed workdays, poor quality of life, and decreased 
economic productivity (30). Establishing a standard-of-care model that reduces the incidence and mortality of 
CDI would have a major global impact on reducing annual costs related to CDI.
1.4 Laboratory Testing for CDI
Stool culture with cytotoxin neutralization assay is considered the most accurate test for the presence 
of toxigenic C. difficile; however, the test is extremely time-consuming and few laboratories perform these tests 
routinely (16, 22, 31). Enzyme immunoassay (EIA) can be used to detect the presence of toxin A and toxin B. 
This test is inexpensive, easy to run, and rapid, but lacks sensitivity (16, 22, 31). There is evidence that a 
positive EIA is more predictive of significant CDI (32). Commercial polymerase chain reaction (PCR) assays 
directly detect the presence of the toxin B gene (tcdB) in stool. Toxin B has been found in nearly all cases of 
CDI, and the molecular assay for the tcdB is highly sensitive for detection of strains of C. difficile associated 
with CDI (33). In several studies, sensitivities for PCR-based C. difficile assays were in the range of 83.6%-
96.4% compared to 66%-67.2% for the EIA for toxins A and B (33-36). PCR-based assays represent a 
significant improvement in laboratory testing for C. difficile, but the inherent sensitivity of the test makes 
diagnosis of CDI more difficult, since it will easily detect colonization and could lead to over diagnosis of CDI 
(32). C. difficile colonization can be easily detected using PCR testing in formed stools or using swabs (37, 38). 
At our institution detection rates doubled when our standard testing modality changed from EIA to PCR.
1.5 Asymptomatic Colonization: Role in CDI
1.5.1 Overall Rate of Asymptomatic Colonization
Numerous studies have looked at the rate of asymptomatic colonization with C. difficile. The estimates 
in hospitalized patients vary from 4%-21% (11, 39-51), and not all studies separate colonization with toxin-
producing strains from non-toxigenic strains, or assay patients early in their admission to the hospital. Studies 
of patients in long-term care or rehabilitation facilities show even higher levels of colonization from 17%-51% 
(52, 53). In healthy patients outside the healthcare environment, studies show overall colonization rates from 
6.6%-11%, with toxigenic colonization rates from 4.3%-8.4% (54-57). The newer studies show higher rates of 
colonization in hospitalized patients, which is easily explained by changes to more sensitive detection methods 
and the epidemiology of C. difficile. The most recent estimates of colonization with toxigenic C. difficile at the 
time of admission to the hospital range from 8%-15% (11, 39, 42, 43, 49).
1.5.2 Is There a Protective Effect of Asymptomatic Colonization with C. difficile?  
There has been debate in the clinical community of the role colonization with C. difficile plays in the risk 
of developing CDI. A meta-analysis by Shim et al. (58) performed in 1998 stated that non-colonized patients 
were four times more likely to develop CDI than colonized patients, but could not explain the mechanism 
behind the apparent protection. Kyne et al. (48) performed a study in 2000 to prospectively examine the 
immune response to colonization. This study found that newly acquired colonization with C. difficile did not 
progress to CDI if the patients had high levels of pre-existing IgG against toxin A, which they went on to 
suggest was the mechanism behind Shin’s findings. This paper has historically been cited in the CDI field as 
demonstrating that colonization with C. difficile is protective against developing CDI. However, due to the 
prospective design of Kyne’s study, patients who were already colonized on admission to the hospital were 
dropped from analysis. The paper did not truly conclude that colonization was protective; instead, the authors 
stated that patients with IgG against toxin A were protected from progressing from newly established 
colonization to infection. The protective effect of antibodies against C. difficile toxin has been demonstrated in 
several clinical trials using monoclonal antibodies against C. difficile toxins to prevent recurrence of CDI (59-
61). Kyne’s paper did not provide commentary on whether pre-existing colonization influenced development of 
CDI. Shin’s meta-analysis has recently been challenged by Zacharioudakis et al. (11) as it did not separate 
whether the protection was based on colonization with toxigenic or non-toxigenic C. difficile, and two of the four 
studies used in the meta-analysis did not assay for colonization at the time of admission to the hospital. Shin’s 
study was performed prior to the emergence of the hypervirulent strain and thus may not be reflective of 
current issues. 
More recently, it has been made clear in both an animal model (62-64) and a clinical trial (65) that it is 
colonization with non-toxigenic C. difficile that is protective against CDI. The proposed mechanism is 
that the non-toxigenic C. difficile inhabits the same ecological niche in the colon and prevents establishment of 
the toxigenic strains by outcompeting them.
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1.5.3 Asymptomatic Toxigenic C. difficile Colonization is Associated with CDI Development
Recent studies have looked specifically at colonization with toxigenic C. difficile as a risk for CDI. In a 
systematic review and meta-analysis, Zacharioudakis and colleagues identified that 8% of patients at the time 
of hospital admission (10% in North America) were carriers of toxigenic C. difficile and were six times more 
likely to develop CDI (21.8%) than non-carriers, indicating the predominant role toxigenic colonization plays in 
development of CDI (11). It is thought that colonization becomes a problem to the carrier after they are treated 
with antibiotics when the asymptomatic state can blossom into CDI (22). Riggs et al. found that 20% of patients 
in long-term care facilities who were colonized with toxigenic C. difficile developed CDI during follow up (53) 
and Merciniak et al. found 44% of patients in rehabilitation units colonized with toxigenic C. difficile developed 
CDI during follow up (52). Neither of these studies were limited to patients who received antibiotics. Hung and 
colleagues prospectively demonstrated that patients with toxigenic C. difficile colonization had a four times 
higher increased risk for developing CDI than patients admitted who were not colonized (66), while Gupta et al. 
conducted a large multicenter prospective trial of the epidemiology of hospital-acquired C. difficile colonization 
and CDI, and found that patients with asymptomatic toxigenic C. difficile colonization were 11.7 times more 
likely to develop CDI (9) and 45% of hospital onset cases of CDI were in colonized patients. Tschudin et al. 
found pre-existing colonization with toxigenic C. difficile conferred a 10.29 relative risk for developing CDI (10).
Epidemiologic investigations using molecular techniques have demonstrated that many new hospital-
onset cases of CDI are not attributable to transmission from known cases of CDI in the hospital (42, 67-71). 
Prior prevailing thought was that CDI was preceded immediately by acquisition of C. difficile from other 
hospitalized patients when the patient’s colon was rendered susceptible to infection with C. difficile due to 
antibiotics altering the protective flora. This data illustrates the likelihood that prior colonization with toxigenic 
C. difficile is a major risk factor for CDI. In addition, in studies using molecular typing, relapse of infection with 
the same strain of C. difficile has been shown to occur out as far as 26 weeks, long past what is generally 
considered the limit for relapse of CDI (8 weeks), also suggesting that persistent colonization with toxigenic C. 
difficile leads to increased risk of CDI (72, 73). The mean age of toxigenic colonization is ~58 (10, 39), 
disproportionately affecting older patients. Multiple factors associated with aging have been shown to increase 
this risk (74).
1.6 The Downfalls of Current Practices for Prevention of CDI
1.6.1 Infection Control
The conventional assumption is that patients with CDI and perhaps asymptomatic carriers are the 
major reservoirs for C. difficile and spread the infection within the hospital. Careful adherence to infection 
control policies is the status quo for the control of C. difficile at hospitals, nursing facilities, and long-term care 
and rehabilitation facilities (16, 75, 76). Standard practice in infection control places patients who have CDI in 
isolation or cohorts them with other CDI patients. Use of personal protective equipment and hand washing is 
required of all those who enter the room (16, 75). While infection control procedures have proven helpful, there 
is limited ability to assure compliance with isolation and hand hygiene procedures. 
Ultimately, infection control procedures do not solve the problem of CDI. Eyre et al. found that 
while rare, spread from an asymptomatic carrier may be a risk factor for development of CDI due to the sheer 
number of cases of asymptomatic carriers (77). Walker et al. showed that in a setting with strict infection 
control measures, contact with patients found positive for C. difficile was not related to new cases of CDI. The 
authors found that 75% of new cases were not linked to a patient source. This indicates that 75% of the cases 
of CDI could not be stopped by isolating patients with active diarrhea due to C. difficile (70). In a separate 
study, Eyre et al. demonstrated that most cases of CDI presenting in the hospital are either genetically distinct 
from other known cases in the hospital or share no known epidemiologic contacts (68). Therefore, it is 
imperative that novel avenues are developed beyond basic infection control practices to combat the rising 
incidence of CDI.
1.6.2 Antibiotic Stewardship
Antibiotic stewardship in regard to C. difficile seeks to limit inappropriate use of antibiotics, such as 
those known to be more likely to disrupt colonic flora and induce CDI (75, 76). While this approach also has 
some success in decreasing rates of CDI, it is not possible to eliminate the use of high-risk antibiotics, as they 
are an important part of the antimicrobial armamentarium. Stewardship efforts, while important, cannot 
reduce the risk of CDI in the face of decreasing effective therapies for other infections. 
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1.7 The Need for New Approaches for Prevention of CDI
The emergence of the hypervirulent strain of C. difficile exacerbated an already significant problem to 
the point where it is now one of the three top infectious threats facing healthcare today. The cost in terms of 
both dollars and human lives is staggering. Current prevention strategies, while they help, are not enough to 
deter the ever-increasing problem of CDI. Colonization with toxigenic C. difficile has been shown to increase 
the risk of CDI in hospitalized patients at least six-fold, and the use of high-risk antibiotics is the single largest 
risk factor for CDI. Current molecular assays are sensitive enough to detect toxigenic C. difficile in 
asymptomatic patients with formed stools, and being able to detect those patients admitted to the hospital with 
significantly higher risk for CDI is the first step in being able to intervene and prevent it.
2. Innovation
2.1 A Novel Approach to Prevention of CDI in At-Risk Patients
The proposed study addresses AHRQ’s Key Question #2 for C. difficile, “What are effective prevention 
strategies?” and has the potential to cause transformative change in the methodology of preventing CDI, 
and to alter the standard of care when using high-risk antibiotics in the hospital setting. 
Multiple studies using sensitive molecular techniques have now shown that colonization with toxigenic 
C. difficile is a risk factor for developing CDI (9, 18, 22, 53, 66). Therefore, it is critical that innovative methods 
are established to provide efficient and long-term mechanisms to screen carriers of C. difficile to halt 
progression of CDI. We hypothesize that by determining which patients are colonized with toxigenic C. 
difficile, and therefore are at higher risk for developing CDI when treated with high-risk antibiotics, we can 
initiate an intervention to reduce that risk. The most effective, and affordable, intervention, we believe, is 
prophylactic treatment with vancomycin, which is efficacious against C. difficile (1). Our goal for this study is to 
implement a large-scale first-of-its-kind clinical trial to test our hypothesis by: 1) screening high-risk inpatients 
for the presence of toxigenic C. difficile; and 2) providing prophylactic treatment to prevent CDI by using 
vancomycin during the at-risk period when patients are treated with high-risk antibiotics known to induce CDI. 
In our opinion, the proposed research is innovative because it presents a significant departure from the 
current standard of care model for prevention of CDI, which is based on infection control and antibiotic 
stewardship. In this innovative model, highly sensitive PCR-based assays will be used to screen patient stool 
samples followed by strategic prophylactic treatment with vancomycin that will reduce C. difficile levels during 
the critical window when antibiotics have depressed the normal flora of the colon and the patient is at risk for 
onset of CDI. The inherent sensitivity of the PCR-based test makes it ideal for screening the asymptomatic 
population for presence of toxigenic C. difficile (33) even in formed stools (37, 38).
2.2 Primary Prophylaxis: The New Frontier in CDI Control
No studies to date have considered primary prophylaxis in the appropriate subgroup of patients to 
prevent CDI, despite the fact that prophylaxis is a universally accepted method of preventing the occurrence of 
infection in diverse populations of patients (78-81). The largest barrier to such studies is identifying the 
subgroup of patients who would benefit from prophylaxis. Many clinicians have taken to using secondary 
prophylaxis with either vancomycin or metronidazole in patients with a prior history of CDI to prevent 
recurrence. Several retrospective studies support this practice. Van Hise et al. reported a reduction in CDI 
recurrence from 35% to 1% using vancomycin prophylaxis (82). Wong and Riska presented similar findings 
with a reduction in recurrence rates from 20% to 7%, but included metronidazole as a prophylaxis agent (83). 
In a recent retrospective review of CDI cases, Drekonja et al. observed that patients who required other 
antibiotics during treatment for CDI had no increased risk for recurrence whereas patients who required other 
antibiotics after completing treatment for CDI had a significant increase in CDI recurrence (84). This indicates 
the potential role prophylactic treatment can play in reducing CDI cases if patients are treated in the optimal 
window. Rodriguez et al. performed a retrospective analysis of 12,000 patients at high risk for CDI they found 
patients who received incidental metronidazole for an indication other than CDI had an odds ratio of 0.21 for 
developing CDI compared to patients who did not receive metronidazole (85). Dupont, in an editorial of 
Rodriguez’s study, described the concept of chemoprophylaxis against CDI as a potentially important concept, 
but raised concerns with use of metronidazole given its systemic absorption and potential side effects as well 
as its low efficacy against the hypervirulent strain (86). Dupont also discussed several other antibiotics with 
potential for use as prophylaxis against CDI, but most are highly expensive and would be difficult to justify. Oral 
vancomycin, however, is the most commonly used agent for treatment of CDI, and when compounded, as is 
common practice at most hospitals, would be affordable as prophylaxis. The concern was raised about use of 
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vancomycin for prophylaxis against CDI leading to an increase in colonization with vancomycin-resistant 
Enterococcus (VRE), which would need to be monitored. Another concern is the possibility that overuse of 
vancomycin will lead to resistance in C. difficile; however, despite high levels of use for the treatment of CDI, 
resistance to vancomycin remains essentially unseen (87-89). Dubberke’s recent study on C. difficile 
colonization (43) also raised the point that several studies suggested that antimicrobial prophylaxis might 
prevent C. difficile colonization or CDI, but rightly suggested caution in using this as an approach to CDI 
prevention. Clinical trials would certainly be needed to prove that antimicrobial prophylaxis to prevent CDI is 
both effective and safe, which is the goal of this study. 
Johnson et al. demonstrated that oral vancomycin was able to suppress C. difficile in asymptomatic C. 
difficile carriers in a randomized placebo controlled trial (34). Their study, though small, showed that 9 of 10 
patients receiving vancomycin became culture-negative during and immediately after treatment, compared to 3 
of 10 receiving metronidazole and 2 of 10 receiving a placebo. However, this decolonization was transient, and 
most patients became re-colonized within weeks. Thus, vancomycin appears to be able to suppress C. difficile 
in colonized patients, at least temporarily. The goal of prophylaxis is not to eradicate the colonization but 
to suppress it at the critical time when the risk for CDI is greatest. This makes vancomycin attractive as 
an option for primary prophylaxis against CDI. 
It has been estimated that even a 5% decrease in the incidence of CDI could lead to a net cost savings 
in direct healthcare expenditures of $150 million a year (12, 28, 30). This savings would need to be balanced 
against the increased cost of screening and prophylaxis. The key is that while universal prophylaxis would be 
prohibitively expensive, prophylaxis based on screening for risk would likely bring about a significant decrease 
in healthcare expenditures as well as morbidity and mortality from CDI.
2.3 Clinical Trial to Prove Best Clinical Practice: Screening to Prophylax against CDI (SToP CDI) 
There is an urgent need to develop a clinical protocol that will effectively reduce CDI incidence and 
mortality rates in patients at high risk for CDI. To date, no prospective studies have evaluated or identified 
preventative methods to limit the onset of CDI. Probiotics have been suggested many times, but data in the 
literature is contradictory and various preparations are highly variable in both content and viability (90, 91).The 
objective of this proposed clinical study is to determine whether screening for toxigenic C. difficile colonization 
among admitted patients receiving high-risk antibiotics predicts whether these patients will develop CDI when 
compared to non-colonized patients (Specific Aim 1), and if treating those patients prophylactically with 
vancomycin will decrease CDI incidence, associated symptoms, and mortality rates (Specific Aim 2). Our 
expected outcome is that prophylaxis with vancomycin will significantly reduce the rate of CDI in patients who 
are carriers of toxigenic C. difficile and are exposed to high-risk antibiotics. 
We believe this contribution will be significant because it has the potential to reverse the increasing 
trend associated with CDI incidence and mortality rates, decrease the economic burden associated with the 
disease, and improve patient quality of life. If our hypothesis is confirmed, screening for and prophylaxis of 
carriers of toxigenic C. difficile with vancomycin will be cost effective and can be easily implemented as routine 
care with minimal discomfort and adverse impact to patients. This method has the potential to revolutionize the 
current standard of care.
3. Approach
Specific Aims
Aim 1: Determine the prevalence of toxigenic C. difficile colonization among the inpatient population 
and the incidence of CDI in patients treated with high-risk antibiotics with respect to their state of 
colonization with toxigenic C. difficile.
1.1 Assay inpatients initiated on high-risk antibiotics for the presence of toxigenic C. difficile in their stool.
1.2 Determine the incidence of CDI in toxigenic C. difficile-positive patients treated with high-risk antibiotics.
1.3 Determine the incidence of CDI in toxigenic C. difficile-negative patients treated with high-risk antibiotics.
Aim 2: Determine the effect of vancomycin prophylaxis on patients receiving high-risk antibiotics who 
are colonized with toxigenic C. difficile based on molecular testing.
2.1 Determine the incidence of CDI in this subgroup of patients.
2.2 Determine the severity and outcome of CDI in this subgroup of patients.
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3.1 Research Design 
3.1.1 Clinical Study Overview
Beaumont Health is an eight-hospital regional health care system with a total of 3,337 beds, 35,000 
employees and 5,000 physicians in Southeast Michigan. Beaumont Hospital – Royal Oak is a 1,070-bed, major 
academic, research, and referral center with Level I trauma designation. In 2014 there were 58,539 admissions 
and 48,387 surgeries, among the highest in the United States. In 2015, 13,812 C. difficile PCR tests were run 
at our institution. Our infectious diseases clinical trials unit runs numerous clinical trials at the Beaumont – 
Royal Oak. We have the necessary population and tools in place to make this study a success.
Screening to Prophylax against CDI 
(SToP CDI) will be a prospective, multi-center, 
double-blinded, 
randomized, 
placebo-
controlled study of the effectiveness of 
vancomycin vs. placebo for preventing CDI in 
patients colonized with toxigenic C. difficile 
and receiving high-risk antibiotics (Figure 1). 
We plan to enroll 2500 inpatients from 
Beaumont for the initial screening. Based on 
Zacharioudakis et al. (11) we expect 8% of the 
screened patients to be positive for C. difficile 
colonization. Colonized participants will be 
randomized to one of two arms with 100 
subjects per arm. We plan to evaluate all 
subjects 
for 
development, 
severity, 
and 
outcome of CDI. Patients who are initiated on 
high-risk antibiotics for a minimum expected 
duration of three days will be identified via an 
automated search of the Electronic Medical 
Record (EMR), which has already been built 
and is currently used to identify potential 
patients for clinical trials. After initial screening 
for inclusion and exclusion criteria, the 
patients will be approached to participate in 
the study. Written informed consent will be 
obtained 
from 
all 
study 
participants. 
Consented patients will have a stool sample 
collected and tested for presence of toxigenic 
C. difficile by PCR using the BD Max assay 
(Becton Dickinson), which is used for routine testing for C. difficile at our institution. Patients who test negative 
(are not colonized with toxigenic C. difficile) will simply be followed for development, severity and outcome of 
CDI. Patients who test positive (are colonized with C. difficile) will be randomized to one of two arms:
Arm 1: Patients receive 125 mg vancomycin PO q6 hours as prophylaxis against C. difficile for the duration of 
their antibiotic treatment +3 days. 
Arm 2: Patients receive placebo PO q6 hours for the duration of their antibiotic treatment +3 days (serves as 
the control group). 
3.1.2 Preliminary Data
Beaumont possesses the patient volume as well as the necessary clinical and research expertise to 
carry out the SToP CDI study. Our research group has a successful history of high recruitment and specifically 
high recruitment into C. difficile trials. Recruitment feasibility of patients who develop CDI after admission to our 
institution was determined from the previous three years of epidemiologic data for hospital-onset cases of CDI 
within our institution (Table 1). The National Healthcare Safety Network defines a case of hospital-onset CDI 
as any positive laboratory test for C. difficile which occurs >72 hours after admission. This will reflect a certain 
amount of colonization; as such, our Department of Epidemiology reviews all cases of laboratory-identified 
hospital-onset CDI via the 
EMR to attempt to limit 
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this to clinical cases. They define a case as any non-relapsed episode of CDI occurring >72 hours after 
admission and during the admission or within 30 days of discharge in patients without another potential cause 
of diarrhea. The actual number of hospital-onset cases likely lies somewhere in between, as many discharged 
patients who develop CDI as an outpatient may be missed and some of the cases felt to have an alternative 
explanation from review of the EMR may actually have CDI. 
We currently have a search engine built within the EPIC EMR at our institution that finds all 
patients ≥18 years of age who are started within a preset time on high-risk antibiotics for CDI. All study 
personnel have the capability of accessing this search. On a typical day, this search will identify 50-200 
patients initiated on antibiotics. Day-to-day repeat patients are noted, and the actual number of patients 
suitable for recruitment is expected to be closer to 50 per day than 200 per day.  
A previous prospective observational study at our institution determined that the hypervirulent strain 
was present in 60% of cases of CDI (24). Given the nature of the hypervirulent strain, we expect that our 
estimate of the percentage of patients who are carriers of toxigenic C. difficile is likely accurate or even low.
3.1.3 Patient Recruitment
Dr. Sims has served as PI on numerous multicenter phase II, phase III, phase IV, and registry trials. He 
was part of the design team for the Discover Registry for Fidaxomicin use. In addition to the investigators, a 
fulltime nurse coordinator a fulltime research coordinator, as well as several volunteers, will be 100% dedicated 
to help conduct this clinical trial. The nurse coordinator for this trial has been lead coordinator on all of the 
interventional CDI trials run by Dr. Sims. Our team has a record of high recruitment for these trials and, given 
the nature of this trial, we estimate that the recruitment success rate for this study will be at least 10% of 
patients approached. In order to complete study enrollment in four years, an average of 1.7 patients per 
day would need to be enrolled, recruiting an average of 3 patients per day will complete enrollment in 
just over 2 years and 3 months. Subjects will be identified through review of the EMR, which will 
automatically narrow the search to patients in the appropriate age range (both female and male patients), and 
exclude patients using antibiotics with activity against C. difficile. The inclusion and exclusion criteria for the 
study are listed in Table 2.
Review will be performed 
by the study coordinator with 
additional review of any subjects 
with unclear eligibility criteria by 
Dr. Sims or one of the sub-
investigators when he is not 
available. The eligible patients 
will 
be 
approached 
for 
participation in the study by a 
study coordinator or a physician 
member of the study team. The 
purpose and basic requirements 
of the study will be explained, 
the patient will be given the 
opportunity to ask questions 
regarding the trial, and can 
choose to speak with one of the 
physicians 
if 
they 
desire. 
Subjects who meet inclusion and 
exclusion criteria and express 
interest 
will 
be 
given 
the 
informed consent document to 
review. The background, purpose, benefits, and risks of the trial will be explained to the patient, who will then 
be invited to ask questions to their satisfaction. The cost of the study drug and any study procedures will be 
covered by the study with no expense to the patient. The patient must provide written informed consent prior to 
enrollment. Failure to provide written informed consent will render the patient ineligible to participate in the trial. 
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8
3.1.4 Study Procedure
A. Patient Baseline Data
All patients enrolled in the study will have the following data recorded using a standardized data 
collection form: 1) admission diagnosis; 2) diagnosis leading to initiation of antibiotics; 3) medication record; 4) 
medical and surgical history; 5) present status of bowel movements: number per day and consistency; 6) vital 
signs; 7) white blood cell count (WBC) and differential; 8) baseline and current serum creatinine; 9) other 
laboratory indicators of systemic disease if available (i.e., C-reactive protein, procalcitonin); 10) current 
abdominal pain, nausea, vomiting, or abdominal bloating; 11) allergies; 12) demographic information, including 
age, race, sex; 13) social information, including marital status, place of residence, and who they reside with; 
and 14) contact information, the best phone number to reach them at, and the best times they can be reached.
B. Interventions
The following interventions will be administered to the randomized patients in the following study arms:
Arm 1: Vancomycin 125 mg PO q6 hours (using compounded liquid vancomycin)
The patient will take vancomycin 125 mg PO q6 hours as prophylaxis against CDI from enrollment until 72 
hours after completing their planned course of antibiotics. The rationale behind this arm is that the vancomycin 
will suppress the overgrowth of C. difficile required to develop CDI.
Arm 2:  Placebo PO q6 hours 
The patient will take a placebo PO q6 hours from enrollment until 72 hours after completing their planned 
course of antibiotics. Vitamins will be added in order to confer a bitter taste and preserve the blind.
C. Laboratory Evaluations
Immediately after randomization, stool from all randomized patients will be tested for: the presence of 
the hypervirulent strain using the Xpert C. difficile/Epi test (Cepheid); detectable production of toxins A and B 
(not simply presence of the tcdB gene) by EIA (C. difficile Premier toxins A and B; Meridian Biosciences); and 
pre-existing colonization with VRE by stool culture. In addition, a single blood draw, timed with routine labs, will 
be drawn to assay for pre-existing antibodies to the C. difficile toxins (Quest Diagnostics). Patients will be given 
the option to have stool frozen for possible future studies of C. difficile including possible microbiome analysis.
D. Inpatient Follow Up
During the inpatient period, the subject will be evaluated daily via the EMR and seen at a minimum 
weekly by study personnel (study coordinator, research assistant, or study physician) (Figure 2). Upon each 
evaluation they will have the following data 
recorded: 
1) 
present 
status 
of 
bowel 
movements: number per day and consistency; 
2) vital signs (including maximum temperature 
and minimum blood pressure); 3) available 
laboratory data (including WBC and serum 
creatinine); 4) any current abdominal pain, 
nausea, vomiting, or abdominal bloating; 5) any 
signs of adverse reaction to the study 
medication; 6) changes in medications; 7) 
planned date of discharge; and 8) compliance 
with study medication. If at any time a subject 
shows signs or symptoms of CDI, particularly at 
least 3 episodes of diarrhea in a 24-hour period 
for 2 days in a row, they will be tested for C. 
difficile and evaluated by Dr. Sims, or one of 
the physician sub-investigators, to determine if 
a clinical diagnosis of CDI exists. If diagnosed 
with CDI, the patient will be treated per 
standard of care. Any evaluation and treatment 
for CDI will not be covered by this study as it is 
under standard of care. If their stool is positive 
for C. difficile by PCR, it will be tested by EIA 
for toxin production and the EIA will be covered 
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9
by the study, as it is not standard of care. In the case of patients who were already C. difficile toxin-positive by 
EIA at randomization, the PI will rely on continued production of toxin as ascertained by EIA and clinical 
judgment based on symptoms.
During an episode of CDI, the following information will be collected daily: 1) general clinical status; 2) 
present status of bowel movements: number per day and consistency; 3) maximum temperature in the last 24 
hours; 4) presence of hypotension; 5) available laboratory data (including WBC and serum creatinine); 6) any 
current abdominal pain, nausea, vomiting, or abdominal bloating; 7) current treatment regimen; 8) imaging 
studies of the colon, if available; 9) evidence of toxic megacolon, pancolitis, ileus, or intestinal perforation; 10) 
colonoscopy results, if performed; and 11) need for, and results of, any surgery for treatment of CDI.
E. Outpatient Follow Up
Patients who tested negative for colonization with C. difficile and were not randomized to a treatment 
arm will be followed for 12 weeks after stopping antibiotics. These patients will receive a phone call 12 weeks 
after completing antibiotic treatment. Patients who were randomized to a treatment arm will be followed weekly 
while on the study medication and for 12 weeks after completion of the study medication. The randomized 
patients will receive phone calls at the end of treatment, 4 weeks post treatment completion, 8 weeks post 
treatment completion, and at 12 weeks post treatment completion. The exact duration of time for which use of 
antibiotics places one at risk for CDI is unclear. Various studies have shown the risk to continue anywhere from 
4 to 26 weeks (31, 72, 73, 92). We reviewed recent CDI trials on clinicaltrials.gov and found they follow for 
recurrence from 4 to 12 weeks, we elected to use the longest follow-up period of 12 weeks for this study. All 
patients enrolled in the study will be followed for 12 weeks by a phone call (Figure 3). At each contact, all 
patients will be asked the following questions:
1) What is the present status of your bowel 
movements: number per day and 
consistency?
2) Have you had a fever? If so, how high?
3) Do you have any abdominal pain, nausea, 
vomiting, or abdominal bloating?
4) Have you been readmitted to the hospital 
since discharge from the hospital?
5) Have you started any antibiotics since 
discharge from the hospital?
6) Have you been diagnosed with CDI since 
discharge from the hospital?
7) Have you experienced any other changes to 
your heath since discharge from the 
hospital?
The following additional questions will be 
asked of randomized patients who go home 
on study medications only, until medications 
are complete (a diary form will be supplied 
for them to record each dose taken at home 
and any noted side effects):
8) Have you missed any doses of the study 
medication and if so which?
9) Have you had any adverse reaction to the 
study medication?
At the end of the study medication and 
at the end of follow up, all randomized patients 
in both arms will be asked to submit a stool 
sample for retesting for C. difficile colonization and colonization with VRE to determine the rate of clearance of 
toxigenic C. difficile colonization and the rate of acquisition of VRE based on the intervention.
In order for a randomized patient to be considered fully evaluable, they must submit the end of 
treatment stool sample, respond to the questions at the time of the phone call monthly, and have completed 
the final phone call between 12 and 15 weeks after study treatment ended. If a patient misses their monthly 
IRB NUMBER: 2016-254
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10
phone call, and we cannot contact them by phone for more than a week, they will be contacted by certified 
letter. If any patient is suspected of having CDI based on the phone call, they will be called in for evaluation by 
Dr. Sims or one of the physician sub-investigators, to determine if a clinical diagnosis of CDI exists. They will 
be offered testing and treatment as per standard of care if CDI is found to have occurred. Any evaluation and 
treatment for CDI will not be covered by this study as it is under standard of care.
Patients with CDI 
Patients who develop CDI will be treated as per standard of care by their physicians. They will be 
followed as an outpatient for an additional 12 weeks after resolution of symptoms. They will be contacted by 
phone at 16 weeks, 20 weeks and 24 weeks after the initial 12 week follow up has ceased. The following 
information will be obtained from the patient: 1) general clinical status; 2) present status of bowel movements: 
number per day and consistency; 3) any fever in the last 24 hours; 4) any current abdominal pain, nausea, 
vomiting, or abdominal bloating; 5) current treatment regimen; 6) readmission to the hospital since last 
discharge; 7) initiation of antibiotic use since discharge from the hospital; and 8) diagnosis of CDI recurrence 
since discharge from the hospital. All relevant laboratory studies available through the EMR (including EPIC 
Everywhere to access data from other institutions that use EPIC) will be collected. Patients with recurrent CDI 
will be followed an additional 12 weeks out to 24 weeks at weeks 16, 20 and 24 by phone, to observe the 
natural history of their recurrences.
3.1.5 Study Endpoints
The primary endpoint of the study is development of CDI as ascertained by clinical presentation and 
laboratory testing. The secondary endpoints of the study include the following: 1) Severity of CDI as measured 
by clinical presentation and laboratories based on current Infectious Diseases Society of America (IDSA) 
guidelines; 2) Rate of conversion from colonization to CDI as related to presence of C. difficile toxin IgG; and 3) 
Rate of colonization with VRE after prophylaxis with vancomycin. 
The IDSA guidelines define severity as follows: mild CDI is defined as diarrhea alone; moderate CDI is 
defined as diarrhea in combination with associated signs or symptoms of system toxicity but not meeting the 
definition for severe CDI; severe CDI is defined by the presence of a WBC ≥15,000 cells/μL and/or a creatinine 
≥1.5 times the premorbid level; and severe complicated CDI shows hypotension, shock, toxic megacolon, or 
ileus (58). We recently performed a review of CDI severity at our institution and found 54.6% mild/moderate, 
35.8% severe, and 9.6% severe complicated (93). 
The outcome of treatment for CDI definitions includes the following: 1) cure is defined as complete 
resolution of symptoms at the end of follow up; 2) treatment failure is defined as requiring a change in therapy 
due to inadequate response; and 3) relapse is defined as a return of symptoms within 12 weeks after cessation 
of therapy.
3.1.6 Study Timeline
We propose a 5-year clinical trial. Recruitment will begin immediately after grant award and final IRB 
approval is obtained, and is expected to continue for just under four years. The intent is for the first patient to 
be recruited at start of Quarter 2, Year 1. At an average of 2 patients recruited per day, which we feel is 
reasonable, and allowing an extra six months for potential unforeseen circumstances or slow recruitment, we 
plan for recruitment to be complete by the end of Quarter 1, Year 5. Given the nature of the follow up, and 
based on experience with questionnaire-based studies, we estimate the dropout rate will be at most 10%. The 
200 randomized subjects should provide at least 180 evaluable subjects. We will benchmark our progress 
based on the number of patients recruited, number of patients who complete the follow up, number of samples 
collected, total cases of CDI, and positive VRE cultures in the patient population. Follow up of patients in the 
study is expected to be completed by the end of Quarter 2, Year 5, with the possibility that a small number of 
subjects with recurrent 
CDI may need to be 
followed for up to an 
additional Quarter. Data 
analysis and manuscript 
preparation will begin at 
the start of Quarter 3, 
year 5, and will conclude 
by the end of Year 5 
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IRB APPROVAL DATE: 12/20/2019


11
(Figure 4).
3.2 Statistical Analysis
3.2.1 Sample Size Calculation
The current rate of asymptomatic toxigenic C. difficile carriers in the hospitalized population is 
estimated to be a minimum of 8% based on multiple studies (11, 39, 42, 43, 49). We plan to obtain consent 
from 2500 patients, of which 8% would yield 200 subjects to randomize. 
For the purposes of this sample size estimation, we began our calculation based on the assumption 
that 50% of patients colonized with toxigenic C. difficile will convert to CDI when taking high-risk antibiotics. 
Zacharioudakis et al. noted a 21.8% CDI rate among hospitalized patients admitted with toxigenic C. difficile 
colonization independent of antibiotic risk, so this was our lower limit for an assumed conversion rate from 
colonization to infection. Based on current literature, we felt a 60% reduction in conversion to CDI after 
receiving the vancomycin treatment proposed in this study may be reasonably expected (34, 48, 82, 83, 85, 
94). Group sample sizes of 44 in each arm achieve 80% power to detect a difference between the group 
proportions of 60%. Initially, the proportion in the treatment group was assumed to be 0.50 under the null 
hypothesis, and 0.20 under the alternative hypothesis. The proportion in the control group is assumed to be 
0.50. The test statistic used is the two-sided Fisher's exact test, with the significance level set at 0.0500. 
However, since we are not sure what the frequency of CDI will be in either group, we completed various 
sample size calculations using PASS 13 Power Analysis and Sample Size Software, 2014 (NCSS, LLC. 
Kaysville, Utah, USA, ncss.com/software/pass). Based on all of these variations (Table 3), our proposed 
sample size of 200 should be sufficient to detect a 60% difference between prophylaxis and placebo, allowing 
for at least 
10% drop-
outs 
if 
patients 
colonized 
with 
toxigenic 
C. difficile develop CDI when placed on high-risk antibiotics at least 30% of the time.
3.2.2 Data Analysis
A. Data Collection and Data Management
A patient identification log will be kept to permit easy identification of each patient during and after the 
study. The patient identification log will be confidential and will be kept in a secure location in the study office. 
To ensure confidentiality, no copy will be made. The log will link the patient’s name and medical record number 
to the unique study identification number. An electronic list of patients in the study, only available to study 
personnel, will be kept within the EMR of our healthcare system. Data will be collected using study-specific 
source documents in which the author of an entry is easily identifiable. The number of study personnel who will 
be responsible for data collection will be kept minimal to ensure the fidelity of the data. Study personnel will 
transcribe the data from source documents into a secure hospital-based computer system with password 
protection. All patient identifiers will be removed from the collected data to ensure HIPAA compliance and 
patient confidentiality. Patient data will be identified using initials and a patient study number. Any 
communication relating to the study, study documents, and electronic databases, will identify patients by initials 
and their assigned number only. In accordance with ICH/GCP guidelines, the study team will maintain all 
source documents that support the data collected from each patient as well as all study documents specified in 
ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical Trial, and all study documents as 
specified by appropriate regulatory requirements. All documents related to the study will be kept in a secure 
location in the study office, and will be preserved for a minimum of 11 years as required by internal policy in the 
study office or another approved location for long-term secure storage.
B. Data Monitoring, Quality Control, and Safety
This study protocol will employ rigorous methods to ensure data safety. Human subjects’ safeguards 
will include, at a minimum, NIH Computer Security Awareness Training, completion of Human Subjects 
Protection Training, and signing a legally binding Assurance of Confidentiality. This study is felt to be minimal 
risk, however, Roger MacArthur, an attending infectious diseases physician from an outside group with 
significant research and data safety monitoring experience will serve as the Medical Monitor for the trial, and 
IRB NUMBER: 2016-254
IRB APPROVAL DATE: 12/20/2019


12
will review Adverse Events and Significant Adverse Events for data safety monitoring for the duration of the 
proposed project. In the event that any study participant has a significant adverse reaction related to the study, 
the PI will, if needed, break blinding in consultation with the lead research pharmacist, Dr. John Koerber, and 
the medical monitor. Standard of care treatment for the participant will be followed.
C. Proposed Statistical Analysis
Descriptive statistics will be given for all data collected. Missing data will not be replaced by 
substitutions or interpolations. Categorical variables will be reported as counts and percent frequencies. 
Continuous variables will be examined for normality. Normally distributed variables will be provided as mean 
+/-SD (standard deviation) followed by the median. Non-normally distributed variables will be provided as 
medians, 25th, and 75th percentiles. We will compare the two randomized arms for demographics, ages, 
laboratory results, and other collected data, to determine any imbalances between the arms. Categorical 
variables will be examined using Pearson’s chi-square tests where appropriate (expected frequency>5), 
otherwise Fisher’s exact tests will be used. Normally distributed continuous variables will be examined with t-
tests, while non-normally distributed continuous variables will be examined with non-parametric Wilcoxon rank 
tests. The 95% confidence limits and odds ratios (or relative risks) will be calculated wherever appropriate. 
The total number of non-randomized patients who did not develop CDI will be reported as count and 
percent frequency. The primary endpoint of development of CDI will be examined between the two randomized 
arms using a Fisher’s exact test, and will be reported along with the odds ratio and 95% confidence limit. The 
secondary endpoints of severity of CDI, rate of conversion from colonization as related to presence of C. 
difficile toxin IgG, and rate of colonization with VRE after prophylaxis with vancomycin will be examined with 
Pearson’s chi-square tests where appropriate (expected frequency >5), otherwise Fisher’s exact tests will be 
used. Various exploratory analyses, such as impact of age, impact of comorbidities, and mortality, may be 
completed to explore relationships with CDI and other data collected. These analyses will be completed using 
appropriate statistical methods by a Beaumont research biostatistician using R or The SAS® System for 
Windows Version 9.3 or higher (Cary, NC).
3.2.3 Randomization
Once patients have met all inclusion and exclusion criteria and have signed consent, they will be 
randomized in a 1:1 ratio of prophylactic vancomycin vs. placebo. This is a double-blind study, and the patients 
and their caregivers will not have knowledge of the arm to which the patient will be randomized. A 
randomization list will be prepared by a Beaumont research biostatistician in varying block design. This will 
insure that the number in both groups will be equal periodically. The list will be provided to the research 
pharmacist. He will provide the medications prepared by the Research Pharmacy for the patients in the 
sequential order according to the randomization list provided.
3.3 Potential Problems and Approaches to Minimize Their Impact
3.3.1 Low Recruitment
Our estimate for recruitment is based on prior experience in conducting multiple clinical trials and the 
size of the target population. Since vancomycin has been approved and marketed for years, the perception of 
risk associated with this clinical trial is reduced and one of the major roadblocks to recruitment has already 
been removed. However, given the size of the eligible population in our institution, if recruitment is below the 
needed 1.7 patients per day, additional efforts to approach larger numbers of patients will be undertaken. 
3.3.2 Low Estimation of the Asymptomatic Toxigenic Carrier State
Our estimate of the percentage of patients who are asymptomatic carriers of toxigenic C. difficile is 
based on multiple prior studies in several different types of institutions (41, 52, 53, 55, 57, 95-98). The 
assumed 8% carrier rate is a conservative estimate. However, if the carrier rate is significantly lower than 
expected, this issue should become apparent early in the study, as screening for carriage is not blinded. To 
address this, we would plan to increase screening. However, prior to taking this step we will contact the 
program manager at AHRQ to discuss the issue and determine if increased screening can be accommodated 
within the budgetary considerations.
3.3.3 Low Estimation of Conversion of the Asymptomatic Carrier State to CDI
Our estimate of the percentage of asymptomatic carriers of C. difficile who will develop CDI when 
exposed to antibiotics is a conservative one based on multiple studies of development of CDI in colonized 
patients (48). Our study limits recruitment to patients started on high-risk antibiotics and the conversion rate 
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13
may actually be higher. It is reasonable to expect that the hypervirulent strain would be more likely to convert 
from asymptomatic carriage to CDI than previous strains. In our institution, the hypervirulent strain accounts for 
60% of CDI (24), which we would expect to be reflected in the conversion rate.
3.3.4 Low Effectiveness of the Intervention
If the effectiveness of the intervention is significantly lower than expected, we will not be able to reach 
significance with the study as planned. However, given existing data (34, 82, 83, 85, 94), we have chosen a 
conservative level of effectiveness that should be reachable.
3.3.5 Difficulty in Establishing a Diagnosis of CDI
Since all patients in the randomized groups, by definition, had stool that tested positive for C. difficile, 
the use of the laboratory assay in defining CDI is limited. The diagnosis must therefore be made on a clinical 
basis. As such, any diagnosis of CDI will require a minimum of 2 days with ≥3 unformed stools per day, and 
toxin production will be determined for all patients who were determined to have CDI by EIA. Cases will be 
reviewed by Dr. Sims or one of the physician sub-investigators, all of whom have extensive experience in 
diagnosing and treating CDI. All investigators will be blinded to the treatment group.
3.3.6 Confounders from Outside the Study
 
Since patients in the trial will not generally be under the direct care of the study physicians, there is a 
possibility that care from outside physicians will interfere with the data integrity of the trial. First, should a 
patient be diagnosed with CDI by an outside physician and treated without clinical confirmation of the disease, 
the patient must be considered a CDI case though they may not truly have CDI. Second, any antibiotics started 
as an outpatient, during or after the receipt of the study medication, may cause a case of CDI. Despite these 
confounding issues, we must include these patients and count them as not having benefited from the 
therapeutic intervention. We will attempt to limit this problem by maintaining direct communication with treating 
physicians for inpatients and with primary care physicians for outpatients.
4. Future Directions:
If the SToP CDI study is successful, planned future studies will include the following: 1) a larger, multi-center 
trial will be conducted to confirm the results of this study; 2) patients known to be at risk for CDI, but with 
shorter healthcare exposures, such as those receiving antibiotic prophylaxis for surgical procedures, including 
bowel surgery, will be screened and treated prophylactically; 3) outpatient populations receiving high-risk 
antibiotics will be screened for C. difficile and treated prophylactically; and 4) alternative dosing or timing of 
prophylaxis using lower dose, lower frequency, or later initiation of prophylaxis for CDI will need to be studied 
in clinical trials to determine the most cost-effective strategies for CDI care.
IRB NUMBER: 2016-254
IRB APPROVAL DATE: 12/20/2019

ICF_000.pdf: 
STUDY TITLE: SCREENING TO PROPHYLAX AGAINST CLOSTRIDIUM DIFFICILE 
INFECTION (StoP CDI) 
 
NCT#: 02996487 
 
Document Date: 5/20/2022 


IRB # 2016-254                                                                                                                                                        Page 1 of 7 
Version Date: 04.22.2022
                       
                                          
CONSENT FORM AND AUTHORIZATION FOR DISCLOSURE OF
PROTECTED HEALTH INFORMATION
 
STUDY TITLE: SCREENING TO PROPHYLAX AGAINST CLOSTRIDIUM DIFFICILE INFECTION (StoP 
CDI)
Principal Investigator: Matthew Sims, MD PhD
Address:  
                3601 West 13 Mile Road
                Royal Oak, MI 48073
Hospital: specify location(s) by checking the box(s) 
 William Beaumont Hospital (Royal Oak, Troy and Grosse Pointe)
 Beaumont Hospital - Dearborn 
 Beaumont Hospital - Farmington
 Beaumont Hospital - Other ________________
Individually and collectively referred to as “Beaumont” throughout this consent.
Study Sponsor: Agency for Healthcare Research and Quality (AHRQ)
INTRODUCTION 
Why is this study being done?
You are being asked to participate in a research study.  The purpose of research is to look at the nature of 
disease and try to develop improved methods to diagnose and treat disease. The doctor or clinician in charge 
of the study believes you meet the initial requirements to take part in the study.  Before agreeing to 
participate, it is important for you to read and understand the following explanation of the research 
procedures.  This Consent and Authorization form describes the purpose, procedures, benefits, risks and 
discomforts of the study.  It also describes the alternatives available to you, and your right to withdraw (quit) 
from the study at any time.  
Please read this information carefully and ask as many questions as you like before deciding whether or not 
you would like to take part in this research study.
Clostridium difficile (C. diff) is a germ which may cause diarrhea in patients who are treated with antibiotics. 
Many people carry C. diff in their stool, but it is simply there and does not cause disease. This is called being 
colonized with C. diff. When patients who are colonized are given antibiotics which kill the good bacteria in the 
colon, C. diff is left behind and may cause an infection. The C. diff infection (CDI) produces toxins which cause 
diarrhea and can be severe or even life threatening. When a person gets CDI a commonly used treatment is 
an antibiotic called vancomycin which is given orally. 
The goal of this study is to evaluate whether using vancomycin orally can prevent CDI in patients who are 
colonized with C. diff who are admitted to the hospital and need antibiotics for another infection.
A total of 200 patients will take part in this portion of the study at Beaumont.
How long will I be in the study?
If you decide to take part in this study, your participation is expected to last 12 weeks from the time you finish 
your antibiotics. If you get CDI, you will continue to be followed for an additional 12 weeks for a total of 24 
weeks of study participation. You may not take part in this study if you are currently enrolled in another 
related research study which could alter or influence the study results.
IRB NUMBER: 2016-254
IRB APPROVAL DATE: 05/20/2022
IRB EXPIRATION DATE: 05/19/2023


IRB # 2016-254                                                                                                                                                        Page 2 of 7 
Version Date: 04.22.2022
                       
                                          
DESCRIPTION OF THE STUDY
What will happen if I take part in the research study?
You are being asked to take part in this research study because you have been diagnosed with an infection 
requiring antibiotics while in the hospital. Treatment with certain antibiotics, including those you are being 
treated with, have been shown to be a risk for developing CDI. Another risk for developing CDI is being 
colonized with C. diff when you receive antibiotics. You have previously been found to be colonized with C. diff 
so your risk to develop CDI is higher than normal.
If you agree to take part in this study, you will be randomly assigned to one of 2 treatment groups. 
Randomization is like “the flip of a coin”. 
The treatment groups are:  
A. Vancomycin 125 mg by mouth every 6 hours.
B. Placebo by mouth every 6 hours. The placebo will look like the drug being studied, but will have no 
active ingredients, in this case it will be fruit punch with vitamins added to mimic the taste of 
vancomycin.
In case of an emergency, the treatment can be unblinded to determine which therapy you have been 
receiving.
Below is a table describing what will occur at each study visit:
The study team will instruct you on the location of where to submit the stool samples: Beaumont Hospital 
Royal Oak, Troy, or Dearborn.
FDA Clinical Trial Information 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. 
This Web site will not include information that can identify you. At most, the Web site will include a summary 
of the results. You can search this Web site at any time. 
PARTICIPANT RESPONSIBILITIES 
You will be asked to note any side effects or medical problems you may experience while you are taking part 
in this study.  For any illnesses or injuries, you should contact the study doctor immediately at the number 
listed in this Consent and Authorization form or in an emergency situation call 911 (or go to the nearest 
hospital emergency room). 
IRB NUMBER: 2016-254
IRB APPROVAL DATE: 05/20/2022
IRB EXPIRATION DATE: 05/19/2023


IRB # 2016-254                                                                                                                                                        Page 3 of 7 
Version Date: 04.22.2022
                       
                                          
BIOLOGICAL SPECIMEN BANKING 
In this study, a sample of your stool will be kept for possible future research. The sample will have a code that 
only Dr. Sims will be able to link back to you as a patient and will not have your personal information on the 
tube in which it is stored. The future research may involve determining what other bacteria are in the stool of 
patients who are colonized with C. diff or develop CDI, all future research with the sample will be related to C. 
diff and CDI. No genetic testing of human cells will be performed as part of future research. Only Dr. Sims and 
his team will have access to the samples, and you may change your mind at any point and request the sample 
to be destroyed. The samples will be kept a maximum of 10 years from the end of the study. You will not be 
notified of any findings.
Do you wish to take part in this additional, optional part of this study?
 Yes
 No
___________ _______
Participant’s Signature
RISKS, SIDE EFFECTS AND DISCOMFORTS
Ask your doctor what the standard of care risks are as well as the study risks.
What side effects or risks can I expect from being in the study?
Risks of Oral Vancomycin:
Less Frequent (occurring from 1% to 10% of the time):

Indigestion

Stomach ache

Nausea

Vomiting

Diarrhea
Rare (occurring less than 1% of the time):

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of 
the mouth, face, lips, or tongue)
There are a number of risks associated with giving vancomycin intravenously (directly into the body using a 
vein) such as kidney failure and hearing loss.  Since oral vancomycin does not easily get absorbed into the 
body, these side effects are not expected to occur
Since all antibiotics can cause bacteria exposed to them to become resistant to the antibiotic there is a chance 
that some of the bacteria in your colon may become resistant to vancomycin. It is very rare that C. diff itself 
becomes resistant to vancomycin but there is another bacteria in the colon called Enterococcus which can 
become resistant to vancomycin and there is a risk, though how significant is unknown, that you may acquire 
vancomycin resistant Enterococcus from being exposed to vancomycin. This has not been a significant clinical 
concern in patients treated for CDI with vancomycin.
There is a rare risk of breach of confidentiality (release of information which personally identifies you).  
Risks of Blood Drawing: 
Most Frequent (occurring more than 10% of the time):

Pain

Bleeding

Bruising at the needle puncture site
Rare (occurring less than 1% of the time):

Blood clot

Infection
IRB NUMBER: 2016-254
IRB APPROVAL DATE: 05/20/2022
IRB EXPIRATION DATE: 05/19/2023


IRB # 2016-254                                                                                                                                                        Page 4 of 7 
Version Date: 04.22.2022
                       
                                          

Feeling lightheaded

Fainting
Not all possible effects are known. With any drug unusual, unexpected or previously unreported side effects 
may occur. You will be informed of any significant new findings, which develop during the course of this 
research study which may change your decision to continue participating in this study.
Pregnancy Warning 
If you are a woman who is pregnant or becomes pregnant during the research study, there could be harmful 
effects to you or your unborn child. It is important you are not pregnant or breast-feeding during the 
approximately 10-17 days you are taking the study medication. Women of childbearing potential must agree to 
use birth control. If you are a woman of childbearing potential, you must have a negative pregnancy test 
before entering the study.
BENEFITS
What are the benefits of taking part in this study?
We expect that using vancomycin prophylaxis will lower your chance to develop CDI however there may be no 
direct benefit to you from taking part in this study. Information gained from the results of this study may be of 
benefit to others in the future, with a similar medical condition. 
ALTERNATIVE OPTIONS
What are my choices other than taking part in this study?  
You do not have to take part in this study to receive treatment for your condition. There are no current ways 
to screen for and prevent CDI in patients receiving antibiotics. 
ECONOMIC CONSIDERATIONS
What are the costs of taking part in this study?
The study medication will be provided to you at no cost. There will be no cost to you for the study procedures 
described in this consent (e.g., pregnancy test, stool collection and testing, blood samples collected and 
tested, and questionnaires).  Routine procedures you would have had done even if you were not taking part in 
this study will be billed to your health insurance company and/or group health plans as usual. If these routine 
care costs are not covered by your health insurance/group health plan, the cost will be your responsibility. 
You are asked to attend a visit to the Research office at the end of the study. You will need to bring a stool 
sample. You will be reimbursed $50 for your time and travel for this visit which will be paid by a check sent via 
the mail after the visit.
COMPENSATION
What happens if I am injured because I took part in this study?
Your involvement in this study is voluntary. The possible risks and side effects which might occur during the 
course of the research study have been described in this Consent and Authorization form.
A research injury is any physical injury or illness caused by the medications, devices, or procedures required 
by the study which are administered, used, or performed appropriately.  These medications, devices, or 
procedures are different from the medical treatment you would have received if you had not taken part in the 
study.
Should you experience a research injury, there are no designated funds provided for subsequent medical care 
or compensation by either the study doctor/clinician or Beaumont. 
What are my rights if I take part in this study?
You are not giving up any of your legal rights by signing this form.
IRB NUMBER: 2016-254
IRB APPROVAL DATE: 05/20/2022
IRB EXPIRATION DATE: 05/19/2023


IRB # 2016-254                                                                                                                                                        Page 5 of 7 
Version Date: 04.22.2022
                       
                                          
CONFIDENTIALITY, DISCLOSURE AND USE OF YOUR INFORMATION
Will my medical information be kept private?
We will keep your personal health information as confidential as possible.  It is not likely your information will 
be given to others without your permission.  In order for this research study to take place, you must also 
authorize the researchers to access and use some of your protected health information (PHI). PHI is 
information which could identify you as an individual such as name, address, date of birth, etc. By signing this 
Consent and Authorization Form, you give Beaumont permission to use and/or disclose (release) your health 
information related to this research. Your medical and billing records collected for the purpose of the study will 
remain confidential, but may be disclosed (released) or used by the following and/or their representatives: 

The investigators (study doctor/clinician, research staff)

Beaumont and its’ parent, Beaumont Health and affiliated hospitals

The Food and Drug Administration

Other governmental regulatory agencies (domestic and/or foreign) 

The study sponsor, AHRQ and agents of the sponsor involved in this study.

Your health insurance company and/or group health plans and their intermediaries (companies contracted 
to process claims) may also have access to your medical and billing records of the study.

Primary Care Physician 
Optional Notification to the Primary Physician
The research doctor would like to inform your primary physician of your participation in the research study.  If 
you agree, we will need you to give us the name of the primary physician to allow us to contact them.
  I do not have a Primary Physician
  You may contact my Primary Physician
  You may not contact my Primary Physician.
________________
_______________
Participant’s Initials
Date
The purpose for this disclosure (release) or use is, for example, to assure compliance with the study protocol, 
to evaluate the effectiveness of the study, and/or to provide protection to you as a research study participant. 
The disclosure and use of your information will continue after your involvement in the study has ended. There 
is no expiration date for the use of your medical and billing records from the study. Any information about you 
disclosed to the parties identified above may be re-disclosed by them; however, such re-disclosure is not 
under the protections of this Consent and Authorization. 
You will not be identified in any publication or other release of study results, data, and other information (such 
as in professional writings, at professional meetings, and in the study sponsor’s product information, and/or 
advertising or other promotional materials). 
If you decide to withdraw your authorization for the researchers to access and use your protected health 
information before the end of the study, you will be withdrawn from the research study. However, where the 
study relied on your Consent and Authorization for the time you participated in the study, your Consent and 
Authorization cannot be withdrawn, and the information already collected may still be used and disclosed as 
you previously authorized. 
STOPPING STUDY PARTICIPATION
What if I decide to stop taking part in the study?
Taking part in this research study is completely voluntary. You may choose not to take part or to stop being in 
the study (withdraw) at any time without penalty or loss of benefits to which you are otherwise entitled, or 
without jeopardizing your medical care by your doctor at Beaumont. However, if you do not agree to sign this 
Consent and Authorization form, you will not be able to take part in this study. 
IRB NUMBER: 2016-254
IRB APPROVAL DATE: 05/20/2022
IRB EXPIRATION DATE: 05/19/2023


IRB # 2016-254                                                                                                                                                        Page 6 of 7 
Version Date: 04.22.2022
                       
                                          
If you decide to withdraw from the study you will need to notify the study doctor/clinician, in writing, of your 
decision to stop taking part in the study. This notice may be sent to Dr. Matthew Sims at William Beaumont 
Hospital – Research Institute, 3811 West 13 Mile Road/Suite 401, Royal Oak, MI 48073.
Your participation in this study may be stopped by the study doctor/clinician or study sponsor, without your 
consent, for any reason, which will be explained to you. Examples include:

The study medication or procedures appear to be medically harmful to you. 

You fail to follow directions for participating in the study. 

It is discovered you do not meet the study requirements. 

The study is canceled. 

It is determined to be in your best interest (for example, your disease has progressed despite 
treatment).
As this is a placebo controlled or otherwise blinded study you may not review your research medical records 
during the course of the study, regardless of whether or not you continue in the study. If your study 
doctor/clinician stops your participation, or you decide not to continue, you may be asked to have a final study 
visit or examination, in order for you to be discontinued from the study in a safe and orderly manner. In 
addition, the type of treatment you are getting will not be able to be disclosed to you/your doctor until the 
study is completed.
CONTACTS
Who can answer my questions about the study?
You may talk to the study doctor/clinicians about any questions or concerns regarding your study participation, 
or you think you may have suffered a research-related injury. The doctor/clinician in charge of the study Dr. 
Sims may be reached at: 248-551-0027 to answer your questions. In an emergency after hours call 248-898-
5000, ask the operator to page Dr. Sims or the physician covering him (24-hours). Your contact person is 
Marithel Sandoval-Yemmans, RN or Loni Lampkins CRC II. You may contact them at (248) 551-1556 or (248) 
551-2151. 
If you have questions regarding your rights as a research participant, or have problems, concerns, complaints, 
want information or would like to offer input, you may contact the Institutional Review Board Chairperson at 
(248) 551-0662.  The Institutional Review Board is charged with the oversight of all human participant 
research conducted at Beaumont facilities.
IRB NUMBER: 2016-254
IRB APPROVAL DATE: 05/20/2022
IRB EXPIRATION DATE: 05/19/2023


IRB # 2016-254                                                                                                                                                        Page 7 of 7 
Version Date: 04.22.2022
                       
                                          
STATEMENT OF VOLUNTARY PARTICIPATION
I have read the above, have asked questions and have received answers about this study to my satisfaction. I 
understand what I have read and willingly give my consent to participate in SCREENING TO PROPHYLAX 
AGAINST CLOSTRIDIUM DIFFICILE INFECTION (StoP CDI). I understand I will receive a signed copy 
of this document and will be promptly informed of any new findings regarding this study.  I further authorize 
the use or disclosure of my health and personal information contained in records as described above. 
______________________________________
RESEARCH PARTICIPANT NAME (PLEASE PRINT)
      
______________________________________             _______________     ___________________
 RESEARCH PARTICIPANT SIGNATURE
DATE
TIME
*WITNESS TO THE ENTIRE CONSENT PROCESS AND SIGNATURE ARE REQUIRED IF THE PARTICIPANT IS 
VISUALLY IMPAIRED, ILLITERATE OR NON-ENGLISH SPEAKING ONLY
_______________________________________
WITNESS NAME (PLEASE PRINT)
_______________________
     ________________
       ____________
WITNESS SIGNATURE              
          DATE
TIME
AUTHORIZED CONSENT PROVIDER STATEMENT:
I have explained this study and have offered the study participant an opportunity for any further discussion or 
clarification.
_________________________________               ____________                 ___________________
NAME (PLEASE PRINT) 
            CREDENTIALS
          
         PHONE NUMBER
_________________________________                __________________          ____________
SIGNATURE
                                                                DATE 
             TIME
IRB NUMBER: 2016-254
IRB APPROVAL DATE: 05/20/2022
IRB EXPIRATION DATE: 05/19/2023