Prevention of Recurrent Clostridium Difficile Infection (CDI) in Patients With Inflammatory Bowel Disease (IBD).
Phase: PHASE4
Conditions: Inflammatory Bowel Diseases, Ulcerative Colitis, Crohn Disease, C. Diff. Infections
Sponsor: David Binion, MD

 
 
NCT04626947    
 
Title: 
Prevention of Recurrent Clostridium Difficile Infection (CDI) in Patients With     
Inflammatory Bowel Disease (IBD) 
 
Protocol:   
Version 1. 10/25/2019 
 
Study Title:  Prevention of recurrent Clostridium difficile infection (CDI) in patients with 
inflammatory bowel disease (IBD) 
 
Institution Name:  
     University of Pittsburgh School of Medicine 
 
Principal Investigator:   David G. Binion, MD, AGAF, FACG 
Professor of Medicine, Clinical and Translational Science 
Co-Director, UPMC Inflammatory Bowel Disease Center 
Director, Translational Inflammatory Bowel Disease Research 
Director, Nutrition Support Service 
Division of Gastroenterology, Hepatology and Nutrition 
Department of Medicine. University of Pittsburgh School of Medicine 
 
Investigator Contact Information: BST WR  11 - 200 Lothrop Street. Pittsburgh, PA  15213 
412-647-7827 binion@pitt.edu 
 
 
1. Objectives & Hypotheses  
 
a. Primary objective: Compare the short term tolerability and effectiveness of enhanced 
CDI therapy with Bezlotuxumab in patients with IBD after CDI. Special attention will be 
paid to rates of recurrent CDI, healthcare utilization, quality of life and disease activity.  
 
b. Secondary objective:  
Evaluate the long term clinical outcomes of enhanced CDI therapy with Bezlotuxumab in 
patients with IBD. 90 days, 1 year and 2 year patterns of recurrent CDI, healthcare 
utilization, quality of life and disease activity will be assessed. We will use our published 
control population as well as patients who agree to be monitored but do not receive 
enhanced therapy as the control population.  
 
Hypothesis: Administration of a human monoclonal antibody that binds to Clostridium 
difficile toxin B (Bezlotoxumab) in IBD patients with documented CDI will safely and 
effectively improved long-term clinical outcomes assessed by reduced rates of recurrent 
CDI, healthcare utilization, quality of life and disease activity and reduced overall 
charges associated with two year patterns of care.  
 
2. Background & Rationale, Significance of Selected Topic & Preliminary Data 
 
Inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis are 
lifelong chronic inflammatory conditions characterized by multiple remitting and relapsing 
events. During their lifetime, patients will experience multiple hospitalizations and 
surgical interventions as a part of the natural course of their disease. IBD patients 
frequently require corticosteroids, immunomodulators and biologic agents to induce and 

 
 
maintain remission, which may pose a risk for infectious complications. In addition to this 
iatrogenic risk from immunosuppression, IBD patients have frequent contact with the 
healthcare environment (hospitalization, emergency department and clinic) which can 
further increase their risk for infection, including enteric infection with Clostridium difficile 
(C difficile)(1)(2). New evidence suggests that the gut microbiome in patients with IBD is 
dysbiotic, with a reduced diversity of microflora, which may predispose these patients to 
develop enteric infectious complications, including C difficile infection (CDI).(3) 
Epidemiologic evidence and single center studies have demonstrated that IBD patients 
are at increased risk of developing C difficile infection (CDI) and recurrent CDI, likely due 
to an underlying dysbiosis in their enteric flora as well as their impaired ability to mount 
an immune response to C difficile toxin, which may be linked to iatrogenic side effects of 
immunosuppression with systemic corticosteroids, immunomodulators and biologic 
agents(4).  
 
Our group has previously demonstrated that IBD patients are at increased susceptibility 
for developing CDI and clinical outcomes of CDI in the IBD patient population are overall 
worse, with increased morbidity and mortality(5)(6). This work was performed prior to the 
advent of enhanced immunotherapeutics targeting C difficile toxins (i.e. bezlotuximab) 
(7). Due to the need for uniformity in the short term clinical response to anti-C difficile 
therapy, and a clinical read out emphasizing diarrhea resolution, IBD patients were 
excluded from many of the pivotal trials on new agents for the treatment and prevention 
of CDI over the past decade. This was necessary as CDI will frequently trigger a “flare” 
of underlying IBD related inflammation, which will make interpretation of C. difficile 
treatment too difficult. As a result of this pragmatic trial necessity, there is very limited 
data regarding the effectiveness, tolerability and long-term impact of these newer agents 
on a high risk population of patients, who would theoretically have the most benefit from 
improved CDI treatment. This lack of evidence has unfortunately been used as a barrier, 
preventing IBD patients from gaining access to enhanced CDI treatment. Thus a “Catch-
22” scenario has emerged, where IBD patients, who suffer from complex and severe 
CDI which frequently precipitates flare of their underlying IBD, where excluded from the 
pivotal trials (out of necessity), but the resulting lack of evidence now functions as a 
barrier to their ability to receive these more effective, albeit more costly upfront 
treatments.  
This proposal seeks to address this knowledge gap by specifically treating IBD patients 
with C difficile antibody approaches to demonstrate effectiveness as well as improved 
long-term outcomes and overall cost-effectiveness.  
 
In order to demonstrate an improved long-term natural history following enhanced C 
difficile therapy in IBD, our group had to first demonstrate the natural, multiyear history of 
CDI on patients with IBD using existing treatment modalities. Our recently published 
manuscript characterizing the long-term natural history of IBD following CDI clearly 
demonstrates that the underlying IBD accelerates in many of the patients experiencing 
this infection. This project, performed with the support of an investigator initiated study 
(IIS) from Merck, used a propensity score matching strategy to determine an appropriate 
IBD control population to assess the impact of CDI over the year of infection and the 
year following infection. This work led to important insights regarding CDI in IBD(5). The 
propensity score matching was performed in the year preceding the CDI, and the 
matching was carried out for 24 criteria known to be relevant for the development of CDI. 
IBD patients at risk for CDI were in general sicker than the average patient, with higher 
rates of steroid exposure, hospitalization and antibiotic exposure, compared with the 

 
 
average patient in the clinic. As expected, C difficile exerted a negative effect on the 
natural history of IBD and is associated with an increase in IBD severity and healthcare 
utilization. During the year of CDI, IBD patients had an increased objective evidence of 
inflammation, increased disease activity scores and lower quality of life scores when 
compared to those who did not have CDI.  Most importantly, we demonstrated that 
within this vulnerable population, CDI has a long lasting, negative effect on patient 
clinical trajectories, which was clearly evident in the year after infection. IBD patients 
with CDI continued to require antibiotics and demonstrated a 6 fold increase in 
healthcare charges compared with matched individuals who did not experience CDI.  
IBD patients with CDI generated mean healthcare charges (irrespective of pharmacy 
charges) of $48,000 annually, compared with an expected median charge of $7,000 in 
the matched control population.  
Thus, we proposed to prospectively assess the short and long-term impact of enhanced 
CDI therapy in the IBD patient population with Bezlotuxumab. Having defined the natural 
history of CDI over a 2 year time period, we will use an identical structure to determine if 
there is an improvement in clinical trajectory with enhanced CDI therapy the year after 
infection.  
 
3. Study Design:  
 
This is a prospective, single center, non-randomized, observational, open label study to 
compare tolerability, efficacy, and short and long term clinical outcomes of 
Bezlotuxumab in CDI IBD patients.  
A total number of 50 patients will be enrolled. Patients who agreed to receive 
Bezlotuxumab will be compared to our recently published historical controls as well as 
IBD registry patients who do not elect to receive enhanced C difficile therapy.  
 
Patient population will include any patient who receives care at the Digestive Disorder 
Center at UPMC Presbyterian Hospital.  
 
Inclusion criteria: >18 years old, diagnosis of IBD and CDI.  
Exclusion criteria: <18 years old, no IBD, no CDI, history of colectomy.  
 
4. Study Flowchart  
 
Data collection:  
 
Visit 1 (Enrollment) 
a. 
Demographic information 
b. 
type of IBD  
c. 
disease duration 
d. 
history of bowel resection 
e. 
current medications 
f. 
inflammatory markers: CRP, ESR, Albumin 
g. 
CBC 
h. 
quantitative immunoglobulins 
i. 
Vitamin levels (Vit D and Vit B) 
j. 
Disease related quality of life (SIBDQ) 
k. 
Disease activity scores (HBI-UCAI) 
l. 
Dietary intake (sugar and fat intake) 

 
 
m. 
Stool sample 
 
Visit 2 (90 days after enrollment) 
Clinic visit or Telephone call 
a. 
inflammatory markers: CRP, ESR, Albumin (if available as a standard of care) 
b. 
CBC (if available as a standard of care) 
c. 
Disease related quality of life (SIBDQ) 
d. 
Disease activity scores (HBI-UCAI) 
e. 
ED visits 
f. 
Hospital admissions 
 
Visit 3 (1 year after enrollment) 
Clinic visit or Telephone call 
a. 
inflammatory markers: CRP, ESR, Albumin (if available as a standard of care) 
b. 
CBC (if available as a standard of care) 
c. 
Disease related quality of life (SIBDQ) 
d. 
Disease activity scores (HBI-UCAI) 
e. 
ED visits 
f. 
Hospital admissions 
 
Visit 4 (24 months after enrollment) 
Clinic visit or Telephone call 
a. 
inflammatory markers: CRP, ESR, Albumin (if available as a standard of care) 
b. 
CBC (if available as a standard of care) 
c. 
Disease related quality of life (SIBDQ) 
d. 
Disease activity scores (HBI-UCAI) 
e. 
ED visits 
f. 
Hospital admissions 
g. 
Total charges associated with cost of care 
 
5. Study Procedures:  
 
This is a prospective observational study comparing the effectiveness of Bezlotuxumab 
to reduce rates of CDI in patients with IBD. We will evaluate short and long-term clinical 
outcomes after treatment with Bezlotuxumab.  
 
Patients who are part of the IBD Registry and have a defined IBD diagnosis and CDI will 
be approached to be consented for this study. Randomly the study treatment will be 
offered to 50 patients.  
Diagnosis of CDI will be accomplished using the standard CLIA certified strategies 
employed in our microbiology/virology clinical laboratories, which include PCR 
amplification, two step GDH /gene amplification of liquid/unformed stool samples.  
Patients will be divided into 2 groups of treatment and followed in a parallel fashion for 
the next 2 years: 1. Those who agree to receive Bezlotuxumab (Case) and 2. Those who 
do not agree to received Bezlotuxumab (controls).   
 
6. Study Duration:  
 
Total duration time:  5 years. 36 months enrollment and 24 months follow up.   
 

 
 
7. Statistical Analysis and Sample Size Justification: 
 
Sample size: 50 (Based on the prevalence of CDI within our patient population) 
 
Descriptive statistics of baseline characteristics will be used to characterize the 50 IBD 
CDI patients who agree to receive Bezlotuxumab. The baseline characteristics under 
consideration include demographic data, type of IBD, duration of IBD, current 
medications, inflammatory markers, SIBDQ, HBI-UCAI and others collected at the time 
of enrollment. Mean, standard deviation, median and interquartile range will be reported 
on continuous variables and proportions reported on discrete variables.   
Similar baseline characteristics will be collected at enrollment among historical controls 
and IBD registry patients who do not elect/ not offered to receive enhanced C difficile 
therapy. Similar descriptive statistics will be used to characterize these controls.  A 
logistic regression model will be developed to predict the status of receiving 
Bezlotuxumab from the extensive list of baseline characteristics. Subsequently each 
study participant, including both the 50 patients who receive Bezlotuxumab and the 
controls, will be assigned a predicted probability of treatment based on this propensity 
score model.  The inverse probability weighting method will be used to compare the 
Bezlotuxumab-treated IBD CDI patients and the controls in baseline characteristics to 
demonstrate balanced baseline characteristics between the two groups after inverse 
probability weighting (8).  
 
In the primary analysis, we will compare the risk of recurrent CDI between the 50 treated 
and 118 controls at 90 days after enrollment. The inverse propensity score-weighted 
method will be used to estimate the proportion of recurrence CDI at 90 days under 
Bezlotuxumab among IBD CDI patients seen in the clinics and compared with that for 
IBD CDI patients without Bezlotuxumab. Other long-term outcomes for comparison 
include, number of healthcare utilization (emergency room visits and hospitalization), 
overall charges during the second year after the study enrollment; inflammatory markers 
and CBC (in continuum and binary: abnormal vs normal), SIBDQ, HBI-UCAI, dietary 
intake at the 90 days, 12-month and 24-month visits. The inverse probability-weighted 
method will be used to compare these outcomes between Bezlotuxumab-treated and 
controls with IBD CDI. Cardiac failure will be closely monitored throughout this study and 
the proportions of cardiac failure among the 50-treated patients by the first 90 days, 12 
months and 24 months will be estimated.  The paired t-test or the nonparametric signed-
rank test will be used to test the change baseline to the 24-month visit in continuous 
outcomes and the McNemar test will be used to for discrete outcomes.(9)  
 
Using data from the 50 IBD CDI patients, linear-mixed models and generalized linear-
mixed models will be used to explore the longitudinal change in the repeatedly 
measured assessments of disease activity and quality of life, including current 
medications, inflammatory markers, annual overall financial charges, annual use of 
healthcare facilities (such as emergency room visit and number of hospitalizations) 
SIBDQ, and HBI-UCAI. Trajectory analyses on these multiple longitudinal patient 
outcomes will be used to identify IBD CDI patients who have responded to the treatment 
and who have not.  Subsequently we will compare the baseline patient characteristics 
between the treatment responders and non-responders and the results will be invaluable 
in guiding future management of IBD CDI patients.  
 

 
 
Based on data from 28 IBD CDI patients, it was reported that the proportion of IBD 
patients with recurrent CDI within 12 weeks of follow-up was 26.7% among 
Bezlotuxumab-treated and 53.8% among those without Bezlotoxumab (10-11). With 118 
controls and 50 Bezlotuxumab-treated patients, we will have 88% power to detect the 
same difference by using the Fisher’s Exact test with a 2-sided alpha level at 0.05.  
 
8. Specific Drug Supply Requirements:  
 
Bezlotuxumab: single 10-mg/kg dose administered as an IV infusion over 60 minutes. 
Commercial product open label of Bezlotuxumab will be required from MSD. (for 55 
patients) 
 
9. Adverse Experience Reporting:  
 
All serious adverse events (SAEs) and unanticipated problems (UPs), regardless of the 
causality to the study drug will be reported to the Principal Investigator and also to the 
University of Pittsburgh IRB. All SAEs and UPs must be reported Within 24 hours of first 
awareness of the event. 
 
10. References: 
 
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difficile infection in acute flares of inflammatory bowel disease: A prospective study. Dig 
Liver Dis. 2017 Jan 30;  
2.  Stoica O, Trifan A, Cojocariu C, Gîrleanu I, Maxim R, Stanciu MC. Incidence and risk 
factors of Clostridium difficile infection in patients with inflammatory bowel disease. Rev 
Med Chir Soc Med Nat Iasi. 2015 Mar;119(1):81–86.  
3.  Bien J, Palagani V, Bozko P. The intestinal microbiota dysbiosis and Clostridium difficile 
infection: is there a relationship with inflammatory bowel disease? Therap Adv 
Gastroenterol. 2013 Jan;6(1):53–68.  
4.  Maharshak N, Barzilay I, Zinger H, Hod K, Dotan I. Clostridium difficile infection in 
hospitalized patients with inflammatory bowel disease: Prevalence, risk factors, and 
prognosis. Medicine. 2018 Feb;97(5):e9772.  
5.  Anderson A, Click B, Ramos-Rivers C, Cheng D, Babichenko D, Koutroubakis IE, et al. 
Lasting Impact of Clostridium difficile Infection in Inflammatory Bowel Disease: A Propensity 
Score Matched Analysis. Inflamm Bowel Dis. 2017;23(12):2180–2188.  
6.  Anderson AJ, Click B, Ramos-Rivers C, Babichenko D, Koutroubakis IE, Hartman DJ, et al. 
Development of an Inflammatory Bowel Disease Research Registry Derived from 
Observational Electronic Health Record Data for Comprehensive Clinical Phenotyping. Dig 
Dis Sci. 2016 Sep 12;61(11):3236–3245.  
7.  Wilcox MH, Gerding DN, Poxton IR, Kelly C, Nathan R, Birch T, et al. Bezlotoxumab for 
Prevention of Recurrent Clostridium difficile Infection. N Engl J Med. 2017 Jan 
26;376(4):305–317.  
8.     Robins, JM; Rotnitzky, A; Zhao, LP (1994). "Estimation of regression coefficients when 
some regressors are not always observed". Journal of the American Statistical Association. 
89 (427): 846–866. doi:10.1080/01621459.1994.10476818.) 
9.     Agresti, Alan (2002). Categorical Data Analysis. Hooken, New Jersey: John Wiley & Sons, 
Inc.) To adjust for multiple testings, the Hochberg’s step-up procedure will be used to 
control the familywise error rate at 0.05. (Reference: Hochberg, Yosef (1988). "A Sharper 
Bonferroni Procedure for Multiple Tests of Significance". Biometrika. 75 (4): 800–802. 

 
 
10. Wilcox MH, et al. N Engl J Med 2017;376:305–317.  
11. Kelly CP et al, Gastroentoroloty, 2018, 155: 1270-1271).