Conditions: Clostridium Difficile Infection (CDI)
Keywords: vancomycin fidaxomicin CDI diarrhea
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 144
Healthy volunteers: no

Brief summary:
Administration of concomitant antibiotics (CA) is a known risk factor for treatment failure in the treatment of CDI, as well as for recurrence of CDI. Recent data suggested that among patients receiving CA, fidaxomicin is superior to vancomycin. While these data are encouraging, many clinicians remain unclear on how to apply these data to patient care. Additionally, patients were excluded from the trials presented to the FDA if it was expected that they would require ≥ 7 days of CA. Therefore, the clinical question still remains of how to apply these data to the real world patient who requires a long course of CA and develops CDI while on therapy. We therefore propose an open label, comparative and prospective study of fidaxomicin 200 mg twice daily vs oral vancomycin 125 mg four times daily for the treatment of CDI among patients who are receiving a long course of CA.

We hypothesize that fidaxomicin will be superior to vancomycin with respect to clinical cure for patients with CDI.

Detailed description:

Arms:
arm 1: Fidaxomicin 200 mg PO BID for 10 days or until the end of the duration of concomitant antibiotic exposure, whichever is longer. arm 2: Vancomycin 125 mg PO QID for 10 days or until the end of the duration of concomitant antibiotic exposure, whichever is longer.

Interventions: intervention 1: Fidaxomicin intervention 2: Vancomycin
Intervention descriptions: intervention 1: Eligible patients randomized to receive open-label Fidaxomicin will receive 200 mg twice daily for 10 days or until the end of the duration of concomitant antibiotics exposure, whichever is longer. intervention 2: Eligible patients randomized to Vancomycin will receive 125 mg orally four times daily for 10 days or until the end of the duration of concomitant antibiotics exposure, whichever is longer.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A comparison of fidaxomicin and oral vancomycin for the 
treatment of Clostridium difficile infection (CDI) in 
hospitalized patients receiving concomitant antibiotics for the 
treatment of concurrent infections 
 
 
 
NCT02692651 
 
 
September 4, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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  Study Title: 
A comparison of fidaxomicin and oral vancomycin for the treatment of Clostridium 
difficile infection (CDI) in hospitalized patients receiving concomitant antibiotics for 
the treatment of concurrent infections 
 Protocol Version Date: 
04Sep2019 
 Protocol Version Number: 
4.0 
 Primary Study Principal Investigator Name: 
Krishna Rao, MD, MS 
Primary Coordinating Center Address: 
University of Michigan Health System 
1500 E. Medical Center Drive  
Ann Arbor, MI  48109 
Secondary Performance Site Address:  
St. Joseph Mercy Ann Arbor Hospital 
5301 McAuley Dr. 
Ypsilanti, MI 48197 
Site Principal Investigator:  
Anurag Malani, MD 
 
1 
STUDY RATIONALE/BACKGROUND 
Administration of concomitant antibiotics (CA) is a known risk factor for treatment failure in 
the treatment of CDI, as well as for recurrence of CDI. Recent data suggested that among 
patients receiving CA, fidaxomicin 200 mg twice daily is superior to oral vancomycin 125 
mg four times daily with clinical cure rates of 90.0% and 79.4%, respectively (p= 0.04)1. 
While these data are encouraging, many clinicians remain unclear on how to apply these 
data to patient care as a conservative definition for CA was used in this trial (any patient 
who received ≥ 1 dose of antibiotic was considered to have CA.) Additionally, patients were 
excluded from the trial if it was expected that they would require ≥ 7 days of CA2.  
Therefore, the clinical question still remains of how to apply these data to the real world 
patient who requires a long course of CA and develops CDI while on therapy. We therefore 
propose an open label, comparative and prospective study to compare fidaxomicin 200 mg 
twice daily vs oral vancomycin 125 mg four times daily for the treatment of CDI among 
patients who are receiving a long course of CA. 
 
2 
STUDY HYPOTHESIS 
Fidaxomicin will be superior to vancomycin with respect to clinical cure for patients with 
CDI requiring a long course of broad spectrum CA for the treatment of concomitant 
systemic infections. 
 
 
2.1 PRELIMINARY DATA 


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          The only preliminary data are the Mullane paper data, which are described above. 
 
3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
STUDY OBJECTIVES 
3.1.1 PRIMARY OBJECTIVES: 
To compare the clinical cure rate using fidaxomicin compared to oral vancomycin for 
the treatment of CDI in patients requiring CA. 
3.1.2 SECONDARY OBJECTIVES: 
To compare the impact of therapy (fidaxomicin versus vancomycin) on recurrence, 
length of stay, ICU length of stay (when applicable), time to resolution of diarrhea*, 
rates of colectomy, and 30 day mortality (both attributable and all cause) in patients 
with CDI requiring CA for concomitant systemic infections. 
 
* Two definitions of time to resolution of diarrhea will be analyzed. The first, which 
will be a component of clinical cure, is consistent with published CDI literature and 
will be defined as ≤ 3 unformed stools for 2 consecutive days maintained until the 
end of therapy and for 2 days afterward. The second definition, which has important 
infection control implications, is complete resolution of diarrhea, which would 
facilitate removal of the patient from contact isolation. 
 
3.2 STUDY ENDPOINTS 
3.2.1 PRIMARY ENDPOINT: 
Clinical cure 
3.2.1.1 PRIMARY ENDPOINT DEFINITION: 
Resolution of diarrhea (≤3 unformed stools for 2 consecutive days maintained 
until the end of therapy and for 2 days afterward). Clinical failure will be 
defined as persistent diarrhea and/or the need for additional treatment for 
CDI at the end of study therapy. 
 
3.2.2 SECONDARY ENDPOINT(S): 
Recurrence, length of stay (LOS), ICU LOS, time to resolution of diarrhea (total), 
rates of colectomy due to CDI, 30 day mortality, and 30 day readmission. 
 
3.2.2.1 SECONDARY ENDPOINT DEFINITION(S): 
Recurrence:  defined as all three of the following within 4 weeks after 
successfully completing study treatment: reappearance of symptoms of CDI 
(>3 unformed stools in a 24 hour period), a positive stool test for C. difficile 
(Figure 1), and the need for retreatment with an agent active against C. 
difficile. 
 
Length of Stay:  defined as the length of stay from the time of study 
enrollment until discharge from the hospital. 
 
ICU length of stay:  pertinent to patients in the ICU at the time of study 


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enrollment and patients admitted to the ICU within 48 hours after study 
enrollment/C. difficile onset. Defined as the length of stay from enrollment in 
the study until discharge from the ICU. 
 
•  Time from study enrollment to resolution of diarrhea (as 
defined earlier in 3.1.2)  
• 
Rates of colectomy due to CDI 
• 
30 day mortality, both overall and attributable 
 
Subgroup analysis:  A subgroup analysis will be performed analyzing the above 
outcomes in patients with severe disease (defined as Scr ≥ 1.5 mg/dL or WBC 
≥ 15,000 cells/mm3) and also for those with mild-moderate disease. 
 
4 
STUDY DESIGN 
4.1 
SITE 
This study will be performed at The University of Michigan and at St. Joseph’s 
Mercy Ann Arbor Hospital. 
4.2 
INCLUSION/EXCLUSION CRITERIA 
4.2.1 INCLUSION CRITERIA 
▪ 
Patients 18 years of age or older with >3 unformed stools/24 hours with 
positive stool test for C. difficile. 
 
▪ 
Patients receiving ≥ 1 high or medium risk antibiotic for treatment of an 
infection other than CDI, for an anticipated duration of ≥ 5 days from the 
time of enrollment 
•  High risk: carbapenems, 2nd-4th generation cephalosporins, 
fluoroquinolones, clindamycin, and beta-lactam/beta-lactamase 
inhibitor combinations  
• 
Medium risk: 1st generation cephalosporin, macrolides*, and 
aztreonam 
o *The macrolide would be considered to be low risk  if 
patients are receiving intermittent macrolides for 
prophylaxis only and not for treatment of an acute 
infection 
 
4.2.2 EXCLUSION CRITERIA 
• Patients with severe-complicated disease that would compromise oral 
therapy (hypotension or shock, ileus or bowel obstruction, megacolon) 
 
• Patients with an allergy to oral vancomycin or fidaxomicin 
 


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• Patients anticipated to receive metronidazole after enrollment 
 
• Patients who already received oral vancomycin or metronidazole (either oral 
or intravenous) for > 24 hours within the preceding 72 hours at the time of 
enrollment 
 
• Patients anticipated to receive adjunctive C. difficile therapy (rifaxamin, 
nitazoxanide, tigecycline) after enrollment 
 
• Patients who are on laxatives before they are enrolled into the study, such as 
lactulose, if: 
o Patients have had a recent dose adjustment; 
o Baseline number of bowel movement while on laxatives is unknown.  
o Number of bowel movements and/or consistency has not changed from 
baseline. 
• Patients who have had colostomy or ileostomy  
• Patients who will have colostomy or ileostomy after enrollment and before 
study ends 
• Patients who are or will be on long-term (>12 weeks) medium or high-risk 
antibiotics prophylaxis after enrollment  
 
4.3 
SAMPLE SIZE 
4.3.1 NUMBER OF CHARTS TO BE REVIEWED 
Not applicable 
 
4.3.2 NUMBER OF SUBJECTS TO BE ENROLLED 
1500 patients will be expected over the study period (2.5 years) at the sites. During 
study assessment it was determined that ~ 41% of all patients at the sites would be 
eligible for the study (having CDI while on a high or medium risk CA for an 
expected duration of ≥ 5 days, and having not received 24 hours of pre-treatment of 
vancomycin or metronidazole) leaving 615 eligible patients over the study period. 
Given the open label nature of this study we anticipate being able to enroll 200 of 
these eligible patients, 100 to each treatment arm, based on the low drop-out rate 
(<2%) that we have seen thus far.  This would allow us to have approximately 100 
evaluable patients in each study arm. 
 
4.3.3 SAMPLE SIZE DETERMINATION 
We hypothesize that the clinical cure discrepancy should be greater than the 
discrepancy reported by Mullane and colleagues because more patients who are 
receiving long course of CA will fail to reach clinical cure on vancomycin. 
Therefore, our power calculations are based off an expected 90% cure rate with 
fidaxomicin and 75% with vancomycin, and a total sample number of 200. In order 
to have 80% power, with an alpha of 0.05, 100 patients will need to be randomized 
into each arm (total n = 200). 
 


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4.4 
SCREENING, RANDOMIZATION, BLINDING 
4.4.1 SCREENING PROCEDURE 
Patients will be screened for inclusion by real time surveillance of positive C. 
difficile results per the local standard of care C. difficile testing platform and 
assessed for eligibility using the Stool Testing Algorithm for C. difficile (Figure 1). 
Study personnel will receive all positive results in real time and will then screen 
the patient for inclusion and exclusion criteria. Screening will occur 7 days a 
week. If a patient meets inclusion criteria the study staff will approach the primary 
team and with their approval the patient for enrollment. 
4.4.2 RANDOMIZATION 
Patients will be stratified for randomization based on two criteria: severity of CDI, 
and CDI episode (stratified into first episode/first recurrence or > 1 recurrence). 
 
Once a patient is enrolled in the study, study staff will randomize patients utilizing 
a randomization binder stored electronically by the coordinating center. The patient 
will be placed in an open label treatment arm as described below. 
 
4.4.3 BLINDING 
The study is open label so this is not applicable. 
 
4.5 
REGULATORY AND ETHICS 
4.5.1 INFORMED CONSENT 
Study staff will acquire informed consent at the time of patient enrollment either 
from the patient or their legally authorized representative (LAR). 
 
4.5.2 INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE 
The coordinating center IRB, IRBMED at the University of Michigan, will review 
and approve the protocol followed by local IRBs at all performance sites. 
 
4.5.3 INVESTIGATIONAL NEW DRUG (IND) FILING 
Not applicable. Both agents are standard of care treatments for C. difficile infection 
and have an FDA indication for treatment of C. difficile infection. 
 
5 
STUDY PROCEDURES 
5.1 
TREATMENT 
All patients with a positive stool test for C. difficile (Figure 1) at the study 
hospitals will be screened for inclusion. Patients will be eligible for inclusion if 
they are being treated with ≥ 1 concomitant high risk or medium risk antibiotic 
for treatment of another systemic infection and the anticipated duration of therapy 
with the CA per the physician of record is ≥ 5 days from the time of study 
enrollment (i.e. enrollment day.) Eligible patients will be randomized to receive 
open-label fidaxomicin 200 mg twice daily or vancomycin 125 mg orally four 
times daily for 10 days or until the end of the duration of CA exposure, whichever 
is longer. Patients will be allowed to have received up to 24 hours of C. difficile 


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therapy prior to study enrollment. 
Intervention:  Fidaxomicin 200 mg PO BID vs. Vancomycin 125 mg PO QID 
5.2 
PROCEDURES 
Schedule of Procedures / Study Events 
Scheduled Assessment or Procedure 
Study Day 
-1 to 1 
(Baseline) 
Daily while 
in hospital 
EOT 
TOC 
Physical Exam 
X 
Standard of care lab results 
X 
X 
X 
X 
Temperature 
X 
X 
X 
X 
Number of unformed bowel movements/24 hours 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
 
* Laboratory values will be recorded as ordered and evaluated by attending team 
caring for the patient outside of this study. The standard of care lab results that 
will be collected from subject medical records as a part of the study are your 
white blood cell count, platelets, ALT, AST, total bilirubin, albumin, 
prothrombin time, serum creatinine, lactic acid, and carbon dioxide. No 
laboratory values will be ordered by study personnel or charged to the study. If 
the patient has left the hospital before end of treatment (EOT) or Test of Cure 
(TOC), they will be instructed to monitor their symptoms daily and keep note of 
fevers and number of bowel movements. Follow up phone calls to assess cure and 
recurrence will be made at the EOT and TOC dates when necessary.  
 
5.3 
ADVERSE EVENT REPORTING 
5.3.1 
DEFINITIONS 
A mild adverse event is one that is noticeable to the investigator, physicians 
caring for the patient and/or the patient, however does not interfere with routine 
clinical care and requires no specific intervention. An example of this would be 
mild nausea from study medication. 
A moderate adverse event interferes with routine clinical care, however responds 
to symptomatic management. An example would be vomiting that responds to 
anti-emetic therapy. 
A severe adverse event is one that limits the subject’s ability to perform 
routine activities and does not respond to symptomatic treatment. An adverse 
event would also be considered severe if it worsens clinical prognosis, 
requires escalation in level of care (i.e. ICU admission), or negatively impacts 
outcome variables. An example of this   would be anaphylactic shock 
secondary to the study medications. 
5.3.2 
RELATIONSHIP TO STUDY MEDICATION 
The following criteria will be used to determine relatedness to the study medication: 
 
Not Related: an AE with a temporal relationship to the drug administered that 
makes a causal relationship improbable, and/or for which other drugs or 
underlying or concurrent disease provide a plausible explanation. 
Unlikely Related: an AE that has a plausible temporal relationship to the drug 


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administered, but for which other causative factor(s) more likely account for the 
event and where dechallenge (withdrawal of drug treatment) or dose reduction 
was not felt clinically indicated or improvements on dechallenge or dose 
reduction have not been observed. 
Possibly Related: an AE that has a plausible temporal relationship to the drug 
administered, but for which other causative factor(s) could account for the event 
and where improvements on dechallenge or dose reduction may or may not have 
been observed. 
5.3.3 EXPECTEDNESS OF AE 
An AE is considered unexpected if the specificity or severity is not consistent 
with the applicable product information for either fidaxomicin or vancomycin. 
 
5.3.4 RECORDING AND REPORTING A SAE 
5.3.4.1 STUDIES NOT PERFORMED UNDER AN IND 
Adverse Events (AEs) will be recorded on the case report form in REDCap. 
Serious Adverse Events (SAEs) and non-serious AEs will be reported to the 
performance site IRBs in accordance with local guidelines.  SAEs meeting the 
NIH definition of Unanticipated Problem will be reported to the FDA. 
Coordinating center staff will also work with Cubist/Merck as necessary to 
address any AE's related to study product. 
 
5.3.4.2 STUDIES PERFORMED UNDER YOUR OWN IND 
          Not Applicable. 
 
6 
DATA COLLECTION AND ANALYSIS 
6.1 
DATA COLLECTION 
Data collection will be completed by performance site using a standardized data 
collection form provided by the coordinating center through REDCap with all 
relevant patient-specific and treatment-related information. 
6.2 
DATA VALIDATION 
 
Members of each performance site’s study team who do not participate in data entry 
will validate clinical outcomes, as reported in the data collection form, in 10% of 
patient cases. If significant discrepancies are found in ≥ 10% of the analyzed cases, 
then full validation will occur for all patient cases. 
 
6.3 
DATA / STATISTICAL ANALYSIS 
All statistical analyses will be performed by the coordinating center via SAS version 
9.3. For objective 1, the clinical cure rates of the two treatment arms will be compared 
using Fisher’s exact test. Other analyses relevant to objective 1 will be performed with 
Chi Square test, Student t test and Wilcoxon rank sum test. Multivariate models will be 
constructed using logistic regressions to identify individual factors associated with 
either cure or failure. Variables associated with cure or failure in the bivariate analyses 
with p values < 0.10 will be put into the multivariate models. Treatment arm will be 
forced into the model as appropriate and other variables that the investigators deem 


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clinically relevant may be placed in the model as appropriate. For objective 2, analyses 
will be conducted using the same tests as above and multivariate modeling will also be 
performed. For the time to resolution of diarrhea, cox proportional hazard models will 
be performed to compare the two groups. 
 
For patients who are lost to follow up, their endpoints that have not yet been assessed 
(recurrence, readmission, and potentially cure) will be considered indeterminate. Two 
analyses will be done, one where these patients are omitted (clinically evaluable 
population), and one where these patients are failures (intent to treat). 
 
7 
PUBLICATION 
It is expected that this will be a high impact article and we will target Clinical Infectious 
Diseases for publication.  Interscience Conference on Antimicrobial Agents and Chemotherapy 
(ICAAC), IDWeek, or European Congress of Clinical Microbiology and Infectious Diseases 
(ECCMID) are potential places for abstract submission depending on the time of year that 
results are finalized. 
 
8 
TIMELINE 
IRB approval x 3 months  
Study duration x 48 months 
Manuscript preparation x 3 months 
 
 9 
REFERENCES 
Mullane KM et.al. Efficacy of Fidaxomicin Versus Vancomycin as Therapy for 
Clostridium Difficile Infection in Individuals Taking Concomitant Antibiotics for Other 
Concurrent Infections. Clin Infect Dis. 2011; 53(5): 440-7. 
 
Louie TJ et al.  Fidaxomicin versus Vancomycin for Clostridium difficile Infection. N Engl J 
Med 2011; 364:422-431. 
 
Cohen SH, et al.  Clinical practice guidelines for Clostridium difficile infection in adults: 
2010 update by the society for healthcare epidemiology of America (SHEA) and the 
infectious diseases society of America (IDSA).  Infect Control Hosp Epidemiol. 2010; 
31(5):431-55. 
 


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Figure 1. Performance site Stool Testing Algorithm for C. difficile, 
Abbreviations: EIA, enzyme immunoassay; GDH, glutamate dehydrogenase.