Prospective, Open-label Trial to Evaluate Efficacy of 30-day Duration of Fidaxomicin in Patients With Recurrent C. Difficile Infection
Phase: PHASE3
Conditions: Clostridium Difficile Infection
Sponsor: McMaster University

 
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Study Title: 
Prospective, open-label trial to evaluate efficacy of 30-day 
duration of fidaxomicin in patients with recurrent Clostridioides 
(Clostridium) difficile infection. 
Protocol Version Date/Number 
ClinicalTrial.gov 
Protocol No: 
01OCT2020  Version No. 5 
NCT02395848 
CDI.FIDAXOMICIN.1 
Primary Investigator Name: 
Christine H. Lee 
Primary Investigator Address: 
Safety Reporting: 
Vancouver Island Health Authority1952 Bay Street.  Victoria, BC  
V8R 1J8 
Vancouver Island Health Authority Clinical Research Ethics Board   
1 
STUDY RATIONALE/BACKGROUND 
 
Clostridioides difficile (C. difficile) infection (CDI) is one of the most frequent causes of 
healthcare associated infections and its rates are also growing in the community.  The case fatality 
rate associated with CDI is 6%.  CDI is also problematic as it can lead to chronic diarrhea and has 
been the source of outbreaks in many hospitals.1-6 
The efficacy of standard antibiotics especially for recurrent CDI is limited as oral vancomycin 
and metronidazole also suppress the growth of anaerobic bacteria such as Bacteroides fragilis (B. 
fragilis) group which protect against proliferation of C. difficile.  In contrast, in vitro study has 
shown that fidaxomicin has negligible activity against B. fragilis.  The persistent disruption of 
healthy colonic flora may be the reason for recurrences following a course of treatment with 
metronidazole or vancomycin.    Fidaxomicin has shown to reduce recurrences by approximately 
50% when compared to oral vancomycin for primary or 1st episode of recurrent CDI.   
 
There is a growing concern regarding failure rates for metronidazole, which is recommended as 
the first line therapy for uncomplicated CDI; as it has risen from 2.5% to greater than 18% since 
2000.1  Recurrence of CDI following a course of standard antibiotic (metronidazole/oral 
vancomycin) therapy is high, especially in the elderly patients over 65 years of age, in 
hospitalized and in the immunocompromised patients.  Rates of recurrences are greater than 50% 
for those over the age 65.9 The risk of further recurrence is over 60% for patients who have failed 
3 or more episodes of standard antimicrobial therapies.9-12  Fecal microbiota transplantation 
(FMT) has shown to be very effective for multiple recurrent CDI.13 Although effective, FMT has 
limitations as the majority of healthcare facilities, worldwide do not have the infrastructure 
available to offer the treatment as it requires readily available donors and laboratory capacity to 
screen donors and manufacture FMT in timely manner. There are also potential risks associated 
with FMT such as transmission of pathogens, including SARS-CoV-2, antibiotic resistant 
organism, development of bacteremia especially in immunocompromised hosts, peritonitis and 
intestinal perforation.14-16    
 
Determining the efficacy and safety of 30-day duration of fidaxomicin for recurrent CDI through 
an open label clinical trial has important implications for policy making related to the drug 
reimbursement programs.  In addition, the results of this study will be instrumental in 
demonstrating to the scientific and healthcare communities there may be a  role for the 30-day 

 
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course of fidaxomicin as a treatment modality for recurrent CDI.  Curing CDI will restore the 
health and quality of life not just at the individual patient level but to the healthcare communities 
as well.  Patients with refractory CDI require prolonged hospital admission, which increases the 
organism burden within the healthcare facilities.  This in turn leads to the spread of the infection 
to other vulnerable patients.  If a 30-day course of fidaxomicin proves to be safe and effective in 
curing patients with recurrent CDI, it will reduce the risk of severe complications in each patient 
and reduce transmission of CDI to other susceptible patients.  All these will also reduce 
healthcare costs.   
2 
STUDY HYPOTHESIS 
 
Thirty-day duration of fidaxomicin will be effective in reducing the rates of recurrence of CDI.  
Fidaxomicin has shown to reduce recurrences by 50% when compared to oral vancomycin for 
primary or 1st episode of recurrent CDI.  In vitro study has shown that fidaxomicin has virtually 
no activity against B. fragilis and may explain the significant reduction in C. difficile recurrences. 
3 
STUDY OBJECTIVE AND ENDPOINTS 
3.1 
STUDY OBJECTIVE 
To study the outcome of patients treated with a 30-day course of fidaxomicin for recurrent CDI 
3.2 
STUDY ENDPOINTS 
3.2.1 
PRIMARY  EFFICACY ENDPOINT  
1. Clinical response at study day 30, in this context, clinical response will be defined as those 
participants who have improvement in the number of bowel movements as determined by ≤ 3 
unformed stools in a 24-hour period for 2 consecutive days during treatment and remaining well 
through study day 30. 
2. Sustained clinical response as defined by those participants who achieved clinical response by 
study day 30 and did not experience a recurrence of CDI at the end of the follow-up period, 
evaluated at 8 weeks after the completion of treatment.   
3. Recurrence of CDI as defined by return of diarrhea (a minimum of 3 unformed bowel movements 
or  200 mL of stool for individuals with a stool collection device such as rectal tube or 
colostomy within a 24-hour period) and positive stool test after a period of symptom resolution 
within study period and has received at least a 10-day course of standard antibiotic therapy.   
4. Treatment failure as defined by patients not meeting the definition of cure and requiring 
additional treatment(s) for current CDI episode. 
3.2.2 
SECONDARY ENDPOINT(S):   
 
The evaluation of safety of 30-day duration of fidaxomicin (200mg twice daily x 10 days and 
200mg once daily x 20 days). 
o Assessment for adverse reactions by history, complete blood count and chemistry panel 
at day 10 (-3, +1d), followed by history on day 30 (+/-3d) and week 8 post treatment 
(week 12) of the study period.  
 
Any serious adverse events up to and including week 12 for any of the following: 
o Death or a life-threatening event 
o New hospitalization or prolongation of current hospitalization 
o A significant new incapacity to conduct normal life functions 

 
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4 
STUDY DESIGN 
4.1 
SITES  
            Vancouver Island Health Authority 
4.2 
INCLUSION/EXCLUSION CRITERIA 
4.2.1 
INCLUSION CRITERIA 
1. Age 18 years or older. 
2. Able to provide informed consent.  
3. Willing and able to comply with all the required study procedures. 
4. A positive stool test for C. difficile toxin/gene using either PCR or enzyme immunoassay within 3 
months of recruitment. 
5. History of at least ≥ 2 recurrent CDI within 6 months where recurrence is deﬁned as return of 
diarrhea consistent with CDI within 8 weeks following CDI symptom resolution for at least 24 
hours after a minimum of 10-day course of standard antibiotic therapy and positive stool test for 
C. difficile toxin or toxin gene and/or ongoing symptoms consistent with CDI despite at least 5 
days of treatment using oral vancomycin. 
6. Has more than three unformed bowel movements or  200 mL of stool for individuals with a 
stool collection device such as rectal tube or colostomy during a 24-hour period at the time of 
initiation of fidaxomicin.  Participants will be enrolled when they meet inclusion criteria 1 – 5; 
will be initiated on fidaxomicin when they have CDI symptoms and stool will be tested for C. 
difficile toxin/gene.  Only those with positive stool for C. difficile toxin/gene with current episode 
of CDI will continue with the study 
7. Females of child bearing potential must be willing to use acceptable birth control as per the 
Health Canada Guidance Document: Considerations for Inclusion of Women in Clinical Trials 
and Analysis of Sex Differences. 
4.2.2 
EXCLUSION CRITERIA 
1. Planned or actively taking an investigational product for another study. 
2. Prior fidaxomicin use. 
3. Hypersensitivity to fidaxomicin or to any ingredient in the formulation or component of the 
container. 
4. Evidence of toxic megacolon or gastrointestinal perforation or life expectancy of less than 72 
hours. 
5. Active gastroenteritis due to Salmonella, Shigella, E. coli 0157H7, Yersinia or Campylobacter. 
6. Anticipated requirement for systemic antibiotic therapy for more than 7 days during the study 
period. 
7. Actively taking Saccharomyces boulardii or other probiotics other than yogurt. 
8. Any condition that, in the opinion of the investigator, that the treatment may pose a health risk to 
the subject. 
9. Pregnant or lactating.  
4.3 
SAMPLE SIZE 
4.3.1 
NUMBER OF SUBJECTS TO BE ENROLLED 
A sample size of 50 is planned.  
 

 
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4.4 
SCREENING, RANDOMIZATION, BLINDING 
4.4.1 
SCREENING PROCEDURE 
Potential participants will be screened for eligibility based on the inclusion and exclusion criteria 
when the PI receives consultation request for recurrent CDI.Patients will be recruited to 
participate in the trial when they meet the inclusion criteria (1 to 5) and do not have any exclusion 
ones.  The eligible participants with active diarrhea with clinical criteria for CDI will be initiated 
on fidaxomicin.  For those without diarrhea at baseline will be instructed to phone the research 
office when they experience recurrent symptoms consistent with their previous episodes of CDI.  
They will be assessed within 48 hours of symptom onset and will be started on fidaxomicin if 
they continue to meet the inclusion criteria and do not have any exclusion ones.  The stool sample 
collected during the onset of this particular CDI episode will be tested for C. difficile toxin.  If 
positive then they will complete the 30-day course of fidaxomicin.  If the stool tested negative for 
C. difficile toxin then they will be excluded from further participation of this study and standard 
of care for this particular episode of diarrhea will be provided based on the most likely etiology. 
 
Females of child bearing potential must be willing to use contraception methods of birth control 
to participate in the study. Highly effective methods may include: hormonal contraceptives (e.g. 
combined oral contraceptives, patch, vaginal ring, injectables, and implants); intrauterine device 
(IUD) or intrauterine system (IUS); vasectomy and tubal ligation. Highly effective methods of 
contraception might not always be achievable in the clinical trial setting and, therefore, the most 
effective alternative can be achieved using methods in combination. Effective methods may 
include: barrier methods of contraception (e.g. male condom, female condom, cervical cap, 
diaphragm, contraceptive sponge). 
 
Use of therapeutic products where the risk of fetal abnormality is not known or is unclear (e.g. 
lack of adequate reproduction toxicity data), animal studies have failed to reveal evidence of fetal 
harm and use of fidaxomicin, however there are no controlled data in human pregnancy: therefore 
at least one highly effective method of contraception or two forms of effective contraception 
methods need to be used. 
The half-life of fidaxomicin is 11.7 +/- 4.8 hours therefore will specify to continue with 
contraception for 48 hours after the last dose of fidaxomicin. 
 
4.5 
REGULATORY AND ETHICS 
4.5.1 
INFORMED CONSENT 
Informed consent will be obtained from each participant.   
4.5.2 
INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE 
The study protocol and informed consent form and amendments will be submitted to the 
Vancouver Island Health Authority Clinical Research Ethics Board. 
4.5.3 
INVESTIGATIONAL NEW DRUG (IND) FILING  
No Objection Letter will be obtained from Health Canada. 

 
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5 
STUDY PROCEDURES  
5.1 
TREATMENT 
Participants will take fidaxomicin 200 mg by mouth (PO) twice daily for 10 days, followed by 
200 mg PO once daily for 20 days. 
 
5.2 
STUDY PROCEDURES SCHEDULE 
 
 
Baseline/Day 1 
 
 
Unscheduled visit 
 
Day 10 (-3 to +1d) 
 
Week 3 to 12 
 Procedure 
 
Eligibility screen 
 
Obtain consent 
 
Medical and CDI history 
 
Physical examination 
 
Laboratory testing if active 
diarrhea 
 
Active diarrhea 
consistent with CDI, 
collect stool sample 
and bring to clinic 
 
Weekly phone 
call 
 
 
 
Laboratory 
Testing 
 
CBC, chemistry, 
creatinine, albumin, 
sodium, potassium, 
chloride, alanine 
transaminase, alkaline 
phosphatase, bilirubin 
 
 
Stool testing for CD toxin 
 
Pregnancy test for females 
of child bearing potential 
 
 
 
CBC, chemistry, 
creatinine, albumin, 
sodium, potassium, 
chloride, alanine 
transaminase, alkaline 
phosphatase, bilirubin 
 
Stool testing for CD 
toxin, only if active 
diarrhea 
 
 
 
 
CBC, chemistry, creatinine, 
albumin, sodium, potassium, 
chloride, alanine transaminase, 
alkaline phosphatase, bilirubin 
 
 
 
 
 

 
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5.3 
STUDY TREATMENT SCHEDULE 
 
Day 1 to 10 
Day 11 to 30 
Treatment 
Fidaxomicin 200mg by 
mouth twice daily for 10 
days  
Fidaxomicin 200mg by mouth once daily for 20 days 
 
 
 
 
6 
SERIOUS ADVERSE DRUG REACTIONS 
6.1.1 
DEFINITONS 
Each serious adverse drug reaction (SADR) which is subject to expedited reporting to Health 
Canada should be reported individually in accordance with the data element(s) specified in the 
Health Canada/ICH Guidance Document E2A: "Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting". Expedited reports are required for events that meet all of 
these three criteria:  serious, unexpected and a suspected causal relationship. 
                       Serious:  Any untoward medical occurrence that at any dose:  
 
Results in death 
 
Life-threatening 
 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
 
Persistent or significant disability/incapacity 
 
Congenital anomaly/birth defect. 
6.1.2 
RELATIONSHIP TO STUDY MEDICATION 
Event reaction causality scoring system will be used to determine the probability of relationship 
to study medication 
6.1.3 
EXPECTEDNESS OF ADR 
An "unexpected" adverse reaction is one in which the nature or severity is not consistent with 
information in the relevant source document(s), such as the IB or Product Monograph.  
 
6.1.4 
RECORDING AND REPORTING SADR 
SADRs which are unexpected, serious AND suspected causal relationship to the study medication 
will be reported to the research ethics board within 24 hours of the PI being aware of the event. 
This information will also be reported to Health Canada: 
 
Health Canada 
Office of Clinical Trials 

 
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Therapeutic Products Directorate 
5th Floor, Holland Cross, Tower B 
A/L 3015A 
1600 Scott Street 
Ottawa, Ontario 
Canada K1A 0K9 
Fax: 613-941-2121 
7 
DATA COLLECTION AND ANALYSIS 
7.1 
DATA COLLECTION 
Data will be collected at baseline, at initiation of fidaxomicin, on day 10, day 30 and 8 weeks post  
treatment (week 12 of study) using source documents 
7.2 
DATA VALIDATION 
All data collected during the study will be validated by a second research staff using the 
investigator’s clinical notes, electronic medical records, and laboratory results comparing to the 
source documents 
7.3 
DATA / STATISTICAL ANALYSIS 
The clinical cure rate will be determined using standard binary outcome protocols. Also, logistic 
regression and survival analysis methods will be performed. The primary endpoints of clinical 
response, sustained clinical response, time to resolution of diarrhea (TTROD), recurrence of CDI, 
and treatment failure will be analyzed by logistical regression.  
8 
PUBLICATION 
 
The abstract will be submitted for presentation at Infectious Diseases Society of America or 
Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).  The manuscript 
will be submitted to a medical journal. 
9 
REFERENCES 
1. Kelly CP, LaMont JT Clostridium difficile-more difficult than ever. N Engl J Med 
2008;359:1932-40.  
2. Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multi-institutional outbreak of 
Clostridium difficile -associated diarrhea with high morbidity and mortality. N Engl J Med 
2005;353:2442-9. 
3. Lavallée C, Laufer B, Pépin J, Mitchell A, Dubé S, Labbé AC. Fatal Clostridium difficile enteritis 
caused by the BI/NAP1/027 strain: a case series of ileal C. difficile infections. Clin
 
Microbiol Infect 2009:15:1093-9. 
4. O’Connor JR, Johnson S, Gerding DN.  Clostridium difficile infection caused by the epidemic 
BI/NAP1/027 strain.  Gastroenterology 2009;136:1913-24. 
5. Quesada-Gómez C, Rodríguez C, Gamboa-Coronado Mdel M, Rodríguez-Cavallini E, Du T, 
Mulvey MR, Villalobos-Zúñiga M, Boza-Cordero R. Emergence of Clostridium difficile NAP1 in 
Latin America.  J Clin Microbiol 2010;48:669-70.  
6. Pillai DR, Longtin J, Low DE. Surveillance data on outbreaks of Clostridium difficile infection in 
Ontario, Canada, in 2008-2009.  Clin Infect Dis 2010;50:1685-1686.  

 
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7. Vonberg RP, Reichardt C, Behnke M. et. al.  Cost of nosocomial Clostridium difficile-associated 
diarrhea.  J Hosp Infect 2008;70:15-20. 
8. Dubberke ER, Olsen MA.  Burden of Clostridium difficile on the healthcare system.  Clin Infect 
Dis 2012;55(suppl 2): S88-92. 
9. O’Horo JC, Jindai K, Kunzer B, Safdar N. Treatment of recurrent Clostridium difficile infection: 
a systematic review. Infection. 2014;42(1):43-59. doi:10.1007/s15010-013-0496-x. 
10. Petrella L a., Sambol SP, Cheknis A, et al. Decreased cure and increased recurrence rates for 
clostridium difficile infection caused by the Epidemic C. difficile BI strain. Clin Infect Dis. 
2012;55(3):351-357. doi:10.1093/cid/cis430 
11. Pépin J, Saheb N, Coulombe M-A, et al. Emergence of fluoroquinolones as the predominant risk 
factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. 
Clin Infect Dis. 2005;41(9):1254-1260. 
12. McFarland L V., Elmer GW, Surawicz CM. Breaking the cycle: Treatment strategies for 163 
cases of recurrent Clostridium difficile disease. Am J Gastroenterol. 2002;97(7):1769-1775. 
13. van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper 
EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ. Duodenal infusion of donor 
feces for recurrent Clostridium difficile. N Engl J Med. 2013 Jan 31;368(5):407-15. 
14. Guo B, Harstall C, Louie T, Veldhuyzen van Zanten S, Dieleman L.  Systematic review:  faecal 
transplantation for the treatment of Clostridium difficle-associated disease.  Aliment Pharmacol 
Ther 2012;35:865-875. 
15. Gough E, Shaikh H, Manges AR.  Systematic Review of Intestinal Microbiota Transplantation 
(Fecal Bacteriotherapy) for Recurrent Clostridium difficile Infection. Clin Infect Dis 
2011;53(10):994-1002.  
16. Kassam Z, Lee CH, Yuan Y, Hunt RH. Fecal microbiota transplantation for Clostridium difficile 
infection: systematic review and meta-analysis. Am J Gastroenterol. 2013;108(4):500-8. 
doi:10.1038/ajg.2013.59. 
17. Louie T, Miller M, Mullane K, Weiss K, Lentnek A. et.al.   Fidaxomicin versus Vancomycin for 
Clostridium difficile infection.  N Engl J Med 2011;364:422-31. 
18. Louie T, Emery J, Krulicki W, Byrne B, Mah M.  OPT-80 Eliminates Clostridium difficile and Is 
Sparing of Bacteroides Species during Treatment of C. difficile Infection.  Antimicrob. Agents 
Chemother  2009;53: 261-263. 
19. Health Canada Guidance Document For Clinical Trial Sponsors: Clinical Trial Applications dated 
May 29, 2013. Available at: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-
ld/clini/ctdcta_ctddec-eng.php. Accessed 2015-Feb-18.  
20. Health Canada Guidance Document: Considerations for Inclusion of Women in Clinical Trials 
and Analysis of Sex Differences.  Appendix A: Considerations in using contraceptives in clinical 
trials.  Dated May 29, 2013.    Available at:  http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-
demande/guide-ld/clini/womct_femec-eng.php#aa.  Accessed 2015-Feb-18. 
 
 
 
 
 
 
 

 
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Appendix A: Telephone Script 
 
PHONE CONTACT SCHEDULE AND SCRIPT 
Weekly contact by phone –Week 3 to 8  
 
Participant phone follow-up script: 
 
Participant  ID: __ __ __ - __ __ __ 
 
 
 
 
Date: _____ / _____ / _______   
 
 
Time: __ __ : __ __ 
 
Hi, my name is ______________ from Vancouver Island Health Authority.  I would like to speak to 
Mr./Mrs./Ms.___________________ in regards to his/her participation in the research study for the 
treatment of Clostridioides difficile infection.  Mr./Mrs./Ms._________________, May I ask you a couple 
of questions in follow-up to your participation in this study?   All of the information that you share with 
me will remain strictly confidential.  
 Daily contact in person or by phone:   
 
1. How has your overall health been since we last spoke? 
2. Have you experienced any unformed bowel movement since we last spoke?  Yes/No 
 
If yes, have you had three or more unformed bowel movements in any 24 hour period during the follow-
up?   If yes, you will need to return for assessment, bloodwork and stool collection.  
 
Thank you for your time and your participation in this important research project.