Journal Club and Article Critique presented during an Internal Medicine Rotation at the Miami VA in June 2011.

1. Fidaxomicin versus
Vancomycin for Clostridium
Difficile Infection
N Engl J Med 2011:364:422-31
Authors: Louie TJ, Miller MA, Mullane KM et. al.
Joy A. Awoniyi, PharmD Candidate 2012
Florida Agricultural and Mechanical University
June 20, 2011
Preceptor: Dr. Helen Yotseff, PharmD
Internal Medicine
Miami Veterans Affairs Medical Center

2. Background – C. Difficile
Clostridium Difficile
• Gram-positive, anaerobic, spore-forming
bacillus
• Infection is a result of a disturbance of the
normal flora of the colon
• Responsible for development of antibiotic-
associated diarrhea and colitis
• Incidence and severity of infection is
increasing
• Emergence of a hypervirulent strain:
NAP1/B1/027
• Reduced clinical response, increased recurrence

3. Background – C. Difficile
SHEA-IDSA 2010 Clinical Practice Guideline
Recommendations
Nature of Recommendation
Infection
Mild-Moderate Metronidazole 500mg orally three times daily for
10-14 days
Severe Vancomycin 125mg orally four times daily for 10-
14 days
Severe, Vancomycin 500mg orally or rectally 4 times daily
Complicated -with or without-
Metronidazole intravenously 500mg every 8
hours

4. Background - Fidaxomicin
• Macrolytic Antibiotic
• 8 times more active than
Vancomycin in vitro against
isolates of C. Difficile
• Highly active, but more
selective
• Associated with a low rate
of recurrence in a Phase 2
Trial(2009)

5. Study Objective
The stated purpose of this study
was to “compare the efficacy and
safety of fidaxomicin with those of
vancomycin in treating Clostridium
Difficile infection”

6. Methods
Study Design Research and Analysis
• Double-blind • Written, informed consent
provided by each patient
• Randomized
• Sponsored by Optimer
• Parallel Group Pharmaceuticals
• Multi-center • Analysis performed by the
authors and one investigator
at Optimer Pharmaceuticals

7. Methods
Inclusion Criteria Exclusion Criteria
• Life-threatening or fulminant infection
• 16 years or older
• Toxic megacolon
• Clostridium Difficile diagnosis
• Previous exposure to fidaxomicin
• Diarrhea with more than 3
unformed stools within 24 hours • History of ulcerative colitis or Chron’s
• Toxin A, B or both in stool disease
specimen obtained 48 hours
before randomization • More than one occurrence of C. Difficile
infection three months before the start
of the study
Note: Patients may have received up to 4 doses of Metronidazole or
Vancomycin in the 24 hour period prior to randomization

8. Methods
Study Population
• 692 patients enrolled
• 596 in the modified intention-to-treat
population
• 548 in the per-protocol population
• Centers located in the United States and
Canada
• Stratified according to whether infection was
the first or second episode within 3 months

9. Baseline Characteristics

10. Intervention
• Each subject was randomized to receive a study
medication orally every 6 hours for ten days
• All pills were encapsulated to look the same
Fidaxomicin Group Vancomycin Group
• 200mg every 12 hours • 125mg every 6 hours
• Intervening doses of • No placebo
placebo

11. Assessment
• Patients were assessed daily for clinical cure
or failure
• Recurrence was recorded by a weekly
assessment for 28 days after the last dose
• Patient-initiated reassessment was
performed if diarrhea occurred

12. Study Outcomes
Primary Endpoint
• Rate of clinical cure in the modified intention-
to-treat and per-protocol populations
Secondary Endpoints
• Recurrence of infection during the 4-week
period after the end of the course of therapy
• Global cure in the modified intention to treat
and per-protocol populations

13. Definitions
• Resolution of diarrhea and maintenance of
resolution for the duration of therapy and no
further requirement
•Persistence of diarrhea and need for
additional therapy
•Resolution of diarrhea without
recurrence
• Reappearance of more than 3 diarrheal
stools per 24 hour period within 4 weeks
after the cessation of therapy

14. Statistical Analysis
Rate of Clinical Cure One-sided lower 95.7%
confidence interval
Recurrence and Overall Cure Post Hoc Hypothesis Tests
*Significance level of 0.05
Treatment differences Post Hoc Analysis
• Age
• Inpatient vs. Outpatient
• Prior Occurrence
• Disease Severity
• Strain Type
Time to Resolution of Diarrhea Kaplan-Meier Method
Comparison of time to resolution Gehan-Wilcoxon Test

15. Results
Primary Endpoint
Clinical Cure
• Modified Intention to Treat
• 88.26% with Fidaxomicin
• 85.80% with Vancomycin
Lower boundary of 97.5% CI for
difference of -3.1 percentage points
• Per-protocol
• 92.1% with Fidaxomicin
• 89.8% with Vancomycin
Lower boundary of 97.5% CI for
difference of -2.6 percentage points

16. Results
Secondary Endpoint
Recurrence rate was significantly lower
for patients treated with fidaxomicin
• Modified Intention to Treat (P=0.005)
• 15.4% with Fidaxomicin
• 25.3% with Vancomycin
95% CI, -16.6 to -2.9
• Per-protocol (P=0.004)
• 13.3% with Fidaxomicin
• 24.0% with Vancomycin
95% CI, -17.9 to -3.3

17. Results
• Rates of recurrence were similar among both groups when
comparing patients infected with the resistant strain
• With other strains, the rate of recurrence was lower with
fidaxomicin
•Results represented a 69% relative reduction in recurrences
Recurrence Rates
BI/NAP/027 Strain Other Strains
24.40% 23.60% 25.50%
7.80%
Fidaxomicin Vancomycin

18. Results
Secondary Endpoint
Global Cure – Higher rates of resolution of
diarrhea without recurrence were seen
with fidaxomicin.
• Modified Intention to Treat (P=0.006)
• 74.6% with fidaxomicin
• 64.1% with vancomycin
95% CI, 3.1 to 17.7
• Per-protocol (P=0.006)
• 77.7% with Fidaxomicin
• 67.1% with Vancomycin
95% CI, 3.1 to 17.9

19. Results
Notable Adverse Reactions Reported in the Safety
Population
Event Fidaxomicin Vancomycin P-Value
(N=300) (N =323)
Any Adverse Event 187 (62.3%) 10(60.4%) 0.6224
Chills 1(0.3%) 8 (2.5%) 0.0389
Dizziness 12 (4%) 4 (1.2%) 0.0405
Rash 9 (3%) 2 (0.6%) 0.0315
Any Serious Adverse 75 (25%) 78 (24.1%) 0.8523
Event
Laboratory 14 (4.7%) 4 (1.2%) 0.0148
Abnormalities*
All Cause Mortality 16 (5.3%) 21 (6.5%) 0.6122
*Laboratory Abnormalities included hyperuricemia and increased ALT/AST but the differences
between groups seemed to be of incidental, unrelated findings.

20. Author’s Conclusions
• Rates of clinical cure after treatment with fidaxomicin
were non-inferior to those after treatment with
vancomycin
• Fidaxomicin was associated with a lower rate of recurrence
of C. Difficile infection associated with non-North American
Pulsed Field type 1 strains

21. Article Critique

22. Title
Fidaxomicin versus Vancomycin for Clostridium Difficile
infection
• Un-biased
• Overall, reflective of the study question and study
outcome
• Severity of disease not mentioned, while “treatment of
Clostridium Difficile” is guided by severity
• “Versus” may imply superiority, which was not the
objective of the study

23. Abstract
• Well structured
• Background
• Methods
• Results
• Conclusions
• Study endpoints were addressed in each
segment, directly or indirectly

24. Introduction and Background
Good Could Be Better
• Addressed the current clinical • The disease state, C. Difficile
relevance of the study Associated Diarrhea, is not
adequately described
• Referenced outcomes of a • Risk factors
previous Phase II trial of • Clinical Presentation
Fidaxomicin (“diarrhea” never
• Links past findings to the mentioned)
study objective
• Emphasis on burden to
facility, rather than burden to
patient

25. Study Design
Good Could Be Better
• Appropriate time frame • Analysis of data was
(5/2006 – 8/2009) performed by the authors,
• Double-blinded and which included employees
Randomized by computer and stock-owners for
• Medication kit and number Optimer Pharmaceuticals,
to each patient manufacturer of the study
• Utilized both Modified drug
intention-to-treat and Per
protocol populations
• IRB Approved

26. Study Population
Good Could Be Better
• Multi-centered • Possible confounding
factors
• Informed consent • Use of proton-pump
Inhibitors/ H-2 Antagonists
• Characteristics evenly
distributed among • Selection Bias: Inclusion of
treatment groups patients previously treated
with vancomycin but not
• Appropriate age group: fidaxomicin
Advanced age is a risk
factor
• mITT mean age: 61.6 16.9
• PP mean age: 61.3 17.1

27. Intervention and Assessment
Good Could Be Better
• Treatment guidelines were • Clinical cure and failure
followed appropriately was determined by need
• Vancomycin dosing for further treatment in
• Diagnosis of C. Difficile the opinion of the
infection
investigator
• Blinding maintained by
similar daily dosing schedule • Vancomycin treatment
duration for 10 days vs. 14
• Use of other potentially days
effective treatments not
permitted

28. Statistical Analysis
Good Could Be Better
• Non-inferiority margin • No mention of study power
defined as -10 percentage goal or achievement
points
• Time to resolution of
• Appropriate statistical diarrhea measured in hours,
methods used to analyze while assessed daily
primary and secondary
outcomes

29. Results
Good Could Be Better
• Results of each identified study • Adherence was measured to
outcome is addressed for both be similar but no mention as
mITT and PP population and a
to the method of adherence
chart included
testing
• Subgroup analysis performed
• Success of blinding not
• Adverse effects were reported measured
and well documented
• No subjects discontinued the
study due to intolerance or
allergy to the study medication

30. Effect of Severity on
Fidaxomicin
• Clinical Cure
Vancomycin seemed to show increased trend in clinical cure with
increasing severity, while fidaxomicin seemed to show a decrease
• P-Values were not given
94% 92.2% 96% 94.9% 94.3%
91.9%
92% 94%
90% 92% 93.0%
88% 88.6%
90%
86%
85.0% 88% 88.1%
84% 88.7%
83.0% 86%
82% 82.1%
86.3%
80% 84%
Severity vs. Clinical Cure Severity vs. Clinical Cure
Modified ITT Population Per-Protocol Population
* Graphs generated from data found in Table 2.

31. Discussion and Conclusion
Good Could Be Better
• Primary and Secondary • No limitations are identified
conclusions were valid and
supported by the presented • Laboratory abnormalities
data were of statistical
significance, but not
• Issue of the inability to reduce addressed
the rate of recurrence with
the resistant strain was
addressed
• Discussion is comprehensive
and establishes study value

32. Overall Impression
• Study was ethical, appropriately conducted, and produced useful
results
• Bias may be present, considering the conductors of data analysis
were affiliated with the drug manufacturer
• Non-inferiority of fidaxomicin to vancomycin was established
• Confounders not considered
• Origin of infection
• H-2 antagonist and Proton Pump Inhibitor use
• Need for a reassessment of fidaxomicin versus vancomycin in
patients with severe Clostridium Difficile infection

33. Study Applications
• This study aided in the FDA decision for approval of
Fidaxomicin (Dificid®) in May 2011
• Proving non-inferiority, fidaxomicin provides a reasonable
alternative to vancomycin in the treatment of Clostridium
Difficile associated diarrhea in the future
• Currently being investigated are new indications for the
drug and an oral suspension formulation

34. QUESTIONS?

35. References
• Article Supplementary Appendix. New England Journal of Medicine Website. Available online
at: http://www.nejm.org/doi/suppl/10.1056/NEJMoa0910812/suppl_file/nejmoa0910812
_appendix.pdf. Accessed: 6/10/11.
• Aseeri M, Schroeder T, Kramer J, et al. “Gastric Acid Suppression by Proton-pump Inhibitors
as a Risk Factor for Clostridium difficile- Associated Diarrhea in Hospitalized Patients”.
Am J Gastroenterol. 2008;103: 2308-2313.
• Cohen SH, Gerding DN, Johnson S, 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): 000-000.
• Louie TJ, Miller MA, Mullane KM, et al. “Fidaxomicin versus Vancomycin for Clostridium
difficile Infection”. N Eng J Med. 2011; 364(5): 422-31.