Fidaxomicin versus Vancomycin for
Clostridium Difficile Infection
Joy A. Awoniyi, PharmD Candidate 2012Florida Agricultural and Mechanical University
June 20, 2011
Preceptor: Dr. Helen Yotseff, PharmDInternal Medicine
Miami Veterans Affairs Medical Center
N Engl J Med 2011:364:422-31
Authors: Louie TJ, Miller MA, Mullane KM et. al.
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
Background – C. Difficile
SHEA-IDSA 2010 Clinical Practice Guideline Recommendations
Nature of Infection
Recommendation
Mild-Moderate Metronidazole 500mg orally three times daily for 10-14 days
Severe Vancomycin 125mg orally four times daily for 10-14 days
Severe, Complicated
Vancomycin 500mg orally or rectally 4 times daily
-with or without-Metronidazole intravenously 500mg
every 8 hours
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)
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”
Methods
Study Design
• Double-blind
• Randomized
• Parallel Group
• Multi-center
Research and Analysis
• Written, informed consent provided by each patient
• Sponsored by Optimer Pharmaceuticals
• Analysis performed by the authors and one investigator at Optimer Pharmaceuticals
MethodsInclusion Criteria
• 16 years or older
• Clostridium Difficile diagnosis
• Diarrhea with more than 3 unformed stools within 24 hours
• Toxin A, B or both in stool specimen obtained 48 hours before randomization
Exclusion Criteria• Life-threatening or fulminant
infection
• Toxic megacolon
• Previous exposure to fidaxomicin
• History of ulcerative colitis or Chron’s disease
• 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
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
Baseline Characteristics
There were no significant between-group differences
Intervention
Fidaxomicin Group
• 200mg every 12 hours
• Intervening doses of placebo
Vancomycin Group
• 125mg every 6 hours
• No placebo
• Each subject was randomized to receive a study medication orally every 6 hours for ten days
• All pills were encapsulated to look the same
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
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
Definitions• Resolution of diarrhea and
maintenance of resolution for the duration of therapy and no further requirement
Clinical Cure
• Persistence of diarrhea and need for additional therapy
Clinical Failure
• Resolution of diarrhea without recurrence
Global Cure
• Reappearance of more than 3 diarrheal stools per 24 hour period within 4 weeks after the cessation of therapy
Clinical Recurrence
Statistical AnalysisRate of Clinical Cure One-sided lower 95.7%
confidence intervalRecurrence and Overall Cure
Post Hoc Hypothesis Tests*Significance level of 0.05
Treatment differences• Age• Inpatient vs. Outpatient• Prior Occurrence• Disease Severity• Strain Type
Post Hoc Analysis
Time to Resolution of Diarrhea
Kaplan-Meier Method
Comparison of time to resolution
Gehan-Wilcoxon Test
ResultsPrimary 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
ResultsSecondary 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
Results
Fidaxomicin Vancomycin
24.40%23.60
%
7.80%
25.50%
Recurrence Rates
BI/NAP/027 Strain Other Strains
• 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
ResultsSecondary 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
Results Notable Adverse Reactions Reported in the Safety
Population
Event Fidaxomicin (N=300)
Vancomycin (N =323)
P-Value
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 Event
75 (25%) 78 (24.1%) 0.8523
Laboratory Abnormalities*
14 (4.7%) 4 (1.2%) 0.0148
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.
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
Article Critique
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
Abstract
• Well structured• Background• Methods• Results• Conclusions
• Study endpoints were addressed in each segment, directly or indirectly
Introduction and Background
Good
• Addressed the current clinical relevance of the study
• Referenced outcomes of a previous Phase II trial of Fidaxomicin• Links past findings to
the study objective
Could Be Better
• The disease state, C. Difficile Associated Diarrhea, is not adequately described• Risk factors• Clinical Presentation
(“diarrhea” never mentioned)
• Emphasis on burden to facility, rather than burden to patient
Study Design
Good
• Appropriate time frame (5/2006 – 8/2009)
• Double-blinded and Randomized by computer• Medication kit and number
to each patient
• Utilized both Modified intention-to-treat and Per protocol populations
• IRB Approved
Could Be Better
• Analysis of data was performed by the authors, which included employees and stock-owners for Optimer Pharmaceuticals, manufacturer of the study drug
Study Population
Good• Multi-centered
• Informed consent
• Characteristics evenly distributed among treatment groups
• Appropriate age group: Advanced age is a risk factor• mITT mean age: 61.6 ±
16.9
• PP mean age: 61.3 ± 17.1
Could Be Better• Possible confounding
factors• Use of proton-pump
Inhibitors/ H-2 Antagonists
• Selection Bias: Inclusion of patients previously treated with vancomycin but not fidaxomicin
Intervention and Assessment
Good
• Treatment guidelines were followed appropriately• Vancomycin dosing• Diagnosis of C. Difficile
infection
• Blinding maintained by similar daily dosing schedule
• Use of other potentially effective treatments not permitted
Could Be Better
• Clinical cure and failure was determined by need for further treatment in the opinion of the investigator
• Vancomycin treatment duration for 10 days vs. 14 days
Statistical Analysis
Good• Non-inferiority margin
defined as -10 percentage points
• Appropriate statistical methods used to analyze primary and secondary outcomes
Could Be Better• No mention of study
power goal or achievement
• Time to resolution of diarrhea measured in hours, while assessed daily
Results
Good
• Results of each identified study outcome is addressed for both mITT and PP population and a chart included
• Subgroup analysis performed
• Adverse effects were reported and well documented
• No subjects discontinued the study due to intolerance or allergy to the study medication
Could Be Better
• Adherence was measured to be similar but no mention as to the method of adherence testing
• Success of blinding not measured
Effect of Severity on FidaxomicinClinical 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
75%
80%
85%
90%
95%
85.0%83.0%
88.6%
92.2%91.9%
82.1%
82%84%86%88%90%92%94%96%
88.7%
86.3%
93.0%
94.9% 94.3%
88.1%
Severity vs. Clinical Cure
Modified ITT Population
Severity vs. Clinical CurePer-Protocol Population
* Graphs generated from data found in Table 2.
Discussion and Conclusion
Good• Primary and Secondary
conclusions were valid and supported by the presented data
• Issue of the inability to reduce the rate of recurrence with the resistant strain was addressed
• Discussion is comprehensive and establishes study value
Could Be Better• No limitations are
identified
• Laboratory abnormalities were of statistical significance, but not addressed
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
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
QUESTIONS?
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.