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.