Fidaxomicin versus vancomycin for clostridium difficile infection: journal

club presentation

Hager ElGeed

Doua AlSaad

BSc Pharm, PharmD Candidates

Why this paper?

1. Recently published paper

2. New medication approved by FDA

3. C. difficile infection is a common complaint in hospital

settings

4. Pharmacists should always be updated in new drugs

approved!

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Study Summary

Aim

Compare the efficacy and safety of fidaxomicin with those of vancomycin in treating C. difficile infection

Method

Prospective, double-blind, randomized, non-inferiority trial

Fidaxomicin (200 mg twice daily) or vancomycin (125 mg four times daily) orally for 10 days

Primary outcome: rate of clinical cure of C.difficile

Secondary outcomes: recurrence of C.difficile and global cure

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Study Summary

Results

Primary outcome (rate of clinical cure): 88.2% with fidaxomicin and 85.8% with vancomycin (ITT)

Secondary outcome (recurrence): 15.4% with fidaxomicin vs. 25.3% with vancomycin, P=0.005 (ITT)

Secondary outcome (global cure): 74.6% with fidaxomicin vs 64.1% with vancomycin, P=0.006 (ITT)

Conclusion

The rates of clinical cure after treatment with fidaxomicin were non-inferior to those after treatment with vancomycin

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About the journal

NEJM is the most widely read, cited, and influential general

medical periodical in the world.

It publishes articles since 1812 in research and key

information at the intersection of biomedical science and

clinical practice.

Peer-reviewed articles

This journal usually has the highest impact factor of the

journals of clinical medicine (53.48 in 2010).

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Authors 6

Authors 7

Title

Accurate but not adequate

Unbiased

Does not describe the study appropriately: a randomized phase III trial

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Introduction Current problem

Fidaxomicin and its properties

Previous trial

Rationale

Aim??

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Introduction

Funnel-like introduction

Sufficient description of the study rationale

Insufficient description of phase II trial

Aim was not clear

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Methodology

Design

Prospective, multicenter, double blind, randomized, parallel group trial

Conducted between May 2006 and August 2008

Ethical approval and consent

Company involvement!!

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Methodology

Populations

The study was conducted multiple centers in the US and Canada

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Inclusion criteria Exclusion criteria

Adults (16 years or older) Life threatening infection

Diagnosed with c. difficile and its toxins in stool specimen

Toxic megacolon

Patients may have received up to 4 doses of metronidazole or vancomycin in 24hrs period before radomization

More than one occurrence of c. difficile infection within 3 months

Previous exposure to fidaxomicin

History of ulcerative colitis or Crohn’s disease

Methodology 13

Randomizations and treatment

An interactive voice-response system and computer generated randomization schedule

Each patient was provided a randomization number and medication kit number

Treatment

200 mg of fidaxomicin every 12 hours with intervening matching doses of placebo

125 mg of vancomycin every 6 hours

Treatment duration: 10 days

Methodology 14

Definitions

Clinical cure:

The resolution of diarrhea (i.e., three or fewer unformed stools for 2 consecutive days), with maintenance of resolution for the duration of therapy and no further requirement

Clinical failure:

The persistence of diarrhea, the need for additional therapy for C. difficile infection, or both.

Global cure:

The resolution of diarrhea without recurrence

Clinical recurrence:

The reappearance of more than three diarrheal stools per 24- hour period within 4 weeks after the cessation of therapy; C. difficile toxins, in stool; and a need for retreatment for C. difficile infection.

Methodology 15

Outcomes:

Efficacy Safety

The primary efficacy end point was the rate of clinical cure

The assessment included a physical examination, electrocardiography, and clinical laboratory testing, including hematologic and biochemical tests and urinalysis.

The secondary efficacy end point was recurrence of C. difficile infection during the 4-week period after the end of the course of therapy and global cure in the modified intention-to-treat and per-protocol populations.

Adverse events were classified according to the terms used in the Medical Dictionary for Regulatory Activities.

Methodology 16

Other outcomes

Statistical analysis

Primary end point

Non-inferiority with margin of -10 points

One-sided with 97.5% CI

Secondary end points

Two-sided tests

Significance level of 0.05

Treatment differences according to age, inpatient vs outpatient status, prior occurrence of C. difficile infection vs no prior, occurrence, disease severity, and strain type

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Statistical analysis

Secondary end point (cont’)

Severity score (mild, moderate, severe disease)

Time to resolution: Kaplan–Meier method, with a Gehan–Wilcoxon test

Continuous variables: means ±SD

Categorical variables: numbers and percentages

Modified intention-to-treat and per-protocol analysis

Sample size and power??

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Results 19

Results 20

Results 21

Results 22

Results 23

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Results 25

Results 26

Results 27

Results 28

Results

Rate of adverse

events

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Results

Incidence of

serious adverse

event

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Results

Microbiological Evaluation

Pharmacokinetic Evaluation

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Discussion 32

Discussion 33

Discussion 34

Criteria for a good discussion:

1. No any new data in this section

2. Comparing results of the trial to the results of similar previous trials

3. Explanation of any differences found

4. Limitations

5. How the limitations might have affected the results?

Conclusion & External Validity

Comprehensive

Words selection!

No future studies

were suggested

Limited

generalizability

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Funds & Conflict of Interest

Optimer Pharmaceuticals

ClinicalTrials.gov

(NCT0031495)

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References

1986-2010

Authors cited themselves in 5 out of 36 articles

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Abstract

Well structured

Some important info-

rmation are missed

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