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HAVARA KAUSAR AKBAR

PRESEPTOR :
DR. HJ IHSANIL HUSNA, SP.PD

Havara Kausar Akbar

1/3/17

ARRANGED BY:

Background C. 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/BI/027

Reduced clinical response, increased recurrence

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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

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Study Objective

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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

Double-blind

Randomized

Parallel Group

Multi-center

Written, informed
consent provided by
each patient

Sponsored by Optimer
Pharmaceuticals

Analysis performed by
the authors and one
investigator at Optimer
Pharmaceuticals

Havara Kausar Akbar

Research and
Analysis

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Study Design

Methods
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

Life-threatening or fulminant
infection

Toxic megacolon

Previous exposure to
fidaxomicin

History of ulcerative colitis or


Chrons disease

More than one occurrence of C.


Difficile infection three months
before the start of the study

Havara Kausar Akbar

Exclusion
Criteria

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Inclusion
Criteria

Havara Kausar Akbar


1/3/17

Baseline Characteristics

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Intervention

All pills were encapsulated to look the


same
Fidaxomicin Group
Vancomycin Group

200mg every 12
hours

Intervening doses
of placebo

125mg every 6
hours

No placebo

Havara Kausar Akbar

Each subject was randomized to receive


a study medication orally every 6 hours
for ten days

1/3/17

Assessment

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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

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Study Outcomes

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Rate of clinical cure in the modified intention-totreat 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

Havara Kausar Akbar

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Primary Endpoint

Definitions

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

Havara Kausar Akbar

Clinical
Recurrence

Resolution of diarrhea and maintenance of


resolution for the duration of therapy and
no further requirement

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Clinical
Cure
Clinical
Failure
Global
Cure

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Statistical Analysis

Treatment differences
Age
Inpatient vs. Outpatient
Prior Occurrence
Disease Severity
Strain Type

Post Hoc Analysis

Time to Resolution of Diarrhea

Kaplan-Meier Method
Gehan-Wilcoxon Test

Comparison of time to resolution

Havara Kausar Akbar

Recurrence and Overall Cure

One-sided lower 95.7%


confidence interval
Post Hoc Hypothesis Tests
*Significance level of 0.05

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Rate of Clinical Cure

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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

Havara Kausar Akbar

Clinical Cure

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Results
Primary Endpoint

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

Havara Kausar Akbar

Recurrence rate was significantly


lower for patients treated with
fidaxomicin

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Results
Secondary Endpoint

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

Havara Kausar Akbar

Global Cure Higher rates of resolution of


diarrhea without recurrence were seen with
fidaxomicin.

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Results
Secondary Endpoint

Conclusions

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Fidaxomicin and vancomycin have similar


effectiveness with respect to the clinical resolution of
acute diarrheal disease due to C. difficile infection,
but more sustained or durable resolution of disease is
achieved with fidaxomicin a finding that may be
attributable to lesser impairment of the intestinal
microbiome during treatment of the infection.

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