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S. aureus Bacteremia and Endocarditis Study Efficacy Results Helen Whamond Boucher, MD Assistant Professor of Medicine Director, Infectious Diseases Fellowship Program Division of Infectious Diseases and Geographic Medicine Tufts University - New England Medical Center

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s aureus bacteremia and endocarditis study efficacy results

S. aureus Bacteremia and Endocarditis Study Efficacy Results

Helen Whamond Boucher, MD

Assistant Professor of Medicine

Director, Infectious Diseases Fellowship Program

Division of Infectious Diseases and Geographic Medicine

Tufts University - New England Medical Center

Boston, Massachusetts

study objective and statistical considerations
Study Objective and Statistical Considerations
  • Hypothesis tested
    • Daptomycin is not inferior to standard therapy in the treatment of S. aureus bacteremia and infective endocarditis as assessed by Adjudication Committee outcome at Test of Cure (TOC)
  • Non-inferiority design
    • Sample size calculation
      • 80% power
      • Delta 20%
      • Assumed 65% success rates in both groups
      • ITT required 90 per arm
key inclusion and exclusion criteria
Key Inclusion and Exclusion Criteria
  • Inclusion criteria
    • Written informed consent
    •  18 years of age
    • Documented S. aureus bacteremia
  • Exclusion criteria
    • Intravascular foreign material
    • Prosthetic heart valve
    • Creatinine clearance < 30 mL/minute
    • Known pneumonia, osteomyelitis
    • Polymicrobial bacteremia
    • Moribund
study design
Blood Culture+ S. aureus

Work-up includes TEE within 5 days

End of Therapy (EOT)

Test of Cure (TOC)

6 weeks

-2

Daptomycin 6 mg/kg IV q24h

Outcome

Outcome

PrimaryEndpoint

  • Comparator
  • Vancomycin 1 g IV q12h+ Gentamicin 1 mg/kg IV q8h x 4 days
  • Anti-staphylococcal penicillin 2 g IV q4h+ Gentamicin 1 mg/kg IV q8h x 4 days
Study Design
blinded independent external adjudication committee
Entry Diagnosis using Modified Duke Criteria
    • Definite Endocarditis
    • Possible Endocarditis
    • Not Endocarditis
  • Final Diagnosis
    • Uncomplicated Bacteremia
    • Complicated Bacteremia
    • Right-sided Endocarditis
    • Left-sided Endocarditis

End of Therapy (EOT)

Test of Cure (TOC)

6 weeks

-2

Outcome

Outcome

PrimaryEndpoint

Blinded Independent External Adjudication Committee
outcome definitions
Outcome Definitions

Success (all of the following required)

  • Clinically cured or improved
  • Negative blood culture
  • Did not receive a potentially effective non-study antibiotic
  • Received minimum amount of study medication per Investigator

Failure (any of the following)

  • Persisting or relapsing S. aureus
  • Death
  • Clinical failure
  • Received a potentially effective non-study antibiotic
  • Discontinued study medication prematurely due to either:
    • Adverse event
    • Microbiological failure
    • Clinical failure
  • No blood culture at Test of Cure
study conduct
Study Conduct
  • 44 sites treated patients; 4 countries
    • August 2002 - February 2005
  • 236 treated
    • 200 US
    • 36 EU
  • Resource intensive for investigators and patients
  • Amendment to allow LIE April 2004
patient disposition
246Randomized

Daptomycin

Comparator

122

124

Did not receive study drug

116

120

Safety population

LIE prior to amendment to allow LIE

115

120

Intent-To-Treat population

Protocol adherence criteria

60

79

Per-Protocol population

Patient Disposition
study compliance itt
Study Compliance (ITT)

235

Patients in ITT

157

Completed therapy

78

Withdrawn from therapy

148

Met TOC visit requirements

9

No contact or culture at TOC

69

Completed studyrequirements

9

W/D consent or lost to follow-up

217/235 (92.3%) completed study requirements

pre specified efficacy analyses
Pre-specified Efficacy Analyses
  • Primary efficacy endpoint
    • Success at Test of Cure
    • Success in subgroups
      • MRSA/MSSA
      • Entry diagnosis
      • Final diagnosis
    • Success at End of Therapy
primary endpoint success at test of cure per adjudication committee itt pp
Difference in Success

Rates (95% CI):

2.4% (-10.2, 15.1)

Difference in Success Rates (95% CI):

1.1% (-15.6, 17.8)

70

Daptomycin

60

Comparator

54.4

53.3

50

44.2

41.7

40

% Success

3260

43 79

30

53 120

48 115

20

10

0

ITT

PP

Primary Endpoint: Success at Test of Cure per Adjudication Committee (ITT/PP)
mrsa and mssa success at test of cure pathogen specific therapy per adjudication committee itt
Difference in Success

Rates (95% CI):

11.9% (-8.3, 32.1)

Difference in Success Rates (95% CI):

-2.1% (-19.0, 14.9)

Daptomycin

Vancomycin

SSP

46.7

32.6

20 45

14 43

33 74

2860

MRSA and MSSA Success at Test of Cure:Pathogen Specific Therapy per Adjudication Committee (ITT)

70

60

50

44.6

44.4

40

% Success

30

20

10

0

MRSA

MSSA

entry diagnosis per adjudication committee itt
Daptomycin GroupN = 120

Comparator GroupN = 115

Definite IE14%

Definite IE17%

Not IE 25%

Not IE 21%

Possible IE61%

Possible IE62%

Entry Diagnosis per Adjudication Committee (ITT)
entry diagnosis success at test of cure per adjudication committee itt
70

60

Daptomycin

Comparator

45.6

45.8

50

40.7

40.0

40

% Success

30

20

10

4190

3791

1230

1124

0

Definite or PossibleEndocarditis

Not Endocarditis

Entry Diagnosis: Success at Test of Cure per Adjudication Committee (ITT)
final diagnosis per adjudication committee itt
Daptomycin GroupN = 120

Comparator GroupN = 115

LIE8%

LIE8%

RIE16%

RIE14%

uBAC27%

uBAC25%

cBAC50%

cBAC53%

Final Diagnosis per Adjudication Committee (ITT)
final diagnosis success at test of cure per adjudication committee itt
Daptomycin

Comparator

19

29

26 60

23 61

8 19

716

18 32

16 29

Final Diagnosis: Success at Test of Cure per Adjudication Committee (ITT)

70

56.3

60

55.2

50

43.8

43.3

42.1

37.7

40

% Success

30

22.2

20

11.1

10

0

uBAC

cBAC

RIE

LIE

right sided endocarditis success at test of cure itt
Daptomycin

Comparator

819

716

914

816

Right Sided Endocarditis: Success at Test of Cure (ITT)

70

64.3

60

50.0

50

43.8

42.1

40

% Success

30

20

10

0

Adjudication Committee

Investigator

left sided endocarditis itt
Left Sided Endocarditis (ITT)

Comparator patient 001 entered study with LIE prior to LIE amendment Success at EOT, failed at TOC due to sepsis and death (no valve replacement surgery)

end of therapy and test of cure success per adjudication committee itt
70

61.7

60.9

60

Daptomycin

Comparator

50

44.2

41.7

40

% Success

30

70 115

53 120

48 115

74 120

20

10

0

End of Therapy

Test of Cure

End of Therapy and Test of Cure: Success per Adjudication Committee (ITT)
secondary endpoint time to clearance of s aureus bacteremia itt
Secondary Endpoint: Time to Clearance of S. aureus Bacteremia (ITT)

Daptomycin (N = 62)

Comparator (N = 65)

1.0

0.9

0.8

Wilcoxon p = 0.165

0.7

0.6

0.5

Probability of Clearance

0.4

0.3

0.2

0.1

0.0

0

10

20

30

40

50

60

70

Time (Days)

vancomycin failures with mic 2
Vancomycin Failures With MIC  2
  • 1 vancomycin patient failed with vancomycin MIC 2 µg/mL at Central Lab
    • Failed due to persisting or relapsing S. aureus
  • 5 additional vancomycin patients failed with vancomycin MIC  2 µg/mL at Local Lab
    • 3 failed due to persisting or relapsing S. aureus

Sakoulas et al. JCM 2004.

sensitivity analyses itt toc
Sensitivity Analyses (ITT TOC)

Success considering failure based only on

Daptomycin

N = 120

n (%)

Comparator

N = 115

n (%)

Differences In

Success Rates

(95% CI)

Non-evaluable

111 (92.5)

101 (87.8)

N/A

sensitivity analyses itt toc29
Sensitivity Analyses (ITT TOC)

Success considering failure based only on

Daptomycin

N = 120

n (%)

Comparator

N = 115

n (%)

Differences In

Success Rates

(95% CI)

Non-evaluable

111 (92.5)

101 (87.8)

N/A

Persisting/relapsing S. aureus (PRSA)

92 (76.7)

90 (78.3)

-1.6% (-12.3, 9.1)

sensitivity analyses itt toc30
Sensitivity Analyses (ITT TOC)

Success considering failure based only on

Daptomycin

N = 120

n (%)

Comparator

N = 115

n (%)

Differences In

Success Rates

(95% CI)

Non-evaluable

111 (92.5)

101 (87.8)

N/A

Persisting/relapsing S. aureus (PRSA)

92 (76.7)

90 (78.3)

-1.6% (-12.3, 9.1)

+Death

86 (71.7)

81 (70.4)

1.2% (-10.4, 12.8)

sensitivity analyses itt toc31
Sensitivity Analyses (ITT TOC)

Success considering failure based only on

Daptomycin

N = 120

n (%)

Comparator

N = 115

n (%)

Differences In

Success Rates

(95% CI)

Non-evaluable

111 (92.5)

101 (87.8)

N/A

Persisting/relapsing S. aureus (PRSA)

92 (76.7)

90 (78.3)

-1.6% (-12.3, 9.1)

+Death

86 (71.7)

81 (70.4)

1.2% (-10.4, 12.8)

+Clinical failure

84 (70.0)

79 (68.7)

1.3% (-10.5, 13.1)

sensitivity analyses itt toc32
Sensitivity Analyses (ITT TOC)

Success considering failure based only on

Daptomycin

N = 120

n (%)

Comparator

N = 115

n (%)

Differences In

Success Rates

(95% CI)

Non-evaluable

111 (92.5)

101 (87.8)

N/A

Persisting/relapsing S. aureus (PRSA)

92 (76.7)

90 (78.3)

-1.6% (-12.3, 9.1)

+Death

86 (71.7)

81 (70.4)

1.2% (-10.4, 12.8)

+Clinical failure

84 (70.0)

79 (68.7)

1.3% (-10.5, 13.1)

+Treatment-limiting adverse event

77 (64.2)

67 (58.3)

5.9% (-6.5, 18.3)

sensitivity analyses itt toc33
Sensitivity Analyses (ITT TOC)

Success considering failure based only on

Daptomycin

N = 120

n (%)

Comparator

N = 115

n (%)

Differences In

Success Rates

(95% CI)

Non-evaluable

111 (92.5)

101 (87.8)

N/A

Persisting/relapsing S. aureus (PRSA)

92 (76.7)

90 (78.3)

-1.6% (-12.3, 9.1)

+Death

86 (71.7)

81 (70.4)

1.2% (-10.4, 12.8)

+Clinical failure

84 (70.0)

79 (68.7)

1.3% (-10.5, 13.1)

+Treatment-limiting adverse event

77 (64.2)

67 (58.3)

5.9% (-6.5, 18.3)

+PENS

62 (51.7)

58 (50.4)

1.2% (-11.6, 14.0)

sensitivity analyses itt toc34
Sensitivity Analyses (ITT TOC)

Success considering failure based only on

Daptomycin

N = 120

n (%)

Comparator

N = 115

n (%)

Differences In

Success Rates

(95% CI)

Non-evaluable

111 (92.5)

101 (87.8)

N/A

Persisting/relapsing S. aureus (PRSA)

92 (76.7)

90 (78.3)

-1.6% (-12.3, 9.1)

+Death

86 (71.7)

81 (70.4)

1.2% (-10.4, 12.8)

+Clinical failure

84 (70.0)

79 (68.7)

1.3% (-10.5, 13.1)

+Treatment-limiting adverse event

77 (64.2)

67 (58.3)

5.9% (-6.5, 18.3)

+PENS

62 (51.7)

58 (50.4)

1.2% (-11.6, 14.0)

+No blood culture

55 (45.8)

49 (42.6)

3.2% (-9.5, 15.9)

sensitivity analyses itt toc35
Sensitivity Analyses (ITT TOC)

Success considering failure based only on

Daptomycin

N = 120

n (%)

Comparator

N = 115

n (%)

Differences In

Success Rates

(95% CI)

Non-evaluable

111 (92.5)

101 (87.8)

N/A

Persisting/relapsing S. aureus (PRSA)

92 (76.7)

90 (78.3)

-1.6% (-12.3, 9.1)

+Death

86 (71.7)

81 (70.4)

1.2% (-10.4, 12.8)

+Clinical failure

84 (70.0)

79 (68.7)

1.3% (-10.5, 13.1)

+Treatment-limiting adverse event

77 (64.2)

67 (58.3)

5.9% (-6.5, 18.3)

+PENS

62 (51.7)

58 (50.4)

1.2% (-11.6, 14.0)

+No blood culture

55 (45.8)

49 (42.6)

3.2% (-9.5, 15.9)

+D/C for reason other than AE

53 (44.2)

48 (41.7)

2.4% (-10.2, 15.1)

kaplan meier survival curve itt
Comparator

Daptomycin

Kaplan-Meier Survival Curve (ITT)

100

75

50

% Survival

25

Wilcoxon p=0.823; Log-rank p=0.976

0

0

25

50

75

100

125

150

175

Days

deaths in patients with endocarditis and persisting or relapsing s aureus
Deaths in Patients With Endocarditis and Persisting or Relapsing S. aureus

Safety Population

known or suspected endocarditis success at test of cure itt
70

60

53.9

Daptomycin

50.5

Comparator

45.6

50

40.7

40

% Success

30

20

4190

3791

4889

4793

10

0

Definite or Possible IEAdjudication Committee

Definite or Possible IEInvestigator

Known or Suspected Endocarditis: Success at Test of Cure (ITT)
efficacy conclusions
Efficacy Conclusions
  • Primary efficacy endpoint met in ITT and PP populations
  • Daptomycin response higher than vancomycin response in MRSA
  • Efficacy results robust and consistent
    • Across pre-specified subgroups
    • Per Adjudication Committee and Investigator
efficacy conclusions40
Efficacy Conclusions
  • Daptomycin 6 mg/kg IV once daily was efficacious in the treatment of patients with S. aureus bacteremia including those with known or suspected endocarditis
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