S. aureus Bacteremia and Endocarditis Study Efficacy Results

1
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

2
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

3
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
• Known pneumonia, osteomyelitis
• Polymicrobial bacteremia
• Moribund

4
Study Design
5
Blinded Independent External Adjudication
Committee
6
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

7
S. aureus Bacteremia and Endocarditis Study

• Results

8
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

9
Patient Disposition
10
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78 Withdrawn from therapy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
11
Demographics (ITT)
12
Infecting Pathogen and Risk Factors (ITT)
13
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

14
Primary Endpoint Success at Test of Cure per
Adjudication Committee (ITT/PP)
15
MRSA and MSSA Success at Test of CurePathogen
Specific Therapy per Adjudication Committee (ITT)
70
60
50
44.6
44.4
40
Success
30
20
10
0
MRSA
MSSA
16
Entry Diagnosis per Adjudication Committee (ITT)
17
Entry Diagnosis Success at Test of Cure per
Adjudication Committee (ITT)
18
Final Diagnosis per Adjudication Committee (ITT)
19
Final Diagnosis Success at Test of Cure per
Adjudication Committee (ITT)
70
56.3
55.2
60
50
43.8
43.3
42.1
37.7
40
Success
30
22.2
20
11.1
10
0
uBAC
cBAC
RIE
LIE
20
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
21
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)
22
End of Therapy and Test of Cure Success per
Adjudication Committee (ITT)
23
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)
24
All Reasons for Failure at Test of Cure (ITT)

25
Failure Due to Persisting/Relapsing S.
aureusEmergence of Reduced Susceptibility to
Daptomycin
26
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.
27
Sensitivity Analysis Treatment-limiting Adverse
Events Not Considered Failure (ITT TOC)
28
Sensitivity Analyses (ITT TOC)
Differences In Success Rates (95 CI)
Comparator N 115 n ()
Daptomycin N 120 n ()
Success considering failure based only on
N/A
101 (87.8)
111 (92.5)
Non-evaluable
29
Sensitivity Analyses (ITT TOC)
Differences In Success Rates (95 CI)
Comparator N 115 n ()
Daptomycin N 120 n ()
Success considering failure based only on
N/A
101 (87.8)
111 (92.5)
Non-evaluable
-1.6 (-12.3, 9.1)
90 (78.3)
92 (76.7)
Persisting/relapsing S. aureus (PRSA)
30
Sensitivity Analyses (ITT TOC)
Differences In Success Rates (95 CI)
Comparator N 115 n ()
Daptomycin N 120 n ()
Success considering failure based only on
N/A
101 (87.8)
111 (92.5)
Non-evaluable
-1.6 (-12.3, 9.1)
90 (78.3)
92 (76.7)
Persisting/relapsing S. aureus (PRSA)
1.2 (-10.4, 12.8)
81 (70.4)
86 (71.7)
Death
31
Sensitivity Analyses (ITT TOC)
Differences In Success Rates (95 CI)
Comparator N 115 n ()
Daptomycin N 120 n ()
Success considering failure based only on
N/A
101 (87.8)
111 (92.5)
Non-evaluable
-1.6 (-12.3, 9.1)
90 (78.3)
92 (76.7)
Persisting/relapsing S. aureus (PRSA)
1.2 (-10.4, 12.8)
81 (70.4)
86 (71.7)
Death
1.3 (-10.5, 13.1)
79 (68.7)
84 (70.0)
Clinical failure
32
Sensitivity Analyses (ITT TOC)
Differences In Success Rates (95 CI)
Comparator N 115 n ()
Daptomycin N 120 n ()
Success considering failure based only on
N/A
101 (87.8)
111 (92.5)
Non-evaluable
-1.6 (-12.3, 9.1)
90 (78.3)
92 (76.7)
Persisting/relapsing S. aureus (PRSA)
1.2 (-10.4, 12.8)
81 (70.4)
86 (71.7)
Death
1.3 (-10.5, 13.1)
79 (68.7)
84 (70.0)
Clinical failure
5.9 (-6.5, 18.3)
67 (58.3)
77 (64.2)
Treatment-limiting adverse event
33
Sensitivity Analyses (ITT TOC)
Differences In Success Rates (95 CI)
Comparator N 115 n ()
Daptomycin N 120 n ()
Success considering failure based only on
N/A
101 (87.8)
111 (92.5)
Non-evaluable
-1.6 (-12.3, 9.1)
90 (78.3)
92 (76.7)
Persisting/relapsing S. aureus (PRSA)
1.2 (-10.4, 12.8)
81 (70.4)
86 (71.7)
Death
1.3 (-10.5, 13.1)
79 (68.7)
84 (70.0)
Clinical failure
5.9 (-6.5, 18.3)
67 (58.3)
77 (64.2)
Treatment-limiting adverse event
1.2 (-11.6, 14.0)
58 (50.4)
62 (51.7)
PENS
34
Sensitivity Analyses (ITT TOC)
Differences In Success Rates (95 CI)
Comparator N 115 n ()
Daptomycin N 120 n ()
Success considering failure based only on
N/A
101 (87.8)
111 (92.5)
Non-evaluable
-1.6 (-12.3, 9.1)
90 (78.3)
92 (76.7)
Persisting/relapsing S. aureus (PRSA)
1.2 (-10.4, 12.8)
81 (70.4)
86 (71.7)
Death
1.3 (-10.5, 13.1)
79 (68.7)
84 (70.0)
Clinical failure
5.9 (-6.5, 18.3)
67 (58.3)
77 (64.2)
Treatment-limiting adverse event
1.2 (-11.6, 14.0)
58 (50.4)
62 (51.7)
PENS
3.2 (-9.5, 15.9)
49 (42.6)
55 (45.8)
No blood culture
35
Sensitivity Analyses (ITT TOC)
Differences In Success Rates (95 CI)
Comparator N 115 n ()
Daptomycin N 120 n ()
Success considering failure based only on
N/A
101 (87.8)
111 (92.5)
Non-evaluable
-1.6 (-12.3, 9.1)
90 (78.3)
92 (76.7)
Persisting/relapsing S. aureus (PRSA)
1.2 (-10.4, 12.8)
81 (70.4)
86 (71.7)
Death
1.3 (-10.5, 13.1)
79 (68.7)
84 (70.0)
Clinical failure
5.9 (-6.5, 18.3)
67 (58.3)
77 (64.2)
Treatment-limiting adverse event
1.2 (-11.6, 14.0)
58 (50.4)
62 (51.7)
PENS
3.2 (-9.5, 15.9)
49 (42.6)
55 (45.8)
No blood culture
2.4 (-10.2, 15.1)
48 (41.7)
53 (44.2)
D/C for reason other than AE
36
Kaplan-Meier Survival Curve (ITT)
100
75
50
Survival
25
Wilcoxon p0.823 Log-rank p0.976
0
0
25
50
75
100
125
150
175
Days
37
Deaths in Patients With Endocarditis and
Persisting or Relapsing S. aureus
Safety Population
38
Known or Suspected Endocarditis Success at Test
of Cure (ITT)
39
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

40
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