# Presentation: 675394

## 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

**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

**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

## Blinded Independent External Adjudication Committee

## 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**

## S. aureus Bacteremia and Endocarditis Study

**Results**

## 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

## Study Compliance (ITT)

**217/235 (92.3%) completed study requirements**

**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**Withdrawn from therapy**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 study****requirements**

**9**
**W/D consent or ****lost to follow-up**

## Demographics (ITT)

|  | DaptomycinN = 120n (%) | ComparatorN = 115n (%) |
| --- | --- | --- |
| Age (years, mean) | 52.6 | 56.4 |
| Gender |  |  |
| 	Male  | 70 (58.3) | 71 (61.7) |
| 	Female | 50 (41.7) | 44 (38.3) |
| Race |  |  |
| 	Caucasian | 75 (62.5) | 81 (70.4) |
| 	Black | 32 (26.7) | 23 (20.0) |
| 	Other | 13 (10.8) | 11 (9.6) |
| Creatinine Clearance (ml/min) |  |  |
| 	< 30 | 2 (1.7) | 3 (2.6) |
| 	30 - < 50 | 17 (14.2) | 19 (16.5) |
| 	50 - 80 | 34 (28.3) | 34 (29.6) |
| 	> 80 | 67 (55.8) | 59 (51.3) |

## Infecting Pathogen and Risk Factors (ITT) 

| Infecting Pathogen | DaptomycinN = 120n (%) | ComparatorN = 115n (%) |
| --- | --- | --- |
| MRSA | 45 (37.5) | 44 (38.3) |
| Risk Factor |  |  |
| 	SIRS present | 89 (74.2) | 87 (75.7) |
| 	Surgery within prior 30 days | 49 (40.8) | 36 (31.3) |
| 	Diabetes mellitus | 44 (36.7) | 42 (36.5) |
| 	Prosthetic material/devices | 40 (33.3) | 40 (34.8) |
| 	Injection drug use | 25 (20.8) | 25 (21.7) |
| 	Pre-existing valvular heart disease | 16 (13.3) | 9 (7.8) |
| 	Septic pulmonary emboli | 10 (8.3) | 13 (11.3) |

| 4 or more risk factors | 26 (21.7) | 13 (11.3) |
| --- | --- | --- |

## 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)

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

**44.6**

**44.4**

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

**% Success**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**MRSA**

**MSSA**

## Entry Diagnosis per Adjudication Committee (ITT)

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

## Final Diagnosis per Adjudication Committee (ITT)

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

**56.3**

**43.3**

**42.1**

**11.1**

**55.2**

**37.7**

**43.8**

**22.2**

**uBAC**

**cBAC**

**RIE**

**LIE**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**% Success**

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

**42.1**

**64.3**

**43.8**

**50.0**

**Adjudication Committee**

**Investigator**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**% Success**

## Left Sided Endocarditis (ITT)

|  | DaptomycinN = 9 
n (%) | Comparator
N = 9 
n (%) |
| --- | --- | --- |
| Adjudication Committee Success |  |  |
| End of Therapy | 4 (44.4) | 3 (33.3) |
| Test of Cure | 1 (11.1) | 2 (22.2) |
| 	MRSA | 0/5 | 0/4 |
| 	MSSA | 1/4 (25.0) | 2/5 (40.0) |
| Survival | 6 (66.7) | 4 (44.4) |

**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)

## Secondary Endpoint: Time to Clearance of S. aureus Bacteremia (ITT)

**1.0**

**0.9**

**0.8**

**0.7**

**0.6**

**0.5**

**0.4**

**0.3**

**0.2**

**0.1**

**0.0**

**Probability of Clearance**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**Time (Days)**

**Daptomycin (N = 62)**

**Comparator (N = 65)**

**Wilcoxon p = 0.165**

|  | DaptomycinMedian # Days | ComparatorMedian # Days |
| --- | --- | --- |
| Overall | 5 | 4 |
| MRSA | 8 | 9 |
| MSSA | 4 | 3 |

## All Reasons for Failure at Test of Cure (ITT)

|  | DaptomycinN = 120n (%) | ComparatorN = 115n (%) |
| --- | --- | --- |
| Overall failure | 67 (55.8) | 67 (58.3) |
| 	Reason for Failure (more than one reason may be indicated for each patient) |  |  |
| Persisting or relapsing S. aureus infection | 19 (15.8) | 11 (9.6) |
| Death | 13 (10.8) | 13 (11.3) |
| Clinical failure without persisting/relapsing S. aureus | 4 (3.3) | 4 (3.5) |
| Treatment-limiting adverse events | 8 (6.7) | 17 (14.8) |
| Non-study antibiotics   | 20 (16.7) | 16 (13.9) |
| No blood culture |  9 (7.5) | 12 (10.4) |
| 	Non-evaluable (e.g., withdrew consent, left AMA) |  9 (7.5) | 14 (12.2) |

** **

## Failure Due to Persisting/Relapsing S. aureusEmergence of Reduced Susceptibility to Daptomycin

| Patient ID | Final Diagnosis | BaselinePathogen | Duration ofTherapy (days) | Baseline MIC(μg/mL) | HighestMIC(μg/mL) | Clinical Summary |
| --- | --- | --- | --- | --- | --- | --- |
| 037 | LIE | MRSA | 7 | 0.25 | 2 | Mitral/aortic IE |
| 183 | LIE | MRSA | 8 | 0.5 | 2 | Mitral IE, stroke |
| 152 | cRIE | MSSA | 20 | 0.25 | 4 | Tricuspid IE, large pulmonary emboli, tunnel infection |
| 212 | cBAC | MRSA | 14 | 0.25 | 2 | IV port infection |
| 105 | cBAC | MRSA | 23 | 0.25 | 2 | Septic arthritis |
| 136 | cBAC | MRSA | 35 | 0.5 | 2 | Undiagnosed retroperitoneal abscess |

## 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 Analysis: Treatment-limiting Adverse Events Not Considered Failure (ITT TOC)

| Test of Cure | DaptomycinN = 120n (%) | ComparatorN = 115n (%) | Difference inSuccess Rates(95% CI) |
| --- | --- | --- | --- |
| Adverse Event = Success | 59 (49.2) | 56 (48.7) | 0.5% (-12.3, 13.3) |

## Sensitivity Analyses (ITT TOC)

**N/A**

**101 (87.8)**

**111 (92.5)**

**Non-evaluable**

**Differences In**
**Success Rates**
**(95% CI)**

**Comparator**
**N = 115    **
**n (%)**

**Daptomycin**
**N = 120**
**n (%)**

**Success considering failure ****based only on**

## Sensitivity Analyses (ITT TOC)

**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)**

**Differences In**
**Success Rates**
**(95% CI)**

**Comparator**
**N = 115    **
**n (%)**

**Daptomycin**
**N = 120**
**n (%)**

**Success considering failure ****based only on**

## Sensitivity Analyses (ITT TOC)

**N/A**

**101 (87.8)**

**111 (92.5)**

**Non-evaluable**

**1.2% (-10.4, 12.8)**

**81 (70.4)**

**86 (71.7)**

**	****+Death**

**-1.6% (-12.3, 9.1)**

**90 (78.3)**

**92 (76.7)**

**Persisting/relapsing *****S. aureus *****(PRSA)**

**Differences In**
**Success Rates**
**(95% CI)**

**Comparator**
**N = 115    **
**n (%)**

**Daptomycin**
**N = 120**
**n (%)**

**Success considering failure ****based only on**

## Sensitivity Analyses (ITT TOC)

**N/A**

**101 (87.8)**

**111 (92.5)**

**Non-evaluable**

**1.3% (-10.5, 13.1)**

**79 (68.7)**

**84 (70.0)**

**	****+Clinical failure**

**1.2% (-10.4, 12.8)**

**81 (70.4)**

**86 (71.7)**

**	****+Death**

**-1.6% (-12.3, 9.1)**

**90 (78.3)**

**92 (76.7)**

**Persisting/relapsing *****S. aureus *****(PRSA)**

**Differences In**
**Success Rates**
**(95% CI)**

**Comparator**
**N = 115    **
**n (%)**

**Daptomycin**
**N = 120**
**n (%)**

**Success considering failure ****based only on**

## Sensitivity Analyses (ITT TOC)

**N/A**

**101 (87.8)**

**111 (92.5)**

**Non-evaluable**

**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% (-10.4, 12.8)**

**81 (70.4)**

**86 (71.7)**

**	****+Death**

**-1.6% (-12.3, 9.1)**

**90 (78.3)**

**92 (76.7)**

**Persisting/relapsing *****S. aureus *****(PRSA)**

**Differences In**
**Success Rates**
**(95% CI)**

**Comparator**
**N = 115    **
**n (%)**

**Daptomycin**
**N = 120**
**n (%)**

**Success considering failure ****based only on**

## Sensitivity Analyses (ITT TOC)

**N/A**

**101 (87.8)**

**111 (92.5)**

**Non-evaluable**

**1.2% (-11.6, 14.0)**

**58 (50.4)**

**62 (51.7)**

**	****+PENS**

**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% (-10.4, 12.8)**

**81 (70.4)**

**86 (71.7)**

**	****+Death**

**-1.6% (-12.3, 9.1)**

**90 (78.3)**

**92 (76.7)**

**Persisting/relapsing *****S. aureus *****(PRSA)**

**Differences In**
**Success Rates**
**(95% CI)**

**Comparator**
**N = 115    **
**n (%)**

**Daptomycin**
**N = 120**
**n (%)**

**Success considering failure ****based only on**

## Sensitivity Analyses (ITT TOC)

**N/A**

**101 (87.8)**

**111 (92.5)**

**Non-evaluable**

**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**

**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% (-10.4, 12.8)**

**81 (70.4)**

**86 (71.7)**

**	****+Death**

**-1.6% (-12.3, 9.1)**

**90 (78.3)**

**92 (76.7)**

**Persisting/relapsing *****S. aureus *****(PRSA)**

**Differences In**
**Success Rates**
**(95% CI)**

**Comparator**
**N = 115    **
**n (%)**

**Daptomycin**
**N = 120**
**n (%)**

**Success considering failure ****based only on**

## Sensitivity Analyses (ITT TOC)

**N/A**

**101 (87.8)**

**111 (92.5)**

**Non-evaluable**

**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**

**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% (-10.4, 12.8)**

**81 (70.4)**

**86 (71.7)**

**	****+Death**

**-1.6% (-12.3, 9.1)**

**90 (78.3)**

**92 (76.7)**

**Persisting/relapsing *****S. aureus *****(PRSA)**

**Differences In**
**Success Rates**
**(95% CI)**

**Comparator**
**N = 115    **
**n (%)**

**Daptomycin**
**N = 120**
**n (%)**

**Success considering failure ****based only on**

## Kaplan-Meier Survival Curve (ITT)

**100**

**75**

**50**

**25**

**0**

**0**

**25**

**50**

**75**

**100**

**125**

**150**

**175**

**Days**

** ****% Survival**

**Wilcoxon p=0.823; Log-rank p=0.976**

|  | DaptomycinN = 120n (%) | ComparatorN = 115n (%) |
| --- | --- | --- |
| Overall deaths | 18 (15.0) | 18 (15.7) |
| Deaths on treatment | 2 (1.7) | 3 (2.6) |

## Deaths in Patients With Endocarditis and Persisting or Relapsing S. aureus

| Endocarditis Deaths | DaptomycinN = 28n (%) | ComparatorN = 26n (%) | Odds Ratio(95% CI) |
| --- | --- | --- | --- |
| Death by day 42 post therapy | 3 (10.7) | 5 (19.2) | 0.50 (0.11, 2.36) |
| Death at end of study | 3 (10.7) | 8 (30.8) | 0.27 (0.06, 1.16) |
| Persisting or Relapsing S. aureus Deaths  | DaptomycinN = 19n (%) | ComparatorN = 11n (%) | Odds Ratio(95% CI) |
| Death by day 42 post therapy | 7 (36.8) | 3 (27.3) | 1.56 (0.31, 7.87) |
| Death at end of study | 8 (42.1) | 7 (63.6) | 0.42 (0.09, 1.92) |

***Safety Population***

## Known or Suspected Endocarditis: Success at Test of Cure (ITT) 

## 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 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**