Catheter-Related Blood Stream Infections A Phase 2 Randomized, Controlled Trial of Dalbavancin vs. Vancomycin

1. Catheter-Related Blood Stream InfectionsA Phase 2 Randomized, Controlled Trial of Dalbavancin vs. Vancomycin Tim Henkel, MD, PhD Executive VP and Chief Medical Officer Vicuron Pharmaceuticals

2. CR-BSI: Regulatory History 1993 AIDAC recommended elimination of bacteremic sepsis indication 1998 AIDAC discussion of CR-BSI 1999 Draft Guidance for CR-BSI 2004 No drug approved for CR-BSI

3. Review of Controlled Trials Raad et al, Quinupristin/Dalfopristin vs. Vancomycin • Eur J Clin Microbiol Infect Dis (1999) 18199

4. Study Design • Phase 2 • Randomized, controlled, open label • Clinical and microbiological entry criteria • Gram-positive CR-BSI • Primary endpointglobal response at FU • Sample size planned 60/group • Descriptive statistics with 95 CIs

5. Inclusion criteria • Documented Gram-positive bacteremia or • Empiric enrollment allowed pending cultures if 2 signs • core temperature 38.0C or 36.0C • WBC count 12,000, 4,000 or 10 bands • tachycardia • tachypnea • transient hypotension

6. Exclusion criteria • 24 hrs of prior antibiotic therapy (Gram ) • Alternate focus of infection identified • Recent S. aureus bacteremia from a source other than a CVC • 2 weeks antibiotic therapy anticipated • Creatinine clearance  50 ml/min, • Neutropenia (ANC 100/mm3 for  72 hours) • Use of chronic immunosuppressive drugs • Documented resistance to either study drug

7. Microbiological Methods • Catheter cultures • Time to positivity of catheter vs. peripheral cultures • Insertion site exudate cultures • Identity of paired cultures confirmed by • Antibiograms • PFGE

8. Outcome Definitions • Clinical: • Success improvement in signs/ symptoms and no additional therapy required • Failure: persistence of signs and symptoms and additional therapy required. • Microbiological • success • Failure

9. Categories of Infection • Definite CR-BSI: one of the following: • 1 positive peripheral blood culture, plus one of: • positive semi quantitative (catheter tip, 15 CFU) • quantitative (lumen wash, 102 CFU/mL) catheter culture • positive hub or tunnel exudate culture • 5-fold increase in CFU/mL of identical pathogen from central vs. peripheral blood culture • 2 hour longer time to positivity for the peripheral culture relative to the central culture

10. Categories of Infection • Probable CR-BSI: • S. aureus: 1 positive peripheral blood culture(in absence of other source of infection) • All other organisms: 2 blood cultures positive for identical species, at least 1 peripheral

11. Phase 2 CRBSI – Enrollment • 34 centers in North America • Enrollment period of 17 months • 2639 patients screened • 75 patients enrolled

12. Reasons for Screening Failures

13. Conclusions • A common disease, but challenging to study • Heterogeneous population • Inclusion/Exclusion criteria may result in population not representative of true disease spectrum • Microbiological methods not standard of care • No approved comparator • Phase 3 study with current CRBSI design not feasible • Alternate approaches to bacteremia indications and study design needed