DOTS: Dalbavancin as an Option for Treatment of Staphylococcus Aureus Bacteremia

Dalbavancin as an Option for Treatment of S. Aureus Bacteremia (DOTS): A Phase 2b, Multicenter, Randomized, Open-Label, Assessor-Blinded Superiority Study to Compare the Efficacy and Safety of Dalbavancin to Standard of Care Antibiotic Therapy for the Completion of Treatment of Patients With Complicated S. Aureus Bacteremia

This is a Phase 2b clinical study, multicenter, randomized, open-label, assessor-blinded, superiority study. The study will compare dalbavancin to standard of care antibiotic therapy for the completion of therapy in patients with complicated bacteremia or right-sided native valve Infective Endocarditis (IE) caused by S. aureus who have cleared their baseline bacteremia. Approximately 200 subjects will be randomized 1:1 to receive either dalbavancin or a standard of care antibiotic regimen that is based upon the identification and antibiotic susceptibility pattern of the baseline organism. Subjects randomized to the dalbavancin treatment group will receive 2 doses of dalbavancin intravenously (IV) 1 week apart (1500 mg on Day 1 and Day 8 after randomization, with renal dose adjustment if appropriate). Subjects randomized to the standard of care antibiotic therapy treatment group will receive an antibiotic regimen considered to be standard of care based on the methicillin susceptibility pattern of the pathogen isolated at baseline for a duration of 4 to 6 weeks and up to 8 weeks for patients with vertebral osteomyelitis/discitis. The primary objective is to compare the Desirability of Outcome Ranking (DOOR) at Day 70 of dalbavancin to that of standard of care antibiotic therapy used to consolidate therapy for the treatment of subjects with complicated S. aureus bacteremia in the intent-to-treat population (ITT).

This is a Phase 2b clinical study, multicenter, randomized, open-label, assessor-blinded, superiority study. The study will compare dalbavancin to standard of care antibiotic therapy for the completion of therapy in patients with complicated bacteremia or right-sided native valve Infective Endocarditis (IE) caused by S. aureus who have cleared their baseline bacteremia. Approximately 200 subjects will be randomized 1:1 to receive either dalbavancin or a standard of care antibiotic regimen that is based upon the identification and antibiotic susceptibility pattern of the baseline organism. Subjects randomized to the dalbavancin treatment group will receive 2 doses of dalbavancin intravenously (IV) 1 week apart (1500 mg on Day 1 and Day 8 after randomization, with renal dose adjustment if appropriate). Subjects randomized to the standard of care antibiotic therapy treatment group will receive an antibiotic regimen considered to be standard of care based on the methicillin susceptibility pattern of the pathogen isolated at baseline for a duration of 4 to 6 weeks and up to 8 weeks for patients with vertebral osteomyelitis/discitis. The primary objective is to compare the Desirability of Outcome Ranking (DOOR) at Day 70 of dalbavancin to that of standard of care antibiotic therapy used to consolidate therapy for the treatment of subjects with complicated S. aureus bacteremia in the intent-to-treat population (ITT). The secondary objectives are 1) to compare the clinical outcomes of dalbavancin with the standard of care antibiotic therapy at day 70 in the modified intent-to-treat population (mITT). 2) to compare the safety of dalbavancin with that of the standard of care treatment in the modified intent-to-treat population (mITT). 3) to compare each individual component of the Desirability of Outcome Ranking (DOOR) outcome by treatment arm, in the intent-to-treat population.

Inclusion Criteria:

1. Written informed consent obtained from the patient or legally authorized representative before the initiation of any study-specific procedures.

2. Patients > / = to 18 years old.

3. A diagnosis of complicated Staphylococcus aureus (either Methicillin-sensitive Staphylococcus aureus or Methicillin-resistant Staphylococcus aureus) bloodstream infection.

4. Treated with effective antibiotic therapy for at least 72 hours (maximum 10 days).*

   *Ten consecutive days prior to randomization is the maximum allowed treatment duration. If a subject has received intermittent or incomplete therapy earlier in the treatment course for this episode of S. aureus bacteremia, then discuss with the protocol PI and DMID Medical Officer prior to enrollment.

5. Subsequent defervescence for at least 24 hours and clearance of bacteremia from the qualifying pathogen (at Screening), with negative blood culture incubated for at least 48 hours.**

   **Two negative blood cultures incubated for 48 hours are preferred. However, if only a single blood culture set is drawn, no growth at 48 hours will be considered adequate to demonstrate clearance. If more than one culture set is drawn, all must show no growth at 48 hours to be considered evidence of clearance (e.g., 1 of 2 positive cultures would still be considered as ongoing bacteremia).

6. Provider willing to treat with either dalbavancin for two doses, or standard of care intravenous monotherapy for at least 4 and no more than 8 weeks from randomization.

7. Patients must be willing and able, if discharged, to return to the hospital or designated clinic for scheduled treatment, laboratory tests, or other procedures as required by the protocol.

8. According to the site Principal Investigator or sub-investigator assessment, patients must be expected to survive with appropriate antibiotic therapy and appropriate supportive care throughout the study.

Exclusion Criteria:

1. Uncomplicated bacteremia.*

   *Uncomplicated Staphylococcus aureus bacteremia is defined as all of the following: exclusion of endocarditis by echocardiography; catheter-associated bacteremia and removal of catheter; no implanted prostheses; follow-up blood cultures drawn within 48 hours after initial set that do not grow screening pathogen and all follow-up blood cultures thereafter do not grow the screening pathogen; defervescence within 72 hours of initiating effective therapy; and no evidence of metastatic sites of infection.

2. Infectious Central Nervous System events, including septic emboli, ischemic or hemorrhagic stroke, epidural abscess, or meningitis (prior/unrelated Central Nervous System events are not exclusion criteria).

3. Known or suspected left-sided endocarditis or presence of a perivalvular abscess.

4. Planned right-sided valve replacement surgery in the first 3 days following randomization.

5. Presence of prosthetic heart valve, cardiac device** UNLESS removal is planned within 4 days post-randomization.

   **Implantable cardioverter defibrillator (ICD), permanent pacemaker, valve support ring, ventricular assist device (VAD).

6. Presence of intravascular graft or intravascular material*** UNLESS removal is planned within 4 days post-randomization

   ***Excluding cardiac stents, inferior vena cava filters in place for >6 weeks, vascular stents in place for >6 weeks, non-hemodialysis grafts in place >90 days, and hemodialysis grafts not used within the past 12 months and not previously infected. A fistula constructed from native veins or a biologic vascular graft (without synthetic graft material) does not count as intravascular graft/material.

7. Infected prosthetic joint or extravascular hardware UNLESS removal is planned within 4 days post-randomization OR hardware was placed >60 days before bacteremia and clinically appears uninfected.

8. Polymicrobial bacteremia unless the non-Staphylococcus aureus organism is a contaminant.****

   ****Note: If a gram-negative bacteremia or fungemia develops after the qualifying S. aureus blood culture, AND the patient does not have right-sided endocarditis, AND the infection can be treated with an antibiotic without efficacy against the patient's S. aureus isolate (e.g. aztreonam), then the patient may remain eligible. Discussion with the DMID Medical Officer is strongly encouraged.

9. Significant hepatic insufficiency (Child-Pugh class C or aspartate transaminase (AST)/alanine aminotransferase (ALT) values >5x Upper Limit Normal at the time of randomization).

10. Immunosuppression*****

    *****On chemotherapy or immunotherapy for active hematologic malignancy expected to cause > 7 days of absolute neutrophil count (ANC) < 100 cells/mm3, recent bone marrow transplant (in the past 90 days), solid organ transplantation within prior 3 months or receipt of augmented immunosuppression for rejection within 3 months, chronic granulomatous disease, human immunodeficiency virus (HIV) infection with a cluster of differentiation 4 (CD4) cell count < 50 cells/mm3 based on last known measurement or patient-reported value.

11. History of hypersensitivity reaction to dalbavancin or other drugs of the glycopeptide class of antibiotics.

12. Treatment with either dalbavancin or oritavancin in the 60 days prior to enrollment.

13. Infection with Staphylococcus aureus not susceptible to dalbavancin (dalbavancin mean inhibitory concentration Minimum Inhibitory Concentration (MIC) > 0.25 µg/mL) or vancomycin (vancomycin Minimum Inhibitory Concentration (MIC) > 2 µg/mL).

14. Planned treatment with concomitant systemic antibacterial therapy with potential efficacy against the patient's qualifying Staphylococcus aureus isolate, other than that allowed in the protocol.

15. Pregnant/ nursing females.

16. Females of childbearing potential must have a negative pregnancy test****** within 48h of randomization and use effective contraception for trial duration.

    ******If the serum pregnancy test results cannot be obtained before randomization, a urine pregnancy test may be used for enrollment.

17. Other medical or psychiatric condition that may, in the judgment of the investigator, increase the risk of study participation or interfere with interpretation of study results.

18. Unwilling or unable to follow study procedures.

19. Treatment with an investigational drug within 30 days preceding the first dose of study medication.