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

NCT ID: NCT04775953

Last Updated: 2024-12-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-04-22
• Study Completion Date: 2023-12-01

Brief Summary

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).

Detailed Description

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.

Conditions

Staphylococcal Bacteraemia

Keywords

Bacteremia; Dalbavancin; DOTS; Efficacy; Safety; Staphylococcus aureus

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm 1 (Dalbavancin)

Dalbavancin 1500 mg will be administrated intravenously (IV) over 30 (-/+10) minutes on Day 1 and 1500 mg IV over 30 (-/+10) minutes on Day 8, renally dose-adjusted to 1125 mg for subjects with Creatinine Clearance (CrCl) \<30 and not on dialysis. N=100

Group Type: EXPERIMENTAL

Dalbavancin

Intervention Type: DRUG

A second-generation lipoglycopeptide antibiotic synthesized from a fermentation product of Nonomuraea species

Arm 2 (Standard of Care)

For Methicillin-sensitive Staphylococcus aureus (MSSA): nafcillin (2 g will be administrated intravenously (IV) every 4 hours for 4-6 weeks) OR oxacillin (2 g will be administrated intravenously (IV) every 4 hours for 4-6 weeks OR cefazolin (2 g will be administrated intravenously (IV) every 8 hours for 4-6 weeks) For Methicillin-resistant Staphylococcus aureus (MRSA): vancomycin (dose per local standard of care × 4-6 weeks) OR daptomycin (6-10 mg/kg will be administrated intravenously (IV) daily for 4-6 weeks). N=100

Group Type: ACTIVE_COMPARATOR

Cefazolin

Intervention Type: DRUG

Cefazolin is a semisynthetic cephalosporin analog with broad-spectrum antibiotic action due to inhibition of bacterial cell wall synthesis. Cefazolin (2 g will be administrated intravenously (IV) every 8 hours for 4-6 weeks)

Daptomycin

Intervention Type: DRUG

Daptomycin (USA) or Cubicin (Spain) is a cyclic lipopeptide antibiotic that inhibits gram-positive bacteria. Daptomycin (6-10 mg/kg will be administrated intravenously (IV) daily for 4-6 weeks

Nafcillin

Intervention Type: DRUG

Nafcillin is a semi-synthetic antibiotic related to penicillin. Nafcillin (2 g will be administrated intravenously (IV) every 4 hours for 4-6 weeks)

Oxacillin

Intervention Type: DRUG

Oxacillin is an antibiotic used in resistant staphylococci infections. Oxacillin (2 g will be administrated intravenously (IV) every 4 hours for 4-6 weeks

Vancomycin

Intervention Type: DRUG

Vancomycin is a glycopeptide antibiotic product of the organism Amycolatopsis orientalis. Vancomycin (dose per local standard of care × 4-6 weeks)

Interventions

Cefazolin

Cefazolin is a semisynthetic cephalosporin analog with broad-spectrum antibiotic action due to inhibition of bacterial cell wall synthesis. Cefazolin (2 g will be administrated intravenously (IV) every 8 hours for 4-6 weeks)

Intervention Type: DRUG

Dalbavancin

A second-generation lipoglycopeptide antibiotic synthesized from a fermentation product of Nonomuraea species

Intervention Type: DRUG

Daptomycin

Daptomycin (USA) or Cubicin (Spain) is a cyclic lipopeptide antibiotic that inhibits gram-positive bacteria. Daptomycin (6-10 mg/kg will be administrated intravenously (IV) daily for 4-6 weeks

Intervention Type: DRUG

Nafcillin

Nafcillin is a semi-synthetic antibiotic related to penicillin. Nafcillin (2 g will be administrated intravenously (IV) every 4 hours for 4-6 weeks)

Intervention Type: DRUG

Oxacillin

Oxacillin is an antibiotic used in resistant staphylococci infections. Oxacillin (2 g will be administrated intravenously (IV) every 4 hours for 4-6 weeks

Intervention Type: DRUG

Vancomycin

Vancomycin is a glycopeptide antibiotic product of the organism Amycolatopsis orientalis. Vancomycin (dose per local standard of care × 4-6 weeks)

Intervention Type: DRUG

Eligibility Criteria

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.

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

University of Alabama Hospital - Infectious Diseases

Birmingham, Alabama, United States

University of California Davis Medical Center - Internal Medicine - Infectious Disease

Sacramento, California, United States

Harbor UCLA Medical Center - Medicine - Infectious Diseases

Torrance, California, United States

Torrance Memorial Medical Center

Torrance, California, United States

University of Florida Health - Shands Hospital - Division of Infectious Diseases and Global Medicine

Gainesville, Florida, United States

University of South Florida Health - Internal Medicine

Tampa, Florida, United States

Rush University Medical Center

Chicago, Illinois, United States

Ochsner Health - Ochsner Medical Center - Department of Infectious Diseases

New Orleans, Louisiana, United States

Henry Ford Health System - Henry Ford Hospital

Detroit, Michigan, United States

Corewell Health - Infectious Disease

Royal Oak, Michigan, United States

University of Nebraska Medical Center - Infectious Diseases

Omaha, Nebraska, United States

South Jersey Infectious Disease

Somers Point, New Jersey, United States

New York Presbyterian Hospital - Weill Cornell Medical Center - Infectious Diseases

New York, New York, United States

SUNY Upstate Medical University - Infectious Disease Division

Syracuse, New York, United States

Atrium Health ID Consultants & Infusion Care Specialists

Charlotte, North Carolina, United States

Duke University Hospital - Infectious Diseases

Durham, North Carolina, United States

East Carolina University - Infectious Diseases and Tropical/Travel Medicine Clinic

Greenville, North Carolina, United States

Wake Forest Baptist Medical Center

Winston-Salem, North Carolina, United States

Oregon Health and Science University - Adult Infectious Diseases Clinic

Portland, Oregon, United States

University of Pittsburgh - Medicine - Infectious Diseases

Pittsburgh, Pennsylvania, United States

Prisma Health - Greenville Health System - Infectious Disease

Greenville, South Carolina, United States

The University of Texas - MD Anderson Cancer Center - Infectious Diseases

Houston, Texas, United States

Carilion Roanoke Memorial Hospital

Roanoke, Virginia, United States

McGill University Health Centre

Montreal, , Canada

Countries

United States; Canada

References

Turner NA, Hamasaki T, Doernberg SB, Lodise TP, King HA, Ghazaryan V, Cosgrove SE, Jenkins TC, Liu C, Sharma S, Zaharoff S, Wahid L, Renard VJ, Cook P, Raad I, Hachem R, Chaftari AM, Sims M, DeMarco C, Miller LG, McCarthy MW, Morse CG, Lucasti C, Forrest GN, Cherabuddi K, Polk C, Fazili T, Rupp ME, Thompson GR 3rd, Kim K, Strnad L, Schnee AE, McKinnell JA, Ramesh M, Silveira FP, McCarty TP, Lee TC, McDonald EG, Paolino K, Wiegand K, Wall A, Riccobene T, Patel R, Rappo U, Evans S, Chambers HF, Fowler VG Jr, Holland TL; Antibacterial Resistance Leadership Group. Dalbavancin for Treatment of Staphylococcus aureus Bacteremia: The DOTS Randomized Clinical Trial. JAMA. 2025 Aug 13:e2512543. doi: 10.1001/jama.2025.12543. Online ahead of print.

Reference Type: DERIVED

PMID: 40802264 (View on PubMed)

Turner NA, Zaharoff S, King H, Evans S, Hamasaki T, Lodise T, Ghazaryan V, Beresnev T, Riccobene T, Patel R, Doernberg SB, Rappo U, Fowler VG Jr, Holland TL; Antibacterial Resistance Leadership Group (ARLG). Dalbavancin as an option for treatment of S. aureus bacteremia (DOTS): study protocol for a phase 2b, multicenter, randomized, open-label clinical trial. Trials. 2022 May 16;23(1):407. doi: 10.1186/s13063-022-06370-1.

Reference Type: DERIVED

PMID: 35578360 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

5UM1AI104681-12

Identifier Type: NIH

Identifier Source: secondary_id

View Link

20-0002

Identifier Type: -

Identifier Source: org_study_id