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

NCT04775953 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 20-00025UM1AI104681-12
• Study Type: interventional
• Target: 200
• Locations: 2 countries
• Sites: 24

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).

Conditions

Staphylococcal Bacteraemia

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Desirability of Outcome Ranking (DOOR)

  DOOR is a composite endpoint assessed by: (1) Clinical Failure: Lack of resolution of clinical signs and symptoms of S. aureus bacteremia such that no additional antibiotic therapy is required or anticipated for its treatment; (2) Infectious Complications such as: Endocarditis, New evidence of metastatic foci of infection, relapse - isolation of baseline S. aureus pathogen from a blood culture drawn after randomization, readmission for subsequent care of indication under study, need for additional unplanned source control procedures, or change in antibiotic therapy due to inadequate clinical response; (3) Serious Adverse Events (SAEs); (4) Adverse Events (AEs) Leading to Study Drug Discontinuation; and (5) Death. Clinical failure and infectious complications were assessed by a blinded adjudication committee. Participants missing clinical failure were treated as having clinical failure for calculation of DOOR.

  Day 70

Secondary Outcomes (8)

• Frequency of Clinical Efficacy

  Day 70

• Frequency of SAEs

  Day 1 through Day 180

• Frequency of AEs Leading to Study Drug Discontinuation

  Day 1 through Day 180

• Frequency of Clinical Failure (A Component of DOOR)

  Day 70

• Frequency of Infectious Complications (A Component of DOOR)

  Day 1 through Day 70

Study Arms (2)

Arm 1 (Dalbavancin)

EXPERIMENTAL

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

Drug: Dalbavancin

Arm 2 (Standard of Care)

ACTIVE COMPARATOR

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

Drug: Cefazolin; Drug: Daptomycin; Drug: Nafcillin; Drug: Oxacillin; Drug: Vancomycin

Interventions

Cefazolin 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)

Arm 2 (Standard of Care)

Dalbavancin DRUG

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

Arm 1 (Dalbavancin)

Daptomycin 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

Arm 2 (Standard of Care)

Nafcillin 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)

Arm 2 (Standard of Care)

Oxacillin 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

Arm 2 (Standard of Care)

Vancomycin DRUG

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

Arm 2 (Standard of Care)

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent obtained from the patient or legally authorized representative before the initiation of any study-specific procedures.
• Patients \> / = to 18 years old.
• A diagnosis of complicated Staphylococcus aureus (either Methicillin-sensitive Staphylococcus aureus or Methicillin-resistant Staphylococcus aureus) bloodstream infection.
• 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.
• 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).
• 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.
• 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.
• 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.

You may not qualify if:

• Uncomplicated bacteremia.\*
• Known or suspected left-sided endocarditis or presence of a perivalvular abscess.
• Planned right-sided valve replacement surgery in the first 3 days following randomization.
• 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).
• 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.
• 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.
• 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.
• Significant hepatic insufficiency (Child-Pugh class C or aspartate transaminase (AST)/alanine aminotransferase (ALT) values \>5x Upper Limit Normal at the time of randomization).
• 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.
• History of hypersensitivity reaction to dalbavancin or other drugs of the glycopeptide class of antibiotics.
• Treatment with either dalbavancin or oritavancin in the 60 days prior to enrollment.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (24)

University of Alabama Hospital - Infectious Diseases

Birmingham, Alabama, 35233, United States

Location

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

Sacramento, California, 95817-1460, United States

Location

Harbor UCLA Medical Center - Medicine - Infectious Diseases

Torrance, California, 90502-2006, United States

Location

Torrance Memorial Medical Center

Torrance, California, 90505, United States

Location

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

Gainesville, Florida, 32610, United States

Location

University of South Florida Health - Internal Medicine

Tampa, Florida, 22612, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Ochsner Health - Ochsner Medical Center - Department of Infectious Diseases

New Orleans, Louisiana, 70121, United States

Location

Henry Ford Health System - Henry Ford Hospital

Detroit, Michigan, 48202-2608, United States

Location

Corewell Health - Infectious Disease

Royal Oak, Michigan, 48073-6757, United States

Location

University of Nebraska Medical Center - Infectious Diseases

Omaha, Nebraska, 68198-5400, United States

Location

South Jersey Infectious Disease

Somers Point, New Jersey, 08244, United States

Location

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

New York, New York, 10065-4870, United States

Location

SUNY Upstate Medical University - Infectious Disease Division

Syracuse, New York, 13210, United States

Location

Atrium Health ID Consultants & Infusion Care Specialists

Charlotte, North Carolina, 28209, United States

Location

Duke University Hospital - Infectious Diseases

Durham, North Carolina, 27710, United States

Location

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

Greenville, North Carolina, 27834-9997, United States

Location

Wake Forest Baptist Medical Center

Winston-Salem, North Carolina, 27157, United States

Location

Oregon Health and Science University - Adult Infectious Diseases Clinic

Portland, Oregon, 97239-3098, United States

Location

University of Pittsburgh - Medicine - Infectious Diseases

Pittsburgh, Pennsylvania, 15213, United States

Location

Prisma Health - Greenville Health System - Infectious Disease

Greenville, South Carolina, 29605, United States

Location

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

Houston, Texas, 77030-4000, United States

Location

Carilion Roanoke Memorial Hospital

Roanoke, Virginia, 24014, United States

Location

McGill University Health Centre

Montreal, Canada

Location

Related Publications (2)

• 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.

  PMID: 40802264 DERIVED

• 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.

  PMID: 35578360 DERIVED

MeSH Terms

Conditions

Bacteremia; Staphylococcal Infections

Interventions

Cefazolin; dalbavancin; Daptomycin; Nafcillin; Oxacillin; Vancomycin

Condition Hierarchy (Ancestors)

Bacterial Infections; Bacterial Infections and Mycoses; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Gram-Positive Bacterial Infections

Intervention Hierarchy (Ancestors)

Cephalosporins; beta-Lactams; Lactams; Amides; Organic Chemicals; Thiazines; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Lipopeptides; Lipids; Peptides; Amino Acids, Peptides, and Proteins; Penicillins; Glycopeptides; Glycoconjugates; Carbohydrates

Results Point of Contact

• Title: Thomas L. Holland, MD
• Organization: Duke University

thomas.holland@duke.edu

919-613-4268

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 25, 2021
• First Posted: March 1, 2021
• Study Start: April 22, 2021
• Primary Completion: October 6, 2023
• Study Completion: December 1, 2023
• Last Updated: December 10, 2024
• Results First Posted: October 22, 2024

Record last verified: 2022-02-10

Locations

CA (1); US (23)