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

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ClinicalTrials.gov Identifier: NCT04775953
Recruitment Status : Recruiting
First Posted : March 1, 2021
Last Update Posted : September 24, 2021
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

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).

Condition or disease Intervention/treatment Phase
Staphylococcal Bacteraemia Drug: Cefazolin Drug: Dalbavancin Drug: Daptomycin Drug: Nafcillin Drug: Oxacillin Drug: Vancomycin Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : August 9, 2021
Estimated Primary Completion Date : August 1, 2023
Estimated Study Completion Date : August 1, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antibiotics

Arm Intervention/treatment
Experimental: 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
Drug: Dalbavancin
A second-generation lipoglycopeptide antibiotic synthesized from a fermentation product of Nonomuraea species

Active Comparator: 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
Drug: 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)

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

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)

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

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




Primary Outcome Measures :
  1. Desirability of Outcome Ranking (DOOR) for the treatment of subjects with complicated Staphylococcus aureus bacteremia [ Time Frame: Day 70 ]
    Desirability of Outcome Ranking (DOOR) will be assessed by: 1.Clinical Success: Resolution of clinical signs and symptoms of S. aureus bacteremia such that no additional antibiotic therapy is required or anticipated for its treatment. 2. Clinical Failure: Absence of clinical success. 3. Infectious Complications such as: Endocarditis, New evidence of metastatic foci of infection (osteomyelitis, visceral abscess, septic joint), 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 (abscess debridement or drainage, cardiac valve replacement), change in antibiotic therapy due to inadequate clinical response.


Secondary Outcome Measures :
  1. Incidence of all-cause mortality [ Time Frame: Day 1 through Day 180 ]
  2. Proportion of participants who experienced a clinical efficacy of antibiotic therapy [ Time Frame: Day 1 through Day 180 ]
    Clinical efficacy, defined as none of 1) Clinical failure; 2) Infectious complications; 3) All-cause mortality

  3. Proportion of participants who experienced any adverse event (AE) leading to study drug discontinuation [ Time Frame: Day 1 through Day 180 ]
  4. Proportion of participants who experienced any serious adverse event (SAE) leading to study drug discontinuation [ Time Frame: Day 1 through Day 180 ]
  5. Proportion of participants who experienced clinical success of antibiotic therapy [ Time Frame: Day 1 through Day 180 ]
    Clinical Success: Resolution of clinical signs and symptoms of S. aureus bacteremia such that no additional antibiotic therapy is required or anticipated for its treatment

  6. Proportion of participants with infectious complications [ Time Frame: Day 1 through Day 180 ]
    Infectious Complications such as: Endocarditis, New evidence of metastatic foci of infection (osteomyelitis, visceral abscess, septic joint), 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 (abscess debridement or drainage, cardiac valve replacement), change in antibiotic therapy due to inadequate clinical response.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).
  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 (excluding cardiac stents) UNLESS removal is planned within 4 days post-randomization
  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 absolute neutrophil count (ANC) < 500 cells/mm3 lasting > 7 days during the study period, 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 high dose oral steroids (equivalent of > / = 20 mg prednisolone per day for or equivalent, for >2 weeks within the last month), chronic granulomatous disease, human immunodeficiency virus (HIV) infection with a cluster of differentiation 4 (CD4) cell count < 100 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04775953


Contacts
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Contact: Thomas L. Holland 19196134268 thomas.holland@duke.edu

Locations
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Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT04775953    
Other Study ID Numbers: 20-0002
5UM1AI104681-09 ( U.S. NIH Grant/Contract )
First Posted: March 1, 2021    Key Record Dates
Last Update Posted: September 24, 2021
Last Verified: March 1, 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Bacteremia
Dalbavancin
DOTS
Efficacy
Safety
Staphylococcus aureus
Additional relevant MeSH terms:
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Bacteremia
Bacterial Infections
Bacterial Infections and Mycoses
Infections
Sepsis
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Vancomycin
Cefazolin
Daptomycin
Dalbavancin
Oxacillin
Nafcillin
Anti-Bacterial Agents
Anti-Infective Agents