A Phase 2 interventional study of Cefazolin and Dalbavancin in Staphylococcal Bacteraemia, sponsored by National Institute of Allergy and Infectious Diseases (NIAID). Completed at 24 sites in 2 countries. Open to participants aged 18 Years to 99 Years. Per ClinicalTrials.gov, last updated 2024-12-10.
Sponsored by National Institute of Allergy and Infectious Diseases (NIAID) · Phase 2, Interventional, and Treatment
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.
328 studies on the registry are indexed under Bacteremia; 50 are open to participants now.
This study's enrollment of 200 is above the median of 149 across 173 interventional studies indexed under Bacteremia.
Browse Bacteremia studies →National Institute of Allergy and Infectious Diseases (NIAID) is the lead sponsor of 2,445 studies on the registry; 182 are open to participants now.
Of its 402 completed or terminated interventional studies of FDA-regulated products, 300 (75%) have results posted.
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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).
Exclusion Criteria:
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.
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.
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.
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.
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.
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
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
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)
A second-generation lipoglycopeptide antibiotic synthesized from a fermentation product of Nonomuraea species
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 is a semi-synthetic antibiotic related to penicillin. Nafcillin (2 g will be administrated intravenously (IV) every 4 hours for 4-6 weeks)
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 is a glycopeptide antibiotic product of the organism Amycolatopsis orientalis. Vancomycin (dose per local standard of care × 4-6 weeks)
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.
Time frame: Day 70
Frequency of Clinical Efficacy
Number of participants that had clinical efficacy at Day 70. Clinical efficacy is defined as none of: (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; and (3) Death. Clinical failure and infectious complications are assessed by a blinded adjudication committee. Participants missing clinical failure are treated as not having clinical efficacy.
Time frame: Day 70
Frequency of SAEs
Number of participants that experience any SAEs from Day 1 to study completion (Day 70 or Day 180 for participants in the osteomyelitis subset). An AE is considered serious if, in the view of either the site principal investigator or sponsor, it results in: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.
Time frame: Day 1 through Day 180
Frequency of AEs Leading to Study Drug Discontinuation
Number of participants that experience any AEs leading to study drug discontinuation from Day 1 to study completion (Day 70 or Day 180 for participants in the osteomyelitis subset).
Time frame: Day 1 through Day 180
Frequency of Clinical Failure (A Component of DOOR)
Number of participants who had clinical failure at Day 70, used for DOOR at Day 70. Clinical Failure is defined as 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. Clinical failure is assessed by a blinded adjudication committee. Participants missing clinical failure are treated as having clinical failure.
Time frame: Day 70
Frequency of Infectious Complications (A Component of DOOR)
Number of participants that experience any infectious complications from Day 1 through Day 70, used for DOOR at Day 70. Infectious complications include 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. Infectious complications are assessed by a blinded adjudication committee.
Time frame: Day 1 through Day 70
Frequency of SAEs (A Component of DOOR)
Number of participants that experience any SAEs from Day 1 to Day 70, used for DOOR at Day 70. An AE is considered serious if, in the view of either the site principal investigator or sponsor, it results in: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.
Time frame: Day 1 through Day 70
Frequency of AEs Leading to Study Drug Discontinuation (A Component of DOOR)
Number of participants that experience any AEs leading to study drug discontinuation from Day 1 to Day 70, used for DOOR at Day 70.
Time frame: Day 1 through Day 70
Frequency of All-Cause Mortality (A Component of DOOR)
Number of participants who passed away from Day 1 to Day 70, used for DOOR at Day 70.
Time frame: Day 1 through Day 70
Participants were recruited from 23 clinical sites within the United States and Canada. The first participant was enrolled on April 22, 2021, and the last participant was enrolled on July 6, 2023.
| Milestone | Dalbavancin | Standard of Care |
|---|---|---|
| Started | 100 | 100 |
| Completed | 84 | 81 |
| Not completed | 16 | 19 |
| Withdrew: Lost to follow-up | 6 | 11 |
| Withdrew: Death | 5 | 4 |
| Withdrew: Withdrawal by subject | 3 | 3 |
| Withdrew: Protocol violation | 2 | 0 |
| Withdrew: Participant non-compliance | 0 | 1 |
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.
| Participants | Dalbavancin | Standard of Care |
|---|---|---|
| Rank 1: Alive with none of clinical failure, infectious comp, or SAE or AE leading to trt discont | 49 | 49 |
| Rank 2: Alive with one of clinical failure, infectious comp, or SAE or AE leading to trt discont | 34 | 37 |
| Rank 3: Alive with two of clinical failure, infectious comp, or SAE or AE leading to trt discont | 9 | 7 |
| Rank 4: Alive with all of clinical failure, infectious comp, and SAE or AE leading to trt discont | 4 | 3 |
| Rank 5: Death | 4 | 4 |
Number of participants that had clinical efficacy at Day 70. Clinical efficacy is defined as none of: (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; and (3) Death. Clinical failure and infectious complications are assessed by a blinded adjudication committee. Participants missing clinical failure are treated as not having clinical efficacy.
| Participants | Dalbavancin | Standard of Care |
|---|---|---|
| Frequency of Clinical Efficacy | 73 | 72 |
Number of participants that experience any SAEs from Day 1 to study completion (Day 70 or Day 180 for participants in the osteomyelitis subset). An AE is considered serious if, in the view of either the site principal investigator or sponsor, it results in: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.
| Participants | Dalbavancin | Standard of Care |
|---|---|---|
| Frequency of SAEs | 43 | 37 |
Number of participants that experience any AEs leading to study drug discontinuation from Day 1 to study completion (Day 70 or Day 180 for participants in the osteomyelitis subset).
| Participants | Dalbavancin | Standard of Care |
|---|---|---|
| Frequency of AEs Leading to Study Drug Discontinuation | 3 | 12 |
Number of participants who had clinical failure at Day 70, used for DOOR at Day 70. Clinical Failure is defined as 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. Clinical failure is assessed by a blinded adjudication committee. Participants missing clinical failure are treated as having clinical failure.
| Participants | Dalbavancin | Standard of Care |
|---|---|---|
| Frequency of Clinical Failure (A Component of DOOR) | 20 | 22 |
Number of participants that experience any infectious complications from Day 1 through Day 70, used for DOOR at Day 70. Infectious complications include 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. Infectious complications are assessed by a blinded adjudication committee.
| Participants | Dalbavancin | Standard of Care |
|---|---|---|
| Frequency of Infectious Complications (A Component of DOOR) | 13 | 12 |
Number of participants that experience any SAEs from Day 1 to Day 70, used for DOOR at Day 70. An AE is considered serious if, in the view of either the site principal investigator or sponsor, it results in: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.
| Participants | Dalbavancin | Standard of Care |
|---|---|---|
| Frequency of SAEs (A Component of DOOR) | 40 | 34 |
Number of participants that experience any AEs leading to study drug discontinuation from Day 1 to Day 70, used for DOOR at Day 70.
| Participants | Dalbavancin | Standard of Care |
|---|---|---|
| Frequency of AEs Leading to Study Drug Discontinuation (A Component of DOOR) | 3 | 12 |
Number of participants who passed away from Day 1 to Day 70, used for DOOR at Day 70.
| Participants | Dalbavancin | Standard of Care |
|---|---|---|
| Frequency of All-Cause Mortality (A Component of DOOR) | 4 | 4 |
Collected over All unsolicited AEs grade 3 or higher, including laboratory abnormalities, as well as adverse events of special interest (AESIs) of any severity from time of first dose of study drug (i.e., dalbavancin or standard of care antibiotic) after randomization through follow-up (Day 70 or Day 180 for participants in osteomyelitis subset) were reported.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Dalbavancin | 5/100 (5%) | 43/100 (43%) | 5/100 (5%) |
| Standard of Care | 4/100 (4%) | 37/100 (37%) | 1/100 (1%) |
| Event | Dalbavancin | Standard of Care |
|---|---|---|
| OsteomyelitisInfections and infestations | 2/100 | 5/100 |
| Acute kidney injuryRenal and urinary disorders | 2/100 | 4/100 |
| PneumoniaInfections and infestations | 2/100 | 3/100 |
| Staphylococcal bacteraemiaInfections and infestations | 2/100 | 3/100 |
| Pulmonary embolismRespiratory, thoracic and mediastinal disorders | 3/100 | 1/100 |
| Cardiac failure chronicCardiac disorders | 2/100 | 0/100 |
| PyrexiaGeneral disorders | 2/100 | 0/100 |
| SepsisInfections and infestations | 2/100 | 0/100 |
| CellulitisInfections and infestations | 2/100 | 1/100 |
| Diabetic foot infectionInfections and infestations | 2/100 | 0/100 |
| Event | Dalbavancin | Standard of Care |
|---|---|---|
| Aspartate aminotransferase increasedInvestigations | 5/100 | 1/100 |
The intent-to-treat (ITT) population includes all randomized participants.
| Age, Continuous(years) | Dalbavancin | Standard of Care | Total |
|---|---|---|---|
| Mean | 54.3 ± 15.7 | 54.0 ± 16.8 | 54.1 ± 16.2 |
| Sex: Female, Male(Participants) | Dalbavancin | Standard of Care | Total |
|---|---|---|---|
| Female | 30 | 32 | 62 |
| Male | 70 | 68 | 138 |
| Ethnicity (NIH/OMB)(Participants) | Dalbavancin | Standard of Care | Total |
|---|---|---|---|
| Hispanic or Latino | 11 | 14 | 25 |
| Not Hispanic or Latino | 84 | 84 | 168 |
| Unknown or Not Reported | 5 | 2 | 7 |
| Race (NIH/OMB)(Participants) | Dalbavancin | Standard of Care | Total |
|---|---|---|---|
| American Indian or Alaska Native | 2 | 0 | 2 |
| Asian | 5 | 1 | 6 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 20 | 29 | 49 |
| White | 68 | 69 | 137 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 5 | 1 | 6 |
| Region of Enrollment(participants) | Dalbavancin | Standard of Care | Total |
|---|---|---|---|
| Canada | 2 | 0 | 2 |
| United States | 98 | 100 | 198 |
| Baseline Pathogen(Participants) | Dalbavancin | Standard of Care | Total |
|---|---|---|---|
| MRSA | 34 | 32 | 66 |
| MSSA | 66 | 68 | 134 |
| Body Mass Index (BMI)(kg/m^2) | Dalbavancin | Standard of Care | Total |
|---|---|---|---|
| Mean | 28.83 ± 6.91 | 29.03 ± 8.08 | 28.93 ± 7.50 |
Documents are hosted by the registry — open the source record to download them.
Ran from Apr 2021 to primary completion in Oct 2023, 29 months.
Results were first posted in Oct 2024, 1 year after primary completion.
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Studies of the drug tested here: Dalbavancin
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