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

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Recruiting

CT.gov ID

NCT04775953

Collaborator

(none)

200

Enrollment

Locations

Arms

30.6

Anticipated Duration (Months)

8.3

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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

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

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.

Study Design

Study Type:

Interventional

Anticipated 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 :

Apr 22, 2021

Anticipated Primary Completion Date :

Jun 10, 2023

Anticipated Study Completion Date :

Nov 9, 2023

Arms and Interventions

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)

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)

Outcome Measures

Primary Outcome Measures

Desirability of Outcome Ranking (DOOR) for the treatment of subjects with complicated Staphylococcus aureus bacteremia [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

Incidence of all-cause mortality [Day 1 through Day 180]
Proportion of participants who experienced a clinical efficacy of antibiotic therapy [Day 1 through Day 180]
Clinical efficacy, defined as none of 1) Clinical failure; 2) Infectious complications; 3) All-cause mortality
Proportion of participants who experienced any adverse event (AE) leading to study drug discontinuation [Day 1 through Day 180]
Proportion of participants who experienced any serious adverse event (SAE) leading to study drug discontinuation [Day 1 through Day 180]
Proportion of participants who experienced clinical success of antibiotic therapy [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
Proportion of participants with infectious complications [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 99 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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.

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.

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).
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 (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.
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).
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.
Pregnant/ nursing females.
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.

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.
Unwilling or unable to follow study procedures.
Treatment with an investigational drug within 30 days preceding the first dose of study medication.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama Hospital - Infectious Diseases	Birmingham	Alabama	United States	35233
2	University of California Davis Medical Center - Internal Medicine - Infectious Disease	Sacramento	California	United States	95817-1460
3	Harbor UCLA Medical Center - Medicine - Infectious Diseases	Torrance	California	United States	90502-2006
4	Torrance Memorial Medical Center	Torrance	California	United States	90505
5	University of Florida Health - Shands Hospital - Division of Infectious Diseases and Global Medicine	Gainesville	Florida	United States	32610
6	University of South Florida Health - Internal Medicine	Tampa	Florida	United States	22612
7	Rush University Medical Center	Chicago	Illinois	United States	60612
8	Ochsner Health - Ochsner Medical Center - Department of Infectious Diseases	New Orleans	Louisiana	United States	70121
9	Henry Ford Health System - Henry Ford Hospital	Detroit	Michigan	United States	48202-2608
10	William Beaumont Hospital - Royal Oak Campus - Infectious Disease	Royal Oak	Michigan	United States	48073-6757
11	University of Nebraska Medical Center - Infectious Diseases	Omaha	Nebraska	United States	68198-5400
12	South Jersey Infectious Disease	Somers Point	New Jersey	United States	08244
13	New York Presbyterian Hospital - Weill Cornell Medical Center - Infectious Diseases	New York	New York	United States	10065-4870
14	SUNY Upstate Medical University - Infectious Disease Division	Syracuse	New York	United States	13210
15	Atrium Health ID Consultants & Infusion Care Specialists	Charlotte	North Carolina	United States	28209
16	Duke University Hospital - Infectious Diseases	Durham	North Carolina	United States	27710
17	East Carolina University - Infectious Diseases and Tropical/Travel Medicine Clinic	Greenville	North Carolina	United States	27834-9997
18	Wake Forest Baptist Medical Center	Winston-Salem	North Carolina	United States	27157
19	Oregon Health and Science University - Adult Infectious Diseases Clinic	Portland	Oregon	United States	97239-3098
20	University of Pittsburgh - Medicine - Infectious Diseases	Pittsburgh	Pennsylvania	United States	15213
21	Prisma Health - Greenville Health System - Infectious Disease	Greenville	South Carolina	United States	29605
22	The University of Texas - MD Anderson Cancer Center - Infectious Diseases	Houston	Texas	United States	77030-4000
23	Carilion Roanoke Memorial Hospital	Roanoke	Virginia	United States	24014
24	McGill University	Montreal	PQ	Canada	H4A3S1