Clinical trial NCT05117398: Dalbavancin Versus Standard Antibiotic Therapy for Catheter-related Bloodstream Infections Due to Staphylococcus Aureus
Official title: Randomized Open-label Controlled Trial Evaluating a Single-dose Intravenous Dalbavancin Versus Standard Antibiotic Therapy During Catheter-related Bloodstream Infections Due to Staphylococcus Aureus
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Catheter Bacteremia
Staphylococcus Aureus Infection
Keywords: catheter-related bloodstream infections
Staphylococcus aureus infection
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Centre Hospitalier de Perigueux
name: Advanz Pharma
name: Nantes University Hospital
name: Centre National de Référence des staphylocoques
First posted: 2021-11-11
Enrollment: 406
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase III, pragmatic, open-label, non-inferiority, randomized (1:1), multicenter trial, in patients with non-complicated CR-BSI due to S. aureus, with two parallel groups receiving 14 days of active antimicrobial therapy.
Primary purpose: TREATMENT

Brief summary: The primary objective of the study is to demonstrate, among patients with non-complicated CR-BSIs due to S. aureus, that a single-dose of intravenous (IV) dalbavancin 1500 mg is non-inferior to standard documented antibiotic therapy for 14 days according to national guidelines at DAY 30 (Long follow up visit).

As the secondary objectives, the study aims to evaluate according to treatment group:

1. Cure rate at DAY 14 and DAY 90 (EOS);
2. Mortality rate within 90 days of follow-up;
3. Time to negativation of blood cultures;
4. Patient's quality of life;
5. Hospitalization length of stay;
6. Cost-utility analyses;
7. Occurrence of any adverse event (AE and SAE), until Day 90 (EOS).

Detailed description: Catheter-related bloodstream infections (CR-BSIs) are the most common nosocomial bloodstream infections, with an incidence as high as 8.5 to 19.8 infections per 1000 catheter-days. Staphylococcus aureus is involved in about 20% of CR-BSIs and associated with significant morbidity, mortality (9.3%), prolonged hospital stay (+ 9 days), and healthcare costs (35 000 € to 65 000 € per case). S. aureus CR-BSIs occurs mainly in frail patients with a port of catheter for chemotherapy or parenteral nutrition.

According to international guidelines, management of CR-BSIs due to S. aureus includes the removal and replacement of the infected catheter and a 14-day intravenous (IV) antibiotic therapy. Therefore, the management of CR-BSIs due to S. aureus requires the insertion of a new intravenous catheter. In turn, the new catheter can also lead to new septic complications and limit the patients' autonomy. Non-adherence to these recommendations leads to over-mortality and costs.

Following of the positive results of the SABATO trial in 2021 to determine whether early switch to oral antibiotic therapy is safe and effective in patients with uncomplicated BSA, oral switch during staphylococcal bacteremia, will likely become the standard of care. It is therefore justified to allow oral switch in the control arm.

The usual practice in some centers is already to switch to oral antibiotics, after a minimum of 7 days of intravenous treatment.

Dalbavancin is a new glycopeptide antibiotic, with an excellent bactericidal activity against Gram-positive bacteria, especially S. aureus, and a prolonged half-life of 14 to 15 days. As a comparison, half-life of antibiotics usually used for CR-BSIs due to S. aureus, i.e. penicillin or glycopeptide, as-per sensitivity to methicillin is much lower: 1.5 to 9 hours. Such prolonged half-life allows one IV injection to be sufficient and effective over 14 days of treatment. This remarkable characteristic should allow patients to be promptly discharged from hospital without monitoring.

The hypothesis of the study is that in patients with CR-BSIs due to S. aureus, after catheter removal, dalbavancin could be administered intravenously in a single administration after catheter removal and be as effective as standard documented antibiotic therapy for 14 days according to national guidelines.

Eligibility criteria: Inclusion Criteria:

* Patients aged at least 18 years;
* Blood cultures positive for S. aureus, obtained within 72 hours before randomization (the date considered is the date of the sampling, not the results);
* CR-BSI, defined as:

  * One positive blood culture AND Local signs of infection at the catheter site; OR
  * at least one positive blood culture obtained from the catheter and the peripheral vein; AND
  * A differential period between catheter versus peripheral blood culture positivity of at least 2h as recommended; AND
  * Same S. aureus isolate (same phenotype) identified from the catheter and the peripheral vein blood cultures; OR
  * One positive blood culture; AND
  * Strong presumption of catheter-related infection according to clinical opinion.
* Intravascular catheter - implantable venous access device (port-a-cath and Piccline) - removed before randomization;
* Informed consent form date and signed by the patient.

Exclusion Criteria:

* Polymicrobial infection;
* Dalbavancin resistant strain;
* More than 72 hours of active antibiotic treatment targeting S. aureus (in-vitro susceptibility) administered prior to randomization;
* Patient with known valvulopathy, previous history of endocarditis, or suspicion of infective endocarditis by physician in charge;
* Suspicion of any other deep focus infections, such as arthritis, pneumonia, osteomyelitis, or meningitis, presence of cerebral or peripheral emboli (arterial occlusion);
* Thrombophlebitis;
* Failure to remove any intravascular catheter which was present when first positive blood culture;
* Signs of infection associated with quick SOFA score ≥ 2 at randomization;
* Patients with foreign bodies such as: prosthetic heart valve, endovascular prosthesis, ventriculo-atrial shunt, pacemaker, or an automated implantable cardioverter defibrillator (AICD) device;
* Severe liver disease (Child-Pugh C);
* Severely immunocompromised patients:

  * Neutropenia (\< 500 neutrophils/µL) at randomization;
  * Hematopoietic stem cell transplantation within the past 6 months or planned during treatment period;
  * Solid organ transplant;
* Contraindication to dalbavancin and/or glycopeptide;
* Life expectancy \< 3 months;
* Active injection drug user;
* Pregnant or breastfeeding women;
* For premenopausal women: failure to use highly-effective contraceptive methods for 1 month after receiving study drug;
* Participation in other interventional trials ongoing;
* Persons held in an institution by legal or official order;
* Patients under legal protection;
* Patients under guardianship or curators;
* Patients unable to give a free and informed consent;
* Patient not affiliated to a social security scheme: obligation of affiliation to a social security scheme or to be a beneficiary.

Primary outcomes:
measure: Cure rate
timeFrame: DAY 30
Secondary outcomes:
measure: Cure rate
timeFrame: DAY 14;DAY 90 (EOS)
measure: Mortality rate
timeFrame: DAY 90
measure: Bloodstream clearance
timeFrame: DAY 14
measure: Patient's quality of life
timeFrame: BASELINE; DAY 14; DAY 30; DAY 90 (EOS)
measure: Hospitalization length of stay
timeFrame: DAY 90
measure: Cost-utility analyses
timeFrame: DAY 90
measure: Incidence of any adverse event (AE and SAE)
timeFrame: DAY 90
Other outcomes:
Locations:
city: Garches
country: France
facility: Infectious Diseases Department, Raymond-Poincaré Hospital - APHP
city: Périgueux
country: France
facility: Infectious Diseases Department, CH PERIGUEUX
Study officials:
affiliation: CH de Perigueux
name: Bernard CASTAN, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: APHP - RAYMOND POINCARE
name: Aurélien DINH, MD, PhD
role: STUDY_DIRECTOR
References: