Trial document




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  DRKS00004741

Trial Description

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Title

EARLY ORAL SWITCH THERAPY IN LOW-RISK
STAPHYLOCOCCUS AUREUS BLOODSTREAM INFECTION

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Trial Acronym

SABATO

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URL of the Trial

[---]*

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Brief Summary in Lay Language

The study aims to demonstrate that in patients with low-risk Staphylococcus aureus bloodstream infection (SAB) a switch from intravenous to oral antimicrobial therapy is as safe and effective as a conventional course of intravenous therapy. Furthermore, it will be evaluated whether patients with oral therapy can be discharged from hospital earlier and suffer less complications.
Patients with low-risk SAB can be enrolled after 5-7 days of adequate antimicrobial therapy. They will receive 7-9 days of either oral or intraveneous antimicrobial therapy.

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Brief Summary in Scientific Language

Increasing resistance to antibiotic agents has been recognized as a major health problem worldwide that will even aggravate due to the lack of new antimicrobial agents within the next decade. This threat underscores the need to maximize clinical utility of existing antibiotics, through more rational prescription, e.g. optimizing duration of treatment.

Staphylococcus aureus bloodstream infection (SAB) is a common disease with about 200,000 cases occurring annually in Europe. A course of at least 14 days of intravenous antimicrobials is considered standard therapy in low-risk SAB. This relatively long course serves to prevent SAB-related complications (such as endocarditis and vertebral osteomyelitis) that may result from hematogenous dissemination to distant sites. However, there is insufficient evidence that a full course of intravenous antibiotic therapy is always required in patients with a low risk of SAB-related complications.

In a multicenter, open-label, randomized controlled trial we aim to demonstrate that an early switch from intravenous to oral antimicrobial therapy is non-inferior to a conventional 14-days course of intravenous therapy regarding efficacy and safety. An early switch from intravenous to oral therapy would provide several benefits such as earlier discharge, fewer complications associated with intravenous therapy, increased quality of life, and cost savings.

Due to a protocol amendment (Amendment 1, Ethics Comittee of the University Cologne, pos. vote 29/12/2014) the in- and exclusion criteria were altered as well as an additional follow-up contact, a new time window for the control blood culture and the possibility to conduct the baseline visit one day prior to therapy switch were introduced.

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Organizational Data

  •   DRKS00004741
  •   2013/10/04
  •   2013/02/13
  •   yes
  •   Approved
  •   13-130, Ethik-Kommission der Medizinischen Fakultät der Universität zu Köln
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Secondary IDs

  •   2013-000577-77 
  •   NCT01792804  (clinicaltrials.gov)
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Health Condition or Problem studied

  •   A41.0 -  Sepsis due to Staphylococcus aureus
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Interventions/Observational Groups

  •   Experimental: Orally administered antibiotic
    First choice (MRSA and MSSA): trimethoprim-sulfamethoxazole, or Second choice (MSSA): clindamycin, or Second choice (MRSA): linezolid
    administered for 7-9 days
  •   Experimental: Intravenously administered antibiotic

    First choice (MSSA): flucloxacillin [Spain: cloxacillin] or cefazolin, or Second choice (MSSA): vancomycin, or First choice (MRSA): vancomycin, or Second choice (MRSA): daptomycin) administered for 7-9 days
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Open (masking not used)
  •   [---]*
  •   Active control (effective treament of control group)
  •   Treatment
  •   Parallel
  •   III
  •   Yes
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Primary Outcome

- SAB-related complications (relapsing SAB, deep-seated infection with S. aureus, or attributable mortality) within 90 days

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Secondary Outcome

- Length of hospital stay

Other variables:

- 14, 30, and 90-day survival

- Complications of intravenous therapy

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Countries of Recruitment

  •   Germany
  •   Spain
  •   France
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Locations of Recruitment

  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • Medical Center 
  • University Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
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Recruitment

  •   Actual
  •   2013/11/05
  •   215
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

•Age at least 18 years

•Not legally incapacitated

•Written informed consent from the trial subject has been obtained

•Blood culture positive for S. aureus not considered to represent contamination

•At least one negative follow-up blood culture obtained within 24-96 hours after the start of adequate antimicrobial therapy to rule out persistent bacteremia and absence of a blood culture positive for S. aureus at the same time or thereafter.

•Five to seven full days of appropriate i.v. antimicrobial therapy administered prior to randomization documented in the patient chart. Appropriate therapy has all of the following characteristics:
oAntimicrobial therapy has to be initiated within 72h after the first positive blood culture was drawn.
oProvided in-vitro susceptibility and adequate dosing (as judged by the principle investigator) preferred agents for pre-randomization antimicrobial therapy are: flucloxacillin, cloxacillin, vancomycin, and daptomycin. However, the following parenteral antimicrobials are allowed:
oMSSA: penicillinase-resistant penicillins (e.g. flucloxacillin, cloxacillin), β-lactam plus β-lactamase-inhibitors (e.g. ampicillin+sulbactam, piperacillin+tazobactam), cephalosporins (except ceftazidime), carbapenems, clindamycin, fluoroquinolones, trimethoprim-sulfamethoxazole, doxycycline, tigecycline, vancomycin, teicoplanin, telavancin, linezolid, daptomycin, ceftaroline, ceftobiprole, and macrolides.
oMRSA: vancomycin, teicoplanin, telavancin, fluoroquinolones, clindamycin, trimethoprim-sulfamethoxazole, doxycycline, tigecycline, linezolid, daptomycin, macrolides, ceftaroline, and ceftobiprole.

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Exclusion Criteria

•Polymicrobial bloodstream infection, defined as isolation of pathogens other than S. aureus from a blood culture obtained in the time from two days prior to the first positive blood culture with S. aureus until randomization. Common skin contaminants (coagulase-negative staphylococci, diphteroids, Bacillus spp., and Propionibacterium spp.) detected in one of several blood cultures will not be considered to represent polymicrobial infection

•Recent history (within 3 months) of prior S. aureus bloodstream infection

•In vitro resistance of S. aureus to all oral or all i.v. study drugs

•Contraindications in reference document for all oral or all i.v. study drugs

•Previously planned treatment with active drug against S. aureus during intervention phase (e.g. cotrimoxazol prohylaxis)

•Signs and symptoms of complicated SAB as judged by an ID physician. Complicated infection is defined as at least one of the following:
odeep-seated focus: e.g. endocarditis, pneumonia, undrained abscess, empyema, and osteomyelitis
oseptic shock, as defined by the AACP criteria (23), within 4 days before randomization
oprolonged bacteremia: positive follow-up blood culture more than 72h after the start of adequate antimicrobial therapy
obody temperature >38 °C on two separate days within 48h before randomization

•Presence of the following non-removable foreign bodies (if not removed 2 days or more before randomization):
oprosthetic heart valve
odeep-seated vascular graft with foreign material (e.g. PTFE or dacron graft). Hemodialysis shunts are not considered deep-seated vascular grafts (s. below).
oventriculo-atrial shunt

•Presence of a prosthetic joint (if not removed 2 days or more before randomization). This is not an exclusion criterion, if all of the following conditions are fulfilled:
oprosthetic joint was implanted at least 6 months prior, and
ocatheter-related infection, skin and soft tissue infection, or surgical wound infection is present (as defined below), and
ojoint infection unlikely (no clinical or imaging signs)
•Presence of a pacemaker or an automated implantable cardioverter defibrillator (AICD) device (if not removed 2 days or more before randomization). This is not an exclusion criterion, if all of the following conditions are fulfilled: o pacemaker or AICD was implanted at least 6 months prior, and
ocatheter-related infection, skin and soft tissue infection, or surgical wound infection is present (as defined below), and
ono clinical signs of infective endocarditis, and
oinfective endocarditis unlikely by echocardiography (preferably TEE), and
opocket infection unlikely (no clinical or imaging signs)

•Failure to remove any intravascular catheter which was present when first positive blood culture was drawn within 4 days of the first positive blood culture

•Severe liver disease. This is not an exclusion criterion, if the following condition is fulfilled: o catheter-related infection, skin and soft tissue infection, or surgical wound infection is present (as defined below)

•End-stage renal disease. This is not an exclusion criterion, if all of the following conditions are fulfilled:
ocatheter-related infection, skin and soft tissue infection, or surgical wound infection is present (as defined below), and
ono clinical signs of infective endocarditis, and
oinfective endocarditis unlikely by echocardiography (preferably TEE), and
oin patients with a hemodialysis shunt with a non-removable foreign body (e.g. synthetic PTFE loop): no clinical signs of a shunt infection

•Severe immunodeficiency o primary immunodeficiency disorders
oneutropenia (<500 neutrophils/μl) at randomization or neutropenia expected during intervention phase due to immunosuppressive treatment
ouncontrolled disease in HIV-positive patients
ohigh-dose steroid therapy (>1 mg/kg prednisone or equivalent doses given for >4 weeks or planned during intervention)
oimmunosuppressive combination therapy with two or more drugs with different mode of action
ohematopoietic stem cell transplantation within the past 6 months or planned during treatment period
osolid organ transplant
otreatment with biologicals within the previous year

•Life expectancy < 3 months

•Inability to take oral drugs

•Injection drug user

•Expected low compliance with drug regimen

•Participation in other interventional trials within the previous three months or ongoing

•Pregnant women and nursing mothers

•For premenopausal women: Failure to use highly-effective contraceptive methods for 1 month after receiving study drug. The following contraceptive methods with a Pearl Index lower than 1% are regarded as highly-effective:
o oral hormonal contraception (‘pill’)
odermal hormonal contraception
ovaginal hormonal contraception (NuvaRing®)
ocontraceptive plaster
olong-acting injectable contraceptives
oimplants that release progesterone (Implanon®)
otubal ligation (female sterilisation)
ointrauterine devices that release hormones (hormone spiral)
odouble barrier methods

This means that the following are not regarded as safe: condom plus spermicide, simple barrier methods (vaginal pessaries, condom, female condoms), copper spirals, the rhythm method, basal temperature method, and the withdrawal method (coitus interruptus). Due to possible interactions and side effects of the study medication (applies to cotrimoxazol, clindamycin, and flucloxacillin), hormonal contraception may not be safe and another highly-effective contraceptive method needs to be employed.

•Persons with any kind of dependency on the investigator or employed by the sponsor or investigator

•Persons held in an institution by legal or official order

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Addresses

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Sources of Monetary or Material Support

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    • DFG; Deutsche Forschungsgemeinschaft
    • Kennedyallee 40
    • 53175  Bonn
    • Germany
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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