- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01898338
Efficacy of Daptomycin Plus Fosfomycin Versus Daptomycin for Treatment of MRSA Bacteremia
January 16, 2018 updated by: Miquel Pujol
Randomized Multicenter Study to Assess Efficacy of Daptomycin Plus Fosfomycin Versus Daptomycin Monotherapy for Treatment of Methicillin Resistant Staphylococcus Aureus Bacteremia in Hospitalized Patients
To demonstrate that the combination of daptomycin and fosfomycin is superior to daptomycin alone in the treatment of methicillin resistant Staphylococcus aureus (MRSA) bacteremia.
Study Overview
Status
Completed
Intervention / Treatment
Detailed Description
The mortality associated to MRSA bacteremia remains higher than 30% of episodes despite the availability of new antibiotics.
Objective: To demonstrate that the combination of daptomycin and fosfomycin is superior to daptomycin alone in the treatment of methicillin resistant Staphylococcus aureus (MRSA) bacteremia.
Design: Randomized, open-label and multicenter study.
Intervention: Patients with MRSA bacteremia will be randomized (1:1) in Group 1: daptomycin 10mg/Kg/24h intravenous (iv) and Group 2: daptomycin 10 mg/kg/24 iv plus fosfomycin and 2g/6h iv.
Duration of therapy will be 10-14 days for uncomplicated bacteremia and up to 42 days for complicated bacteremia.
Follow up: There will be a clinical and microbiological evaluation at baseline, during treatment and at week 6 after the end of therapy (test of cure visit, TOC).
Complicated bacteremia was considered if: a) persistence of a positive blood culture at 72-96 h from the start of antibiotic, b) evidence of spread of infection (metastatic infection) c) infection involving a non-removable device in less than 4 days.
Sample size: Assuming 60% cure rate with daptomycin and a 20% difference in cure rates between both groups, we estimated that 103 patients will be needed for each group (α:0.05,
ß: 0.2).
Main endpoint: clinical and microbiological response at the TOC visit.
Treatment success was defined as the resolution of clinical signs and symptoms and negative blood culture.
Treatment failure was defined if any of the following situations: a) lack of clinical response at 72 h or more after initiation of the study therapy b) persistent bacteremia (positive blood culture on day 7 after randomization), c) withdrawal of treatment due to adverse effects or for any other reason based on clinical judgment.
d) relapse of MRSA bacteremia before the TOC visit e) death for any reason before the TOC visit.
Secondary endpoints: evaluation in both groups of clinical and microbiological response at end of therapy (EOT visit); mortality at EOT and TOC visit; persistent MRSA bacteremia; recurrence of MRSA bacteremia (positive blood culture when previous ones were negative); emergence of daptomycin or fosfomycin resistance and severe adverse effects.
Study Type
Interventional
Enrollment (Actual)
167
Phase
- Phase 3
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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-
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Barakaldo, Spain, 48903
- Hospital Universitario de Cruces
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Barcelona, Spain, 08035
- Hospital Vall d'Hebron
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Barcelona, Spain, 08036
- Hospital Clínic
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Barcelona, Spain, 08025
- Hospital de la Santa Creu i Sant Pau
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Barcelona, Spain, 08003
- Hospital del Mar- Parc de Salut Mar
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Granada, Spain, 18014
- Hospital Universitario Virgen de las Nieves
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Lleida, Spain, 25198
- Hospital Universitari Arnau de Vilanova
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Lugo, Spain, 27004
- Hospital Universitario Lucus Augusti
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Madrid, Spain, 28041
- Hospital Universitario 12 de octubre
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Madrid, Spain, 28034
- Hospital Ramón y Cajal
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Madrid, Spain, 28007
- Hospital General Gregorio Maranon
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Palma de Mallorca, Spain, 07120
- Complejo Asistencial Son Espases
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Sevilla, Spain, 41071
- Hospital Virgen Macarena
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Tarragona, Spain, 43007
- Hospital Universitari Joan Xxiii
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Barcelona
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Hospitalet de Llobregat, Barcelona, Spain, 08907
- Hospital Universitari de Bellvitge
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Sabadell, Barcelona, Spain, 08208
- Hospital Parc Tauli
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Terrassa, Barcelona, Spain, 08227
- Hospital de Terrassa
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Terrassa, Barcelona, Spain, 08221
- Hospital Universitari Mutua de Terrassa
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-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years to 99 years (ADULT, OLDER_ADULT)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
- Patients with at least 1 positive blood culture to MRSA within 72h up to randomization
- Adult patients, equal or older than 18 years old
- Signed informed consent
- Mandatory use of contraception methods for fertile women during the study period and for 6 months after stopping antibiotic therapy
Exclusion Criteria:
- Polymicrobial bacteremia
- Pneumonia associated to the bacteremia
- Severe clinical status with expected survival of less than 24 hours
- Allergy to daptomycin or fosfomycin
- A positive pregnancy test at the time of inclusion
- Any clinical condition that requires additional antibiotic therapy with microbiological activity against MRSA
- Patient already included in another clinical trial
- Prior history of eosinophilic pneumonia
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: RANDOMIZED
- Interventional Model: PARALLEL
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
EXPERIMENTAL: Fosfomycin and Daptomycin
fosfomycin 2gr/6h + 10mg/kg/24h iv during 14 or 28 days
|
|
ACTIVE_COMPARATOR: Daptomycin
daptomycin 10mg/kg/cada 24h iv during 14 or 28 days
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Therapy response
Time Frame: at week 6 after end of therapy (an average of 8 to 12 weeks from the beginnig of therapy)
|
Therapy response is considered if clinical and microbiological response is achieved at week 6 after end of therapy
|
at week 6 after end of therapy (an average of 8 to 12 weeks from the beginnig of therapy)
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Mortality
Time Frame: participants will be followed an average of 8 to 12 weeks from the begining of therapy
|
participants will be followed an average of 8 to 12 weeks from the begining of therapy
|
|
Severe adverse effects
Time Frame: participants will be followed an average of 8 to 12 weeks from the begining of therapy
|
whatever
|
participants will be followed an average of 8 to 12 weeks from the begining of therapy
|
Number of persistent bacteremia
Time Frame: participants will be followed an average of 8 to 12 weeks from the begining of therapy
|
Defined as a positive blood culture on day 7 after starting the study therapy
|
participants will be followed an average of 8 to 12 weeks from the begining of therapy
|
Bacteremia recurrence
Time Frame: participants will be followed an average of 8 to 12 weeks from the begining of therapy
|
Defined as a positive blood culture to MRSA when previous ones were negative
|
participants will be followed an average of 8 to 12 weeks from the begining of therapy
|
Therapy response at end of therapy (EOT visit)
Time Frame: at end of therapy
|
Success is considered if clinical resolution and negative blood culture at end of therapy.
|
at end of therapy
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Investigators
- Study Director: Miquel Pujol, MD, PhD, (Infectious Diseases Service) Hospital Universitari de Bellvitge
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Cosgrove SE, Sakoulas G, Perencevich EN, Schwaber MJ, Karchmer AW, Carmeli Y. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis. 2003 Jan 1;36(1):53-9. doi: 10.1086/345476. Epub 2002 Dec 13.
- Chang FY, Peacock JE Jr, Musher DM, Triplett P, MacDonald BB, Mylotte JM, O'Donnell A, Wagener MM, Yu VL. Staphylococcus aureus bacteremia: recurrence and the impact of antibiotic treatment in a prospective multicenter study. Medicine (Baltimore). 2003 Sep;82(5):333-9. doi: 10.1097/01.md.0000091184.93122.09.
- Fowler VG Jr, Boucher HW, Corey GR, Abrutyn E, Karchmer AW, Rupp ME, Levine DP, Chambers HF, Tally FP, Vigliani GA, Cabell CH, Link AS, DeMeyer I, Filler SG, Zervos M, Cook P, Parsonnet J, Bernstein JM, Price CS, Forrest GN, Fatkenheuer G, Gareca M, Rehm SJ, Brodt HR, Tice A, Cosgrove SE; S. aureus Endocarditis and Bacteremia Study Group. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006 Aug 17;355(7):653-65. doi: 10.1056/NEJMoa053783.
- Rehm SJ, Boucher H, Levine D, Campion M, Eisenstein BI, Vigliani GA, Corey GR, Abrutyn E. Daptomycin versus vancomycin plus gentamicin for treatment of bacteraemia and endocarditis due to Staphylococcus aureus: subset analysis of patients infected with methicillin-resistant isolates. J Antimicrob Chemother. 2008 Dec;62(6):1413-21. doi: 10.1093/jac/dkn372. Epub 2008 Sep 8.
- Gudiol F, Aguado JM, Pascual A, Pujol M, Almirante B, Miro JM, Cercenado E, Dominguez Mde L, Soriano A, Rodriguez-Bano J, Valles J, Palomar M, Tornos P, Bouza E; Sociedad Espanola de Enfermedades Infecciosas y Microbiologia Clinica. [Consensus document for the treatment of bacteremia and endocarditis caused by methicillin-resistent Staphylococcus aureus. Sociedad Espanola de Enfermedades Infecciosas y Microbiologia Clinica]. Enferm Infecc Microbiol Clin. 2009 Feb;27(2):105-15. doi: 10.1016/j.eimc.2008.09.003. Epub 2009 Feb 11. Spanish.
- Popovic M, Steinort D, Pillai S, Joukhadar C. Fosfomycin: an old, new friend? Eur J Clin Microbiol Infect Dis. 2010 Feb;29(2):127-42. doi: 10.1007/s10096-009-0833-2. Epub 2009 Nov 14.
- Kastoris AC, Rafailidis PI, Vouloumanou EK, Gkegkes ID, Falagas ME. Synergy of fosfomycin with other antibiotics for Gram-positive and Gram-negative bacteria. Eur J Clin Pharmacol. 2010 Apr;66(4):359-68. doi: 10.1007/s00228-010-0794-5. Epub 2010 Feb 26.
- Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, Kaplan SL, Karchmer AW, Levine DP, Murray BE, J Rybak M, Talan DA, Chambers HF. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary. Clin Infect Dis. 2011 Feb 1;52(3):285-92. doi: 10.1093/cid/cir034.
- Wu G, Abraham T, Rapp J, Vastey F, Saad N, Balmir E. Daptomycin: evaluation of a high-dose treatment strategy. Int J Antimicrob Agents. 2011 Sep;38(3):192-6. doi: 10.1016/j.ijantimicag.2011.03.006. Epub 2011 May 6.
- Chen LY, Huang CH, Kuo SC, Hsiao CY, Lin ML, Wang FD, Fung CP. High-dose daptomycin and fosfomycin treatment of a patient with endocarditis caused by daptomycin-nonsusceptible Staphylococcus aureus: case report. BMC Infect Dis. 2011 May 26;11:152. doi: 10.1186/1471-2334-11-152.
- Miro JM, Entenza JM, Del Rio A, Velasco M, Castaneda X, Garcia de la Maria C, Giddey M, Armero Y, Pericas JM, Cervera C, Mestres CA, Almela M, Falces C, Marco F, Moreillon P, Moreno A; Hospital Clinic Experimental Endocarditis Study Group. High-dose daptomycin plus fosfomycin is safe and effective in treating methicillin-susceptible and methicillin-resistant Staphylococcus aureus endocarditis. Antimicrob Agents Chemother. 2012 Aug;56(8):4511-5. doi: 10.1128/AAC.06449-11. Epub 2012 May 29.
- Kullar R, Davis SL, Levine DP, Zhao JJ, Crank CW, Segreti J, Sakoulas G, Cosgrove SE, Rybak MJ. High-dose daptomycin for treatment of complicated gram-positive infections: a large, multicenter, retrospective study. Pharmacotherapy. 2011 Jun;31(6):527-36. doi: 10.1592/phco.31.6.527.
- Gasch O, Ayats J, Angeles Dominguez M, Tubau F, Linares J, Pena C, Grau I, Pallares R, Gudiol F, Ariza J, Pujol M. Epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection: secular trends over 19 years at a university hospital. Medicine (Baltimore). 2011 Sep;90(5):319-327. doi: 10.1097/MD.0b013e31822f0b54.
- Gasch O, Camoez M, Dominguez MA, Padilla B, Pintado V, Almirante B, Molina J, Lopez-Medrano F, Ruiz E, Martinez JA, Bereciartua E, Rodriguez-Lopez F, Fernandez-Mazarrasa C, Goenaga MA, Benito N, Rodriguez-Bano J, Espejo E, Pujol M; REIPI/GEIH Study Groups. Predictive factors for mortality in patients with methicillin-resistant Staphylococcus aureus bloodstream infection: impact on outcome of host, microorganism and therapy. Clin Microbiol Infect. 2013 Nov;19(11):1049-57. doi: 10.1111/1469-0691.12108. Epub 2013 Jan 17.
- Garrigos C, Murillo O, Lora-Tamayo J, Verdaguer R, Tubau F, Cabellos C, Cabo J, Ariza J. Fosfomycin-daptomycin and other fosfomycin combinations as alternative therapies in experimental foreign-body infection by methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2013 Jan;57(1):606-10. doi: 10.1128/AAC.01570-12. Epub 2012 Oct 22.
- Lai CC, Sheng WH, Wang JT, Cheng A, Chuang YC, Chen YC, Chang SC. Safety and efficacy of high-dose daptomycin as salvage therapy for severe gram-positive bacterial sepsis in hospitalized adult patients. BMC Infect Dis. 2013 Feb 4;13:66. doi: 10.1186/1471-2334-13-66.
- Pujol M, Miro JM, Shaw E, Aguado JM, San-Juan R, Puig-Asensio M, Pigrau C, Calbo E, Montejo M, Rodriguez-Alvarez R, Garcia-Pais MJ, Pintado V, Escudero-Sanchez R, Lopez-Contreras J, Morata L, Montero M, Andres M, Pasquau J, Arenas MD, Padilla B, Murillas J, Jover-Saenz A, Lopez-Cortes LE, Garcia-Pardo G, Gasch O, Videla S, Hereu P, Tebe C, Pallares N, Sanllorente M, Dominguez MA, Camara J, Ferrer A, Padulles A, Cuervo G, Carratala J; MRSA Bacteremia (BACSARM) Trial Investigators. Daptomycin Plus Fosfomycin Versus Daptomycin Alone for Methicillin-resistant Staphylococcus aureus Bacteremia and Endocarditis: A Randomized Clinical Trial. Clin Infect Dis. 2021 May 4;72(9):1517-1525. doi: 10.1093/cid/ciaa1081.
- Shaw E, Miro JM, Puig-Asensio M, Pigrau C, Barcenilla F, Murillas J, Garcia-Pardo G, Espejo E, Padilla B, Garcia-Reyne A, Pasquau J, Rodriguez-Bano J, Lopez-Contreras J, Montero M, de la Calle C, Pintado V, Calbo E, Gasch O, Montejo M, Salavert M, Garcia-Pais MJ, Carratala J, Pujol M; Spanish Network for Research in Infectious Diseases (REIPI RD12/0015); Instituto de Salud Carlos III, Madrid, Spain; GEIH (Hospital Infection Study Group). Daptomycin plus fosfomycin versus daptomycin monotherapy in treating MRSA: protocol of a multicentre, randomised, phase III trial. BMJ Open. 2015 Mar 11;5(3):e006723. doi: 10.1136/bmjopen-2014-006723.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
December 1, 2013
Primary Completion (ACTUAL)
January 10, 2018
Study Completion (ACTUAL)
January 10, 2018
Study Registration Dates
First Submitted
July 2, 2013
First Submitted That Met QC Criteria
July 9, 2013
First Posted (ESTIMATE)
July 12, 2013
Study Record Updates
Last Update Posted (ACTUAL)
January 17, 2018
Last Update Submitted That Met QC Criteria
January 16, 2018
Last Verified
January 1, 2018
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- BACSARM
- 2013-000586-37 (EUDRACT_NUMBER)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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