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Safety & Efficacy of Daptomycin Versus Standard of Care (SOC) in 1 - 17 Year Olds With Staphylococcus Aureus Bacteremia (MK-3009-005)

Primary Purpose

Bacteremia

Status
Completed
Phase
Phase 4
Locations
Study Type
Interventional
Intervention
Daptomycin
Comparator
Sponsored by
Cubist Pharmaceuticals LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bacteremia

Eligibility Criteria

1 Year - 17 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

To be included in this study, participants must:

  • Sign a parental consent form; if appropriate, sign an assent form
  • Be between 1 and 17 years of age
  • Have proven or probable bacteremia caused by S. aureus based on the traditional culture result, rapid diagnostic test or Gram stain
  • If female of childbearing potential, must not be pregnant or nursing and take appropriate measures to not get pregnant during the study
  • If male, must take appropriate measures to not get partner pregnant
  • Able to comply with the protocol requirements

Exclusion Criteria:

Participants will not be allowed into the study if they:

  • Have received a certain amount of antibacterial therapy specific for current bacteremia unless it is demonstrated that the organism is resistant to the given antibacterial;
  • Anticipate to require other antibiotics that may be potentially effective against S. aureus;
  • Have shock or hypotension unresponsive to standard therapy;
  • Have received an investigational product or have participated in an experimental procedure within 30 days;
  • Have an intolerance or hypersensitivity to daptomycin;
  • Have renal insufficiency;
  • Have prior history or current evidence of muscle damage (rhabdomyolysis; significant CPK elevation);
  • Have history of clinically significant muscular disease, nervous system or seizure disorder, including unexplained muscular weakness, history of peripheral neuropathy, Guillain-Barré or spinal cord injury;
  • Have S. aureus pneumonia, empyema, meningitis, or endocarditis

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm 4

    Arm 5

    Arm 6

    Arm Type

    Experimental

    Active Comparator

    Experimental

    Experimental

    Active Comparator

    Active Comparator

    Arm Label

    Daptomycin - 12 to 17 year olds

    Comparator - 12 to 17 year olds

    Daptomycin - 7 to 11 year olds

    Daptomycin - 1 to 6 year olds

    Comparator - 7 to 11 year olds

    Comparator - 1 to 6 year olds

    Arm Description

    Participants ages 12-17 years old were administered daptomycin 7 mg/kg infused once daily, intravenously (IV), over 30 minutes; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-42 days. After conclusion of IV therapy, can continue on oral therapy (not daptomycin, but at discretion of investigator).

    Participants ages 12-17 years old received IV vancomycin or semi-synthetic penicillin or first-generation cephalosporins or clindamycin, given as per local guidelines or site-specific prescribing information; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-42 days. IV comparator and subsequent oral therapy were at the discretion of the investigator.

    Participants ages 7 to 11 years old were administered daptomycin 9 mg/kg, infused once daily, IV over 30 minutes; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-28 days. After conclusion of IV therapy, can continue on oral therapy (not daptomycin, but at discretion of investigator).

    Participants ages 1 to 6 years old were administered daptomycin 12 mg/kg, infused once daily, IV over 60 minutes; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-28 days. After conclusion of IV therapy, can continue on oral therapy (not daptomycin, but at discretion of investigator).

    Participants ages 7-11 years old received IV vancomycin, or semi-synthetic penicillin, or first-generation cephalosporins, clindamycin; given as per local guidelines or site-specific prescribing information; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-28 days. IV comparator and subsequent oral therapy were at the discretion of the investigator.

    Participants ages 1-6 years old received IV vancomycin, or semi-synthetic penicillin, or first-generation cephalosporins, clindamycin; given as per local guidelines or site-specific prescribing information; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-28 days. IV comparator and subsequent oral therapy were at the discretion of the investigator.

    Outcomes

    Primary Outcome Measures

    Number of Participants With One or More Adverse Events (AEs)
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.
    Number of Participants With One or More Serious Adverse Events (SAEs)
    An SAE is any adverse experience occurring at any dose that results in any of the following outcomes: death, life threatening experience, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is considered to be an important medical event.
    Percentage of Participants With Maximum Post-Baseline Creatine Phosphokinase (CPK) Elevations Above Upper Limit of Normal
    Blood was drawn from baseline up to the end of therapy visit to determine the percentage of participants with maximum post-baseline CPK elevations above the upper limit of 500 Units Per Liter (U/L) .
    Percentage of Participants With Sustained CPK Elevations
    Blood was drawn from baseline up to the end of therapy visit to determine the percentage of participants with sustained CPK elevations, defined as two consecutive post-baseline values above the upper limit of normal (ULN)
    Number of Participants With Abnormal Focused (Peripheral) Neurological Assessments at Test of Cure (TOC)
    Focused neurological examinations were done at the TOC/Safety Visit. These examinations include assessments of sensation, pupillary reflex and tracking, peripheral reflexes (biceps, patellar tendon, ankle jerk and plantar response), muscle tone and strength (upper and lower limbs), coordination (finger to nose) and tremor of the hands/fingers.

    Secondary Outcome Measures

    Percentage of Participants With Clinical Success at TOC/Safety Visit
    Clinical success was determined by assessing resolution/improvement of signs and symptoms. An assessment of cure or improved is considered clinical success. Cure: resolution of clinically significant signs and symptoms associated with admission infection; no further antibiotic therapy is required for the primary infection under study. Improvement: partial resolution of clinical signs/symptoms of infection such that no further antibiotic therapy is required for the primary infection under study.
    Percentage of Participants With Overall Success at TOC Visit
    Overall success is based on microbiologic responses after initiating study drug and clinical response at TOC/Safety Visit. Overall outcome is a success if both clinical and microbiologic outcomes are successes. An assessment of cure or improved is considered clinical success. Microbiological Success: a participant for whom all baseline infecting pathogens were eradicated (presumed or documented) within 7 days from the start of study drug for uncomplicated bacteremia with no source of infection present, and 10 days for complicated bacteremia or when the source of infection has not been removed.
    Trough Plasma Concentration of Daptomycin
    Plasma concentrations of daptomycin were measured on Days 3 through 6 of IV dosing. Trough concentrations were collected 22 to 26 hours following the end of the previous day's end of infusion and before the next infusion. Concentrations below the limit of quantification were excluded.
    Maximum Plasma Concentration (Cmax) of Daptomycin
    Plasma concentrations of daptomycin were measured on Days 3 through 6 of IV dosing. Peak concentrations were collected up to 15 minutes following the end of infusion. Concentrations below the limit of quantification were excluded.

    Full Information

    First Posted
    November 5, 2012
    Last Updated
    July 31, 2018
    Sponsor
    Cubist Pharmaceuticals LLC
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    1. Study Identification

    Unique Protocol Identification Number
    NCT01728376
    Brief Title
    Safety & Efficacy of Daptomycin Versus Standard of Care (SOC) in 1 - 17 Year Olds With Staphylococcus Aureus Bacteremia (MK-3009-005)
    Official Title
    A Comparative Evaluation of the Safety and Efficacy of Daptomycin Versus Standard of Care in Pediatric Subjects One - Seventeen Years of Age With Bacteremia Caused by Staphylococcus Aureus.
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    July 2018
    Overall Recruitment Status
    Completed
    Study Start Date
    November 29, 2012 (Actual)
    Primary Completion Date
    January 20, 2016 (Actual)
    Study Completion Date
    January 20, 2016 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Cubist Pharmaceuticals LLC

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    The intent of this study is to describe the safety and efficacy of daptomycin versus standard of care (SOC) in pediatric participants aged 1-17 years with bacteremia caused by Staphylococcus aureus (S. aureus).
    Detailed Description
    S. aureus causes a series of invasive diseases in adults and children, including bacteremia. Infections due to S. aureus in children, particularly those due to methicillin resistant S. aureus (MRSA), are a growing world-wide public health concern. Daptomycin, a cyclic lipopeptide antibacterial agent, shows rapid in vitro bactericidal activity with concentration-dependent killing for Gram-positive organisms, including S. aureus. Surveillance studies have demonstrated a daptomycin MIC90 of 0.5µg/ml for both methicillin-susceptible S. aureus (MSSA) and MRSA with >99% of MRSA isolates being categorized as susceptible by the Food and Drug Administration (FDA), European Committee of antimicrobial susceptibility testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) breakpoints (5). Clinical trials in adults demonstrated that daptomycin was safe and efficacious in complicated skin and skin structure infections (cSSSI) and bloodstream infections caused by S. aureus, including right-sided infective endocarditis (RIE). However, information on the safety and efficacy of daptomycin for use in children is lacking. The intent of this study in children is to confirm the safety of daptomycin at mean steady state systemic exposures (AUC) similar to those reported for adults treated at 6 mg/kg for bacteremia.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Bacteremia

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 4
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    82 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Daptomycin - 12 to 17 year olds
    Arm Type
    Experimental
    Arm Description
    Participants ages 12-17 years old were administered daptomycin 7 mg/kg infused once daily, intravenously (IV), over 30 minutes; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-42 days. After conclusion of IV therapy, can continue on oral therapy (not daptomycin, but at discretion of investigator).
    Arm Title
    Comparator - 12 to 17 year olds
    Arm Type
    Active Comparator
    Arm Description
    Participants ages 12-17 years old received IV vancomycin or semi-synthetic penicillin or first-generation cephalosporins or clindamycin, given as per local guidelines or site-specific prescribing information; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-42 days. IV comparator and subsequent oral therapy were at the discretion of the investigator.
    Arm Title
    Daptomycin - 7 to 11 year olds
    Arm Type
    Experimental
    Arm Description
    Participants ages 7 to 11 years old were administered daptomycin 9 mg/kg, infused once daily, IV over 30 minutes; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-28 days. After conclusion of IV therapy, can continue on oral therapy (not daptomycin, but at discretion of investigator).
    Arm Title
    Daptomycin - 1 to 6 year olds
    Arm Type
    Experimental
    Arm Description
    Participants ages 1 to 6 years old were administered daptomycin 12 mg/kg, infused once daily, IV over 60 minutes; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-28 days. After conclusion of IV therapy, can continue on oral therapy (not daptomycin, but at discretion of investigator).
    Arm Title
    Comparator - 7 to 11 year olds
    Arm Type
    Active Comparator
    Arm Description
    Participants ages 7-11 years old received IV vancomycin, or semi-synthetic penicillin, or first-generation cephalosporins, clindamycin; given as per local guidelines or site-specific prescribing information; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-28 days. IV comparator and subsequent oral therapy were at the discretion of the investigator.
    Arm Title
    Comparator - 1 to 6 year olds
    Arm Type
    Active Comparator
    Arm Description
    Participants ages 1-6 years old received IV vancomycin, or semi-synthetic penicillin, or first-generation cephalosporins, clindamycin; given as per local guidelines or site-specific prescribing information; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-28 days. IV comparator and subsequent oral therapy were at the discretion of the investigator.
    Intervention Type
    Drug
    Intervention Name(s)
    Daptomycin
    Other Intervention Name(s)
    Cubicin
    Intervention Description
    Intravenous daptomycin given at 7 mg/kg (ages 12-17 years); 9 mg/kg (ages 7-11 years); 12 mg/kg (ages 1-6 years) infused once daily, intravenously, over 30 or 60 minutes. Participants may be switched to oral therapy following completion of IV study drug administration provided they showed clear clinical improvement and the pathogen was susceptible to an oral agent.
    Intervention Type
    Drug
    Intervention Name(s)
    Comparator
    Intervention Description
    Vancomycin, Semi-synthetic penicillin, First-generation cephalosporins, Clindamycin: administered per standard of care. Participants may be switched to oral therapy following completion of IV study drug administration provided they showed clear clinical improvement and the pathogen was susceptible to an oral agent.
    Primary Outcome Measure Information:
    Title
    Number of Participants With One or More Adverse Events (AEs)
    Description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.
    Time Frame
    Administration of first dose through the last follow-up visit (up to 77 days)
    Title
    Number of Participants With One or More Serious Adverse Events (SAEs)
    Description
    An SAE is any adverse experience occurring at any dose that results in any of the following outcomes: death, life threatening experience, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is considered to be an important medical event.
    Time Frame
    Administration of first dose through the last follow-up visit (up to 77 days)
    Title
    Percentage of Participants With Maximum Post-Baseline Creatine Phosphokinase (CPK) Elevations Above Upper Limit of Normal
    Description
    Blood was drawn from baseline up to the end of therapy visit to determine the percentage of participants with maximum post-baseline CPK elevations above the upper limit of 500 Units Per Liter (U/L) .
    Time Frame
    Baseline up to end of therapy visit (up to 49 days)
    Title
    Percentage of Participants With Sustained CPK Elevations
    Description
    Blood was drawn from baseline up to the end of therapy visit to determine the percentage of participants with sustained CPK elevations, defined as two consecutive post-baseline values above the upper limit of normal (ULN)
    Time Frame
    Baseline up to end of therapy visit (up to 44 days)
    Title
    Number of Participants With Abnormal Focused (Peripheral) Neurological Assessments at Test of Cure (TOC)
    Description
    Focused neurological examinations were done at the TOC/Safety Visit. These examinations include assessments of sensation, pupillary reflex and tracking, peripheral reflexes (biceps, patellar tendon, ankle jerk and plantar response), muscle tone and strength (upper and lower limbs), coordination (finger to nose) and tremor of the hands/fingers.
    Time Frame
    TOC Safety Visit (up to 56 days)
    Secondary Outcome Measure Information:
    Title
    Percentage of Participants With Clinical Success at TOC/Safety Visit
    Description
    Clinical success was determined by assessing resolution/improvement of signs and symptoms. An assessment of cure or improved is considered clinical success. Cure: resolution of clinically significant signs and symptoms associated with admission infection; no further antibiotic therapy is required for the primary infection under study. Improvement: partial resolution of clinical signs/symptoms of infection such that no further antibiotic therapy is required for the primary infection under study.
    Time Frame
    7-14 days after the last dose of study medication (up to 56 days)
    Title
    Percentage of Participants With Overall Success at TOC Visit
    Description
    Overall success is based on microbiologic responses after initiating study drug and clinical response at TOC/Safety Visit. Overall outcome is a success if both clinical and microbiologic outcomes are successes. An assessment of cure or improved is considered clinical success. Microbiological Success: a participant for whom all baseline infecting pathogens were eradicated (presumed or documented) within 7 days from the start of study drug for uncomplicated bacteremia with no source of infection present, and 10 days for complicated bacteremia or when the source of infection has not been removed.
    Time Frame
    7-14 days after the last dose of study medication (up to 56 days)
    Title
    Trough Plasma Concentration of Daptomycin
    Description
    Plasma concentrations of daptomycin were measured on Days 3 through 6 of IV dosing. Trough concentrations were collected 22 to 26 hours following the end of the previous day's end of infusion and before the next infusion. Concentrations below the limit of quantification were excluded.
    Time Frame
    Days 3, 4, 5 or 6 of treatment at pre-dose
    Title
    Maximum Plasma Concentration (Cmax) of Daptomycin
    Description
    Plasma concentrations of daptomycin were measured on Days 3 through 6 of IV dosing. Peak concentrations were collected up to 15 minutes following the end of infusion. Concentrations below the limit of quantification were excluded.
    Time Frame
    Days 3, 4, 5 or 6 of treatment at end of infusion

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    1 Year
    Maximum Age & Unit of Time
    17 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: To be included in this study, participants must: Sign a parental consent form; if appropriate, sign an assent form Be between 1 and 17 years of age Have proven or probable bacteremia caused by S. aureus based on the traditional culture result, rapid diagnostic test or Gram stain If female of childbearing potential, must not be pregnant or nursing and take appropriate measures to not get pregnant during the study If male, must take appropriate measures to not get partner pregnant Able to comply with the protocol requirements Exclusion Criteria: Participants will not be allowed into the study if they: Have received a certain amount of antibacterial therapy specific for current bacteremia unless it is demonstrated that the organism is resistant to the given antibacterial; Anticipate to require other antibiotics that may be potentially effective against S. aureus; Have shock or hypotension unresponsive to standard therapy; Have received an investigational product or have participated in an experimental procedure within 30 days; Have an intolerance or hypersensitivity to daptomycin; Have renal insufficiency; Have prior history or current evidence of muscle damage (rhabdomyolysis; significant CPK elevation); Have history of clinically significant muscular disease, nervous system or seizure disorder, including unexplained muscular weakness, history of peripheral neuropathy, Guillain-Barré or spinal cord injury; Have S. aureus pneumonia, empyema, meningitis, or endocarditis
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Medical Director
    Organizational Affiliation
    Merck Sharp & Dohme LLC
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing Plan Description
    https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf
    IPD Sharing URL
    http://engagezone.msd.com/ds_documentation.php
    Citations:
    PubMed Identifier
    29406465
    Citation
    Arrieta AC, Bradley JS, Popejoy MW, Bensaci M, Grandhi A, Bokesch P, Glasser C, Du L, Patino H, Kartsonis NA. Randomized Multicenter Study Comparing Safety and Efficacy of Daptomycin Versus Standard-of-care in Pediatric Patients With Staphylococcal Bacteremia. Pediatr Infect Dis J. 2018 Sep;37(9):893-900. doi: 10.1097/INF.0000000000001926.
    Results Reference
    derived

    Learn more about this trial

    Safety & Efficacy of Daptomycin Versus Standard of Care (SOC) in 1 - 17 Year Olds With Staphylococcus Aureus Bacteremia (MK-3009-005)

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