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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blinded Comparative Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Daptomycin Versus Active Comparator in Pediatric Subjects With Acute Hematogenous Osteomyelitis Due to Gram-Positive Organisms

    Summary
    EudraCT number
    		 2013-000864-28
    Trial protocol
    		 DE   HU   IT   ES   GR   LV   GB   EE   BG   FR   SI   Outside EU/EEA  
    Global end of trial date
    20 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jun 2017
    First version publication date
    18 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3009-006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01922011
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Cubist: DAP-PEDOST-11-03
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of the study was to determine whether daptomycin is effective and safe in the treatment of pediatric participants with Acute Hematogenous Osteomyelitis (AHO) when compared to vancomycin (or equivalent) or nafcillin (or β-lactam equivalent). The primary hypothesis is that daptomycin is non-inferior compared with vancomycin (or equivalent) or nafcillin (or β-lactam equivalent) with respect to improvement in Pain, Inflammation, and Limb Function on or before study Day 5.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Sep 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    Chile: 3
    Country: Number of subjects enrolled
    Estonia: 1
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Georgia: 1
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Greece: 5
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Latvia: 8
    Country: Number of subjects enrolled
    Malaysia: 1
    Country: Number of subjects enrolled
    Panama: 1
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    South Africa: 12
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    Ukraine: 31
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 41
    Worldwide total number of subjects
    149
    EEA total number of subjects
    48
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    8
    Children (2-11 years)
    94
    Adolescents (12-17 years)
    47
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Pediatric participants from ages 1 year to < 18 years with acute hematogenous osteomyelitis (AHO) were enrolled in this study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Daptomycin
    Arm description
    		 Intravenous (IV) daptomycin 7, 9, or 12 mg/kg once daily and ≤3 dummy infusions daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daptomycin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV daptomycin Infusion A in 12 to <18 years old (7 mg/kg); in 7 to < 12 year olds (9 mg/kg); in 24 months to <7 year olds (12 mg/kg); in 12 to <24 month olds (12 mg/kg). Infused over 60 minutes ± 10 minutes once daily followed by up to 3 dummy infusions q6h infused over 60 (± 10) min to maintain the blind.

    Arm title
    		 Vancomycin or Nafcillin
    Arm description
    		 IV vancomycin (or equivalent), 10 to 15 mg/kg every six hours (q6h) or IV nafcillin (or β-lactam equivalent) 100-200 mg/kg/day, in divided doses q6h
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nafcillin (or equivalent)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV nafcillin (or β-lactam equivalent) (Infusions A,B,C,D) at 100-200 mg/kg/day, in divided doses infused over 60 (± 10) min q6h (± 1 hour)

    Investigational medicinal product name
    Vancomycin (or equivalent)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV vancomycin (or equivalent) (Infusions A,B,C,D), 10 to 15 mg/kg, infused over 60 (± 10) minutes q6h (± 1 hour)

    Number of subjects in period 1
    		Daptomycin Vancomycin or Nafcillin
    Started
    75
    74
    Completed
    69
    69
    Not completed
    6
    5
         Randomized in error
    1
    -
         Physician decision
    -
    1
         Not Treated
    1
    -
         Parent/Guardian Decision
    3
    -
         Lack of willing home health agency
    1
    -
         Missed Test-of-Cure Visit
    -
    2
         Lost to follow-up
    -
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Daptomycin
    Reporting group description
    		 Intravenous (IV) daptomycin 7, 9, or 12 mg/kg once daily and ≤3 dummy infusions daily

    Reporting group title
    Vancomycin or Nafcillin
    Reporting group description
    		 IV vancomycin (or equivalent), 10 to 15 mg/kg every six hours (q6h) or IV nafcillin (or β-lactam equivalent) 100-200 mg/kg/day, in divided doses q6h

    Reporting group values
    		 Daptomycin Vancomycin or Nafcillin Total
    Number of subjects
    		 75 74 149
    Age Categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 5 3 8
        Children (2-11 years)
    		 46 48 94
        Adolescents (12-17 years)
    		 24 23 47
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.1 ± 4.4 9.2 ± 4.1 -
    Gender Categorical
    Units: Subjects
        Female
    		 31 25 56
        Male
    		 44 49 93

    End points

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    End points reporting groups
    Reporting group title
    Daptomycin
    Reporting group description
    		 Intravenous (IV) daptomycin 7, 9, or 12 mg/kg once daily and ≤3 dummy infusions daily

    Reporting group title
    Vancomycin or Nafcillin
    Reporting group description
    		 IV vancomycin (or equivalent), 10 to 15 mg/kg every six hours (q6h) or IV nafcillin (or β-lactam equivalent) 100-200 mg/kg/day, in divided doses q6h

    Subject analysis set title
    Daptomycin 12 - < 24 months old
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    IV daptomycin 12 mg/kg once daily and ≤3 dummy infusions daily for ages 12 - < 24 months old only.

    Subject analysis set title
    Daptomycin 24 months - < 7 yrs old
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    IV daptomycin 12 mg/kg once daily and ≤3 dummy infusions daily for ages 24 months - < 7 yrs old only.

    Subject analysis set title
    Daptomycin 7 - < 12 yrs old
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    IV daptomycin 9, mg/kg once daily and ≤3 dummy infusions daily for ages 7 - < 12 yrs old only.

    Subject analysis set title
    Daptomycin 12 - < 18 yrs old
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    IV daptomycin 7 mg/kg once daily and ≤3 dummy infusions daily for ages 12 - < 18 yrs old only.

    Primary: Percentage of participants with clinical improvement in the 3 general categories of Pain, Inflammation, and Limb Function based on the Investigator's overall assessment of severity of each of the symptom categories by study day 5.

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    End point title
    		 Percentage of participants with clinical improvement in the 3 general categories of Pain, Inflammation, and Limb Function based on the Investigator's overall assessment of severity of each of the symptom categories by study day 5.
    End point description
    Clinical improvement was based on the Investigator’s overall assessment of severity based on the following definition: If 3 general categories are present at baseline: at least a 1-point improvement (i.e. severe to moderate, moderate to mild, mild to absent) in at least 2 and no worsening in the other. If 2 general categories are present at baseline: at least a 2-point improvement (i.e. severe to mild, moderate to absent) in at least 1 and no worsening or new findings in the others OR at least a 1-point improvement in both and no new findings in the other. If 1 general category is present at baseline: at least a 2-point improvement (i.e., severe to mild, moderate to absent) and no new findings in the others. All randomized participants who received any amount of IV study drug and who had a confirmed or suspected diagnosis of AHO, excluding those with confirmed culture of a gram-negative organism from any baseline specimen.
    End point type
    Primary
    End point timeframe
    Up to study Day 5
    End point values
    		 Daptomycin Vancomycin or Nafcillin
    Number of subjects analysed
    71
    70
    Units: Percentage of participants
        number (confidence interval 95%)
    77.5 (67.7 to 87.2)
    82.9 (74 to 91.7)
    Statistical analysis title
    		 Daptomycin vs Vancomycin or Nafcillin
    Statistical analysis description
    95% confidence interval of the common difference was based on stratified Newcombe confidence interval (CI) with minimum risk weights, with age cohort as the stratification factor.
    Comparison groups
    Daptomycin v Vancomycin or Nafcillin
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.421
    Method
    		 Wald
    Parameter type
    		 Common Difference
    Point estimate
    -6.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.4
         upper limit
    		 7.4
    Notes
    [1] - Non-inferiority was concluded if the lower bound of the 2-sided 95% CI is greater than -15%

    Secondary: Percentage of participants with clinical improvement measured as a composite end point of pain, inflammation, limb function, body temperature, and C-reactive protein at End-of IV (EOIV) therapy visit.

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    End point title
    		 Percentage of participants with clinical improvement measured as a composite end point of pain, inflammation, limb function, body temperature, and C-reactive protein at End-of IV (EOIV) therapy visit.
    End point description
    A participant had a favorable outcome in this composite endpoint if all 3 of the following criteria were met: Clinical improvement in the general symptom categories of Pain, Inflammation, and Limb Function on or before Study Day 5; Body temperature ≤ 38°C (100.4°F) over the preceding 24 hours; and C-reactive Protein (CRP) decreased from baseline for participants who had a baseline CRP >ULN (upper limit of normal)) or remain <=ULN for participants who had a baseline <=ULN on or before Study Day 5. The EOIV visit is within 24 hours after the last dose of IV study drug and before switch to optional open label (PO) therapy, if applicable. All randomized participants who received any amount of IV study drug and who had a confirmed diagnosis of AHO (Categories I, II and III), excluding participants with confirmed culture of a gram negative organism from any baseline specimen, and who did not have all clinical assessments performed at the time point.
    End point type
    Secondary
    End point timeframe
    End of IV treatment"
    End point values
    		 Daptomycin Vancomycin or Nafcillin
    Number of subjects analysed
    69
    68
    Units: Percentage of participants
        number (confidence interval 95%)
    71 (60.3 to 81.7)
    76.5 (66.4 to 86.6)
    Statistical analysis title
    		 Daptomycin vs Vancomycin or Nafcillin
    Statistical analysis description
    95% confidence interval of the common difference ( Daptomycin minus Vancomycin or Nafcillin) is based on stratified Newcombe confidence interval (CI) with minimum risk weights, with age cohort as the stratification factor.
    Comparison groups
    Daptomycin v Vancomycin or Nafcillin
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.467
    Method
    		 Wald
    Parameter type
    		 Common difference
    Point estimate
    -7.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.6
         upper limit
    		 7.9

    Secondary: Percentage of participants with a favorable clinical outcome

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    End point title
    		 Percentage of participants with a favorable clinical outcome
    End point description
    Favorable clinical outcomes are clinical recovery and clinical cure. Clinical cure is resolution of all acute symptoms of AHO or improvement where no further intravenous antibacterial therapy is required. Clinical recovery is defined as clinical improvement in the composite end point three general categories of Pain, Inflammation, and Limb Function on or before Study Day 5, and no development of new symptoms of AHO; body temperature ≤ 38°C (100.4°F) for 24 hours; no new or additional infection such that no further antibacterial therapy or surgery are required; no hematogenous metastatic infection or bacteremia. The End of Therapy (EOT) visit is within 48 hours of last dose of PO therapy. All randomized participants who received any amount of IV study drug and who had a confirmed diagnosis of AHO (Categories I, II and III), excluding participants with confirmed culture of a gram-negative organism from any baseline specimen.
    End point type
    Secondary
    End point timeframe
    Baseline (within 48 hours prior to first dose of IV study drug) - and up to Test of Cure (21-35 days after last dose of IV study drug) (up to Day 77)
    End point values
    		 Daptomycin Vancomycin or Nafcillin
    Number of subjects analysed
    71
    70
    Units: Percentage of participants
    number (confidence interval 95%)
        At End of IV (EOIV) Therapy (n= 71,69)
    85.9 (77.8 to 94)
    91.3 (84.7 to 98)
        At End of Therapy (EOT) (n= 71,69)
    83.1 (74.4 to 91.8)
    89.9 (82.7 to 97)
        At Test Of Cure (TOC) (n= 71,70)
    81.7 (72.7 to 90.7)
    87.1 (79.3 to 95)
    Statistical analysis title
    		 At EOIV visit
    Statistical analysis description
    95% confidence interval of the common difference ( Daptomycin minus Vancomycin or Nafcillin) is based on stratified Newcombe confidence interval (CI) with minimum risk weights, with age cohort as the stratification factor.
    Comparison groups
    Daptomycin v Vancomycin or Nafcillin
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.313
    Method
    		 Wald
    Parameter type
    		 Common difference
    Point estimate
    -6.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.5
         upper limit
    		 5
    Statistical analysis title
    		 At EOT visit
    Statistical analysis description
    95% confidence interval of the common difference ( Daptomycin minus Vancomycin or Nafcillin) is based on stratified Newcombe confidence interval (CI) with minimum risk weights, with age cohort as the stratification factor.
    Comparison groups
    Daptomycin v Vancomycin or Nafcillin
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.239
    Method
    		 Wald
    Parameter type
    		 Common difference
    Point estimate
    -7.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.8
         upper limit
    		 4
    Statistical analysis title
    		 At TOC visit
    Statistical analysis description
    95% confidence interval of the common difference ( Daptomycin minus Vancomycin or Nafcillin) is based on stratified Newcombe confidence interval (CI) with minimum risk weights, with age cohort as the stratification factor
    Comparison groups
    Daptomycin v Vancomycin or Nafcillin
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.37
    Method
    		 Wald
    Parameter type
    		 Common difference
    Point estimate
    -6.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.1
         upper limit
    		 5.8

    Secondary: Percentage of participants with a clinical cure categorized by baseline pathogen at Test of Cure

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    End point title
    		 Percentage of participants with a clinical cure categorized by baseline pathogen at Test of Cure
    End point description
    At Test Of Cure (TOC) clinical cure is resolution of all acute symptoms of AHO or improvement where no further antibacterial therapy is required. Favorable microbiological outcomes are where the the original baseline pathogen was absent; or where the source specimen was not available to culture, and the participant was assessed as a clinical cure. For a favorable microbiological response, the outcome for each participant's baseline pathogen must be eradicated or presumed eradicated. Other pathogens include Arcanobacterium haemolyticum, Gram positive cocci, Staphylococcus epidermidis, Streptococcus (Strep.) dysgalactiae, Strep. mitis group and Strep. pyogenes. All randomized participants who received IV study drug and had a confirmed diagnosis of AHO, excluding participants with confirmed culture of a gram-negative organism; but including those where at least one bacterial pathogen was isolated from an appropriate microbiological specimen at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (within 48 hours prior to first dose of IV study drug) - and Test of Cure (21-35 days after last dose of IV study drug) (up to Day 77)
    End point values
    		 Daptomycin Vancomycin or Nafcillin
    Number of subjects analysed
    45
    47
    Units: Percentage of participants
    number (confidence interval 95%)
        Overall Baseline Infecting Pathogen (n =45,47)
    77.8 (65.6 to 89.9)
    87.2 (77.7 to 96.8)
        Staphylococcus Aureus (SA) (n= 43,42)
    76.7 (64.1 to 89.4)
    88.1 (78.3 to 97.9)
        Methicillin Susceptible SA (MSSA) (n= 39,37)
    79.5 (66.8 to 92.2)
    94.6 (87.3 to 100)
        Methicillin Resistant SA (MRSA) (n= 4,4)
    50 (1 to 99)
    25 (0 to 67.4)
        Other Pathogens (n= 2,7)
    100 (100 to 100)
    85.7 (59.8 to 100)
    Statistical analysis title
    		 Overall Baseline Infecting Pathogen
    Statistical analysis description
    95% confidence interval of the common difference ( Daptomycin minus Vancomycin or Nafcillin) is based on stratified Newcombe confidence interval (CI) with minimum risk weights, with age cohort as the stratification factor.
    Comparison groups
    Daptomycin v Vancomycin or Nafcillin
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.23
    Method
    		 Wald
    Parameter type
    		 Common difference
    Point estimate
    -10.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.3
         upper limit
    		 5.4
    Statistical analysis title
    		 Daptomycin vs Vancomycin or Nafcillin SA
    Statistical analysis description
    95% confidence interval of the common difference ( Daptomycin minus Vancomycin or Nafcillin) is based on stratified Newcombe confidence interval (CI) with minimum risk weights, with age cohort as the stratification factor.
    Comparison groups
    Daptomycin v Vancomycin or Nafcillin
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.164
    Method
    		 Wald
    Parameter type
    		 Common difference
    Point estimate
    -12.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.5
         upper limit
    		 4.4
    Statistical analysis title
    		 Daptomycin vs Vancomycin or Nafcillin MSSA
    Statistical analysis description
    95% confidence interval of the common difference ( Daptomycin minus Vancomycin or Nafcillin) is based on stratified Newcombe confidence interval (CI) with minimum risk weights, with age cohort as the stratification factor.
    Comparison groups
    Daptomycin v Vancomycin or Nafcillin
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.043
    Method
    		 Wald
    Parameter type
    		 Common difference
    Point estimate
    -15.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.2
         upper limit
    		 1.1
    Statistical analysis title
    		 Daptomycin vs Vancomycin or Nafcillin MRSA
    Comparison groups
    Daptomycin v Vancomycin or Nafcillin
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.45
    Method
    		 Wald
    Confidence interval
    Statistical analysis title
    		 Other Pathogen
    Comparison groups
    Daptomycin v Vancomycin or Nafcillin
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.28
    Method
    		 Wald
    Confidence interval

    Secondary: Percentage of participants with sustained clinical improvement

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    End point title
    		 Percentage of participants with sustained clinical improvement
    End point description
    Sustained clinical improvement was defined as participants with clinical improvement who further met the definition of clinical cure. Clinical improvement was in the three general categories of Pain, Inflammation, and Limb Function on or before Study Day 5. Clinical cure is defined as resolution of all acute symptoms of AHO or improvement to such an extent that no further intravenous antibacterial therapy is required. The EOT visit is within 48 hours of last dose of PO therapy. All randomized participants who received any amount of IV study drug and who had a confirmed or suspected diagnosis of AHO, excluding those with confirmed culture of a gram negative organism from any baseline specimen; and had non-missing clinical outcome.
    End point type
    Secondary
    End point timeframe
    Baseline (within 48 hours prior to first dose of IV study drug) - up to Test of Cure (21-35 days after last dose of IV study drug) (up to Day 77)
    End point values
    		 Daptomycin Vancomycin or Nafcillin
    Number of subjects analysed
    71
    70
    Units: Percentage of participants
    number (confidence interval 95%)
        EOT (n= 55,57)
    89.1 (80.9 to 97.3)
    94.7 (88.9 to 100)
        TOC (n= 55,58)
    87.3 (78.5 to 96.1)
    91.4 (84.2 to 98.6)
    Statistical analysis title
    		 Daptomycin vs Vancomycin or Nafcillin at EOT
    Statistical analysis description
    95% confidence interval of the common difference ( Daptomycin minus Vancomycin or Nafcillin) is based on stratified Newcombe confidence interval (CI) with minimum risk weights, with age cohort as the stratification factor.
    Comparison groups
    Daptomycin v Vancomycin or Nafcillin
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.272
    Method
    		 Wald
    Parameter type
    		 Common difference
    Point estimate
    -6.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.2
         upper limit
    		 5.5
    Statistical analysis title
    		 Daptomycin vs Vancomycin or Nafcillin at TOC
    Statistical analysis description
    95% confidence interval of the common difference ( Daptomycin minus Vancomycin or Nafcillin) is based on stratified Newcombe confidence interval (CI) with minimum risk weights, with age cohort as the stratification factor.
    Comparison groups
    Daptomycin v Vancomycin or Nafcillin
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.48
    Method
    		 Wald
    Parameter type
    		 Common difference
    Point estimate
    -4.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.6
         upper limit
    		 7.9

    Secondary: Percentage of participants with a favorable microbiological response categorized by baseline pathogen at Test of Cure

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    End point title
    		 Percentage of participants with a favorable microbiological response categorized by baseline pathogen at Test of Cure
    End point description
    Favorable microbiological outcomes are either eradication where the source specimen demonstrated absence of the original baseline pathogen; or presumed eradication where the source specimen was not available to culture, and the participant was assessed as a clinical cure. For a favorable microbiological response, the outcome for each baseline pathogen must be eradicated or presumed eradicated. Other pathogens include Arcanobacterium haemolyticum, Gram positive cocci, Staphylococcus epidermidis, Streptococcus dysgalactiae, Streptococcus mitis group and Streptococcus pyogenes. All randomized participants who received IV study drug and had a confirmed diagnosis of AHO, excluding participants with confirmed culture of a gram negative organism; but including those where at least one bacterial pathogen was isolated from an appropriate microbiological specimen at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (within 48 hours prior to first dose of IV study drug) - and Test of Cure (21-35 days after last dose of IV study drug) (up to Day 77)
    End point values
    		 Daptomycin Vancomycin or Nafcillin
    Number of subjects analysed
    45
    47
    Units: Percentage of participants
    number (confidence interval 95%)
        Overall Baseline Infecting Pathogen (n =45,47)
    82.2 (71.1 to 93.4)
    91.5 (83.5 to 99.5)
        SA (n= 43,42)
    81.4 (69.8 to 93)
    92.9 (85.1 to 100)
        MSSA (n= 39,37)
    84.6 (73.3 to 95.9)
    94.6 (87.3 to 100)
        MRSA (n= 4,4)
    50 (1 to 99)
    75 (32.6 to 100)
        Other Pathogens (n= 2,7)
    100 (100 to 100)
    85.7 (59.8 to 100)
    Statistical analysis title
    		 Overall Baseline Infecting Pathogen
    Statistical analysis description
    95% confidence interval of the common difference ( Daptomycin minus Vancomycin or Nafcillin) is based on stratified Newcombe confidence interval (CI) with minimum risk weights, with age cohort as the stratification factor.
    Comparison groups
    Daptomycin v Vancomycin or Nafcillin
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Common difference
    Point estimate
    -10.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.8
         upper limit
    		 4.2
    Statistical analysis title
    		 Daptomycin vs Vancomycin or Nafcillin SA
    Statistical analysis description
    95% confidence interval of the common difference ( Daptomycin minus Vancomycin or Nafcillin) is based on stratified Newcombe confidence interval (CI) with minimum risk weights, with age cohort as the stratification factor.
    Comparison groups
    Daptomycin v Vancomycin or Nafcillin
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Common difference
    Point estimate
    -12.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.2
         upper limit
    		 2.8
    Statistical analysis title
    		 Daptomycin vs Vancomycin or Nafcillin MSSA
    Statistical analysis description
    95% confidence interval of the common difference ( Daptomycin minus Vancomycin or Nafcillin) is based on stratified Newcombe confidence interval (CI) with minimum risk weights, with age cohort as the stratification factor.
    Comparison groups
    Daptomycin v Vancomycin or Nafcillin
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Common difference
    Point estimate
    -10.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.4
         upper limit
    		 5.2

    Other pre-specified: Number of participants with 1 or more Adverse Events (AEs)

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    End point title
    		 Number of participants with 1 or more Adverse Events (AEs)
    End point description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, clinically significant laboratory finding, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Treated participants based on the treatment received.
    End point type
    Other pre-specified
    End point timeframe
    Administration of first dose up to approximately six and a half months after last dose of study drug
    End point values
    		 Daptomycin Vancomycin or Nafcillin
    Number of subjects analysed
    74
    72
    Units: Participants
        number (not applicable)
    34
    45
    No statistical analyses for this end point

    Other pre-specified: Number of participants with 1 or more Serious Adverse Events (SAEs)

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    End point title
    		 Number of participants with 1 or more Serious Adverse Events (SAEs)
    End point description
    An SAE is any untoward medical occurrence that at any dose results in death; is life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; or is a congenital anomaly/birth defect. Treated participants based on the treatment received.
    End point type
    Other pre-specified
    End point timeframe
    Administration of first dose through the last follow-up visit; an expected time of up to 6.5 months
    End point values
    		 Daptomycin Vancomycin or Nafcillin
    Number of subjects analysed
    74
    72
    Units: Participants
        number (not applicable)
    5
    4
    No statistical analyses for this end point

    Other pre-specified: Concentration of serum creatine kinase (CK)

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    End point title
    		 Concentration of serum creatine kinase (CK)
    End point description
    Serum was collected at Baseline and at End of Therapy IV, from which the concentration of CK was determined.
    End point type
    Other pre-specified
    End point timeframe
    Baseline and End of Therapy IV (up to Day 42)
    End point values
    		 Daptomycin Vancomycin or Nafcillin
    Number of subjects analysed
    74
    72
    Units: U/L
    arithmetic mean (standard deviation)
        Baseline (n = 68,72)
    141.7 ± 188.7
    99.9 ± 95
        End of Therapy IV (n= 35,41)
    89.4 ± 66.55
    82.4 ± 95.03
    No statistical analyses for this end point

    Other pre-specified: Change from baseline in number of participants with abnormal focused (peripheral) neurological assessments

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    End point title
    		 Change from baseline in number of participants with abnormal focused (peripheral) neurological assessments
    End point description
    Focused neurological examinations include assessments of alertness, 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.
    End point type
    Other pre-specified
    End point timeframe
    Baseline and up to Test of Cure (21-35 days after last dose of IV study drug) (up to Day 77)
    End point values
    		 Daptomycin Vancomycin or Nafcillin
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: Participants
        number (not applicable)
    Notes
    [2] - Data were only summarized for each visit; but not analyzed.
    [3] - Data were only summarized for each visit; but not analyzed.
    No statistical analyses for this end point

    Other pre-specified: Plasma concentration of daptomycin at the end of IV infusion

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    End point title
    		 Plasma concentration of daptomycin at the end of IV infusion
    End point description
    Blood samples were collected, after infusion of IV study drug between the end of infusion on study day 3, up to Day 42. Participants who received a known amount of daptomycin and who had at least one blood sample collected. Participants treated with vancomycin, nafcillin or equivalent were not analyzed.
    End point type
    Other pre-specified
    End point timeframe
    Day 3 up to Day 42
    End point values
    		 Daptomycin 12 - < 24 months old Daptomycin 24 months - < 7 yrs old Daptomycin 7 - < 12 yrs old Daptomycin 12 - < 18 yrs old
    Number of subjects analysed
    1
    6
    5
    10
    Units: μg/mL
        arithmetic mean (standard deviation)
    36.8 ± 0
    75.772 ± 39.1156
    58.94 ± 27.4149
    68.907 ± 56.6695
    No statistical analyses for this end point

    Other pre-specified: Plasma concentration of daptomycin at 15 minutes to 1 hour after the end of IV infusion

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    End point title
    		 Plasma concentration of daptomycin at 15 minutes to 1 hour after the end of IV infusion
    End point description
    Blood samples were collected, after infusion of IV study drug between the end of infusion on study day 3, up to Day 42. Participants who received a known amount of daptomycin and who had at least one blood sample collected. Participants treated with vancomycin, nafcillin or equivalent were not analyzed.
    End point type
    Other pre-specified
    End point timeframe
    Day 3 up to Day 42
    End point values
    		 Daptomycin 12 - < 24 months old Daptomycin 24 months - < 7 yrs old Daptomycin 7 - < 12 yrs old Daptomycin 12 - < 18 yrs old
    Number of subjects analysed
    3
    8
    12
    10
    Units: μg/mL
        arithmetic mean (standard deviation)
    65.533 ± 30.8468
    84.564 ± 35.0179
    70.342 ± 35.0196
    57.37 ± 61.5616
    No statistical analyses for this end point

    Other pre-specified: Plasma concentration of daptomycin at 2 to 3 hours after the end of IV

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    End point title
    		 Plasma concentration of daptomycin at 2 to 3 hours after the end of IV
    End point description
    Participants who received a known amount of daptomycin and who had at least one blood sample collected. Participants treated with vancomycin, nafcillin or equivalent were not analyzed.
    End point type
    Other pre-specified
    End point timeframe
    Day 3 up to Day 42
    End point values
    		 Daptomycin 12 - < 24 months old Daptomycin 24 months - < 7 yrs old Daptomycin 7 - < 12 yrs old Daptomycin 12 - < 18 yrs old
    Number of subjects analysed
    0 [4]
    6
    5
    9
    Units: μg/mL
        arithmetic mean (standard deviation)
    ±
    51.15 ± 16.1179
    31.2 ± 14.7027
    46.756 ± 51.2678
    Notes
    [4] - Values were treated as missing, as concentrations were below the limit of quantification.
    No statistical analyses for this end point

    Other pre-specified: Plasma concentration of daptomycin at 4 to 5 hours after the end of IV infusion

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    End point title
    		 Plasma concentration of daptomycin at 4 to 5 hours after the end of IV infusion
    End point description
    Participants who received a known amount of daptomycin and who had at least one blood sample collected. Participants treated with vancomycin, nafcillin or equivalent were not analyzed.
    End point type
    Other pre-specified
    End point timeframe
    Day 3 up to Day 42
    End point values
    		 Daptomycin 12 - < 24 months old Daptomycin 24 months - < 7 yrs old Daptomycin 7 - < 12 yrs old Daptomycin 12 - < 18 yrs old
    Number of subjects analysed
    3
    7
    11
    10
    Units: μg/mL
        arithmetic mean (standard deviation)
    35.933 ± 6.3956
    53.059 ± 21.8879
    50.809 ± 26.0469
    41.447 ± 57.8657
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious Adverse Events (AEs): Up to approximately six and a half months after last dose of study drug. Non-serious AEs (NSAEs): Up to 35 days after last dose of study drug
    Adverse event reporting additional description
    Treated participants based on the treatment received
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Vancomycin or Nafcillin
    Reporting group description
    		 IV vancomycin (or equivalent), 10 to 15 mg/kg q6h, or IV nafcillin (or β-lactam equivalent) 100-200 mg/kg/day, in divided doses q6h

    Reporting group title
    Daptomycin
    Reporting group description
    		 IV daptomycin 7, 9, or 12 mg/kg once daily and ≤3 dummy infusions daily

    Serious adverse events
    		 Vancomycin or Nafcillin Daptomycin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 72 (5.56%)
    5 / 74 (6.76%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Red man syndrome
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Vancomycin or Nafcillin Daptomycin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 72 (33.33%)
    6 / 74 (8.11%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 72 (5.56%)
    0 / 74 (0.00%)
         occurrences all number
    4
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    5 / 72 (6.94%)
    2 / 74 (2.70%)
         occurrences all number
    6
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    6 / 72 (8.33%)
    1 / 74 (1.35%)
         occurrences all number
    6
    1
    Diarrhoea
         subjects affected / exposed
    4 / 72 (5.56%)
    1 / 74 (1.35%)
         occurrences all number
    4
    1
    Vomiting
         subjects affected / exposed
    6 / 72 (8.33%)
    3 / 74 (4.05%)
         occurrences all number
    6
    3
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    5 / 72 (6.94%)
    1 / 74 (1.35%)
         occurrences all number
    5
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 72 (5.56%)
    0 / 74 (0.00%)
         occurrences all number
    5
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Sep 2013
    Amendment 1: Revised criteria for eligibility and discontinuations due to safety; clarified that local approved product information was to be used for the active comparator; and added a subsection about CPK elevations.
    10 Apr 2014
    Amendment 2: Added text about the timing of infusions to maintain the blind; and added a stepwise enrollment plan that began with participants aged 2 to <18 years then broadened enrollment to 12 months to <18 years of age after review by the Data Monitoring Committee. Other revisions clarified the maximum concentration of final diluted daptomycin, vancomycin dose adjustments, and clinical assessments for participants who remained hospitalized and on IV trial treatment after Study Day 5. Inclusion criteria were changed to clarify baseline disease parameters and to reflect stepwise enrollment.
    08 Sep 2014
    Amendment 3: Revised eligibility criteria, added teicoplanin as an alternative to vancomycin; clarified culture and induration specifications; added 2 antibiotics for the oral switch, and clarified blinding requirements. Clarified reference information for daptomycin, Keflex®, Cleocin®, Zyvox®, Bactrim®, Augmentin®, and vancomycin.
    15 Sep 2015
    Amendment 4: Included a decrease in the trial sample size, and changed the AE collection period. The AE reporting timeframe and SAE follow-up period were revised; text was added about CPK increases, and language was added to clarify that the IV comparators and oral antibiotics listed were recommendations. Inclusion criteria and an exclusion criterion were changed to include participants with suspect or confirmed AHO; better define AHO compared with chronic osteomyelitis, and allow pelvic AHO, respectively. Exclusion criterion was added to exclude subjects with suspected or confirmed pneumonia, empyema, meningitis, or endocarditis. The recommended length of IV trial treatment was revised to a minimum of 4 days.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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