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    Clinical Trial Results:
    A Randomized, Double-Blind, Double Dummy, Comparative , Multicenter Study to Assess the Safety and Efficacy of Topical Retapamulin Ointment, 1%, versus Oral Linezolid in the Treatment of Secondarily-Infected Traumatic Lesions and Impetigo Due to Methicillin Resistant Staphylococcus aureus

    Summary
    EudraCT number
    2015-004886-98
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    27 Sep 2010

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Feb 2017
    First version publication date
    12 Feb 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    110978
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    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
    09 Dec 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Sep 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the clinical and bacteriological efficacy of topical retapamulin ointment, 1%, versus oral linezolid, in the treatment of subjects with secondarily-infected traumatic lesions (SITL: excluding abscesses) or impetigo due to methicillin-resistant Staphylococcus aureus (MRSA).
    Protection of trial subjects
    Not applicable
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Apr 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 404
    Worldwide total number of subjects
    404
    EEA total number of subjects
    0
    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)
    14
    Children (2-11 years)
    68
    Adolescents (12-17 years)
    38
    Adults (18-64 years)
    256
    From 65 to 84 years
    24
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    In total, 410 participants were enrolled in the study, 267 received at least 1 dose of retapamulin arm and 137 received at least 1 dose of linezolid. Of these participants, 234 retapamulin participants and 122 linezolid participants completed the study.

    Pre-assignment
    Screening details
    One participant was randomized to retapamulin but received linezolid. This participant is summarized in the linezolid group for all baseline and safety tables, but is summarized in the retapamulin group for all efficacy tables.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Retapamulin ointment, 1% (weight/weight) plus oral placebo
    Arm description
    Retapamulin ointment was administered topically twice daily (BID) for 5 days. The ointment formulation was to be applied to the infected lesion(s) at a dose of approximately 10 milligrams (mg) per centimeter squared (cm^2). Placebo was to be dosed, depending on participant age, either BID or three times a day (TID) for 10 days. Placebo oral suspension and oral tablet were formulated to appear identical to the linezolid formulations. Adolescent and adult participants (>=12 years of age) were dosed BID with 600 mg placebo tablets, pediatric participants 5 to 11 years of age were dosed with oral suspension at 0.5 milliliters (ml)/kilogram (kg) BID, and pediatric participants less than 5 years of age were dosed with oral suspension at 0.5 ml/kg TID.
    Arm type
    Experimental

    Investigational medicinal product name
    Retapamulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    1% (w/w) ointment, twice daily for 5 days

    Arm title
    Linezolid plus placebo ointment
    Arm description
    Linezolid was to be dosed, depending on participant age, either BID or TID for 10 days. Adolescent and adult participants (>=12 years of age) were dosed BID with 600 mg tablets for 10 days. Pediatric participants who were 5-11 years of age were dosed with a 100 mg/5 ml oral suspension at a dose of 10 mg/kg BID for 10 days. Pediatric participants who were <5 years of age were dosed with a 100 mg/5 ml oral suspension at a dose of 10 mg/kg TID for 10 days. Placebo ointment was administered topically BID for 5 days.
    Arm type
    Active comparator

    Investigational medicinal product name
    Linezolid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600mg tablet, q12h for 10 days (>= 12 years of age) 100 mg/5 mL oral suspension; 10 mg/kg q12h for 10 days (5-11 years of age) 100 mg/5 mL oral suspension; 10 mg/kg q8h for 10 days (<5 years of age)

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment, Oral suspension, Tablet
    Routes of administration
    Oral use, Topical use
    Dosage and administration details
    Topical ointment, twice daily for 5 days. Tablet BID for 10 days (>= 12 years of age). Suspension BID for 10 days (5-11 years of age). Suspension TID for 10 days (<5 years of age).

    Number of subjects in period 1
    Retapamulin ointment, 1% (weight/weight) plus oral placebo Linezolid plus placebo ointment
    Started
    267
    137
    Completed
    234
    122
    Not completed
    33
    15
         Protocol deviation
    1
    2
         Lack of efficacy
    15
    3
         Investigator Discretion
    2
    3
         Adverse event, non-fatal
    10
    3
         Consent withdrawn by subject
    3
    1
         Lost to follow-up
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Retapamulin ointment, 1% (weight/weight) plus oral placebo
    Reporting group description
    Retapamulin ointment was administered topically twice daily (BID) for 5 days. The ointment formulation was to be applied to the infected lesion(s) at a dose of approximately 10 milligrams (mg) per centimeter squared (cm^2). Placebo was to be dosed, depending on participant age, either BID or three times a day (TID) for 10 days. Placebo oral suspension and oral tablet were formulated to appear identical to the linezolid formulations. Adolescent and adult participants (>=12 years of age) were dosed BID with 600 mg placebo tablets, pediatric participants 5 to 11 years of age were dosed with oral suspension at 0.5 milliliters (ml)/kilogram (kg) BID, and pediatric participants less than 5 years of age were dosed with oral suspension at 0.5 ml/kg TID.

    Reporting group title
    Linezolid plus placebo ointment
    Reporting group description
    Linezolid was to be dosed, depending on participant age, either BID or TID for 10 days. Adolescent and adult participants (>=12 years of age) were dosed BID with 600 mg tablets for 10 days. Pediatric participants who were 5-11 years of age were dosed with a 100 mg/5 ml oral suspension at a dose of 10 mg/kg BID for 10 days. Pediatric participants who were <5 years of age were dosed with a 100 mg/5 ml oral suspension at a dose of 10 mg/kg TID for 10 days. Placebo ointment was administered topically BID for 5 days.

    Reporting group values
    Retapamulin ointment, 1% (weight/weight) plus oral placebo Linezolid plus placebo ointment Total
    Number of subjects
    267 137
    Age categorical
    Units: Subjects
    Age continuous
    Baseline characteristics were collected in all participants in the Intent-to-Treat Clinical (ITTC) Population, comprised of all randomized participants who took at least one dose of study medication. Three participants in both treatment groups were randomized but did not receive study medication.
    Units: years
        arithmetic mean (standard deviation)
    34.6 ± 21.37 33.8 ± 22.38 -
    Gender categorical
    Baseline characterisitcs were collected in all participants in the Intent-to-Treat Clinical (ITTC) Popluation, comprised of all randomized participants who took at least one dose of study medication. Three participants in both treatment groups were randomized but did not receive study medication.
    Units: Subjects
        Female
    108 49 157
        Male
    159 88 247
    Race/Ethnicity, Customized
    Baseline characterisitcs were collected in all participants in the Intent-to-Treat Clinical (ITTC) Popluation, comprised of all randomized participants who took at least one dose of study medication. Three participants in both treatment groups were randomized but did not receive study medication.
    Units: Subjects
        African American/African Heritage
    16 10 26
        American Indian or Alaska Native
    5 0 5
        Central/South Asian Heritage
    1 1 2
        East Asian Heritage
    0 1 1
        Japanese Heritage
    5 2 7
        South East Asian Heritage
    3 0 3
        Native Hawaiian or other Pacific Islander
    5 1 6
        Arabic/North African Heritage
    0 3 3
        White/Caucasian/European
    222 118 340
        White - Mixed Race
    10 1 11

    End points

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    End points reporting groups
    Reporting group title
    Retapamulin ointment, 1% (weight/weight) plus oral placebo
    Reporting group description
    Retapamulin ointment was administered topically twice daily (BID) for 5 days. The ointment formulation was to be applied to the infected lesion(s) at a dose of approximately 10 milligrams (mg) per centimeter squared (cm^2). Placebo was to be dosed, depending on participant age, either BID or three times a day (TID) for 10 days. Placebo oral suspension and oral tablet were formulated to appear identical to the linezolid formulations. Adolescent and adult participants (>=12 years of age) were dosed BID with 600 mg placebo tablets, pediatric participants 5 to 11 years of age were dosed with oral suspension at 0.5 milliliters (ml)/kilogram (kg) BID, and pediatric participants less than 5 years of age were dosed with oral suspension at 0.5 ml/kg TID.

    Reporting group title
    Linezolid plus placebo ointment
    Reporting group description
    Linezolid was to be dosed, depending on participant age, either BID or TID for 10 days. Adolescent and adult participants (>=12 years of age) were dosed BID with 600 mg tablets for 10 days. Pediatric participants who were 5-11 years of age were dosed with a 100 mg/5 ml oral suspension at a dose of 10 mg/kg BID for 10 days. Pediatric participants who were <5 years of age were dosed with a 100 mg/5 ml oral suspension at a dose of 10 mg/kg TID for 10 days. Placebo ointment was administered topically BID for 5 days.

    Primary: Number of participants achieving clinical response at follow-up who had methicillin-resistant Staphylococcus aureus (MRSA) as a baseline pathogen

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    End point title
    Number of participants achieving clinical response at follow-up who had methicillin-resistant Staphylococcus aureus (MRSA) as a baseline pathogen
    End point description
    Follow-up is defined as 7-9 days post-therapy: Day 12-14 for retapamulin; Day 17-19 for linezolid. Clinical success at follow-up was defined as the resolution of clinically meaningful signs and symptoms of infection recorded at baseline, including a pus/exudate skin infection rating scale (SIRS) score of "0." The SIRS is used by the investigator to evaluate infected lesions. Scores on the SIRS range from 0 (absent) to 6 (severe). Intent-to-Treat MRSA (ITTMRSA) Population: all randomized participants who took at least one dose of study medication and who had an MRSA isolated at baseline.
    End point type
    Primary
    End point timeframe
    7-9 days post-therapy; Day 12-14 for retapamulin and Day 17-19 for linezolid
    End point values
    Retapamulin ointment, 1% (weight/weight) plus oral placebo Linezolid plus placebo ointment
    Number of subjects analysed
    72 [1]
    38 [2]
    Units: participants
    41
    32
    Notes
    [1] - Intent-to-Treat MRSA (ITTMRSA) Population.
    [2] - Intent-to-Treat MRSA (ITTMRSA) Population.
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Linezolid plus placebo ointment v Retapamulin ointment, 1% (weight/weight) plus oral placebo
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    [3]
    Method
    Parameter type
    percentage of participants
    Point estimate
    56.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    45.5
         upper limit
    68.4
    Notes
    [3] - Percentage of participants in Retapamulin ointment
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Retapamulin ointment, 1% (weight/weight) plus oral placebo v Linezolid plus placebo ointment
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    [4]
    Method
    Parameter type
    Percentage of participants
    Point estimate
    84.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    72.6
         upper limit
    95.8
    Notes
    [4] - Percentage of participants in Linezolid plus placebo ointment

    Secondary: Number of participants achieving microbiological response (MR) at follow-up (FU) who had MRSA as a baseline pathogen (BP)

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    End point title
    Number of participants achieving microbiological response (MR) at follow-up (FU) who had MRSA as a baseline pathogen (BP)
    End point description
    MR was defined as microbiological success if, (1) for participants (par.) whose clinical outcome at end of therapy (EOT) was “clinical success (CS)/improvement,” the BP was eradicated/presumed to be eradicated at EOT, or the BP was present at EOT and absent at FU, or the BP was eradicated/presumed to be eradicated at EOT, or the BP was present at EOT and par. was a “CS” such that no culture was obtained due to lack of culturable material secondary to adequate clinical response; or (2) a pathogen not previously identified at baseline was isolated at FU in a par. identified at FU as a “CS.” Intent-to-Treat MRSA (ITTMRSA) Population: all randomized participants who took at least one dose of study medication and who had an MRSA isolated at baseline.
    End point type
    Secondary
    End point timeframe
    7-9 days post-therapy; Day 12-14 for retapamulin and Day 17-19 for linezolid
    End point values
    Retapamulin ointment, 1% (weight/weight) plus oral placebo Linezolid plus placebo ointment
    Number of subjects analysed
    72 [5]
    38 [6]
    Units: participants
    41
    32
    Notes
    [5] - Intent-to-Treat MRSA (ITTMRSA) Population.
    [6] - Intent-to-Treat MRSA (ITTMRSA) Population.
    No statistical analyses for this end point

    Secondary: Number of participants with clinical response at follow-up

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    End point title
    Number of participants with clinical response at follow-up
    End point description
    Follow-up is defined as 7-9 days post-therapy: Day 12-14 for retapamulin; Day 17-19 for linezolid. Clinical success at follow-up was defined as the resolution of clinically meaningful signs and symptoms of infection recorded at baseline, including a pus/exudate skin infection rating scale (SIRS) score of "0." The SIRS is used by the investigator to evaluate infected lesions. Scores on the SIRS range from 0 (absent) to 6 (severe). Intent-to-Treat Clinical (ITTC) Population: all randomized participants (par.) who took at least one dose of study medication. One par. was randomized to retapamulin but received linezolid. This par. is summarized in the linezolid group for all baseline and safety tables, but is summarized in the retapamulin group for all efficacy tables.
    End point type
    Secondary
    End point timeframe
    7-9 days post-therapy; Day 12-14 for retapamulin and Day 17-19 for linezolid
    End point values
    Retapamulin ointment, 1% (weight/weight) plus oral placebo Linezolid plus placebo ointment
    Number of subjects analysed
    267 [7]
    137 [8]
    Units: participants
    161
    112
    Notes
    [7] - One par. was randomized to retapamulin but received linezolid; therefore, n=268.
    [8] - One par. was randomized to retapamulin but received linezolid; therefore, n=136.
    No statistical analyses for this end point

    Secondary: Number of participants who achieved microbiological response (MR) at follow-up (FU) who had a baseline pathogen (BP)

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    End point title
    Number of participants who achieved microbiological response (MR) at follow-up (FU) who had a baseline pathogen (BP)
    End point description
    MR was defined as microbiological success if, (1) for participants (par.) whose clinical outcome at end of therapy (EOT) was “clinical success (CS)/improvement,” the BP was eradicated/presumed to be eradicated at EOT, or the BP was present at EOT and absent at FU, or the BP was eradicated/presumed to be eradicated at EOT, or the BP was present at EOT and par. was a “CS” such that no culture was obtained due to lack of culturable material secondary to adequate clinical response; or (2) a pathogen not previously identified at baseline was isolated at FU in a par. identified at FU as a “CS.” Intent-to-Treat Bacteriology (ITTB) Population: all randomized participants who took at least one dose of study medication and who had a pathogen isolated at base line .
    End point type
    Secondary
    End point timeframe
    7-9 days post-therapy; Day 12-14 for retapamulin and Day 17-19 for linezolid
    End point values
    Retapamulin ointment, 1% (weight/weight) plus oral placebo Linezolid plus placebo ointment
    Number of subjects analysed
    177 [9]
    78 [10]
    Units: participants
    100
    65
    Notes
    [9] - Intent-to-Treat Bacteriology (ITTB) Population.
    [10] - Intent-to-Treat Bacteriology (ITTB) Population.
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated clinical (clin.) outcome at the end of therapy (EOT) who had MRSA as a baseline (BL) pathogen

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    End point title
    Number of participants with the indicated clinical (clin.) outcome at the end of therapy (EOT) who had MRSA as a baseline (BL) pathogen
    End point description
    Clin. improvement (imp.)=imp. of signs/symptoms (S/S) of infection recorded at BL to such an extent that no further antimicrobial therapy is necessary. Clin. failure (CF)=insufficient imp./deterioration of S/S of the infection recorded at BL, such that additional antibiotic therapy is required. Clin. success at follow-up (FU)=resolution of clinically meaningful S/S of infection recorded at BL, including a pus/exudate SIRS score of "0." Unable to determine (UTD)=refusal to consent to a clin. examination, lost to FU. Participants who are "CF"/"UTD" at EOT are considered such at FU as well.
    End point type
    Secondary
    End point timeframe
    2-4 days post-therapy; Day 7-9 for retapamulin and Day 12-14 for linezolid
    End point values
    Retapamulin ointment, 1% (weight/weight) plus oral placebo Linezolid plus placebo ointment
    Number of subjects analysed
    72 [11]
    38 [12]
    Units: participants
        Clinical success
    20
    28
        Clinical improvement
    42
    9
        Clinical failure
    8
    1
        Unable to determine
    2
    0
    Notes
    [11] - ITTMRSA Population
    [12] - ITTMRSA Population
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated microbiological outcome at the end of therapy who had MRSA as a baseline (BL) pathogen

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    End point title
    Number of participants with the indicated microbiological outcome at the end of therapy who had MRSA as a baseline (BL) pathogen
    End point description
    Eradication is the elimination of BL pathogens. Presumed eradication and presumed improvement are clinical outcomes of success or improvement, respectively, such that no culture was obtained due to lack of culturable material, secondary to adequate clinical response, and is documented in the electronic Case Report Form. Persistence is defined as BL pathogens still being present. Presumed persistence is defined as a participant that is a clinical failure with no obtained culture. "Unable to determine" was used if no determination of BL pathogen microbiological response could be made.
    End point type
    Secondary
    End point timeframe
    2-4 days post-therapy; Day 7-9 for retapamulin and Day 12-14 for linezolid
    End point values
    Retapamulin ointment, 1% (weight/weight) plus oral placebo Linezolid plus placebo ointment
    Number of subjects analysed
    72 [13]
    38 [14]
    Units: participants
        Eradication
    1
    0
        Presumed eradication
    20
    28
        Presumed improvement
    42
    9
        Persistence
    4
    1
        Presumed persistence
    4
    0
        Unable to determine
    1
    0
    Notes
    [13] - ITTMRSA Population
    [14] - ITTMRSA Population
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated clinical (clin.) outcome at the end of therapy (EOT)

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    End point title
    Number of participants with the indicated clinical (clin.) outcome at the end of therapy (EOT)
    End point description
    Clin. improvement (imp.)=imp. of signs/symptoms (S/S) of infection recorded at BL to such an extent that no further antimicrobial therapy is necessary. Clin. failure (CF)=insufficient imp./deterioration of S/S of the infection recorded at BL, such that additional antibiotic therapy is required. Clin. success at follow-up (FU)=resolution of clinically meaningful S/S of infection recorded at BL, including a pus/exudate SIRS score of "0." Unable to determine (UTD)=refusal to consent to a clin. examination, lost to FU. Participants who are "CF"/"UTD" at EOT are considered such at FU as well. ITTC Population. One par. was randomized to retapamulin but received linezolid. This par. is summarized in the linezolid group for all baseline and safety tables, but is summarized in the retapamulin group for all efficacy tables.
    End point type
    Secondary
    End point timeframe
    2-4 days post-therapy; Day 7-9 for retapamulin and Day 12-14 for linezolid
    End point values
    Retapamulin ointment, 1% (weight/weight) plus oral placebo Linezolid plus placebo ointment
    Number of subjects analysed
    267 [15]
    137 [16]
    Units: participants
        Clinical success
    92
    96
        Clinical improvement
    155
    34
        Clinical failure
    16
    4
        Unable to determine
    5
    2
    Notes
    [15] - One par. was randomized to retapamulin but received linezolid; therefore, n=268.
    [16] - One par. was randomized to retapamulin but received linezolid; therefore, n=136.
    No statistical analyses for this end point

    Secondary: Number of baseline pathogens with the indicated microbiological outcome at the end of therapy

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    End point title
    Number of baseline pathogens with the indicated microbiological outcome at the end of therapy
    End point description
    Eradication is the elimination of BL pathogens. Presumed eradication and presumed improvement are clinical outcomes of success or improvement, respectively, such that no culture was obtained due to lack of culturable material, secondary to adequate clinical response, and is documented in the electronic Case Report Form. Persistence is defined as BL pathogens still being present. Presumed persistence is defined as a participant that is a clinical failure with no obtained culture. "Unable to determine" was used if no determination of BL pathogen microbiological response could be made.
    End point type
    Secondary
    End point timeframe
    2-4 days post-therapy; Day 7-9 for retapamulin and Day 12-14 for linezolid
    End point values
    Retapamulin ointment, 1% (weight/weight) plus oral placebo Linezolid plus placebo ointment
    Number of subjects analysed
    177 [17]
    78 [18]
    Units: pathogens
        Eradication
    2
    1
        Presumed eradication
    63
    70
        Presumed improvement
    120
    21
        Persistence
    7
    1
        Presumed persistence
    9
    1
        Unable to determine
    1
    0
    Notes
    [17] - ITTB Population
    [18] - ITTB Population
    No statistical analyses for this end point

    Secondary: Number of participants with therapeutic response at follow-up

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    End point title
    Number of participants with therapeutic response at follow-up
    End point description
    Therapeutic response is defined as the combined clinical and microbiological response. Therapeutic response iss a measure of the overall efficacy response, and a therapeutic success refers to participants who had been deemed both a “clinical success” and a “microbiological success." All other combinations (other than “clinical success” + “microbiological success”) were deemed failures for therapeutic response.
    End point type
    Secondary
    End point timeframe
    7-9 days post-therapy; Day 12-14 for retapamulin and Day 17-19 for linezolid
    End point values
    Retapamulin ointment, 1% (weight/weight) plus oral placebo Linezolid plus placebo ointment
    Number of subjects analysed
    177 [19]
    78 [20]
    Units: participants
    100
    65
    Notes
    [19] - ITTB Population
    [20] - ITTB Population
    No statistical analyses for this end point

    Secondary: Mean scores on the Skin Infection Rating Scale at Visits 1, 2, 3, 4, and 5

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    End point title
    Mean scores on the Skin Infection Rating Scale at Visits 1, 2, 3, 4, and 5
    End point description
    The investigator evaluated skin infections by grading the infected lesion for exudate (a fluid that leaks out of blood vessels into surrounding tissue)/pus, crusting, erythema (redness of the skin)/ inflammation (E/I), tissue warmth, tissue edema (swelling), itching, and pain, according to the Skin Infection Rating Scale. All parameters were graded on a scale of 0 (absent) to 6 (severe). The total score is calculated by summing the individual scores from the 7 parameters; the total score ranges from 0 to 42. ITTC Population. Only participants with non-missing Skin Infection Rating Scale scores were included in this analysis. One par. was randomized to retapamulin but received linezolid. This par. is summarized in the linezolid group for all baseline and safety tables, but is summarized in the retapamulin group for all efficacy tables.
    End point type
    Secondary
    End point timeframe
    Visits 1 (Day 1), 2 (Day 3-4), 3 (Day 7-9), 4 (Day 12-14), and 5 (Day 17-19)
    End point values
    Retapamulin ointment, 1% (weight/weight) plus oral placebo Linezolid plus placebo ointment
    Number of subjects analysed
    267 [21]
    137 [22]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Pus/exudate, Visit 1, n=268, 136
    3.6 ± 0.82
    3.6 ± 0.8
        Pus/exudate, Visit 2, n=265, 135
    1.7 ± 1.37
    1.4 ± 1.25
        Pus/exudate, Visit 3, n=255, 130
    0.6 ± 1.05
    0.4 ± 0.74
        Pus/exudate, Visit 4, n=237, 125
    0.2 ± 0.59
    0.1 ± 0.34
        Pus/exudate, Visit 5, n=238, 122
    0.1 ± 0.39
    0 ± 0.29
        Crusting, Visit 1, n=268, 136
    2.2 ± 1.48
    2.1 ± 1.49
        Crusting, Visit 2, n=265, 135
    1.3 ± 1.21
    1.2 ± 1.15
        Crusting, Visit 3, n=255, 130
    0.9 ± 1.08
    0.8 ± 0.91
        Crusting, Visit 4, n=237, 125
    0.6 ± 0.95
    0.5 ± 0.83
        Crusting, Visit 5, n=238, 122
    0.3 ± 0.59
    0.3 ± 0.73
        E/I, Visit 1, n=268, 136
    3.4 ± 1.09
    3.4 ± 1.08
        E/I, Visit 2, n=265, 135
    2.2 ± 1.19
    2.2 ± 1.26
        E/I, Visit 3, n=255, 130
    1.1 ± 1.15
    1 ± 0.93
        E/I, Visit 4, n=237, 125
    0.5 ± 0.69
    0.5 ± 0.73
        E/I, Visit 5, n=238, 122
    0.2 ± 0.54
    0.2 ± 0.54
        Tissue warmth, Visit 1, n=268, 136
    2.8 ± 1.33
    2.6 ± 1.29
        Tissue warmth, Visit 2, n=265, 135
    1.4 ± 1.22
    1.3 ± 1.22
        Tissue warmth, Visit 3, n=255, 130
    0.6 ± 0.97
    0.4 ± 0.69
        Tissue warmth, Visit 4, n=237, 125
    0.1 ± 0.41
    0.1 ± 0.34
        Tissue warmth, Visit 5, n=238, 122
    0.1 ± 0.38
    0 ± 0.2
        Tissue edema, Visit 1, n=268, 136
    2.8 ± 1.24
    2.7 ± 1.3
        Tissue edema, Visit 2, n=265, 135
    1.6 ± 1.23
    1.5 ± 1.19
        Tissue edema, Visit 3, n=255, 130
    0.7 ± 1.02
    0.7 ± 0.86
        Tissue edema, Visit 4, n=237, 125
    0.3 ± 0.6
    0.2 ± 0.55
        Tissue edema, Visit 5, n=238, 122
    0.1 ± 0.35
    0.1 ± 0.36
        Itching, Visit 1, n=268, 136
    1.6 ± 1.51
    1.8 ± 1.51
        Itching, Visit 2, n=265, 135
    1 ± 1.27
    0.9 ± 1.11
        Itching, Visit 3, n=255, 130
    0.7 ± 1.24
    0.6 ± 1.08
        Itching, Visit 4, n=237, 125
    0.3 ± 0.79
    0.4 ± 0.76
        Itching, Visit 5, n=238, 122
    0.1 ± 0.42
    0.2 ± 0.66
        Pain, Visit 1, n=268, 136
    3.2 ± 1.57
    3 ± 1.65
        Pain, Visit 2, n=265, 135
    1.5 ± 1.56
    1.2 ± 1.39
        Pain, Visit 3, n=255, 130
    0.6 ± 1.14
    0.4 ± 0.96
        Pain, Visit 4, n=237, 125
    0.2 ± 0.6
    0.1 ± 0.56
        Pain, Visit 5, n=238, 122
    0.1 ± 0.39
    0.1 ± 0.45
        Total score, Visit 1, n=268, 136
    19.5 ± 5.69
    19.2 ± 5.56
        Total score, Visit 2, n=265, 135
    10.7 ± 6.78
    9.7 ± 6.32
        Total score, Visit 3, n=255, 130
    5.2 ± 5.83
    4.1 ± 4.16
        Total score, Visit 4, n=237, 125
    3.6 ± 6.13
    2.5 ± 4.13
        Total score, Visit 5, n=238, 122
    2.5 ± 6.14
    1.6 ± 3.92
    Notes
    [21] - One par. was randomized to retapamulin but received linezolid; therefore, n=268.
    [22] - One par. was randomized to retapamulin but received linezolid; therefore, n=136.
    No statistical analyses for this end point

    Secondary: Mean wound size at Visits 1, 2, 3, 4, and 5

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    End point title
    Mean wound size at Visits 1, 2, 3, 4, and 5
    End point description
    Lesion sized was measured in centimeters squared at Visits 1, 2, 3, 4, and 5. ITTC Population. Only participants with non-missing data were included in this analysis. One par. was randomized to retapamulin but received linezolid. This par. is summarized in the linezolid group for all baseline and safety tables, but is summarized in the retapamulin group for all efficacy tables.
    End point type
    Secondary
    End point timeframe
    Visits 1 (Day 1), 2 (Day 3-4), 3 (Day 7-9), 4 (Day 12-14), and 5 (Day 17-19)
    End point values
    Retapamulin ointment, 1% (weight/weight) plus oral placebo Linezolid plus placebo ointment
    Number of subjects analysed
    267 [23]
    137 [24]
    Units: centimeters squared (cm^2)
    arithmetic mean (standard deviation)
        Visit 1, n=268, 136
    7.942 ± 13.3124
    5.62 ± 9.6215
        Visit 2, n=265, 135
    4.963 ± 8.5492
    4.115 ± 9.4305
        Visit 3, n=255, 130
    3.27 ± 10.8663
    1.776 ± 6.7537
        Visit 4, n=237, 125
    1.556 ± 5.2201
    0.812 ± 3.4217
        Visit 5, n=237, 122
    0.741 ± 3.5977
    0.588 ± 3.3623
    Notes
    [23] - One par. was randomized to retapamulin but received linezolid; therefore, n=268.
    [24] - One par. was randomized to retapamulin but received linezolid; therefore, n=136
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All on-treatment serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment day 1 and until the follow-up visit day 19.
    Adverse event reporting additional description
    Serious adverse events and non-serious adverse events were collected in the Intent-to-Treat Clinical (ITTC) Population, comprised of all randomized participants who took at least one dose of study medication.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Retapamulin ointment, 1% (weight/weight) plus oral placebo
    Reporting group description
    Retapamulin ointment was administered topically twice daily (BID) for 5 days. The ointment formulation was to be applied to the infected lesion(s) at a dose of approximately 10 milligrams (mg) per centimeter squared (cm^2). Placebo was to be dosed, depending on participant age, either BID or three times a day (TID) for 10 days. Placebo oral suspension and oral tablet were formulated to appear identical to the linezolid formulations. Adolescent and adult participants (>=12 years of age) were dosed BID with 600 mg placebo tablets, pediatric participants 5 to 11 years of age were dosed with oral suspension at 0.5 milliliters (ml)/kilogram (kg) BID, and pediatric participants less than 5 years of age were dosed with oral suspension at 0.5 ml/kg TID.

    Reporting group title
    Linezolid plus placebo ointment
    Reporting group description
    Linezolid was to be dosed, depending on participant age, either BID or TID for 10 days. Adolescent and adult participants (>=12 years of age) were dosed BID with 600 mg tablets for 10 days. Pediatric participants who were 5-11 years of age were dosed with a 100 mg/5 ml oral suspension at a dose of 10 mg/kg BID for 10 days. Pediatric participants who were <5 years of age were dosed with a 100 mg/5 ml oral suspension at a dose of 10 mg/kg TID for 10 days. Placebo ointment was administered topically BID for 5 days.

    Serious adverse events
    Retapamulin ointment, 1% (weight/weight) plus oral placebo Linezolid plus placebo ointment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 267 (1.12%)
    3 / 137 (2.19%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    2 / 267 (0.75%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 137 (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
    Retapamulin ointment, 1% (weight/weight) plus oral placebo Linezolid plus placebo ointment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 267 (4.87%)
    22 / 137 (16.06%)
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    8 / 267 (3.00%)
    16 / 137 (11.68%)
         occurrences all number
    8
    16
    Nausea
         subjects affected / exposed
    6 / 267 (2.25%)
    10 / 137 (7.30%)
         occurrences all number
    6
    10

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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