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    Clinical Trial Results:
    Phase IIa, Randomised, Controlled, Open-Label Trial of Rosuvastatin for the Prevention of Aminoglycoside-Induced Kidney Toxicity in Children with Cystic Fibrosis

    Summary
    EudraCT number
    		 2014-002387-32
    Trial protocol
    		 GB  
    Global end of trial date
    17 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Nov 2018
    First version publication date
    01 Nov 2018
    Other versions
    Summary report(s)
    		 Final Analysis Report v2.0

    Trial information

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    Trial identification
    Sponsor protocol code
    UoL001019
    Additional study identifiers
    ISRCTN number
    		 ISRCTN26104255
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 REC number: 14/NW/1067, IRAS project ID: 137736
    Sponsors
    Sponsor organisation name
    University of Liverpool
    Sponsor organisation address
    2nd Floor Block D Waterhouse Building, 3 Brownlow Street, Liverpool, United Kingdom, L69 3GL
    Public contact
    Ashley Jones, Clinical Trials Research Centre, University of Liverpool, +44 151 795 8751, ctrcqa@liverpool.ac.uk
    Scientific contact
    Ashley Jones, Clinical Trials Research Centre, University of Liverpool, +44 151 795 8751, ctrcqa@liverpool.ac.uk
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Apr 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Feb 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Does rosuvastatin protect against kidney damage caused by aminoglycoside antibiotics? This will be assessed by comparing the difference in the change in the urine biomarker KIM-1 from baseline to 'highest concentration' during exposure to tobramycin between the rosuvastatin treated arm and control arm.
    Protection of trial subjects
    The patient was instructed in the correct use of the medications dispensed. Further guidance was available throughout the remainder of the trial where necessary. Study visits and study assessments were set around routine clinical care to minimise the inconvenience for patients and families.
    Background therapy
    		 This study included only children with CF treated with the aminoglycoside antibiotic tobramycin given intravenously. IV tobramycin is usually given once daily, but can also be given three times per day. Participants could receive tobramycin at either frequency (as decided by the local CF team on clinical grounds), and was specified in the study CRFs with the time and amount of each dose.
    Evidence for comparator
    		 For full details refer to the protocol. In summary, given the mechanism of action of aminoglycosides in causing nephrotoxicity, statins are a possible intervention. Statins are drugs widely used in cardiovascular disease in adults, with proven efficacy and safety. Statins are also used in children having been licensed principally for the treatment of hyperlipidaemia.
    Actual start date of recruitment
    29 Jun 2015
    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
    United Kingdom: 50
    Worldwide total number of subjects
    50
    EEA total number of subjects
    50
    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)
    0
    Children (2-11 years)
    22
    Adolescents (12-17 years)
    28
    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
    		 The first site was opened on 14-May-2015 and the first participant was randomised on 29-Jun-2015. The last participant was randomised on 23-Jan-2017.

    Pre-assignment
    Screening details
    		 258 were assessed for eligibility, of which 126 (49%) were eligible and 50 (40%) were randomised.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Control
    Arm description
    		 Non intervention arm
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Rosuvastatin
    Arm description
    		 Oral rosuvastatin 10 milligram (mg) dose, once daily, for the duration of a treatment course of IV tobramycin (usually 14 days)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rosuvastatin
    Investigational medicinal product code
    Other name
    Brand name: Crestor®
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral rosuvastatin 10 milligram (mg) dose, once daily, for the duration of a treatment course of IV tobramycin (usually 14 days)

    Number of subjects in period 1
    		Control Rosuvastatin
    Started
    27
    23
    Completed
    26
    23
    Not completed
    1
    0
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Control
    Reporting group description
    		 Non intervention arm

    Reporting group title
    Rosuvastatin
    Reporting group description
    		 Oral rosuvastatin 10 milligram (mg) dose, once daily, for the duration of a treatment course of IV tobramycin (usually 14 days)

    Reporting group values
    		 Control Rosuvastatin Total
    Number of subjects
    		 27 23 50
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 8 14 22
        Adolescents (12-17 years)
    		 19 9 28
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 13.30 ± 2.65 12.09 ± 2.74 -
    Gender categorical
    Units: Subjects
        Female
    		 19 13 32
        Male
    		 8 10 18
    Ethnic origin
    Units: Subjects
        White
    		 27 21 48
        Other White
    		 0 1 1
        Mixed: White and Black African
    		 0 1 1
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 151.93 ± 16.07 148.43 ± 15.79 -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 44.67 ± 15.58 40.63 ± 14.98 -
    Serum creatinine
    Units: μmol/L
        arithmetic mean (standard deviation)
    		 45.30 ± 10.56 43.57 ± 11.52 -
    Estimated Glomerular Filtration Rate
    Units: mL/min/1.73m^2
        arithmetic mean (standard deviation)
    		 139.90 ± 29.69 142.21 ± 27.02 -
    Aspartate transaminase
    Units: iu/L
        arithmetic mean (standard deviation)
    		 28.77 ± 11.09 33.41 ± 17.69 -
    Alanine transaminase
    Units: iu/L
        arithmetic mean (standard deviation)
    		 25.48 ± 16.53 27.77 ± 17.09 -
    HDL cholesterol
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 1.06 ± 0.32 1.09 ± 0.40 -
    LDL cholesterol
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 1.47 ± 0.54 1.25 ± 0.55 -
    Total cholesterol
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 2.80 ± 0.67 2.75 ± 0.66 -
    Triglycerides
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 1.17 ± 0.77 1.00 ± 0.53 -
    Creatine kinase
    Units: iu/L
        arithmetic mean (standard deviation)
    		 67.15 ± 33.13 83.83 ± 55.31 -
    C Reactive Protein
    Units: mg/L
        arithmetic mean (standard deviation)
    		 10.46 ± 14.29 7.48 ± 8.41 -
    FEV in 1 second
    Units: litre(s)
        arithmetic mean (standard deviation)
    		 2.10 ± 1.30 1.86 ± 0.91 -
    FEV in 1 second (% predicted)
    Units: percent
        arithmetic mean (standard deviation)
    		 74.05 ± 17.57 73.98 ± 19.59 -
    KIM-1 (normalised to urinary creatinine)
    Units: ng/mgCr
        arithmetic mean (standard deviation)
    		 1.94 ± 2.45 0.67 ± 0.45 -
    NGAL (normalised to urinary creatinine)
    Units: ng/mgCr
        arithmetic mean (standard deviation)
    		 61.08 ± 89.55 22.46 ± 22.99 -

    End points

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    End points reporting groups
    Reporting group title
    Control
    Reporting group description
    		 Non intervention arm

    Reporting group title
    Rosuvastatin
    Reporting group description
    		 Oral rosuvastatin 10 milligram (mg) dose, once daily, for the duration of a treatment course of IV tobramycin (usually 14 days)

    Subject analysis set title
    Intention-to-treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants with valid (non-missing) data were analysed according to the groups to which they were randomised.

    Primary: Primary Outcome

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    End point title
    		 Primary Outcome
    End point description
    The primary outcome measure is the difference in mean fold-change in urinary KIM-1 from baseline to peak concentration during exposure to tobramycin between the rosuvastatin treated group and control group.
    End point type
    Primary
    End point timeframe
    Duration of exposure to tobramycin treatment.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    24 [1]
    20 [2]
    Units: N/A - Average mean fold-change
        number (not applicable)
    1.85
    2.00
    Notes
    [1] - 3 baseline samples were invalid.
    [2] - 1 baseline sample was invalid; 2 withdrew after baseline and had missing baseline samples.
    Statistical analysis title
    		 Primary efficacy assessment
    Statistical analysis description
    An ANCOVA model was used, comparing log-transformed mean fold-change from baseline to peak KIM-1 normalised to urinary creatinine between the treatment groups, controlling for the baseline normalised KIM-1. The model estimates were exponentiated to be interpretable on the normal scale.
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.48
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.35

    Secondary: Change in serum concentration of creatinine during tobramycin exposure

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    End point title
    		 Change in serum concentration of creatinine during tobramycin exposure
    End point description
    A random intercept model including an interaction term between time and treatment was used to compare serum concentration of creatinine during tobramycin exposure between the treatment groups at each of the specified time points.
    End point type
    Secondary
    End point timeframe
    Duration of exposure to tobramycin treatment.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    27
    23
    Units: mmol/L
    number (not applicable)
        Baseline
    44.81
    43.87
        T+1
    54.55
    46.67
        T+8
    48.23
    46.09
        T+13/last treatment
    42.84
    42.00
        Overall
    47.61
    44.66
    Statistical analysis title
    		 Random intercept model
    Statistical analysis description
    Difference in serum concentration of creatinine during tobramycin exposure between the rosuvastatin and control group: Random intercept model results
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.61
         upper limit
    		 3.71
    Notes
    [3] - T+1: P=0.07 T+8: P=0.62 T+13/last treatment: P=0.88

    Secondary: Change in eGFR during tobramycin exposure

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    End point title
    		 Change in eGFR during tobramycin exposure
    End point description
    A random intercept model including an interaction term between time and treatment was used to compare eGFR during tobramycin exposure between the treatment groups at each of the specified time points.
    End point type
    Secondary
    End point timeframe
    Duration of exposure to tobramycin treatment.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    27
    23
    Units: mmol/L
    number (not applicable)
        Baseline
    139.90
    142.21
        T+8
    144.84
    137.46
        T+13/last treatment
    141.30
    142.09
        Overall
    142.01
    140.59
    Statistical analysis title
    		 Random intercept model
    Statistical analysis description
    Difference in eGFR during tobramycin exposure between the rosuvastatin and control group: Random intercept model results
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.85 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.64
         upper limit
    		 13.78
    Notes
    [4] - T+8: P=0.43 T+13/last treatment: P=0.95

    Secondary: Difference in other urinary and plasma biomarkers of renal injury during tobramycin exposure

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    End point title
    		 Difference in other urinary and plasma biomarkers of renal injury during tobramycin exposure
    End point description
    A random intercept model including an interaction term between time and treatment was used to compare NGAL during tobramycin exposure between the treatment groups at each of the specified time points.
    End point type
    Secondary
    End point timeframe
    Duration of exposure to tobramycin treatment.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    27
    21 [5]
    Units: ng/mgCr
    number (not applicable)
        Baseline
    58.78
    21.94
        T+1
    105.92
    79.03
        T+2
    83.18
    31.33
        T+3
    66.82
    33.60
        T+4
    100.14
    38.47
        T+5
    86.73
    33.88
        T+6
    97.70
    37.15
        T+7
    109.27
    40.46
        T+8
    92.43
    39.02
        T+9
    111.59
    42.35
        T+10
    110.65
    87.44
        T+11
    152.56
    81.02
        T+12
    100.16
    54.86
        T+13
    88.28
    50.59
        T+14
    162.05
    34.51
        Overall
    101.75
    47.04
    Notes
    [5] - 2 participants withdrew after baseline and had missing baseline samples.
    Statistical analysis title
    		 Random intercept model
    Statistical analysis description
    A random intercept model including an interaction term between time and treatment was used to compare NGAL during tobramycin exposure between the treatment groups at each of the specified time points.
    Comparison groups
    Rosuvastatin v Control
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -54.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -102.25
         upper limit
    		 -7.16
    Notes
    [6] - T+1: p=0.47 T+2: p=0.18 T+3: p=0.39 T+4: p=0.12 T+5: p=0.17 T+6: p=0.12 T+7: p=0.09 T+8: p=0.17 T+9: p=0.09 T+10: p=0.57 T+11: p=0.08 T+12: p=0.28 T+13: p=0.41 T+14: p=0.19

    Secondary: Difference in tobramycin concentrations between rosuvastatin treated group and the control group to identify any pharmacokinetic interaction between rosuvastatin and the tobramycin

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    End point title
    		 Difference in tobramycin concentrations between rosuvastatin treated group and the control group to identify any pharmacokinetic interaction between rosuvastatin and the tobramycin
    End point description
    The non-linear mixed model did not converge and thus the analysis outlined in the Statistical Analysis Plan was not possible.
    End point type
    Secondary
    End point timeframe
    A blood sample to measure tobramycin concentrations was taken on T+1, T+8 and T+13 days (or final day of tobramycin treatment if earlier than T+13), final day of tobramycin (if later than T+13) during tobramycin exposure and at any unscheduled visits.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    27
    21 [7]
    Units: N/A
        number (not applicable)
    27
    21
    Notes
    [7] - 2 participants withdrew after baseline and had missing baseline samples.
    No statistical analyses for this end point

    Secondary: Difference in Forced Expiratory Volume in 1 second (FEV1)

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    End point title
    		 Difference in Forced Expiratory Volume in 1 second (FEV1)
    End point description
    A random intercept model including an interaction term between time and treatment was used to compare FEV1 during tobramycin exposure between the treatment groups at each of the specified time points.
    End point type
    Secondary
    End point timeframe
    Duration of exposure to tobramycin treatment.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    27
    21 [8]
    Units: Litres
    number (not applicable)
        Baseline
    2.10
    1.86
        T+8
    1.88
    2.00
        T+13/last treatment
    1.84
    1.94
        Overall
    1.94
    1.93
    Notes
    [8] - 2 participants withdrew after baseline and had missing baseline samples.
    Statistical analysis title
    		 Random intercept model
    Statistical analysis description
    A random intercept model including an interaction term between time and treatment was used to compare FEV1 during tobramycin exposure between the treatment groups at each of the specified time points.
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.98 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 0.49
    Notes
    [9] - T+8: p=0.67 T+13/last treatment: p=0.77

    Secondary: Difference in C Reactive Protein (CRP)

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    End point title
    		 Difference in C Reactive Protein (CRP)
    End point description
    A random intercept model including an interaction term between time and treatment was used to compare CRPduring tobramycin exposure between the treatment groups at each of the specified time points.
    End point type
    Secondary
    End point timeframe
    Duration of exposure to tobramycin treatment.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    27
    23
    Units: mg/L
    number (not applicable)
        Baseline
    10.46
    7.48
        T+1
    15.63
    7.42
        T+8
    4.96
    4.75
        T+13/last treatment
    4.95
    3.93
        Overall
    9.00
    5.89
    Statistical analysis title
    		 Random intercept model
    Statistical analysis description
    A random intercept model including an interaction term between time and treatment was used to compare CRP during tobramycin exposure between the treatment groups at each of the specified time points.
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.68
         upper limit
    		 1.46

    Secondary: Relationship between plasma rosuvastatin concentrations achieved in children randomised to the intervention group and change in urinary KIM-1

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    End point title
    		 Relationship between plasma rosuvastatin concentrations achieved in children randomised to the intervention group and change in urinary KIM-1 [10]
    End point description
    The mean (SD) rosuvastatin levels were compared against the mean (SD) KIM-1 normalised to urinary creatinine at each time point. See Final Analysis Report upload for full results.
    End point type
    Secondary
    End point timeframe
    Duration of exposure to tobramycin treatment.
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was only applicable to participants in the rosuvastatin arm
    End point values
    		 Rosuvastatin
    Number of subjects analysed
    16 [11]
    Units: Rosuvastatin level
    arithmetic mean (standard deviation)
        T0
    0.10 ± 0.36
        T+1
    3.25 ± 4.88
        T+8
    1.56 ± 1.13
        T+13
    1.22 ± 1.37
        4 weeks following treatment cessation
    0.33 ± 1.09
    Notes
    [11] - Only subjects with a valid rosuvastatin sample were included.
    No statistical analyses for this end point

    Other pre-specified: Primary Outcome - Sensitivity Analysis 1

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    End point title
    		 Primary Outcome - Sensitivity Analysis 1
    End point description
    Sensitivity analysis 1 compared the difference in normalised KIM-1 from baseline to final day of treatment. For participants with a missing sample on day of last treatment, the result from the latest sample taken before the end of treatment was used. An ANCOVA model was used, comparing log-transformed mean fold-change from baseline to last day of treatment between the treatment groups, controlling for baseline normalised KIM-1.The model estimates were exponentiated to be interpretable on the normal scale.
    End point type
    Other pre-specified
    End point timeframe
    Duration of exposure to tobramycin treatment.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    24 [12]
    20 [13]
    Units: N/A - Average mean fold-change
        number (not applicable)
    1.36
    1.48
    Notes
    [12] - 3 baseline samples were invalid.
    [13] - 1 baseline sample was invalid; 2 withdrew after baseline and had missing baseline samples.
    Statistical analysis title
    		 Primary Outcome - Sensitivity Analysis 1
    Statistical analysis description
    An ANCOVA model was used, comparing log-transformed mean fold-change from baseline to last day of treatment between the treatment groups, controlling for baseline normalised KIM-1. The model estimates were exponentiated to be interpretable on the normal scale.
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.48
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.39

    Other pre-specified: Primary Outcome – Sensitivity Analysis 2

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    End point title
    		 Primary Outcome – Sensitivity Analysis 2
    End point description
    Sensitivity analysis 2 was a repeat of the analysis of the primary outcome, excluding those who returned less than 50% of urine samples. Two participants, each with 57% of samples missing, one in the control group and one in the rosuvastatin group, were excluded from this analysis.
    End point type
    Other pre-specified
    End point timeframe
    Duration of exposure to tobramycin treatment.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    23 [14]
    19 [15]
    Units: N/A - Average mean fold-change
        number (not applicable)
    1.89
    2.03
    Notes
    [14] - 3 baseline samples were invalid; 1 had >50% of samples missing.
    [15] - 1 baseline sample was invalid; 2 withdrew at baseline; one had >50% of samples missing.
    Statistical analysis title
    		 Primary Outcome – Sensitivity Analysis 2
    Statistical analysis description
    Sensitivity analysis 2 was a repeat of the analysis of the primary outcome, excluding those who returned less than 50% of urine samples. Two participants, each with 57% of samples missing, one in the control group and one in the rosuvastatin group, were excluded from this analysis.
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.52
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.34

    Other pre-specified: Primary Outcome - Sensitivity Analysis 3

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    End point title
    		 Primary Outcome - Sensitivity Analysis 3
    End point description
    Sensitivity analysis 3 was a repeat of the analysis of the primary outcome, including participants who had a missing baseline sample by imputing their baseline result as the mean normalised KIM-1 value over all observed baseline KIM-1 values.
    End point type
    Other pre-specified
    End point timeframe
    Duration of exposure to tobramycin treatment.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    27
    21 [16]
    Units: N/A - Average mean fold-change
        number (not applicable)
    2.10
    1.35
    Notes
    [16] - 2 participants withdrew after baseline and had missing baseline samples.
    Statistical analysis title
    		 Primary Outcome – Sensitivity Analysis 3
    Statistical analysis description
    An ANCOVA model was used, comparing log-transformed mean fold-change from baseline to peak KIM-1 normalised to urinary creatinine between the treatment groups, controlling for the baseline normalised KIM-1. The model estimates were exponentiated to be interpretable on the normal scale.
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 1.1

    Other pre-specified: Primary Outcome – Sensitivity Analysis 4

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    End point title
    		 Primary Outcome – Sensitivity Analysis 4
    End point description
    Sensitivity analysis 4 was a repeat of the analysis of the primary outcome, accounting for a random effect for centre using a random intercept model.
    End point type
    Other pre-specified
    End point timeframe
    Duration of exposure to tobramycin treatment.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    24 [17]
    20 [18]
    Units: N/A - Average mean fold-change
        number (not applicable)
    1.82
    1.99
    Notes
    [17] - 3 baseline samples were invalid.
    [18] - 1 baseline sample was invalid; 2 withdrew at baseline and had missing samples.
    Statistical analysis title
    		 Primary Outcome - Sensitivity Analysis 4
    Statistical analysis description
    An ANCOVA model was used, comparing log-transformed mean fold-change from baseline to peak concentration between the treatment groups, controlling for baseline normalised KIM-1, including centre as a random effect. The model estimates were exponentiated to be interpretable on the normal scale.
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.34

    Other pre-specified: Primary Outcome – Sensitivity Analysis 5

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    End point title
    		 Primary Outcome – Sensitivity Analysis 5
    End point description
    Sensitivity analysis 5 was a repeat of the analysis of the primary outcome, excluding any normalised KIM-1 results which were greater than the upper quartile plus 1.5 times the interquartile range (IQR) or lower than the lower quartile minus 1.5 times the IQR.
    End point type
    Other pre-specified
    End point timeframe
    Duration of exposure to tobramycin treatment.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    18 [19]
    20 [20]
    Units: N/A - Average mean fold-change
        number (not applicable)
    1.89
    1.92
    Notes
    [19] - Analysis excluded statistical outliers
    [20] - Analysis excluded statistical outliers
    Statistical analysis title
    		 Primary Outcome – Sensitivity Analysis 5
    Statistical analysis description
    An ANCOVA model was used, comparing log-transformed mean fold-change from baseline to last day of treatment between the treatment groups, controlling for baseline normalised KIM-1. The model estimates were exponentiated to be interpretable on the normal scale.
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.85
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.24

    Other pre-specified: Primary Outcome – Additional Analysis: Area under the curve (AUC)

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    End point title
    		 Primary Outcome – Additional Analysis: Area under the curve (AUC)
    End point description
    The area under the curve (AUC) of normalised KIM-1 was compared between the two treatment groups using a T-test.
    End point type
    Other pre-specified
    End point timeframe
    Duration of exposure to tobramycin treatment.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    27
    21 [21]
    Units: ng/mgCr
        arithmetic mean (standard deviation)
    23.05 ± 33.02
    10.65 ± 6.11
    Notes
    [21] - 2 participants withdrew after baseline and had missing samples.
    Statistical analysis title
    		 Primary Outcome – Additional Analysis: AUC
    Statistical analysis description
    The area under the curve (AUC) of normalised KIM-1 was compared between the two treatment groups using a T-test.
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.07
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    12.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.89
         upper limit
    		 25.7

    Other pre-specified: Change in serum concentration of creatinine during tobramycin exposure - Sensitivity Analysis

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    End point title
    		 Change in serum concentration of creatinine during tobramycin exposure - Sensitivity Analysis
    End point description
    A random intercept model including an interaction term between time and treatment was used to compare serum concentration of creatinine during tobramycin exposure between the treatment groups at each of the specified time points.
    End point type
    Other pre-specified
    End point timeframe
    Duration of exposure to tobramycin treatment.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    27
    23
    Units: mmol/L
    number (not applicable)
        Baseline
    44.81
    43.87
        T+1
    50.15
    44.98
        T+8
    45.21
    46.04
        T+13/last treatment
    45.00
    41.83
        Overall
    46.29
    44.18
    Statistical analysis title
    		 Random intercept model
    Statistical analysis description
    A random intercept model including an interaction term between time and treatment was used to compare serum concentration of creatinine during tobramycin exposure between the treatment groups at each of the specified time points. A sensitivity analysis was undertaken excluding any serum creatinine results which were greater than the upper quartile plus 1.5 times the interquartile range (IQR) or lower than the lower quartile minus 1.5 times the IQR.
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.48 [22]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.12
         upper limit
    		 3.9
    Notes
    [22] - T+1: P=0.13 T+8: P=0.80 T+13/last treatment: P=0.40

    Other pre-specified: Change in eGFR during tobramycin exposure - Sensitivity Analysis

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    End point title
    		 Change in eGFR during tobramycin exposure - Sensitivity Analysis
    End point description
    A random intercept model including an interaction term between time and treatment was used to compare eGFR during tobramycin exposure between the treatment groups at each of the specified time points.
    End point type
    Other pre-specified
    End point timeframe
    Duration of exposure to tobramycin treatment.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    27
    22 [23]
    Units: mmol/L
    number (not applicable)
        Baseline
    139.90
    139.03
        T+8
    144.81
    135.79
        T+13/last treatment
    141.38
    140.27
        Overall
    142.03
    138.37
    Notes
    [23] - Statistical outliers removed
    Statistical analysis title
    		 Random intercept model
    Statistical analysis description
    A random intercept model including an interaction term between time and treatment was used to compare eGFR during tobramycin exposure between the treatment groups at each of the specified time points. A sensitivity analysis was undertaken excluding any serum creatinine results which were greater than the upper quartile plus 1.5 times the interquartile range (IQR) or lower than the lower quartile minus 1.5 times the IQR.
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.62
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.36
         upper limit
    		 11.03

    Other pre-specified: Difference in other urinary and plasma biomarkers of renal injury during tobramycin exposure - Sensitivity Analysis

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    End point title
    		 Difference in other urinary and plasma biomarkers of renal injury during tobramycin exposure - Sensitivity Analysis
    End point description
    A random intercept model including an interaction term between time and treatment was used to compare NGAL during tobramycin exposure between the treatment groups at each of the specified time points. A sensitivity analysis was undertaken excluding any NGAL results which were greater than the upper quartile plus 1.5 times the interquartile range (IQR) or lower than the lower quartile minus 1.5 times the IQR.
    End point type
    Other pre-specified
    End point timeframe
    Duration of exposure to tobramycin treatment.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    25 [24]
    21 [25]
    Units: ng/mgCr
    number (not applicable)
        Baseline
    41.26
    21.94
        T+1
    42.01
    34.12
        T+2
    38.42
    31.33
        T+3
    43.13
    34.20
        T+4
    41.34
    39.89
        T+5
    55.29
    29.98
        T+6
    41.24
    32.93
        T+7
    38.65
    36.71
        T+8
    49.65
    27.79
        T+9
    50.08
    43.22
        T+10
    48.64
    31.64
        T+11
    45.85
    34.64
        T+12
    40.24
    26.02
        T+13
    50.59
    38.53
        T+14
    41.29
    27.14
        Overall
    44.51
    32.67
    Notes
    [24] - Statistical outliers were excluded
    [25] - Statistical outliers were excluded
    Statistical analysis title
    		 Random intercept model
    Statistical analysis description
    A random intercept model including an interaction term between time and treatment was used to compare NGAL during tobramycin exposure between the treatment groups at each of the specified time points. A sensitivity analysis was undertaken excluding any NGAL results which were greater than the upper quartile plus 1.5 times the interquartile range (IQR) or lower than the lower quartile minus 1.5 times the IQR.
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12 [26]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -11.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.96
         upper limit
    		 3.28
    Notes
    [26] - T+1: p=0.46 T+2: p=0.50 T+3: p=0.40 T+4: p=0.90 T+5: p=0.02 T+6: p=0.45 T+7: p=0.86 T+8: p=0.05 T+9: p=0.54 T+10: p=0.15 T+11: p=0.32 T+12: p=0.23 T+13: p=0.33 T+14: p=0.61

    Other pre-specified: Change from baseline to peak NGAL

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    End point title
    		 Change from baseline to peak NGAL
    End point description
    Comparison of the difference in mean fold-change in urinary KIM-1 from baseline to peak concentration during exposure to tobramycin between the rosuvastatin treated group and control group.
    End point type
    Other pre-specified
    End point timeframe
    Duration of tobramycin exposure.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    24 [27]
    20 [28]
    Units: N/A - Average mean fold-change
        number (not applicable)
    8.90
    4.99
    Notes
    [27] - 3 baseline samples were invalid.
    [28] - 1 baseline sample was invalid; 2 withdrew after baseline and had missing samples.
    Statistical analysis title
    		 Change from baseline to peak NGAL
    Statistical analysis description
    An ANCOVA model was used, comparing log-transformed mean fold-change from baseline to peak NGAL normalised to urinary creatinine between the treatment groups, controlling for the baseline normalised NGAL. The model estimates were exponentiated to be interpretable on the normal scale.
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.11
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 1.15

    Other pre-specified: Change from baseline to peak NGAL - Sensitivity Analysis

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    End point title
    		 Change from baseline to peak NGAL - Sensitivity Analysis
    End point description
    Comparison of the difference in mean fold-change in urinary KIM-1 from baseline to peak concentration during exposure to tobramycin between the rosuvastatin treated group and control group removing statistical outliers.
    End point type
    Other pre-specified
    End point timeframe
    Duration of tobramycin exposure.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    24 [29]
    20 [30]
    Units: N/A - Mean fold-change
        number (not applicable)
    3.32
    3.26
    Notes
    [29] - 3 baseline samples were invalid.
    [30] - 1 baseline sample was invalid; 2 withdrew after baseline and had missing samples.
    Statistical analysis title
    		 Change from baseline to peak NGAL
    Statistical analysis description
    An ANCOVA model was used, comparing log-transformed mean fold-change from baseline to peak NGAL between the treatment groups, controlling for the baseline normalised NGAL. The model estimates were exponentiated to be interpretable on the normal scale. This sensitivity analysis excluded any normalised NGAL results which were greater than the upper quartile plus 1.5 times the interquartile range (IQR) or lower than the lower quartile minus 1.5 times the IQR.
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.95
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 1.72

    Other pre-specified: NGAL: Area Under the Curve

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    End point title
    		 NGAL: Area Under the Curve
    End point description
    The area under the curve (AUC) of normalised NGAL was compared between the two treatment groups using a T-test.
    End point type
    Other pre-specified
    End point timeframe
    Duration of tobramycin exposure.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    27
    21 [31]
    Units: (ng/mgCr)^2
        arithmetic mean (standard deviation)
    1139.4 ± 1106.1
    581.6 ± 630.8
    Notes
    [31] - 2 participants withdrew at baseline
    Statistical analysis title
    		 NGAL: AUC
    Statistical analysis description
    The area under the curve (AUC) of normalised NGAL was compared between the two treatment groups using a T-test.
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    557.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 46.5
         upper limit
    		 1069.2

    Other pre-specified: Difference in Forced Expiratory Volume in 1 second (FEV1) - Sensitivity Analysis

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    End point title
    		 Difference in Forced Expiratory Volume in 1 second (FEV1) - Sensitivity Analysis
    End point description
    A random intercept model including an interaction term between time and treatment was used to compare FEV1 during tobramycin exposure between the treatment groups at each of the specified time points excluding statistical outliers.
    End point type
    Other pre-specified
    End point timeframe
    Duration of exposure to tobramycin treatment.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    25 [32]
    20 [33]
    Units: Litres
    number (not applicable)
        Baseline
    1.80
    1.75
        T+8
    1.85
    1.87
        T+13/last treatment
    1.87
    1.89
        Overall
    1.84
    1.84
    Notes
    [32] - Statistical outliers were excluded
    [33] - Statistical outliers were excluded
    Statistical analysis title
    		 Random intercept model
    Statistical analysis description
    A random intercept model including an interaction term between time and treatment was used to compare FEV1 during tobramycin exposure between the treatment groups at each of the specified time points. A sensitivity analysis was undertaken excluding any FEV1 results which were greater than the upper quartile plus 1.5 times the interquartile range (IQR) or lower than the lower quartile minus 1.5 times the IQR.
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.99 [34]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.002
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.43
         upper limit
    		 0.42
    Notes
    [34] - T+8: p=0.93 T+13/last treatment: p=0.93

    Other pre-specified: Difference in C Reactive Protein (CRP) - Sensitivity Analysis

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    End point title
    		 Difference in C Reactive Protein (CRP) - Sensitivity Analysis
    End point description
    A random intercept model including an interaction term between time and treatment was used to compare CRP during tobramycin exposure between the treatment groups at each of the specified time points excluding statistical outliers.
    End point type
    Other pre-specified
    End point timeframe
    Duration of exposure to tobramycin treatment.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    22 [35]
    19 [36]
    Units: mg/L
    number (not applicable)
        Baseline
    4.98
    4.21
        T+1
    5.59
    4.34
        T+8
    4.48
    3.97
        T+13/last treatment
    3.65
    3.94
        Overall
    4.67
    4.12
    Notes
    [35] - Statistical outliers were excluded.
    [36] - Statistical outliers were excluded.
    Statistical analysis title
    		 Random intercept
    Statistical analysis description
    A random intercept model including an interaction term between time and treatment was used to compare CRP during tobramycin exposure between the treatment groups at each of the specified time points. A sensitivity analysis was undertaken excluding any CRP results which were greater than the upper quartile plus 1.5 times the interquartile range (IQR) or lower than the lower quartile minus 1.5 times the IQR.
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25 [37]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.52
         upper limit
    		 0.41
    Notes
    [37] - T+1: p=0.07 T+8: p=0.41 T+13/last treatment: p=0.69

    Post-hoc: Primary outcome adjusted for age

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    End point title
    		 Primary outcome adjusted for age
    End point description
    The primary outcome analysis was repeated, controlling for age.
    End point type
    Post-hoc
    End point timeframe
    Duration of exposure to tobramycin treatment.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    24 [38]
    20 [39]
    Units: N/A - Average mean fold-change
        number (not applicable)
    1.88
    1.95
    Notes
    [38] - 3 baseline samples were invalid.
    [39] - 1 baseline sample was invalid; 2 withdrew after baseline and had missing samples.
    Statistical analysis title
    		 Primary Outcome adjusted for age: ANCOVA results
    Statistical analysis description
    An ANCOVA model was used, comparing log-transformed mean fold-change from baseline to peak KIM-1 normalised to urinary creatinine between the treatment groups, controlling for the baseline normalised KIM-1 and age. The model estimates were exponentiated to be interpretable on the normal scale.
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    44
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.75
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.29

    Post-hoc: Primary Outcome: Area under the curve - Sensitivity Analysis

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    End point title
    		 Primary Outcome: Area under the curve - Sensitivity Analysis
    End point description
    End point type
    Post-hoc
    End point timeframe
    Duration of exposure to tobramycin treatment.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    23 [40]
    21 [41]
    Units: (ng/mgCr)^2
        arithmetic mean (standard deviation)
    10.79 ± 6.66
    10.07 ± 5.31
    Notes
    [40] - Statistical outliers were excluded.
    [41] - Statistical outliers were excluded.
    Statistical analysis title
    		 KIM-1 AUC: Sensitivity analysis – T-test results
    Statistical analysis description
    The area under the curve (AUC) of normalised KIM-1 was repeated, excluding any results which were greater than the upper quartile plus 1.5 times the interquartile range (IQR) or lower than the lower quartile minus 1.5 times the IQR.
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    44
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.69
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.92
         upper limit
    		 4.38

    Post-hoc: NGAL: Area under the curve - Sensitivity Analysis

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    End point title
    		 NGAL: Area under the curve - Sensitivity Analysis
    End point description
    The area under the curve (AUC) of normalised NGAL was repeated, excluding any results which were greater than the upper quartile plus 1.5 times the interquartile range (IQR) or lower than the lower quartile minus 1.5 times the IQR.
    End point type
    Post-hoc
    End point timeframe
    Duration of exposure to tobramycin treatment.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    27
    21 [42]
    Units: (ng/mgCr)^2
        arithmetic mean (standard deviation)
    511.0 ± 341.6
    416.6 ± 350.4
    Notes
    [42] - 2 participants withdrew at baseline
    Statistical analysis title
    		 NGAL AUC: Sensitivity analysis – T-test results
    Statistical analysis description
    The area under the curve (AUC) of normalised KIM-1 was repeated, excluding any results which were greater than the upper quartile plus 1.5 times the interquartile range (IQR) or lower than the lower quartile minus 1.5 times the IQR.
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    48
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.35
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    94.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -108.9
         upper limit
    		 297.9

    Post-hoc: Difference in tobramycin concentrations between rosuvastatin treated group and the control group to identify any pharmacokinetic interaction between rosuvastatin and the tobramycin groups

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    End point title
    		 Difference in tobramycin concentrations between rosuvastatin treated group and the control group to identify any pharmacokinetic interaction between rosuvastatin and the tobramycin groups
    End point description
    A linear mixed model was fitted to the tobramycin concentration data using a random intercept and adjusting for time since last dose of tobramycin; an interaction between visit and treatment group was included.
    End point type
    Post-hoc
    End point timeframe
    Duration of exposure to tobramycin treatment.
    End point values
    		 Control Rosuvastatin
    Number of subjects analysed
    25 [43]
    20 [44]
    Units: mg/L
    number (not applicable)
        T+1
    0.34
    0.40
        T+8
    0.45
    0.58
        T+13/last treatment
    3.63
    2.72
        Overall
    1.24
    1.47
    Notes
    [43] - Only subjects with a valid tobramycin concentration were included.
    [44] - Only subjects with a valid tobramycin concentration were included.
    Statistical analysis title
    		 Random intercept model
    Statistical analysis description
    A linear mixed model was fitted to the tobramycin concentration data using a random intercept and adjusting for time since last dose of tobramycin; an interaction between visit and treatment group was included.
    Comparison groups
    Control v Rosuvastatin
    Number of subjects included in analysis
    45
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.7 [45]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.49
         upper limit
    		 1.02
    Notes
    [45] - T+1: p=0.95 T+8: p=0.90 T+13/last treatment: p=0.41

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Safety events were recorded from the point that the participant provides informed consent and throughout the trial treatment period up until the date of the follow-up assessment (3-5 weeks after the patient has taken the final dose of IMP).
    Adverse event reporting additional description
    Only adverse reactions (ARs) and serious adverse events (SAEs) were collected.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Control
    Reporting group description
    		 Non intervention arm

    Reporting group title
    Rosuvastatin
    Reporting group description
    		 Oral rosuvastatin 10 milligram (mg) dose, once daily, for the duration of a treatment course of IV tobramycin (usually 14 days)

    Serious adverse events
    		 Control Rosuvastatin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 21 (4.76%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Blood test
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 21 (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: 0%
    Non-serious adverse events
    		 Control Rosuvastatin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 27 (0.00%)
    5 / 21 (23.81%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Blood cholesterol decreased
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Blood triglycerides decreased
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Blood triglycerides increased
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Paraesthesia oral
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Nov 2014
    Protocol was updated from version 1.0 to 2.0. Changes were as follows: • Updated inclusion/exclusion criteria. • Changes in randomisation process/contact details and addition of backup randomisation. • The addition of ‘Assessment of changes in sputum microbiome’. • Change in the minimum volume of blood collection. • Addition of Sputum sampling. • Simplification on severity/grading of AEs (Section 10.6). • Typographical errors and clarifications were also made throughout.
    29 May 2015
    Protocol was amended from v2.0 to v3.0 on 03/02/2015. Change was a non-substantial amendment. Protocol was amended from v3.0 to v4.0 on 29/05/2015. Changes were as follows: • The participant approach process has been updated in the Protocol. Sites may now approach participants as soon as they present in the clinic, even if they have had the study information for <24hrs. • Addition of Simepravir to exclusion criteria 5. • Changes to recruitment process for main and substudy.
    01 Jul 2015
    Protocol was updated from version 4.0 to 5.0. Changes were as follows: • Update to allow flexibility in terms of when participants can be randomised in the trial so that the research pathway can follow the participant’s clinical pathway. • Exclusion criteria 9 (proposing to use safety test result from the past 12 weeks). • Adding Simepravir to ‘Medications Not Permitted’.
    28 Apr 2016
    Protocol was updated from version 6.0 to 7.0. Changes were as follows: • Removal of Itraconozole from the medications in exclusion criteria • Removal of Indian ancestry from the exclusion criteria • Addition of ‘Participants with current elevation in creatine kinase exceeding 2x the upper limit of normal at baseline, or in the past 12 weeks’ to exclusion criteria.
    07 Jan 2017
    Protocol was updated from version 5.0 to 6.0. Changes were as follows: • Insertion of Schwartz formula.
    06 Feb 2017
    Protocol was updated from version 7.0 to 8.0.

    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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