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    Clinical Trial Results:
    A phase III, randomised, comparative, open-label study of intravenous iron isomaltoside 1000 (Monofer®) administered as maintenance therapy by single or repeated bolus injections in comparison with intravenous iron sucrose in subjects with stage 5 chronic kidney disease on dialysis therapy (CKD-5D)

    Summary
    EudraCT number
    2010-023471-26
    Trial protocol
    GB   SE   DK   PL  
    Global end of trial date
    28 Oct 2013

    Results information
    Results version number
    v2(current)
    This version publication date
    07 Apr 2016
    First version publication date
    15 Jul 2015
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Incorrect data was discovered during the review process.

    Trial information

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    Trial identification
    Sponsor protocol code
    P-Monofer-CKD-03
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01222884
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pharmacosmos A/S
    Sponsor organisation address
    Roervangsvej 30, Holbaek, Denmark, Dk-4300
    Public contact
    Clinical trial disclosure desk, Pharmacosmos A/S, 045 59485935, trial@pharmacosmos.com
    Scientific contact
    Clinical trial disclosure desk, Pharmacosmos A/S, 045 59485935, trial@pharmacosmos.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Oct 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Oct 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary efficacy objective of the study was to demonstrate that IV iron isomaltoside 1000 is non-inferior to IV iron sucrose determined as ability to maintain haemoglobin (Hb) between 9.5 and 12.5 g/dL in subjects with CKD-5D who were on maintenance iron therapy.
    Protection of trial subjects
    The protocol and amendments were approved by local ethics committees/Institutional Review Boards and competent authorities. The trial was conducted in accordance with good clinical practice and the Declaration of Helsinki. Informed consent was obtained in writing prior to any trial-related activities.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    14 Jun 2011
    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
    Poland: 13
    Country: Number of subjects enrolled
    Sweden: 10
    Country: Number of subjects enrolled
    United Kingdom: 187
    Country: Number of subjects enrolled
    Denmark: 11
    Country: Number of subjects enrolled
    India: 72
    Country: Number of subjects enrolled
    Romania: 26
    Country: Number of subjects enrolled
    Russian Federation: 9
    Country: Number of subjects enrolled
    Switzerland: 19
    Country: Number of subjects enrolled
    United States: 4
    Worldwide total number of subjects
    351
    EEA total number of subjects
    247
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    195
    From 65 to 84 years
    146
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were screened in the period 14 June 2011 to 10 September 2013. The trial took place at 48 sites (hospitals or private dialysis clinics); 16 centres in India, 14 centres in the UK, 4 in Russia, 4 in Poland, 3 in Sweden, 3 in Switzerland, 2 in Romania, 1 in Denmark, and 1 in the USA.

    Pre-assignment
    Screening details
    Subjects ≥ 18 years of age with a diagnosis of CKD and on haemodialysis therapy for at least 90 days, Hb between 9.5 and 12.5 g/dL (inclusive both values) both at screening visit 1a and screening visit 1b, serum-ferritin < 800 ng/mL, TSAT < 35%, and receiving ESA treatment with stable dose for the previous 4 weeks prior to screening were enrolled.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group A, iron isomaltoside 1000
    Arm description
    All subjects received a cumulative dose of 500 mg iron isomaltoside 1000. Subjects in subgroup A1 were administered iron isomaltoside 1000 as a single undiluted IV bolus injection of 500 mg over approximately 2 min at baseline, subjects in subgroup A2 were administered undiluted iron isomaltoside 1000 in split doses of 100 mg at baseline and 200 mg each at week 2 and 4 as IV bolus injections over approximately 2 min.
    Arm type
    Experimental

    Investigational medicinal product name
    Iron isomaltoside 1000
    Investigational medicinal product code
    ATC code: B03AC
    Other name
    Monofer, Monover, Monofar, Monoferro
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All subjects received a cumulative dose of 500 mg iron isomaltoside 1000. Subjects in subgroup A1 were administered iron isomaltoside 1000 as a single undiluted IV bolus injection of 500 mg over approximately 2 min at baseline, subjects in subgroup A2 were administered undiluted iron isomaltoside 1000 in split doses of 100 mg at baseline and 200 mg each at week 2 and 4 as IV bolus injections over approximately 2 min. Iron isomaltoside 1000 is available as a dark brown, non-transparent aqueous solution for injection/infusion containing 100 mg iron/mL with pH between 5.0 and 7.0.

    Arm title
    Group B, iron sucrose
    Arm description
    All subjects received a cumulative dose of 500 mg iron sucrose. Subjects in group B were administered undiluted iron sucrose in split doses of 100 mg at baseline and 200 mg each at week 2 and 4.
    Arm type
    Active comparator

    Investigational medicinal product name
    Iron sucrose
    Investigational medicinal product code
    ATC code: B03AB02,B03AC02
    Other name
    Venofer
    Pharmaceutical forms
    Concentrate for solution for infusion, Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects in group B were administered undiluted iron sucrose in split doses of 100 mg at baseline and 200 mg each at week 2 and 4. The doses of iron sucrose were administered as per local summary product of characteristics or package insert and/or local hospital guidelines, as applicable. All dosages were administered during dialysis, at least 30 min after the start and at least 1 h before the end of dialysis.

    Number of subjects in period 1
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Started
    234
    117
    Completed
    210
    113
    Not completed
    24
    4
         Physician decision
    1
    -
         Subject decided to go on holiday for 8 we
    1
    -
         Transplant
    -
    1
         Adverse event, serious fatal
    3
    -
         Did not fulfil the inclusion/exclusion criteria
    3
    -
         Patient had been given IV iron by dialysis staff
    1
    -
         Adverse event, non-fatal
    8
    1
         Consent withdrawn by subject
    6
    2
         Kidney transplantation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A, iron isomaltoside 1000
    Reporting group description
    All subjects received a cumulative dose of 500 mg iron isomaltoside 1000. Subjects in subgroup A1 were administered iron isomaltoside 1000 as a single undiluted IV bolus injection of 500 mg over approximately 2 min at baseline, subjects in subgroup A2 were administered undiluted iron isomaltoside 1000 in split doses of 100 mg at baseline and 200 mg each at week 2 and 4 as IV bolus injections over approximately 2 min.

    Reporting group title
    Group B, iron sucrose
    Reporting group description
    All subjects received a cumulative dose of 500 mg iron sucrose. Subjects in group B were administered undiluted iron sucrose in split doses of 100 mg at baseline and 200 mg each at week 2 and 4.

    Reporting group values
    Group A, iron isomaltoside 1000 Group B, iron sucrose Total
    Number of subjects
    234 117 351
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Age is calculated by subtracting the screening visit date with the birth date.
    Units: years
        arithmetic mean (standard deviation)
    60.2 ± 16.2 59.5 ± 15.4 -
    Gender categorical
    Units: Subjects
        Female
    76 43 119
        Male
    158 74 232
    Subject analysis sets

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety population (N=344) included all subjects who were randomized and received at least one dose of the trial drug.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The full analysis set (FAS) population (N=341) included all subjects who were randomized into the trial, received at least one dose of the trial drug, and had at least one post-baseline Hb assessment.

    Subject analysis set title
    Per protocol (PP) analysis set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The per protocol (PP) population (N=306) included all subjects in the FAS who did not have any major protocol deviation of clinical or statistical relevance.

    Subject analysis sets values
    Safety analysis set Full analysis set (FAS) Per protocol (PP) analysis set
    Number of subjects
    344
    341
    306
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Age is calculated by subtracting the screening visit date with the birth date.
    Units: years
        arithmetic mean (standard deviation)
    60 ± 16
    60.1 ± 15.9
    59.6 ± 15.9
    Gender categorical
    Units: Subjects
        Female
    117
    117
    100
        Male
    227
    224
    206

    End points

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    End points reporting groups
    Reporting group title
    Group A, iron isomaltoside 1000
    Reporting group description
    All subjects received a cumulative dose of 500 mg iron isomaltoside 1000. Subjects in subgroup A1 were administered iron isomaltoside 1000 as a single undiluted IV bolus injection of 500 mg over approximately 2 min at baseline, subjects in subgroup A2 were administered undiluted iron isomaltoside 1000 in split doses of 100 mg at baseline and 200 mg each at week 2 and 4 as IV bolus injections over approximately 2 min.

    Reporting group title
    Group B, iron sucrose
    Reporting group description
    All subjects received a cumulative dose of 500 mg iron sucrose. Subjects in group B were administered undiluted iron sucrose in split doses of 100 mg at baseline and 200 mg each at week 2 and 4.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety population (N=344) included all subjects who were randomized and received at least one dose of the trial drug.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The full analysis set (FAS) population (N=341) included all subjects who were randomized into the trial, received at least one dose of the trial drug, and had at least one post-baseline Hb assessment.

    Subject analysis set title
    Per protocol (PP) analysis set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The per protocol (PP) population (N=306) included all subjects in the FAS who did not have any major protocol deviation of clinical or statistical relevance.

    Primary: Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at week 6, FAS

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    End point title
    Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at week 6, FAS
    End point description
    Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at week 6. The analysis was performed on the FAS.
    End point type
    Primary
    End point timeframe
    Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at week 6.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    226
    115
    Units: Proportion of subjects
        Responder
    187
    95
        Non-responder
    39
    20
    Statistical analysis title
    Non-inferiority tested by risk difference
    Statistical analysis description
    A generalised linear model using the identity link function was used to compare the proportion of subjects with Hb concentration between 9.5 and 12.5 g/dL (both values included) at week 6 using the last observation carried forward approach. The number of subjects may differ from the analysis population if data is missing.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    P-value
    = 0.0106 [2]
    Method
    Risk differences
    Parameter type
    Risk difference (RD)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.4
         upper limit
    9.4
    Notes
    [1] - Treatment and stratum (serum-ferritin (<100 versus ≥100 ng/mL) were used as factors and baseline value as a covariate. With a 2:1 randomisation, a two-sided significance level of 0.05, and a non-inferiority margin of 10 % points, there was approximately 80 % power to demonstrate non-inferiority with 214 subjects in group A and 107 subjects in group B.
    [2] - As the trial was designed to demonstrate non-inferiority, the analyses of FAS and PP population would lead to similar conclusions and therefore the analyses for both analysis sets needed to be powered properly.

    Primary: Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at week 6, PP

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    End point title
    Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at week 6, PP
    End point description
    Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at week 6. The analysis was performed on the PP analysis set.
    End point type
    Primary
    End point timeframe
    Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at week 6.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    199
    107
    Units: Proportion of subjects
        Responder
    167
    88
        Non-responder
    32
    19
    Statistical analysis title
    Non-inferiority tested by risk difference
    Statistical analysis description
    A generalised linear model using the identity link function was used to compare the proportion of subjects with Hb concentration between 9.5 and 12.5 g/dL (both values included) at week 6 using the last observation carried forward approach. The number of subjects may differ from the analysis population if data is missing.
    Comparison groups
    Group B, iron sucrose v Group A, iron isomaltoside 1000
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [3]
    P-value
    = 0.0057 [4]
    Method
    Risk difference
    Parameter type
    Risk difference (RD)
    Point estimate
    2.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.4
         upper limit
    10.9
    Notes
    [3] - Treatment and stratum (serum-ferritin (<100 versus ≥100 ng/mL) were used as factors and baseline value as a covariate. With a 2:1 randomisation, a two-sided significance level of 0.05, and a non-inferiority margin of 10 % points, there was approximately 80 % power to demonstrate non-inferiority with 214 subjects in group A and 107 subjects in group B.
    [4] - As the trial was designed to demonstrate non-inferiority, the analyses of FAS and PP population would lead to similar conclusions and therefore the analyses for both analysis sets needed to be powered properly.

    Secondary: Change in Hb concentration from baseline to week 2

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    End point title
    Change in Hb concentration from baseline to week 2
    End point description
    Change in Hb concentration from baseline to week 2. Analysis performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in Hb concentration from baseline to week 2.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    219
    115
    Units: g/dL
        arithmetic mean (standard deviation)
    0.04 ± 0.71
    -0.05 ± 0.69
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1239
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    0.1138
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.031
         upper limit
    0.259
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0737

    Secondary: Change in Hb concentration from baseline to week 4

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    End point title
    Change in Hb concentration from baseline to week 4
    End point description
    Change in Hb concentration from baseline to week 4. Analysis performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in Hb concentration from baseline to week 4.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    213
    114
    Units: g/dL
        arithmetic mean (standard deviation)
    0.01 ± 0.91
    -0.03 ± 0.68
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5233
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    0.0546
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.113
         upper limit
    0.223
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0854

    Secondary: Change in Hb concentration from baseline to week 6.

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    End point title
    Change in Hb concentration from baseline to week 6.
    End point description
    Change in Hb concentration from baseline to week 6. Analysis performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in Hb concentration from baseline to week 6.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    216
    113
    Units: g/dL
        arithmetic mean (standard deviation)
    -0.07 ± 1.11
    -0.06 ± 0.99
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8557
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.0069
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.204
         upper limit
    0.246
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1143

    Secondary: Change in s-iron concentration from baseline to week 1

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    End point title
    Change in s-iron concentration from baseline to week 1
    End point description
    Change in s-iron concentration from baseline to week 1. Analysis performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in s-iron concentration from baseline to week 1.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    221
    112
    Units: micromol/L
        arithmetic mean (standard deviation)
    1.45 ± 4.35
    0.75 ± 3.3
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1429
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    0.5793
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.197
         upper limit
    1.355
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3942

    Secondary: Change in s-iron concentration from baseline to week 2

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    End point title
    Change in s-iron concentration from baseline to week 2
    End point description
    Change in s-iron concentration from baseline to week 2. Analysis performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in s-iron concentration from baseline to week 2.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    220
    115
    Units: micromol/L
        arithmetic mean (standard deviation)
    1.07 ± 4.12
    0.64 ± 5.75
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5277
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    0.3761
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.797
         upper limit
    1.549
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.5943

    Secondary: Change in s-iron concentration from baseline to week 4

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    End point title
    Change in s-iron concentration from baseline to week 4
    End point description
    Change in s-iron concentration from baseline to week 4. Analysis performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in s-iron concentration from baseline to week 4.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    212
    114
    Units: micromol/L
        arithmetic mean (standard deviation)
    0.81 ± 4.14
    1.08 ± 4.21
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.438
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.3576
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.265
         upper limit
    0.549
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4603

    Secondary: Change in s-iron concentration from baseline to week 6

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    End point title
    Change in s-iron concentration from baseline to week 6
    End point description
    Change in s-iron concentration from baseline to week 6. Analysis performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in s-iron concentration from baseline to week 6.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    216
    113
    Units: micromol/L
        arithmetic mean (standard deviation)
    0.82 ± 5.21
    0.76 ± 4.18
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9894
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    0.0066
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.965
         upper limit
    0.978
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4932

    Secondary: Change in transferrin saturation (TSAT) concentration from baseline to week 1

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    End point title
    Change in transferrin saturation (TSAT) concentration from baseline to week 1
    End point description
    Change in transferrin saturation (TSAT) concentration from baseline to week 1. Analysis performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in transferrin saturation (TSAT) concentration from baseline to week 1.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    221
    111
    Units: percentage
        arithmetic mean (standard deviation)
    2.8 ± 18.47
    9.16 ± 78.44
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group B, iron sucrose v Group A, iron isomaltoside 1000
    Number of subjects included in analysis
    332
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.386
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    -6.5236
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -21.376
         upper limit
    8.329
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.4956

    Secondary: Change in transferrin saturation (TSAT) concentration from baseline to week 2

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    End point title
    Change in transferrin saturation (TSAT) concentration from baseline to week 2
    End point description
    Change in transferrin saturation (TSAT) concentration from baseline to week 2. Analysis performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in transferrin saturation (TSAT) concentration from baseline to week 2.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    220
    115
    Units: percentage
        arithmetic mean (standard deviation)
    2.45 ± 20.75
    1.44 ± 9.62
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.355
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    1.1992
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.35
         upper limit
    3.748
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.294

    Secondary: Change in transferrin saturation (TSAT) concentration from baseline to week 4

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    End point title
    Change in transferrin saturation (TSAT) concentration from baseline to week 4
    End point description
    Change in transferrin saturation (TSAT) concentration from baseline to week 4. Analysis performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in transferrin saturation (TSAT) concentration from baseline to week 4.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    212
    114
    Units: percentage
        arithmetic mean (standard deviation)
    1.8 ± 19.26
    2.85 ± 8.98
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3487
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.9972
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.09
         upper limit
    1.095
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.0617

    Secondary: Change in transferrin saturation (TSAT) concentration from baseline to week 6

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    End point title
    Change in transferrin saturation (TSAT) concentration from baseline to week 6
    End point description
    Change in transferrin saturation (TSAT) concentration from baseline to week 6. Analysis performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in transferrin saturation (TSAT) concentration from baseline to week 6.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    216
    113
    Units: percentage
        arithmetic mean (standard deviation)
    2.29 ± 19.43
    2.42 ± 8.62
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9845
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.0207
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.118
         upper limit
    2.077
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.0654

    Secondary: Change in s-ferritin concentration from baseline to week 1

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    End point title
    Change in s-ferritin concentration from baseline to week 1
    End point description
    Change in s-ferritin concentration from baseline to week 1. Analysis performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in s-ferritin concentration from baseline to week 1.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    221
    113
    Units: microg/L
        arithmetic mean (standard deviation)
    156.75 ± 148.91
    48.43 ± 75.36
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    107.8382
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    87.987
         upper limit
    127.689
    Variability estimate
    Standard error of the mean
    Dispersion value
    10.0818

    Secondary: Change in s-ferritin concentration from baseline to week 2

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    End point title
    Change in s-ferritin concentration from baseline to week 2
    End point description
    Change in s-ferritin concentration from baseline to week 2. Analysis performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in s-ferritin concentration from baseline to week 2.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    220
    115
    Units: microg/L
        arithmetic mean (standard deviation)
    142.58 ± 187.82
    20.85 ± 94.84
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    123.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    96.449
         upper limit
    150.271
    Variability estimate
    Standard error of the mean
    Dispersion value
    13.6719

    Secondary: Change in s-ferritin concentration from baseline to week 4

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    End point title
    Change in s-ferritin concentration from baseline to week 4
    End point description
    Change in s-ferritin concentration from baseline to week 4. Analysis performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in s-ferritin concentration from baseline to week 4.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    212
    114
    Units: microg/L
        arithmetic mean (standard deviation)
    128.04 ± 157.75
    86.33 ± 126.79
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    49.3393
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    18.174
         upper limit
    80.505
    Variability estimate
    Standard error of the mean
    Dispersion value
    15.8282

    Secondary: Change in s-ferritin concentration from baseline to week 6

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    End point title
    Change in s-ferritin concentration from baseline to week 6
    End point description
    Change in s-ferritin concentration from baseline to week 6. Analysis performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in s-ferritin concentration from baseline to week 6.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    216
    114
    Units: microg/L
        arithmetic mean (standard deviation)
    136.2 ± 154.59
    156.3 ± 183.63
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    330
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4489
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    -15.0585
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -54.196
         upper limit
    24.079
    Variability estimate
    Standard error of the mean
    Dispersion value
    19.8434

    Secondary: Change in reticulocyte count from baseline to week 1

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    End point title
    Change in reticulocyte count from baseline to week 1
    End point description
    Change in reticulocyte count from baseline to week 1. Analysis performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in reticulocyte count from baseline to week 1.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    212
    108
    Units: percentage
        arithmetic mean (standard deviation)
    0.12 ± 0.42
    -0.02 ± 0.38
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    320
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0006
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    0.154
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.066
         upper limit
    0.242
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0445

    Secondary: Change in reticulocyte count from baseline to week 2

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    End point title
    Change in reticulocyte count from baseline to week 2
    End point description
    Change in reticulocyte count from baseline to week 2. Analysis performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in reticulocyte count from baseline to week 2.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    211
    111
    Units: percentage
        arithmetic mean (standard deviation)
    0.05 ± 0.45
    0.02 ± 0.4
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3448
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    0.0439
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.047
         upper limit
    0.135
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0464

    Secondary: Change in reticulocyte count from baseline to week 4

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    End point title
    Change in reticulocyte count from baseline to week 4
    End point description
    Change in reticulocyte count from baseline to week 4. Analysis performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in reticulocyte count from baseline to week 4.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    204
    110
    Units: percentage
        arithmetic mean (standard deviation)
    0.05 ± 0.47
    0.03 ± 0.36
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5171
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    0.0302
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.061
         upper limit
    0.122
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0465

    Secondary: Change in reticulocyte count from baseline to week 6

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    End point title
    Change in reticulocyte count from baseline to week 6
    End point description
    Change in reticulocyte count from baseline to week 6. Analysis performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in reticulocyte count from baseline to week 6.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    207
    109
    Units: percentage
        arithmetic mean (standard deviation)
    0.06 ± 0.53
    0 ± 0.4
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1564
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    0.0727
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.028
         upper limit
    0.173
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0512

    Secondary: Number of subjects in each randomisation group who discontinued study because of lack of response or intolerance of investigational drugs

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    End point title
    Number of subjects in each randomisation group who discontinued study because of lack of response or intolerance of investigational drugs
    End point description
    Number of subjects in each randomisation group who discontinued study because of lack of response or intolerance of investigational drugs. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    The endpoint covers the complete trial period.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    226
    115
    Units: Number of subjects
        Discontinued due to intolerance/lack of response
    1
    0
        Discontinued due to other reasons
    15
    2
    Statistical analysis title
    Superiority tested by Fisher Exact
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.9999
    Method
    Fisher exact
    Confidence interval

    Secondary: Change in total quality of life (QoL) score (LASA: Energy level) from baseline to week 4

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    End point title
    Change in total quality of life (QoL) score (LASA: Energy level) from baseline to week 4
    End point description
    Change in total quality of life (QoL) score (LASA: Energy level) from baseline to week 4. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in total quality of life (QoL) score (LASA: Energy level) from baseline to week 4.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    208
    111
    Units: QoL score
        arithmetic mean (standard deviation)
    3.7 ± 19.64
    1.2 ± 16.74
    Statistical analysis title
    Superiority tested by MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4653
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    1.4173
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.402
         upper limit
    5.237
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.9379

    Secondary: Change in total quality of life (QoL) score (LASA: Energy level) from baseline to week 6

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    End point title
    Change in total quality of life (QoL) score (LASA: Energy level) from baseline to week 6
    End point description
    Change in total quality of life (QoL) score (LASA: Energy level) from baseline to week 6. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in total quality of life (QoL) score (LASA: Energy level) from baseline to week 6.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    204
    113
    Units: QoL score
        arithmetic mean (standard deviation)
    3.9 ± 18.91
    2.3 ± 17.54
    Statistical analysis title
    Superiority tested by MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9539
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    0.1111
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.667
         upper limit
    3.889
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.9182

    Secondary: Change in total quality of life (QoL) score (LASA: Ability to do daily activities) from baseline to week 4

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    End point title
    Change in total quality of life (QoL) score (LASA: Ability to do daily activities) from baseline to week 4
    End point description
    Change in total quality of life (QoL) score (LASA: Ability to do daily activities) from baseline to week 4. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in total quality of life (QoL) score (LASA: Ability to do daily activities) from baseline to week 4.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    208
    111
    Units: QoL score
        arithmetic mean (standard deviation)
    2.2 ± 21.03
    -0.2 ± 14.25
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4086
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    1.5719
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.168
         upper limit
    5.312
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.8991

    Secondary: Change in total quality of life (QoL) score (LASA: Ability to do daily activities) from baseline to week 6

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    End point title
    Change in total quality of life (QoL) score (LASA: Ability to do daily activities) from baseline to week 6
    End point description
    Change in total quality of life (QoL) score (LASA: Ability to do daily activities) from baseline to week 6. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in total quality of life (QoL) score (LASA: Ability to do daily activities) from baseline to week 6.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    204
    113
    Units: QoL score
        arithmetic mean (standard deviation)
    3.3 ± 19.6
    2.8 ± 17.91
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6734
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.8519
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.829
         upper limit
    3.125
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.0186

    Secondary: Change in total quality of life (QoL) score (LASA: Overall quality of life) from baseline to week 4

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    End point title
    Change in total quality of life (QoL) score (LASA: Overall quality of life) from baseline to week 4
    End point description
    Change in total quality of life (QoL) score (LASA: Overall quality of life) from baseline to week 4. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in total quality of life (QoL) score (LASA: Overall quality of life) from baseline to week 4.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    208
    111
    Units: QoL score
        arithmetic mean (standard deviation)
    1.7 ± 17.88
    -0.3 ± 15.63
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5711
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    1.0565
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.614
         upper limit
    4.727
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.8621

    Secondary: Change in total quality of life (QoL) score (LASA: Overall quality of life) from baseline to week 6

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    End point title
    Change in total quality of life (QoL) score (LASA: Overall quality of life) from baseline to week 6
    End point description
    Change in total quality of life (QoL) score (LASA: Overall quality of life) from baseline to week 6. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in total quality of life (QoL) score (LASA: Overall quality of life) from baseline to week 6.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    204
    113
    Units: QoL score
        arithmetic mean (standard deviation)
    2 ± 18.56
    0.1 ± 15.65
    Statistical analysis title
    Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measures includes treatment, visit, treatment*visit interactions and stratum (s-ferritin (<100 vs. >=100 ng/mL)) ,country as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7964
    Method
    MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    0.4718
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.125
         upper limit
    4.069
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.8264

    Secondary: Change in restless legs syndrome (RLS) symptoms (Cambridge Hopkins-RLS questionnaire (CH-RLSq) score) from baseline to week 6 in subjects with RLS symptoms at baseline

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    End point title
    Change in restless legs syndrome (RLS) symptoms (Cambridge Hopkins-RLS questionnaire (CH-RLSq) score) from baseline to week 6 in subjects with RLS symptoms at baseline
    End point description
    Change in restless legs syndrome (RLS) symptoms (Cambridge Hopkins-RLS questionnaire (CH-RLSq) score) from baseline to week 6 in subjects with RLS symptoms at baseline. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change in restless legs syndrome (RLS) symptoms (Cambridge Hopkins-RLS questionnaire (CH-RLSq) score) from baseline to week 6 in subjects with RLS symptoms at baseline.
    End point values
    Group A, iron isomaltoside 1000 Group B, iron sucrose
    Number of subjects analysed
    68
    40
    Units: RLS score
        arithmetic mean (standard deviation)
    -0.7 ± 7.6
    -1.3 ± 5.37
    Statistical analysis title
    Superiority tested by ANCOVA
    Statistical analysis description
    The ANCOVA mixed model includes treatment and stratum as factors and baseline value as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, iron sucrose
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7267
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.4033
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.88
         upper limit
    2.686
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.1507

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time a subject had signed the ICF and until he/she had completed the study, all AEs/SAEs were collected in the CRF. The SAEs occurring after study termination were re-ported if considered related to the study treatment.
    Adverse event reporting additional description
    The principle investigator (PI) was responsible for ensuring that all AEs observed by PI or reported by the subject were properly collected and recorded in the subject’s medical record as well as on the AE form.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Group B, iron sucrose
    Reporting group description
    All subjects received a cumulative dose of 500 mg iron sucrose. Subjects in group B were administered undiluted iron sucrose in split doses of 100 mg at baseline and 200 mg each at week 2 and 4.

    Reporting group title
    Group A, iron isomaltoside 1000
    Reporting group description
    All subjects received a cumulative dose of 500 mg iron isomaltoside 1000. Subjects in subgroup A1 were administered iron isomaltoside 1000 as a single undiluted IV bolus injection of 500 mg over approximately 2 min at baseline, subjects in subgroup A2 were administered undiluted iron isomaltoside 1000 in split doses of 100 mg at baseline and 200 mg each at week 2 and 4 as IV bolus injections over approximately 2 min.

    Serious adverse events
    Group B, iron sucrose Group A, iron isomaltoside 1000
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 114 (5.26%)
    22 / 230 (9.57%)
         number of deaths (all causes)
    0
    3
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Puncture site haemorrhage
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 230 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anaesthetic complication
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 230 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula site haemorrhage
         subjects affected / exposed
    0 / 114 (0.00%)
    2 / 230 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 114 (0.00%)
    3 / 230 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 230 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular graft occlusion
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 230 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain stem infarction
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gingival bleeding
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Arteriovenous fistula site infection
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected fistula
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 114 (0.88%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 230 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Group B, iron sucrose Group A, iron isomaltoside 1000
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 114 (13.16%)
    38 / 230 (16.52%)
    Injury, poisoning and procedural complications
    Procedural hypotension
         subjects affected / exposed
    1 / 114 (0.88%)
    5 / 230 (2.17%)
         occurrences all number
    2
    18
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    1 / 114 (0.88%)
    6 / 230 (2.61%)
         occurrences all number
    1
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 114 (3.51%)
    7 / 230 (3.04%)
         occurrences all number
    5
    7
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 114 (1.75%)
    5 / 230 (2.17%)
         occurrences all number
    2
    5
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 114 (0.00%)
    5 / 230 (2.17%)
         occurrences all number
    0
    6
    Metabolism and nutrition disorders
    Hyperphosphataemia
         subjects affected / exposed
    4 / 114 (3.51%)
    5 / 230 (2.17%)
         occurrences all number
    4
    5
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 114 (2.63%)
    3 / 230 (1.30%)
         occurrences all number
    3
    4
    Nasopharyngitis
         subjects affected / exposed
    1 / 114 (0.88%)
    6 / 230 (2.61%)
         occurrences all number
    1
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jan 2012
    • Primary endpoint was changed from “change in Hb concentrations from baseline to week 6” to “proportion of subjects able to maintain Hb between 10 and 12.5 g/dl (both values included) at week 6” • In the secondary endpoint “change in Hb concentration from baseline to week 2 and 4”, additional time point “week 6” was added • Study design was revised in terms of number of treatment groups and extension of enrolment period to 18 months, and study centre at Norway was removed from the list of participating countries • Text regarding iron isomaltoside 1000 was updated • Inclusion criteria pertaining to Hb, ESA treatment, and subjects not on IV iron and exclusion criterion 3 were modified to bring more clarity to text • Study flowchart was revised to clarify that height should be measured only at screening • The option of performing blood pregnancy test instead of UPT was added • Iron sucrose infusion time was changed to “according to SmPC” • Iron sucrose test dose administration was changed to “according to SmPC or local guidelines” • Statistical section was revised as per changes in the study endpoints (primary endpoint and first secondary endpoint) • The possibility of re-screening the screen-failure subjects once 2 weeks after the screening visit was added • Appendix 2 related to CH-RLSq was updated
    10 Jul 2012
    • Total study duration was increased to approximately 19 months, and study centres were rephrased as Europe, USA, and India • In inclusion criterion # 5, the target Hb range between “10 and 12.5 g/dL” was revised to “9.5 and 12.5 g/dL” • Additional text was included in sections: dosage and administration, prohibited medication, screen failure, and rescreening • Re-screening was allowed “up to 3 times” • The frequency of planned review by safety review committee was decreased from one meeting every 2 months to one meeting every 4 months for a feasible study conduct

    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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