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    Clinical Trial Results:
    A randomized comparative, open-label study of intravenous iron isomaltoside 1000 (Monofer®) administered by high single dose infusions or standard medical care in women after postpartum haemorrhage

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2012-005782-12
    Trial protocol
    		 DK  
    Global end of trial date
    16 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Apr 2016
    First version publication date
    15 Apr 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    P-Monofer-PP-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01895218
    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 , Pharmacosmos A/S, +45 59485935, trial@pharmacosmos.com
    Scientific contact
    Clinical trial disclosure desk, Pharmacosmos A/S, Pharmacosmos A/S, +45 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
    16 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Dec 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare efficacy of IV high single dose infusion of iron isomaltoside 1000 to standard medical care in women with PPH evaluated as physical fatigue.
    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
    03 May 2013
    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
    Denmark: 200
    Worldwide total number of subjects
    200
    EEA total number of subjects
    200
    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)
    200
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were screened in the period 03 May 2013 to 19 September 2015. The trial took place at one site in Denmark.

    Pre-assignment
    Screening details
    		 Women who were ≥18 years of age with PPH ≥ 700 and ≤ 1000 mL or PPH > 1000 mL and Hb > 6.5 g/dL (4.0 mmol/L) measured > 12 hours after delivery were able to participate.

    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
    		 1200 mg iron isomaltoside 1000 was administered over approximately 15 min as a single IV infusion.
    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
    1200 mg iron isomaltoside 1000 was administered over approximately 15 min as a single IV infusion. 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, standard care
    Arm description
    		 Usually women with PPH are recommended to continue oral iron supplementation as recommended during pregnancy or to take 100 mg oral iron 1-2 times per day for a variable unspecified time period.
    Arm type
    		 standard care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Group A, iron isomaltoside 1000 Group B, standard care
    Started
    100
    100
    Completed
    97
    99
    Not completed
    3
    1
         Consent withdrawn by subject
    2
    -
         Adverse event, non-fatal
    1
    -
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A, iron isomaltoside 1000
    Reporting group description
    		 1200 mg iron isomaltoside 1000 was administered over approximately 15 min as a single IV infusion.

    Reporting group title
    Group B, standard care
    Reporting group description
    		 Usually women with PPH are recommended to continue oral iron supplementation as recommended during pregnancy or to take 100 mg oral iron 1-2 times per day for a variable unspecified time period.

    Reporting group values
    		 Group A, iron isomaltoside 1000 Group B, standard care Total
    Number of subjects
    		 100 100 200
    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)
    		 32.2 ± 4.4 32.6 ± 4.5 -
    Gender categorical
    Units: Subjects
        Female
    		 100 100 200
        Male
    		 0 0 0
    Subject analysis sets

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set included all subjects who were randomised and received the trial drug

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS consisted of all randomised subjects, who received the trial drug, had a baseline physical fatigue score, and had at least 1 post-baseline physical fatigue score.

    Subject analysis set title
    Per protocol analysis set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population included all subjects in the FAS who did not have any major PDs (received ‘rescue’ allogenic RBC transfusion, received less than 80 % or more than 120 % of planned dose, or received prohibited concomitant medication during the trial).

    Subject analysis sets values
    		 Safety analysis set Full analysis set Per protocol analysis set
    Number of subjects
    198
    196
    191
    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)
    32.3 ± 4.4
    32.4 ± 4.4
    32.3 ± 4.2
    Gender categorical
    Units: Subjects
        Female
    198
    196
    191
        Male
    0
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Group A, iron isomaltoside 1000
    Reporting group description
    		 1200 mg iron isomaltoside 1000 was administered over approximately 15 min as a single IV infusion.

    Reporting group title
    Group B, standard care
    Reporting group description
    		 Usually women with PPH are recommended to continue oral iron supplementation as recommended during pregnancy or to take 100 mg oral iron 1-2 times per day for a variable unspecified time period.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set included all subjects who were randomised and received the trial drug

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS consisted of all randomised subjects, who received the trial drug, had a baseline physical fatigue score, and had at least 1 post-baseline physical fatigue score.

    Subject analysis set title
    Per protocol analysis set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population included all subjects in the FAS who did not have any major PDs (received ‘rescue’ allogenic RBC transfusion, received less than 80 % or more than 120 % of planned dose, or received prohibited concomitant medication during the trial).

    Primary: Aggregated change in physical fatigue score from baseline to week 12 (area under the curve (AUC)) in the 2 treatment arms measured by the Multidimensional Fatigue Inventory (MFI), FAS

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    End point title
    		 Aggregated change in physical fatigue score from baseline to week 12 (area under the curve (AUC)) in the 2 treatment arms measured by the Multidimensional Fatigue Inventory (MFI), FAS
    End point description
    Aggregated change in physical fatigue score from baseline to week 12 (area under the curve (AUC)) in the 2 treatment arms measured by the Multidimensional Fatigue Inventory (MFI). Analysis performed on the FAS.
    End point type
    Primary
    End point timeframe
    Aggregated change in physical fatigue score from baseline to week 12 (area under the curve (AUC)) in the 2 treatment arms
    End point values
    		 Group A, iron isomaltoside 1000 Group B, standard care
    Number of subjects analysed
    97
    99
    Units: Score
        arithmetic mean (standard deviation)
    -3.47 ± 3.97
    -2.75 ± 2.82
    Statistical analysis title
    		 Analysis of covariance (ANCOVA) model
    Statistical analysis description
    The primary endpoint was analysed using an analysis of covariance (ANCOVA) model, with treatment and PPH (700-1000 mL, >1000 mL) as factors and baseline MFI physical fatigue score as covariate. The estimated treatment differences (IV iron isomaltoside 1000 – standard medical care) expressed as contrasts of the adjusted means will be presented with corresponding 95 % CI and the p-value.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, standard care
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.65
         upper limit
    		 -0.28

    Primary: Aggregated change in physical fatigue score from baseline to week 12 (area under the curve (AUC)) in the 2 treatment arms measured by the Multidimensional Fatigue Inventory (MFI), PP

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    End point title
    		 Aggregated change in physical fatigue score from baseline to week 12 (area under the curve (AUC)) in the 2 treatment arms measured by the Multidimensional Fatigue Inventory (MFI), PP
    End point description
    Aggregated change in physical fatigue score from baseline to week 12 (area under the curve (AUC)) in the 2 treatment arms measured by the Multidimensional Fatigue Inventory (MFI). Analysis performed on the PP analysis set.
    End point type
    Primary
    End point timeframe
    Aggregated change in physical fatigue score from baseline to week 12 (area under the curve (AUC)) in the 2 treatment arms.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, standard care
    Number of subjects analysed
    95
    96
    Units: Score
        arithmetic mean (standard deviation)
    -3.44 ± 3.98
    -2.71 ± 2.84
    Statistical analysis title
    		 Analysis of covariance (ANCOVA) model
    Statistical analysis description
    The primary endpoint was analysed using an analysis of covariance (ANCOVA) model, with treatment and PPH (700-1000 mL, >1000 mL) as factors and baseline MFI physical fatigue score as covariate. The estimated treatment differences (IV iron isomaltoside 1000 – standard medical care) expressed as contrasts of the adjusted means will be presented with corresponding 95 % CI and the p-value.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, standard care
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0066
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.67
         upper limit
    		 -0.27

    Secondary: Change in haemoglobin from baseline to week 1

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    End point title
    		 Change in haemoglobin from baseline to week 1
    End point description
    Change in haemoglobin from baseline to week 1. Analysis performed on FAS.
    End point type
    Secondary
    End point timeframe
    Change in haemoglobin from baseline to week 1.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, standard care
    Number of subjects analysed
    93
    97
    Units: g/dL
        arithmetic mean (standard deviation)
    1.56 ± 0.76
    1.26 ± 0.92
    Statistical analysis title
    		 Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measurements (MMRM) included visit, treatment-by-visit, and PPH (700-1000 mL, >1000 mL) as factors, baseline value as covariate, and subject as random effect.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, standard care
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0198
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 0.51

    Secondary: Change in haemoglobin from baseline to week 3

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    End point title
    		 Change in haemoglobin from baseline to week 3
    End point description
    Change in haemoglobin from baseline to week 3. Analysis performed on FAS.
    End point type
    Secondary
    End point timeframe
    Change in haemoglobin from baseline to week 3.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, standard care
    Number of subjects analysed
    93
    97
    Units: g/dL
        arithmetic mean (standard deviation)
    2.97 ± 0.99
    2.36 ± 1.11
    Statistical analysis title
    		 Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measurements (MMRM) included visit, treatment-by-visit, and PPH (700-1000 mL, >1000 mL) as factors, baseline value as covariate, and subject as random effect.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, standard care
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 0.84

    Secondary: Change in haemoglobin from baseline to week 8

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    End point title
    		 Change in haemoglobin from baseline to week 8
    End point description
    Change in haemoglobin from baseline to week 8. Analysis performed on FAS.
    End point type
    Secondary
    End point timeframe
    Change in haemoglobin from baseline to week 8.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, standard care
    Number of subjects analysed
    94
    99
    Units: g/dL
        arithmetic mean (standard deviation)
    3.63 ± 1.36
    3.19 ± 1.27
    Statistical analysis title
    		 Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measurements (MMRM) included visit, treatment-by-visit, and PPH (700-1000 mL, >1000 mL) as factors, baseline value as covariate, and subject as random effect.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, standard care
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.21
         upper limit
    		 0.67

    Secondary: Change in haemoglobin from baseline to week 12

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    End point title
    		 Change in haemoglobin from baseline to week 12
    End point description
    Change in haemoglobin from baseline to week 12. Analysis performed on FAS.
    End point type
    Secondary
    End point timeframe
    Change in haemoglobin from baseline to week 12.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, standard care
    Number of subjects analysed
    94
    95
    Units: g/dL
        arithmetic mean (standard deviation)
    3.84 ± 1.53
    3.34 ± 1.42
    Statistical analysis title
    		 Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measurements (MMRM) included visit, treatment-by-visit, and PPH (700-1000 mL, >1000 mL) as factors, baseline value as covariate, and subject as random effect.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, standard care
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 0.73

    Secondary: Change in s-ferritin from baseline to day 3

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    End point title
    		 Change in s-ferritin from baseline to day 3
    End point description
    Change in s-ferritin from baseline to day 3. Analysis performed on FAS.
    End point type
    Secondary
    End point timeframe
    Change in s-ferritin from baseline to day 3.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, standard care
    Number of subjects analysed
    93
    95
    Units: ng/mL
        arithmetic mean (standard deviation)
    910.2 ± 329.2
    -2 ± 23.5
    Statistical analysis title
    		 Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measurements (MMRM) included visit, treatment-by-visit, and PPH (700-1000 mL, >1000 mL) as factors, baseline value as covariate, and subject as random effect.
    Comparison groups
    Group B, standard care v Group A, iron isomaltoside 1000
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    911.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 864.95
         upper limit
    		 958.42

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

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    End point title
    		 Change in s-ferritin from baseline to week 1
    End point description
    Change in s-ferritin from baseline to week 1. Analysis performed on FAS.
    End point type
    Secondary
    End point timeframe
    Change in s-ferritin from baseline to week 1.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, standard care
    Number of subjects analysed
    94
    95
    Units: ng/mL
        arithmetic mean (standard deviation)
    872.1 ± 336.7
    -11.3 ± 30.5
    Statistical analysis title
    		 Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measurements (MMRM) included visit, treatment-by-visit, and PPH (700-1000 mL, >1000 mL) as factors, baseline value as covariate, and subject as random effect.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, standard care
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    882.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 835.65
         upper limit
    		 928.96

    Secondary: Change in s-ferritin from baseline to week 3

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    End point title
    		 Change in s-ferritin from baseline to week 3
    End point description
    Change in s-ferritin from baseline to week 3. Analysis performed on FAS.
    End point type
    Secondary
    End point timeframe
    Change in s-ferritin from baseline to week 3.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, standard care
    Number of subjects analysed
    93
    96
    Units: ng/mL
        arithmetic mean (standard deviation)
    310.3 ± 166.6
    -28.4 ± 33.3
    Statistical analysis title
    		 Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measurements (MMRM) included visit, treatment-by-visit, and PPH (700-1000 mL, >1000 mL) as factors, baseline value as covariate, and subject as random effect.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, standard care
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    337.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 290.4
         upper limit
    		 383.72

    Secondary: Change in s-ferritin from baseline to week 8

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    End point title
    		 Change in s-ferritin from baseline to week 8
    End point description
    Change in s-ferritin from baseline to week 8. Analysis performed on FAS.
    End point type
    Secondary
    End point timeframe
    Change in s-ferritin from baseline to week 8.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, standard care
    Number of subjects analysed
    94
    97
    Units: ng/mL
        arithmetic mean (standard deviation)
    132.8 ± 107
    -29.9 ± 34.2
    Statistical analysis title
    		 Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measurements (MMRM) included visit, treatment-by-visit, and PPH (700-1000 mL, >1000 mL) as factors, baseline value as covariate, and subject as random effect.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, standard care
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    164.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 117.96
         upper limit
    		 210.93

    Secondary: Change in s-ferritin from baseline to week 12

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    End point title
    		 Change in s-ferritin from baseline to week 12
    End point description
    Change in s-ferritin from baseline to week 12. Analysis performed on FAS.
    End point type
    Secondary
    End point timeframe
    Change in s-ferritin from baseline to week 12.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, standard care
    Number of subjects analysed
    94
    93
    Units: ng/mL
        arithmetic mean (standard deviation)
    37 ± 22.3
    -31.9 ± 37.5
    Statistical analysis title
    		 Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measurements (MMRM) included visit, treatment-by-visit, and PPH (700-1000 mL, >1000 mL) as factors, baseline value as covariate, and subject as random effect.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, standard care
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    139.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 92.19
         upper limit
    		 186.02

    Secondary: Change in transferrin saturation from baseline to day 3

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    End point title
    		 Change in transferrin saturation from baseline to day 3
    End point description
    Change in transferrin saturation from baseline to day 3. Analysis performed on FAS.
    End point type
    Secondary
    End point timeframe
    Change in transferrin saturation from baseline to day 3.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, standard care
    Number of subjects analysed
    92
    94
    Units: Percentage
        arithmetic mean (standard deviation)
    33.5 ± 21.5
    1.7 ± 9
    Statistical analysis title
    		 Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measurements (MMRM) included visit, treatment-by-visit, and PPH (700-1000 mL, >1000 mL) as factors, baseline value as covariate, and subject as random effect.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, standard care
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    31.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 28.5
         upper limit
    		 34.74

    Secondary: Change in transferrin saturation from baseline to week 1

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    End point title
    		 Change in transferrin saturation from baseline to week 1
    End point description
    Change in transferrin saturation from baseline to week 1. Analysis performed on FAS.
    End point type
    Secondary
    End point timeframe
    Change in transferrin saturation from baseline to week 1.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, standard care
    Number of subjects analysed
    93
    93
    Units: Percentage
        arithmetic mean (standard deviation)
    9.1 ± 8.6
    1.1 ± 8
    Statistical analysis title
    		 Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measurements (MMRM) included visit, treatment-by-visit, and PPH (700-1000 mL, >1000 mL) as factors, baseline value as covariate, and subject as random effect.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, standard care
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    7.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.62
         upper limit
    		 10.86

    Secondary: Change in transferrin saturation from baseline to week 3

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    End point title
    		 Change in transferrin saturation from baseline to week 3
    End point description
    Change in transferrin saturation from baseline to week 3. Analysis performed on FAS.
    End point type
    Secondary
    End point timeframe
    Change in transferrin saturation from baseline to week 3.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, standard care
    Number of subjects analysed
    91
    96
    Units: Percentage
        arithmetic mean (standard deviation)
    19 ± 9
    8.8 ± 11.7
    Statistical analysis title
    		 Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measurements (MMRM) included visit, treatment-by-visit, and PPH (700-1000 mL, >1000 mL) as factors, baseline value as covariate, and subject as random effect.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, standard care
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    10.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.28
         upper limit
    		 13.51

    Secondary: Change in transferrin saturation from baseline to week 8

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    End point title
    		 Change in transferrin saturation from baseline to week 8
    End point description
    Change in transferrin saturation from baseline to week 8. Analysis performed on FAS.
    End point type
    Secondary
    End point timeframe
    Change in transferrin saturation from baseline to week 8.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, standard care
    Number of subjects analysed
    93
    97
    Units: Percentage
        arithmetic mean (standard deviation)
    20.6 ± 10.3
    12.6 ± 12.5
    Statistical analysis title
    		 Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measurements (MMRM) included visit, treatment-by-visit, and PPH (700-1000 mL, >1000 mL) as factors, baseline value as covariate, and subject as random effect.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, standard care
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    7.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.86
         upper limit
    		 11.05

    Secondary: Change in transferrin saturation from baseline to week 12

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    End point title
    		 Change in transferrin saturation from baseline to week 12
    End point description
    Change in transferrin saturation from baseline to week 12. Analysis performed on FAS.
    End point type
    Secondary
    End point timeframe
    Change in transferrin saturation from baseline to week 12.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, standard care
    Number of subjects analysed
    92
    93
    Units: Percentage
        arithmetic mean (standard deviation)
    21.7 ± 10.6
    13.3 ± 11.5
    Statistical analysis title
    		 Test for superiority, MMRM
    Statistical analysis description
    The mixed model for repeated measurements (MMRM) included visit, treatment-by-visit, and PPH (700-1000 mL, >1000 mL) as factors, baseline value as covariate, and subject as random effect.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, standard care
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    8.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.35
         upper limit
    		 11.6

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time a subject had signed the informed consent form and until she had completed the trial, all AEs/SAEs were reported in the electronic case report form.
    Adverse event reporting additional description
    An AE was described in the following manner: The nature of the event will be described in precise, standard medical terminology (i.e. not necessarily the exact words used by the subject). If known, a specific diagnosis was stated. Furthermore the Investigator described an AE regarding seriousness, severity, relatedness, and outcome.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Group A, iron isomaltoside 1000
    Reporting group description
    		 1200 mg iron isomaltoside 1000 was administered over approximately 15 min as a single IV infusion.

    Reporting group title
    Group B, standard care
    Reporting group description
    		 Usually women with PPH were recommended to continue oral iron supplementation as recommended during pregnancy or to take 100 mg oral iron 1-2 times per day for a variable unspecified time period.

    Serious adverse events
    		 Group A, iron isomaltoside 1000 Group B, standard care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 98 (9.18%)
    8 / 100 (8.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic pseudo-obstruction
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Galactostasis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 98 (0.00%)
    2 / 100 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometritis
         subjects affected / exposed
    2 / 98 (2.04%)
    2 / 100 (2.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    4 / 98 (4.08%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perineal infection
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group A, iron isomaltoside 1000 Group B, standard care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 98 (46.94%)
    41 / 100 (41.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 98 (10.20%)
    8 / 100 (8.00%)
         occurrences all number
    12
    10
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    18 / 98 (18.37%)
    19 / 100 (19.00%)
         occurrences all number
    18
    19
    Haemorrhoids
         subjects affected / exposed
    13 / 98 (13.27%)
    8 / 100 (8.00%)
         occurrences all number
    13
    8
    Infections and infestations
    Cystitis
         subjects affected / exposed
    8 / 98 (8.16%)
    3 / 100 (3.00%)
         occurrences all number
    8
    4
    Fungal infection
         subjects affected / exposed
    7 / 98 (7.14%)
    3 / 100 (3.00%)
         occurrences all number
    8
    3
    Mastitis
         subjects affected / exposed
    7 / 98 (7.14%)
    8 / 100 (8.00%)
         occurrences all number
    8
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Apr 2013
    • In order to have a clear and robust primary endpoint, the primary endpoint was changed from change by visit to average aggregated change in physical fatigue score, i.e. calculated as the AUC of the change from baseline to last visit divided by sched-uled time from baseline to last visit. • In order to further strengthen the endpoints related to fatigue in the puerperal women, the postpartum questionnaire was included as an additional secondary efficacy end-point. • The maximum storage time for maternal milk samples was added in order to define the scope of the research bio-bank. • Drugs potentially yielding a decrease in oral iron absorption were deleted from the list of prohibited medication during the trial (for the standard medical care treatment group), as the aim of the standard medical care treatment group was to reflect clinical practice.
    26 Aug 2013
    • Inclusion criterion 1 was changed in order to align with current clinical practice: The minimum PPH was increased from 500 mL to 700 mL, and the minimum Hb concen-tration for subjects with PPH > 1000 mL was decreased from 8.0 g/dL (5.0 mmol/L) to 6.5 g/dL (4.0 mmol/L). • It was specified that only subjects living within a radius of 30 kilometres from the hospital were eligible for inclusion in the trial. This restriction was in order to ease the logistics associated with the visits in the subject’s home. • Recording of anaemia and gastrointestinal symptoms was included as an additional objective and endpoint in order to investigate one of the main effects of iron deficiency as well as a well-known adverse effect of oral iron treatment, respectively, within the trial. • Visit windows were enlarged for visit 2 (from ±8 hours to ±1 day) and visit 5 (from ±2 days to ±1 week) in order to ensure full follow-up for as many subjects as possible. • It was specified that in cases where the infusion of iron isomaltoside 1000 was interrupted, it was allowed to restart the infusion after clinical assessment by the Principal Investigator or sub-investigator. • It was specified that admission to the maternity hotel was not considered to meet the regulatory definition for a SAE due to hospitalisation, and that admission of the new-born to the neonatal intensive care unit was evaluated case by case for seriousness.
    11 Feb 2014
    • Timing of maternal milk sample collection was changed from baseline, day 1, 2, and 3 to day 3 and week 1, and should be done in all subjects when possible. At the time of implementing this amendment, collection of milk samples from baseline and onwards had not been possible in any subjects. • It was specified that a ‘current smoker’ was defined as smoking within the last 6 months. • The reference document for SARs was changed from the SmPC to the IB for iron isomaltoside 1000, as the trial investigated a new indication for iron isomaltoside 1000. • It was specified that informed consent was obtained either by the investigator or by a project midwife.

    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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