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    Clinical Trial Results:
    A randomised double-blind controlled phase III study to compare the efficacy and safety of intravenous ferric carboxymaltose with placebo in patients with anaemia undergoing major open abdominal surgery

    Summary
    EudraCT number
    2012-002786-35
    Trial protocol
    GB  
    Global end of trial date
    10 May 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Oct 2020
    First version publication date
    09 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    12/0246
    Additional study identifiers
    ISRCTN number
    ISRCTN67322816
    US NCT number
    NCT01692418
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Gower Street, London, United Kingdom, WC1E 6BT
    Public contact
    Toby Richards, University of Western Australia, toby.richards@uwa.edu.au
    Scientific contact
    Toby Richards, University of Western Australia, toby.richards@uwa.edu.au
    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 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    10 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine if a single dose of intravenous iron given to patients with anaemia prior to major open abdominal surgery, reduces the need for peri-operative blood transfusion (the peri-operative period is defined as from randomisation to the trial until 30 days following operation)
    Protection of trial subjects
    This trial was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. All subjects provided written informed consent before undergoing any trial related procedures. The trial was reviewed and approved by a Research Ethics Committee (REC) and the Medicines & Healthcare products Regulatory Agency (MHRA). Administration of the IMP was given in a hospital setting with appropriate resuscitation facility and staff available in the event of an emergency. Patients were administered the study medication by the unblinded person. Patients were closely monitored for signs of hypersensitivity during and for at least 30 minutes following the administration of the treatment.
    Background therapy
    N/A
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Sep 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 487
    Worldwide total number of subjects
    487
    EEA total number of subjects
    487
    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)
    234
    From 65 to 84 years
    248
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    The trial was conducted in 46 sites in England and Wales. 487 subjects were randomised, the first on 06/01/2014 and the last on 28/09/2018.

    Pre-assignment
    Screening details
    Patients with a planned major abdominal surgery were screened for the trial. During screening conformance with inclusion/exclusion criteria was assessed.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject
    Blinding implementation details
    Blinding will be obtained by shielding the patients from seeing preparation of the study drug and having unblinded study personnel not involved in any study assessments (efficacy or safety) responsible for preparing and administering the study treatment. This will be achieved by preparing and administering the study drug behind a screen or curtain. The drug will then be shielded from vision (light protection bags) and administered through black tubing.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Ferinject (ferric carboxymaltose)
    Arm description
    1000 mg of ferric carboxymaltose will be administered as an i.v. infusion (100ml normal saline) over a minimum of 15 minutes using a black infusion kit
    Arm type
    Experimental

    Investigational medicinal product name
    Ferinject (ferric carboxymaltose)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    One off dose of 1000 mg of ferric carboxymaltose will be administered as an i.v. infusion (100ml normal saline) over a minimum of 15 minutes using a black infusion kit

    Arm title
    Placebo
    Arm description
    Normal saline will be administered as an i.v. infusion (100ml normal saline) over a minimum of 15 minutes using a black infusion kit
    Arm type
    Placebo

    Investigational medicinal product name
    Normal saline (0.9% weight/volume (w/v) NaCl)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    One off dose of normal saline will be administered as an i.v. infusion (100ml normal saline) over a minimum of 15 minutes using a black infusion kit

    Number of subjects in period 1
    Ferinject (ferric carboxymaltose) Placebo
    Started
    244
    243
    Completed
    226
    226
    Not completed
    18
    17
         Patient died
    12
    10
         Consent withdrawn by subject
    4
    4
         Lost to follow-up
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ferinject (ferric carboxymaltose)
    Reporting group description
    1000 mg of ferric carboxymaltose will be administered as an i.v. infusion (100ml normal saline) over a minimum of 15 minutes using a black infusion kit

    Reporting group title
    Placebo
    Reporting group description
    Normal saline will be administered as an i.v. infusion (100ml normal saline) over a minimum of 15 minutes using a black infusion kit

    Reporting group values
    Ferinject (ferric carboxymaltose) Placebo Total
    Number of subjects
    244 243 487
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    111 123 234
        From 65-84 years
    131 117 248
        85 years and over
    2 3 5
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    66 (57 to 72) 65 (50 to 72) -
    Gender categorical
    Units: Subjects
        Female
    125 142 267
        Male
    119 101 220
    Ethnicity
    Units: Subjects
        Caucasian
    211 217 428
        Afro-caribbean
    14 19 33
        Asian
    18 6 24
        Other
    1 1 2
    American Society Anesthesiologists (ASA) grade
    Units: Subjects
        Grade I
    30 31 61
        Grade II
    147 141 288
        Grade III
    56 65 121
        Grade IV
    1 1 2
        Missing
    10 5 15
    Smoking history
    Units: Subjects
        Never
    113 116 229
        Ex
    108 107 215
        Current
    22 19 41
        Missing
    1 1 2
    Iron tablets
    Is the patient taking iron tablets?
    Units: Subjects
        Yes
    46 49 95
        No
    197 194 391
        Missing
    1 0 1
    Medical history - Myocardial infarction
    Units: Subjects
        Yes
    12 20 32
        No
    232 223 455
    Medical history - Angina/chest pain
    Units: Subjects
        Yes
    15 16 31
        No
    229 227 456
    Medical history - Heart failure
    Units: Subjects
        Yes
    9 3 12
        No
    235 240 475
    Medical history - Hypertension
    Units: Subjects
        Yes
    89 93 182
        No
    155 150 305
    Medical history - Breathlessness
    Units: Subjects
        Yes
    25 28 53
        No
    219 215 434
    Medical history - Liver disease
    Units: Subjects
        Yes
    14 8 22
        No
    230 235 465
    Medical history - Kidney/urinary problems
    Units: Subjects
        Yes
    39 37 76
        No
    205 206 411
    Medical history - Bleeding tendencies
    Units: Subjects
        Yes
    11 7 18
        No
    233 236 469
    Medical history - Iron deficiency
    Units: Subjects
        Yes
    70 69 139
        No
    174 174 348
    Medical history - COPD/bronchitis/asthma
    Units: Subjects
        Yes
    27 37 64
        No
    217 206 423
    Medical history - Acid reflux/stomach ulcer
    Units: Subjects
        Yes
    54 54 108
        No
    190 189 379
    Medical history - Hiatus hernia
    Units: Subjects
        Yes
    17 23 40
        No
    227 220 447
    Medical history - Coeliac disease
    Units: Subjects
        Yes
    0 2 2
        No
    244 241 485
    Medical history - Inflammatory bowel disease
    Units: Subjects
        Yes
    13 13 26
        No
    231 230 461
    Medical history - CVA/TIA
    Units: Subjects
        Yes
    4 13 17
        No
    240 230 470
    Medical history - Rheumatoid arthritis
    Units: Subjects
        Yes
    10 12 22
        No
    233 231 464
        Missing
    1 0 1
    Medical history - Diabetes
    Units: Subjects
        Yes
    37 38 75
        No
    207 205 412
    Pre-op chemotherapy
    Is the patient having pre‐op chemotherapy?
    Units: Subjects
        Yes
    50 59 109
        No
    194 184 378
    Pre-op radiotherapy
    Is the patient having pre‐op radiotherapy?
    Units: Subjects
        Yes
    7 6 13
        No
    237 237 474
    Current medication that affects bleeding - Warfarin
    Units: Subjects
        Yes
    7 4 11
        No
    237 239 476
    Current medication that affects bleeding - Aspirin
    Units: Subjects
        Yes
    23 28 51
        No
    221 215 436
    Current medication that affects bleeding - Clopidogrel
    Units: Subjects
        Yes
    3 5 8
        No
    241 238 479
    Current medication that affects bleeding - Other
    Units: Subjects
        Yes
    22 25 47
        No
    222 218 440

    End points

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    End points reporting groups
    Reporting group title
    Ferinject (ferric carboxymaltose)
    Reporting group description
    1000 mg of ferric carboxymaltose will be administered as an i.v. infusion (100ml normal saline) over a minimum of 15 minutes using a black infusion kit

    Reporting group title
    Placebo
    Reporting group description
    Normal saline will be administered as an i.v. infusion (100ml normal saline) over a minimum of 15 minutes using a black infusion kit

    Primary: Blood transfusion or death at 30 days

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    End point title
    Blood transfusion or death at 30 days
    End point description
    End point type
    Primary
    End point timeframe
    From randomisation to 30 days post-operation
    End point values
    Ferinject (ferric carboxymaltose) Placebo
    Number of subjects analysed
    237
    237
    Units: None
        Yes
    69
    67
        No
    168
    170
    Statistical analysis title
    Blood transfusion or death
    Statistical analysis description
    The number and percentage of patients with the composite endpoint of blood transfusion or death will be reported by treatment group. A risk ratio (treatment versus placebo) and 95% confidence interval will be calculated using binomial regression (binary outcome with a log link). A p-value will be calculated using a likelihood ratio test.
    Comparison groups
    Ferinject (ferric carboxymaltose) v Placebo
    Number of subjects included in analysis
    474
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.84
    Method
    Binomial regression with a log link
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.78
         upper limit
    1.37

    Primary: Transfusions episodes at 30 days

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    End point title
    Transfusions episodes at 30 days
    End point description
    End point type
    Primary
    End point timeframe
    From randomisation to 30 days post-operation
    End point values
    Ferinject (ferric carboxymaltose) Placebo
    Number of subjects analysed
    237
    237
    Units: None
        0 transfusions
    169
    170
        1 transfusion
    49
    37
        2 transfusions
    9
    22
        3 transfusions
    5
    5
        4 transfusions
    3
    1
        5 transfusions
    1
    1
        6 transfusions
    1
    1
    Statistical analysis title
    Transfusions episodes
    Statistical analysis description
    A rate ratio and 95% confidence interval were calculated using a negative binomial regression model and a likelihood ratio test p-value reported. As some patients died before the end of the time period, the length of each patient’s period of observation was included as an exposure in the model.
    Comparison groups
    Ferinject (ferric carboxymaltose) v Placebo
    Number of subjects included in analysis
    474
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.93
    Method
    Negative binomial regression
    Parameter type
    Rate ratio
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.68
         upper limit
    1.43

    Secondary: Total number of units of blood or blood products transfused at 30 days (excluding large transfusions)

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    End point title
    Total number of units of blood or blood products transfused at 30 days (excluding large transfusions)
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to 30 days post-operation
    End point values
    Ferinject (ferric carboxymaltose) Placebo
    Number of subjects analysed
    237
    237
    Units: None
        0 units
    171
    173
        1 unit
    21
    14
        2 units
    31
    28
        3 units
    7
    12
        4 units
    1
    6
        5 units
    3
    2
        6+ units
    3
    2
    Statistical analysis title
    Total units of blood or blood products transfused
    Statistical analysis description
    A rate ratio (treatment versus placebo) and 95% confidence interval were calculated using a negative binomial regression model. A p-value was calculated using a likelihood ratio test.
    Comparison groups
    Ferinject (ferric carboxymaltose) v Placebo
    Number of subjects included in analysis
    474
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.92
    Method
    Negative binomial regression
    Parameter type
    Rate ratio
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.65
         upper limit
    1.47

    Secondary: Total number of units of blood or blood products transfused at 6 months (excluding large transfusions)

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    End point title
    Total number of units of blood or blood products transfused at 6 months (excluding large transfusions)
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to 6 months post-operation
    End point values
    Ferinject (ferric carboxymaltose) Placebo
    Number of subjects analysed
    220
    224
    Units: None
        0 units
    148
    151
        1 unit
    21
    13
        2 units
    32
    31
        3 units
    10
    15
        4 units
    2
    7
        5 units
    2
    2
        6+ units
    5
    5
    Statistical analysis title
    Total units of blood or blood products transfused
    Statistical analysis description
    A rate ratio (treatment versus placebo) and 95% confidence interval were calculated using a negative binomial regression model. A p-value was calculated using a likelihood ratio test.
    Comparison groups
    Ferinject (ferric carboxymaltose) v Placebo
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.56
    Method
    Negative binomial regression
    Parameter type
    Rate ratio
    Point estimate
    0.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    1.32

    Secondary: Days alive and out of hospital at 30 days

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    End point title
    Days alive and out of hospital at 30 days
    End point description
    End point type
    Secondary
    End point timeframe
    From the index operation to 30 days post-operation
    End point values
    Ferinject (ferric carboxymaltose) Placebo
    Number of subjects analysed
    232
    226
    Units: days
        arithmetic mean (standard deviation)
    19.7 ± 7.0
    19.8 ± 7.5
    Statistical analysis title
    Days alive and out of hospital (DAOH)
    Statistical analysis description
    This end point was analysed using linear regression as described by Ariti et al (see reference below). CA. Ariti, JGF. Cleland, SJ. Pocock et al. Days alive and out of hospital and the patient journey in patients with heart failure: Insights from the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program, American Heart Journal, Volume 162, Issue 5, 2011, Pages 900-906
    Comparison groups
    Ferinject (ferric carboxymaltose) v Placebo
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.84
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    1.2

    Secondary: Post-operative complications up to discharge

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    End point title
    Post-operative complications up to discharge
    End point description
    Post-operative complications during the inpatient period were classified using the Clavien-Dindo (CD) system. For each patient, the most severe post-operative complication was identified and used for analysis.
    End point type
    Secondary
    End point timeframe
    From the index operation to discharge
    End point values
    Ferinject (ferric carboxymaltose) Placebo
    Number of subjects analysed
    233
    227
    Units: None
        None
    138
    139
        Grade I
    28
    24
        Grade II
    45
    40
        Grade III
    14
    17
        Grade IV
    8
    5
        Grade V
    0
    2
    Statistical analysis title
    Post-operative complications
    Statistical analysis description
    The number and percentage of patients with any moderate or severe (Clavien-Dindo Grade III or above) are reported by treatment group. A risk ratio (treatment versus placebo) and 95% confidence interval were calculated using binomial regression (binary outcome with a log link). A p-value was calculated using a likelihood ratio test.
    Comparison groups
    Ferinject (ferric carboxymaltose) v Placebo
    Number of subjects included in analysis
    460
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.69
    Method
    Binomial regression with a log link
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.52
         upper limit
    1.55

    Secondary: EQ-5D-5L utility score at 6 months

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    End point title
    EQ-5D-5L utility score at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to 6 months post-operation
    End point values
    Ferinject (ferric carboxymaltose) Placebo
    Number of subjects analysed
    177
    173
    Units: None
        arithmetic mean (standard deviation)
    0.82 ± 0.22
    0.82 ± 0.21
    Statistical analysis title
    EQ-5D-5L
    Statistical analysis description
    Differences in mean (treatment versus placebo) levels of the total score were calculated using analysis of covariance (ANCOVA) techniques with the baseline score included in the model.
    Comparison groups
    Ferinject (ferric carboxymaltose) v Placebo
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.02
         upper limit
    0.05

    Secondary: MFI total score at 6 months

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    End point title
    MFI total score at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to 6 months post-operation
    End point values
    Ferinject (ferric carboxymaltose) Placebo
    Number of subjects analysed
    177
    171
    Units: None
        arithmetic mean (standard deviation)
    48.8 ± 18.9
    47.4 ± 19.1
    Statistical analysis title
    MFI
    Statistical analysis description
    Differences in mean (treatment versus placebo) levels of the total score were calculated using analysis of covariance (ANCOVA) techniques with the baseline score included in the model.
    Comparison groups
    Ferinject (ferric carboxymaltose) v Placebo
    Number of subjects included in analysis
    348
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.94
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.5
         upper limit
    3.2

    Secondary: SQOM total score at 6 months

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    End point title
    SQOM total score at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to 6 months post-operation
    End point values
    Ferinject (ferric carboxymaltose) Placebo
    Number of subjects analysed
    178
    172
    Units: None
        arithmetic mean (standard deviation)
    1.35 ± 1.70
    1.26 ± 1.83
    Statistical analysis title
    SQOM
    Statistical analysis description
    Differences in mean (treatment versus placebo) levels of the total score were calculated using analysis of covariance (ANCOVA) techniques with the baseline score included in the model.
    Comparison groups
    Ferinject (ferric carboxymaltose) v Placebo
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.69
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    0.46

    Secondary: Readmission to hospital at 8 weeks

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    End point title
    Readmission to hospital at 8 weeks
    End point description
    This end point excludes planned readmissions.
    End point type
    Secondary
    End point timeframe
    From discharge from the index operation to 8 weeks post-operation
    End point values
    Ferinject (ferric carboxymaltose) Placebo
    Number of subjects analysed
    234
    234
    Units: None
        0 readmissions
    203
    183
        1+ readmissions
    31
    51
    Statistical analysis title
    Readmission to hospital
    Statistical analysis description
    A risk ratio (treatment versus placebo) and 95% confidence interval were calculated using binomial regression (binary outcome with a log link). A p-value was calculated using a likelihood ratio test.
    Comparison groups
    Ferinject (ferric carboxymaltose) v Placebo
    Number of subjects included in analysis
    468
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.015
    Method
    Binomial regression with a log link
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    0.91

    Secondary: Readmission to hospital at 6 months

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    End point title
    Readmission to hospital at 6 months
    End point description
    This end point excludes planned readmissions.
    End point type
    Secondary
    End point timeframe
    From discharge from the index operation to 6 months post-operation
    End point values
    Ferinject (ferric carboxymaltose) Placebo
    Number of subjects analysed
    227
    223
    Units: None
        0 readmissions
    169
    150
        1+ readmissions
    58
    73
    Statistical analysis title
    Readmission to hospital
    Statistical analysis description
    A risk ratio (treatment versus placebo) and 95% confidence interval were calculated using binomial regression (binary outcome with a log link). A p-value was calculated using a likelihood ratio test.
    Comparison groups
    Ferinject (ferric carboxymaltose) v Placebo
    Number of subjects included in analysis
    450
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.09
    Method
    Binomial regression with a log link
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.58
         upper limit
    1.04

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Any adverse events which occur within 30 days of the trial treatment will be recorded in the CRF
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Ferinject (ferric carboxymaltose)
    Reporting group description
    1000 mg of ferric carboxymaltose will be administered as an i.v. infusion (100ml normal saline) over a minimum of 15 minutes using a black infusion kit

    Reporting group title
    Placebo
    Reporting group description
    Normal saline will be administered as an i.v. infusion (100ml normal saline) over a minimum of 15 minutes using a black infusion kit

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: The threshold for reporting non-serious adverse events is set at 5%. There were no non-serious adverse events which exceeded that threshold.
    Serious adverse events
    Ferinject (ferric carboxymaltose) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 240 (9.17%)
    24 / 241 (9.96%)
         number of deaths (all causes)
    12
    10
         number of deaths resulting from adverse events
    0
    1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic leak
         subjects affected / exposed
    1 / 240 (0.42%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chemical peritonitis
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iatrogenic injury
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal excoriation
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative ileus
         subjects affected / exposed
    5 / 240 (2.08%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound complication
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention postoperative
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Post procedural drainage
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal replacement therapy
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Inflammatory marker increased
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         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
    Acute respiratory failure
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Parkinson's disease
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Transient ischaemic attack
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal fluid collection
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 240 (0.00%)
    2 / 241 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethritis noninfective
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Jaundice cholestatic
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal sepsis
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         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 / 240 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 240 (0.42%)
    4 / 241 (1.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 240 (0.42%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Ferinject (ferric carboxymaltose) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 240 (0.00%)
    0 / 241 (0.00%)

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Oct 2012
    Changes were requested by the MHRA: - Protocol section 8.6 now clarifies that the IMP administration will be done in an in-patient setting with appropriate resuscitation facilities & staff available - Protocol section 8.6 now clearly documents that the study treatment must stop immediately in the event of intolerance or allergic reaction during administration. Section 8.11 also clarifies this - Protocol section 2.0 flowchart time point for follow-up now clarifies that it is post operation - Protocol section 11.4 now states that SAEs will be reported to LSHTM CTU within 24 hours of their knowledge - Protocol section 8.4 now clarifies that the treating clinical physician will have the final decision to unblind, & that the reason & rational will be discussed with the PREVENTT office at UCL
    23 May 2013
    Summary of the main changes: - Physical Examination removed as this data will not be collected or needed and ECG monitoring removed from post baseline assessments as ECG monitoring not required by safety profile of IMP and some sites do not routinely perform this - Clarification to co-primary endpoint relating to risk of blood transfusion or death, and have added that deaths will be adjusted for in the analysis. - POMS: this data also needs to be collected at day 5, due to patients being discharged much sooner nowadays - Health Economics: these sections revised following review and update from the trial Health Economist - TSC & DSMC: membership of both these committees has been added, now they have been approved by the HTA - AE section: revised to reflect the LSHTM CTU AE processes (because the sponsor has delegated this responsibility to the LSHTM CTU) - Restarting treatment: following on from review by the TSC it was agreed that the treatment could be restarted under certain conditions
    14 Jan 2014
    Summary of main changes: - Changes made in light of updated advice from the MHRA on IV iron: a) added two new exclusion criteria (patients with severe asthma or severe allergy, patients unfit for elective surgery), and b) added the new information that patients should be monitored for at least 30 minutes following treatment - Updated the side effects to reflect changes in the latest version of the SmPC - Changes made to the preoperative visit: this additional visit to hospital has been removed and the preoperative QoL forms will now be completed at home, and the central bloods done on admission to hospital (sites had difficulties fitting in this extra visit) - Changes to the timelines from treatment to surgery: the lower limit of this timeline shortened from 14 to 10 days, as sites found this restrictive when trying to recruit and it also meant cancer patients were excluded (agreed by the TSC that 10 days was sufficient time for the IV iron to take effect) - Further clarified documentation for drug returns and drug destruction to ensure blinding is not compromised by blinded staff at site and the wording relating to destruction of remaining drug has been removed - Included the system which will be used to document the post-operative complications (Clavien) - Included UE tests as a requirement rather than if available in follow-up visits as this is needed to calculate eGFR - Further clarification to haemoglobin measurements, immunosuppressive therapy in exclusion criteria, timing of screening pregnancy test, vital signs assessment, DSUR and APR anniversary dates and non exclusion of those on oral iron supplements’ - Clarified IMP administration masking with iodine so that it allows flexibility of other methods in the event of those patients who are allergic to iodine - Added additional details so sites can call patients prior to consenting (as requested by site R&Ds)
    10 Apr 2015
    Summary of main changes: - Changed inclusion criteria to increase the upper limit of haemoglobin for men, to match the WHO definition of anaemia, and to help aid recruitment - Amended the definition of major surgery, so sites can now include patients having surgery which doesn’t include the removal of an organ - Changed the exclusion criteria so that is it clear that only untreated B12/folate deficiency would make a patient ineligible - Added in how severe asthma/allergy is defined in the exclusion criteria - Increased the number of sites from 20 to 35, to help aid recruitment - Removed brand names of masking IV bags and giving sets to allow flexibility across sites - Included 200ml vials of Ferinject to allow flexibility in use of hospital stocks across sites - SAE form can be submitted via online AE database - Data monitoring changed to reflect new Monitoring SOP requirements - Administrative changes to update TSC members and observers
    05 Sep 2016
    Summary of main changes: - Changed exclusion criteria for Liver Function Tests (LFTs) to reflect local hospital practise and pathways - Changed exclusion criteria so that patients who have had a previous blood transfusion within the previous 12 weeks can still be included in the trial - Changed assessment of LFTs at baseline to clarify this is only done if clinically indicated according to local hospital practice and pathways - Updated the risk/benefits section of the protocol to reflect the change to the exclusion criteria for patients who have not had their LFTs checked - Increased the number of sites from 35 to 40 to help with recruitment - Update to reflect the approval by the funder of an additional 2 years of recruitment - Updated summary of product characteristics

    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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