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    Clinical Trial Results:
    A pilot trial of intravenous iron for the treatment of iron deficiency in adult patients with cystic fibrosis

    Summary
    EudraCT number
    2018-002366-39
    Trial protocol
    GB  
    Global end of trial date
    30 Sep 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Apr 2023
    First version publication date
    23 Apr 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    12800
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03632525
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Oxford / Clinical Trials and Research Governance
    Sponsor organisation address
    Joint Research Office, Boundary Brook House, Churchill Drive, Headington, Oxford, United Kingdom, OX3 7LE
    Public contact
    CTRG, University of Oxford / Clinical Trials and Research Governance, 00 000000, ctrg@admin.ox.ac.uk
    Scientific contact
    CTRG, University of Oxford / Clinical Trials and Research Governance, 00 000000, ctrg@admin.ox.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    02 May 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the early safety profile of IV iron in adults with CF by comparing the incidence of new infective events during the 4 weeks before and after IV iron
    Protection of trial subjects
    The trial interventions were all standard clinical interventions to which the participants could be exposed in routine clinical practice, and all were delivered with the same safeguards/safety measures that would have been used in routine clinical practice. Trial-specific data and samples were handled /managed according to standard GCP and clinical trial regulations.
    Background therapy
    Participants continued on their standard background therapy for cystic fibrosis, including antibiotics and mucolytic therapy. The details of this therapy varied between participants, and was not influenced by participation in the clinical trial.
    Evidence for comparator
    This was an interventional cohort study in which all participants received the main study intervention (intravenous iron, as ferric carboxymaltose). The primary comparison was between the incidence of new infective events in the four weeks before and the four weeks after the study intervention.
    Actual start date of recruitment
    11 Mar 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    20
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were all recruited in a single centre (Oxford) in the UK, during the period 11/03/2019 to 12/12/2019.

    Pre-assignment
    Screening details
    Participants with iron deficiency were identified by the clinical team, and screened for eligibility based on the inclusion/exclusion criteria.

    Pre-assignment period milestones
    Number of subjects started
    20
    Number of subjects completed
    20

    Period 1
    Period 1 title
    Pre iron
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    No blinding or allocation method - all participants received the study intervention (intravenous ferric carboxymaltose) in an open label design.

    Arms
    Arm title
    All participants (pre iron)
    Arm description
    Participants were studied as a single group in this intervention cohort study, in which the primary comparison is bring made between the pre- and post-iron periods for the cohort.
    Arm type
    Experimental

    Investigational medicinal product name
    Ferric carboxymaltose (Ferinject)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dose of ferric carboxymaltose (Ferinject) used was 20 mg/kg, up to a maximum dose of 1000 mg for patients with a haemoglobin concentration less than 14 g/dL or a maximum of 500 mg for patients with a haemoglobin concentration more than or equal to 14 g/dL. The appropriate dose was given in 250 ml of normal (0.9%) saline over 15 minutes.

    Number of subjects in period 1
    All participants (pre iron)
    Started
    20
    Visit 1 (baseline, 4 weeks pre iron)
    20
    Visit 2 (day of iron administration)
    20
    Completed
    20
    Period 2
    Period 2 title
    Post iron
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    No blinding or allocation method - all participants received the study intervention (intravenous ferric carboxymaltose) in an open label design

    Arms
    Arm title
    All participants (post iron)
    Arm description
    Participants were studied as a single group in this intervention cohort study, in which the primary comparison is bring made between the pre- and post-iron periods for the cohort.
    Arm type
    Experimental

    Investigational medicinal product name
    Ferric carboxymaltose (Ferinject)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dose of ferric carboxymaltose (Ferinject) used was 20 mg/kg, up to a maximum dose of 1000 mg for patients with a haemoglobin concentration less than 14 g/dL or a maximum of 500 mg for patients with a haemoglobin concentration more than or equal to 14 g/dL. The appropriate dose was given in 250 ml of normal (0.9%) saline over 15 minutes.

    Number of subjects in period 2
    All participants (post iron)
    Started
    20
    Visit 3 (4 weeks post iron)
    20
    Visit 4 (12 weeks post iron)
    20
    Completed
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pre iron
    Reporting group description
    -

    Reporting group values
    Pre iron Total
    Number of subjects
    20 20
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    20 20
    Age continuous
    Age of participants at recruitment
    Units: years
        arithmetic mean (standard deviation)
    30.1 ± 10.2 -
    Gender categorical
    Units: Subjects
        Female
    10 10
        Male
    10 10
    Chronic Pseudomonas colonisation
    Number of patients known to have chronic Pseudomonas colonisation.
    Units: Subjects
        Pseudomonas colonisation
    10 10
        No Pseudomonas colonisation
    10 10
    Body mass index
    Units: kg/m2
        arithmetic mean (standard deviation)
    22.7 ± 4.4 -
    Forced expiratory volume in 1 second (FEV1)
    Units: % predicted value
        arithmetic mean (standard deviation)
    63 ± 22.2 -
    Ferritin
    Units: microgram(s)/litre
        arithmetic mean (standard deviation)
    11.9 ± 10.1 -
    Haemoglobin
    Blood haemoglobin concentration
    Units: gram(s)/litre
        arithmetic mean (standard deviation)
    124 ± 21 -
    Subject analysis sets

    Subject analysis set title
    All participants
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All participants

    Subject analysis sets values
    All participants
    Number of subjects
    20
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    20
    Age continuous
    Age of participants at recruitment
    Units: years
        arithmetic mean (standard deviation)
    30.1 ± 10.2
    Gender categorical
    Units: Subjects
        Female
    10
        Male
    10
    Chronic Pseudomonas colonisation
    Number of patients known to have chronic Pseudomonas colonisation.
    Units: Subjects
        Pseudomonas colonisation
    10
        No Pseudomonas colonisation
    10
    Body mass index
    Units: kg/m2
        arithmetic mean (standard deviation)
    22.7 ± 4.4
    Forced expiratory volume in 1 second (FEV1)
    Units: % predicted value
        arithmetic mean (standard deviation)
    63 ± 22.2
    Ferritin
    Units: microgram(s)/litre
        arithmetic mean (standard deviation)
    11.9 ± 10.1
    Haemoglobin
    Blood haemoglobin concentration
    Units: gram(s)/litre
        arithmetic mean (standard deviation)
    124 ± 21

    End points

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    End points reporting groups
    Reporting group title
    All participants (pre iron)
    Reporting group description
    Participants were studied as a single group in this intervention cohort study, in which the primary comparison is bring made between the pre- and post-iron periods for the cohort.
    Reporting group title
    All participants (post iron)
    Reporting group description
    Participants were studied as a single group in this intervention cohort study, in which the primary comparison is bring made between the pre- and post-iron periods for the cohort.

    Subject analysis set title
    All participants
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All participants

    Primary: New infective events (4 weeks)

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    End point title
    New infective events (4 weeks)
    End point description
    The primary outcome is a comparison of the incidence of new infective events in the 4-week period before iron infusion (i.e. between the baseline visit and visit 2) and the 4-week period after iron infusion (i.e. between visits 2 and 3). A deterioration of infective status was defined as ANY one of the following: • New microbiological isolate in sputum (i.e. an organism not cultured during the prior 12 months) • Clinical infection requiring intravenous antibiotics (as judged by the clinical team) • Admission to hospital for infection-related reason (as judged by clinical team) • More than 10% fall in FEV1, not otherwise explained (as judged by clinical team)
    End point type
    Primary
    End point timeframe
    Comparison of infective events in four weeks prior to IV ferric carboxymaltose and four weeks following
    End point values
    All participants (pre iron) All participants (post iron) All participants
    Number of subjects analysed
    20 [1]
    20 [2]
    20
    Units: % experiencing infective event
        number (not applicable)
    20
    20
    20
    Attachments
    Baseline characteristics and primary outcome
    Notes
    [1] - Cohort study: the 20 patients in the pre-iron group are the same as those in the post-iron group.
    [2] - Cohort study: the 20 patients in the pre-iron group are the same as those in the post-iron group.
    Statistical analysis title
    Incidence of infective events (primary outcome)
    Statistical analysis description
    Comparison on incidence of infective events in four weeks prior to iron, compared with four weeks after iron administration, using McNemar's test.
    Comparison groups
    All participants (pre iron) v All participants (post iron)
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    > 0.9 [4]
    Method
    Mcnemar
    Confidence interval
    Notes
    [3] - This is an interventional cohort study in which the primary comparison is between the four week period before iron administration and the four week period after iron administration. All 20 participants (i.e. the whole study cohort) are included in the analysis. The automatically populated data above wrongly suggests that 40 participants are included because the pre- and post-iron groups (which are in fact the same participants) have been added together.
    [4] - No evidence for any difference in the incidence of infective events in the four week period before iron compared with the four week period after iron administration.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of baseline visit to end of final study visit
    Adverse event reporting additional description
    All adverse events included, whether before or after iron. Note that the protocol includes a list of symptoms/clinical events that occur commonly in patients with cystic fibrosis. These symptoms/events were recorded as adverse events only if new or worse than usual for the patients (or if felt to be directly attributable to iron administration).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    All participants
    Reporting group description
    This is an interventional cohort study, so there is a single reporting group. All 20 participants received a single dose of ferric carboxymaltose. Adverse events occuring both before and after the iron administration are included.

    Serious adverse events
    All participants
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 20 (35.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Gastrointestinal disorders
    Distal intestinal obstruction syndrome
    Additional description: Distal intestinal obstruction syndrome (DIOS) requiring admission.
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
    Additional description: Haemoptysis requiring admission
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Respiratory tract infection
    Additional description: Infective exacerbation of cystic fibrosis, requiring admission to hospital. This study is investigating whether iron may indirectly contribute to infective episodes (see primary outcome), but none was felt to be directly attributable to iron.
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    All participants
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 20 (100.00%)
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Headache
    Additional description: Headache, new or worse than normal for participant.
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    6
    General disorders and administration site conditions
    Fatigue
    Additional description: Fatigue, new or worse than usual for participant, and not felt to be attributable to infective exacerbation.
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    5
    Flu-like symptoms
    Additional description: Flu-like symptoms, not felt to be attributable to infective exacerbation (or other infection).
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    4
    Myalgia
    Additional description: Myalgia, new or worse than normal for participant, and not felt to be attributable to infective exacerbation.
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Fever
    Additional description: Fever, not felt to be attributable to infection.
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Gastrointestinal upset
    Additional description: Diarrhoea/gastrointestinal upset, new or worse than normal for participant.
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    4
    Sore throat
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Respiratory tract infection
    Additional description: Infective exacerbation not requiring admission (including those for which intravenous antibiotics were given at home).
         subjects affected / exposed
    12 / 20 (60.00%)
         occurrences all number
    15
    Haemoptysis
    Additional description: Haemoptysis not requiring admission, and not felt to be attributable to infective exacerbation.
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    6
    Cough
    Additional description: Cough, new or worse than normal for participant, and not felt to be attributable to infective exacerbation.
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Chest tightness
    Additional description: Chest tightness or wheeze, new or worse than normal for participant, and not felt to be attributable to infective exacerbation.
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Chest pain
    Additional description: Chest or rib pain, new or worse than normal for participant, and not felt to be attributable to infective exacerbation.
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Dyspnoea
    Additional description: Dyspnoea, new or worse than normal for participant, and not felt to be attributable to infective exacerbation.
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Sputum increased
    Additional description: Increased sputum production, worse than normal for participant, and not felt to be attributable to infective exacerbation.
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Hepatobiliary disorders
    High ALP
    Additional description: Elevated alkaline phosphatase, not normal for patient.
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Tongue blistering
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Muscle cramps
    Additional description: Muscle cramps, new or worse than normal for participant.
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Infections and infestations
    Sputum culture positive
    Additional description: Isolation of new organism in sputum culture (i.e. not identified in previous 12 months). Long term/recurrent isolates were not regarded as an adverse event, as this is normal finding in this patient group.
         subjects affected / exposed
    7 / 20 (35.00%)
         occurrences all number
    10
    High CRP
    Additional description: High c-reactive protein (CRP), not normal for participant, and not felt to be attributable to infective exacerbation.
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
    Additional description: Hyperglycaemia, worse than normal for participant, and not felt to be attributable to infective exacerbation.
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Nov 2019
    The primary purpose of this substantial amendment was to update the list of foreseeable events, and clarify the procedure for recording/collections of these events. The amendment also included some changes to the wording of several other sections, including around safety monitoring and assessment of adverse events, to reflect changes to the standard wording used by the Sponsor for clinical studies.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    27 Mar 2020
    Following the final study visit, the analysis and laboratory work associated with the study was paused due to the global COVID-19 pandemic.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The results of the primary outcome have been posted, along with baseline characteristics and adverse events. The analysis of secondary outcomes will be completed and published in due course.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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