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    Clinical Trial Results:
    Exploratory multicentre prospective double blinded randomised controlled pilot study of the effect of intravenous iron supplementation(Monofer)in iron deficient but not anaemic patients with Chronic Kidney Disease stages 3b or worse on functional status and cardiac structure and function.

    Summary
    EudraCT number
    2014-004133-16
    Trial protocol
    GB  
    Global end of trial date
    21 May 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    21 May 2022
    First version publication date
    21 May 2022
    Other versions
    Summary report(s)
    doi: 10.1186/s12882-021-02308-y

    Trial information

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    Trial identification
    Sponsor protocol code
    R1766
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Hull University Teaching Hospitals NHS Trust
    Sponsor organisation address
    Castle Road, Cottingham, United Kingdom, HU16 5JQ
    Public contact
    Research and Development Office , Hull University Teaching Hospitals NHS Trust , +44 01482 461903, research.development@hey.nhs.uk
    Scientific contact
    Academic Renal Research Office , Hull University Teaching Hospitals NHS Trust , +44 01482 605260, sunil.bhandari@hey.nhs.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    21 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether IV iron supplementation in iron deficient non-anaemic CKD patients improves physical and functional status assessed by the 6MWT and questionnaires (KDQoL and MLHF).
    Protection of trial subjects
    Safety assessment will occur continuously throughout the trial. Medical history at baseline will be recorded. A Physical examination along with blood sampling for routine biochemistry paying particular attention to renal excretory function and electrolytes as in the attached Table. Participants will be contacted by phone by a study nurse after 1 week for a safety assessment and evidence of adverse events will be sought at each routine follow-up visit. The participant will be asked to contact their study nurse if they have any concerns about safety at any time in between routine follow-up visits for the trial. Serious adverse events will be identified and documented on the CRF at routine visits, based on participant reports and primary or secondary care reports. In addition, episodes of infection requiring hospitalisation and other infection episodes will be documented. In addition, haemoglobin, ferritin, platelet levels, and other laboratory measurements detailed above will be monitored.
    Background therapy
    Intravenous saline was used as placebo for this trial. No other treatment was used in the trial apart from the trial drug and placebo.
    Evidence for comparator
    Trial evidence on the effectiveness and safety of Monofer® in CKD is sparse but expanding; this is reflected in current guidelines, which provide no specific didactic instructions for its administration in patients with CKD. Thus, the proposed trial logically follows on from initial studies, and proposes an exploratory randomized double blinded placebo controlled pilot trial (using dummy solution normal saline without the added drug) in patients with CKD stages G3b to 5 (pre-dialysis) to address this issue further and fill the gap in knowledge. Also within the trial are mechanistic studies which will add to and advance our scientific understanding of these data.
    Actual start date of recruitment
    02 Mar 2015
    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: 54
    Worldwide total number of subjects
    54
    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)
    54
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants will be recruited from at least 3 renal units in the UK. Currently, patients with CKD under the care of a nephrologist are reviewed every 3-4 months in a hospital outpatient clinic. Potential trial participants will be identified when presenting for their routine hospital clinic visits. This reflects the proposed research care.

    Pre-assignment
    Screening details
    Fifty–four patients aged 18 years or over with CKD (stage G3b to G5) will be enrolled. Each patient must meet all of the inclusion criteria, and none of the exclusion criteria, at entry to the trial. Patients who meet the entry criteria may be recruited by the investigator or any medically qualified member of the local trial team who has delegated.

    Period 1
    Period 1 title
    Visit 1
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Test
    Arm description
    Addition of IV Monofer® 1g. Patient will receive 100ml of normal saline 0.9% with addition of Iron Isomaltoside (Monofer®) 1000mg infused intravenously over 30 minutes as a single total dose infusion.
    Arm type
    Active comparator

    Investigational medicinal product name
    IV Monofer 1g
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Addition of IV Monofer® 1g. Patient will receive 100ml of normal saline 0.9% with addition of Iron Isomaltoside (Monofer®) 1000mg infused intravenously over 30 minutes as a single total dose infusion.

    Arm title
    Placebo
    Arm description
    Placebo – IV inert solution (no iron therapy). Patient will receive placebo (100ml of normal saline 0.9% only) infused intravenously over 30 minutes as a single total dose infusion.
    Arm type
    Placebo

    Investigational medicinal product name
    0.9% Saline solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patient will receive placebo (100ml of normal saline 0.9% only) infused intravenously over 30 minutes as a single total dose infusion.

    Number of subjects in period 1
    Test Placebo
    Started
    26
    28
    Completed
    26
    28
    Period 2
    Period 2 title
    Visit 2
    Is this the baseline period?
    Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Test
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    IV Monofer 1g
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Addition of IV Monofer® 1g. Patient will receive 100ml of normal saline 0.9% with addition of Iron Isomaltoside (Monofer®) 1000mg infused intravenously over 30 minutes as a single total dose infusion.

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    0.9% Saline solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patient will receive placebo (100ml of normal saline 0.9% only) infused intravenously over 30 minutes as a single total dose infusion.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Visit 1 is the screening visit performed at week -4 to -2 to ensure compliance with the eligibility criteria.
    Number of subjects in period 2
    Test Placebo
    Started
    26
    28
    Completed
    26
    28
    Period 3
    Period 3 title
    Visit 3
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Test
    Arm description
    Addition of IV Monofer® 1g. Patient will receive 100ml of normal saline 0.9% with addition of Iron Isomaltoside (Monofer®) 1000mg infused intravenously over 30 minutes as a single total dose infusion.
    Arm type
    Active comparator

    Investigational medicinal product name
    IV Monofer 1g
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Addition of IV Monofer® 1g. Patient will receive 100ml of normal saline 0.9% with addition of Iron Isomaltoside (Monofer®) 1000mg infused intravenously over 30 minutes as a single total dose infusion.

    Arm title
    Placebo
    Arm description
    Placebo – IV inert solution (no iron therapy). Patient will receive placebo (100ml of normal saline 0.9% only) infused intravenously over 30 minutes as a single total dose infusion.
    Arm type
    Placebo

    Investigational medicinal product name
    0.9% Saline solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patient will receive placebo (100ml of normal saline 0.9% only) infused intravenously over 30 minutes as a single total dose infusion.

    Number of subjects in period 3
    Test Placebo
    Started
    26
    28
    Completed
    26
    28
    Period 4
    Period 4 title
    Visit 4
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Test
    Arm description
    Addition of IV Monofer® 1g. Patient will receive 100ml of normal saline 0.9% with addition of Iron Isomaltoside (Monofer®) 1000mg infused intravenously over 30 minutes as a single total dose infusion.
    Arm type
    Active comparator

    Investigational medicinal product name
    IV Monofer 1g
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Addition of IV Monofer® 1g. Patient will receive 100ml of normal saline 0.9% with addition of Iron Isomaltoside (Monofer®) 1000mg infused intravenously over 30 minutes as a single total dose infusion.

    Arm title
    Placebo
    Arm description
    Placebo – IV inert solution (no iron therapy). Patient will receive placebo (100ml of normal saline 0.9% only) infused intravenously over 30 minutes as a single total dose infusion.
    Arm type
    Placebo

    Investigational medicinal product name
    0.9% Saline solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patient will receive placebo (100ml of normal saline 0.9% only) infused intravenously over 30 minutes as a single total dose infusion.

    Number of subjects in period 4
    Test Placebo
    Started
    26
    28
    Completed
    26
    28
    Period 5
    Period 5 title
    Visit 5
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Test
    Arm description
    Addition of IV Monofer® 1g. Patient will receive 100ml of normal saline 0.9% with addition of Iron Isomaltoside (Monofer®) 1000mg infused intravenously over 30 minutes as a single total dose infusion.
    Arm type
    Active comparator

    Investigational medicinal product name
    IV Monofer 1g
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Addition of IV Monofer® 1g. Patient will receive 100ml of normal saline 0.9% with addition of Iron Isomaltoside (Monofer®) 1000mg infused intravenously over 30 minutes as a single total dose infusion.

    Arm title
    Placebo
    Arm description
    Placebo – IV inert solution (no iron therapy). Patient will receive placebo (100ml of normal saline 0.9% only) infused intravenously over 30 minutes as a single total dose infusion.
    Arm type
    Placebo

    Investigational medicinal product name
    0.9% Saline solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patient will receive placebo (100ml of normal saline 0.9% only) infused intravenously over 30 minutes as a single total dose infusion.

    Number of subjects in period 5
    Test Placebo
    Started
    26
    28
    Completed
    26
    28

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    Test
    Reporting group description
    Addition of IV Monofer® 1g. Patient will receive 100ml of normal saline 0.9% with addition of Iron Isomaltoside (Monofer®) 1000mg infused intravenously over 30 minutes as a single total dose infusion.

    Reporting group title
    Placebo
    Reporting group description
    Placebo – IV inert solution (no iron therapy). Patient will receive placebo (100ml of normal saline 0.9% only) infused intravenously over 30 minutes as a single total dose infusion.
    Reporting group title
    Test
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -
    Reporting group title
    Test
    Reporting group description
    Addition of IV Monofer® 1g. Patient will receive 100ml of normal saline 0.9% with addition of Iron Isomaltoside (Monofer®) 1000mg infused intravenously over 30 minutes as a single total dose infusion.

    Reporting group title
    Placebo
    Reporting group description
    Placebo – IV inert solution (no iron therapy). Patient will receive placebo (100ml of normal saline 0.9% only) infused intravenously over 30 minutes as a single total dose infusion.
    Reporting group title
    Test
    Reporting group description
    Addition of IV Monofer® 1g. Patient will receive 100ml of normal saline 0.9% with addition of Iron Isomaltoside (Monofer®) 1000mg infused intravenously over 30 minutes as a single total dose infusion.

    Reporting group title
    Placebo
    Reporting group description
    Placebo – IV inert solution (no iron therapy). Patient will receive placebo (100ml of normal saline 0.9% only) infused intravenously over 30 minutes as a single total dose infusion.
    Reporting group title
    Test
    Reporting group description
    Addition of IV Monofer® 1g. Patient will receive 100ml of normal saline 0.9% with addition of Iron Isomaltoside (Monofer®) 1000mg infused intravenously over 30 minutes as a single total dose infusion.

    Reporting group title
    Placebo
    Reporting group description
    Placebo – IV inert solution (no iron therapy). Patient will receive placebo (100ml of normal saline 0.9% only) infused intravenously over 30 minutes as a single total dose infusion.

    Primary: 6MWT

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    End point title
    6MWT
    End point description
    Adjusting for baseline 6MWT, the 6MWT in the main study participants at 1 month and 3 months showed no statistically significant difference between FDI and placebo arms (p = 0.736 and 0.741 respectively). (Fig. 1). Analysis of change in 6MWT showed that the mean (SD) change for FDI patients from baseline to 3 months was 6.0 (89.1) metres compared to 1.9 (111.2) metres for the placebo arm patients (Suppl Table 1). During follow up there was a greater than 25 m increase in 6MWT observed in 8/22 (36.4%) of patients at 1 month and 10/20 (50%) at 3 months in the FDI arm vs 8/25 (32% - 1 month) and 10/24 (41.7% - 3 months) patients in the placebo arm, respectively (p = 0.753, p = 0.580).
    End point type
    Primary
    End point timeframe
    1month and 3 month
    End point values
    Test Placebo Test Placebo
    Number of subjects analysed
    22 [1]
    25 [2]
    20 [3]
    24 [4]
    Units: meters
        arithmetic mean (standard deviation)
    3.5 ± 108.1
    5.0 ± 58.8
    6.0 ± 89.1
    1.9 ± 111.2
    Notes
    [1] - Some participant's could not perform the 6 minute walking test due to other health conditions.
    [2] - Some participant's could not perform the 6 minute walking test due to other health conditions.
    [3] - Some participant's could not perform the 6 minute walking test due to other health conditions.
    [4] - Some participant's could not perform the 6 minute walking test due to other health conditions.
    Statistical analysis title
    Change from baseline to 1 month, 6MWT
    Comparison groups
    Test v Placebo
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Chi-squared corrected
    Parameter type
    N/A
    Point estimate
    0
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0
         upper limit
    0
    Statistical analysis title
    Change from baseline to 1 month, 6MWT
    Comparison groups
    Test v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.895
    Method
    Chi-squared
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0
         upper limit
    0
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Safety assessment will occur continuously throughout the trial and at each follow-up.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Test (IV Iron)
    Reporting group description
    Arm of the trial under test.

    Reporting group title
    Placebo
    Reporting group description
    Arm of the study under placebo.

    Serious adverse events
    Test (IV Iron) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 28 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Test (IV Iron) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 26 (34.62%)
    9 / 28 (32.14%)
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    General disorders and administration site conditions
    Hypoglycaemia
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    Lung cancer
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    Gout
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    Had IV fluid for elective CT scan
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    Blood and lymphatic system disorders
    Poor blood pressure control
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    Respiratory, thoracic and mediastinal disorders
    shortness of breath
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    Cough
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    Skin and subcutaneous tissue disorders
    per rectal bleeding
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    Influenza
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    Chronic obstructive pulmonary disease
    Additional description: Exacerbation.
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jan 2016
    Protocol • Protocol page 18 – Condoms have been added to the list of acceptable contraceptives in the first exclusion criterion • Protocol page 18 – Added ‘N.B. Women of childbearing potential using condoms only as a contraceptive method will require a pregnancy test at the baseline visit, prior to administration of Monofer® therapy’ to first exclusion criterion • Protocol page 21 – Added ‘Women of childbearing potential using condoms only as a contraceptive method will additionally require a pregnancy test at the baseline visit, prior to administration of Monofer® therapy.’
    07 Dec 2016
    Protocol • In the original CT application, Question A28 “Will any participants be recruited by publicity through posters, leaflets, adverts or websites?” was answered “No”. This has now been changed to “Yes”. The study may now be advertised on patient facing websites and newsletters. • The number of patients in, Control Group 2 – patients with Chronic Kidney Disease without iron deficiency and anaemia, has been reduced from 20 to 10. This reduction in size does not affect the primary outcome. The following non-substantial amendments were also made: • An extension to the end date of study from 01.04.16 to 01.07.18. • In the Safety Reporting section of the protocol we have added some clarification to the type of infection that requires recording in the Case Report Form.
    27 Mar 2017
    Protocol • This amendment only affects the Hull site. Page numbers amended: 14, 16, 20, 21, 22, 35 and 39. The number of patients in the parallel sub-study (Group 4) has been changed from 6 to 4.

    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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    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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