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    Clinical Trial Results:
    A Randomized, Open-Label, Active-Controlled Study of the Safety, Efficacy, and Pharmacokinetics of Ferumoxytol Compared with Oral Iron for the Treatment of Iron Deficiency Anemia in Pediatric Subjects with Chronic Kidney Disease.

    Summary
    EudraCT number
    		 2010-019387-37
    Trial protocol
    		 DE   GB   HU   ES   RO   LT   BG  
    Global end of trial date
    24 Jun 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Dec 2017
    First version publication date
    13 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AMAG-FER-CKD-251
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01155375
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AMAG Pharmaceuticals, Inc.
    Sponsor organisation address
    1100 Winter Street, Waltham , United States, 02451
    Public contact
    Medical Information, AMAG Pharmaceuticals, Inc., +1 877-411-2510, amag@druginfo.com
    Scientific contact
    Medical Information, AMAG Pharmaceuticals, Inc., +1 877-411-2510, amag@druginfo.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000373-PIP02-09
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Jun 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jun 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jun 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This study (AMAG-FER-CKD-251) was a study evaluating the efficacy and safety of intravenous (IV) ferumoxytol in pediatric participants with dialysis-dependent chronic kidney disease (CKD). Study AMAG-FER-CKD-252 (2010-019388-12) was a study evaluating the efficacy and safety of IV ferumoxytol in pediatric participants with nondialysis-dependent CKD. Due to significant challenges with enrollment for both studies, Study AMAG-FER-CKD-252 was combined with Study AMAG-FER-CKD-251, and enrollment continued under Study AMAG-FER-CKD-251. The significant challenges with enrollment then led the sponsor to discontinue the combined AMAG FER-CKD-251 and AMAG FER-CKD-252 studies. The analysis of the primary completion data and the results for the combined studies are included in this record. The enrollment number (n=14) includes the number of participants for both AMAG-FER-CKD-251 and AMAG-FER-CKD-252 studies, combined.
    Protection of trial subjects
    These studies were conducted according to international standards of Good Clinical Practice, International Conference on Harmonization (ICH), United States Food and Drug Administration regulations, applicable government regulations, and institutional research policies and procedures. AMAG will also continue to support the principles of the Declaration of Helsinki. All participants were to remain in the clinic for 1 hour following each IV injection of ferumoxytol, with frequent monitoring of vital signs and close observation for adverse events.
    Background therapy
    		 There was no background therapy administered across all participant groups.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Oct 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 5
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Peru: 4
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Germany: 1
    Worldwide total number of subjects
    14
    EEA total number of subjects
    3
    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)
    1
    Adolescents (12-17 years)
    13
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study population will consist of pediatric participants (6 months to <18 years of age) with iron deficiency anemia defined as hemoglobin <12.0 grams/deciliter and with either transferrin saturation ≤40%, or ferritin <100 nanograms/milliliter (mL) and CKD.

    Pre-assignment
    Screening details
    		 Screening was to take place within 2 weeks of the start of the study. Screening assessments included review of inclusion/exclusion criteria, signature of informed consent, medical history, vital signs measurement, physical examination, clinical laboratory assessments including iron panel, and start of AE capture.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was a randomized, open-label (not blinded) study. Participants were to be randomized to either IV ferumoxytol or oral iron supplementation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ferumoxytol
    Arm description
    		 Participants received 1 of the following 2 ferumoxytol dose regimens: - Four IV injections of ferumoxytol 3.5 milligrams (mg) oral iron (Fe)/kilogram (kg) (maximum of 255 mg/dose) administered on nonconsecutive days within a 14-day period as follows: Day 1 (dose 1), Days 3* through 10 (dose 2), Days 5 through 12 (dose 3), and Days 7 through 14 (dose 4). *Participants participating in pharmacokinetic (PK) sampling received the second dose on Day 4 after the 72-hour PK sample was collected. - Two IV injections of ferumoxytol 7.0 mg Fe/kg (maximum of 510 mg/dose), the first administered on Day 1 and the second on Days 3 through 9.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ferumoxytol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ferumoxytol for IV injection: Each 20 mL single-use vial contains 17 mL of ferumoxytol that consists of iron, at a concentration of 30 mg Fe/mL, and mannitol, at a concentration of 44 mg/mL, in a black to reddish brown sterile, aqueous, colloidal, isotonic solution. The product contains no preservatives. Osmolality: 270-330 milliosmoles/kg; pH: 6-8. Administration was either 4 IV injections of ferumoxytol 3.5 mg Fe/kg (maximum 255 mg/dose) administered on nonconsecutive days within a 14-day period as follows: Day 1 (dose 1), Days 3* through 10 (dose 2), Days 5 through 12 (dose 3), and Days 7 through 14 (dose 4); or 2 IV injections of ferumoxytol 7.0 mg Fe/kg (maximum 510 mg/dose), the first administered on Day 1 and the second on Days 3* through 9. *Participants participating in PK sampling were to receive the second dose on Day 4 after the 72-hour PK sample was collected.

    Arm title
    		 Oral Iron
    Arm description
    		 Participants received oral iron (2.5 mg Fe/kg) twice daily (maximum 100 mg/dose) on Days 1 through 35.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ferrous Fumarate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    Liquid oral iron preparation (ferrous fumarate) 2.5 mg Fe/kg, administered twice daily (maximum of 100 mg/dose) on Days 1 through 35.

    Number of subjects in period 1
    		Ferumoxytol Oral Iron
    Started
    8
    6
    Received at Least One Dose of Study Drug
    8
    6
    Completed
    7
    6
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ferumoxytol
    Reporting group description
    		 Participants received 1 of the following 2 ferumoxytol dose regimens: - Four IV injections of ferumoxytol 3.5 milligrams (mg) oral iron (Fe)/kilogram (kg) (maximum of 255 mg/dose) administered on nonconsecutive days within a 14-day period as follows: Day 1 (dose 1), Days 3* through 10 (dose 2), Days 5 through 12 (dose 3), and Days 7 through 14 (dose 4). *Participants participating in pharmacokinetic (PK) sampling received the second dose on Day 4 after the 72-hour PK sample was collected. - Two IV injections of ferumoxytol 7.0 mg Fe/kg (maximum of 510 mg/dose), the first administered on Day 1 and the second on Days 3 through 9.

    Reporting group title
    Oral Iron
    Reporting group description
    		 Participants received oral iron (2.5 mg Fe/kg) twice daily (maximum 100 mg/dose) on Days 1 through 35.

    Reporting group values
    		 Ferumoxytol Oral Iron Total
    Number of subjects
    		 8 6 14
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 1 1
        Adolescents (12-17 years)
    		 8 5 13
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
        12 to <18 years old
    		 0 0 0
        6 to <12 years
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.2 ( 1.65 ) 13.8 ( 4.52 ) -
    Gender categorical
    Units: Subjects
        Female
    		 5 1 6
        Male
    		 3 5 8

    End points

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    End points reporting groups
    Reporting group title
    Ferumoxytol
    Reporting group description
    		 Participants received 1 of the following 2 ferumoxytol dose regimens: - Four IV injections of ferumoxytol 3.5 milligrams (mg) oral iron (Fe)/kilogram (kg) (maximum of 255 mg/dose) administered on nonconsecutive days within a 14-day period as follows: Day 1 (dose 1), Days 3* through 10 (dose 2), Days 5 through 12 (dose 3), and Days 7 through 14 (dose 4). *Participants participating in pharmacokinetic (PK) sampling received the second dose on Day 4 after the 72-hour PK sample was collected. - Two IV injections of ferumoxytol 7.0 mg Fe/kg (maximum of 510 mg/dose), the first administered on Day 1 and the second on Days 3 through 9.

    Reporting group title
    Oral Iron
    Reporting group description
    		 Participants received oral iron (2.5 mg Fe/kg) twice daily (maximum 100 mg/dose) on Days 1 through 35.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population includes all randomized participants who had any exposure to study drug (ferumoxytol or oral iron); the safety analysis is based on actual treatment received. Data are for the combined AMAG-FER-CKD-251 and AMAG-FER-CKD-252 studies.

    Subject analysis set title
    Intent-to-Treat (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT Population included all randomized participants who had received at least one dose of study drug. Sample data were collected, but not run through any analysis to obtain end point data. As such, summary of the data set is not possible.

    Subject analysis set title
    PK Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The PK Population included all randomized participants who received at least 1 dose of study drug and consented to PK sampling. Of the 14 participants who participated in the studies, only 1 participated in the PK sampling of the study. Sample data were collected, but not run through any analysis to obtain end point data. As such, summary of the data set is not possible.

    Primary: Mean Change In Hemoglobin From Baseline To Week 5

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    End point title
    		 Mean Change In Hemoglobin From Baseline To Week 5 [1]
    End point description
    Mean changes in hemoglobin from Baseline to Week 5 were to be presented. Despite efforts to complete the studies as designed, several factors contributed to significant challenges in enrollment and led the sponsor to discontinue the combined AMAG FER-CKD-251 and AMAG FER-CKD-252 studies. Blood samples were collected, but not run through an analysis to obtain outcome measure data. As such, the data set for this primary end point cannot be summarized nor can the statistical analysis, as described in the protocol, be provided in a way that will provide any significant data based upon the limited study datasets.
    End point type
    Primary
    End point timeframe
    Baseline, Week 5
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Sample data were collected, but not run through any analysis to obtain end point data. As such, summary and statistical analysis of the data set is not possible.
    End point values
    		 Ferumoxytol Oral Iron
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: participants
    Notes
    [2] - Sample data were collected, but not run through any analysis to obtain end point data.
    [3] - Sample data were collected, but not run through any analysis to obtain end point data.
    No statistical analyses for this end point

    Secondary: Pharmacokinetics Area Under The Curve Of Ferumoxytol

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    End point title
    		 Pharmacokinetics Area Under The Curve Of Ferumoxytol
    End point description
    Ferumoxytol concentrations were to be determined using a drug-specific nuclear magnetic resonance assay. Blood samples were to be collected at specified times predose and postdose at the time of the first dose from 6 participants in each age-dose group. Sampling for participants <6 years of age was to be minimized to the fewest number of time points required for population PK analysis based on preliminary PK data from the first two age cohorts. Blood samples were collected, but not run through an analysis to obtain end point data. As such, the data set for this secondary end point cannot be summarized in a way that will provide any significant data based upon the limited study datasets.
    End point type
    Secondary
    End point timeframe
    Baseline, 10, 30, 120, and 360 minutes and 24, 48, and 72 hours postdose
    End point values
    		 Ferumoxytol Oral Iron
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: participants
    Notes
    [4] - No analyses were performed as there was only 1 participant in the PK portion.
    [5] - No analyses were performed as there was only 1 participant in the PK portion.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Randomization up to 7 weeks (Follow-up)
    Adverse event reporting additional description
    Due to significant challenges with enrollment for both studies, Study AMAG-FER-CKD-251 was combined with Study AMAG-FER-CKD-252 (2010-019388-12) and enrollment continued under Study AMAG-FER-CKD-251. The adverse events for the combined studies are included in this record.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Ferumoxytol
    Reporting group description
    		 Participants received 1 of 2 of the following ferumoxytol dose regimens: - Four IV injections of ferumoxytol 3.5 mg Fe/kg (maximum of 255 mg/dose) administered on nonconsecutive days within a 14-day period as follows: Day 1 (dose 1), Days 3* through 10 (dose 2), Days 5 through 12 (dose 3), and Days 7 through 14 (dose 4). *Participants participating in PK sampling received the second dose on Day 4 after the 72-hour PK sample was collected. - Two IV injections of ferumoxytol 7.0 mg Fe/kg (maximum of 510 mg/dose), the first administered on Day 1 and the second on Days 3 through 9.

    Reporting group title
    Oral Iron
    Reporting group description
    		 Participants received oral iron (2.5 mg Fe/kg) twice daily (maximum 100 mg/dose) on Days 1 through 35.

    Serious adverse events
    		 Ferumoxytol Oral Iron
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Infections and infestations
    Acute gastroenteritis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ferumoxytol Oral Iron
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 8 (75.00%)
    5 / 6 (83.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Investigations
    Residual urine volume decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Procedural hypotension
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Procedural nausea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Skin injury
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Cardiac disorders
    Ventricular flutter
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Food poisoning
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Chronic sinusitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Viral pharyngitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Fluid retention
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Hypermagnesaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 May 2013
    Major changes included: combined dialysis and nondialysis-dependent participants (nondialysis-dependent participants previously studied separately in CKD-252 were combined with CKD-251); updated total number of participants from 144 to 288; inclusion/exclusion criteria changes; administrative changes. Rationale for changes included: conducting a single protocol in CKD participants aligned with the current approved label (potential efficiencies gained in the conduct of a single protocol); modification of entry criteria based on feedback from physicians regarding iron treatment protocols in this population.
    12 Jul 2013
    Major change was the change in comparator sourcing. The rationale for the change was that the original comparator supply (ferrous sulfate) expired on 30-Jun-2013 and was no longer being manufactured. As such, the Sponsor identified a new comparator product (ferrous fumarate) to be used in the clinical study.

    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.
    While sample data were collected, it was not run through any analysis to obtain the necessary end point data. As such, summary of the data set is not possible.
    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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