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    Clinical Trial Results:
    An Open-Label Multi-center, Multiple Dose Study to Determine the Optimum Starting Dose of Intravenous MIRCERA for Maintenance Treatment of Anemia in Pediatric Participants With chronic Kidney Disease on Hemodialysis

    Summary
    EudraCT number
    		 2007-007758-70
    Trial protocol
    		 BE   DE   ES   FR   HU   IT  
    Global end of trial date
    28 Mar 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    24 Aug 2017
    First version publication date
    15 Oct 2016
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    NH19707
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00717366
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000172-PIP01-07
    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
    28 Mar 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the optimum starting dose of methoxy polyethylene glycol-epoetin beta (MIRCERA) in pediatric participants with chronic kidney disease (CKD) on hemodialysis when switching from stable maintenance treatment with epoetin alfa, epoetin beta or darbepoetin alfa; to demonstrate changes in hemoglobin (Hb) over time in response to different intravenous (IV) doses of MIRCERA; to study the pharmacokinetics (PK) and exposure-response relationship of MIRCERA; to assess the safety and tolerability of multiple doses of MIRCERA; and to document long-term safety and efficacy of MIRCERA.
    Protection of trial subjects
    The study was conducted in full conformance with the principles of the “Declaration of Helsinki” or with the laws and regulations of the country in which the research was conducted, whichever affords the greater protection to the individual. The study fully adhered to the principles outlined in “Guideline for Good Clinical Practice (GCP)” International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Tripartite Guideline and ensured compliance with the EU Clinical Trial Directive [2001/20/EC]. Approval from the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and the relevant Competent Authority was obtained before study start.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jul 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    France: 22
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Thailand: 2
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Ukraine: 3
    Worldwide total number of subjects
    64
    EEA total number of subjects
    59
    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)
    25
    Adolescents (12-17 years)
    39
    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
    		 -

    Pre-assignment
    Screening details
    		 A total of 112 participants were screened at 28 sites in 10 countries, of which 64 participants were enrolled (16 initially in MIRCERA Group 1 and then 48 in MIRCERA Group 2, following a preliminary analysis of MIRCERA Group 1).

    Period 1
    Period 1 title
    Core Study Period (20 weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MIRCERA Group 1: Intermediate-Conversion-Factor Group
    Arm description
    		 Participants received MIRCERA IV injection at a starting dose based on an intermediate conversion factor from their previous Erythropoiesis-Stimulating Agent (ESA) dose (4 * previous weekly epoetin dose [international units {IU}]/250 or 4 * previous weekly darbepoetin alfa dose [micrograms {mcg}]/1.1) once every 4 weeks for 20 weeks. Participants who completed the 20 weeks of treatment and had hemoglobin (Hb) level within ± 1 grams per deciliter (g/dL) of their baseline Hb level and within the target range of 10-12 g/dL, entered an optional 52-weeks safety extension period. During this period, the participants continued to receive MIRCERA IV injection once every 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methoxy Polyethylene Glycol-Epoetin Beta
    Investigational medicinal product code
    RO0503821
    Other name
    MIRCERA
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intravenous use
    Dosage and administration details
    MIRCERA was administered IV, every 4 weeks.

    Arm title
    		 MIRCERA Group 2: High-Conversion-Factor Group
    Arm description
    		 Participants received MIRCERA IV injection based on a high conversion factor from their previous ESA dose (4 * previous weekly epoetin dose [IU]/125 or 4 * previous weekly darbepoetin alfa dose [mcg]/0.55) once every 4 weeks for 20 weeks. Participants who completed the 20 weeks of treatment and had Hb level within ± 1 g/dL of their baseline Hb level and within the target range of 10-12 g/dL, entered an optional 52-weeks safety extension period. During this period, the participants continued to receive MIRCERA IV injection once every 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methoxy Polyethylene Glycol-Epoetin Beta
    Investigational medicinal product code
    RO0503821
    Other name
    MIRCERA
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intravenous use
    Dosage and administration details
    MIRCERA was administered IV, every 4 weeks.

    Number of subjects in period 1
    		MIRCERA Group 1: Intermediate-Conversion-Factor Group MIRCERA Group 2: High-Conversion-Factor Group
    Started
    16
    48
    Completed
    12
    35
    Not completed
    4
    13
         Death
    -
    1
         Refused treatment/Did not cooperate
    -
    1
         Renal transplant
    4
    9
         Admin/Other than specified
    -
    2
    Period 2
    Period 2 title
    Extension Period (52 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MIRCERA Group 1: Intermediate-Conversion-Factor Group
    Arm description
    		 Participants received MIRCERA IV injection at a starting dose based on an intermediate conversion factor from their previous ESA dose (4 * previous weekly epoetin dose [IU]/250 or 4 * previous weekly darbepoetin alfa dose [mcg]/1.1) once every 4 weeks for 20 weeks. Participants who completed the 20 weeks of treatment and had Hb level within ± 1 g/dL of their baseline Hb level and within the target range of 10-12 g/dL, entered an optional 52-weeks safety extension period. During this period, the participants continued to receive MIRCERA IV injection once every 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methoxy Polyethylene Glycol-Epoetin Beta
    Investigational medicinal product code
    RO0503821
    Other name
    MIRCERA
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intravenous use
    Dosage and administration details
    MIRCERA was administered IV, every 4 weeks.

    Arm title
    		 MIRCERA Group 2: High-Conversion-Factor Group
    Arm description
    		 Participants received MIRCERA IV injection based on a high conversion factor from their previous ESA dose (4 * previous weekly epoetin dose [IU]/125 or 4 * previous weekly darbepoetin alfa dose [mcg]/0.55) once every 4 weeks for 20 weeks. Participants who completed the 20 weeks of treatment and had Hb level within ± 1 g/dL of their baseline Hb level and within the target range of 10-12 g/dL, entered an optional 52-weeks safety extension period. During this period, the participants continued to receive MIRCERA IV injection once every 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methoxy Polyethylene Glycol-Epoetin Beta
    Investigational medicinal product code
    RO0503821
    Other name
    MIRCERA
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intravenous use
    Dosage and administration details
    MIRCERA was administered IV, every 4 weeks.

    Number of subjects in period 2 [1]
    		MIRCERA Group 1: Intermediate-Conversion-Factor Group MIRCERA Group 2: High-Conversion-Factor Group
    Started
    9
    28
    Received Visit/Week 21 Dose
    8
    28
    Completed
    5
    12
    Not completed
    4
    16
         Renal transplant
    3
    13
         Withdrew consent
    1
    1
         Admin/Other than specified
    -
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 3 participants of Group 1 and 7 participants of Group 2, who completed core study period, did not enter safety extension period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MIRCERA Group 1: Intermediate-Conversion-Factor Group
    Reporting group description
    		 Participants received MIRCERA IV injection at a starting dose based on an intermediate conversion factor from their previous Erythropoiesis-Stimulating Agent (ESA) dose (4 * previous weekly epoetin dose [international units {IU}]/250 or 4 * previous weekly darbepoetin alfa dose [micrograms {mcg}]/1.1) once every 4 weeks for 20 weeks. Participants who completed the 20 weeks of treatment and had hemoglobin (Hb) level within ± 1 grams per deciliter (g/dL) of their baseline Hb level and within the target range of 10-12 g/dL, entered an optional 52-weeks safety extension period. During this period, the participants continued to receive MIRCERA IV injection once every 4 weeks.

    Reporting group title
    MIRCERA Group 2: High-Conversion-Factor Group
    Reporting group description
    		 Participants received MIRCERA IV injection based on a high conversion factor from their previous ESA dose (4 * previous weekly epoetin dose [IU]/125 or 4 * previous weekly darbepoetin alfa dose [mcg]/0.55) once every 4 weeks for 20 weeks. Participants who completed the 20 weeks of treatment and had Hb level within ± 1 g/dL of their baseline Hb level and within the target range of 10-12 g/dL, entered an optional 52-weeks safety extension period. During this period, the participants continued to receive MIRCERA IV injection once every 4 weeks.

    Reporting group values
    		 MIRCERA Group 1: Intermediate-Conversion-Factor Group MIRCERA Group 2: High-Conversion-Factor Group Total
    Number of subjects
    		 16 48 64
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 11.3 ± 3.24 13 ± 3.06 -
    Gender categorical
    Units: Subjects
        Female
    		 5 25 30
        Male
    		 11 23 34

    End points

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    End points reporting groups
    Reporting group title
    MIRCERA Group 1: Intermediate-Conversion-Factor Group
    Reporting group description
    		 Participants received MIRCERA IV injection at a starting dose based on an intermediate conversion factor from their previous Erythropoiesis-Stimulating Agent (ESA) dose (4 * previous weekly epoetin dose [international units {IU}]/250 or 4 * previous weekly darbepoetin alfa dose [micrograms {mcg}]/1.1) once every 4 weeks for 20 weeks. Participants who completed the 20 weeks of treatment and had hemoglobin (Hb) level within ± 1 grams per deciliter (g/dL) of their baseline Hb level and within the target range of 10-12 g/dL, entered an optional 52-weeks safety extension period. During this period, the participants continued to receive MIRCERA IV injection once every 4 weeks.

    Reporting group title
    MIRCERA Group 2: High-Conversion-Factor Group
    Reporting group description
    		 Participants received MIRCERA IV injection based on a high conversion factor from their previous ESA dose (4 * previous weekly epoetin dose [IU]/125 or 4 * previous weekly darbepoetin alfa dose [mcg]/0.55) once every 4 weeks for 20 weeks. Participants who completed the 20 weeks of treatment and had Hb level within ± 1 g/dL of their baseline Hb level and within the target range of 10-12 g/dL, entered an optional 52-weeks safety extension period. During this period, the participants continued to receive MIRCERA IV injection once every 4 weeks.
    Reporting group title
    MIRCERA Group 1: Intermediate-Conversion-Factor Group
    Reporting group description
    		 Participants received MIRCERA IV injection at a starting dose based on an intermediate conversion factor from their previous ESA dose (4 * previous weekly epoetin dose [IU]/250 or 4 * previous weekly darbepoetin alfa dose [mcg]/1.1) once every 4 weeks for 20 weeks. Participants who completed the 20 weeks of treatment and had Hb level within ± 1 g/dL of their baseline Hb level and within the target range of 10-12 g/dL, entered an optional 52-weeks safety extension period. During this period, the participants continued to receive MIRCERA IV injection once every 4 weeks.

    Reporting group title
    MIRCERA Group 2: High-Conversion-Factor Group
    Reporting group description
    		 Participants received MIRCERA IV injection based on a high conversion factor from their previous ESA dose (4 * previous weekly epoetin dose [IU]/125 or 4 * previous weekly darbepoetin alfa dose [mcg]/0.55) once every 4 weeks for 20 weeks. Participants who completed the 20 weeks of treatment and had Hb level within ± 1 g/dL of their baseline Hb level and within the target range of 10-12 g/dL, entered an optional 52-weeks safety extension period. During this period, the participants continued to receive MIRCERA IV injection once every 4 weeks.

    Primary: Change in Average Hb Concentration Between Baseline and Evaluation Period

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    End point title
    		 Change in Average Hb Concentration Between Baseline and Evaluation Period [1]
    End point description
    A time adjusted average baseline Hb concentration for each individual was calculated using an area under the curve (AUC) approach from all available Hb measurements taken during the baseline period (Day -20 to Day 1). The average evaluation period Hb concentration for each individual was calculated using the same method, from all their available measurements taken during the evaluation period (Week 17 to Week 21). The change in Hb concentration between the baseline and evaluation periods was calculated by subtracting the baseline Hb concentration from the evaluation period Hb concentration. Intention-to-treat (ITT) population included all enrolled participants. Hb values within 21 days after blood transfusion(s) were excluded from analysis. Here ‘n’ signifies number of participants evaluable at specified time-points.
    End point type
    Primary
    End point timeframe
    Baseline (Day -20 to Day 1), Evaluation Period (Week 17 to Week 21)
    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: Since analysis is descriptive in nature, statistical data could not be provided.
    End point values
    		 MIRCERA Group 1: Intermediate-Conversion-Factor Group MIRCERA Group 2: High-Conversion-Factor Group
    Number of subjects analysed
    16
    48
    Units: g/dL
    arithmetic mean (standard deviation)
        Baseline (n=16,48)
    11.26 ± 0.496
    11.08 ± 0.493
        Change at Evaluation Period (n=12,36)
    -0.78 ± 1.237
    -0.15 ± 1.014
    No statistical analyses for this end point

    Secondary: Number of Participants With an Average Hb Concentration During the Evaluation Period Within ±1 g/dL of Their Baseline Hb

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    End point title
    		 Number of Participants With an Average Hb Concentration During the Evaluation Period Within ±1 g/dL of Their Baseline Hb
    End point description
    Baseline Hb value was defined as the average Hb concentration from all available Hb measurements taken during the baseline period (Day -20 to Day 1). The evaluation period Hb concentration was defined as the average Hb concentration from all available Hb measurements taken during the evaluation period (Week 17 to Week 21). ITT population. Hb values within 21 days after blood transfusion(s) were excluded from analysis. Number of participants analyzed = participants with Hb concentration assessment at specified time-points.
    End point type
    Secondary
    End point timeframe
    Evaluation Period (Week 17 to Week 21)
    End point values
    		 MIRCERA Group 1: Intermediate-Conversion-Factor Group MIRCERA Group 2: High-Conversion-Factor Group
    Number of subjects analysed
    12
    36
    Units: participants
    7
    27
    No statistical analyses for this end point

    Secondary: Number of Participants With an Average Hb Concentration During the Evaluation Period Above, Within or Below the Range of 10-12 g/dL

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    End point title
    		 Number of Participants With an Average Hb Concentration During the Evaluation Period Above, Within or Below the Range of 10-12 g/dL
    End point description
    The evaluation period Hb concentration was defined as the average Hb concentration from all available Hb measurements taken during the evaluation period (Week 17 to Week 21). ITT population. Hb values within 21 days after blood transfusion(s) were excluded from analysis. Number of participants analyzed = participants with Hb concentration assessment at specified time-points.
    End point type
    Secondary
    End point timeframe
    Evaluation Period (Week 17 to Week 21)
    End point values
    		 MIRCERA Group 1: Intermediate-Conversion-Factor Group MIRCERA Group 2: High-Conversion-Factor Group
    Number of subjects analysed
    12
    36
    Units: participants
        Above 12 g/dL
    0
    3
        Within 10-12 g/dL
    9
    29
        Below 10 g/dL
    3
    4
    No statistical analyses for this end point

    Secondary: Number of Participants With Blood Transfusions

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    End point title
    		 Number of Participants With Blood Transfusions
    End point description
    ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 20
    End point values
    		 MIRCERA Group 1: Intermediate-Conversion-Factor Group MIRCERA Group 2: High-Conversion-Factor Group
    Number of subjects analysed
    16
    48
    Units: participants
    1
    2
    No statistical analyses for this end point

    Secondary: Change in Average Reticulocyte Count Between the Baseline and Evaluation Period

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    End point title
    		 Change in Average Reticulocyte Count Between the Baseline and Evaluation Period
    End point description
    A time adjusted average baseline reticulocyte count for each individual was calculated using an AUC approach from all available reticulocyte counts taken during the baseline period (Day -20 to Day 1). The average evaluation period reticulocyte count for each individual was calculated using the same method, from all their available measurements taken during the evaluation period (Week 17 to Week 21). The change in reticulocyte count between the baseline and evaluation periods was calculated by subtracting the baseline reticulocyte count from the evaluation period reticulocyte count. Relative reticulocytes were recorded conversion to absolute values was performed. ITT population. Reticulocyte values within 21 days after blood transfusion(s) were excluded from analysis. Here, number of participants analyzed = participants evaluable for this outcome measure and 'n' signifies number of participants evaluable at specified time-points.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -20 to Day 1), Evaluation Period (Week 17 to Week 21)
    End point values
    		 MIRCERA Group 1: Intermediate-Conversion-Factor Group MIRCERA Group 2: High-Conversion-Factor Group
    Number of subjects analysed
    15
    48
    Units: 10^3 cells/microliter
    arithmetic mean (standard deviation)
        Baseline (n=15,48)
    46.08 ± 26.472
    43.7 ± 25.984
        Change at Evaluation Period (n=11,36)
    23.38 ± 29.279
    24.8 ± 32.428
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) of MIRCERA

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    End point title
    		 Maximum Observed Serum Concentration (Cmax) of MIRCERA
    End point description
    PK evaluable population included all enrolled participants who received at least one dose of study drug and had evaluable PK assessment.
    End point type
    Secondary
    End point timeframe
    Pre-dose (with 1 hour before drug administration) and 2, 48 hours post dose on Week 9, at Weeks 10, 11, and 12, pre-dose (with 1 hour before drug administration) on Week 13
    End point values
    		 MIRCERA Group 1: Intermediate-Conversion-Factor Group MIRCERA Group 2: High-Conversion-Factor Group
    Number of subjects analysed
    12
    34
    Units: picograms per milliliter (pg/mL)
        geometric mean (geometric coefficient of variation)
    37700 ± 74.5
    66100 ± 149.5
    No statistical analyses for this end point

    Secondary: Area Under the Serum Concentration-Time Curve From 0 to 672 Hours (AUC0-672h) of MIRCERA

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    End point title
    		 Area Under the Serum Concentration-Time Curve From 0 to 672 Hours (AUC0-672h) of MIRCERA
    End point description
    Area under the serum concentration versus time curve over 672 hours. AUC0-672h represents area under the serum concentration versus time curve from time zero to end of dosing interval (AUC0-tau). PK evaluable population. Number of participants analyzed = participants with AUC0-672h assessment at specified time-points.
    End point type
    Secondary
    End point timeframe
    Pre-dose (with 1 hour before drug administration) and 2, 48 hours post dose on Week 9, at Weeks 10, 11, and 12, pre-dose (with 1 hour before drug administration) on Week 13
    End point values
    		 MIRCERA Group 1: Intermediate-Conversion-Factor Group MIRCERA Group 2: High-Conversion-Factor Group
    Number of subjects analysed
    11
    32
    Units: picograms*hour/milliliter (pg*h/mL)]
        geometric mean (geometric coefficient of variation)
    3630000 ± 91.8
    7170000 ± 140
    No statistical analyses for this end point

    Secondary: Time to Reach Cmax (Tmax) of MIRCERA

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    End point title
    		 Time to Reach Cmax (Tmax) of MIRCERA
    End point description
    PK evaluable population.
    End point type
    Secondary
    End point timeframe
    Pre-dose (with 1 hour before drug administration) and 2, 48 hours post dose on Week 9, at Weeks 10, 11, and 12, pre-dose (with 1 hour before drug administration) on Week 13
    End point values
    		 MIRCERA Group 1: Intermediate-Conversion-Factor Group MIRCERA Group 2: High-Conversion-Factor Group
    Number of subjects analysed
    12
    34
    Units: hours
        median (full range (min-max))
    2 (1.98 to 2.17)
    2 (1.83 to 164)
    No statistical analyses for this end point

    Secondary: Apparent Terminal Phase Half-Life (t1/2) of MIRCERA

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    End point title
    		 Apparent Terminal Phase Half-Life (t1/2) of MIRCERA
    End point description
    PK evaluable population. Number of participants analyzed = participants evaluable for t1/2 assessments.
    End point type
    Secondary
    End point timeframe
    Pre-dose (with 1 hour before drug administration) and 2, 48 hours post dose on Week 9, at Weeks 10, 11, and 12, pre-dose (with 1 hour before drug administration) on Week 13
    End point values
    		 MIRCERA Group 1: Intermediate-Conversion-Factor Group MIRCERA Group 2: High-Conversion-Factor Group
    Number of subjects analysed
    11
    32
    Units: hours
        geometric mean (geometric coefficient of variation)
    147 ± 30.1
    121 ± 43.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Week 73
    Adverse event reporting additional description
    Safety population included all participants who received at least one dose of study drug and had a safety follow-up visit.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    MIRCERA Group 1: Intermediate-Conversion-Factor Group
    Reporting group description
    		 Participants received MIRCERA IV injection at a starting dose based on an intermediate conversion factor from their previous ESA dose (4 * previous weekly epoetin dose [IU]/250 or 4 * previous weekly darbepoetin alfa dose [mcg]/1.1) once every 4 weeks for 20 weeks. Participants who completed the 20 weeks of treatment and had Hb level within ± 1 g/dL of their baseline Hb level and within the target range of 10-12 g/dL, entered an optional 52-weeks safety extension period. During this period, the participants continued to receive MIRCERA IV injection once every 4 weeks.

    Reporting group title
    MIRCERA Group 2: High-Conversion-Factor Group
    Reporting group description
    		 Participants received MIRCERA IV injection based on a high conversion factor from their previous ESA dose (4 * previous weekly epoetin dose [IU]/125 or 4 * previous weekly darbepoetin alfa dose [mcg]/0.55) once every 4 weeks for 20 weeks. Participants who completed the 20 weeks of treatment and had Hb level within ± 1 g/dL of their baseline Hb level and within the target range of 10-12 g/dL, entered an optional 52-weeks safety extension period. During this period, the participants continued to receive MIRCERA IV injection once every 4 weeks.

    Serious adverse events
    		 MIRCERA Group 1: Intermediate-Conversion-Factor Group MIRCERA Group 2: High-Conversion-Factor Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 16 (25.00%)
    17 / 48 (35.42%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 48 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial injury
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 48 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant failure
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 48 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Pericarditis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Intracranial haematoma
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Thrombosis in device
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 48 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine haemorrhage
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Lupus nephritis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 48 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal scalded skin syndrome
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 48 (2.08%)
         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
    		 MIRCERA Group 1: Intermediate-Conversion-Factor Group MIRCERA Group 2: High-Conversion-Factor Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 16 (68.75%)
    28 / 48 (58.33%)
    Investigations
    Haemoglobin
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    2
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 16 (6.25%)
    9 / 48 (18.75%)
         occurrences all number
    1
    12
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    1 / 16 (6.25%)
    13 / 48 (27.08%)
         occurrences all number
    1
    25
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 48 (6.25%)
         occurrences all number
    1
    3
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 16 (0.00%)
    4 / 48 (8.33%)
         occurrences all number
    0
    5
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    2
    0
    Ear pain
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 48 (6.25%)
         occurrences all number
    1
    3
    Vomiting
         subjects affected / exposed
    2 / 16 (12.50%)
    5 / 48 (10.42%)
         occurrences all number
    2
    5
    Abdominal pain upper
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    Nausea
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 16 (0.00%)
    4 / 48 (8.33%)
         occurrences all number
    0
    5
    Oropharyngeal pain
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 48 (4.17%)
         occurrences all number
    1
    2
    Endocrine disorders
    Hyperparathyroidism secondary
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 16 (0.00%)
    14 / 48 (29.17%)
         occurrences all number
    0
    16
    Urinary tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 48 (4.17%)
         occurrences all number
    1
    2
    Bronchitis
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 48 (6.25%)
         occurrences all number
    1
    4
    Pharyngitis
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    4
    Gastroenteritis
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    Viral infection
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 48 (4.17%)
         occurrences all number
    1
    3
    Catheter site infection
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    H1N1 influenza
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 48 (0.00%)
         occurrences all number
    2
    0
    Oral herpes
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hyperphosphataemia
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    3
    Hyperkalaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 48 (6.25%)
         occurrences all number
    3
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Apr 2008
    - Changes were made in reporting guidelines for serious adverse events (SAEs) and roles were clarified within the Data and Safety Monitoring Board (DSMB).
    21 Nov 2008
    - Use of pre-filled syringes adopted instead of vials. - Medical judgment rather than numerical values was used to assess hypertension as an exclusion criterion.
    09 Nov 2012
    - The sample size increased from 25 to 36 participants for the optimal conversion-factor group due to high variability seen in the preliminary analysis and clarification of replacement for early drop-outs was made. - Updates were made due to a planned change in the electronic data capture system. - Handling of missing Hb values for the analysis was changed.
    23 Jul 2014
    - Clarifications were made regarding informed consent, prior medications, exclusion of pregnant participants. - Guidance was added in case of suspected antierythropoietin antibody-mediated pure red cell aplasia.

    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
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