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    Clinical Trial Results:
    An open-label, phase II, randomized, pilot study to assess the effect in terms of erythroid improvement of deferasirox combined with erythropoietin compared to erythropoietin alone in patients with low- and int-1-risk myelodysplastic syndrome

    Summary
    EudraCT number
    		 2013-000981-12
    Trial protocol
    		 IT   SE   GB   ES  
    Global end of trial date
    22 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Apr 2018
    First version publication date
    06 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CICL670A2421
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01868477
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    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
    22 Mar 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Mar 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to assess the effect of treatment with deferasirox (DFX) + erythropoietin (EPO) vs. erythropoietin (EPO) alone on erythropoiesis after 12 weeks of treatment
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Jan 2014
    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
    Canada: 2
    Country: Number of subjects enrolled
    China: 6
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 2
    Worldwide total number of subjects
    23
    EEA total number of subjects
    14
    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)
    3
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Twenty-three patients were randomized into the trial

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Erythropoietin alpha
    Arm description
    		 Starting dose was erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement was inadequate, dose was escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement was inadequate, participants were switched to the combination arm. At any time when erythroid response was achieved, erythropoietin treatment was stopped until end of study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Erythropoietin alpha
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Erythropoietin alpha (EPO): provided as available in the respective country and is delivered subcutaneous injection

    Arm title
    		 Deferasirox + Erythropoietin alpha
    Arm description
    		 Starting dose was deferasirox dispersible tablet (DT) 10 mg/kg/day or deferasirox film-coated tablet FCT) 7 mg/kg/day in combination with erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement was inadequate, erythropoietin dose was escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement was inadequate, participants were discontinued from the study. At any time when erythroid response was achieved, erythropoietin treatment was stopped study and Deferasirox treatment was continued until end of study
    Arm type
    		 Experimental

    Investigational medicinal product name
    deferasirox dispersible tablets
    Investigational medicinal product code
    DFX DT
    Other name
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    supplied in 125, 250, 500 mg dispersible tablets

    Investigational medicinal product name
    deferasirox film-coated tablets
    Investigational medicinal product code
    Other name
    DFX FCT
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    supplied in 90,180, 360 mg film-coated tablets

    Number of subjects in period 1
    		Erythropoietin alpha Deferasirox + Erythropoietin alpha
    Started
    12
    11
    Completed
    8
    6
    Not completed
    4
    5
         Consent withdrawn by subject
    1
    -
         Disease progression
    1
    1
         Adverse event, non-fatal
    2
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Erythropoietin alpha
    Reporting group description
    		 Starting dose was erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement was inadequate, dose was escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement was inadequate, participants were switched to the combination arm. At any time when erythroid response was achieved, erythropoietin treatment was stopped until end of study.

    Reporting group title
    Deferasirox + Erythropoietin alpha
    Reporting group description
    		 Starting dose was deferasirox dispersible tablet (DT) 10 mg/kg/day or deferasirox film-coated tablet FCT) 7 mg/kg/day in combination with erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement was inadequate, erythropoietin dose was escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement was inadequate, participants were discontinued from the study. At any time when erythroid response was achieved, erythropoietin treatment was stopped study and Deferasirox treatment was continued until end of study

    Reporting group values
    		 Erythropoietin alpha Deferasirox + Erythropoietin alpha Total
    Number of subjects
    		 12 11 23
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 74.5 ( 5.84 ) 71.1 ( 7.54 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 8 5 13
        Male
    		 4 6 10
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian|
    		 8 7 15
        Asian|
    		 4 4 8

    End points

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    End points reporting groups
    Reporting group title
    Erythropoietin alpha
    Reporting group description
    		 Starting dose was erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement was inadequate, dose was escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement was inadequate, participants were switched to the combination arm. At any time when erythroid response was achieved, erythropoietin treatment was stopped until end of study.

    Reporting group title
    Deferasirox + Erythropoietin alpha
    Reporting group description
    		 Starting dose was deferasirox dispersible tablet (DT) 10 mg/kg/day or deferasirox film-coated tablet FCT) 7 mg/kg/day in combination with erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement was inadequate, erythropoietin dose was escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement was inadequate, participants were discontinued from the study. At any time when erythroid response was achieved, erythropoietin treatment was stopped study and Deferasirox treatment was continued until end of study

    Subject analysis set title
    EPO+DFX (12 weeks)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients randomized to EPO alone with inadequate response at 12 weeks who had been switched over to combination EPO+DFX

    Subject analysis set title
    EPO (24 weeks)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients who were in EPO alone group and were not switched to EPO+DFX after 12 weeks,

    Subject analysis set title
    EPO+DFX at 12
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients randomized to EPO alone with inadequate response at 12 weeks who had been switched over to combination EPO+DFX

    Subject analysis set title
    EPO+DFX at 12 weeks
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This analysis included patients randomized either to EPO or DFX+EPO at baseline as well as patients who did not have erythroid response at week 12 in the EPO group and switched to combination therapy. The time-course of Hb and its absolute changes from baseline was summarized by descriptive statistics by visit and erythroid response. Patients randomized to EPO and not switching after 12 weeks to EPO+DFX would consist of only responders

    Primary: Summary of erythroid response within 12 weeks, by treatment group (Full Analysis Set)

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    End point title
    		 Summary of erythroid response within 12 weeks, by treatment group (Full Analysis Set)
    End point description
    Difference in percentage of patients achieving an erythroid response within 12 weeks of treatment between the two arms according to modified IWG 2006 criteria increase in hemoglobin (Hb) ≥ 1.5 g/dL). Erythroid response is defined as the increase in Hb from baseline ≥ 1.5 g/dL. Patients achieving erythroid response at least once within 12 weeks were considered responders
    End point type
    Primary
    End point timeframe
    Baseline up to 12 weeks
    End point values
    		 Erythropoietin alpha Deferasirox + Erythropoietin alpha
    Number of subjects analysed
    12
    11
    Units: percentage of participants
        number (confidence interval 95%)
    41.7 (15.2 to 72.3)
    27.3 (6.02 to 61.0)
    Statistical analysis title
    		 EPO vs EPO + DFX
    Comparison groups
    Erythropoietin alpha v Deferasirox + Erythropoietin alpha
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    14.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24
         upper limit
    		 48.16
    Notes
    [1] - difference

    Secondary: Summary of hematologic response in patients randomized to EPO+DFX and EPO alone, within 24 weeks of treatment (Full Analysis Set)

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    End point title
    		 Summary of hematologic response in patients randomized to EPO+DFX and EPO alone, within 24 weeks of treatment (Full Analysis Set)
    End point description
    Hematological response criteria defined as: Erythroid response: hemoglobin (Hb) increase from baseline >= 1.5 g/dL (baseline < 11 g/dL), neutrophil response: increase from baseline >= 100% and increase > 0.5 × 10^9/L (baseline <1 × 10^9/L), platelet response: increase from baseline >= 30 × 109/L (baseline <100 × 10^9/L) according to modified IWG 2006 criteria
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 weeks
    End point values
    		 Erythropoietin alpha Deferasirox + Erythropoietin alpha
    Number of subjects analysed
    12
    11
    Units: participants
        arithmetic mean (standard deviation)
    1.8 ( 0.21 )
    2.1 ( 0.61 )
    No statistical analyses for this end point

    Secondary: Summary of hematologic improvement in patients randomized to EPO+DFX and EPO alone, within 24 weeks of treatment (Full Analysis Set)

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    End point title
    		 Summary of hematologic improvement in patients randomized to EPO+DFX and EPO alone, within 24 weeks of treatment (Full Analysis Set)
    End point description
    Percentage of participants achieving an hematologic improvement defined as: neutrophil improvement: increase from baseline >0.5 × 109/L (baseline = 1.0 × 10^9/L ), platelet improvement: increase from baseline ≥ 30 × 10^9/L (baseline = 100 × 10^9/L), hemoglobin improvement: Hb increase from baseline ≥ 1 g/dL (baseline<11 g/dL)
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 weeks
    End point values
    		 Erythropoietin alpha Deferasirox + Erythropoietin alpha
    Number of subjects analysed
    12
    11
    Units: percentage of participants
        Hematologic improvement|
    100
    46
        Neutropil improvement|
    67
    80
        Platelet improvement|
    50
    80
        Hemoglobin improvement|
    67
    60
    No statistical analyses for this end point

    Secondary: Absolute change in hemoglobin values up to 24 weeks

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    End point title
    		 Absolute change in hemoglobin values up to 24 weeks
    End point description
    Absolute change in hemoglobin values for patients showing improvement: Hemoglobin improvement Hb increase from baseline ≥ 1 g/dL (baseline<11 g/dL)
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 weeks
    End point values
    		 Erythropoietin alpha Deferasirox + Erythropoietin alpha
    Number of subjects analysed
    8
    3
    Units: g/dL
        arithmetic mean (standard deviation)
    1.3 ( 0.37 )
    1.4 ( 0.55 )
    No statistical analyses for this end point

    Secondary: Absolute change in platelets and neutrophil levels up to 24 weeks

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    End point title
    		 Absolute change in platelets and neutrophil levels up to 24 weeks
    End point description
    Absolute change in platelets and neutrophil levels for patients showing improvement: neutrophil improvement: increase from baseline >0.5 × 10^9/L (baseline = 1.0 × 10^9/L ), platelet improvement: increase from baseline ≥ 30 × 10^9/L (baseline = 100 × 10^9/L)
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 weeks
    End point values
    		 Erythropoietin alpha Deferasirox + Erythropoietin alpha
    Number of subjects analysed
    12
    11
    Units: 10^9/L
    arithmetic mean (standard deviation)
        Platelets n=6,4|
    58.7 ( 23.93 )
    66.3 ( 22.74 )
        Neutrophils n=8,4
    1.2 ( 1.16 )
    2.4 ( 1.57 )
    No statistical analyses for this end point

    Secondary: Summary of erythroid response in participants randomized to EPO alone at baseline and switched to EPO+DFX after 12 weeks of treatment (Full Analysis Set)

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    End point title
    		 Summary of erythroid response in participants randomized to EPO alone at baseline and switched to EPO+DFX after 12 weeks of treatment (Full Analysis Set)
    End point description
    Erythroid response: hemoglobin increase from baseline > = 1.5 g/dL (baseline <11 g/dL). Percentages are based on N. Confidence intervals are calculated using Clopper-Pearson method. Hemoglobin value is at time of first response
    End point type
    Secondary
    End point timeframe
    Week 13 up to 24 weeks
    End point values
    		 EPO+DFX (12 weeks)
    Number of subjects analysed
    5
    Units: participants
    0
    No statistical analyses for this end point

    Secondary: Summary of erythroid response within 24 weeks in participants randomized to EPO at baseline and not switched to EPO+DFX after 12 weeks of treatment (Full Analysis set)

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    End point title
    		 Summary of erythroid response within 24 weeks in participants randomized to EPO at baseline and not switched to EPO+DFX after 12 weeks of treatment (Full Analysis set)
    End point description
    Erythroid response: hemoglobin increase from baseline > = 1.5 g/dL (baseline <11 g/dL). Percentages are based on N. Confidence intervals are calculated using Clopper-Pearson method. Hemoglobin value is at time of first response
    End point type
    Secondary
    End point timeframe
    baseline up to 24 weeks
    End point values
    		 EPO (24 weeks)
    Number of subjects analysed
    7
    Units: percentage of participants
        number (confidence interval 95%)
    71.4 (47.8 to 100.0)
    No statistical analyses for this end point

    Secondary: Absolute change in serum ferritin up to 24 weeks for erythropoietin alpha arm (Full Analysis Set)

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    End point title
    		 Absolute change in serum ferritin up to 24 weeks for erythropoietin alpha arm (Full Analysis Set) [2]
    End point description
    Absolute change in serum ferritin from baseline
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 weeks
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was done
    End point values
    		 Erythropoietin alpha
    Number of subjects analysed
    7
    Units: ng/mL
    median (full range (min-max))
        Responders - Week 5 n=5|
    -98.5 (-323 to -73.5)
        Responders - Week 9 n=5|
    -79.0 (-381 to 54.0)
        Responders - Week 13 n=4|
    24.8 (-179 to 104)
        Responders - Week 17 n=4|
    -57.8 (-140 to 258.0)
        Responders - Week 21 n=2|
    -39.8 (-44.0 to -35.5)
        Non-responders - Week 5 n=2|
    -352 (-523 to -182)
        Non-responders - Week 9 n=2|
    -189 (-572 to 194.5)
        Non-responders - Week 13 n=2|
    -44.5 (-621 to 531.5)
    No statistical analyses for this end point

    Secondary: Absolute change in serum ferritin up to 24 weeks for Deferasirox + erythropoietin alpha arm (Full Analysis Set)

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    End point title
    		 Absolute change in serum ferritin up to 24 weeks for Deferasirox + erythropoietin alpha arm (Full Analysis Set) [3]
    End point description
    Absolute change in serum ferritin from baseline
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 weeks
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was done
    End point values
    		 Deferasirox + Erythropoietin alpha
    Number of subjects analysed
    11
    Units: ng/mL
    median (full range (min-max))
        Responders - Week 5| n=3|
    -82.5 (-243 to 1068)
        Responders - Week 9| n=3|
    -139 (-292 to 702.0)
        Responders - Week 13| n=3|
    -121 (-338 to 0.0)
        Responders - Week 17| n=3|
    16.5 (-143 to 722.0)
        Responders - Week 21| n=3|
    -95.5 (-189 to 173.0)
        Non-responders - Week 5| n=7|
    -38.0 (-315 to 111.0)
        Non-responders - Week 9| n=4|
    -144 (-435 to 1.0)
        Non-responders - Week 13| n=3|
    -155 (-225 to -127)
        Non-responders - Week 17| n=2|
    -123 (-154 to -91.0)
        Non-responders - Week 21|n=1|
    -291 (-291 to -291)
    No statistical analyses for this end point

    Secondary: Absolute change in serum ferritin up to 24 weeks for EPO+DFX at 12 weeks arm (Full Analysis Set)

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    End point title
    		 Absolute change in serum ferritin up to 24 weeks for EPO+DFX at 12 weeks arm (Full Analysis Set)
    End point description
    Absolute change in serum ferritin from baseline
    End point type
    Secondary
    End point timeframe
    Baseline up 24 weeks
    End point values
    		 EPO+DFX at 12
    Number of subjects analysed
    5
    Units: ng/mL
    median (full range (min-max))
        Responders - Week 5| n=1|
    -116 (-116 to -116)
        Responders - Week 9| n=1|
    -136 (-136 to -136)
        Responders - Week 13| n=1|
    59.5 (59.5 to 59.5)
        Responders - Week 17| n=1|
    74.5 (74.5 to 74.5)
        Non-responders - Week 5| n=4|
    -68.3 (-144 to 221.3)
        Non-responders - Week 9| n=3|
    -148 (-319 to 321.3)
        Non-responders - Week 13| n=4|
    220.4 (-228 to 635.3)
        Non-responders - Week 17| n=2|
    -16.6 (-28.5 to -4.7)
        Non-responders - Week 21|n=3|
    -10.5 (-463 to 367.3)
    No statistical analyses for this end point

    Secondary: Absolute change in hemoglobin (Hb) from baseline for erythropoietin alpha arm (Full Analysis Set)

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    End point title
    		 Absolute change in hemoglobin (Hb) from baseline for erythropoietin alpha arm (Full Analysis Set) [4]
    End point description
    This analysis included patients randomized either to EPO or DFX+EPO at baseline as well as patients who did not have erythroid response at week 12 in the EPO group and switched to combination therapy. The time-course of Hb and its absolute changes from baseline was summarized by descriptive statistics by visit and erythroid response. Patients randomized to EPO and not switching after 12 weeks to EPO+DFX, would consist of only responders.
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 weeks
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was done
    End point values
    		 Erythropoietin alpha
    Number of subjects analysed
    7
    Units: g/dL
    median (full range (min-max))
        Responders - Week 5 n=5|
    1.5 (1.1 to 3.2)
        Responders - Week 9 n=5|
    1.9 (1.3 to 4.4)
        Responders - Week 13 n=4|
    1.7 (1.5 to 3.4)
        Responders - Week 17 n=4|
    1.6 (-0.3 to 1.8)
        Responders - Week 21 n=3|
    0.8 (-0.7 to 1.8)
        Non-responders - Week 5 n=2|
    -0.9 (-1.7 to -0.1)
        Non-responders - Week 9 n=2|
    -1.7 (-2.0 to -1.4)
        Non-responders - Week 13 n=2|
    -2.5 (-2.8 to -2.1)
    No statistical analyses for this end point

    Secondary: Absolute change in hemoglobin (Hb) from baseline for Deferasirox + erythropoietin alpha arm (Full Analysis Set)

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    End point title
    		 Absolute change in hemoglobin (Hb) from baseline for Deferasirox + erythropoietin alpha arm (Full Analysis Set) [5]
    End point description
    This analysis included patients randomized either to EPO or DFX+EPO at baseline as well as patients who did not have erythroid response at week 12 in the EPO group and switched to combination therapy. The time-course of Hb and its absolute changes from baseline was summarized by descriptive statistics by visit and erythroid response. Patients randomized to EPO and not switching after 12 weeks to EPO+DFX would consist of only responders.
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 weeks
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was done
    End point values
    		 Deferasirox + Erythropoietin alpha
    Number of subjects analysed
    11
    Units: g/dL
    median (full range (min-max))
        Responders - Week 5 n=|n=3|
    0.7 (0.6 to 2.0)
        Responders - Week 9| n=3|
    1.6 (1.0 to 2.6)
        Responders - Week 13| n=3|
    2.9 (2.8 to 3.0)
        Responders - Week 17| n=3|
    2.4 (0.6 to 3.0)
        Responders - Week 21| n=3|
    1.7 (-1.3 to 2.4)
        Non-responders - Week 5 n=7|
    -0.1 (-2.3 to 0.1)
        Non-responders - Week 9| n=4|
    0.0 (-0.8 to 0.5)
        Non-responders - Week 13 n=3|
    0.2 (0.1 to 0.5)
        Non-responders - Week 17| n=1|
    -0.5 (-0.5 to 0.5)
        Non-responders - Week 21|n=1|
    -0.6 (-0.6 to 0.6)
    No statistical analyses for this end point

    Secondary: Absolute change in hemoglobin (Hb) from baseline for EPO+DFX at 12 weeks arm (Full Analysis Set)

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    End point title
    		 Absolute change in hemoglobin (Hb) from baseline for EPO+DFX at 12 weeks arm (Full Analysis Set)
    End point description
    This analysis included patients randomized either to EPO or DFX+EPO at baseline as well as patients who did not have erythroid response at week 12 in the EPO group and switched to combination therapy. The time-course of Hb and its absolute changes from baseline was summarized by descriptive statistics by visit and erythroid response. Patients randomized to EPO and not switching after 12 weeks to EPO+DFX would consist of only responders.
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 weeks
    End point values
    		 EPO+DFX at 12 weeks
    Number of subjects analysed
    5
    Units: g/dL
    median (full range (min-max))
        Responders - Week 5 n=|n=1|
    1.2 (1.2 to 1.2)
        Responders - Week 9| n=1|
    1.8 (1.8 to 1.8)
        Responders - Week 13| n=1|
    0.7 (0.7 to 0.7)
        Responders - Week 17| n=1|
    -0.6 (-0.6 to -0.6)
        Non-responders - Week 5 n=4||
    0.3 (-0.5 to 0.6)
        Non-responders - Week 9| n=3|
    0.5 (-0.4 to 0.8)
        Non-responders - Week 13 n=3||
    0.4 (0.2 to 1.0)
        Non-responders - Week 17| n=3|
    0.0 (-0.1 to 0.9)
        Non-responders - Week 21|n=3|
    0.0 (-0.7 to 0.8)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit up to approximately 24 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    EPO a
    Reporting group description
    		 EPO alpha

    Reporting group title
    EPO+DFX DT
    Reporting group description
    		 EPO+DFX DT

    Reporting group title
    EPO+DFX FCT
    Reporting group description
    		 EPO+DFX FCT

    Reporting group title
    Switched to DFX+EPO after 12 weeks
    Reporting group description
    		 Switched to DFX+EPO after 12 weeks

    Serious adverse events
    		 EPO a EPO+DFX DT EPO+DFX FCT Switched to DFX+EPO after 12 weeks
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 10 (10.00%)
    1 / 1 (100.00%)
    1 / 5 (20.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    1 / 1 (100.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    1 / 1 (100.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 EPO a EPO+DFX DT EPO+DFX FCT Switched to DFX+EPO after 12 weeks
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 7 (57.14%)
    10 / 10 (100.00%)
    1 / 1 (100.00%)
    5 / 5 (100.00%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Blood uric acid increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Heart rate increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 10 (20.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    2
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Gravitational oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injection site bruising
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    2
    Anal fissure
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 10 (30.00%)
    1 / 1 (100.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    3
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Inguinal hernia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Toothache
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Rash
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    0
    1
    Back pain
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 10 (10.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Herpes zoster
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hordeolum
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Influenza
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Localised infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    0
    0
    2
    Lung infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Nov 2013
    - Change inclusion criteria of lower hemoglobin (Hb) threshold value of > 6 g/dl to ≥ 8 g/dL - Clarify that patients with performance status (PS) > 2 must not be enrolled in the study - Clarify that patients with need of transfusion must not be enrolled in the study and they must be withdrawn from the study anytime when transfusion as rescue therapy is needed - Delete prophylactic hydrocortisone to prevent transfusion reaction from the list of allowed concurrent therapy - Standardize term for trial design from exploratory to pilot - Addition of inflammatory biomarkers IL-1, IL-6 and IFN-γ
    14 Nov 2014
    - Changed the inclusion criterion of upper limit of documented diagnosis of MDS disease from < 2 years to < 3 years - Changed the inclusion criterion of lower limit of creatinine clearance from ≥ 60 mL/min to above the concentration limit in locally approved prescribing information - Inclusion of patients with stable steroid treatment for other chronic medical conditions than adrenal failure was allowed - Excluded patients with hepatic impairment fulfilling criteria of Child-Pugh Class B or C - Guidance on treating patients with Stevens-Johnson syndrome - Guidance on concomitant administration of deferasirox with CYP1A2 substrates that have a narrow therapeutic index and the concomitant use of bile acid sequestrates - Introduction of Per Protocol set, grouping for safety analyses and supportive analyses - Revision of analysis sets of primary and secondary objectives
    06 Aug 2015
    - Addition of DFX FCT as optional study medication -Patients with creatinine clearance between 40 mL/min and < 60 mL/min, who do not present with additional risk factors that may impair renal function, might have been eligible at the discretion of the investigator. -Changed the inclusion criterion of upper limit of Serum Ferritin from 1,000 ng/mL to 1,500 ng/mL (Values within 10% difference above 1500 ng/mL or 10% difference below 300 ng/mL might have been accepted at discretion of the investigator if the patient represented the investigational population.

    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.
    This study did not meet the original enrollment objective of 60 patients and was terminated without extending enrollment past original planned LPFV of 31-Oct-2016.
    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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