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    Clinical Trial Results:
    A randomised, double-blind, placebo-controlled, parallel-design, multi-centre study to investigate the efficacy to reduce chemotherapy-induced neutropenia (CIN), effects on the haematopoietic system, safety and pharmacokinetics of Myelo001 in patients receiving adjuvant or neoadjuvant chemotherapy for the treatment of breast cancer

    Summary
    EudraCT number
    		 2015-003610-25
    Trial protocol
    		 DE  
    Global end of trial date
    20 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Dec 2018
    First version publication date
    05 Dec 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CT-MT001-2-2015-1
    Additional study identifiers
    ISRCTN number
    		 ISRCTN10853057
    US NCT number
    		 NCT02692742
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Myelo Therapeutics GmbH
    Sponsor organisation address
    Kastanienallee 56, Berlin, Germany, 10119
    Public contact
    Clinical Project Management, Myelo Therapeutics GmbH, clinicaltrials@myelotherapeutics.com
    Scientific contact
    Clinical Project Management, Myelo Therapeutics GmbH, clinicaltrials@myelotherapeutics.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
    20 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Oct 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of repeated doses of Myelo001 100 mg tablets taken once per day (QD) per os (p.o.) to reduce chemotherapy induced neutropenia (CIN) in patients receiving chemotherapy for the treatment of breast cancer
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki (2008) and that are consistent with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines (ICH E6) and applicable local regulatory requirements and laws. The clinical study protocol and informed consent forms were reviewed and approved by an Independent Ethics Committee (IEC). Safety assessments used in this study included standard measurements that are used routinely in clinical studies of investigational drugs, such as assessment of AEs, physical examinations, vital signs, ECGs, and clinical laboratory evaluations. A Data Safety Monitoring Board (DSMB) evaluated patients' safety in scheduled intervals.
    Background therapy
    		 Neoadjuvant or adjuvant standard of care poly-chemotherapy regimen containing anthracyclines in combination with cyclophosphamide (CP) defined as EC standard regimen (with or without treatment with taxanes afterwards) served as inclusion criterion. The EC standard regimen the patient needed to be assigned for prior to being informed about the trial was Epirubicin (E) combined with CP: Epirubicin 90 mg/m² BSA (body surface area) + CP 600 mg/m² BSA q21d (every 21 days). Permitted taxane treatments after EC standard regime were paclitaxel (P) and docetaxel (D).
    Evidence for comparator
    		 In this phase 2a trial, Myelo001 was compared to placebo only.
    Actual start date of recruitment
    01 Mar 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 137
    Worldwide total number of subjects
    137
    EEA total number of subjects
    137
    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)
    108
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at multiple trial sites in Germany. Patients were recruited from March 2016 to September 2017.

    Pre-assignment
    Screening details
    		 145 patients consented to participate. 1 patient withdraw consent prior to screening. 3 patients were not eligible to participate in the study, because inclusion criterion 8 was not met (Haematologic, laboratory and chemistry thresholds at baseline). 4 patients declined participation in the study after screening. 137 patients were enrolled.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Myelo001
    Arm description
    		 Patients received Myelo001 (100 mg) once daily orally for scheduled 23 days from 5 days prior to the first chemotherapy cycle until 3 days prior to the second chemotherapy cycle (epirubicin/cyclophosphamide). The first batch of the investigational medicinal product (IMP) was exchanged with an exchange IMP batch after 49 patients were randomized. Altogether, 67 patients were treated with Myelo001. Of these, 26 patients were treated with Myelo001 tablets (#216) of the initial IMP batch and are referred in post-hoc analyses as subgroup Myelo001 IMP Batch 1. The other 41 patients were treated with Myelo001 tablets (#416) of the exchange IMP batch and are referred as subgroup Myelo001 IMP Batch 2. After no positive treatment effect was evident from the main study results (per protocol set: 65 patients treated with Myelo001), the sponsor authorized further statistical analyses of the effects of the two sets of batches. The statistical analyses were identical for main and subgroups.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Myelo001 tablet (100 mg)
    Investigational medicinal product code
    Other name
    Imidazolyl ethanamide pentandioic acid, Vitaglutam, Dicarbamin, Dicarbamine
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients took Myelo001 (100 mg), one tablet orally daily around the same time in the morning. Intake started 5 days prior to the first chemotherapy treatment cycle and was continued until 3 days prior to the second chemotherapy cycle. Based on the standard schedule of the epirubicin/cyclophosphamide chemotherapy selected for this trial, investigational medicinal product intake was 23 days. If the start of the second chemotherapy cycle was delayed, the investigator could decide to prolong Myelo001 treatment to a maximum intake duration of 28 days.

    Arm title
    		 Placebo
    Arm description
    		 Patients received matching placebo once daily orally for scheduled 23 days from 5 days prior to the first chemotherapy cycle until 3 days prior to the second chemotherapy cycle (epirubicin/cyclophosphamide). The first batch of the investigational medicinal product (IMP) was exchanged with an exchange IMP batch after 49 patients were randomized. Altogether, 67 patients were treated with placebo. Of these, 23 patients were treated with placebo tablets (#116) of the initial IMP batch and are referred in post-hoc analyses as subgroup Placebo IMP Batch 1. The other 44 patients were treated with placebo tablets (#316) of the exchange IMP batch and are referred as subgroup Placebo IMP Batch 2. After no positive treatment effect was evident from the main study results (per protocol set: 65 patients treated with placebo), the sponsor authorized further statistical analyses of the effects of the two sets of batches. The statistical analyses were identical for main and subgroups.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients took matching placebo, one tablet orally daily around the same time in the morning. Intake started 5 days prior to the first chemotherapy treatment cycle and was continued until 3 days prior to the second chemotherapy cycle. Based on the standard schedule of the epirubicin/cyclophosphamide chemotherapy selected for this trial, investigational medicinal product (IMP) intake was 23 days. If the start of the second chemotherapy cycle was delayed, the investigator could decide to prolong IMP intake to a maximum intake duration of 28 days.

    Number of subjects in period 1
    		Myelo001 Placebo
    Started
    68
    69
    Completed
    63
    65
    Not completed
    5
    4
         Consent withdrawn by subject
    4
    2
         Physician decision
    -
    2
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Myelo001
    Reporting group description
    		 Patients received Myelo001 (100 mg) once daily orally for scheduled 23 days from 5 days prior to the first chemotherapy cycle until 3 days prior to the second chemotherapy cycle (epirubicin/cyclophosphamide). The first batch of the investigational medicinal product (IMP) was exchanged with an exchange IMP batch after 49 patients were randomized. Altogether, 67 patients were treated with Myelo001. Of these, 26 patients were treated with Myelo001 tablets (#216) of the initial IMP batch and are referred in post-hoc analyses as subgroup Myelo001 IMP Batch 1. The other 41 patients were treated with Myelo001 tablets (#416) of the exchange IMP batch and are referred as subgroup Myelo001 IMP Batch 2. After no positive treatment effect was evident from the main study results (per protocol set: 65 patients treated with Myelo001), the sponsor authorized further statistical analyses of the effects of the two sets of batches. The statistical analyses were identical for main and subgroups.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients received matching placebo once daily orally for scheduled 23 days from 5 days prior to the first chemotherapy cycle until 3 days prior to the second chemotherapy cycle (epirubicin/cyclophosphamide). The first batch of the investigational medicinal product (IMP) was exchanged with an exchange IMP batch after 49 patients were randomized. Altogether, 67 patients were treated with placebo. Of these, 23 patients were treated with placebo tablets (#116) of the initial IMP batch and are referred in post-hoc analyses as subgroup Placebo IMP Batch 1. The other 44 patients were treated with placebo tablets (#316) of the exchange IMP batch and are referred as subgroup Placebo IMP Batch 2. After no positive treatment effect was evident from the main study results (per protocol set: 65 patients treated with placebo), the sponsor authorized further statistical analyses of the effects of the two sets of batches. The statistical analyses were identical for main and subgroups.

    Reporting group values
    		 Myelo001 Placebo Total
    Number of subjects
    		 68 69 137
    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
    arithmetic mean (standard deviation)
    Units: years
        arithmetic mean (standard deviation)
    		 54.4 ± 10.51 55.5 ± 10.61 -
    Gender categorical
    Units: Subjects
        Female
    		 68 69 137
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Myelo001
    Reporting group description
    		 Patients received Myelo001 (100 mg) once daily orally for scheduled 23 days from 5 days prior to the first chemotherapy cycle until 3 days prior to the second chemotherapy cycle (epirubicin/cyclophosphamide). The first batch of the investigational medicinal product (IMP) was exchanged with an exchange IMP batch after 49 patients were randomized. Altogether, 67 patients were treated with Myelo001. Of these, 26 patients were treated with Myelo001 tablets (#216) of the initial IMP batch and are referred in post-hoc analyses as subgroup Myelo001 IMP Batch 1. The other 41 patients were treated with Myelo001 tablets (#416) of the exchange IMP batch and are referred as subgroup Myelo001 IMP Batch 2. After no positive treatment effect was evident from the main study results (per protocol set: 65 patients treated with Myelo001), the sponsor authorized further statistical analyses of the effects of the two sets of batches. The statistical analyses were identical for main and subgroups.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients received matching placebo once daily orally for scheduled 23 days from 5 days prior to the first chemotherapy cycle until 3 days prior to the second chemotherapy cycle (epirubicin/cyclophosphamide). The first batch of the investigational medicinal product (IMP) was exchanged with an exchange IMP batch after 49 patients were randomized. Altogether, 67 patients were treated with placebo. Of these, 23 patients were treated with placebo tablets (#116) of the initial IMP batch and are referred in post-hoc analyses as subgroup Placebo IMP Batch 1. The other 44 patients were treated with placebo tablets (#316) of the exchange IMP batch and are referred as subgroup Placebo IMP Batch 2. After no positive treatment effect was evident from the main study results (per protocol set: 65 patients treated with placebo), the sponsor authorized further statistical analyses of the effects of the two sets of batches. The statistical analyses were identical for main and subgroups.

    Subject analysis set title
    Myelo001 (IMP Batch 1)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients of the per protocol set receiving Myelo001 of investigational medicinal product (IMP) batch 1. The results of post-hoc analyses for ANC related endpoints revealed a strong batch effect and a significant interaction between IMP batch and treatment (p < 0.03) for all three primary / co-primary endpoints.

    Subject analysis set title
    Placebo (IMP Batch 1)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients of the per protocol set receiving placebo of investigational medicinal product (IMP) batch 1. The results of post-hoc analyses for ANC related endpoints revealed a strong batch effect and a significant interaction between IMP batch and treatment (p < 0.03) for all three primary / co-primary endpoints.

    Subject analysis set title
    Myelo001 (IMP Batch 2)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients of the per protocol set receiving Myelo001 of investigational medicinal product (IMP) batch 2. The results of post-hoc analyses for ANC related endpoints revealed a strong batch effect and a significant interaction between IMP batch and treatment (p < 0.03) for all three primary / co-primary endpoints.

    Subject analysis set title
    Placebo (IMP Batch 2)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients of the per protocol set receiving placebo of investigational medicinal product (IMP) batch 2. The results of post-hoc analyses for ANC related endpoints revealed a strong batch effect and a significant interaction between IMP batch and treatment (p < 0.03) for all three primary / co-primary endpoints.

    Primary: Threshold area over the curve (AOC1) of absolute neutrophil count (ANC) in the study period of d1/c1 to d22/c1

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    End point title
    		 Threshold area over the curve (AOC1) of absolute neutrophil count (ANC) in the study period of d1/c1 to d22/c1
    End point description
    Area below the threshold line [ANC 2.0x10exp9/L classified as grade 1 neutropenia according to Common Terminology Criteria for Adverse Events (CTCAE), v4.03, 2010] and above the individual ANC trajectory in the study period of d1/c1 to d22/c1.
    End point type
    Primary
    End point timeframe
    day 1 to day 22 of chemotherapy cycle 1
    End point values
    		 Myelo001 Placebo Myelo001 (IMP Batch 1) Placebo (IMP Batch 1) Myelo001 (IMP Batch 2) Placebo (IMP Batch 2)
    Number of subjects analysed
    65 [1]
    65 [2]
    24 [3]
    23 [4]
    41 [5]
    42 [6]
    Units: (ANC/nL)*days
        least squares mean (confidence interval 95%)
    13.562 (12.601 to 14.522)
    13.989 (13.041 to 14.936)
    11.993 (10.486 to 13.501)
    14.281 (12.737 to 15.824)
    14.683 (13.520 to 15.847)
    13.761 (12.634 to 14.889)
    Notes
    [1] - per protocol set (PPS)
    [2] - per protocol set (PPS)
    [3] - per protocol set (PPS)
    [4] - per protocol set (PPS)
    [5] - per protocol set (PPS)
    [6] - per protocol set (PPS)
    Statistical analysis title
    		 ANCOVA of AOC1 (total)
    Statistical analysis description
    Analysis-of-covariance model (ANCOVA) with treatment and region as fixed effects and baseline (before first IMP or placebo administration) neutrophil counts as covariate. Point estimates (LS Means) were calculated for each treatment group and a two-sided 95% confidence interval based on the t-distribution and the residual error of the model was computed for the difference between treatment means (Myelo001 minus placebo).
    Comparison groups
    Myelo001 v Placebo
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5242
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 ANCOVA of AOC1 (IMP Batch 1)
    Statistical analysis description
    Analysis-of-covariance model (ANCOVA) with treatment and region as fixed effects and baseline (before first IMP or placebo administration) neutrophil counts as covariate. Point estimates (LS Means) were calculated for each treatment group and a two-sided 95% confidence interval based on the t-distribution and the residual error of the model was computed for the difference between treatment means (Myelo001 minus placebo).
    Comparison groups
    Myelo001 (IMP Batch 1) v Placebo (IMP Batch 1)
    Number of subjects included in analysis
    47
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.0304
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 ANCOVA of AOC1 (IMP Batch 2)
    Statistical analysis description
    Analysis-of-covariance model (ANCOVA) with treatment and region as fixed effects and baseline (before first IMP or placebo administration) neutrophil counts as covariate. Point estimates (LS Means) were calculated for each treatment group and a two-sided 95% confidence interval based on the t-distribution and the residual error of the model was computed for the difference between treatment means (Myelo001 minus placebo).
    Comparison groups
    Myelo001 (IMP Batch 2) v Placebo (IMP Batch 2)
    Number of subjects included in analysis
    83
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.2533
    Method
    		 ANCOVA
    Confidence interval

    Primary: Threshold area over the curve (AOC3) of absolute neutrophil count (ANC) in the study period of d1/c1 to d22/c1

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    End point title
    		 Threshold area over the curve (AOC3) of absolute neutrophil count (ANC) in the study period of d1/c1 to d22/c1
    End point description
    • co-primary endpoint: Area below the threshold line [ANC 1.0x10exp9/L classified as grade 3 neutropenia according to Common Terminology Criteria for Adverse Events (CTCAE), v4.03, 2010] and above the individual ANC trajectory, in the study period of d1/c1 to d22/c1.
    End point type
    Primary
    End point timeframe
    day 1 to day 22 of chemotherapy cycle 1
    End point values
    		 Myelo001 Placebo Myelo001 (IMP Batch 1) Placebo (IMP Batch 1) Myelo001 (IMP Batch 2) Placebo (IMP Batch 2)
    Number of subjects analysed
    65 [7]
    65 [8]
    24 [9]
    23 [10]
    41 [11]
    42 [12]
    Units: (ANC/nL)*days
        least squares mean (confidence interval 95%)
    4.093 (3.565 to 4.621)
    4.284 (3.763 to 4.805)
    3.367 (2.549 to 4.184)
    4.615 (3.778 to 5.452)
    4.636 (3.996 to 5.275)
    4.080 (3.460 to 4.700)
    Notes
    [7] - per protocol set (PPS)
    [8] - per protocol set (PPS)
    [9] - per protocol set (PPS)
    [10] - per protocol set (PPS)
    [11] - per protocol set (PPS)
    [12] - per protocol set (PPS)
    Statistical analysis title
    		 ANCOVA of AOC3 (total)
    Statistical analysis description
    Analysis-of-covariance model (ANCOVA) with treatment and region as fixed effects and baseline (before first IMP or placebo administration) neutrophil counts as covariate. Point estimates (LS Means) were calculated for each treatment group and a two-sided 95% confidence interval based on the t-distribution and the residual error of the model was computed for the difference between treatment means (Myelo001 minus placebo).
    Comparison groups
    Myelo001 v Placebo
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6042
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 ANCOVA of AOC3 (IMP Batch 1)
    Statistical analysis description
    Analysis-of-covariance model (ANCOVA) with treatment and region as fixed effects and baseline (before first IMP or placebo administration) neutrophil counts as covariate. Point estimates (LS Means) were calculated for each treatment group and a two-sided 95% confidence interval based on the t-distribution and the residual error of the model was computed for the difference between treatment means (Myelo001 minus placebo).
    Comparison groups
    Myelo001 (IMP Batch 1) v Placebo (IMP Batch 1)
    Number of subjects included in analysis
    47
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.0293
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 ANCOVA of AOC3 (IMP Batch 2)
    Statistical analysis description
    Analysis-of-covariance model (ANCOVA) with treatment and region as fixed effects and baseline (before first IMP or placebo administration) neutrophil counts as covariate. Point estimates (LS Means) were calculated for each treatment group and a two-sided 95% confidence interval based on the t-distribution and the residual error of the model was computed for the difference between treatment means (Myelo001 minus placebo).
    Comparison groups
    Myelo001 (IMP Batch 2) v Placebo (IMP Batch 2)
    Number of subjects included in analysis
    83
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.2107
    Method
    		 ANCOVA
    Confidence interval

    Primary: Duration of ANC < 1.0x10exp9/L classified as grade 3 neutropenia in the study period of d1/c1 to d22/c1

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    End point title
    		 Duration of ANC < 1.0x10exp9/L classified as grade 3 neutropenia in the study period of d1/c1 to d22/c1
    End point description
    • co-primary endpoint: Duration of ANC < 1.0x10exp9/L classified as grade 3 neutropenia [according to Common Terminology Criteria for Adverse Events (CTCAE), v4.03, 2010] in the study period of d1/c1 to d22/c1
    End point type
    Primary
    End point timeframe
    day 1 to day 22 of chemotherapy cycle 1
    End point values
    		 Myelo001 Placebo Myelo001 (IMP Batch 1) Placebo (IMP Batch 1) Myelo001 (IMP Batch 2) Placebo (IMP Batch 2)
    Number of subjects analysed
    65 [13]
    65 [14]
    24 [15]
    23 [16]
    41 [17]
    42 [18]
    Units: days
        least squares mean (confidence interval 95%)
    7.403 (6.837 to 7.969)
    7.824 (7.265 to 8.382)
    6.343 (5.434 to 7.253)
    7.923 (6.992 to 8.854)
    8.121 (7.461 to 8.781)
    7.703 (7.063 to 8.342)
    Notes
    [13] - per protocol set (PPS)
    [14] - per protocol set (PPS)
    [15] - per protocol set (PPS)
    [16] - per protocol set (PPS)
    [17] - per protocol set (PPS)
    [18] - per protocol set (PPS)
    Statistical analysis title
    		 ANCOVA of duration of AOC3 (total)
    Statistical analysis description
    Analysis-of-covariance model (ANCOVA) with treatment and region as fixed effects and baseline (before first IMP or placebo administration) neutrophil counts as covariate. Point estimates (LS Means) were calculated for each treatment group and a two-sided 95% confidence interval based on the t-distribution and the residual error of the model was computed for the difference between treatment means (Myelo001 minus placebo).
    Comparison groups
    Myelo001 v Placebo
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2879
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 ANCOVA of duration of AOC3 (IMP Batch 1)
    Statistical analysis description
    Analysis-of-covariance model (ANCOVA) with treatment and region as fixed effects and baseline (before first IMP or placebo administration) neutrophil counts as covariate. Point estimates (LS Means) were calculated for each treatment group and a two-sided 95% confidence interval based on the t-distribution and the residual error of the model was computed for the difference between treatment means (Myelo001 minus placebo).
    Comparison groups
    Myelo001 (IMP Batch 1) v Placebo (IMP Batch 1)
    Number of subjects included in analysis
    47
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.014
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 ANCOVA of duration of AOC3 (IMP Batch 2)
    Statistical analysis description
    Analysis-of-covariance model (ANCOVA) with treatment and region as fixed effects and baseline (before first IMP or placebo administration) neutrophil counts as covariate. Point estimates (LS Means) were calculated for each treatment group and a two-sided 95% confidence interval based on the t-distribution and the residual error of the model was computed for the difference between treatment means (Myelo001 minus placebo).
    Comparison groups
    Myelo001 (IMP Batch 2) v Placebo (IMP Batch 2)
    Number of subjects included in analysis
    83
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.36
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Threshold area over the curve (AOC1) of lymphocytes in the study period of d1/c1 to d22/c1

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    End point title
    		 Threshold area over the curve (AOC1) of lymphocytes in the study period of d1/c1 to d22/c1
    End point description
    Area below the threshold line [classified as grade 1 according to Common Terminology Criteria for Adverse Events (CTCAE), v4.03, 2010] and above the individual absolute lymphocyte count trajectory in the study period of d1/c1-d22/c1.
    End point type
    Secondary
    End point timeframe
    day 1 to day 22 of chemotherapy cycle 1
    End point values
    		 Myelo001 Placebo Myelo001 (IMP Batch 1) Placebo (IMP Batch 1) Myelo001 (IMP Batch 2) Placebo (IMP Batch 2)
    Number of subjects analysed
    65 [19]
    65 [20]
    24 [21]
    23 [22]
    41 [23]
    42 [24]
    Units: (lymphocytes/nL)*days
        least squares mean (confidence interval 95%)
    1.548 (1.148 to 1.948)
    1.712 (1.318 to 2.107)
    1.283 (0.518 to 2.048)
    2.061 (1.278 to 2.843)
    1.689 (1.211 to 2.166)
    1.465 (1.004 to 1.927)
    Notes
    [19] - per protocol set (PPS)
    [20] - per protocol set (PPS)
    [21] - per protocol set (PPS)
    [22] - per protocol set (PPS)
    [23] - per protocol set (PPS)
    [24] - per protocol set (PPS)
    Statistical analysis title
    		 ANCOVA of AOC1 (total)
    Statistical analysis description
    Analysis-of-covariance model (ANCOVA) with treatment and region as fixed effects and baseline (before first IMP or placebo administration) lymphocyte counts as covariate. Point estimates (LS Means) were calculated for each treatment group and a two-sided 95% confidence interval based on the t-distribution and the residual error of the model was computed for the difference between treatment means (Myelo001 minus placebo).
    Comparison groups
    Placebo v Myelo001
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5561
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 ANCOVA of AOC1 (IMP Batch 1)
    Statistical analysis description
    Analysis-of-covariance model (ANCOVA) with treatment and region as fixed effects and baseline (before first IMP or placebo administration) lymphocyte counts as covariate. Point estimates (LS Means) were calculated for each treatment group and a two-sided 95% confidence interval based on the t-distribution and the residual error of the model was computed for the difference between treatment means (Myelo001 minus placebo).
    Comparison groups
    Myelo001 (IMP Batch 1) v Placebo (IMP Batch 1)
    Number of subjects included in analysis
    47
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.1423
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 ANCOVA of AOC1 (IMP Batch 2)
    Statistical analysis description
    Analysis-of-covariance model (ANCOVA) with treatment and region as fixed effects and baseline (before first IMP or placebo administration) lymphocyte counts as covariate. Point estimates (LS Means) were calculated for each treatment group and a two-sided 95% confidence interval based on the t-distribution and the residual error of the model was computed for the difference between treatment means (Myelo001 minus placebo).
    Comparison groups
    Myelo001 (IMP Batch 2) v Placebo (IMP Batch 2)
    Number of subjects included in analysis
    83
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.4981
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Threshold area over the curve (AOC1) of leukocytes in the study period of d1/c1 to d22/c1

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    End point title
    		 Threshold area over the curve (AOC1) of leukocytes in the study period of d1/c1 to d22/c1
    End point description
    Area below the threshold line [classified as grade 1 according to Common Terminology Criteria for Adverse Events (CTCAE), v4.03, 2010] and above the individual absolute leukocyte count trajectory in the study period of d1/c1 to d22/c1.
    End point type
    Secondary
    End point timeframe
    day 1 to day 22 of chemotherapy cycle 1
    End point values
    		 Myelo001 Placebo Myelo001 (IMP Batch 1) Placebo (IMP Batch 1) Myelo001 (IMP Batch 2) Placebo (IMP Batch 2)
    Number of subjects analysed
    65 [25]
    65 [26]
    24 [27]
    23 [28]
    41 [29]
    42 [30]
    Units: (leucocytes/nL)*days
        least squares mean (confidence interval 95%)
    19.503 (17.789 to 21.218)
    20.670 (18.979 to 22.362)
    17.237 (14.494 to 19.979)
    21.950 (19.145 to 24.754)
    21.110 (18.914 to 23.305)
    20.016 (17.887 to 22.144)
    Notes
    [25] - per protocol set (PPS)
    [26] - per protocol set (PPS)
    [27] - per protocol set (PPS)
    [28] - per protocol set (PPS)
    [29] - per protocol set (PPS)
    [30] - per protocol set (PPS)
    Statistical analysis title
    		 ANCOVA of AOC1 (total)
    Statistical analysis description
    Analysis-of-covariance model (ANCOVA) with treatment and region as fixed effects and baseline (before first IMP or placebo administration) leukocyte counts as covariate. Point estimates (LS Means) were calculated for each treatment group and a two-sided 95% confidence interval based on the t-distribution and the residual error of the model was computed for the difference between treatment means (Myelo001 minus placebo).
    Comparison groups
    Myelo001 v Placebo
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3304
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 ANCOVA of AOC1 (IMP Batch 1)
    Statistical analysis description
    Analysis-of-covariance model (ANCOVA) with treatment and region as fixed effects and baseline (before first IMP or placebo administration) leukocyte counts as covariate. Point estimates (LS Means) were calculated for each treatment group and a two-sided 95% confidence interval based on the t-distribution and the residual error of the model was computed for the difference between treatment means (Myelo001 minus placebo).
    Comparison groups
    Myelo001 (IMP Batch 1) v Placebo (IMP Batch 1)
    Number of subjects included in analysis
    47
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.0149
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 ANCOVA of AOC1 (IMP Batch 2)
    Statistical analysis description
    Analysis-of-covariance model (ANCOVA) with treatment and region as fixed effects and baseline (before first IMP or placebo administration) leukocyte counts as covariate. Point estimates (LS Means) were calculated for each treatment group and a two-sided 95% confidence interval based on the t-distribution and the residual error of the model was computed for the difference between treatment means (Myelo001 minus placebo).
    Comparison groups
    Myelo001 (IMP Batch 2) v Placebo (IMP Batch 2)
    Number of subjects included in analysis
    83
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.472
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Threshold area over the curve (AOC1) of thrombocytes in the study period d1/c1 to d22/c1

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    End point title
    		 Threshold area over the curve (AOC1) of thrombocytes in the study period d1/c1 to d22/c1
    End point description
    Area below the threshold line [classified as grade 1 according to Common Terminology Criteria for Adverse Events (CTCAE), v4.03, 2010] and above the individual absolute thrombocyte count trajectory in the study period d1/c1 to d22/c1.
    End point type
    Secondary
    End point timeframe
    day 1 to day 22 of chemotherapy cycle 1
    End point values
    		 Myelo001 Placebo Myelo001 (IMP Batch 1) Placebo (IMP Batch 1) Myelo001 (IMP Batch 2) Placebo (IMP Batch 2)
    Number of subjects analysed
    65 [31]
    65 [32]
    24 [33]
    23 [34]
    41 [35]
    42 [36]
    Units: (thrombocytes/nL)*days
        least squares mean (confidence interval 95%)
    114.613 (73.830 to 155.396)
    89.216 (48.771 to 129.660)
    55.726 (-3.667 to 115.119)
    96.190 (35.498 to 156.883)
    145.684 (89.143 to 202.224)
    84.114 (29.310 to 138.918)
    Notes
    [31] - per protocol set (PPS)
    [32] - per protocol set (PPS)
    [33] - per protocol set (PPS)
    [34] - per protocol set (PPS)
    [35] - per protocol set (PPS)
    [36] - per protocol set (PPS)
    Statistical analysis title
    		 ANCOVA of AOC1 (total)
    Statistical analysis description
    Analysis-of-covariance model (ANCOVA) with treatment and region as fixed effects and baseline (before first IMP or placebo administration) thrombocyte counts as covariate. Point estimates (LS Means) were calculated for each treatment group and a two-sided 95% confidence interval based on the t-distribution and the residual error of the model was computed for the difference between treatment means (Myelo001 minus placebo).
    Comparison groups
    Myelo001 v Placebo
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.375
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 ANCOVA of AOC1 (IMP Batch 1)
    Statistical analysis description
    Analysis-of-covariance model (ANCOVA) with treatment and region as fixed effects and baseline (before first IMP or placebo administration) thrombocyte counts as covariate. Point estimates (LS Means) were calculated for each treatment group and a two-sided 95% confidence interval based on the t-distribution and the residual error of the model was computed for the difference between treatment means (Myelo001 minus placebo).
    Comparison groups
    Myelo001 (IMP Batch 1) v Placebo (IMP Batch 1)
    Number of subjects included in analysis
    47
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.3323
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 ANCOVA of AOC1 (IMP Batch 2)
    Statistical analysis description
    Analysis-of-covariance model (ANCOVA) with treatment and region as fixed effects and baseline (before first IMP or placebo administration) thrombocyte counts as covariate. Point estimates (LS Means) were calculated for each treatment group and a two-sided 95% confidence interval based on the t-distribution and the residual error of the model was computed for the difference between treatment means (Myelo001 minus placebo).
    Comparison groups
    Myelo001 (IMP Batch 2) v Placebo (IMP Batch 2)
    Number of subjects included in analysis
    83
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.1173
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Proportion of patients developing febrile neutropenia in the study period of d1/c1 to d22/c1

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    End point title
    		 Proportion of patients developing febrile neutropenia in the study period of d1/c1 to d22/c1
    End point description
    Proportion of patients developing febrile neutropenia [body temperature ≥38.3°C (single tympanic or oral measurement) and ANC ≤0.5x10exp9/L (Grade 4 according to Common Terminology Criteria for Adverse Events (CTCAE), v4.03, 2010)]
    End point type
    Secondary
    End point timeframe
    day 1 to day 22 of chemotherapy cycle 1
    End point values
    		 Myelo001 Placebo Myelo001 (IMP Batch 1) Placebo (IMP Batch 1) Myelo001 (IMP Batch 2) Placebo (IMP Batch 2)
    Number of subjects analysed
    64
    63
    23
    21
    41
    42
    Units: subjects
    1
    1
    1
    0
    0
    1
    No statistical analyses for this end point

    Other pre-specified: Threshold area over the curve (AOC1) of Hemoglobin in the study period of d1/c1 to d22/c1

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    End point title
    		 Threshold area over the curve (AOC1) of Hemoglobin in the study period of d1/c1 to d22/c1
    End point description
    Area below the threshold line [classified as grade 1 according to Common Terminology Criteria for Adverse Events (CTCAE), v4.03, 2010] and above the individual hemoglobin value trajectory in the study period d1/c1 to d22/c1.
    End point type
    Other pre-specified
    End point timeframe
    day 1 to day 22 of chemotherapy cycle 1
    End point values
    		 Myelo001 Placebo Myelo001 (IMP Batch 1) Placebo (IMP Batch 1) Myelo001 (IMP Batch 2) Placebo (IMP Batch 2)
    Number of subjects analysed
    65 [37]
    65 [38]
    24 [39]
    23 [40]
    41 [41]
    42 [42]
    Units: days*(g/dL)
        least squares mean (confidence interval 95%)
    1.462 (0.426 to 2.498)
    1.970 (0.948 to 2.992)
    2.173 (-0.125 to 4.471)
    3.106 (0.756 to 5.455)
    0.989 (0.163 to 1.815)
    1.436 (0.637 to 2.236)
    Notes
    [37] - per protocol set (PPS)
    [38] - per protocol set (PPS)
    [39] - per protocol set (PPS)
    [40] - per protocol set (PPS)
    [41] - per protocol set (PPS)
    [42] - per protocol set (PPS)
    Statistical analysis title
    		 ANCOVA of AOC1 (total)
    Statistical analysis description
    Analysis-of-covariance model (ANCOVA) with treatment and region as fixed effects and baseline (before first IMP or placebo administration) hemoglobin as covariate. Point estimates (LS Means) were calculated for each treatment group and a two-sided 95% confidence interval based on the t-distribution and the residual error of the model was computed for the difference between treatment means (Myelo001 minus placebo).
    Comparison groups
    Myelo001 v Placebo
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4824
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 ANCOVA of AOC1 (IMP Batch 1)
    Statistical analysis description
    Analysis-of-covariance model (ANCOVA) with treatment and region as fixed effects and baseline (before first IMP or placebo administration) hemoglobin as covariate. Point estimates (LS Means) were calculated for each treatment group and a two-sided 95% confidence interval based on the t-distribution and the residual error of the model was computed for the difference between treatment means (Myelo001 minus placebo).
    Comparison groups
    Myelo001 (IMP Batch 1) v Placebo (IMP Batch 1)
    Number of subjects included in analysis
    47
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.5508
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 ANCOVA of AOC1 (IMP Batch 2)
    Statistical analysis description
    Analysis-of-covariance model (ANCOVA) with treatment and region as fixed effects and baseline (before first IMP or placebo administration) hemoglobin as covariate. Point estimates (LS Means) were calculated for each treatment group and a two-sided 95% confidence interval based on the t-distribution and the residual error of the model was computed for the difference between treatment means (Myelo001 minus placebo).
    Comparison groups
    Myelo001 (IMP Batch 2) v Placebo (IMP Batch 2)
    Number of subjects included in analysis
    83
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.4335
    Method
    		 ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Visit 1 (Screening visit) up to the start of the application of the third chemotherapy cycle, i.e. until Visit 12 (End-of-study visit).
    Adverse event reporting additional description
    134 patients were included into the safety analysis set (SAS). During the full trial period, in total 1014 adverse events were reported for the patients of the SAS. Of the adverse event total, 684 (67.5%) were assessed by the investigators as toxicity event related to the background treatment with anti-cancer chemotherapy drugs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Myelo001
    Reporting group description
    		 Patients received Myelo001 (100 mg) once daily orally for scheduled 23 days from 5 days prior to the first chemotherapy cycle until 3 days prior to the second chemotherapy cycle (epirubicin/cyclophosphamide).

    Reporting group title
    Placebo
    Reporting group description
    		 Patients received matching placebo once daily orally for scheduled 23 days from 5 days prior to the first chemotherapy cycle until 3 days prior to the second chemotherapy cycle (epirubicin/cyclophosphamide).

    Serious adverse events
    		 Myelo001 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 67 (7.46%)
    6 / 67 (8.96%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastasis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Poor peripheral circulation
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 67 (1.49%)
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter site pain
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (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: 0%
    Non-serious adverse events
    		 Myelo001 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    67 / 67 (100.00%)
    66 / 67 (98.51%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastasis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Embolism
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Haemodynamic instability
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Hot flush
         subjects affected / exposed
    3 / 67 (4.48%)
    4 / 67 (5.97%)
         occurrences all number
    3
    4
    Hypertension
         subjects affected / exposed
    7 / 67 (10.45%)
    6 / 67 (8.96%)
         occurrences all number
    7
    6
    Hypotension
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Phlebitis
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 67 (0.00%)
         occurrences all number
    2
    0
    Poor peripheral circulation
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Thrombosis
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 67 (1.49%)
    3 / 67 (4.48%)
         occurrences all number
    1
    3
    Catheter site pain
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Chills
         subjects affected / exposed
    1 / 67 (1.49%)
    2 / 67 (2.99%)
         occurrences all number
    2
    2
    Fatigue
         subjects affected / exposed
    27 / 67 (40.30%)
    26 / 67 (38.81%)
         occurrences all number
    29
    29
    Feeling cold
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    2
    General physical health deterioration
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Hypothermia
         subjects affected / exposed
    6 / 67 (8.96%)
    10 / 67 (14.93%)
         occurrences all number
    10
    20
    Implant site irritation
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    2
    Implant site pain
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Influenza like illness
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Mucosal dryness
         subjects affected / exposed
    1 / 67 (1.49%)
    3 / 67 (4.48%)
         occurrences all number
    1
    3
    Mucosal inflammation
         subjects affected / exposed
    13 / 67 (19.40%)
    15 / 67 (22.39%)
         occurrences all number
    13
    15
    Oedema
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Pain
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 67 (1.49%)
         occurrences all number
    1
    1
    Peripheral swelling
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    2 / 67 (2.99%)
    1 / 67 (1.49%)
         occurrences all number
    2
    1
    Reproductive system and breast disorders
    Breast inflammation
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 67 (1.49%)
         occurrences all number
    1
    1
    Dysmenorrhoea
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    1 / 67 (1.49%)
    3 / 67 (4.48%)
         occurrences all number
    1
    4
    Dysphonia
         subjects affected / exposed
    0 / 67 (0.00%)
    2 / 67 (2.99%)
         occurrences all number
    0
    2
    Dyspnoea
         subjects affected / exposed
    0 / 67 (0.00%)
    2 / 67 (2.99%)
         occurrences all number
    0
    2
    Epistaxis
         subjects affected / exposed
    2 / 67 (2.99%)
    1 / 67 (1.49%)
         occurrences all number
    2
    1
    Hiccups
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Nasal septum disorder
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    3 / 67 (4.48%)
    11 / 67 (16.42%)
         occurrences all number
    3
    11
    Pulmonary hypertension
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Throat irritation
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 67 (1.49%)
         occurrences all number
    1
    1
    Insomnia
         subjects affected / exposed
    2 / 67 (2.99%)
    3 / 67 (4.48%)
         occurrences all number
    3
    3
    Mental disorder
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    2
    Restlessness
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 67 (0.00%)
         occurrences all number
    2
    0
    Sleep disorder
         subjects affected / exposed
    0 / 67 (0.00%)
    3 / 67 (4.48%)
         occurrences all number
    0
    3
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 67 (1.49%)
         occurrences all number
    1
    1
    Bile duct pressure
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Blood glucose increased
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    5 / 67 (7.46%)
    6 / 67 (8.96%)
         occurrences all number
    5
    7
    Heart rate increased
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Mean cell volume abnormal
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Monocyte count decreased
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Red blood cell count decreased
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    White blood cells urine positive
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Drug-induced liver injury
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Infusion site thrombosis
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Procedural pain
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Cardiac failure
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Myocardial infarction
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Palpitations
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 67 (1.49%)
         occurrences all number
    1
    1
    Sinus tachycardia
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Nervous system disorders
    Cognitive disorder
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Disturbance in attention
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    7 / 67 (10.45%)
    10 / 67 (14.93%)
         occurrences all number
    7
    12
    Dysgeusia
         subjects affected / exposed
    4 / 67 (5.97%)
    2 / 67 (2.99%)
         occurrences all number
    4
    2
    Head discomfort
         subjects affected / exposed
    0 / 67 (0.00%)
    2 / 67 (2.99%)
         occurrences all number
    0
    2
    Headache
         subjects affected / exposed
    16 / 67 (23.88%)
    19 / 67 (28.36%)
         occurrences all number
    20
    22
    Neuropathy peripheral
         subjects affected / exposed
    0 / 67 (0.00%)
    2 / 67 (2.99%)
         occurrences all number
    0
    2
    Polyneuropathy
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Poor quality sleep
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 67 (1.49%)
    4 / 67 (5.97%)
         occurrences all number
    1
    4
    Febrile neutropenia
         subjects affected / exposed
    2 / 67 (2.99%)
    1 / 67 (1.49%)
         occurrences all number
    2
    1
    Leukocytosis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Leukopenia
         subjects affected / exposed
    55 / 67 (82.09%)
    56 / 67 (83.58%)
         occurrences all number
    62
    60
    Lymphadenopathy
         subjects affected / exposed
    0 / 67 (0.00%)
    2 / 67 (2.99%)
         occurrences all number
    0
    2
    Lymphocytopenia
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Lymphopenia
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Neutropenia
         subjects affected / exposed
    63 / 67 (94.03%)
    65 / 67 (97.01%)
         occurrences all number
    77
    80
    Thrombocytopenia
         subjects affected / exposed
    4 / 67 (5.97%)
    1 / 67 (1.49%)
         occurrences all number
    4
    1
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Ear pain
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    2
    Tinnitus
         subjects affected / exposed
    1 / 67 (1.49%)
    2 / 67 (2.99%)
         occurrences all number
    1
    2
    Vertigo
         subjects affected / exposed
    8 / 67 (11.94%)
    6 / 67 (8.96%)
         occurrences all number
    10
    7
    Eye disorders
    Dry eye
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 67 (0.00%)
         occurrences all number
    2
    0
    Eye swelling
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Visual impairment
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Abdominal pain
         subjects affected / exposed
    2 / 67 (2.99%)
    2 / 67 (2.99%)
         occurrences all number
    3
    2
    Abdominal pain upper
         subjects affected / exposed
    3 / 67 (4.48%)
    8 / 67 (11.94%)
         occurrences all number
    3
    9
    Constipation
         subjects affected / exposed
    18 / 67 (26.87%)
    16 / 67 (23.88%)
         occurrences all number
    19
    16
    Diarrhoea
         subjects affected / exposed
    5 / 67 (7.46%)
    9 / 67 (13.43%)
         occurrences all number
    5
    10
    Dry mouth
         subjects affected / exposed
    1 / 67 (1.49%)
    3 / 67 (4.48%)
         occurrences all number
    1
    5
    Duodenitis
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 67 (1.49%)
    2 / 67 (2.99%)
         occurrences all number
    1
    2
    Eructation
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Flatulence
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Gastrointestinal pain
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 67 (1.49%)
    2 / 67 (2.99%)
         occurrences all number
    1
    2
    Hiatus hernia
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Mouth ulceration
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    37 / 67 (55.22%)
    31 / 67 (46.27%)
         occurrences all number
    40
    38
    Oesophagitis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Stomatitis
         subjects affected / exposed
    2 / 67 (2.99%)
    3 / 67 (4.48%)
         occurrences all number
    2
    3
    Vomiting
         subjects affected / exposed
    4 / 67 (5.97%)
    7 / 67 (10.45%)
         occurrences all number
    4
    7
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Alopecia
         subjects affected / exposed
    37 / 67 (55.22%)
    44 / 67 (65.67%)
         occurrences all number
    37
    45
    dermatitis
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Dry skin
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    1 / 67 (1.49%)
    2 / 67 (2.99%)
         occurrences all number
    2
    2
    Erythema multiforme
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Flushing
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 67 (0.00%)
         occurrences all number
    5
    0
    Miliaria
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Nail discolouration
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Nail disorder
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Pain of skin
         subjects affected / exposed
    0 / 67 (0.00%)
    2 / 67 (2.99%)
         occurrences all number
    0
    2
    Pruritus
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    0 / 67 (0.00%)
    2 / 67 (2.99%)
         occurrences all number
    0
    3
    Skin erosion
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Skin lesion
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 67 (0.00%)
    2 / 67 (2.99%)
         occurrences all number
    0
    2
    Urinary incontinence
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 67 (1.49%)
    3 / 67 (4.48%)
         occurrences all number
    1
    3
    Back pain
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 67 (1.49%)
         occurrences all number
    1
    1
    Bone pain
         subjects affected / exposed
    2 / 67 (2.99%)
    1 / 67 (1.49%)
         occurrences all number
    2
    1
    Muscle spasms
         subjects affected / exposed
    0 / 67 (0.00%)
    3 / 67 (4.48%)
         occurrences all number
    0
    3
    Muscular weakness
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 67 (1.49%)
         occurrences all number
    1
    1
    Myalgia
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Osteolysis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    3 / 67 (4.48%)
    2 / 67 (2.99%)
         occurrences all number
    3
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Cystitis
         subjects affected / exposed
    1 / 67 (1.49%)
    2 / 67 (2.99%)
         occurrences all number
    1
    2
    Device related infection
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Gingivitis
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Herpes virus infection
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 67 (0.00%)
    2 / 67 (2.99%)
         occurrences all number
    0
    2
    Oral candidiasis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Postoperative wound infection
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Skin infection
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 67 (1.49%)
         occurrences all number
    1
    1
    Tonsillitis
         subjects affected / exposed
    0 / 67 (0.00%)
    2 / 67 (2.99%)
         occurrences all number
    0
    2
    Tooth infection
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    3 / 67 (4.48%)
    1 / 67 (1.49%)
         occurrences all number
    4
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 67 (4.48%)
    2 / 67 (2.99%)
         occurrences all number
    3
    2
    Vulvovaginal candidiasis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Appetite disorder
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Decreased appetite
         subjects affected / exposed
    2 / 67 (2.99%)
    4 / 67 (5.97%)
         occurrences all number
    2
    4
    Hypocalcaemia
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    Hyponatraemia
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Increased appetite
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         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
    12 Jul 2016
    In the process of implementing the clinical trial a few changes to the protocol became necessary to add precision and facilitate the per protocol conduct of the trial. The overall trial design remained unchanged. Notable changes included: • Permission to draw the blood sample a day earlier for baseline assessment and urine pregnancy testing as an alternative to analysis in serum • Change of visit schedule allowing shifts by +/- 1 day for certain study visits • Permission to substitute the baseline serum pregnancy test for an equivalent urine pregnancy test (local lab only) • Clarification that the use of (low-dose) dexamethasone for antiemetic use does not fall under the exclusion criteria and definition of maximum dose to achieve an equilibrium of the hematopoietic influence of dexamethasone • Adjustment of laboratory sample volumes to maximum amounts required by the two permitted systems • Consistency in the text that adverse events are followed up from first (screening) to last visit (EOS)
    17 Aug 2017
    Changes are mainly related to the statistical analyses and endpoint section. No procedure for the patient or investigators were changed. The most important changes include: • Revision of primary endpoint(s): Two co-primary endpoints were added • Revision of primary statistical test procedure • Addition of secondary endpoints • Sample size adjustment based on revised statistical procedure • Revised definition of the analysis sets (Revised Full Analysis Set and Per Protocol Set) Importantly, all protocol changes did not entail any procedural or interventional changes, but deepen or expand the analysis of the data generated from existing study procedures.

    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
    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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