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    Clinical Trial Results:
    A Randomized, Single-Blind, Multicenter Phase 2 Study to Evaluate the Activity of 2 Dose Levels of Imetelstat in Subjects with Intermediate-2 or High-Risk Myelofibrosis (MF) Relapsed/Refractory to Janus Kinase (JAK) Inhibitor

    Summary
    EudraCT number
    2015-000946-41
    Trial protocol
    BE   DE   GB   ES   FR   IT  
    Global end of trial date
    07 Feb 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Feb 2021
    First version publication date
    22 Feb 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    63935937MYF2001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02426086
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Geron Corporation
    Sponsor organisation address
    919 E. Hillsdale Boulevard, Suite 250, Foster City, CA, United States, 94404
    Public contact
    Clinical Trial Enquiries, Geron Corporation, myf2001-info@Geron.com
    Scientific contact
    Clinical Trial Enquiries, Geron Corporation, myf2001-info@Geron.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
    07 Feb 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study was to evaluate the efficacy and safety of 2 dose regimens of imetelstat (9.4 milligram/kilogram [mg/kg] and 4.7 mg/kg imetelstat given intravenous [IV] every 3 weeks) in subjects with intermediate-2 or high-risk MF who relapsed after or refractory to JAK inhibitor 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 Aug 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Korea, Republic of: 3
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    United States: 42
    Worldwide total number of subjects
    107
    EEA total number of subjects
    53
    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)
    34
    From 65 to 84 years
    72
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were enrolled at 55 investigative sites in Belgium, Canada, France, Germany, Israel, Italy, Korea, Spain, Taiwan, United Kingdom, and the United States from 28 August 2015 to 25 October 2016. Data analyses include all data through the cut-off date 07 February 2020.

    Pre-assignment
    Screening details
    A total of 107 subjects with Intermediate-2 or High-Risk Myelofibrosis (MF) Relapsed/Refractory to Janus Kinase (JAK) Inhibitor were randomly assigned to 1 of 2 treatment arms into 1:1 ratio to imetelstat 4.7 or imetelstat 9.4 mg/kg of body weight. Disposition data is reported till the end of study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Subject
    Blinding implementation details
    Initially single-blind; treatments unmasked after 1st Interim Analysis and continued as open-label treatment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Imetelstat 4.7 mg/kg
    Arm description
    Subjects received imetelstat 4.7 mg/kg of body weight as intravenous infusion on Day 1 of each 21-day cycle until disease progression, unacceptable toxicity, or study end. After the first interim analysis, treatment for all subjects was unblinded and subjects assigned to the imetelstat 4.7 mg/kg arm could continue with their same imetelstat dose or have it increased to 9.4 mg/kg at the investigator’s discretion. After the end of main study, subjects who were receiving benefit from study treatment opted to continue to receive imetelstat during the Extension Phase until there is loss of benefit or unacceptable toxicity. (Maximum duration on study was approximately 2.3 years and Maximum duration on extension phase was approximately 1.8 years).
    Arm type
    Experimental

    Investigational medicinal product name
    Imetelstat
    Investigational medicinal product code
    Other name
    GRN163L, JNJ-63935937
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received imetelstat 4.7 mg/kg of body weight as intravenous infusion on Day 1 of each 21-day cycle until disease progression, unacceptable toxicity, or study end. After the first interim analysis, treatment for all subjects was unblinded and subjects assigned to the imetelstat 4.7 mg/kg arm could continue with their same imetelstat dose or have it increased to 9.4 mg/kg at the investigator’s discretion. After the end of main study, subjects who were receiving benefit from study treatment opted to continue to receive imetelstat during the Extension Phase until there is loss of benefit or unacceptable toxicity.

    Arm title
    Imetelstat 9.4 mg/kg
    Arm description
    Subjects received imetelstat 9.4 mg/kg of body weight as intravenous infusion on Day 1 of each 21-days cycle until disease progression, unacceptable toxicity, or study end. After the end of the main study, subjects who were receiving benefit from study treatment opted to continue to receive imetelstat during the Extension Phase until there is loss of benefit or unacceptable toxicity. (Maximum duration on study was approximately 2.3 years and Maximum duration on extension phase was approximately 1.8 years).
    Arm type
    Experimental

    Investigational medicinal product name
    Imetelstat 9.4 mg/kg
    Investigational medicinal product code
    Other name
    GRN163L, JNJ-63935937
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received imetelstat 9.4 mg/kg of body weight as intravenous infusion on Day 1 of each 21-days cycle until disease progression, unacceptable toxicity, or study end. After the end of the main study, subjects who were receiving benefit from study treatment opted to continue to receive imetelstat during the Extension Phase until there is loss of benefit or unacceptable toxicity.

    Number of subjects in period 1
    Imetelstat 4.7 mg/kg Imetelstat 9.4 mg/kg
    Started
    48
    59
    Treated
    48
    59
    Completed
    0
    0
    Not completed
    48
    59
         Study Terminated by Sponsor
    5
    14
         Death
    33
    36
         Consent withdrawn by subject
    8
    9
         Lost to follow-up
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Imetelstat 4.7 mg/kg
    Reporting group description
    Subjects received imetelstat 4.7 mg/kg of body weight as intravenous infusion on Day 1 of each 21-day cycle until disease progression, unacceptable toxicity, or study end. After the first interim analysis, treatment for all subjects was unblinded and subjects assigned to the imetelstat 4.7 mg/kg arm could continue with their same imetelstat dose or have it increased to 9.4 mg/kg at the investigator’s discretion. After the end of main study, subjects who were receiving benefit from study treatment opted to continue to receive imetelstat during the Extension Phase until there is loss of benefit or unacceptable toxicity. (Maximum duration on study was approximately 2.3 years and Maximum duration on extension phase was approximately 1.8 years).

    Reporting group title
    Imetelstat 9.4 mg/kg
    Reporting group description
    Subjects received imetelstat 9.4 mg/kg of body weight as intravenous infusion on Day 1 of each 21-days cycle until disease progression, unacceptable toxicity, or study end. After the end of the main study, subjects who were receiving benefit from study treatment opted to continue to receive imetelstat during the Extension Phase until there is loss of benefit or unacceptable toxicity. (Maximum duration on study was approximately 2.3 years and Maximum duration on extension phase was approximately 1.8 years).

    Reporting group values
    Imetelstat 4.7 mg/kg Imetelstat 9.4 mg/kg Total
    Number of subjects
    48 59 107
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    68.0 ± 8.95 66.5 ± 9.39 -
    Gender categorical
    Units: Subjects
        Female
    16 24 40
        Male
    32 35 67
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    2 8 10
        Not Hispanic or Latino
    41 44 85
        Unknown
    2 3 5
        Not Reported
    3 4 7
    Race
    Units: Subjects
        White
    40 48 88
        Black/African American
    2 2 4
        Asian
    2 3 5
        Multiple
    1 0 1
        Not Reported
    3 6 9
    Region
    Units: Subjects
        United States/Canada
    25 18 43
        European Union
    19 34 53
        Rest of World
    4 7 11
    Platelet Count
    Units: Subjects
        <75 (10^9/L)
    1 2 3
        75 - <150 (10^9/L)
    23 31 54
        ≥150 (10^9/L)
    24 26 50
    ECOG Score
    Eastern Cooperative Oncology Group (ECOG) Score has 5 grades.0= Fully active, able to carry on all predisease performance without restriction;1= Restricted in physically strenuous activity but ambulatory, able to carry out work on a light or sedentary nature, eg, light housework, office work;2= Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about > 50% of waking hours;3= Capable of only limited self-care; confined to bed or chair > 50% of waking hours;4= Completely disabled. Cannot carry on any self-care.Totally confined to bed or chair;5=Dead.
    Units: Subjects
        0: Asymptomatic
    11 14 25
        1: Symptomatic fully ambulatory
    26 34 60
        2: Self care
    11 11 22
    DIPSS Score
    The Dynamic International Prognostic Scoring System (DIPSS) stratifies primary myelofibrosis (PMF) into four risk categories (low, intermediate 1, intermediate 2, and high risk), based on 5 clinical factors; Age>65, Hemoglobin <10gm/dL, Leukocytes >10 (9)/L, circulating blasts ≥1%, and constitutional symptoms.
    Units: Subjects
        Intermediate 2
    28 34 62
        High Risk
    19 25 44
        Missing
    1 0 1
    Type of MF
    Units: Subjects
        Primary MF (PMF)
    27 36 63
        Post Essential Thrombocythemia (PET)
    9 10 19
        Post Polycythemia Vera (PPV)
    12 13 25
    Spleen Size by Palpation
    Number (N= 47 for reporting group 1) analyzed signifies the number of subjects with data available for spleen size palpitation.
    Units: centimeter (cm)
        arithmetic mean (standard deviation)
    17.6 ± 7.62 17.3 ± 7.51 -
    Time from Last JAKi Treatment
    Units: months
        median (full range (min-max))
    1.4 (1 to 31) 1.7 (1 to 38) -
    Duration of Prior JAKi Treatment
    Units: months
        median (full range (min-max))
    22.3 (3 to 90) 24.5 (1 to 73) -

    End points

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    End points reporting groups
    Reporting group title
    Imetelstat 4.7 mg/kg
    Reporting group description
    Subjects received imetelstat 4.7 mg/kg of body weight as intravenous infusion on Day 1 of each 21-day cycle until disease progression, unacceptable toxicity, or study end. After the first interim analysis, treatment for all subjects was unblinded and subjects assigned to the imetelstat 4.7 mg/kg arm could continue with their same imetelstat dose or have it increased to 9.4 mg/kg at the investigator’s discretion. After the end of main study, subjects who were receiving benefit from study treatment opted to continue to receive imetelstat during the Extension Phase until there is loss of benefit or unacceptable toxicity. (Maximum duration on study was approximately 2.3 years and Maximum duration on extension phase was approximately 1.8 years).

    Reporting group title
    Imetelstat 9.4 mg/kg
    Reporting group description
    Subjects received imetelstat 9.4 mg/kg of body weight as intravenous infusion on Day 1 of each 21-days cycle until disease progression, unacceptable toxicity, or study end. After the end of the main study, subjects who were receiving benefit from study treatment opted to continue to receive imetelstat during the Extension Phase until there is loss of benefit or unacceptable toxicity. (Maximum duration on study was approximately 2.3 years and Maximum duration on extension phase was approximately 1.8 years).

    Subject analysis set title
    PK: Imetelstat 4.7 mg/kg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received imetelstat 4.7 mg/kg of body weight as intravenous infusion on Day 1 of cycle 1 and those who had serial PK samples collected.

    Subject analysis set title
    PK: Imetelstat 9.4 mg/kg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received imetelstat 9.4 mg/kg of body weight as intravenous infusion on Day 1 of cycle 1 and those who had serial PK samples collected.

    Primary: Percentage of Subjects with Spleen Response

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    End point title
    Percentage of Subjects with Spleen Response [1]
    End point description
    Spleen response rate is defined as the percentage of subjects who achieved ≥35% reduction in spleen volume at Week 24 from baseline performed by the IRC using magnetic resonance imaging (MRI). Treated analysis set included all subjects who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Week 24
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The percentage and 95% CI are the statistical analysis per protocol.
    End point values
    Imetelstat 4.7 mg/kg Imetelstat 9.4 mg/kg
    Number of subjects analysed
    48
    59
    Units: percentage of subjects
        number (confidence interval 95%)
    0 (0 to 7.4)
    10.2 (3.8 to 20.8)
    No statistical analyses for this end point

    Primary: Percentage of Subjects with Symptom Response

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    End point title
    Percentage of Subjects with Symptom Response [2]
    End point description
    Symptom response rate is defined as percentage of subjects who achieved ≥ 50% reduction in total symptom score (TSS) at Week 24 from baseline as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) version 2.0 diary. The MFSAF assessed following symptoms due to Myelofibrosis (MF): night sweats, itchiness, abdominal discomfort, pain under ribs on left side, feeling of fullness, bone or muscle pain and degree of inactivity. Each item is scored on a scale of 0 (absent) to 10 (worst imaginable) with higher scores indicating more severe symptoms and greater inactivity. The total score ranges from 0-70, where 0 indicates absent/as good as it can be and 70 indicates worst imaginable/as bad as it can be. Treated analysis set included all subjects who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Week 24
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The percentage and 95% CI are the statistical analysis per protocol.
    End point values
    Imetelstat 4.7 mg/kg Imetelstat 9.4 mg/kg
    Number of subjects analysed
    48
    59
    Units: percentage of subjects
        number (confidence interval 95%)
    6.3 (1.3 to 17.2)
    32.2 (20.6 to 45.6)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Overall Response as Per Modified 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria

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    End point title
    Percentage of Subjects With Overall Response as Per Modified 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria
    End point description
    Overall response rate (ORR): % of subjects with complete remission (CR) or partial R (PR).CR: bone marrow(BM): normocellular <5% blasts, ≤ Grade 1 fibrosis; immature myeloid cells (IMC) in peripheral blood (PB): <2%; Hb:10 g/dL-upper limit of normal (ULN); neutrophils: 1*10^9/L-ULN; platelets: 100*10^9/L-ULN; spleen: not palpable and ≤ 350ml volume; extramedullary hematopoeisis (EMH): no non-hepato-splenic EMH; symptoms: >70% improvement in symptom score. PR: BM: normocellular: <5% blasts ≤Grade 1 fibrosis/not meeting BM remission criteria; IMC in PB: <2%; Hb: 8.5 -<10 g/dL-ULN or 10 g/dL-ULN; neutrophils: 1*10^9/L-ULN; platelets: 50 -<100*10^9/L-ULN; spleen: ≥35% splenic volumetric reduction by MRI/not palpable; EMH: no non-hepato-splenic EMH; symptoms: >50% improvement in symptom score. Response categories benefit last >12 weeks to qualify as response. Treated analysis set was used. Upper and lower limits of 95% CI not estimable due to limited number of events and indicate by 99999.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
    End point values
    Imetelstat 4.7 mg/kg Imetelstat 9.4 mg/kg
    Number of subjects analysed
    48
    59
    Units: percentage of subjects
        number (confidence interval 95%)
    0 (-99999 to 99999)
    1.7 (0.0 to 9.1)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Clinical Improvement (CI) Per Modified 2013 IWG-MRT Criteria

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    End point title
    Percentage of Subjects With Clinical Improvement (CI) Per Modified 2013 IWG-MRT Criteria
    End point description
    CI per the modified 2013 IWG-MRT criteria defined as the achievement of anemia, spleen or symptoms response without progressive disease or increase in severity of anemia, thrombocytopenia, or neutropenia (Increase in severity of anemia constitutes the occurrence of new transfusion dependency or a ≥ 2.0 g/dL decrease in hemoglobin level from pretreatment baseline that lasts for at least 12 weeks. Increase in severity of thrombocytopenia or neutropenia is defined as a 2-grade decline, from pretreatment baseline, in platelet count or ANC, according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. In addition, assignment to CI requires a minimum platelet count of ≥ 25,000*10^9/L and ANC of ≥0.5*10^9/L.) For all response categories, benefit must last for >12 weeks to qualify as a response. Treated analysis set: subjects who received ≥ 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
    End point values
    Imetelstat 4.7 mg/kg Imetelstat 9.4 mg/kg
    Number of subjects analysed
    48
    59
    Units: percentage of subjects
        number (not applicable)
    16.7
    25.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Clinical Response Per Modified 2013 IWG-MRT

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    End point title
    Percentage of Subjects With Clinical Response Per Modified 2013 IWG-MRT
    End point description
    Clinical response rate (CRR): % of subjects who achieved CR, PR, or CI per modified 2013 IWG-MRT criteria. CR: bone marrow: normocellular <5% blasts, ≤Grade 1 fibrosis; immature myeloid cells in PB: <2%; Hb: 10 g/dL-ULN; neutrophils: 1*10^9/L-ULN; platelets: 100*10^9/L-ULN; spleen: not palpable and ≤350ml volume; EMH: no non-hepato-splenic EMH; symptoms: >70% improvement in symptom score. PR: bone marrow: normocellular: <5% blasts ≤ Grade 1 fibrosis or not meeting bone marrow remission criteria; Immature myeloid cells in PB: <2%; Hb: 8.5 -<10 g/dL-ULN or 10 g/dL-ULN; neutrophils: 1*10^9/L-ULN; platelets: 50 -<100*10^9/L-ULN; spleen: ≥35% splenic volumetric reduction by MRI or not palpable; EMH: no non-hepato-splenic EMH; symptoms: >50% improvement in symptom score. CI: achievement of anemia, spleen or symptoms response without PD or increase in severity of anemia, thrombocytopenia, or neutropenia. Treated analysis set: subjects who received ≥ 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
    End point values
    Imetelstat 4.7 mg/kg Imetelstat 9.4 mg/kg
    Number of subjects analysed
    48
    59
    Units: percentage of subjects
        number (confidence interval 95%)
    16.7 (7.5 to 30.2)
    27.1 (16.4 to 40.3)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Spleen Response Per Modified 2013 IWG-MRT Criteria

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    End point title
    Percentage of Subjects With Spleen Response Per Modified 2013 IWG-MRT Criteria
    End point description
    Spleen response per modified 2013 IWG-MRT criteria. Spleen response: a baseline splenomegaly that is palpable at 5-10 cm, below the left costal margin (LCM), becomes not palpable or a baseline splenomegaly that is palpable at >10 cm, below the LCM, decreases by ≥ 50%; A spleen response requires confirmation by MRI showing >35% spleen volume reduction (SVR). For response categories, benefit must last for >12 weeks to qualify as a response. Subjects who achieved CI per modified IWG-MRT criteria considered as response with clinical improvement. Subjects who met criteria for spleen response but had worsening cytopenias (and therefore did not meet criteria for clinical improvement) were considered to have a response without clinical improvement. Treated analysis set included all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
    End point values
    Imetelstat 4.7 mg/kg Imetelstat 9.4 mg/kg
    Number of subjects analysed
    48
    59
    Units: percentage of subjects
    number (not applicable)
        CI Response: Spleen response
    0
    3.4
        Response without CI: Spleen response
    2.1
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Symptom Response Per Modified 2013 IWG-MRT Criteria

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    End point title
    Percentage of Subjects With Symptom Response Per Modified 2013 IWG-MRT Criteria
    End point description
    Symptom response per modified 2013 IWG-MRT criteria. Symptoms Response: a ≥50% reduction in the modified MFSAF v2.0 TSS. For response category, benefit must last for >12 weeks to qualify as a response. Subjects who achieved CI per modified IWG-MRT criteria considered as response with clinical improvement. Subjects who met criteria for symptom response but had worsening cytopenias (and therefore did not meet criteria for clinical improvement) were considered to have a response without clinical improvement. Treated analysis set included all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
    End point values
    Imetelstat 4.7 mg/kg Imetelstat 9.4 mg/kg
    Number of subjects analysed
    48
    59
    Units: percentage of subjects
    number (not applicable)
        CI Response: Spleen response
    14.6
    22.0
        Response without CI: Spleen response
    4.2
    8.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Anemia Response Per Modified 2013 IWG-MRT Criteria

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    End point title
    Percentage of Subjects With Anemia Response Per Modified 2013 IWG-MRT Criteria
    End point description
    Anemia response per modified 2013 IWG-MRT criteria. Anemia response is defined as subjects with baseline Hb <10 g/dL but not meeting strict criteria for transfusion dependency: a ≥ 2 g/dL increase in Hb; Transfusion dependent subjects at baseline: becoming transfusion independent. Transfusion independence is defined as absence of any pRBC transfusions for at least 12 "rolling" weeks. For response categories, benefit must last for >12 weeks to qualify as a response. Subjects who achieved CI per modified IWG-MRT criteria considered as response with clinical improvement. Subjects who met criteria for anemia response but had worsening cytopenias (and therefore did not meet criteria for clinical improvement) were considered to have a response without clinical improvement. Treated analysis set included all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
    End point values
    Imetelstat 4.7 mg/kg Imetelstat 9.4 mg/kg
    Number of subjects analysed
    48
    59
    Units: percentage of subjects
    number (not applicable)
        CI Response: Spleen response
    4.2
    6.8
        Response without CI: Spleen response
    0
    1.7
    No statistical analyses for this end point

    Secondary: Duration of Response (PR/CI/RWCI) as Per IWG-MRT Criteria

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    End point title
    Duration of Response (PR/CI/RWCI) as Per IWG-MRT Criteria
    End point description
    Duration of response (PR/CI/RWCI) is the duration from the date of initial documentation of a response to date of first documented evidence of PD or death, whichever occurs first. PR: BM: normocellular: <5% blasts ≤Grade 1 fibrosis/not meeting BM remission criteria; IMC in PB: <2%; Hb: 8.5 -<10 g/dL-ULN or 10 g/dL- ULN; neutrophils: 1*10^9/L-ULN; platelets: 50 -<100*10^9/L-ULN; spleen: ≥35% splenic volumetric reduction by MRI/not palpable; EMH: no non-hepato-splenic EMH; symptoms: >50% improvement in symptom score. CI: achievement of anemia, spleen or symptoms response without PD or increase in severity of anemia, thrombocytopenia, neutropenia. RWCI: Subjects who met criteria for response but had worsening cytopenias. PD: Splenomegaly requires MRI showing ≥25% increase in spleen volume. Treated analysis set included all subjects who received at least 1 dose of study drug. Overall number of subjects analysed ("N") = subjects who were responders (PR/CI/RWCI) at any time.
    End point type
    Secondary
    End point timeframe
    From date of initial documentation of a response to the date of first documented evidence of PD or death, whichever occurs first (approximately up to 2.3 years)
    End point values
    Imetelstat 4.7 mg/kg Imetelstat 9.4 mg/kg
    Number of subjects analysed
    11
    21
    Units: weeks
        median (confidence interval 95%)
    36.3 (11.9 to 60.0)
    38.3 (27.0 to 48.3)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    Overall Survival is measured from the date of Cycle 1, Day 1 to the date of the subject’s death. If the subject was alive or the vital status was unknown, OS was censored at the date that the subject is last known to be alive. Treated analysis set included all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 1 (each cycle was of 21 days) up to the date of the subject’s death (approximately up to 4.1 years)
    End point values
    Imetelstat 4.7 mg/kg Imetelstat 9.4 mg/kg
    Number of subjects analysed
    48
    59
    Units: months
        median (confidence interval 95%)
    19.91 (17.05 to 33.87)
    28.09 (22.80 to 31.61)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Clinically Meaningful Improvement in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-30 (QLQ-C30): Global Health Status

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    End point title
    Percentage of Subjects with Clinically Meaningful Improvement in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-30 (QLQ-C30): Global Health Status
    End point description
    EORTC QLQ-C30 is a questionnaire to assess quality of life of cancer subjects. EORTC QLQ-C30 included 30 items resulting in 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) which are based on 4-point scale (1= Not at all to 4= Very much); and 1 global health status scale based on 7-point scale (1= Very poor to 7= Excellent). All scales and items are averaged, transformed to 0-100 scale; higher score=better level of functioning. Clinically meaningful improvement defined as change greater than half of the standard deviation at baseline in QLQ-C30 Global Health Status. Treated analysis set included all subjects who received at least 1 dose of study drug. Here "N"= subjects who had data at both baseline and end of treatment.
    End point type
    Secondary
    End point timeframe
    Up to end of the treatment (approximately up to 2.3 years)
    End point values
    Imetelstat 4.7 mg/kg Imetelstat 9.4 mg/kg
    Number of subjects analysed
    18
    33
    Units: percentage of subjects
    number (not applicable)
        Improvement
    22.2
    36.4
    No statistical analyses for this end point

    Secondary: EuroQol 5 Dimension 5 Level (EQ-5D-5L): Utility Score and Visual Analog Scale (VAS)

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    End point title
    EuroQol 5 Dimension 5 Level (EQ-5D-5L): Utility Score and Visual Analog Scale (VAS)
    End point description
    EQ-5D-5L is standardized health-related quality of life questionnaire developed by EuroQol Group to provide a simple, generic measure of health for clinical and economic appraisal. EQ-5D-5L consists of two components: health state profile and VAS. EQ-5D health state profile comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. 5D-5L systems are converted into single index utility score between 0 to 1, where higher score indicates a better health state. EQ-5D-5L- VAS is designed to rate subject's current health state on scale from 0 to 100, where 0 represents worst imaginable health state and 100 represents best imaginable health state. Treated analysis set was used. “n”= number of subjects with data available for each specified category and "N"= subjects who had data at both baseline and end of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of treatment (approximately up to 2.3 years)
    End point values
    Imetelstat 4.7 mg/kg Imetelstat 9.4 mg/kg
    Number of subjects analysed
    18
    33
    Units: score on scale
    arithmetic mean (standard deviation)
        EQ-5D-5L : Utility Score (n= 18, 32)
    0.498 ± 0.2999
    0.626 ± 0.2117
        EQ-5D-5L :VAS (n= 18, 33)
    51.28 ± 21.143
    47.73 ± 16.398
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Clinically Meaningful Improvement in Brief Pain Inventory (BPI)

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    End point title
    Percentage of Subjects With Clinically Meaningful Improvement in Brief Pain Inventory (BPI)
    End point description
    The BPI rates the intensity of pain on 4 items (right now, worst, least, and average), and the interference in 7 areas (general activity, mood, walking ability, normal work, relations, sleep, enjoyment of life). Minimum value = 0; maximum value = 10. Higher scores indicate greater symptom severity/worse outcomes. Clinically meaningful improvement (Imp) in BPI defined as change greater than half of the standard deviation at baseline. Treated analysis set included all subjects who received at least 1 dose of study drug. Here, “N” signifies number of subjects who had data at both baseline and end of treatment and “n” is the number of subjects with data available for each specified category.
    End point type
    Secondary
    End point timeframe
    Up to end of treatment (approximately up to 2.3 years)
    End point values
    Imetelstat 4.7 mg/kg Imetelstat 9.4 mg/kg
    Number of subjects analysed
    18
    33
    Units: percentage of subjects
    number (not applicable)
        Pain at its Worst:Imp(n=18,33)
    50.0
    75.8
        Pain at its Least:Imp(n=18,33)
    44.4
    51.5
        Pain on the Average:Imp(n=18,33)
    55.6
    66.7
        Pain Right Now:Imp(n=18,33)
    61.1
    66.7
        Relief Pain Treatments Provided:Imp(n=18,32)
    50.0
    53.1
        Pain Interfered General Activity:Imp(n=18,32)
    72.2
    68.8
        Pain Interfered with Mood:Imp(n=18,32)
    50.0
    59.4
        Pain Interfered Walking Ability:Imp(n=18,32)
    38.9
    78.1
        Pain Interfered with Normal Work:Imp(n=18,32)
    61.1
    62.5
        Pain Interfered with Relations:Imp(n=18,32)
    44.4
    53.1
        Pain Interfered with Sleep:Imp(n=18,32)
    61.1
    78.1
        Pain Interfered Enjoyment of Life:Imp(n=18,32)
    61.1
    62.5
    No statistical analyses for this end point

    Secondary: Patient’s Global Impression of Change (PGIC)

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    End point title
    Patient’s Global Impression of Change (PGIC)
    End point description
    The PGIC was used to capture the subject's perspective of improvement or decline in MF symptoms over time. The PGIC had a 7-point response scale ranging from 1 to 7 where, 1=very much improved, 2= somewhat improved, 3= a little improved, 4=no change, 5= a little worse, 6= somewhat worse, 7=very much worse. Treated analysis set included all subjects who received at least 1 dose of study drug. Here, "N" signifies number of subjects who had data at both baseline and end of treatment.
    End point type
    Secondary
    End point timeframe
    Up to end of treatment (approximately up to 2.3 years)
    End point values
    Imetelstat 4.7 mg/kg Imetelstat 9.4 mg/kg
    Number of subjects analysed
    17
    33
    Units: score on a scale
        arithmetic mean (standard deviation)
    4.82 ± 1.237
    3.97 ± 1.571
    No statistical analyses for this end point

    Secondary: Number of Subjects with Treatment-emergent Adverse Events (TEAEs)

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    End point title
    Number of Subjects with Treatment-emergent Adverse Events (TEAEs)
    End point description
    An AE is any untoward medical occurrence in a subject or clinical investigation subjects administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. TEAEs were AEs with onset during or after the first dose of study drug, and within 30 days following the last dose of study drug. Safety analysis set included all subjects who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to end of extension phase (approximately up to 4.2 years)
    End point values
    Imetelstat 4.7 mg/kg Imetelstat 9.4 mg/kg
    Number of subjects analysed
    48
    59
    Units: subjects
        number (not applicable)
    47
    59
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) of Imetelstat

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    End point title
    Maximum Observed Plasma Concentration (Cmax) of Imetelstat
    End point description
    Pharmacokinetic (PK) subset included all subjects who had serial PK sampling during cycle 1 treatment to determine the maximum plasma concentration of Imetelstat by noncompartmental PK analysis.
    End point type
    Secondary
    End point timeframe
    0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days)
    End point values
    PK: Imetelstat 4.7 mg/kg PK: Imetelstat 9.4 mg/kg
    Number of subjects analysed
    11
    17
    Units: μg/mL
        arithmetic mean (standard deviation)
    57.0 ± 72.3
    81.9 ± 40.0
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Imetelstat

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    End point title
    Time to Reach Maximum Observed Plasma Concentration (Tmax) of Imetelstat
    End point description
    PK subset included all subjects who had serial PK sampling during cycle 1 treatment to determine the time to reach maximum plasma concentration of imetelstat by noncompartmental PK analysis.
    End point type
    Secondary
    End point timeframe
    0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days)
    End point values
    PK: Imetelstat 4.7 mg/kg PK: Imetelstat 9.4 mg/kg
    Number of subjects analysed
    11
    17
    Units: hr
        median (full range (min-max))
    2.00 (1.93 to 2.20)
    2.00 (1.00 to 2.75)
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC 0-24) of Imetelstat

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    End point title
    Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC 0-24) of Imetelstat
    End point description
    PK subset included all subjects who had serial PK sampling during cycle 1 treatment to determine the AUC 0-24 of Imetelstat by noncompartmental PK analysis.
    End point type
    Secondary
    End point timeframe
    0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days)
    End point values
    PK: Imetelstat 4.7 mg/kg PK: Imetelstat 9.4 mg/kg
    Number of subjects analysed
    11
    17
    Units: μg*hr/mL
        arithmetic mean (standard deviation)
    171 ± 135
    501 ± 283
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-Time Profile From Time Zero to Infinity (AUC0-inf) of Imetelstat

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    End point title
    Area Under the Plasma Concentration-Time Profile From Time Zero to Infinity (AUC0-inf) of Imetelstat
    End point description
    PK subset included all subjects who had serial PK sampling during cycle 1 treatment to determine AUC 0-inf of Imetelstat by noncompartmental PK analysis.
    End point type
    Secondary
    End point timeframe
    0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days)
    End point values
    PK: Imetelstat 4.7 mg/kg PK: Imetelstat 9.4 mg/kg
    Number of subjects analysed
    11
    17
    Units: μg*hr/mL
        arithmetic mean (standard deviation)
    193 ± 156
    524 ± 297
    No statistical analyses for this end point

    Secondary: Elimination Half-Life (t1/2) of Imetelstat

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    End point title
    Elimination Half-Life (t1/2) of Imetelstat
    End point description
    Elimination half-life (t 1/2) is associated with the terminal slope (lambda [z]) of the semi logarithmic drug concentration-time curve, calculated as 0.693/lambda(z). PK subset included all subjects who had serial PK sampling during cycle 1 treatment to determine the t1/2 of Imetelstat by noncompartmental PK analysis.
    End point type
    Secondary
    End point timeframe
    0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days)
    End point values
    PK: Imetelstat 4.7 mg/kg PK: Imetelstat 9.4 mg/kg
    Number of subjects analysed
    11
    17
    Units: hr
        arithmetic mean (standard deviation)
    4.6 ± 1.6
    5.5 ± 1.5
    No statistical analyses for this end point

    Secondary: Total Systemic Clearance (CL) of Imetelstat

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    End point title
    Total Systemic Clearance (CL) of Imetelstat
    End point description
    PK subset included all subjects who had serial PK sampling during cycle 1 treatment to determine the CL of Imetelstat by noncompartmental PK analysis.
    End point type
    Secondary
    End point timeframe
    0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days)
    End point values
    PK: Imetelstat 4.7 mg/kg PK: Imetelstat 9.4 mg/kg
    Number of subjects analysed
    11
    17
    Units: L/hr/kg
        arithmetic mean (standard deviation)
    0.0329 ± 0.0138
    0.0252 ± 0.0157
    No statistical analyses for this end point

    Secondary: Volume of Distribution (Vd) of Imetelstat

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    End point title
    Volume of Distribution (Vd) of Imetelstat
    End point description
    PK population analysis set included all subjects who received at least 1 dose of study drug and had at least 1 sample collected during treatment to determine the drug concentration.
    End point type
    Secondary
    End point timeframe
    0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days)
    End point values
    PK: Imetelstat 4.7 mg/kg PK: Imetelstat 9.4 mg/kg
    Number of subjects analysed
    11
    17
    Units: L/kg
        arithmetic mean (standard deviation)
    0.198 ± 0.0770
    0.190 ± 0.104
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to end of extension phase (approximately up to 4.2 years)
    Adverse event reporting additional description
    Safety analysis set included all subjects who received at least 1 dose of study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Imetelstat 4.7 mg/kg
    Reporting group description
    Subjects received imetelstat 4.7 mg/kg of body weight as intravenous infusion on Day 1 of each 21-day cycle until disease progression, unacceptable toxicity, or study end. After the first interim analysis, treatment for all subjects was unblinded and subjects assigned to the imetelstat 4.7 mg/kg arm could continue with their same imetelstat dose or have it increased to 9.4 mg/kg at the investigator’s discretion. After the end of main study, subjects who were receiving benefit from study treatment opted to continue to receive imetelstat during the Extension Phase until there is loss of benefit or unacceptable toxicity. (Maximum duration on study was approximately 2.3 years and Maximum duration on extension phase was approximately 1.8 years).

    Reporting group title
    Imetelstat 9.4 mg/kg
    Reporting group description
    Subjects received imetelstat 9.4 mg/kg of body weight as intravenous infusion on Day 1 of each 21-days cycle until disease progression, unacceptable toxicity, or study end. After the end of the main study, subjects who were receiving benefit from study treatment opted to continue to receive imetelstat during the Extension Phase until there is loss of benefit or unacceptable toxicity. (Maximum duration on study was approximately 2.3 years and Maximum duration on extension phase was approximately 1.8 years).

    Serious adverse events
    Imetelstat 4.7 mg/kg Imetelstat 9.4 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 48 (43.75%)
    24 / 59 (40.68%)
         number of deaths (all causes)
    35
    36
         number of deaths resulting from adverse events
    3
    3
    Vascular disorders
    Aneurysm ruptured
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Dyspnoea
         subjects affected / exposed
    4 / 48 (8.33%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolysis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic artery thrombosis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic infarction
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Splenic vein thrombosis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenomegaly
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Failure to thrive
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Listeriosis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 48 (4.17%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Imetelstat 4.7 mg/kg Imetelstat 9.4 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    47 / 48 (97.92%)
    59 / 59 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 48 (6.25%)
    4 / 59 (6.78%)
         occurrences all number
    5
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    9 / 48 (18.75%)
    14 / 59 (23.73%)
         occurrences all number
    11
    21
    Chills
         subjects affected / exposed
    3 / 48 (6.25%)
    8 / 59 (13.56%)
         occurrences all number
    7
    15
    Fatigue
         subjects affected / exposed
    10 / 48 (20.83%)
    15 / 59 (25.42%)
         occurrences all number
    14
    20
    Malaise
         subjects affected / exposed
    2 / 48 (4.17%)
    3 / 59 (5.08%)
         occurrences all number
    2
    5
    Oedema peripheral
         subjects affected / exposed
    13 / 48 (27.08%)
    10 / 59 (16.95%)
         occurrences all number
    18
    12
    Pain
         subjects affected / exposed
    1 / 48 (2.08%)
    3 / 59 (5.08%)
         occurrences all number
    1
    5
    Pyrexia
         subjects affected / exposed
    8 / 48 (16.67%)
    13 / 59 (22.03%)
         occurrences all number
    14
    24
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 48 (12.50%)
    7 / 59 (11.86%)
         occurrences all number
    7
    8
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    3 / 48 (6.25%)
    2 / 59 (3.39%)
         occurrences all number
    3
    3
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 48 (4.17%)
    5 / 59 (8.47%)
         occurrences all number
    2
    7
    Serum ferritin increased
         subjects affected / exposed
    0 / 48 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    0
    5
    Weight decreased
         subjects affected / exposed
    9 / 48 (18.75%)
    8 / 59 (13.56%)
         occurrences all number
    12
    14
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    2 / 48 (4.17%)
    6 / 59 (10.17%)
         occurrences all number
    5
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    15 / 48 (31.25%)
    26 / 59 (44.07%)
         occurrences all number
    35
    95
    Leukocytosis
         subjects affected / exposed
    3 / 48 (6.25%)
    2 / 59 (3.39%)
         occurrences all number
    6
    3
    Leukopenia
         subjects affected / exposed
    3 / 48 (6.25%)
    8 / 59 (13.56%)
         occurrences all number
    12
    30
    Neutropenia
         subjects affected / exposed
    5 / 48 (10.42%)
    21 / 59 (35.59%)
         occurrences all number
    13
    72
    Splenomegaly
         subjects affected / exposed
    0 / 48 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    3
    Thrombocytopenia
         subjects affected / exposed
    11 / 48 (22.92%)
    29 / 59 (49.15%)
         occurrences all number
    26
    121
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 48 (22.92%)
    9 / 59 (15.25%)
         occurrences all number
    17
    12
    Dyspnoea
         subjects affected / exposed
    7 / 48 (14.58%)
    15 / 59 (25.42%)
         occurrences all number
    8
    22
    Epistaxis
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 59 (1.69%)
         occurrences all number
    3
    1
    Oropharyngeal pain
         subjects affected / exposed
    5 / 48 (10.42%)
    4 / 59 (6.78%)
         occurrences all number
    5
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 48 (4.17%)
    10 / 59 (16.95%)
         occurrences all number
    2
    13
    Headache
         subjects affected / exposed
    6 / 48 (12.50%)
    10 / 59 (16.95%)
         occurrences all number
    8
    14
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 48 (4.17%)
    5 / 59 (8.47%)
         occurrences all number
    3
    6
    Abdominal distension
         subjects affected / exposed
    2 / 48 (4.17%)
    4 / 59 (6.78%)
         occurrences all number
    5
    7
    Abdominal pain
         subjects affected / exposed
    9 / 48 (18.75%)
    14 / 59 (23.73%)
         occurrences all number
    9
    21
    Abdominal pain upper
         subjects affected / exposed
    2 / 48 (4.17%)
    4 / 59 (6.78%)
         occurrences all number
    3
    4
    Constipation
         subjects affected / exposed
    9 / 48 (18.75%)
    9 / 59 (15.25%)
         occurrences all number
    14
    11
    Diarrhoea
         subjects affected / exposed
    18 / 48 (37.50%)
    18 / 59 (30.51%)
         occurrences all number
    23
    23
    Dry mouth
         subjects affected / exposed
    4 / 48 (8.33%)
    1 / 59 (1.69%)
         occurrences all number
    4
    1
    Dyspepsia
         subjects affected / exposed
    1 / 48 (2.08%)
    3 / 59 (5.08%)
         occurrences all number
    1
    4
    Nausea
         subjects affected / exposed
    15 / 48 (31.25%)
    20 / 59 (33.90%)
         occurrences all number
    26
    47
    Stomatitis
         subjects affected / exposed
    3 / 48 (6.25%)
    2 / 59 (3.39%)
         occurrences all number
    4
    2
    Toothache
         subjects affected / exposed
    0 / 48 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    3
    Vomiting
         subjects affected / exposed
    9 / 48 (18.75%)
    8 / 59 (13.56%)
         occurrences all number
    11
    13
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    1 / 48 (2.08%)
    4 / 59 (6.78%)
         occurrences all number
    1
    4
    Erythema
         subjects affected / exposed
    1 / 48 (2.08%)
    5 / 59 (8.47%)
         occurrences all number
    9
    5
    Hyperhidrosis
         subjects affected / exposed
    2 / 48 (4.17%)
    4 / 59 (6.78%)
         occurrences all number
    3
    4
    Night sweats
         subjects affected / exposed
    4 / 48 (8.33%)
    4 / 59 (6.78%)
         occurrences all number
    4
    4
    Pruritus
         subjects affected / exposed
    6 / 48 (12.50%)
    8 / 59 (13.56%)
         occurrences all number
    6
    8
    Pruritus generalised
         subjects affected / exposed
    6 / 48 (12.50%)
    2 / 59 (3.39%)
         occurrences all number
    9
    2
    Rash
         subjects affected / exposed
    3 / 48 (6.25%)
    5 / 59 (8.47%)
         occurrences all number
    4
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 48 (10.42%)
    7 / 59 (11.86%)
         occurrences all number
    8
    8
    Back pain
         subjects affected / exposed
    5 / 48 (10.42%)
    6 / 59 (10.17%)
         occurrences all number
    6
    8
    Bone pain
         subjects affected / exposed
    4 / 48 (8.33%)
    5 / 59 (8.47%)
         occurrences all number
    5
    5
    Muscle spasms
         subjects affected / exposed
    6 / 48 (12.50%)
    6 / 59 (10.17%)
         occurrences all number
    6
    7
    Musculoskeletal pain
         subjects affected / exposed
    4 / 48 (8.33%)
    7 / 59 (11.86%)
         occurrences all number
    4
    9
    Myalgia
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 59 (1.69%)
         occurrences all number
    4
    1
    Pain in extremity
         subjects affected / exposed
    5 / 48 (10.42%)
    5 / 59 (8.47%)
         occurrences all number
    9
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    7 / 48 (14.58%)
    10 / 59 (16.95%)
         occurrences all number
    7
    13
    Gout
         subjects affected / exposed
    2 / 48 (4.17%)
    5 / 59 (8.47%)
         occurrences all number
    2
    9
    Hyperkalaemia
         subjects affected / exposed
    2 / 48 (4.17%)
    4 / 59 (6.78%)
         occurrences all number
    3
    9
    Hyperuricaemia
         subjects affected / exposed
    3 / 48 (6.25%)
    4 / 59 (6.78%)
         occurrences all number
    5
    5
    Hypocalcaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    0
    7
    Hypokalaemia
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 59 (0.00%)
         occurrences all number
    7
    0
    Hyponatraemia
         subjects affected / exposed
    3 / 48 (6.25%)
    2 / 59 (3.39%)
         occurrences all number
    8
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 48 (0.00%)
    6 / 59 (10.17%)
         occurrences all number
    0
    7
    Rhinovirus infection
         subjects affected / exposed
    0 / 48 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    4
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 48 (6.25%)
    9 / 59 (15.25%)
         occurrences all number
    5
    14
    Urinary tract infection
         subjects affected / exposed
    2 / 48 (4.17%)
    5 / 59 (8.47%)
         occurrences all number
    3
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Nov 2015
    This amendment included revisions to study eligibility criteria based on feedback from investigators and discussion with the independent Hepatic Expert Committee and clarified some aspects of study conduct.
    29 Sep 2016
    Following the first interim review, this amendment was implemented to suspend enrollment of new subjects into the 9.4 mg/kg arm and permanently close enrollment into the 4.7 mg/kg arm. The study was unblinded and randomization was discontinued. This amendment added a second planned interim review with guidelines for interpretation of results.
    13 Mar 2018
    This amendment confirmed the final study analysis would occur per protocol 18 months after the last subject had been enrolled because sufficient data had been collected. The study was closed to further subject enrollment. An Extension Phase was added to the protocol to allow continued treatment for subjects benefiting from treatment with study drug and to continue collection of survival data for subjects no longer receiving treatment.
    20 Dec 2018
    This amendment extended the Extension Phase from 1 year to 2 years.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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