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    Clinical Trial Results:
    Phase Ib/II clinical trial of ruxolitinib in combination with nilotinib and prednisona for myelofibrosis: RuNiC study

    Summary
    EudraCT number
    		 2016-005214-21
    Trial protocol
    		 ES  
    Global end of trial date
    30 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Mar 2023
    First version publication date
    01 Mar 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RuNiC
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Grupo Español de Enfermedades Mieloproliferativas Crónicas Filadelfia Negativas (GEMFIN)
    Sponsor organisation address
    Carrer del Secretari Coloma, 64-68, Barcelona, Spain, 08024
    Public contact
    Departamento de Ensayos Clínicos, Dynamic Solutions S.L, 34 914561125, a.tello@dynasolutions.com
    Scientific contact
    Departamento de Ensayos Clínicos, Dynamic Solutions S.L, 34 914561125, a.tello@dynasolutions.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
    18 Oct 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to determine the maximum tolerated dose (MTD) and the recommended phase III dose (RP3D) of ruxolitinib when administered in combination with nilotinib 300mg twice a day (BID) and prednisone 50mg every other day (EOD).
    Protection of trial subjects
    This clinical trial was conducted in accordance with the protocol, the principles established in the current revised version of the Declaration of Helsinki on medical research in human subjects (60th WMA General Assembly, Fortaleza, Brazil, 2013), and in accordance with applicable regulatory requirements, in particular the 1996 ICH Harmonised Tripartite Guidelines For Good Clinical Practice and local legislation on Clinical Trials (Royal Decree 1090/2015 that rules clinical drug trials in Spain, Ethics Committees of medicines research and the Spanish Clinical Trials Register), as well as Act No. 14/2007 of 3 July on biomedical research and Royal Decree 1716/2011 of 18 November in all applicable matters. At the time of study initiation, and incorporating the specific provisions for application in Spain of Regulation (EU) No 536/2014 of the European Parliament and of the Council on clinical trials on medicinal products for human use. By signing the protocol, the investigators agreed to follow the instructions and procedures described in the protocol and therefore to comply with the principles of GCP on which it is based. In compliance with Royal Decree 1090/2015, the sponsor submitted the pertinent documentation to the ethics committee. The study did not start until approval by the IEC and the AEMPS has been obtained.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jun 2017
    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: 21
    Worldwide total number of subjects
    21
    EEA total number of subjects
    21
    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)
    8
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between November 2017 and June 2020, a total of 21 patients were included in the study at 6 Spanish sites. Six patients were considered screening failures and did not receive treatment, and were thus not included in the ITT or the PP populations

    Pre-assignment
    Screening details
    		 Patients must be > 18 years, diagnosed with PMF, PPV-MF or PET-MF irrespective of JAK2 mutation status, classified as intermediate risk level 1 (1 or more prognostic factors defined by the International Working Group) with at least one criterion other than age, have palpable spleen of at least 5 cm and active symptoms of MF measured by MPN-SAF TSS.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Patients naïve to JAK inhibitors treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ruxolitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose levels of ruxolitinib ranging from 5 mg twice a day (BID) to 20 mg BID in 28-day treatment cycles in combination with nilotinib and prednisone.

    Investigational medicinal product name
    Nilotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Nilotinib dose of 300 mg of nilotinib twice a day in 28-day treatment cycles.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone dose of 50 mg every other day in 28-day treatment cycles.

    Arm title
    		 Arm B
    Arm description
    		 Patients non-responding to or relapsed after JAK inhibitors treatment. Patients non- responding to or relapsed after JAK inhibitors treatment met one of the following criteria at screening to be eligible for treatment arm B (patients with prior ruxolitinib treatment must meet one of the criteria below after at least 12 weeks on ruxolitinib treatment): • Patients with no improvement in spleen length and may or may not have a corresponding symptomatic improvement. • Patients with less than a 25% spleen length reduction by palpation and may or may not have a corresponding symptomatic improvement. • Patients that have had a 25% to 49% reduction in spleen length by palpation and without symptomatic improvement. • Patients who have lost benefit from prior treatment with a JAK inhibitor as per investigator (i.e., increased spleen length from nadir >40% as measured by palpation and/or return of symptoms as per investigator’s assessment).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ruxolitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose levels of ruxolitinib ranging from 5 mg twice a day (BID) to 20 mg BID in 28-day treatment cycles in combination with nilotinib and prednisone.

    Investigational medicinal product name
    Nilotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Nilotinib dose of 300 mg of nilotinib twice a day in 28-day treatment cycles.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone dose of 50 mg every other day in 28-day treatment cycles.

    Number of subjects in period 1 [1]
    		Arm A Arm B
    Started
    5
    10
    Completed
    1
    5
    Not completed
    4
    5
         Spleen regrowth and presence of some toxicities
    1
    -
         Consent withdrawn by subject
    1
    1
         Physician decision
    1
    -
         Disease progression
    -
    1
         Adverse event
    1
    -
         Disease progression and physician decision
    -
    1
         Lack of efficacy and worsening of the patient
    -
    1
         Lack of efficacy
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Six patients were considered screening failures and did not receive treatment, and thus were excluded.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 15 15
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    		 66.5 (53.4 to 70.8) -
    Gender categorical
    Units: Subjects
        Female
    		 6 6
        Male
    		 9 9
    Ethnicity
    Units: Subjects
        Caucasian
    		 14 14
        Arabic
    		 1 1
    Hematologic diseases
    Units: Subjects
        Yes
    		 7 7
        No
    		 8 8
    Cardiovascular diseases
    Units: Subjects
        Yes
    		 6 6
        No
    		 9 9
    Musculoskeletal disorders
    Units: Subjects
        Yes
    		 5 5
        No
    		 10 10
    Neurologic or psychiatric disorders
    Units: Subjects
        Yes
    		 3 3
        No
    		 12 12
    Gastrointestinal disorders
    Units: Subjects
        Yes
    		 2 2
        No
    		 13 13
    Endocrine disorders
    Units: Subjects
        Yes
    		 2 2
        No
    		 13 13
    Autoimmune disease
    Units: Subjects
        Yes
    		 1 1
        No
    		 14 14
    Respiratory diseases
    Units: Subjects
        Yes
    		 1 1
        No
    		 14 14
    Hepatic diseases
    Units: Subjects
        Yes
    		 1 1
        No
    		 14 14
    Other diseases
    Units: Subjects
        Yes
    		 8 8
        No
    		 7 7
    Patients with transfusion 12 weeks prior screening
    Units: Subjects
        Yes
    		 4 4
        No
    		 11 11
    Abnormal megakaryocyte morphology
    Units: Subjects
        Yes
    		 7 7
        No
    		 8 8
    Physical examination abnormalities
    Units: Subjects
        Bilateral lymphedema in legs
    		 1 1
        Massive splenomegaly
    		 1 1
        Splenomegaly of around 21 cm
    		 1 1
        Splenomegaly of around 13 cm
    		 1 1
        Splenomegaly of at least 5 cm
    		 11 11
    ECOG performance status
    Units: Subjects
        Zero
    		 5 5
        One
    		 7 7
        Two
    		 3 3
    Type of myelofibrosis
    Units: Subjects
        Primary MF
    		 6 6
        Post-polycythemia vera MF
    		 4 4
        Post-essential thrombocythemia MF
    		 4 4
        Not available
    		 1 1
    IPSS risk category
    Units: Subjects
        Low
    		 1 1
        Intermediate 1
    		 5 5
        Intermediate 2
    		 4 4
        High
    		 1 1
        Not available
    		 4 4
    DIPSS risk category
    Units: Subjects
        Intermediate 1
    		 8 8
        Intermediate 2
    		 3 3
        High
    		 1 1
        Not available
    		 3 3
    DIPSS-Plus risk category
    Units: Subjects
        Intermediate 1
    		 5 5
        Intermediate 2
    		 4 4
        Not available
    		 6 6
    Mutations at diagnosis: JAK2 V617F
    Units: Subjects
        Yes
    		 9 9
        No
    		 6 6
    Mutations at diagnosis: CALR Type 1
    Units: Subjects
        Yes
    		 4 4
        No
    		 11 11
    Mutations at diagnosis: TET2 T1884P
    Units: Subjects
        Yes
    		 2 2
        No
    		 13 13
    Other mutations at diagnosis
    Units: Subjects
        Exon 12
    		 1 1
        Allele frequency P.V617F
    		 1 1
        MPL W515L/K
    		 1 1
        TET H1778R
    		 1 1
        None of these
    		 11 11
    Patients undergone Biopsy
    Units: Subjects
        Grade 2
    		 1 1
        Grade 3
    		 2 2
        Unknown
    		 2 2
        None
    		 10 10
    Patients undergone Aspirate
    Units: Subjects
        Grade 1
    		 1 1
        Unknown
    		 2 2
        None
    		 12 12
    Patients undergone Both
    Units: Subjects
        Grade 0
    		 1 1
        Grade 1
    		 1 1
        Grade 3
    		 3 3
        Unknown
    		 2 2
        None
    		 8 8
    Abnormal erythrocyte morphology
    Units: Subjects
        Yes
    		 4 4
        No
    		 4 4
        Not available
    		 7 7
    Abnormal megakaryocyte morphology
    Units: Subjects
        Yes
    		 7 7
        No
    		 2 2
        Not available
    		 6 6
    Diagnostic interpretation
    Units: Subjects
        Absence of infiltrative or granulomatous process
    		 2 2
        Medullary hypoplasia, without evidence of MF
    		 1 1
        Primary MF
    		 1 1
        smPCR type PV/ET without signs of transformation
    		 1 1
        Not available
    		 10 10
    Patients with prior anti-neoplastic therapy
    Units: Subjects
        Yes
    		 13 13
        No
    		 2 2
    Anti-neoplastic therapy type: Hydroxyurea
    Units: Subjects
        Yes
    		 11 11
        No
    		 4 4
    Anti-neoplastic therapy type: Ruxolitinib
    Units: Subjects
        Yes
    		 10 10
        No
    		 5 5
    Other anti-neoplastic therapy types
    Units: Subjects
        Melphalan
    		 1 1
        Adiro, Interferon, Clopidogrel, Vitamin B12
    		 1 1
        Anagrelide, alpha-Interferon, Adiro
    		 1 1
        BKM120
    		 1 1
        Imetelstat
    		 1 1
        Mercaptopurine
    		 1 1
        None of them
    		 9 9
    Patients with prior anti-neoplastic radiotherapy
    Units: Subjects
        Yes
    		 1 1
        No
    		 14 14
    Median peripheral-blood blast count
    Units: Percentage
        median (inter-quartile range (Q1-Q3))
    		 4 (2 to 9) -
    Hemoglobin
    Units: g/dL
        median (inter-quartile range (Q1-Q3))
    		 10.8 (9.2 to 11.7) -
    Platelet count
    Units: x10-9/L
        median (inter-quartile range (Q1-Q3))
    		 230 (92 to 467) -
    Absolute neutrophil count
    Units: x10-9/L
        median (inter-quartile range (Q1-Q3))
    		 7.6 (6.2 to 13.8) -
    White-cell count
    Units: x10-9/L
        median (inter-quartile range (Q1-Q3))
    		 10.6 (4.61 to 13.5) -
    Median spleen length
    Units: cm
        median (inter-quartile range (Q1-Q3))
    		 8 (6 to 20) -
    Time from diagnosis
    Units: Years
        median (inter-quartile range (Q1-Q3))
    		 2.91 (0.59 to 3.98) -

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Patients naïve to JAK inhibitors treatment.

    Reporting group title
    Arm B
    Reporting group description
    		 Patients non-responding to or relapsed after JAK inhibitors treatment. Patients non- responding to or relapsed after JAK inhibitors treatment met one of the following criteria at screening to be eligible for treatment arm B (patients with prior ruxolitinib treatment must meet one of the criteria below after at least 12 weeks on ruxolitinib treatment): • Patients with no improvement in spleen length and may or may not have a corresponding symptomatic improvement. • Patients with less than a 25% spleen length reduction by palpation and may or may not have a corresponding symptomatic improvement. • Patients that have had a 25% to 49% reduction in spleen length by palpation and without symptomatic improvement. • Patients who have lost benefit from prior treatment with a JAK inhibitor as per investigator (i.e., increased spleen length from nadir >40% as measured by palpation and/or return of symptoms as per investigator’s assessment).

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Pooled analysis of patients

    Primary: Percentage of participants experiencing study treatment-related adverse events

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    End point title
    		 Percentage of participants experiencing study treatment-related adverse events [1]
    End point description
    End point type
    Primary
    End point timeframe
    Through the study
    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: This is a descriptive evaluation and no statistical analysis has been performed.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    5
    10
    Units: percentage
        number (not applicable)
    100
    100
    No statistical analyses for this end point

    Secondary: ECOG performance status at cycle 4

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    End point title
    		 ECOG performance status at cycle 4
    End point description
    End point type
    Secondary
    End point timeframe
    At cycle 4 (day 1)
    End point values
    		 ITT population
    Number of subjects analysed
    13
    Units: score
    number (not applicable)
        ECOG 0
    6
        ECOG 1
    5
        Not available
    2
    No statistical analyses for this end point

    Secondary: ECOG performance status at cycle 7

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    End point title
    		 ECOG performance status at cycle 7
    End point description
    End point type
    Secondary
    End point timeframe
    At cycle 7 (day 1)
    End point values
    		 ITT population
    Number of subjects analysed
    9
    Units: score
    number (not applicable)
        ECOG 0
    5
        ECOG 1
    3
        ECOG 2
    1
    No statistical analyses for this end point

    Secondary: ECOG performance status at cycle 12

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    End point title
    		 ECOG performance status at cycle 12
    End point description
    End point type
    Secondary
    End point timeframe
    At cycle 12 (day 1)
    End point values
    		 ITT population
    Number of subjects analysed
    7
    Units: Score
    number (not applicable)
        ECOG 0
    3
        ECOG 1
    3
        Not available
    1
    No statistical analyses for this end point

    Secondary: Spleen length reduction at cycle 7

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    End point title
    		 Spleen length reduction at cycle 7
    End point description
    End point type
    Secondary
    End point timeframe
    From Screening to Cycle 7 (Day 1)
    End point values
    		 ITT population
    Number of subjects analysed
    Units: percentage of reduction
    number (not applicable)
        Patient 2
    100
        Patient 3
    -25
        Patient 4
    83.3
        Patient 5
    100
        Patient 6
    100
        Patient 7
    0
        Patient 10
    57.1
        Patient 12
    100
    No statistical analyses for this end point

    Secondary: Spleen length reduction at cycle 12

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    End point title
    		 Spleen length reduction at cycle 12
    End point description
    End point type
    Secondary
    End point timeframe
    From Screening to Cycle 12 (Day 28)
    End point values
    		 ITT population
    Number of subjects analysed
    5
    Units: percentage of reduction
    number (not applicable)
        Patient 3
    -5
        Patient 4
    100
        Patient 5
    100
        Patient 7
    19
        Patient 10
    100
    No statistical analyses for this end point

    Secondary: Spleen length difference at cycle 7

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    End point title
    		 Spleen length difference at cycle 7
    End point description
    End point type
    Secondary
    End point timeframe
    From Screening to Cycle 7 (Day 1)
    End point values
    		 ITT population
    Number of subjects analysed
    8
    Units: cm
    number (not applicable)
        Patient 2
    -5
        Patient 3
    5
        Patient 4
    -5
        Patient 5
    -7
        Patient 6
    -6
        Patient 7
    0
        Patient 10
    -4
        Patient 12
    -13
    No statistical analyses for this end point

    Secondary: Spleen length difference at cycle 12

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    End point title
    		 Spleen length difference at cycle 12
    End point description
    End point type
    Secondary
    End point timeframe
    From Screening to Cycle 12 (Day 28)
    End point values
    		 ITT population
    Number of subjects analysed
    5
    Units: cm
    number (not applicable)
        Patient 3
    1
        Patient 4
    -6
        Patient 5
    -7
        Patient 7
    -4
        Patient 10
    -7
    No statistical analyses for this end point

    Secondary: MPN-SAF TSS at cycle 4

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    End point title
    		 MPN-SAF TSS at cycle 4
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 4 (Day 1)
    End point values
    		 ITT population
    Number of subjects analysed
    9
    Units: score
    median (inter-quartile range (Q1-Q3))
        Fatigue
    6.0 (5.0 to 8.0)
        Early satiety
    4.0 (0.0 to 5.0)
        Abdominal discomfort
    0.0 (0.0 to 4.0)
        Inactivity
    3.0 (0.0 to 6.0)
        Concentration difficulties
    3.0 (0.0 to 5.0)
        Night sweats
    0.0 (0.0 to 4.0)
        Itching
    2.0 (0.0 to 5.0)
        Bone pain
    2.5 (0.0 to 6.0)
        Fever (>37ºC)
    0.0 (0.0 to 0.0)
        Unintentional weight loss
    0.0 (0.0 to 2.0)
        Total score
    24.0 (14.0 to 33.8)
    No statistical analyses for this end point

    Secondary: MPN-SAF TSS at cycle 7

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    End point title
    		 MPN-SAF TSS at cycle 7
    End point description
    End point type
    Secondary
    End point timeframe
    At Cycle 7 (Day 1)
    End point values
    		 ITT population
    Number of subjects analysed
    8
    Units: score
    median (inter-quartile range (Q1-Q3))
        Fatigue
    6.0 (5.0 to 7.0)
        Early satiety
    4.0 (0.8 to 4.8)
        Abdominal discomfort
    0.5 (0.0 to 4.3)
        Inactivity
    1.0 (0.0 to 2.8)
        Concentration difficulties
    1.0 (0.0 to 2.8)
        Night sweats
    3.0 (0.5 to 5.0)
        Itching
    1.0 (0.0 to 6.8)
        Bone pain
    3.0 (0.0 to 5.8)
        Fever (>37ºC)
    0.0 (0.0 to 0.0)
        Unintentional weight loss
    0.0 (0.0 to 0.0)
        Total score
    23.0 (21.0 to 25.5)
    No statistical analyses for this end point

    Secondary: MPN-SAF TSS at cycle 12

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    End point title
    		 MPN-SAF TSS at cycle 12
    End point description
    End point type
    Secondary
    End point timeframe
    At Cycle 12 (Day 28)
    End point values
    		 ITT population
    Number of subjects analysed
    5
    Units: score
    median (inter-quartile range (Q1-Q3))
        Fatigue
    5.0 (3.5 to 8.5)
        Early satiety
    4.0 (1.0 to 4.5)
        Abdominal discomfort
    1.0 (0.0 to 4.5)
        Inactivity
    1.0 (0.5 to 6.0)
        Concentration difficulties
    2.0 (0.0 to 5.5)
        Night sweats
    1.0 (0.0 to 2.0)
        Itching
    3.0 (1.0 to 4.0)
        Bone pain
    1.0 (0.0 to 9.0)
        Fever (>37ºC)
    0.0 (0.0 to 3.0)
        Unintentional weight loss
    0.0 (0.0 to 0.5)
        Total score
    17.0 (10.0 to 44.0)
    No statistical analyses for this end point

    Secondary: Ruxolitinib dose intensity

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    End point title
    		 Ruxolitinib dose intensity
    End point description
    End point type
    Secondary
    End point timeframe
    At cycles 4, 7 and 12
    End point values
    		 ITT population
    Number of subjects analysed
    15 [2]
    Units: mg/m2/week
    median (inter-quartile range (Q1-Q3))
        Cycle 4 (n=12)
    0.427 (0.185 to 0.635)
        Cycle 7 (n=8)
    0.536 (0.179 to 0.648)
        Cycle 12 (n=7)
    0.417 (0.208 to 0.577)
    Notes
    [2] - At each time point the number of subjects is indicated.
    No statistical analyses for this end point

    Secondary: Nilotinib dose intensity

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    End point title
    		 Nilotinib dose intensity
    End point description
    End point type
    Secondary
    End point timeframe
    At cycles 4, 7 and 12
    End point values
    		 ITT population
    Number of subjects analysed
    15 [3]
    Units: mg/m2/week
    median (inter-quartile range (Q1-Q3))
        Cycle 4 (n=12)
    10.9 (7.29 to 11.1)
        Cycle 7 (n=8)
    11.1 (6.9 to 13.9)
        Cycle 12 (n=7)
    11.1 (7.69 to 12.5)
    Notes
    [3] - At each time point the number of subjects is indicated.
    No statistical analyses for this end point

    Secondary: Prednisone dose intensity

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    End point title
    		 Prednisone dose intensity
    End point description
    End point type
    Secondary
    End point timeframe
    At cycles 4, 7 and 12
    End point values
    		 ITT population
    Number of subjects analysed
    15 [4]
    Units: mg/m2/week
    median (inter-quartile range (Q1-Q3))
        Cycle 4 (n=11)
    1 (0.926 to 1.79)
        Cycle 7 (n=8)
    0.926 (0.678 to 1.67)
        Cycle 12 (n=6)
    0.723 (0.185 to 1.92)
    Notes
    [4] - At each time point the number of subjects is indicated.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE monitoring was continued for at least 30 days following the last dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    		 -

    Serious adverse events
    		 Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 15 (13.33%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 15 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bowen's disease
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Tumour associated fever
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Haematoma
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    10 / 15 (66.67%)
         occurrences all number
    14
    Chest pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Gait inability
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Oedema
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    3
    Oedema peripheral
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    Pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    7
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Catarrh
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Chest pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    Epistaxis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pleural effusion
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Pleuritic pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Productive cough
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Pulmonary hypertension
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Pulmonary thrombosis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Upper-airway cough syndrome
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Disorientation
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Insomnia
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    4
    Investigations
    Alanine aminotransferase
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    11
    Aspartate aminotransferase
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    4
    Blood bilirubin increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Blood creatine phosphokinase
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Blood folate decreased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Gamma-glutamyltransferase
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    3
    Lipase increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Hip fracture
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Congenital, familial and genetic disorders
    Thalassaemia beta
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Cardiac disorders
    Cardiac failure acute
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pericardial effusion
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Tachycardia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Nervous system disorders
    Cerebral small vessel ischaemic
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Cognitive disorder
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Dizziness
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Headache
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    4
    Sciatica
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 15 (33.33%)
         occurrences all number
    22
    Leukocytosis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Splenomegaly
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Thrombocytopenia
         subjects affected / exposed
    5 / 15 (33.33%)
         occurrences all number
    18
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Excessive cerumen production
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Ascites
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Dry mouth
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Flatulence
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    Vomiting
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Cholelithiasis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Cholestasis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    4
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Skin plaque
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Renal and urinary disorders
    Micturition urgency
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pollakiuria
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Renal impairment
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Urinary incontinence
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    4
    Arthritis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Back pain
         subjects affected / exposed
    5 / 15 (33.33%)
         occurrences all number
    5
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Muscle discomfort
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Myopathy
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Denture stomatitis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Otosalpingitis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Parapharyngeal space infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Respiratory tract infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    Urinary tract infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    3
    Hyperglycaemia
         subjects affected / exposed
    5 / 15 (33.33%)
         occurrences all number
    27
    Hyperkalaemia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    3
    Hyperuricaemia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hypocalcaemia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jan 2018
    Change of principal investigator of Hospital del Mar (Barcelona).
    28 Jun 2019
    Change of principal investigator (Dr. Marcio Andrade) of Hospital del Mar (Barcelona).

    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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