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    Clinical Trial Results:
    A MULTIARM, OPEN LABEL, RANDOMIZED PHASE II STUDY OF MLN9708 PLUS ORAL DEXAMETHASONE or PLUS ORAL CYCLOPHOSPHAMIDE AND DEXAMETHASONE or PLUS BENDAMUSTINE AND DEXAMETHASONE or PLUS ORAL THALIDOMIDE AND DEXAMETHASONE FOLLOWED BY MAINTENANCE WITH MLN9708 IN NEWLY DIAGNOSED ELDERLY MULTIPLE MYELOMA PATIENTS.

    Summary
    EudraCT number
    		 2014-004859-31
    Trial protocol
    		 IT  
    Global end of trial date
    14 May 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Jun 2024
    First version publication date
    15 Jun 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UNITO-EMN10
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02586038
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Dipartimento di Biotecnologie Molecolari e Scienze per la Salute - Università degli Studi di Torino
    Sponsor organisation address
    VIa Nizza 52, Torino, Italy, 10126
    Public contact
    Francesco Novelli, Dipartimento di Biotecnologie Molecolari e Scienze per la Salute - Università degli Studi di Torino, 0039 0110243236, clinical.trials@unito.it
    Scientific contact
    Francesco Novelli, Dipartimento di Biotecnologie Molecolari e Scienze per la Salute - Università degli Studi di Torino, 0039 0110243236, clinical.trials@unito.it
    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
    14 May 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 May 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective: - To select the more promising association(s) among three induction treatments, followed by maintenance with MLN9708, including: - MLN9708 plus dexamethasone (MLN-DEX) - MLN9708 plus dexamethasone and cyclophosphamide (MLN-CYCLO-DEX) - MLN9708 plus dexamethasone and thalidomide (MLN-THAL-DEX) in terms of Progression Free Survival (PFS) at 2 years from randomization.
    Protection of trial subjects
    The protocol for this study has been designed in accordance with the general ethical principles outlined in the Declaration of Helsinki. The review of this protocol by the IRB/EC and the performance of all aspects of the study, including the methods used for obtaining informed consent, must also be in accordance with principles enunciated in the declaration, as well as ICH Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 50 Protection of Human Subjects and Part 56 Institutional Review Boards.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 175
    Worldwide total number of subjects
    175
    EEA total number of subjects
    175
    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)
    2
    From 65 to 84 years
    171
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 This is an open-label, multiarm, randomized Phase II trial of MLN9708 combined with different drugs (alkylating or immunomodulatory agents), and followed by MLN9708 maintenance, aiming to select the more promising regimen(s) to consider as an experimental arm in a future randomized phase III trial.

    Pre-assignment
    Screening details
    		 After providing written informed consent to participate in the study, patients will be evaluated for study eligibility. The screening period includes the availability of inclusion criteria described below.

    Period 1
    Period 1 title
    Treatment period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MLN-DEX
    Arm description
    		 MLN-DEX arm for patients already enrolled before amendment 2.0. MLN9708: 4,0 mg orally on days 1, 8, 15 Dexamethasone: 40 mg orally on days 1, 8, 15, 22.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ninlaro
    Investigational medicinal product code
    MLN9708
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    4,0 mg orally on days 1, 8, 15

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg orally on days 1, 8, 15, 22

    Arm title
    		 MLN-DEX-CYCLO
    Arm description
    		 MLN9708: 4,0 mg orally on days 1, 8, 15 Dexamethasone: 40 mg orally on days 1, 8, 15, 22. Cyclophosphamide: 300 mg/sqm orally on days 1, 8, 15
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ninlaro
    Investigational medicinal product code
    MLN9708
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    4,0 mg orally on days 1, 8, 15

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg orally on days 1, 8, 15, 22

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg/sqm orally on days 1, 8, 15

    Arm title
    		 MLN-DEX-THAL
    Arm description
    		 MLN9708: 4,0 mg orally on days 1, 8, 15 Dexamethasone: 40 mg orally on days 1, 8, 15, 22. Thalidomide: 100 mg/day orally
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ninlaro
    Investigational medicinal product code
    MLN9708
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    4,0 mg orally on days 1, 8, 15

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg orally on days 1, 8, 15, 22

    Investigational medicinal product name
    Thalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg/day orally

    Arm title
    		 MLN-DEX-BENDA (First Amendment closed arm)
    Arm description
    		 MLN9708: 4,0 mg orally on days 1, 8, 15 Dexamethasone: 40 mg orally on days 1, 8, 15, 22. Bendamustine: 75 mg/sqm intravenously on days 1, 8
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ninlaro
    Investigational medicinal product code
    MLN9708
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    4,0 mg orally on days 1, 8, 15

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg orally on days 1, 8, 15, 22

    Investigational medicinal product name
    Bedamustine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/sqm intravenously on days 1, 8

    Number of subjects in period 1
    		MLN-DEX MLN-DEX-CYCLO MLN-DEX-THAL MLN-DEX-BENDA (First Amendment closed arm)
    Started
    42
    61
    61
    11
    Completed
    21
    38
    38
    5
    Not completed
    21
    23
    23
    6
         Adverse event, serious fatal
    1
    3
    2
    -
         Consent withdrawn by subject
    2
    3
    -
    1
         Physician decision
    2
    -
    -
    -
         Adverse event, non-fatal
    3
    6
    11
    2
         Lost to follow-up
    -
    2
    -
    -
         Lack of efficacy
    13
    9
    10
    3
    Period 2
    Period 2 title
    Maintenance (up to two years)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 MLN ARM
    Arm description
    		 MLN9708: 4,0 mg orally on days 1, 8, 15 Patients will be stopped at progression disease (PD) or intolerance (maximum duration of maintenance therapy 2 years). In case of dose reduction during induction phase, patients will continue with the same dose, also during maintenance.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ninlaro
    Investigational medicinal product code
    MLN9708
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    4,0 mg orally on days 1, 8, 15

    Number of subjects in period 2
    		MLN ARM
    Started
    102
    Completed
    31
    Not completed
    71
         Adverse event, serious fatal
    3
         Adverse event, non-fatal
    12
         Lack of efficacy
    56

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment period
    Reporting group description
    		 -

    Reporting group values
    		 Treatment period Total
    Number of subjects
    		 175 175
    Age categorical
    Units: Subjects
        < 75
    		 98 98
        >= 75
    		 77 77
    Age continuous
    Units: years
        median (full range (min-max))
    		 74 (53 to 88) -
    Gender categorical
    Units: Subjects
        Female
    		 90 90
        Male
    		 85 85
    ISS Stage
    Units: Subjects
        ISS I
    		 51 51
        ISS II
    		 78 78
        ISS III
    		 46 46
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT

    Subject analysis sets values
    		 ITT
    Number of subjects
    175
    Age categorical
    Units: Subjects
        < 75
    98
        >= 75
    77
    Age continuous
    Units: years
        median (full range (min-max))
    74 (53 to 88)
    Gender categorical
    Units: Subjects
        Female
    90
        Male
    85
    ISS Stage
    Units: Subjects
        ISS I
    51
        ISS II
    78
        ISS III
    46

    End points

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    End points reporting groups
    Reporting group title
    MLN-DEX
    Reporting group description
    		 MLN-DEX arm for patients already enrolled before amendment 2.0. MLN9708: 4,0 mg orally on days 1, 8, 15 Dexamethasone: 40 mg orally on days 1, 8, 15, 22.

    Reporting group title
    MLN-DEX-CYCLO
    Reporting group description
    		 MLN9708: 4,0 mg orally on days 1, 8, 15 Dexamethasone: 40 mg orally on days 1, 8, 15, 22. Cyclophosphamide: 300 mg/sqm orally on days 1, 8, 15

    Reporting group title
    MLN-DEX-THAL
    Reporting group description
    		 MLN9708: 4,0 mg orally on days 1, 8, 15 Dexamethasone: 40 mg orally on days 1, 8, 15, 22. Thalidomide: 100 mg/day orally

    Reporting group title
    MLN-DEX-BENDA (First Amendment closed arm)
    Reporting group description
    		 MLN9708: 4,0 mg orally on days 1, 8, 15 Dexamethasone: 40 mg orally on days 1, 8, 15, 22. Bendamustine: 75 mg/sqm intravenously on days 1, 8
    Reporting group title
    MLN ARM
    Reporting group description
    		 MLN9708: 4,0 mg orally on days 1, 8, 15 Patients will be stopped at progression disease (PD) or intolerance (maximum duration of maintenance therapy 2 years). In case of dose reduction during induction phase, patients will continue with the same dose, also during maintenance.

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT

    Primary: Progression Free Survival

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    End point title
    		 Progression Free Survival
    End point description
    End point type
    Primary
    End point timeframe
    24 months
    End point values
    		 MLN-DEX MLN-DEX-CYCLO MLN-DEX-THAL MLN-DEX-BENDA (First Amendment closed arm)
    Number of subjects analysed
    42
    61
    61
    11
    Units: month
        median (confidence interval 95%)
    10.3 (7 to 20.1)
    17.9 (13.3 to 27.5)
    12.3 (9.7 to 18.2)
    13.9 (3.3 to 99)
    Statistical analysis title
    		 Log rank test
    Comparison groups
    MLN-DEX-CYCLO v MLN-DEX-THAL v MLN-DEX-BENDA (First Amendment closed arm) v MLN-DEX
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.15 [2]
    Method
    		 Logrank
    Parameter type
    		 Log rank test
    Point estimate
    0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 0.15
    Variability estimate
    Standard deviation
    Dispersion value
    0
    Notes
    [1] - Log rank test
    [2] - Log rank test

    Secondary: VGPR Rate

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    End point title
    		 VGPR Rate
    End point description
    End point type
    Secondary
    End point timeframe
    Response rate (VGPR)
    End point values
    		 MLN-DEX MLN-DEX-CYCLO MLN-DEX-THAL MLN-DEX-BENDA (First Amendment closed arm)
    Number of subjects analysed
    39
    58
    60
    11
    Units: patients
        < VGPR
    27
    28
    30
    8
        >= VGPR
    12
    30
    30
    3
    Statistical analysis title
    		 no statistical analysys
    Statistical analysis description
    no statistical analysys
    Comparison groups
    MLN-DEX v MLN-DEX-CYCLO v MLN-DEX-THAL v MLN-DEX-BENDA (First Amendment closed arm)
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0
    Method
    		 no statistical analysys
    Parameter type
    		 no statistical analysys
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0
    Notes
    [3] - no statistical analysys

    Secondary: progression-free survival-2 (PFS2)

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    End point title
    		 progression-free survival-2 (PFS2)
    End point description
    End point type
    Secondary
    End point timeframe
    4 years probability
    End point values
    		 MLN-DEX MLN-DEX-CYCLO MLN-DEX-THAL MLN-DEX-BENDA (First Amendment closed arm)
    Number of subjects analysed
    42
    61
    61
    11
    Units: month
        number (confidence interval 95%)
    0.3 (0.15 to 0.62)
    0.47 (0.3 to 0.72)
    0.4 (0.2 to 0.81)
    0.78 (0.55 to 1)
    Statistical analysis title
    		 Log rank test
    Comparison groups
    MLN-DEX v MLN-DEX-CYCLO v MLN-DEX-THAL v MLN-DEX-BENDA (First Amendment closed arm)
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [4]
    P-value
    		 = 0.52
    Method
    		 Logrank
    Parameter type
    		 Log rank test
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.52
    Variability estimate
    Standard deviation
    Dispersion value
    0
    Notes
    [4] - Log rank test

    Secondary: time to next therapy (TNT)

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    End point title
    		 time to next therapy (TNT)
    End point description
    End point type
    Secondary
    End point timeframe
    time to next therapy (TNT)
    End point values
    		 MLN-DEX MLN-DEX-CYCLO MLN-DEX-THAL MLN-DEX-BENDA (First Amendment closed arm)
    Number of subjects analysed
    42
    61
    61
    11
    Units: month
        median (confidence interval 95%)
    32.4 (30.9 to 38.2)
    33.1 (28.2 to 44.8)
    29.9 (28.7 to 34.4)
    48.4 (37.1 to 99)
    Statistical analysis title
    		 Log rank test
    Statistical analysis description
    Log rank test
    Comparison groups
    MLN-DEX v MLN-DEX-CYCLO v MLN-DEX-THAL v MLN-DEX-BENDA (First Amendment closed arm)
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.2 [5]
    Method
    		 Logrank
    Parameter type
    		 Log rank test
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.2
    Variability estimate
    Standard deviation
    Dispersion value
    0
    Notes
    [5] - Log rank test

    Secondary: time to progression (TTP)

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    End point title
    		 time to progression (TTP)
    End point description
    End point type
    Secondary
    End point timeframe
    time to progression (TTP)
    End point values
    		 MLN-DEX MLN-DEX-CYCLO MLN-DEX-THAL MLN-DEX-BENDA (First Amendment closed arm)
    Number of subjects analysed
    42
    61
    61
    11
    Units: month
        median (confidence interval 95%)
    10.9 (7 to 24.4)
    19.1 (14.1 to 36.3)
    13 (9.9 to 19.5)
    13.8 (3.3 to 99)
    Statistical analysis title
    		 Log rank test
    Statistical analysis description
    Log rank test
    Comparison groups
    MLN-DEX v MLN-DEX-CYCLO v MLN-DEX-THAL v MLN-DEX-BENDA (First Amendment closed arm)
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [6]
    P-value
    		 = 0.1 [7]
    Method
    		 Logrank
    Parameter type
    		 Log rank test
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 0.1
    Variability estimate
    Standard deviation
    Dispersion value
    0
    Notes
    [6] - Log rank test
    [7] - Log rank test

    Secondary: overall survival (OS)

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    End point title
    		 overall survival (OS)
    End point description
    4 years probabiliy
    End point type
    Secondary
    End point timeframe
    overall survival (OS) 4 years probabiliy
    End point values
    		 MLN-DEX MLN-DEX-CYCLO MLN-DEX-THAL MLN-DEX-BENDA (First Amendment closed arm)
    Number of subjects analysed
    42
    61
    61
    11
    Units: month
        number (confidence interval 95%)
    0.65 (0.49 to 0.86)
    0.57 (0.4 to 0.83)
    0.59 (0.39 to 0.91)
    0.78 (0.55 to 1)
    Statistical analysis title
    		 Log rank test
    Statistical analysis description
    Log rank test
    Comparison groups
    MLN-DEX v MLN-DEX-CYCLO v MLN-DEX-THAL v MLN-DEX-BENDA (First Amendment closed arm)
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [8]
    P-value
    		 = 0.74
    Method
    		 Logrank
    Parameter type
    		 Log rank test
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 0.74
    Variability estimate
    Standard deviation
    Dispersion value
    0
    Notes
    [8] - Log rank test

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Per protocol
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Per protocol
    Reporting group description
    		 -

    Serious adverse events
    		 Per protocol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    74 / 171 (43.27%)
         number of deaths (all causes)
    44
         number of deaths resulting from adverse events
    17
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder papilloma
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Papillary renal cell carcinoma
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Prostate cancer
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Oedema peripheral
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Bronchospasm
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skull fracture
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Subdural haematoma
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Aortic valve disease
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 171 (1.75%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    3 / 171 (1.75%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    Cardiac failure
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Cerebral ischaemia
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intracranial mass
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Paraparesis
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    7 / 171 (4.09%)
         occurrences causally related to treatment / all
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cytopenia
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Amaurosis fugax
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Retinal vascular thrombosis
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Volvulus
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 171 (1.75%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cholecystitis
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 171 (2.34%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 1
    Renal colic
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Campylobacter infection
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Fungal infection
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Meningitis listeria
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 171 (4.09%)
         occurrences causally related to treatment / all
    5 / 7
         deaths causally related to treatment / all
    1 / 1
    Sepsis
         subjects affected / exposed
    8 / 171 (4.68%)
         occurrences causally related to treatment / all
    2 / 8
         deaths causally related to treatment / all
    0 / 2
    Superinfection bacterial
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 171 (0.58%)
         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
    		 Per protocol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    157 / 171 (91.81%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 171 (5.26%)
         occurrences all number
    9
    Nervous system disorders
    Peripheral sensory neuropath
         subjects affected / exposed
    32 / 171 (18.71%)
         occurrences all number
    32
    Paraesthesia
         subjects affected / exposed
    29 / 171 (16.96%)
         occurrences all number
    29
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    52 / 171 (30.41%)
         occurrences all number
    52
    Fatigue
         subjects affected / exposed
    35 / 171 (20.47%)
         occurrences all number
    35
    Pyrexia
         subjects affected / exposed
    31 / 171 (18.13%)
         occurrences all number
    31
    Oedema peripheral
         subjects affected / exposed
    30 / 171 (17.54%)
         occurrences all number
    30
    Vomiting
         subjects affected / exposed
    23 / 171 (13.45%)
         occurrences all number
    23
    Influenza like illness
         subjects affected / exposed
    9 / 171 (5.26%)
         occurrences all number
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    28 / 171 (16.37%)
         occurrences all number
    28
    Neutropenia
         subjects affected / exposed
    16 / 171 (9.36%)
         occurrences all number
    16
    Thrombocytopenia
         subjects affected / exposed
    10 / 171 (5.85%)
         occurrences all number
    10
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    37 / 171 (21.64%)
         occurrences all number
    37
    Constipation
         subjects affected / exposed
    32 / 171 (18.71%)
         occurrences all number
    32
    Diarrhoea
         subjects affected / exposed
    32 / 171 (18.71%)
         occurrences all number
    32
    Abdominal pain
         subjects affected / exposed
    9 / 171 (5.26%)
         occurrences all number
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    14 / 171 (8.19%)
         occurrences all number
    14
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    22 / 171 (12.87%)
         occurrences all number
    22
    Rash
         subjects affected / exposed
    12 / 171 (7.02%)
         occurrences all number
    12
    Pruritus
         subjects affected / exposed
    10 / 171 (5.85%)
         occurrences all number
    10
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    15 / 171 (8.77%)
         occurrences all number
    15
    Bronchitis
         subjects affected / exposed
    13 / 171 (7.60%)
         occurrences all number
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jan 2017
    Eliminate an experimental arm, to reduce the sample size of the study.
    26 Mar 2018
    Closure of a treatment arm due to ineffectiveness compared to the expected in the statistical design of the protocol.
    20 Sep 2018
    Change to the total number of patients to be enrolled in the study due to the closure of an experimental arm for ineffectiveness.
    16 Jul 2020
    Updates on side effects of the experimental drug.
    23 Feb 2021
    CRO name change.
    17 Jun 2021
    Updates on side effects of the experimental drug.
    21 Jul 2022
    Clarify timelines and procedures for reporting serious adverse events and SUSARs.
    09 Nov 2023
    Change from CEC to national CET.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34876566
    For support, Contact us.
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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