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    Clinical Trial Results:
    A Phase 1b/2 Multi-Center, Open Label, Dose-Escalation Study To Determine The Maximum Tolerated Dose, Safety, And Efficacy Of Acy-1215 (Ricolinostat) In Combination With Pomalidomide And Low-Dose Dexamethasone In Patients With Relapsed-And Refractory Multiple Myeloma

    Summary
    EudraCT number
    		 2014-002338-29
    Trial protocol
    		 IT   GR  
    Global end of trial date
    29 Feb 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Feb 2025
    First version publication date
    27 Feb 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ACE-MM-102
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussee de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.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
    19 Apr 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Feb 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Feb 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Phase 1b: To determine the maximum tolerated dose (MTD), or if not present, the recommended Phase 2 dose and schedule of ACY-1215 administered in combination with pomalidomide and low-dose dexamethasone in patients with relapsed-and-refractory MM. Phase 2: To determine the efficacy of ACY-1215 administered in combination with pomalidomide and low-dose dexamethasone as treatment for patients with relapsed-and-refractory MM as assessed by overall response rate.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    Greece: 19
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    United States: 62
    Worldwide total number of subjects
    103
    EEA total number of subjects
    25
    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)
    50
    From 65 to 84 years
    52
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study consisted of Phase 1b (dose finding segment) part and Phase 2(dose expansion segment) part.

    Period 1
    Period 1 title
    Overall Study (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
    		 Phase 1b - ACY-1215 Dose Level 1
    Arm description
    		 Participants received 160 mg ACY-1215 and 4 mg pomalidomide daily on Days 1-21 of each 28-day cycle. Participants also received 40 mg (<=75 years) or 20 mg (>75 years) dexamethasone on Days 1, 8, 15, and 22 of each 28-day treatment cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ACY-1215
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    160 mg/day on Days 1-21 of a 28-day cycle

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg PO for patients ≤ 75 years of age or 20 mg for patients > 75 years of age) on Days 1, 8, 15, and 22 of a 28-day cycle.

    Investigational medicinal product name
    Pomalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    4 mg/day on Days 1-21 of a 28-day cycle

    Arm title
    		 Phase 1b - ACY-1215 Dose Level 3
    Arm description
    		 Participants received 160 mg ACY-1215 twice daily in combination with 4 mg pomalidomide once daily on Days 1-21 of each 28-day cycle. Participants also received 40 mg (<=75 years) or 20 mg (>75 years) dexamethasone on Days 1, 8, 15, and 22 of each 28-day treatment cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ACY-1215
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    160 mg twice/day on Days 1-21 of a 28-day cycle

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg PO for patients ≤ 75 years of age or 20 mg for patients > 75 years of age) on Days 1, 8, 15, and 22 of a 28-day cycle.

    Investigational medicinal product name
    Pomalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    4 mg/day on Days 1-21 of a 28-day cycle

    Arm title
    		 Phase 2 - ACY-1215 Dose Level 1
    Arm description
    		 Participants received 160 mg ACY-1215 and 4 mg pomalidomide daily on Days 1-21 of each 28-day cycle. Participants also received 40 mg (<=75 years) or 20 mg (>75 years) dexamethasone on Days 1, 8, 15, and 22 of each 28-day treatment cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ACY-1215
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    160 mg/day on Days 1-21 of a 28-day cycle

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg PO for patients ≤ 75 years of age or 20 mg for patients > 75 years of age) on Days 1, 8, 15, and 22 of a 28-day cycle.

    Investigational medicinal product name
    Pomalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    4 mg/day on Days 1-21 of a 28-day cycle

    Arm title
    		 Phase 2 - ACY-1215 Dose Level 3
    Arm description
    		 Participants received 160 mg ACY-1215 twice daily in combination with 4 mg pomalidomide once daily on Days 1-21 of each 28-day cycle. Participants also received 40 mg (<=75 years) or 20 mg (>75 years) dexamethasone on Days 1, 8, 15, and 22 of each 28-day treatment cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ACY-1215
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    160 mg twice/day on Days 1-21 of a 28-day cycle

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg PO for patients ≤ 75 years of age or 20 mg for patients > 75 years of age) on Days 1, 8, 15, and 22 of a 28-day cycle.

    Investigational medicinal product name
    Pomalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    4 mg/day on Days 1-21 of a 28-day cycle

    Number of subjects in period 1
    		Phase 1b - ACY-1215 Dose Level 1 Phase 1b - ACY-1215 Dose Level 3 Phase 2 - ACY-1215 Dose Level 1 Phase 2 - ACY-1215 Dose Level 3
    Started
    3
    4
    85
    11
    Efficacy evaluable population
    3
    4
    77
    7
    Safety population
    3
    4
    85
    11
    Completed
    0
    0
    0
    0
    Not completed
    3
    4
    85
    11
         Physician decision
    -
    -
    3
    -
         Adverse event, non-fatal
    -
    -
    15
    2
         Withdrawal by participant
    -
    -
    8
    1
         Other reasons
    -
    -
    1
    -
         Progressive disease
    3
    4
    57
    8
         Lost to follow-up
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase 1b - ACY-1215 Dose Level 1
    Reporting group description
    		 Participants received 160 mg ACY-1215 and 4 mg pomalidomide daily on Days 1-21 of each 28-day cycle. Participants also received 40 mg (<=75 years) or 20 mg (>75 years) dexamethasone on Days 1, 8, 15, and 22 of each 28-day treatment cycle.

    Reporting group title
    Phase 1b - ACY-1215 Dose Level 3
    Reporting group description
    		 Participants received 160 mg ACY-1215 twice daily in combination with 4 mg pomalidomide once daily on Days 1-21 of each 28-day cycle. Participants also received 40 mg (<=75 years) or 20 mg (>75 years) dexamethasone on Days 1, 8, 15, and 22 of each 28-day treatment cycle.

    Reporting group title
    Phase 2 - ACY-1215 Dose Level 1
    Reporting group description
    		 Participants received 160 mg ACY-1215 and 4 mg pomalidomide daily on Days 1-21 of each 28-day cycle. Participants also received 40 mg (<=75 years) or 20 mg (>75 years) dexamethasone on Days 1, 8, 15, and 22 of each 28-day treatment cycle.

    Reporting group title
    Phase 2 - ACY-1215 Dose Level 3
    Reporting group description
    		 Participants received 160 mg ACY-1215 twice daily in combination with 4 mg pomalidomide once daily on Days 1-21 of each 28-day cycle. Participants also received 40 mg (<=75 years) or 20 mg (>75 years) dexamethasone on Days 1, 8, 15, and 22 of each 28-day treatment cycle.

    Reporting group values
    		 Phase 1b - ACY-1215 Dose Level 1 Phase 1b - ACY-1215 Dose Level 3 Phase 2 - ACY-1215 Dose Level 1 Phase 2 - ACY-1215 Dose Level 3 Total
    Number of subjects
    		 3 4 85 11 103
    Age Categorical
    Units: Participants
        <=18 years
    		 0 0 0 0 0
        Between 18 and 65 years
    		 2 2 42 4 50
        >=65 years
    		 1 2 43 7 53
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.0 ( 14.42 ) 68.0 ( 6.48 ) 64.6 ( 8.83 ) 67.1 ( 8.81 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 2 1 40 4 47
        Male
    		 1 3 45 7 56
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 1 0 1
        Asian
    		 0 0 3 0 3
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 0 0 7 1 8
        White
    		 3 4 72 10 89
        More than one race
    		 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 2 0 2
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 1 0 1
        Not Hispanic or Latino
    		 3 4 81 11 99
        Unknown or Not Reported
    		 0 0 3 0 3

    End points

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    End points reporting groups
    Reporting group title
    Phase 1b - ACY-1215 Dose Level 1
    Reporting group description
    		 Participants received 160 mg ACY-1215 and 4 mg pomalidomide daily on Days 1-21 of each 28-day cycle. Participants also received 40 mg (<=75 years) or 20 mg (>75 years) dexamethasone on Days 1, 8, 15, and 22 of each 28-day treatment cycle.

    Reporting group title
    Phase 1b - ACY-1215 Dose Level 3
    Reporting group description
    		 Participants received 160 mg ACY-1215 twice daily in combination with 4 mg pomalidomide once daily on Days 1-21 of each 28-day cycle. Participants also received 40 mg (<=75 years) or 20 mg (>75 years) dexamethasone on Days 1, 8, 15, and 22 of each 28-day treatment cycle.

    Reporting group title
    Phase 2 - ACY-1215 Dose Level 1
    Reporting group description
    		 Participants received 160 mg ACY-1215 and 4 mg pomalidomide daily on Days 1-21 of each 28-day cycle. Participants also received 40 mg (<=75 years) or 20 mg (>75 years) dexamethasone on Days 1, 8, 15, and 22 of each 28-day treatment cycle.

    Reporting group title
    Phase 2 - ACY-1215 Dose Level 3
    Reporting group description
    		 Participants received 160 mg ACY-1215 twice daily in combination with 4 mg pomalidomide once daily on Days 1-21 of each 28-day cycle. Participants also received 40 mg (<=75 years) or 20 mg (>75 years) dexamethasone on Days 1, 8, 15, and 22 of each 28-day treatment cycle.

    Subject analysis set title
    Phase 1b - ACY-1215
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received either 160 mg ACY-1215 once per day (Dose Level 1) or 160 mg ACY-1215 twice per day (Dose Level 3) and 4 mg pomalidomide daily on Days 1-21 of each 28-day cycle. Participants also received 40 mg (<=75 years) or 20 mg (>75 years) dexamethasone on Days 1, 8, 15, and 22 of each 28-day treatment cycle.

    Primary: Maximum Tolerated Dose (MTD) of ACY-1215- Phase 1b

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    End point title
    		 Maximum Tolerated Dose (MTD) of ACY-1215- Phase 1b [1]
    End point description
    The maximum tolerated dose (MTD) was defined as the highest dose level at which no more than 1 of 6 patients experienced a dose-limiting toxicity (DLT) within the first 28-day cycle. If no more than 1 of these 6 patients experienced a DLT within the first 28-day cycle, then the last dose level enrolled to meet these criteria was identified as the recommended dose for the Phase 2 segment of the study.
    End point type
    Primary
    End point timeframe
    From first dose until the end of Phase 1b (up to a maximum of approximately 50 weeks).
    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: Only descriptive statistics were planned for this endpoint.
    End point values
    		 Phase 1b - ACY-1215
    Number of subjects analysed
    7
    Units: mg/day
    320
    No statistical analyses for this end point

    Primary: Overall Response Rate (ORR) per Investigator - Phase 2

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    End point title
    		 Overall Response Rate (ORR) per Investigator - Phase 2 [2] [3]
    End point description
    Overall response rate (ORR) is defined as the percentage of participants with a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). sCR: • No detectable myeloma cells in the bone marrow. • Normal free light chain ratio. • Absence of clonal cells in the bone marrow. CR: • Negative immunofixation on the serum and urine. • Disappearance of any soft tissue plasmacytomas. • Less than 5% plasma cells in the bone marrow. VGPR: • Serum and urine M-protein detectable by immunofixation but not on electrophoresis, or • At least a 90% reduction in serum M-protein plus urine M-protein level less than 100 mg per 24 hours. PR: • At least a 50% reduction in serum M-protein. • Reduction in 24-hour urinary M-protein by at least 90% or to less than 200 mg per 24 hours. • For patients with non-secretory myeloma, a reduction of at least 50% in the size of soft tissue plasmacytomas is required.
    End point type
    Primary
    End point timeframe
    From first dose until disease progression, study drug toxicity, end of study, or death due to any cause (up to approximately 120 months).
    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: Only descriptive statistics were planned for this endpoint.
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Prespecified to be reported for Phase 2 only.
    End point values
    		 Phase 2 - ACY-1215 Dose Level 1 Phase 2 - ACY-1215 Dose Level 3
    Number of subjects analysed
    77
    7
    Units: Percent of Participants
        number (confidence interval 95%)
    39.0 (28.0 to 50.8)
    71.4 (29.0 to 96.3)
    No statistical analyses for this end point

    Secondary: Time to Response (TTR)

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    End point title
    		 Time to Response (TTR)
    End point description
    Time to response (TTR) was defined as the time from first dose of study treatment to the first documentation of response (either partial response (PR) or complete response (CR)). CR: • Negative immunofixation on the serum and urine. • Disappearance of any soft tissue plasmacytomas. • Less than 5% plasma cells in the bone marrow. PR: • At least a 50% reduction in serum M-protein. • Reduction in 24-hour urinary M-protein by at least 90% or to less than 200 mg per 24 hours. • For patients with non-secretory myeloma, a reduction of at least 50% in the size of soft tissue plasmacytomas is required.
    End point type
    Secondary
    End point timeframe
    From first dose until disease progression, study drug toxicity, end of study, or death due to any cause (up to approximately 120 months).
    End point values
    		 Phase 1b - ACY-1215 Dose Level 1 Phase 1b - ACY-1215 Dose Level 3 Phase 2 - ACY-1215 Dose Level 1 Phase 2 - ACY-1215 Dose Level 3
    Number of subjects analysed
    2
    0 [4]
    30
    5
    Units: Weeks
        arithmetic mean (full range (min-max))
    8.50 (4.1 to 12.9)
    ( to )
    10.83 (4.1 to 40.1)
    12.96 (7.9 to 31.9)
    Notes
    [4] - No responders in Ph1b at DL3
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR)

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    End point title
    		 Duration of Response (DoR)
    End point description
    Duration of Response (DOR) was defined as the time from first partial response (PR) or complete response (CR) to the first documentation of progressive disease (PD) or death. PR: • >= 50% reduction in serum M-protein. • Reduction in 24-hour urinary M-protein by >= 90% or to less than 200 mg per 24 hours. • For non-secretory myeloma, a reduction of >= 50% in size of soft tissue plasmacytomas. CR: • Negative immunofixation on the serum and urine. • Disappearance of any soft tissue plasmacytomas. • < 5% plasma cells in the bone marrow. PD: • Increase of 25% or more from nadir in serum M-protein, absolute increase of >= 0.5 g/dL. • Increase of 25% or more from nadir in 24-hour urinary M-protein, absolute increase of >=200 mg/24 hours. • Increase of 25% or more in the percentage of bone marrow plasma cells, absolute increase of >=10%. Calculated using Kaplan-Meier estimates.
    End point type
    Secondary
    End point timeframe
    From first dose until disease progression, study drug toxicity, end of study, or death due to any cause (up to approximately 120 months).
    End point values
    		 Phase 1b - ACY-1215 Dose Level 1 Phase 1b - ACY-1215 Dose Level 3 Phase 2 - ACY-1215 Dose Level 1 Phase 2 - ACY-1215 Dose Level 3
    Number of subjects analysed
    2
    0 [5]
    30
    5
    Units: Weeks
        median (confidence interval 95%)
    20.10 (4.10 to 36.10)
    ( to )
    30.30 (13.10 to 43.10)
    62.75 (54.75 to 121.6)
    Notes
    [5] - No responders in Ph1b at DL3
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP)

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    End point title
    		 Time to Progression (TTP)
    End point description
    Time to progression (TTP) was defined as the time from the date of first dose to the date of first documentation of progressive disease (PD). PD: • Increase of 25% or more from nadir in serum M-protein, absolute increase of >= 0.5 g/dL. • Increase of 25% or more from nadir in 24-hour urinary M-protein, absolute increase of >=200 mg/24 hours. • Increase of 25% or more in the percentage of bone marrow plasma cells, absolute increase of >=10%. • New bone lesions or soft tissue plasmacytomas or increase size of existing bone lesions or soft tissue plasmacytomas. • Hypercalcemia attributed to myeloma.
    End point type
    Secondary
    End point timeframe
    From first dose until disease progression, study drug toxicity, end of study, or death due to any cause (up to approximately 120 months).
    End point values
    		 Phase 1b - ACY-1215 Dose Level 1 Phase 1b - ACY-1215 Dose Level 3 Phase 2 - ACY-1215 Dose Level 1 Phase 2 - ACY-1215 Dose Level 3
    Number of subjects analysed
    3
    4
    77
    7
    Units: Weeks
        arithmetic mean (full range (min-max))
    22.43 (8.1 to 48.9)
    6.20 (4.1 to 8.1)
    29.82 (3.9 to 169.1)
    83.22 (7.7 to 183.1)
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS)

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    End point title
    		 Progression-free Survival (PFS)
    End point description
    Progression-free survival (PFS) was defined as the time from first dose of study treatment to the first documentation of progressive disease (PD) or death from any cause during study PD: • Increase of 25% or more from nadir in serum M-protein, absolute increase of >= 0.5 g/dL. • Increase of 25% or more from nadir in 24-hour urinary M-protein, absolute increase of >=200 mg/24 hours. • Increase of 25% or more in the percentage of bone marrow plasma cells, absolute increase of >=10%. • New bone lesions or soft tissue plasmacytomas or increase size of existing bone lesions or soft tissue plasmacytomas. • Hypercalcemia attributed to myeloma. Calculated using Kaplan-Meier estimates.
    End point type
    Secondary
    End point timeframe
    From first dose until disease progression, study drug toxicity, end of study, or death due to any cause (up to approximately 120 months).
    End point values
    		 Phase 1b - ACY-1215 Dose Level 1 Phase 1b - ACY-1215 Dose Level 3 Phase 2 - ACY-1215 Dose Level 1 Phase 2 - ACY-1215 Dose Level 3
    Number of subjects analysed
    3
    4
    77
    7
    Units: Weeks
        median (confidence interval 95%)
    22.43 (8.10 to 48.90)
    6.30 (4.35 to 8.05)
    20.00 (9.10 to 41.60)
    62.70 (19.90 to 99.90)
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR) per Central Adjudication Committee

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    End point title
    		 Overall Response Rate (ORR) per Central Adjudication Committee
    End point description
    Overall response rate (ORR) is defined as the percentage of participants with a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). sCR: • No detectable myeloma cells in the bone marrow. • Normal free light chain ratio. • Absence of clonal cells in the bone marrow. CR: • Negative immunofixation on the serum and urine. • Disappearance of any soft tissue plasmacytomas. • Less than 5% plasma cells in the bone marrow. VGPR: • Serum and urine M-protein detectable by immunofixation but not on electrophoresis, or • At least a 90% reduction in serum M-protein plus urine M-protein level less than 100 mg per 24 hours. PR: • At least a 50% reduction in serum M-protein. • Reduction in 24-hour urinary M-protein by at least 90% or to less than 200 mg per 24 hours. • For patients with non-secretory myeloma, a reduction of at least 50% in the size of soft tissue plasmacytomas is required
    End point type
    Secondary
    End point timeframe
    From first dose until disease progression, study drug toxicity, end of study, or death due to any cause (up to approximately 120 months).
    End point values
    		 Phase 1b - ACY-1215 Dose Level 1 Phase 1b - ACY-1215 Dose Level 3 Phase 2 - ACY-1215 Dose Level 1 Phase 2 - ACY-1215 Dose Level 3
    Number of subjects analysed
    0 [6]
    0 [7]
    0 [8]
    0 [9]
    Units: Percent of Participants
        number (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    ( to )
    Notes
    [6] - Data not collected
    [7] - Data not collected
    [8] - Data not collected
    [9] - Data not collected
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (AEs)

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    End point title
    		 Number of Participants with Adverse Events (AEs)
    End point description
    An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant’s health, including laboratory test values, regardless of etiology. Any worsening (i.e., any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE. Graded according to NCI CTCAE (Version 4.03) guidelines where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, grade 5 = death.
    End point type
    Secondary
    End point timeframe
    From first dose until 30 days after last dose of study drug (assessed for an average of approximately 55 weeks to a maximum of approximately 456 weeks)
    End point values
    		 Phase 1b - ACY-1215 Dose Level 1 Phase 1b - ACY-1215 Dose Level 3 Phase 2 - ACY-1215 Dose Level 1 Phase 2 - ACY-1215 Dose Level 3
    Number of subjects analysed
    3
    4
    85
    11
    Units: Participants
    3
    4
    82
    11
    No statistical analyses for this end point

    Secondary: Number of Participants with Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants with Serious Adverse Events (SAEs)
    End point description
    A serious adverse event (SAE) is defined as any adverse event (AE) occurring at any dose that: • Results in death; • Is life-threatening (ie, in the opinion of the Investigator, the participant is at immediate risk of death from the AE); • Requires inpatient hospitalization or prolongation of existing hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay). • Results in persistent or significant disability/incapacity (a substantial disruption of the participant’s ability to conduct normal life functions); • Is a congenital anomaly/birth defect; • Constitutes an important medical event. Graded according to NCI CTCAE (Version 4) guidelines where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, grade 5 = death.
    End point type
    Secondary
    End point timeframe
    From first dose until 30 days after last dose of study drug (assessed for an average of approximately 55 weeks to a maximum of approximately 456 weeks)
    End point values
    		 Phase 1b - ACY-1215 Dose Level 1 Phase 1b - ACY-1215 Dose Level 3 Phase 2 - ACY-1215 Dose Level 1 Phase 2 - ACY-1215 Dose Level 3
    Number of subjects analysed
    3
    4
    85
    11
    Units: Participants
    0
    2
    37
    7
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (AEs) Leading to Discontinuation

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    End point title
    		 Number of Participants with Adverse Events (AEs) Leading to Discontinuation
    End point description
    An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant’s health, including laboratory test values, regardless of etiology. Any worsening (i.e., any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE. Graded according to NCI CTCAE (Version 4.03) guidelines where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, grade 5 = death.
    End point type
    Secondary
    End point timeframe
    From first dose until 30 days after last dose of study drug (assessed for an average of approximately 55 weeks to a maximum of approximately 456 weeks)
    End point values
    		 Phase 1b - ACY-1215 Dose Level 1 Phase 1b - ACY-1215 Dose Level 3 Phase 2 - ACY-1215 Dose Level 1 Phase 2 - ACY-1215 Dose Level 3
    Number of subjects analysed
    3
    4
    85
    11
    Units: Participants
        ACY-1215
    0
    0
    13
    1
        Pomalidomide
    0
    0
    13
    1
        Dexamethasone
    0
    0
    16
    1
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (AEs) Related to Study Drug

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    End point title
    		 Number of Participants with Adverse Events (AEs) Related to Study Drug
    End point description
    An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant’s health, including laboratory test values, regardless of etiology. Any worsening (i.e., any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE. Graded according to NCI CTCAE (Version 4.03) guidelines where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, grade 5 = death.
    End point type
    Secondary
    End point timeframe
    From first dose until 30 days after last dose of study drug (assessed for an average of approximately 55 weeks to a maximum of approximately 456 weeks)
    End point values
    		 Phase 1b - ACY-1215 Dose Level 1 Phase 1b - ACY-1215 Dose Level 3 Phase 2 - ACY-1215 Dose Level 1 Phase 2 - ACY-1215 Dose Level 3
    Number of subjects analysed
    3
    4
    85
    11
    Units: Participants
        ACY-1215
    1
    4
    63
    9
        Pomalidomide
    3
    4
    62
    11
        Dexamethasone
    2
    3
    57
    9
    No statistical analyses for this end point

    Secondary: Plasma Levels of ACY-1215 and Pomalidomide - Phase 1b

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    End point title
    		 Plasma Levels of ACY-1215 and Pomalidomide - Phase 1b [10]
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1, Cycle 1 Day 2, Cycle 1 Day 8
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Prespecified to be reported for Phase 1b only.
    End point values
    		 Phase 1b - ACY-1215 Dose Level 1 Phase 1b - ACY-1215 Dose Level 3
    Number of subjects analysed
    0 [11]
    0 [12]
    Units: ng/L
        ACY-1215
        Pomalidomide
    Notes
    [11] - Data not collected
    [12] - Data not collected
    No statistical analyses for this end point

    Secondary: Number of Participants with Anti-Drug Antibodies (ADA) - Phase 1b

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    End point title
    		 Number of Participants with Anti-Drug Antibodies (ADA) - Phase 1b [13]
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1, Cycle 1 Day 2, Cycle 1 Day 8
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Prespecified to be reported for Phase 1b only.
    End point values
    		 Phase 1b - ACY-1215 Dose Level 1 Phase 1b - ACY-1215 Dose Level 3
    Number of subjects analysed
    0 [14]
    0 [15]
    Units: Participants
        ACY-1215
        Pomalidomide
    Notes
    [14] - Data not collected
    [15] - Data not collected
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs and Non-Serious AEs were assessed from first dose until 30 days after last dose of study drug (assessed for an average of approximately 55 weeks to a maximum of approximately 456 weeks).
    Adverse event reporting additional description
    Serious Adverse Events and Non-Serious Adverse Events represents all participants that received at least 1 dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Phase 1b - ACY-1215 Dose Level 1
    Reporting group description
    		 Participants received 160 mg ACY-1215 and 4 mg pomalidomide daily on Days 1-21 of each 28-day cycle. Participants also received 40 mg (<=75 years) or 20 mg (>75 years) dexamethasone on Days 1, 8, 15, and 22 of each 28-day treatment cycle.

    Reporting group title
    Phase 2 - ACY-1215 Dose Level 3
    Reporting group description
    		 Participants received 160 mg ACY-1215 twice daily in combination with 4 mg pomalidomide once daily on Days 1-21 of each 28-day cycle. Participants also received 40 mg (<=75 years) or 20 mg (>75 years) dexamethasone on Days 1, 8, 15, and 22 of each 28-day treatment cycle.

    Reporting group title
    Phase 2 -ACY-1215 Dose Level 1
    Reporting group description
    		 Participants received 160 mg ACY-1215 and 4 mg pomalidomide daily on Days 1-21 of each 28-day cycle. Participants also received 40 mg (<=75 years) or 20 mg (>75 years) dexamethasone on Days 1, 8, 15, and 22 of each 28-day treatment cycle.

    Reporting group title
    Phase 1b - ACY-1215 Dose Level 3
    Reporting group description
    		 Participants received 160 mg ACY-1215 twice daily in combination with 4 mg pomalidomide once daily on Days 1-21 of each 28-day cycle. Participants also received 40 mg (<=75 years) or 20 mg (>75 years) dexamethasone on Days 1, 8, 15, and 22 of each 28-day treatment cycle.

    Serious adverse events
    		 Phase 1b - ACY-1215 Dose Level 1 Phase 2 - ACY-1215 Dose Level 3 Phase 2 -ACY-1215 Dose Level 1 Phase 1b - ACY-1215 Dose Level 3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 3 (0.00%)
    7 / 11 (63.64%)
    37 / 85 (43.53%)
    2 / 4 (50.00%)
         number of deaths (all causes)
    2
    3
    39
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    3 / 85 (3.53%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute lymphocytic leukaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 85 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 85 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 85 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    White blood cell count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    3 / 85 (3.53%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pathological fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    3 / 85 (3.53%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Corona virus infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemophilus infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    6 / 85 (7.06%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    2 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pneumonia parainfluenzae viral
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Implant site infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    3 / 85 (3.53%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    3 / 85 (3.53%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase 1b - ACY-1215 Dose Level 1 Phase 2 - ACY-1215 Dose Level 3 Phase 2 -ACY-1215 Dose Level 1 Phase 1b - ACY-1215 Dose Level 3
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    11 / 11 (100.00%)
    79 / 85 (92.94%)
    4 / 4 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vascular disorders
    Peripheral coldness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Flushing
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    5 / 85 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    5
    0
    Hypertension
         subjects affected / exposed
    2 / 3 (66.67%)
    4 / 11 (36.36%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences all number
    4
    7
    3
    0
    Hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    3 / 85 (3.53%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    3
    1
    Orthostatic hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Aortic arteriosclerosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    General disorders and administration site conditions
    Instillation site pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    4 / 85 (4.71%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    4
    1
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    7 / 85 (8.24%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    8
    1
    Chest discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    4 / 85 (4.71%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    4
    1
    Chills
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    4 / 85 (4.71%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    4
    1
    Fatigue
         subjects affected / exposed
    2 / 3 (66.67%)
    8 / 11 (72.73%)
    49 / 85 (57.65%)
    2 / 4 (50.00%)
         occurrences all number
    2
    13
    59
    3
    Feeling jittery
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    5 / 85 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    5
    0
    Local swelling
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    4 / 85 (4.71%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    4
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    13 / 85 (15.29%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    20
    0
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    18 / 85 (21.18%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    26
    2
    Vessel puncture site bruise
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 85 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    5 / 85 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    5
    0
    Immune system disorders
    Hypogammaglobulinaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Acute respiratory failure
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bronchospasm
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 85 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    8 / 85 (9.41%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    9
    0
    Nasal congestion
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 11 (27.27%)
    4 / 85 (4.71%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    4
    0
    Lung infiltration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hiccups
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    4 / 85 (4.71%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    4
    1
    Epistaxis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    8 / 85 (9.41%)
    2 / 4 (50.00%)
         occurrences all number
    0
    1
    8
    3
    Dyspnoea exertional
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    9 / 85 (10.59%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    10
    0
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 11 (27.27%)
    8 / 85 (9.41%)
    1 / 4 (25.00%)
         occurrences all number
    0
    4
    8
    1
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 11 (27.27%)
    15 / 85 (17.65%)
    1 / 4 (25.00%)
         occurrences all number
    0
    4
    21
    1
    Productive cough
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    5 / 85 (5.88%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    5
    1
    Pulmonary hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    3 / 85 (3.53%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    3
    0
    Sinus congestion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Throat irritation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    4 / 85 (4.71%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    4
    0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    3 / 85 (3.53%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    3
    0
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    2
    0
    Delirium
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 85 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 11 (27.27%)
    16 / 85 (18.82%)
    0 / 4 (0.00%)
         occurrences all number
    0
    4
    16
    0
    Mood altered
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 11 (18.18%)
    4 / 85 (4.71%)
    0 / 4 (0.00%)
         occurrences all number
    2
    2
    4
    0
    Depression
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    6 / 85 (7.06%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    6
    0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    2 / 3 (66.67%)
    3 / 11 (27.27%)
    12 / 85 (14.12%)
    1 / 4 (25.00%)
         occurrences all number
    4
    8
    27
    2
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    7 / 85 (8.24%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    8
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 11 (0.00%)
    6 / 85 (7.06%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    7
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    4 / 85 (4.71%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    4
    0
    Blood cholesterol increased
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    7 / 85 (8.24%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    10
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Haematocrit decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    3 / 3 (100.00%)
    3 / 11 (27.27%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    4
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    3
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 11 (36.36%)
    6 / 85 (7.06%)
    0 / 4 (0.00%)
         occurrences all number
    3
    5
    8
    0
    Weight decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    3 / 85 (3.53%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    3
    0
    White blood cell count decreased
         subjects affected / exposed
    2 / 3 (66.67%)
    4 / 11 (36.36%)
    4 / 85 (4.71%)
    0 / 4 (0.00%)
         occurrences all number
    3
    10
    8
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    2 / 85 (2.35%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    2
    2
    Compression fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Periorbital contusion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Scar
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Spinal compression fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    1
    Tricuspid valve disease
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervous system disorders
    Hypoaesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    3 / 85 (3.53%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Headache
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    7 / 85 (8.24%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    7
    0
    Dysgeusia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    11 / 85 (12.94%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    11
    0
    Dizziness postural
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    11 / 85 (12.94%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    12
    1
    Balance disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Memory impairment
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    4 / 85 (4.71%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    4
    0
    VIth nerve paralysis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tremor
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    10 / 85 (11.76%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    10
    0
    Syncope
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Somnolence
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 11 (9.09%)
    4 / 85 (4.71%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    4
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    31 / 85 (36.47%)
    2 / 4 (50.00%)
         occurrences all number
    0
    3
    41
    4
    Febrile neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lymphopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    3 / 85 (3.53%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    6
    0
    Neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 11 (45.45%)
    29 / 85 (34.12%)
    1 / 4 (25.00%)
         occurrences all number
    0
    6
    59
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    17 / 85 (20.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    23
    1
    Leukopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    3 / 85 (3.53%)
    0 / 4 (0.00%)
         occurrences all number
    0
    4
    5
    0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Ear pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tinnitus
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Diplopia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dry eye
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Ectropion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lacrimation increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Vision blurred
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    3 / 85 (3.53%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    3
    1
    Dacryostenosis acquired
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrointestinal disorders
    Flatulence
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    3 / 85 (3.53%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    3
    0
    Abdominal distension
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    7 / 85 (8.24%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    8
    0
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    7 / 85 (8.24%)
    2 / 4 (50.00%)
         occurrences all number
    0
    1
    7
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    6 / 85 (7.06%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    7
    0
    Aphthous stomatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    14 / 85 (16.47%)
    3 / 4 (75.00%)
         occurrences all number
    0
    2
    16
    3
    Diarrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    6 / 11 (54.55%)
    32 / 85 (37.65%)
    4 / 4 (100.00%)
         occurrences all number
    0
    14
    47
    4
    Dyspepsia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    4 / 85 (4.71%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    4
    0
    Dysphagia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    3 / 85 (3.53%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gingival pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypoaesthesia oral
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 11 (27.27%)
    19 / 85 (22.35%)
    0 / 4 (0.00%)
         occurrences all number
    2
    3
    22
    0
    Oral disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Oral pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Sensitivity of teeth
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 11 (9.09%)
    9 / 85 (10.59%)
    0 / 4 (0.00%)
         occurrences all number
    2
    2
    10
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Skin and subcutaneous tissue disorders
    Night sweats
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    5 / 85 (5.88%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    5
    1
    Pruritus
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 11 (18.18%)
    2 / 85 (2.35%)
    1 / 4 (25.00%)
         occurrences all number
    1
    2
    3
    1
    Actinic keratosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Alopecia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Dry skin
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Ecchymosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Erythema multiforme
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hair growth abnormal
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hair texture abnormal
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 11 (27.27%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    2
    0
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    10 / 85 (11.76%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    17
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    1
    1
    Skin disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin lesion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Swelling face
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Renal failure acute
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 85 (2.35%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    2
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tenosynovitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bone disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 11 (27.27%)
    13 / 85 (15.29%)
    0 / 4 (0.00%)
         occurrences all number
    0
    4
    15
    0
    Arthropathy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Arthritis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    13 / 85 (15.29%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    15
    0
    Joint swelling
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    2 / 85 (2.35%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Muscle spasms
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 11 (27.27%)
    17 / 85 (20.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    3
    18
    1
    Muscular weakness
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 11 (18.18%)
    9 / 85 (10.59%)
    1 / 4 (25.00%)
         occurrences all number
    1
    2
    9
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    4 / 85 (4.71%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    4
    0
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    4 / 85 (4.71%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    4
    0
    Osteoarthritis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Osteoporosis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    9 / 85 (10.59%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    11
    0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bone pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    11 / 85 (12.94%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    12
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    3 / 85 (3.53%)
    1 / 4 (25.00%)
         occurrences all number
    0
    4
    3
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    3 / 85 (3.53%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Herpes simplex
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Herpes virus infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    3 / 85 (3.53%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    4
    0
    Localised infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    3 / 85 (3.53%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    8 / 85 (9.41%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    8
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 11 (27.27%)
    21 / 85 (24.71%)
    1 / 4 (25.00%)
         occurrences all number
    1
    9
    31
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    6 / 85 (7.06%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    7
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 11 (27.27%)
    9 / 85 (10.59%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    10
    0
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    2 / 85 (2.35%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    3
    1
    Hypercalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    4 / 85 (4.71%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    4
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    7 / 85 (8.24%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    9
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 85 (1.18%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    3
    Hypermagnesaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    1 / 85 (1.18%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    4 / 85 (4.71%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    5
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    5 / 85 (5.88%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    5
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 85 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    11 / 85 (12.94%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    14
    2
    Hypomagnesaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    3 / 85 (3.53%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    4
    1
    Hyponatraemia
         subjects affected / exposed
    2 / 3 (66.67%)
    3 / 11 (27.27%)
    7 / 85 (8.24%)
    1 / 4 (25.00%)
         occurrences all number
    2
    4
    9
    1
    Hypophosphataemia
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 11 (18.18%)
    7 / 85 (8.24%)
    0 / 4 (0.00%)
         occurrences all number
    1
    7
    7
    0
    Polydipsia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 85 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Feb 2016
    Protocol version. Clerical change in Study Personnel. Clarification for Duration of Survival Follow-up

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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