Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   44335   clinical trials with a EudraCT protocol, of which   7366   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Multicenter, Randomized, Open-label Phase 2 Study Evaluating the Safety and Efficacy of Three Different Regimens of Oral Panobinostat in Combination with Subcutaneous Bortezomib and Oral Dexamethasone in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma Who Have Been Previously Exposed to Immunomodulatory Agents

    Summary
    EudraCT number
    		 2015-001564-19
    Trial protocol
    		 ES   BE   SE   NO   DE   NL   HU   GR   PL   CZ   PT   IT   FR  
    Global end of trial date
    15 Aug 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Sep 2024
    First version publication date
    13 Sep 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLBH589D2222
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02654990
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    pharmaand GmbH
    Sponsor organisation address
    Taborstraße 1, Wien, Austria, 1020
    Public contact
    Medical Information Department, pharmaand GmbH, +43 13560006, medinfo@pharmaand.com
    Scientific contact
    Medical Information Department, pharmaand GmbH, +43 13560006, medinfo@pharmaand.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
    15 Aug 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Aug 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study data was transferred to zr pharma& following the divestment of panobinostat to pharma&. Prior to study completion under the sponsorship of Secura Bio, the study was initiated and conducted in part under the sponsorship of Novartis. The primary objective of the study was to estimate the overall response rate (ORR) of each of 3 treatment regimens of oral panobinostat in combination with subcutaneous bortezomib and oral dexamethasone during up to 8 cycles of therapy, according to the International Myeloma Working Group 2014 (IMWG) criteria, as assessed by an Independent Review Committee (IRC).
    Protection of trial subjects
    The study was performed in compliance with the Declaration of Helsinki, the International Council on Harmonisation Guidelines for Good Clinical Practice, and regulatory requirements as applicable.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Mar 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 12
    Country: Number of subjects enrolled
    Brazil: 28
    Country: Number of subjects enrolled
    Korea, Republic of: 9
    Country: Number of subjects enrolled
    Lebanon: 14
    Country: Number of subjects enrolled
    Russian Federation: 8
    Country: Number of subjects enrolled
    Thailand: 20
    Country: Number of subjects enrolled
    Turkey: 11
    Country: Number of subjects enrolled
    United States: 25
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Norway: 16
    Country: Number of subjects enrolled
    Poland: 35
    Country: Number of subjects enrolled
    Portugal: 20
    Country: Number of subjects enrolled
    Spain: 41
    Country: Number of subjects enrolled
    Sweden: 9
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Czechia: 15
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Greece: 20
    Country: Number of subjects enrolled
    Hungary: 17
    Country: Number of subjects enrolled
    Italy: 4
    Worldwide total number of subjects
    351
    EEA total number of subjects
    224
    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)
    152
    From 65 to 84 years
    196
    85 years and over
    3

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Once randomized, participants were included in the post-treatment follow-up for efficacy until disease progression, death, loss to follow-up or withdrawal of consent, and, thereafter, in the survival follow-up even if they did not receive a dose of study treatment, as applicable.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A - Panobinostat (20 mg, TIW)
    Arm description
    		 Participants received 20 milligrams (mg) panobinostat thrice a week (TIW), 2 weeks on/1 week off in combination with subcutaneous bortezomib and oral dexamethasone.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Panobinostat
    Investigational medicinal product code
    Other name
    PAN, LBH589, Farydak
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Panobinostat (20 mg) TIW, 2 weeks on/1 week off in combination with bortezomib and dexamethasone.

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    BTZ, Velcade
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.3 mg/metre squared (m^2) subcutaneous administration; Cycle 1-4: 2 weeks on/1 week off twice a week for participants ≤75 years at time of screening; once a week for participant >75 years Cycle 5+: once a week for all participants.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Dex
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Pre- and 24 h after BTZ administration; participants ≤75 years at time of screening: 20 mg/dose participants >75 years: 10 mg/dose.

    Arm title
    		 Arm B - Panobinostat (20 mg, BIW)
    Arm description
    		 Participants received 20 mg panobinostat twice a week (BIW), 2 weeks on/1 week off in combination with subcutaneous bortezomib and oral dexamethasone.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Panobinostat
    Investigational medicinal product code
    Other name
    PAN, LBH589, Farydak
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Panobinostat (20 mg) TIW, 2 weeks on/1 week off in combination with bortezomib and dexamethasone.

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    BTZ, Velcade
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.3 mg/m^2 subcutaneous administration; Cycle 1-4: 2 weeks on/1 week off twice a week for participants ≤75 years at time of screening; once a week for participant >75 years Cycle 5+: once a week for all participants.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Dex
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Pre- and 24 h after BTZ administration; participants ≤75 years at time of screening: 20 mg/dose participants >75 years: 10 mg/dose.

    Arm title
    		 Arm C - Panobinostat (10 mg, TIW)
    Arm description
    		 Participants received 10 mg panobinostat TIW, 2 weeks on/1 week off in combination with subcutaneous bortezomib and oral dexamethasone.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Panobinostat
    Investigational medicinal product code
    Other name
    PAN, LBH589, Farydak
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Panobinostat (20 mg) TIW, 2 weeks on/1 week off in combination with bortezomib and dexamethasone.

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    BTZ, Velcade
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.3 mg/m^2 subcutaneous administration; Cycle 1-4: 2 weeks on/1 week off twice a week for participants ≤75 years at time of screening; once a week for participant >75 years Cycle 5+: once a week for all participants.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Dex
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Pre- and 24 h after BTZ administration; participants ≤75 years at time of screening: 20 mg/dose participants >75 years: 10 mg/dose.

    Number of subjects in period 1 [1]
    		Arm A - Panobinostat (20 mg, TIW) Arm B - Panobinostat (20 mg, BIW) Arm C - Panobinostat (10 mg, TIW)
    Started
    82
    83
    83
    Received at Least 1 Dose of Study Drug
    79 [2]
    82 [3]
    80 [4]
    Completed
    82
    83
    83
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of participants reported in the baseline period comprise the full analysis set (FAS): all participants to whom study treatment was assigned by randomization.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants reported in this milestone comprise the Safety Set: all participants who received any study treatment.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants reported in this milestone comprise the Safety Set: all participants who received any study treatment.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants reported in this milestone comprise the Safety Set: all participants who received any study treatment.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Arm A - Panobinostat (20 mg, TIW)
    Reporting group description
    		 Participants received 20 milligrams (mg) panobinostat thrice a week (TIW), 2 weeks on/1 week off in combination with subcutaneous bortezomib and oral dexamethasone.

    Reporting group title
    Arm B - Panobinostat (20 mg, BIW)
    Reporting group description
    		 Participants received 20 mg panobinostat twice a week (BIW), 2 weeks on/1 week off in combination with subcutaneous bortezomib and oral dexamethasone.

    Reporting group title
    Arm C - Panobinostat (10 mg, TIW)
    Reporting group description
    		 Participants received 10 mg panobinostat TIW, 2 weeks on/1 week off in combination with subcutaneous bortezomib and oral dexamethasone.

    Reporting group values
    		 Arm A - Panobinostat (20 mg, TIW) Arm B - Panobinostat (20 mg, BIW) Arm C - Panobinostat (10 mg, TIW) Total
    Number of subjects
    		 82 83 83 248
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 32 39 40 111
        From 65-84 years
    		 50 43 43 136
        85 years and over
    		 0 1 0 1
    Age continuous
    Units: years
        median (full range (min-max))
    		 67.0 (45 to 83) 65.0 (47 to 87) 66.0 (33 to 84) -
    Gender categorical
    Units: Subjects
        Female
    		 40 39 33 112
        Male
    		 42 44 50 136
    Race
    Units: Subjects
        Asian
    		 6 7 10 23
        American Indian or Alaska Native
    		 1 0 0 1
        Black or African American
    		 1 0 2 3
        White
    		 73 72 68 213
        Other
    		 1 4 3 8
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 4 5 9 18
        Not Hispanic or Latino
    		 49 43 38 130
        Unknown/Not Reported
    		 8 8 4 20
        Southeast Asian
    		 4 4 6 14
        Other
    		 17 23 26 66
    Eastern Cooperative Oncology Group Performance Status
    Scale to assess disease progression and disease effects on daily living abilities, as well as determine appropriate treatment and prognosis. Status range includes: 0 (fully active); 1 (restricted physical activity); 2 (unable to carry out work activities); 3 (limited self-care); 4 (completely disabled).
    Units: Subjects
        Status - 0
    		 38 38 42 118
        Status - 1
    		 36 45 35 116
        Status - 2
    		 8 0 6 14
        Status - 3
    		 0 0 0 0
        Status - 4
    		 0 0 0 0

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Arm A - Panobinostat (20 mg, TIW)
    Reporting group description
    		 Participants received 20 milligrams (mg) panobinostat thrice a week (TIW), 2 weeks on/1 week off in combination with subcutaneous bortezomib and oral dexamethasone.

    Reporting group title
    Arm B - Panobinostat (20 mg, BIW)
    Reporting group description
    		 Participants received 20 mg panobinostat twice a week (BIW), 2 weeks on/1 week off in combination with subcutaneous bortezomib and oral dexamethasone.

    Reporting group title
    Arm C - Panobinostat (10 mg, TIW)
    Reporting group description
    		 Participants received 10 mg panobinostat TIW, 2 weeks on/1 week off in combination with subcutaneous bortezomib and oral dexamethasone.

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants to whom study treatment was assigned by randomization.

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants who received any study treatment.

    Subject analysis set title
    Pharmacokinetics Analysis Set (PAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All participants with at least 1 evaluable pharmacokinetics concentration of panobinostat after dosing on Day 1.

    Primary: ORR

    		 Close Top of page
    End point title
    		 ORR [1]
    End point description
    ORR is defined as the percentage of participants with a confirmed partial response (PR) or better (immunophenotypic complete response [iCR] or stringent complete response [sCR] or complete response [CR] or very good partial response [VGPR]) as their best overall response after completion of up to 8 cycles of assigned study regimen. Each cycle was 21 days long. Best overall response was the best post-baseline confirmed overall response observed in a given participant and was determined based on overall responses observed at all post-baseline response assessments, recorded from randomization until progressive disease (PD), death, start of new therapy, withdrawal of consent, or end of study, whatever came first. ORR was assessed blindly per IRC according to IMWG criteria.
    End point type
    Primary
    End point timeframe
    Up to 168 days
    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 (percentage of participants plus confidence interval) are reported for this primary end point, as prespecified in the statistical analysis plan.
    End point values
    		 Arm A - Panobinostat (20 mg, TIW) Arm B - Panobinostat (20 mg, BIW) Arm C - Panobinostat (10 mg, TIW)
    Number of subjects analysed
    82 [2]
    83 [3]
    83 [4]
    Units: Percentage of Participants
        number (confidence interval 95%)
    62.2 (50.8 to 72.7)
    65.1 (53.8 to 75.2)
    50.6 (39.4 to 61.8)
    Notes
    [2] - FAS
    [3] - FAS
    [4] - FAS
    No statistical analyses for this end point

    Secondary: ORR Throughout the Study

    		 Close Top of page
    End point title
    		 ORR Throughout the Study
    End point description
    ORR is defined as the percentage of participants with a confirmed PR or better (iCR or sCR or CR or VGPR) as their best overall response throughout the entire study. Best overall response was the best post-baseline confirmed overall response observed in a given participant and was determined based on overall responses observed at all post-baseline response assessments, recorded from randomization until PD, death, start of new therapy, withdrawal of consent or end of study, whatever came first. ORR was assessed blindly per IRC according to IMWG criteria.
    End point type
    Secondary
    End point timeframe
    Up to 5.2 years
    End point values
    		 Arm A - Panobinostat (20 mg, TIW) Arm B - Panobinostat (20 mg, BIW) Arm C - Panobinostat (10 mg, TIW)
    Number of subjects analysed
    82 [5]
    83 [6]
    83 [7]
    Units: Percentage of Participants
        number (confidence interval 95%)
    62.2 (50.8 to 72.7)
    67.5 (56.3 to 77.4)
    53.0 (41.7 to 64.1)
    Notes
    [5] - FAS
    [6] - FAS
    [7] - FAS
    No statistical analyses for this end point

    Secondary: iCR Rate

    		 Close Top of page
    End point title
    		 iCR Rate
    End point description
    iCR, based on IMWG criteria per blinded IRC assessment, is defined as: negative immunofixation of serum and urine; disappearance of any soft tissue plasmacytoma(s), in the case of any presence of soft tissue plasmacytoma(s) at baseline; less than 5% plasma cells in bone marrow; normal free light chain (FLC) ratio; absence of clonal plasma cells in bone marrow analysed by immunohistochemistry or 2- to 4-color flow cytometry; absence of phenotypically aberrant plasma cells (clonal) in bone marrow (BM) with a minimum of 1 million total BM cells analysed by multiparametric flow cytometry (>4 colours). Results reported as percentage of participants achieving iCR.
    End point type
    Secondary
    End point timeframe
    Up to 5.2 years
    End point values
    		 Arm A - Panobinostat (20 mg, TIW) Arm B - Panobinostat (20 mg, BIW) Arm C - Panobinostat (10 mg, TIW)
    Number of subjects analysed
    82 [8]
    83 [9]
    83 [10]
    Units: Percentage of Participants
        number (not applicable)
    3.7
    1.2
    1.2
    Notes
    [8] - FAS
    [9] - FAS
    [10] - FAS
    No statistical analyses for this end point

    Secondary: sCR Rate

    		 Close Top of page
    End point title
    		 sCR Rate
    End point description
    sCR, based on IMWG criteria per blinded IRC assessment, is defined as: negative immunofixation of serum and urine; disappearance of any soft tissue plasmacytoma(s), in the case of any presence of soft tissue plasmacytoma(s) at baseline; less than 5% plasma cells in bone marrow; normal FLC ratio; absence of clonal plasma cells in bone marrow analysed by immunohistochemistry or 2- to 4-colour flow cytometry. Results reported as percentage of participants achieving sCR.
    End point type
    Secondary
    End point timeframe
    Up to 5.2 years
    End point values
    		 Arm A - Panobinostat (20 mg, TIW) Arm B - Panobinostat (20 mg, BIW) Arm C - Panobinostat (10 mg, TIW)
    Number of subjects analysed
    82 [11]
    83 [12]
    83 [13]
    Units: Percentage of Participants
        number (not applicable)
    1.2
    1.2
    3.6
    Notes
    [11] - FAS
    [12] - FAS
    [13] - FAS
    No statistical analyses for this end point

    Secondary: CR Rate

    		 Close Top of page
    End point title
    		 CR Rate
    End point description
    CR, based on IMWG criteria per blinded IRC assessment, is defined as: negative immunofixation of serum and urine; disappearance of any soft tissue plasmacytoma(s), in the case of any presence of soft tissue plasmacytoma(s) at baseline; less than 5% plasma cells in bone marrow; in case the only measurable disease at baseline is the serum FLC assessment, a normal FLC ratio of 0.26 to 1.65 is required additionally to qualify for CR. Results reported as percentage of participants achieving CR.
    End point type
    Secondary
    End point timeframe
    Up to 5.2 years
    End point values
    		 Arm A - Panobinostat (20 mg, TIW) Arm B - Panobinostat (20 mg, BIW) Arm C - Panobinostat (10 mg, TIW)
    Number of subjects analysed
    82 [14]
    83 [15]
    83 [16]
    Units: Percentage of Participants
        number (not applicable)
    8.5
    8.4
    2.4
    Notes
    [14] - FAS
    [15] - FAS
    [16] - FAS
    No statistical analyses for this end point

    Secondary: VGPR Rate

    		 Close Top of page
    End point title
    		 VGPR Rate
    End point description
    VGPR, based on IMWG criteria per blinded IRC assessment, is defined as: serum and/or urine M protein detectable by immunofixation but not on protein electrophoresis, or ≥90% reduction from baseline in serum) and urine M protein <100 mg/24 hours); in the case of the presence of any soft tissue plasmacytoma(s) at baseline, a reduction in the sum of the products of the cross-diameters by ≥50% from baseline is required; in case the only measurable disease in a participant at baseline is the serum FLC level (that is, no measurable disease in serum and urine protein electrophoresis), a decrease of >90% in the difference between involved and uninvolved FLC levels from baseline is required. Results reported as percentage of participants achieving VGPR.
    End point type
    Secondary
    End point timeframe
    Up to 5.2 years
    End point values
    		 Arm A - Panobinostat (20 mg, TIW) Arm B - Panobinostat (20 mg, BIW) Arm C - Panobinostat (10 mg, TIW)
    Number of subjects analysed
    82 [17]
    83 [18]
    83 [19]
    Units: Percentage of Participants
        number (not applicable)
    19.5
    25.3
    20.5
    Notes
    [17] - FAS
    [18] - FAS
    [19] - FAS
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS)

    		 Close Top of page
    End point title
    		 Progression-free Survival (PFS)
    End point description
    PFS, assessed based on IMWG criteria per blind IRC assessment, is defined as the time from date of randomization to date of first documented disease progression or death (regardless of cause of death).
    End point type
    Secondary
    End point timeframe
    Up to 5.2 years
    End point values
    		 Arm A - Panobinostat (20 mg, TIW) Arm B - Panobinostat (20 mg, BIW) Arm C - Panobinostat (10 mg, TIW)
    Number of subjects analysed
    82 [20]
    83 [21]
    83 [22]
    Units: Months
        median (confidence interval 95%)
    15 (7.4 to 24.7)
    13 (7.0 to 13.8)
    8 (5.0 to 10.7)
    Notes
    [20] - FAS
    [21] - FAS
    [22] - FAS
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

    		 Close Top of page
    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time from date of randomization to the date of death due to any cause. '9999' = Not evaluable due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    Up to 5.2 years
    End point values
    		 Arm A - Panobinostat (20 mg, TIW) Arm B - Panobinostat (20 mg, BIW) Arm C - Panobinostat (10 mg, TIW)
    Number of subjects analysed
    82 [23]
    83 [24]
    83 [25]
    Units: Months
        median (confidence interval 95%)
    35 (27.8 to 9999)
    32 (30.7 to 9999)
    22 (18.6 to 9999)
    Notes
    [23] - FAS
    [24] - FAS
    [25] - FAS
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration (Cmax): Panobinostat

    		 Close Top of page
    End point title
    		 Maximum Plasma Concentration (Cmax): Panobinostat
    End point description
    Serial blood samples were collected for panobinostat Cmax analysis. Here, ‘Number of subjects analysed’ refers to the number of evaluable participants analysed. Results are reported in nanograms/millilitre (ng/mL).
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (Pre-dose, up to 8 hours post dose)
    End point values
    		 Arm A - Panobinostat (20 mg, TIW) Arm B - Panobinostat (20 mg, BIW) Arm C - Panobinostat (10 mg, TIW)
    Number of subjects analysed
    50 [26]
    64 [27]
    62 [28]
    Units: ng/mL
        arithmetic mean (standard deviation)
    14.30 ( 7.77 )
    14.12 ( 8.96 )
    6.13 ( 3.51 )
    Notes
    [26] - PAS
    [27] - PAS
    [28] - PAS
    No statistical analyses for this end point

    Secondary: Cmax: Bortezomib

    		 Close Top of page
    End point title
    		 Cmax: Bortezomib
    End point description
    Serial blood samples were collected for bortezomib Cmax analysis. Here, ‘Number of subjects analysed’ refers to the number of evaluable participants analysed. Results are reported in ng/mL.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (Pre-dose, up to 8 hours post dose)
    End point values
    		 Arm A - Panobinostat (20 mg, TIW) Arm B - Panobinostat (20 mg, BIW) Arm C - Panobinostat (10 mg, TIW)
    Number of subjects analysed
    61 [29]
    69 [30]
    63 [31]
    Units: ng/mL
        arithmetic mean (standard deviation)
    16.67 ( 7.79 )
    19.47 ( 10.00 )
    18.29 ( 8.80 )
    Notes
    [29] - PAS
    [30] - PAS
    [31] - PAS
    No statistical analyses for this end point

    Secondary: Time to Reach Cmax (Tmax): Panobinostat

    		 Close Top of page
    End point title
    		 Time to Reach Cmax (Tmax): Panobinostat
    End point description
    Serial blood samples were collected for panobinostat Tmax analysis. Here, ‘Number of subjects analysed’ refers to the number of evaluable participants analysed. Results are reported in hours.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (Pre-dose, up to 8 hours post dose)
    End point values
    		 Arm A - Panobinostat (20 mg, TIW) Arm B - Panobinostat (20 mg, BIW) Arm C - Panobinostat (10 mg, TIW)
    Number of subjects analysed
    50 [32]
    64 [33]
    62 [34]
    Units: hour
        arithmetic mean (standard deviation)
    1.93 ( 1.53 )
    1.80 ( 1.63 )
    1.82 ( 1.53 )
    Notes
    [32] - PAS
    [33] - PAS
    [34] - PAS
    No statistical analyses for this end point

    Secondary: Tmax: Bortezomib

    		 Close Top of page
    End point title
    		 Tmax: Bortezomib
    End point description
    Serial blood samples were collected for bortezomib Tmax analysis. Here, ‘Number of subjects analysed’ refers to the number of evaluable participants analysed. Results are reported in hours.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (Pre-dose, up to 8 hours post dose)
    End point values
    		 Arm A - Panobinostat (20 mg, TIW) Arm B - Panobinostat (20 mg, BIW) Arm C - Panobinostat (10 mg, TIW)
    Number of subjects analysed
    61 [35]
    69 [36]
    63 [37]
    Units: Hour
        arithmetic mean (standard deviation)
    0.84 ( 0.46 )
    0.77 ( 0.36 )
    0.77 ( 0.39 )
    Notes
    [35] - PAS
    [36] - PAS
    [37] - PAS
    No statistical analyses for this end point

    Secondary: Exposure Response: Cmax for Panobinostat

    		 Close Top of page
    End point title
    		 Exposure Response: Cmax for Panobinostat
    End point description
    The exposure-response relationship was assessed utilizing Cmax (Cycle 1 Day 1) for panobinostat versus the outcomes of ORR, grade 3/4 thrombocytopenia, and grade 3/4 diarrhoea. Two statistical models were used: logistic regression models, in which these 3 outcomes were treated in a binary fashion according to their occurrence; Cox regression models, with the relevant outcomes being the time to occurrence of grade 3/4 thrombocytopenia and the time to occurrence of grade 3/4 diarrhoea. Results are reported as model-based probability. An increase in the model-based probability indicates an increase in the occurrence of the outcomes (ORR, grade 3/4 thrombocytopenia, 3/4 diarrhoea) with increasing values of Cmax (that is, with increasing dose of panobinostat). Here, ‘Number of subjects analysed’ refers to the number of evaluable participants analysed.
    End point type
    Secondary
    End point timeframe
    Up to 5.2 Years
    End point values
    		 Arm A - Panobinostat (20 mg, TIW) Arm B - Panobinostat (20 mg, BIW) Arm C - Panobinostat (10 mg, TIW)
    Number of subjects analysed
    18 [38]
    20 [39]
    18 [40]
    Units: Percent Probability
    number (confidence interval 95%)
        ORR by IRC (up to 8 cycles)
    63.1 (46.7 to 76.9)
    62.2 (47.5 to 75.0)
    35.3 (20.6 to 53.4)
        Grade 3/4 Thrombocytopenia
    23.2 (17.7 to 51.2)
    28.7 (17.5 to 43.4)
    21.7 (10.6 to 39.4)
        Grade 3/4 Diarrhoea
    6.2 (2.1 to 16.7)
    7.5 (3.1 to 17.2)
    2.5 (0.3 to 16.3)
    Notes
    [38] - FAS
    [39] - FAS; ORR (N=19)
    [40] - FAS; ORR (N=17); Thrombocytopenia (N=17)
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organization of Research and Treatment of Cancer (EORTC) Quality of Life Core 30-item Questionnaire (QLQ-C30) Global Health Status (GHS) Score

    		 Close Top of page
    End point title
    		 Change From Baseline in European Organization of Research and Treatment of Cancer (EORTC) Quality of Life Core 30-item Questionnaire (QLQ-C30) Global Health Status (GHS) Score
    End point description
    Health-related quality of life (HRQoL) was assessed by the EORTC QLQ-C30, which is frequently employed in clinical oncology trials and is recognized as reliable and valid. The EORTC QLQ-C30 measures functional dimensions (physical, role, emotional, cognitive, and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 6 single items (dyspnoea, sleep disturbance, appetite loss, constipation, diarrhoea and financial impact), and a GHS and quality-of-life scale. For each domain and item, a linear transformation is applied to standardize the score between 0 and 100. Results are presented specifically for the GHS score. A higher GHS score indicates a higher HRQoL. Each cycle was 21 days long. Here, ‘Number of subjects analysed’ refers to the number of evaluable participants analysed.
    End point type
    Secondary
    End point timeframe
    Cycle 15 Day 1, at approximately 295 days
    End point values
    		 Arm A - Panobinostat (20 mg, TIW) Arm B - Panobinostat (20 mg, BIW) Arm C - Panobinostat (10 mg, TIW)
    Number of subjects analysed
    18 [41]
    16 [42]
    18 [43]
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    6.0 ( 23.01 )
    0.0 ( 30.12 )
    -4.6 ( 24.12 )
    Notes
    [41] - FAS
    [42] - FAS
    [43] - FAS
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Functional Assessment of Cancer Therapy (FACT)/Gynecologic Oncology Group- Neurotoxicity (GOG-Ntx) Neurotoxicity Subscale Score

    		 Close Top of page
    End point title
    		 Change From Baseline in the Functional Assessment of Cancer Therapy (FACT)/Gynecologic Oncology Group- Neurotoxicity (GOG-Ntx) Neurotoxicity Subscale Score
    End point description
    HRQoL was assessed by the FACT/GOG-Ntx, a 38-item questionnaire designed to assess general quality of life and severity and impact of neurotoxicity from systemic chemotherapy. It is frequently employed in clinical oncology trials and is recognized as a reliable and valid measure to assess symptoms associated with neurotoxicity. It focuses on 4 general quality of life domains for physical well-being, functional well-being, social/family well-being, and emotional well-being, and includes the neurotoxicity subscale domain to characterize treatment-related neurotoxicity. Results are presented specifically for the 11-item neurotoxicity subscale, which uses a 5-point rating scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). Each item is scored from 0-4, with the severity of neurotoxicity measured as the sum of the 11 items, ranging from 0 to 44. Lower scores indicate lower neurotoxicity and higher HRQoL. Each cycle was 21 days long.
    End point type
    Secondary
    End point timeframe
    Cycle 15 Day 1, at approximately 295 days
    End point values
    		 Arm A - Panobinostat (20 mg, TIW) Arm B - Panobinostat (20 mg, BIW) Arm C - Panobinostat (10 mg, TIW)
    Number of subjects analysed
    18 [44]
    15 [45]
    18 [46]
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    -3.6 ( 7.39 )
    -3.9 ( 4.19 )
    -0.1 ( 5.71 )
    Notes
    [44] - FAS (Number of subjects analysed = the number of evaluable participants analysed)
    [45] - FAS (Number of subjects analysed = the number of evaluable participants analysed)
    [46] - FAS (Number of subjects analysed = the number of evaluable participants analysed)
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP)

    		 Close Top of page
    End point title
    		 Time to Progression (TTP)
    End point description
    TTP, based on IMWG criteria per blinded IRC assessment, is defined as the time from the date of randomization to the date of the first documented disease progression or death due to multiple myeloma. '9999' = Not evaluable due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    Up to 5.2 years
    End point values
    		 Arm A - Panobinostat (20 mg, TIW) Arm B - Panobinostat (20 mg, BIW) Arm C - Panobinostat (10 mg, TIW)
    Number of subjects analysed
    82 [47]
    83 [48]
    83 [49]
    Units: Months
        median (confidence interval 95%)
    17 (8.35 to 9999)
    13 (7.0 to 16.1)
    8 (5.9 to 11.6)
    Notes
    [47] - FAS
    [48] - FAS
    [49] - FAS
    No statistical analyses for this end point

    Secondary: Time to Response (TTR)

    		 Close Top of page
    End point title
    		 Time to Response (TTR)
    End point description
    TTR, based on IMWG criteria per blinded IRC assessment, is the time between date of randomization to the date of first onset of PR or better response (iCR or sCR or CR or VGPR). '9999' = Not evaluable due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    Up to 5.2 years
    End point values
    		 Arm A - Panobinostat (20 mg, TIW) Arm B - Panobinostat (20 mg, BIW) Arm C - Panobinostat (10 mg, TIW)
    Number of subjects analysed
    82 [50]
    83 [51]
    83 [52]
    Units: Months
        median (confidence interval 95%)
    3 (1 to 9999)
    3 (1 to 9999)
    3 (1 to 9999)
    Notes
    [50] - FAS
    [51] - FAS
    [52] - FAS
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

    		 Close Top of page
    End point title
    		 Duration of Response (DOR)
    End point description
    DOR, based on IMWG criteria per blinded IRC assessment, is defined as the duration from the first documented onset of PR or better (iCR or sCR or CR or VGPR) to the date of first documented disease progression or death due to multiple myeloma. '9999' = Not evaluable due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    Up to 5.2 years
    End point values
    		 Arm A - Panobinostat (20 mg, TIW) Arm B - Panobinostat (20 mg, BIW) Arm C - Panobinostat (10 mg, TIW)
    Number of subjects analysed
    82 [53]
    83 [54]
    83 [55]
    Units: month
        median (confidence interval 95%)
    22 (13.9 to 9999)
    12 (8.8 to 21.3)
    10.429 (6.2 to 14.5)
    Notes
    [53] - FAS
    [54] - FAS
    [55] - FAS
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were assessed for 3 years. All-Cause Mortality was assessed from date of randomization until death, assessed up to 5.2 years.
    Adverse event reporting additional description
    Safety Set: all participants who received any study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Arm A - Panobinostat (20 mg) TIW
    Reporting group description
    		 Participants received panobinostat (20 mg) TIW with bortezomib and dexamethasone.

    Reporting group title
    Arm B - Panobinostat (20 mg) BIW
    Reporting group description
    		 Participants received panobinostat (20 mg) BIW with bortezomib and dexamethasone.

    Reporting group title
    Arm C - Panobinostat (10 mg) TIW
    Reporting group description
    		 Participants received panobinostat (10 mg) TIW with bortezomib and dexamethasone.

    Serious adverse events
    		 Arm A - Panobinostat (20 mg) TIW Arm B - Panobinostat (20 mg) BIW Arm C - Panobinostat (10 mg) TIW
    Total subjects affected by serious adverse events
         subjects affected / exposed
    44 / 78 (56.41%)
    40 / 83 (48.19%)
    36 / 80 (45.00%)
         number of deaths (all causes)
    34
    41
    47
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastrointestinal tract adenoma
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematological malignancy
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 83 (2.41%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug withdrawal syndrome
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    0 / 78 (0.00%)
    3 / 83 (3.61%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 78 (0.00%)
    4 / 83 (4.82%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed [1]
    0 / 39 (0.00%)
    1 / 44 (2.27%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orchitis noninfective
         subjects affected / exposed [2]
    0 / 39 (0.00%)
    1 / 44 (2.27%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypomania
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Troponin C increased
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatine increased
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial necrosis marker increased
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Forearm fracture
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transfusion-related acute lung injury
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    3 / 78 (3.85%)
    2 / 83 (2.41%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 83 (2.41%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bicytopenia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Methaemoglobinaemia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 78 (3.85%)
    2 / 83 (2.41%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 78 (1.28%)
    3 / 83 (3.61%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 83 (2.41%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal motility disorder
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    8 / 78 (10.26%)
    11 / 83 (13.25%)
    9 / 80 (11.25%)
         occurrences causally related to treatment / all
    4 / 8
    7 / 14
    4 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial pyelonephritis
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 83 (2.41%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia parainfluenzae viral
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 78 (1.28%)
    4 / 83 (4.82%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemophilus sepsis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 83 (2.41%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 83 (2.41%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Streptococcal sepsis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    3 / 80 (3.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This adverse event only affected male participants.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This adverse event only affected male participants.
    Frequency threshold for reporting non-serious adverse events: 4.9%
    Non-serious adverse events
    		 Arm A - Panobinostat (20 mg) TIW Arm B - Panobinostat (20 mg) BIW Arm C - Panobinostat (10 mg) TIW
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    78 / 78 (100.00%)
    82 / 83 (98.80%)
    78 / 80 (97.50%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    7 / 78 (8.97%)
    6 / 83 (7.23%)
    1 / 80 (1.25%)
         occurrences all number
    10
    8
    1
    Hypertension
         subjects affected / exposed
    6 / 78 (7.69%)
    4 / 83 (4.82%)
    5 / 80 (6.25%)
         occurrences all number
    13
    4
    6
    Orthostatic hypotension
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
    5 / 80 (6.25%)
         occurrences all number
    0
    1
    6
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    27 / 78 (34.62%)
    25 / 83 (30.12%)
    24 / 80 (30.00%)
         occurrences all number
    66
    54
    43
    Asthenia
         subjects affected / exposed
    25 / 78 (32.05%)
    29 / 83 (34.94%)
    15 / 80 (18.75%)
         occurrences all number
    57
    56
    24
    Oedema peripheral
         subjects affected / exposed
    23 / 78 (29.49%)
    14 / 83 (16.87%)
    14 / 80 (17.50%)
         occurrences all number
    34
    18
    14
    Pyrexia
         subjects affected / exposed
    10 / 78 (12.82%)
    12 / 83 (14.46%)
    10 / 80 (12.50%)
         occurrences all number
    15
    16
    13
    Non-cardiac chest pain
         subjects affected / exposed
    4 / 78 (5.13%)
    3 / 83 (3.61%)
    2 / 80 (2.50%)
         occurrences all number
    4
    3
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 78 (15.38%)
    13 / 83 (15.66%)
    16 / 80 (20.00%)
         occurrences all number
    18
    15
    20
    Dyspnoea
         subjects affected / exposed
    11 / 78 (14.10%)
    8 / 83 (9.64%)
    8 / 80 (10.00%)
         occurrences all number
    13
    13
    8
    Epistaxis
         subjects affected / exposed
    6 / 78 (7.69%)
    4 / 83 (4.82%)
    3 / 80 (3.75%)
         occurrences all number
    7
    5
    3
    Dysphonia
         subjects affected / exposed
    4 / 78 (5.13%)
    3 / 83 (3.61%)
    2 / 80 (2.50%)
         occurrences all number
    4
    4
    2
    Oropharyngeal pain
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 83 (2.41%)
    1 / 80 (1.25%)
         occurrences all number
    4
    2
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 78 (8.97%)
    20 / 83 (24.10%)
    11 / 80 (13.75%)
         occurrences all number
    12
    28
    15
    Depression
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 83 (1.20%)
    3 / 80 (3.75%)
         occurrences all number
    4
    1
    3
    Investigations
    Platelet count decreased
         subjects affected / exposed
    11 / 78 (14.10%)
    9 / 83 (10.84%)
    6 / 80 (7.50%)
         occurrences all number
    52
    25
    7
    Blood creatine increased
         subjects affected / exposed
    9 / 78 (11.54%)
    7 / 83 (8.43%)
    4 / 80 (5.00%)
         occurrences all number
    29
    18
    6
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 78 (10.26%)
    2 / 83 (2.41%)
    2 / 80 (2.50%)
         occurrences all number
    11
    3
    4
    Weight decreased
         subjects affected / exposed
    6 / 78 (7.69%)
    5 / 83 (6.02%)
    3 / 80 (3.75%)
         occurrences all number
    8
    6
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 78 (6.41%)
    2 / 83 (2.41%)
    0 / 80 (0.00%)
         occurrences all number
    7
    3
    0
    C-reactive protein increased
         subjects affected / exposed
    4 / 78 (5.13%)
    3 / 83 (3.61%)
    1 / 80 (1.25%)
         occurrences all number
    4
    8
    4
    Neutrophil count decreased
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 83 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    12
    0
    3
    White blood cell count decreased
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    11
    0
    0
    Weight increased
         subjects affected / exposed
    2 / 78 (2.56%)
    6 / 83 (7.23%)
    0 / 80 (0.00%)
         occurrences all number
    2
    6
    0
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    20 / 78 (25.64%)
    22 / 83 (26.51%)
    14 / 80 (17.50%)
         occurrences all number
    39
    35
    26
    Peripheral sensory neuropathy
         subjects affected / exposed
    16 / 78 (20.51%)
    9 / 83 (10.84%)
    11 / 80 (13.75%)
         occurrences all number
    35
    23
    21
    Dizziness
         subjects affected / exposed
    13 / 78 (16.67%)
    12 / 83 (14.46%)
    5 / 80 (6.25%)
         occurrences all number
    17
    18
    5
    Headache
         subjects affected / exposed
    7 / 78 (8.97%)
    6 / 83 (7.23%)
    3 / 80 (3.75%)
         occurrences all number
    10
    6
    3
    Paraesthesia
         subjects affected / exposed
    4 / 78 (5.13%)
    5 / 83 (6.02%)
    4 / 80 (5.00%)
         occurrences all number
    7
    6
    5
    Polyneuropathy
         subjects affected / exposed
    3 / 78 (3.85%)
    5 / 83 (6.02%)
    5 / 80 (6.25%)
         occurrences all number
    3
    14
    8
    Dysgeusia
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 83 (2.41%)
    4 / 80 (5.00%)
         occurrences all number
    2
    3
    7
    Neuralgia
         subjects affected / exposed
    0 / 78 (0.00%)
    6 / 83 (7.23%)
    0 / 80 (0.00%)
         occurrences all number
    0
    6
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    43 / 78 (55.13%)
    37 / 83 (44.58%)
    26 / 80 (32.50%)
         occurrences all number
    140
    122
    126
    Anaemia
         subjects affected / exposed
    33 / 78 (42.31%)
    22 / 83 (26.51%)
    24 / 80 (30.00%)
         occurrences all number
    83
    58
    74
    Neutropenia
         subjects affected / exposed
    25 / 78 (32.05%)
    16 / 83 (19.28%)
    10 / 80 (12.50%)
         occurrences all number
    71
    57
    37
    Leukopenia
         subjects affected / exposed
    5 / 78 (6.41%)
    1 / 83 (1.20%)
    2 / 80 (2.50%)
         occurrences all number
    12
    4
    2
    Eye disorders
    Cataract
         subjects affected / exposed
    6 / 78 (7.69%)
    3 / 83 (3.61%)
    1 / 80 (1.25%)
         occurrences all number
    7
    3
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    51 / 78 (65.38%)
    53 / 83 (63.86%)
    39 / 80 (48.75%)
         occurrences all number
    233
    187
    159
    Nausea
         subjects affected / exposed
    29 / 78 (37.18%)
    29 / 83 (34.94%)
    13 / 80 (16.25%)
         occurrences all number
    59
    54
    17
    Constipation
         subjects affected / exposed
    21 / 78 (26.92%)
    16 / 83 (19.28%)
    18 / 80 (22.50%)
         occurrences all number
    29
    19
    20
    Vomiting
         subjects affected / exposed
    16 / 78 (20.51%)
    21 / 83 (25.30%)
    6 / 80 (7.50%)
         occurrences all number
    30
    35
    9
    Abdominal pain upper
         subjects affected / exposed
    12 / 78 (15.38%)
    9 / 83 (10.84%)
    1 / 80 (1.25%)
         occurrences all number
    15
    16
    1
    Dyspepsia
         subjects affected / exposed
    9 / 78 (11.54%)
    3 / 83 (3.61%)
    4 / 80 (5.00%)
         occurrences all number
    11
    3
    4
    Abdominal pain
         subjects affected / exposed
    5 / 78 (6.41%)
    11 / 83 (13.25%)
    7 / 80 (8.75%)
         occurrences all number
    5
    13
    11
    Flatulence
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 83 (2.41%)
    1 / 80 (1.25%)
         occurrences all number
    4
    2
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    5 / 78 (6.41%)
    2 / 83 (2.41%)
    1 / 80 (1.25%)
         occurrences all number
    5
    2
    1
    Rash
         subjects affected / exposed
    2 / 78 (2.56%)
    6 / 83 (7.23%)
    3 / 80 (3.75%)
         occurrences all number
    6
    6
    3
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 83 (0.00%)
    5 / 80 (6.25%)
         occurrences all number
    0
    0
    5
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    9 / 78 (11.54%)
    8 / 83 (9.64%)
    10 / 80 (12.50%)
         occurrences all number
    13
    14
    15
    Pain in extremity
         subjects affected / exposed
    9 / 78 (11.54%)
    4 / 83 (4.82%)
    7 / 80 (8.75%)
         occurrences all number
    11
    5
    9
    Bone pain
         subjects affected / exposed
    5 / 78 (6.41%)
    5 / 83 (6.02%)
    0 / 80 (0.00%)
         occurrences all number
    7
    8
    0
    Muscular weakness
         subjects affected / exposed
    5 / 78 (6.41%)
    6 / 83 (7.23%)
    4 / 80 (5.00%)
         occurrences all number
    6
    6
    9
    Arthralgia
         subjects affected / exposed
    3 / 78 (3.85%)
    11 / 83 (13.25%)
    5 / 80 (6.25%)
         occurrences all number
    4
    13
    6
    Musculoskeletal pain
         subjects affected / exposed
    3 / 78 (3.85%)
    5 / 83 (6.02%)
    1 / 80 (1.25%)
         occurrences all number
    4
    6
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 78 (2.56%)
    6 / 83 (7.23%)
    5 / 80 (6.25%)
         occurrences all number
    2
    6
    5
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    20 / 78 (25.64%)
    12 / 83 (14.46%)
    21 / 80 (26.25%)
         occurrences all number
    44
    19
    30
    Respiratory tract infection
         subjects affected / exposed
    13 / 78 (16.67%)
    8 / 83 (9.64%)
    8 / 80 (10.00%)
         occurrences all number
    19
    13
    15
    Urinary tract infection
         subjects affected / exposed
    11 / 78 (14.10%)
    8 / 83 (9.64%)
    2 / 80 (2.50%)
         occurrences all number
    13
    10
    2
    Bronchitis
         subjects affected / exposed
    9 / 78 (11.54%)
    8 / 83 (9.64%)
    1 / 80 (1.25%)
         occurrences all number
    10
    10
    1
    Conjunctivitis
         subjects affected / exposed
    5 / 78 (6.41%)
    4 / 83 (4.82%)
    1 / 80 (1.25%)
         occurrences all number
    5
    5
    1
    Respiratory tract infection viral
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    6
    0
    0
    Gastroenteritis
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 83 (1.20%)
    4 / 80 (5.00%)
         occurrences all number
    2
    1
    5
    Nasopharyngitis
         subjects affected / exposed
    2 / 78 (2.56%)
    6 / 83 (7.23%)
    8 / 80 (10.00%)
         occurrences all number
    2
    10
    13
    Pneumonia
         subjects affected / exposed
    2 / 78 (2.56%)
    5 / 83 (6.02%)
    4 / 80 (5.00%)
         occurrences all number
    2
    5
    5
    Influenza
         subjects affected / exposed
    1 / 78 (1.28%)
    4 / 83 (4.82%)
    6 / 80 (7.50%)
         occurrences all number
    1
    4
    7
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    14 / 78 (17.95%)
    9 / 83 (10.84%)
    7 / 80 (8.75%)
         occurrences all number
    19
    12
    7
    Decreased appetite
         subjects affected / exposed
    13 / 78 (16.67%)
    16 / 83 (19.28%)
    10 / 80 (12.50%)
         occurrences all number
    18
    19
    10
    Hypocalcaemia
         subjects affected / exposed
    7 / 78 (8.97%)
    3 / 83 (3.61%)
    4 / 80 (5.00%)
         occurrences all number
    12
    5
    4
    Hyponatraemia
         subjects affected / exposed
    7 / 78 (8.97%)
    1 / 83 (1.20%)
    2 / 80 (2.50%)
         occurrences all number
    12
    2
    4
    Hypophosphataemia
         subjects affected / exposed
    6 / 78 (7.69%)
    6 / 83 (7.23%)
    2 / 80 (2.50%)
         occurrences all number
    10
    15
    4
    Hyperglycaemia
         subjects affected / exposed
    4 / 78 (5.13%)
    7 / 83 (8.43%)
    3 / 80 (3.75%)
         occurrences all number
    5
    12
    8
    Dehydration
         subjects affected / exposed
    3 / 78 (3.85%)
    2 / 83 (2.41%)
    4 / 80 (5.00%)
         occurrences all number
    3
    2
    4
    Muscle spasms
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 83 (2.41%)
    5 / 80 (6.25%)
         occurrences all number
    1
    2
    6

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Nov 2017
    • Participants with up to 4 prior lines of therapy were included with no limitation on how many participants could be treated with 3 or 4 prior lines of therapy. • Changed the platelet limit for inclusion to = 75 x 10^9/litre (L). Similar expectations applied for absolute neutrophil count (ANC); the ANC inclusion criterion was changed to = 1.0 x 10^9/L. • The bone marrow collection did not have to be repeated, unless participants received alternative anti-myeloma therapy between initial screening and re-screening. • Removal of the mandatory computed tomography/magnetic resonance imaging (CT/MRI) scan at screening if the clinical assessment of soft tissue plasmacytoma (STP) did not suggest the presence of a STP. This was in line with the post baseline assessments of STP when a CT/MRI was only mandatory in case STP was suspected by clinical assessment. • The anti-diarrhoeal medication entries and fluid intake entries were removed; participant’s caregiver or a member of the participant’s family were allowed to make the entries for the participant in case the participant was not able to make the entries her/himself. In addition, the electronic diary to document PAN/Dex dose administration was removed and allowed for this feature to be replaced by a paper diary as per local requirements.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Fri May 09 19:49:25 CEST 2025 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA