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    Clinical Trial Results:
    A Phase II Trial of combination treatment with Vorinostat, Bortezomib and Dexamethasone in participants with Relapsed Multiple Myeloma

    Summary
    EudraCT number
    		 2011-005361-20
    Trial protocol
    		 GB  
    Global end of trial date
    29 Aug 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Nov 2019
    First version publication date
    09 Nov 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HM11/10041
    Additional study identifiers
    ISRCTN number
    		 ISRCTN08577602
    US NCT number
    		 NCT01720875
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Univeristy of Leeds
    Sponsor organisation address
    CTRU, Leeds, United Kingdom, LS2 9JT
    Public contact
    CTRU, University of Leeds CTRU, 0044 0113 343 1478,
    Scientific contact
    CTRU, University of Leeds CTRU, 0044 0113 343 1478,
    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
    03 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 May 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Aug 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the overall response rate (partial response or better) of patients with relapsed multiple myeloma, after combination treatment with vorinostat, bortezomib and dexamethasone.
    Protection of trial subjects
    Patients will be monitored closely throughout the trial and attend regular outpatient appointments. Some visits may involve taking extra blood, urine and bone marrow samples. The additional samples will be taken at the same time as routine samples so will not involve additional needle punctures. Bone marrow tests are potentially painful but are undertaken as part of normal care with pain relief and sedation available if required. The potential side effects of the treatments used in this trial are explained within the patient information sheet. Treatment modifications will be made and supportive care given to minimise the side effects. The frequency of the outpatient appointments during the follow up phase to monitor for disease progression will be more than standard care. These visits will involve taking a blood and urine sample. routine samples so will not involve additional needle punctures. .
    Background therapy
    		 There are no comparators for this trial all participants received the experimental treatment.
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    01 Mar 2013
    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
    United Kingdom: 16
    Worldwide total number of subjects
    16
    EEA total number of subjects
    16
    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)
    4
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment started September 2013 and was planned to take approximately 12 months. Sixteen patients out of 68 were recruited in 13 months. The trial was halted in October 2014 due to low recruitment due to the availability of other drugs, namely pomalidomide. Vorinostat was also not to be developed further for use in myeloma.

    Pre-assignment
    Screening details
    		 Assessments were performed within 21 days prior to registration to ensure they were eligible for the trial. Participants were eligible with 1-3 prior lines of treatment and had to be well enough to receive the treatment in the trial.

    Pre-assignment period milestones
    Number of subjects started
    		 16
    Number of subjects completed
    		 16

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

    Arms
    Arm title
    		 Overall trial
    Arm description
    		 All patients received vorinostat, bortezomib and dexamethasone as initial treatment for 8 cycles, patients who have not progressed continue to receive maintenance vorinostat.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vorinostat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    400mg days 1-4, 8-11 and 15-18

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.3 mg/m2 days 1, 4, 8, 11

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20mg days 1, 2, 4, 5, 8, 9, 11, 12

    Number of subjects in period 1
    		Overall trial
    Started
    16
    Completed
    16

    Baseline characteristics

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

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 16 16
    Age categorical
    Mean (SD) 67.6 (8.43) Median (Range) 69.5 (50.0, 78.0)
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 4 4
        From 65-84 years
    		 12 12
        85 years and over
    		 0 0
    Age continuous
    67.6
    Units: years
        arithmetic mean (standard deviation)
    		 67.6 ( 8.34 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 8 8
    ECOG Performance Status
    ECOG Performance Status
    Units: Subjects
        Zero
    		 9 9
        One
    		 7 7
    Treatment Lines
    Number of prior treatment lines at registration
    Units: Subjects
        One
    		 9 9
        Two
    		 5 5
        Three
    		 2 2
    Tumour Stage Diagnosis (ISS criteria)
    Tumour Stage Diagnosis (ISS Criteria) at registration
    Units: Subjects
        One
    		 5 5
        Two
    		 4 4
        Three
    		 3 3
        Missing
    		 4 4
    Paraprotein Type
    Units: Subjects
        IgG
    		 9 9
        IgA
    		 4 4
        Light chain only
    		 3 3
    Light Chain Type
    Units: Subjects
        Kappa
    		 9 9
        Lambda
    		 7 7
    Tumour Stage Baseline (ISS criteria)
    Units: Subjects
        One
    		 11 11
        Two
    		 4 4
        Three
    		 1 1
    Height
    Height at registration
    Units: cm
        arithmetic mean (standard deviation)
    		 169.5 ( 10.81 ) -
    Weight
    Weight at registration
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 79.5 ( 12.15 ) -
    BSA
    Body surface area at registration
    Units: square meter
        arithmetic mean (standard deviation)
    		 1.9 ( 0.20 ) -
    Time from original diagnosis to registration
    Units: months
        arithmetic mean (standard deviation)
    		 48.0 ( 32.25 ) -
    Time from most recent relapse to registration
    Units: months
        arithmetic mean (standard deviation)
    		 1.8 ( 1.78 ) -
    Time from last dose of systemic anti-myeloma treatment to registration
    Units: months
        arithmetic mean (standard deviation)
    		 14.9 ( 12.91 ) -

    End points

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    End points reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 All patients received vorinostat, bortezomib and dexamethasone as initial treatment for 8 cycles, patients who have not progressed continue to receive maintenance vorinostat.

    Primary: Proportion of participants achieving at least a partial response (PR)

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    End point title
    		 Proportion of participants achieving at least a partial response (PR) [1]
    End point description
    The primary endpoint for the MUKfour trial is overall response rate, measured as the proportion of participants achieving at least a partial response (PR) within 8 cycles of protocol treatment, as defined by modified IWG criteria. 80% confidence intervals correspond to the design of the study, 95% confidence intervals are (54.4, 96.0).
    End point type
    Primary
    End point timeframe
    8 cycles of treatment - 24 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: statistical analysis is by evlauation of confidence intervals as this is a single arm trial
    End point values
    		 Overall trial
    Number of subjects analysed
    16
    Units: Proportion
        number (confidence interval 80%)
    81.3 (62.9 to 92.9)
    No statistical analyses for this end point

    Secondary: Proportion of participants receiving dose reductions of vorinostat or bortezomib, or terminating treatment early due to toxicity

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    End point title
    		 Proportion of participants receiving dose reductions of vorinostat or bortezomib, or terminating treatment early due to toxicity
    End point description
    The dose reduction profile will be summarised as the proportion of participants experiencing a dose reduction of vorinostat or bortezomib (including missed doses due to toxicity) or terminating treatment early due to toxicity during the initial treatment period (i.e. not including maintenance treatment).
    End point type
    Secondary
    End point timeframe
    Duration of the trial
    End point values
    		 Overall trial
    Number of subjects analysed
    16
    Units: Proportion
        number (confidence interval 95%)
    75.0 (47.6 to 92.7)
    No statistical analyses for this end point

    Secondary: Progression free survival at 6 months

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    End point title
    		 Progression free survival at 6 months
    End point description
    Progression free survival is defined as the time from registration until the first documented evidence of disease progression or death. Participants who are alive and progression-free at the time of analysis will be censored on the last day they were known to be alive and progression free. Median PFS was not observed.
    End point type
    Secondary
    End point timeframe
    Duration of the trial treatment
    End point values
    		 Overall trial
    Number of subjects analysed
    16
    Units: Proportion
        number (confidence interval 95%)
    87.50 (58.60 to 96.72)
    No statistical analyses for this end point

    Secondary: Proportion of participants achieving at least a very good partial response (VGPR)

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    End point title
    		 Proportion of participants achieving at least a very good partial response (VGPR)
    End point description
    Proportion of participants achieving at least a VGPR within 8 cycles includes those participants who achieve a VGPR, CR or sCR. If a participant achieves at least a VGPR within 8 cycles of treatment but subsequently progresses (within 8 cycles) or stops treatment (within 8 cycles), the participant will be classed as achieving at least a VGPR within 8 cycles of treatment
    End point type
    Secondary
    End point timeframe
    within 8 cycles of treatment - 24 weeks
    End point values
    		 Overall trial
    Number of subjects analysed
    16
    Units: Proportion
        number (confidence interval 95%)
    37.5 (15.2 to 64.6)
    No statistical analyses for this end point

    Secondary: Number of participants achieving at least a partial response within 8 cycles

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    End point title
    		 Number of participants achieving at least a partial response within 8 cycles
    End point description
    Maximum response is defined as the proportion of participants achieving each of the response categories sCR, CR, VGPR, PR, MR or SD as their maximum response within 8 cycles of treatment and overall. Participants who do not achieve any of the above as their maximum response will be classed as ‘progressive disease’. Response to treatment is assessed following the Modified IWG Uniform Response Criteria.
    End point type
    Secondary
    End point timeframe
    Duration of treatment and at 8 cycles or 24 weeks.
    End point values
    		 Overall trial
    Number of subjects analysed
    16
    Units: Subjects
        Partial response achieved
    13
        Not achieved
    3
    No statistical analyses for this end point

    Secondary: Time to maximum response

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    End point title
    		 Time to maximum response
    End point description
    Time to maximum response is defined as the time from registration until the participant achieves any of the categories sCR, CR, VGPR, PR, MR or SD as their maximum response. Participants who do not achieve maximum response will be censored at the time of disease progression or death, whichever is earlier. Response to treatment is assessed following the Modified IWG Uniform Response Criteria
    End point type
    Secondary
    End point timeframe
    Duration of treatment
    End point values
    		 Overall trial
    Number of subjects analysed
    16
    Units: Months
        median (confidence interval 95%)
    1.46 (1.22 to 2.60)
    No statistical analyses for this end point

    Secondary: Progression free survival at 12 months

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    End point title
    		 Progression free survival at 12 months
    End point description
    Progression free survival is defined as the time from registration until the first documented evidence of disease progression or death. Participants who are alive and progression-free at the time of analysis will be censored on the last day they were known to be alive and progression free. Median PFS was not observed.
    End point type
    Secondary
    End point timeframe
    Duration of the trial
    End point values
    		 Overall trial
    Number of subjects analysed
    16
    Units: Proportion
        number (confidence interval 95%)
    54.00 (19.54 to 79.25)
    No statistical analyses for this end point

    Secondary: Safety: number of patients with 1 or more SAEs

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    End point title
    		 Safety: number of patients with 1 or more SAEs
    End point description
    Has the participant had an SAE?
    End point type
    Secondary
    End point timeframe
    Duration of the trial.
    End point values
    		 Overall trial
    Number of subjects analysed
    16
    Units: Subjects
        Yes: SAR
    4
        No
    12
    No statistical analyses for this end point

    Secondary: Safety: SAEs

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    End point title
    		 Safety: SAEs
    End point description
    Summary statistics of the number of serious adverse events (SAEs) reported
    End point type
    Secondary
    End point timeframe
    Duration of the trial
    End point values
    		 Overall trial
    Number of subjects analysed
    16
    Units: Subjects
        Number of patients with one or more SAEs
    4
        Number of SAEs reported
    6
    No statistical analyses for this end point

    Secondary: Safety: Number of SAEs per patient

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    End point title
    		 Safety: Number of SAEs per patient
    End point description
    End point type
    Secondary
    End point timeframe
    Duration of the trial.
    End point values
    		 Overall trial
    Number of subjects analysed
    4 [2]
    Units: SAEs
        arithmetic mean (standard deviation)
    1.5 ( 0.58 )
    Notes
    [2] - 4 patients had an SAE.
    No statistical analyses for this end point

    Secondary: Safety: Seriousness Criteria for all reported SAEs

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    End point title
    		 Safety: Seriousness Criteria for all reported SAEs
    End point description
    End point type
    Secondary
    End point timeframe
    Duration of the trial
    End point values
    		 Overall trial
    Number of subjects analysed
    6 [3]
    Units: Seriousness Criteria
        Required/prolonged hospitalisation
    6
    Notes
    [3] - There were 6 SAEs in the trial.
    No statistical analyses for this end point

    Secondary: Safety: Outcome for all reported SAEs

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    End point title
    		 Safety: Outcome for all reported SAEs
    End point description
    End point type
    Secondary
    End point timeframe
    Duration of the trial
    End point values
    		 Overall trial
    Number of subjects analysed
    6 [4]
    Units: Outcome
        Recovered
    6
    Notes
    [4] - There were 6 SAEs during this trial
    No statistical analyses for this end point

    Secondary: Participants maximum response within 8 cycles

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    End point title
    		 Participants maximum response within 8 cycles
    End point description
    Maximum response is defined as the proportion of participants achieving each of the response categories sCR, CR, VGPR, PR, MR or SD as their maximum response within 8 cycles of treatment and overall. Participants who do not achieve any of the above as their maximum response will be classed as ‘progressive disease’. Response to treatment is assessed following the Modified IWG Uniform Response Criteria.
    End point type
    Secondary
    End point timeframe
    Duration of treatment and at 8 cycles or 24 weeks.
    End point values
    		 Overall trial
    Number of subjects analysed
    16
    Units: Response
        CR
    4
        VGPR
    2
        PR
    7
        MR
    3
    No statistical analyses for this end point

    Other pre-specified: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival is defined the time from registration to date of death from any cause. Participants alive at the time of analysis will be censored at the last date known to be alive. At the time of final analysis all participants were alive and no deaths had occurred.
    End point type
    Other pre-specified
    End point timeframe
    Duration of the trial
    End point values
    		 Overall trial
    Number of subjects analysed
    16
    Units: Proportion
        number (not applicable)
    100
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From registration until end of duration of the trial.
    Adverse event reporting additional description
    Occurrences reflect number of patients with maximum grade experienced not number of AEs experienced.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 Non-serious adverse events are reported by initial treatment (16 patients) and by maintenance treatment (11 patients).

    Serious adverse events
    		 Overall Trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 16 (25.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Hypotension
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Overall Trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 16 (100.00%)
    Vascular disorders
    Hypertension (initial)
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Hypotension
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    General disorders and administration site conditions
    Fatigue (initial)
         subjects affected / exposed
    15 / 16 (93.75%)
         occurrences all number
    15
    Fatigue (maintenance)
         subjects affected / exposed [1]
    7 / 11 (63.64%)
         occurrences all number
    7
    Edema limbs (initial)
         subjects affected / exposed
    3 / 16 (18.75%)
         occurrences all number
    3
    Fever (initial)
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Pain (initial)
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Fever (maintenance)
         subjects affected / exposed [2]
    1 / 11 (9.09%)
         occurrences all number
    1
    Pain (maintenance)
         subjects affected / exposed [3]
    1 / 11 (9.09%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough (initial)
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Dyspnea (initial)
         subjects affected / exposed
    3 / 16 (18.75%)
         occurrences all number
    3
    Epistaxis (initial)
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Hiccups (initial)
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Sore throat (initial)
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Psychiatric disorders
    Agitation (initial)
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Anxiety (initial)
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Depression (initial)
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Insomnia (initial)
         subjects affected / exposed
    3 / 16 (18.75%)
         occurrences all number
    3
    Investigations
    Alanine aminotransferase increased (initial)
         subjects affected / exposed
    5 / 16 (31.25%)
         occurrences all number
    5
    Alkaline phosphatase increased (initial)
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Creatinine increased (initial)
         subjects affected / exposed
    3 / 16 (18.75%)
         occurrences all number
    3
    Lymphocyte count decreased (initial)
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    White blood cell decreased (initial)
         subjects affected / exposed
    4 / 16 (25.00%)
         occurrences all number
    4
    Lymphocyte count decreased (maintenance)
         subjects affected / exposed [4]
    1 / 11 (9.09%)
         occurrences all number
    1
    White blood cell decreased (maintenance)
         subjects affected / exposed [5]
    2 / 11 (18.18%)
         occurrences all number
    2
    Cardiac disorders
    Palpitations (initial)
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Nervous system disorders
    Sensory and Motor Neuropathy (initial)
         subjects affected / exposed
    12 / 16 (75.00%)
         occurrences all number
    12
    Sensory Neuropathy (maintenance)
         subjects affected / exposed [6]
    7 / 11 (63.64%)
         occurrences all number
    7
    Dizziness (initial)
         subjects affected / exposed
    5 / 16 (31.25%)
         occurrences all number
    5
    Dysgeusia (initial)
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Headache (initial)
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Tremor (initial)
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia (initial)
         subjects affected / exposed
    15 / 16 (93.75%)
         occurrences all number
    15
    Neutropenia (initial)
         subjects affected / exposed
    8 / 16 (50.00%)
         occurrences all number
    8
    Thrombocytopenia (initial)
         subjects affected / exposed
    13 / 16 (81.25%)
         occurrences all number
    13
    Anaemia (maintenance)
         subjects affected / exposed [7]
    8 / 11 (72.73%)
         occurrences all number
    8
    Neutropenia (maintenance)
         subjects affected / exposed [8]
    2 / 11 (18.18%)
         occurrences all number
    2
    Thrombocytopenia (maintenance)
         subjects affected / exposed [9]
    5 / 11 (45.45%)
         occurrences all number
    5
    Eye disorders
    Blurred vision (initial)
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Conjuctivitis (initial)
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Gastrointestinal disorders
    Diarrhoea (initial)
         subjects affected / exposed
    9 / 16 (56.25%)
         occurrences all number
    9
    Nausea (initial)
         subjects affected / exposed
    7 / 16 (43.75%)
         occurrences all number
    7
    Vomiting (initial)
         subjects affected / exposed
    3 / 16 (18.75%)
         occurrences all number
    3
    Constipation (initial)
         subjects affected / exposed
    9 / 16 (56.25%)
         occurrences all number
    9
    Diarrhoea (maintenance)
         subjects affected / exposed [10]
    5 / 11 (45.45%)
         occurrences all number
    5
    Nausea (maintenance)
         subjects affected / exposed [11]
    3 / 11 (27.27%)
         occurrences all number
    3
    Vomiting (maintenance)
         subjects affected / exposed [12]
    2 / 11 (18.18%)
         occurrences all number
    2
    Constipation (maintenance)
         subjects affected / exposed [13]
    2 / 11 (18.18%)
         occurrences all number
    2
    Abdominal pain (initial)
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Bloating (initial)
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Alopecia (initial)
         subjects affected / exposed
    3 / 16 (18.75%)
         occurrences all number
    3
    Rash maculo-papular (initial)
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Alopecia (maintenance)
         subjects affected / exposed [14]
    1 / 11 (9.09%)
         occurrences all number
    1
    Dry skin (maintenance)
         subjects affected / exposed [15]
    2 / 11 (18.18%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Myalgia (initial)
         subjects affected / exposed
    4 / 16 (25.00%)
         occurrences all number
    4
    Back pain (maintenance)
         subjects affected / exposed [16]
    1 / 11 (9.09%)
         occurrences all number
    1
    Myalgia (maintenance)
         subjects affected / exposed [17]
    1 / 11 (9.09%)
         occurrences all number
    1
    Infections and infestations
    Sepsis (initial)
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Upper respiratory infection (initial)
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Urinary tract infection (initial)
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Eye infection (maintenance)
         subjects affected / exposed [18]
    1 / 11 (9.09%)
         occurrences all number
    1
    Skin infection (maintenance)
         subjects affected / exposed [19]
    1 / 11 (9.09%)
         occurrences all number
    1
    Upper respiratory infection (maintenance)
         subjects affected / exposed [20]
    2 / 11 (18.18%)
         occurrences all number
    2
    Urinary tract infection (maintenance)
         subjects affected / exposed [21]
    1 / 11 (9.09%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Anorexia (initial)
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Dehydration (initial)
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Hyperglycemia (initial)
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Hypoalbuminemia (initial)
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Hypocalcemia (initial)
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Hypokalemia (initial)
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Hyponatraemia (initial)
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Hypophosphatemia (initial)
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: These are reported for patients receiving maintenance treatment (n=11)
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: These are reported for patients receiving maintenance treatment (n=11)
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: These are reported for patients receiving maintenance treatment (n=11)
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: These are reported for patients receiving maintenance treatment (n=11)
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: These are reported for patients receiving maintenance treatment (n=11)
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: These are reported for patients receiving maintenance treatment (n=11)
    [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: These are reported for patients receiving maintenance treatment (n=11)
    [8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: These are reported for patients receiving maintenance treatment (n=11)
    [9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: These are reported for patients receiving maintenance treatment (n=11)
    [10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: These are reported for patients receiving maintenance treatment (n=11)
    [11] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: These are reported for patients receiving maintenance treatment (n=11)
    [12] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: These are reported for patients receiving maintenance treatment (n=11)
    [13] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: These are reported for patients receiving maintenance treatment (n=11)
    [14] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: These are reported for patients receiving maintenance treatment (n=11)
    [15] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: These are reported for patients receiving maintenance treatment (n=11)
    [16] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: These are reported for patients receiving maintenance treatment (n=11)
    [17] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: These are reported for patients receiving maintenance treatment (n=11)
    [18] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: These are reported for patients receiving maintenance treatment (n=11)
    [19] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: These are reported for patients receiving maintenance treatment (n=11)
    [20] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: These are reported for patients receiving maintenance treatment (n=11)
    [21] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: These are reported for patients receiving maintenance treatment (n=11)

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    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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