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    Clinical Trial Results:
    An Open-label, Multicenter Study to Evaluate the Safety of Long-term Treatment with Siltuximab in Subjects with Multicentric Castleman’s Disease

    Summary
    EudraCT number
    2010-022837-27
    Trial protocol
    BE   GB   DE   ES  
    Global end of trial date
    02 Mar 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    17 Mar 2018
    First version publication date
    17 Mar 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CR018469
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01400503
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen Research and Development, LLC
    Sponsor organisation address
    Archimedesweg 29, Leiden, Netherlands, 2333CM
    Public contact
    Clinical Registry Group,, Janssen Research and Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group,, Janssen Research and Development, LLC, ClinicalTrialsEU@its.jnj.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
    02 Mar 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to evaluate the long-term safety of siltuximab in subjects with Multicentric Castleman’s Disease Symptom (MCD).
    Protection of trial subjects
    The safety assessments included severity of adverse events (AEs) reported throughout the study, with a focus on infections, hyperlipidemia, neutropenia, thrombocytopenia, gastrointestinal (GI) perforations, infusion-related reactions, liver enzyme abnormalities, and immunogenicity changes; clinical laboratory test values (hematology, biochemistry, and coagulation parameters); vital sign measurements; 12-lead ECG; and physical examination (including weight and height).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Apr 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 1
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    China: 6
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Egypt: 1
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Hong Kong: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 4
    Country: Number of subjects enrolled
    Norway: 2
    Country: Number of subjects enrolled
    New Zealand: 2
    Country: Number of subjects enrolled
    Singapore: 3
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    United States: 27
    Worldwide total number of subjects
    60
    EEA total number of subjects
    11
    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)
    55
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subjects enrolled in this study CNTO328MCD2002 included subjects who were previously enrolled in study C0328T03 (NCT00412321) or CNTO328MCD2001 (NCT01024036) (either placebo or siltuximab treatment arm). A total of 60 subjects from previous MCD studies C0328T03 and CNTO328MCD2001 were found eligible to be enrolled in this study.

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

    Arms
    Arm title
    Siltuximab
    Arm description
    Subjects received siltuximab 11 milligram per kilogram (mg/kg) as a 1-hour intravenous infusion every 3 weeks until disease progression, withdrew, experienced unacceptable toxicity,or until the 6-year data cutoff, whichever occurred first.
    Arm type
    Experimental

    Investigational medicinal product name
    Siltuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received siltuximab 11 milligram per kilogram (mg/kg) as a 1-hour intravenous infusion every 3 weeks until disease progression, withdrew, experienced unacceptable toxicity,or until the 6-year data cutoff, whichever occurred first.

    Number of subjects in period 1
    Siltuximab
    Started
    60
    Completed
    0
    Not completed
    60
         Study terminated by sponsor
    58
         Unspecified
    1
         Consent withdrawn by subject
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Siltuximab
    Reporting group description
    Subjects received siltuximab 11 milligram per kilogram (mg/kg) as a 1-hour intravenous infusion every 3 weeks until disease progression, withdrew, experienced unacceptable toxicity,or until the 6-year data cutoff, whichever occurred first.

    Reporting group values
    Siltuximab Total
    Number of subjects
    60 60
    Title for AgeCategorical
    Units: subjects
        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)
    55 55
        From 65 to 84 years
    5 5
        85 years and over
    0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    45.1 ± 14.51 -
    Title for Gender
    Units: subjects
        Female
    20 20
        Male
    40 40
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    1 1
        Asian
    23 23
        Native Hawaiian or Other Pacific Islander
    2 2
        Black or African American
    3 3
        White
    31 31
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    5 5
        Not Hispanic or Latino
    55 55
        Unknown or Not Reported
    0 0
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    23 23
        Black or African American
    3 3
        Hispanic or Latino
    5 5
        Other
    3 3
        White Non-Hispanic
    26 26

    End points

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    End points reporting groups
    Reporting group title
    Siltuximab
    Reporting group description
    Subjects received siltuximab 11 milligram per kilogram (mg/kg) as a 1-hour intravenous infusion every 3 weeks until disease progression, withdrew, experienced unacceptable toxicity,or until the 6-year data cutoff, whichever occurred first.

    Primary: Number of Subjects with Adverse Events (AEs)

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    End point title
    Number of Subjects with Adverse Events (AEs) [1]
    End point description
    An adverse event (AE) is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Safety analysis set included all enrolled subjects in this study.
    End point type
    Primary
    End point timeframe
    Up to 6 years
    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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Siltuximab
    Number of subjects analysed
    60
    Units: Subjects
    60
    No statistical analyses for this end point

    Secondary: Percentage of Previously Responding Subjects who Maintained Disease Control

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    End point title
    Percentage of Previously Responding Subjects who Maintained Disease Control
    End point description
    Percentage of subjects maintaining disease control (defined as stable or better response) was defined as the percentage of previously responding subjects who had not progressed during the long-term safety extension based on investigator assessment. A worsening in any of the measures will be considered as a progression of the disease.Population included subset of safety analysis set who previously responded to siltuximab treatment ie, did not report disease progression while receiving siltuximab in study C0328T03 or CNTO328MCD2001.
    End point type
    Secondary
    End point timeframe
    Up to 6 years
    End point values
    Siltuximab
    Number of subjects analysed
    57
    Units: percentage of subjects
        number (not applicable)
    96.5
    No statistical analyses for this end point

    Secondary: Percentage of Siltuximab-naive Subjects who Experienced Disease Control

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    End point title
    Percentage of Siltuximab-naive Subjects who Experienced Disease Control
    End point description
    Percentage of subjects experiencing disease control was defined as the percentage of siltuximab-naïve subjects who had stable or better response during the long-term safety extension based on investigator’s judgment. Disease control was defined as stable or better response assessed by the investigators. Population included subset of safety analysis set who were previously Siltuximab-naive i.e., received placebo in study CNTO328MCD2001 and never received siltuximab prior to enrollment in this study.
    End point type
    Secondary
    End point timeframe
    Up to 6 years
    End point values
    Siltuximab
    Number of subjects analysed
    3
    Units: percentage of subjects
        number (not applicable)
    100
    No statistical analyses for this end point

    Secondary: Duration of Disease Control

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    End point title
    Duration of Disease Control
    End point description
    Duration of disease control (DODC) was defined as the time from the first siltuximab administration in this study to disease progression as assessed by the investigator. Disease control was defined as stable or better response assessed by the investigators. Kaplan-Meier method was used to estimate the duration of disease control. '99999' indicates median and CI were not estimable due to insufficient number of subjects with loss of response or disease control (due to high censorship rate). Safety analysis set included all enrolled subjects in this study.
    End point type
    Secondary
    End point timeframe
    Up to 6 years
    End point values
    Siltuximab
    Number of subjects analysed
    60
    Units: years
        median (confidence interval 95%)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    Overall survival was defined as the time between the first study siltuximab administration and death due to any cause. Kaplan-Meier method was used to estimate the overall survival. '99999' indicates median and CI were not estimable due to insufficient number of subjects with death. Safety analysis set included all enrolled subjects in this study.
    End point type
    Secondary
    End point timeframe
    Up to 6 years
    End point values
    Siltuximab
    Number of subjects analysed
    60
    Units: years
        median (confidence interval 95%)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Subjects Positive for Antibodies to Siltuximab

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    End point title
    Number of Subjects Positive for Antibodies to Siltuximab
    End point description
    Serum samples were screened for antibodies binding to siltuximab and number of subjects positive for antibodies to siltuximab was reported.Safety analysis set included all enrolled subjects in this study.
    End point type
    Secondary
    End point timeframe
    Up to 6 years
    End point values
    Siltuximab
    Number of subjects analysed
    60
    Units: Subjects
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 6 years
    Adverse event reporting additional description
    An AE is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Safety analysis set included all enrolled subjects in this study.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Siltuximab
    Reporting group description
    Subjects received siltuximab 11 milligram per kilogram (mg/kg) as a 1-hour intravenous infusion every 3 weeks until disease progression, withdrew, experienced unacceptable toxicity,or until the 6-year data cutoff, whichever occurred first.

    Serious adverse events
    Siltuximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 60 (41.67%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Surgical and medical procedures
    Mastectomy
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign Neoplasm of Testis
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Uterine Leiomyoma
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Haemorrhagic Ovarian Cyst
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Uterine Haemorrhage
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Ankle Fracture
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Avulsion Fracture
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest Injury
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Fractured Sacrum
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ilium Fracture
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pubis Fracture
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rib Fracture
         subjects affected / exposed
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Tibia Fracture
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Polycythaemia
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebrospinal Fluid Leakage
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Micturition Disorder
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary Retention
         subjects affected / exposed
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Henoch-Schonlein Purpura
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal Column Stenosis
         subjects affected / exposed
    1 / 60 (1.67%)
         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 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Siltuximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    58 / 60 (96.67%)
    Vascular disorders
    Hot Flush
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    3
    Hypertension
         subjects affected / exposed
    7 / 60 (11.67%)
         occurrences all number
    7
    Immune system disorders
    Seasonal Allergy
         subjects affected / exposed
    4 / 60 (6.67%)
         occurrences all number
    7
    General disorders and administration site conditions
    Chest Pain
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    3
    Fatigue
         subjects affected / exposed
    18 / 60 (30.00%)
         occurrences all number
    22
    Oedema Peripheral
         subjects affected / exposed
    4 / 60 (6.67%)
         occurrences all number
    5
    Pyrexia
         subjects affected / exposed
    4 / 60 (6.67%)
         occurrences all number
    5
    Psychiatric disorders
    Depression
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    3
    Insomnia
         subjects affected / exposed
    5 / 60 (8.33%)
         occurrences all number
    7
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    4 / 60 (6.67%)
         occurrences all number
    5
    Skin Abrasion
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    3
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    4 / 60 (6.67%)
         occurrences all number
    8
    Blood Creatinine Increased
         subjects affected / exposed
    4 / 60 (6.67%)
         occurrences all number
    13
    Blood Fibrinogen Decreased
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    3
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    4 / 60 (6.67%)
         occurrences all number
    7
    Haemoglobin Increased
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    16
    Weight Increased
         subjects affected / exposed
    5 / 60 (8.33%)
         occurrences all number
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 60 (20.00%)
         occurrences all number
    13
    Epistaxis
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    3
    Dyspnoea
         subjects affected / exposed
    7 / 60 (11.67%)
         occurrences all number
    11
    Oropharyngeal Pain
         subjects affected / exposed
    7 / 60 (11.67%)
         occurrences all number
    9
    Nasal Congestion
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    4
    Productive Cough
         subjects affected / exposed
    5 / 60 (8.33%)
         occurrences all number
    6
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    5
    Neutropenia
         subjects affected / exposed
    4 / 60 (6.67%)
         occurrences all number
    36
    Nervous system disorders
    Neuropathy Peripheral
         subjects affected / exposed
    4 / 60 (6.67%)
         occurrences all number
    5
    Dizziness
         subjects affected / exposed
    5 / 60 (8.33%)
         occurrences all number
    7
    Headache
         subjects affected / exposed
    7 / 60 (11.67%)
         occurrences all number
    8
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    5 / 60 (8.33%)
         occurrences all number
    9
    Paraesthesia
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    4
    Eye disorders
    Cataract
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    5
    Vision Blurred
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    3
    Ear and labyrinth disorders
    Ear Pain
         subjects affected / exposed
    5 / 60 (8.33%)
         occurrences all number
    6
    Vertigo
         subjects affected / exposed
    5 / 60 (8.33%)
         occurrences all number
    7
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    7 / 60 (11.67%)
         occurrences all number
    10
    Abdominal Pain
         subjects affected / exposed
    8 / 60 (13.33%)
         occurrences all number
    10
    Aphthous Ulcer
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    18
    Constipation
         subjects affected / exposed
    11 / 60 (18.33%)
         occurrences all number
    17
    Diarrhoea
         subjects affected / exposed
    16 / 60 (26.67%)
         occurrences all number
    31
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    4 / 60 (6.67%)
         occurrences all number
    4
    Dyspepsia
         subjects affected / exposed
    4 / 60 (6.67%)
         occurrences all number
    4
    Nausea
         subjects affected / exposed
    11 / 60 (18.33%)
         occurrences all number
    17
    Vomiting
         subjects affected / exposed
    6 / 60 (10.00%)
         occurrences all number
    10
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    5 / 60 (8.33%)
         occurrences all number
    5
    Skin and subcutaneous tissue disorders
    Dry Skin
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    4
    Eczema
         subjects affected / exposed
    5 / 60 (8.33%)
         occurrences all number
    7
    Hyperhidrosis
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    4
    Night Sweats
         subjects affected / exposed
    6 / 60 (10.00%)
         occurrences all number
    7
    Rash Maculo-Papular
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    3
    Rash
         subjects affected / exposed
    13 / 60 (21.67%)
         occurrences all number
    25
    Pruritus
         subjects affected / exposed
    7 / 60 (11.67%)
         occurrences all number
    10
    Urticaria
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 60 (25.00%)
         occurrences all number
    36
    Back Pain
         subjects affected / exposed
    14 / 60 (23.33%)
         occurrences all number
    21
    Muscle Spasms
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    3
    Musculoskeletal Pain
         subjects affected / exposed
    6 / 60 (10.00%)
         occurrences all number
    9
    Neck Pain
         subjects affected / exposed
    4 / 60 (6.67%)
         occurrences all number
    7
    Pain in Extremity
         subjects affected / exposed
    10 / 60 (16.67%)
         occurrences all number
    18
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    10 / 60 (16.67%)
         occurrences all number
    13
    Hypercholesterolaemia
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    3
    Gout
         subjects affected / exposed
    4 / 60 (6.67%)
         occurrences all number
    5
    Hypertriglyceridaemia
         subjects affected / exposed
    5 / 60 (8.33%)
         occurrences all number
    8
    Infections and infestations
    Cystitis
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    4
    Ear Infection
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    5
    Gastroenteritis
         subjects affected / exposed
    5 / 60 (8.33%)
         occurrences all number
    6
    Herpes Zoster
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    3
    Nasopharyngitis
         subjects affected / exposed
    4 / 60 (6.67%)
         occurrences all number
    4
    Influenza
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    3
    Otitis Media
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    3
    Respiratory Tract Infection
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    3
    Pneumonia
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    5
    Rhinitis
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    3
    Sinusitis
         subjects affected / exposed
    5 / 60 (8.33%)
         occurrences all number
    10
    Upper Respiratory Tract Infection
         subjects affected / exposed
    26 / 60 (43.33%)
         occurrences all number
    94
    Urinary Tract Infection
         subjects affected / exposed
    3 / 60 (5.00%)
         occurrences all number
    3

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jan 2012
    The overall reason for the amendment was to update the secondary objective for biomarkers, implement the legal entity name change, and make small corrections and clarifications.
    14 Jun 2012
    The overall reason for the amendment was to add a data cutoff for an interim analysis, to add survival follow-up for those who discontinued treatment, to remove an exclusion criterion for those on intervening treatment for Castleman’s disease, and to adapt the Time and Events schedule for the 6-week dosing interval.
    17 Nov 2012
    The overall reason for the amendment was to add additional safety evaluations for those subjects entering the study who are naïve to treatment with siltuximab.
    04 Apr 2014
    The overall reason for the amendment was to extend the duration of this study to fulfill postmarketing commitments to report safety, efficacy, and survival during long-term treatment with siltuximab, and to stop collecting data that are not required for the final study report.

    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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