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    Clinical Trial Results:
    A Phase 2, Randomized, Double-blind, Placebo-controlled, Multicenter Study of Siltuximab (Anti IL 6 Monoclonal Antibody) in Subjects with High-risk Smoldering Multiple Myeloma

    Summary
    EudraCT number
    2011-001735-22
    Trial protocol
    BE   GB   SE   FR   GR   ES   DE  
    Global end of trial date
    10 Oct 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Sep 2020
    First version publication date
    02 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CNTO328SMM2001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01484275
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    1125 Bear Tavern Road, Titusville, United States, NJ 08560
    Public contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & 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
    10 Oct 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Oct 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to demonstrate that siltuximab delays the progression of high-risk smoldering multiple myeloma (SMM) as measured by the 1 year Progression-Free Survival (PFS) rate.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Safety evaluations included routine clinical laboratory tests (hematology, chemistry, lipid panel, and pregnancy), vital signs, physical examination, weight, infusion related reactions, measurement of antibodies to siltuximab, chest X-ray, and electrocardiogram (ECG) assessment.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Mar 2012
    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
    Australia: 8
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Israel: 10
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    85
    EEA total number of subjects
    48
    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)
    51
    From 65 to 84 years
    34
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Total of 85 subjects were enrolled in this study (Intent to treat population), 43 subjects were randomized to receive siltuximab and 42 subjects were randomized to receive placebo.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects received placebo as a 1-hour IV infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last subject).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received placebo as a 1-hour IV infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last subject).

    Arm title
    Siltuximab
    Arm description
    Subjects received 15 milligram per kilogram (mg/kg) of siltuximab as a 1-hour intravenous (IV) infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last subject).
    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 15 mg/kg of siltuximab as a 1-hour IV infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last subject).

    Number of subjects in period 1
    Placebo Siltuximab
    Started
    42
    43
    Completed
    0
    0
    Not completed
    42
    43
         Death
    4
    3
         Study terminated by sponsor
    32
    28
         Unspecified
    -
    10
         Consent withdrawn by subject
    5
    1
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo as a 1-hour IV infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last subject).

    Reporting group title
    Siltuximab
    Reporting group description
    Subjects received 15 milligram per kilogram (mg/kg) of siltuximab as a 1-hour intravenous (IV) infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last subject).

    Reporting group values
    Placebo Siltuximab Total
    Number of subjects
    42 43 85
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    26 25 51
        From 65 to 84 years
    16 18 34
        85 years and over
    0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    59.5 ± 12.03 63.2 ± 10.95 -
    Title for Gender
    Units: subjects
        Female
    20 17 37
        Male
    22 26 48

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo as a 1-hour IV infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last subject).

    Reporting group title
    Siltuximab
    Reporting group description
    Subjects received 15 milligram per kilogram (mg/kg) of siltuximab as a 1-hour intravenous (IV) infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last subject).

    Primary: One-Year Progression-Free Survival (PFS) Rate

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    End point title
    One-Year Progression-Free Survival (PFS) Rate [1]
    End point description
    One-year PFS rate is defined as percentage (%) of subjects surviving 1 year after randomization without progression to multiple myeloma or death estimated by Kaplan-Meier method and based on International Myeloma Working Group (IMWG) calcium, renal, anemia, and bone lesions (CRAB) criteria. Progressive disease (PD) is defined as presence of an M-component in serum plus clonal plasma cells in bone marrow plus 1 or more of following: Calcium elevation (greater than [>] 11.5 milligram per deciliter [mg/dL] [> 2.88 millimoles per liter {mmol/L}]); Renal insufficiency (creatinine > 2 mg/dL [177 micromoles per liter or more]; Anemia (hemoglobin less than [<] 10 gram per deciliter [g/dL] or 2 g/dL lower than lower limit of normal [LLN] [hemoglobin < 6.5 mmol/L or 1.25 mmol/L lower than LLN]); Bone disease (lytic lesions or osteopenia). ITT population included subjects who were randomly assigned to siltuximab or placebo treatment group based on an integrated voice response system (IVRS).
    End point type
    Primary
    End point timeframe
    Up to 1 Year
    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
    Placebo Siltuximab
    Number of subjects analysed
    42
    43
    Units: Percentage of subjects
        number (confidence interval 95%)
    74.4 (57.3 to 85.5)
    84.5 (68.6 to 92.8)
    No statistical analyses for this end point

    Secondary: Progressive Disease Indicator Rate (PDIR) at 6 Months

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    End point title
    Progressive Disease Indicator Rate (PDIR) at 6 Months
    End point description
    PDIR is defined as percentage of subjects who meet any of following criteria occurring within 6 months of start of treatment. a) CRAB criteria: true progression events, b) Serum M-protein: increase by 25 % compared with baseline at 2 consecutive assessments, c) Magnetic resonance imaging: unequivocal increase in focal bone lesions, d) Immunoparesis: decrease by 25% compared with baseline of 2 other non-affected immunoglobulin (Ig) (IgG, IgM, IgA) at 2 consecutive assessments, e) Hemoglobin: decrease of 1.5 g/dL (with at least 1 read below LLN) at 2 consecutive assessments, with no other identifiable cause. Response evaluable population included subjects who had a diagnosis of high-risk SMM and received at least 1 dose of siltuximab/placebo treatment. In addition, subjects were to have at least 1 post-baseline disease assessment.
    End point type
    Secondary
    End point timeframe
    At 6 Months
    End point values
    Placebo Siltuximab
    Number of subjects analysed
    42
    43
    Units: Percentage of subjects
        number (confidence interval 95%)
    42.9 (27.7 to 59.0)
    30.2 (17.2 to 46.1)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival

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    End point title
    Progression-Free Survival
    End point description
    PFS is defined as the time between randomization and initial documented PD according to the CRAB - International Myeloma Working Group (IMWG) criteria or date of death, whichever occurs first. PD is defined as presence of an M-component in serum plus clonal plasma cells in the bone marrow plus 1 or more of the following: Calcium elevation (> 11.5 mg/dL [> 2.88 mmol/L]); Renal insufficiency (creatinine > 2 mg/dL [177 [micro mol/L or more]); Anemia (<10 g/dL or 2 g/dL) lower than LLN) [hemoglobin < 6.5 mmol/L or 1.25 mmol/L lower than LLN]); Bone disease (lytic lesions or osteopenia). Intent-to-treat (ITT) population included subjects who were randomly assigned to siltuximab or placebo treatment group based on an IVRS. Here, '99999' signifies that median and upper limit of confidence interval (CI) was not estimable due to less number of events.
    End point type
    Secondary
    End point timeframe
    Up to 4.7 Years
    End point values
    Placebo Siltuximab
    Number of subjects analysed
    42
    43
    Units: Day
        median (confidence interval 95%)
    715.0 (490 to 1232)
    99999 (703 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Serum M-protein Response

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    End point title
    Percentage of Subjects with Serum M-protein Response
    End point description
    Serum M-protein response is defined as a decrease of greater than or equal to (>=) 50% in serum M-protein compared with baseline at 2 consecutive assessments. ITT population included subjects who were randomly assigned to siltuximab or placebo treatment group based on an IVRS.
    End point type
    Secondary
    End point timeframe
    Up to 4.7 Years
    End point values
    Placebo Siltuximab
    Number of subjects analysed
    42
    43
    Units: Percentage of Subjects
        number (confidence interval 95%)
    0.0 (0.0 to 8.4)
    2.3 (0.1 to 12.3)
    No statistical analyses for this end point

    Secondary: Time to worsening in European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30) Scale Score

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    End point title
    Time to worsening in European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30) Scale Score
    End point description
    Time to worsening in EORTC-QLQ-C30: Time between randomization and first documentation of a worsening in EORTC-QLQ-C-30, it refers to 10 points decrease from baseline, includes 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, social), 3 symptom scales (fatigue, pain, vomiting), global health, quality of life scale, number of single items assessing symptoms (dyspnea, loss of appetite, insomnia, constipation, diarrhoea). Instrument contains 28 items using Likert scale with 4 response: Not at All, A Little, Quite a Bit, Very Much (scored 1-4). 2 additional items use response options (1-7): 1=Very Poor to 7=Excellent. All scale/ item scores range 0-100. Higher score=higher (better) level of functioning/ higher (worse) level of symptoms. ITT population:subjects assigned to siltuximab/placebo group based on IVRS who had 10 points decrease from baseline in physical function scale.
    End point type
    Secondary
    End point timeframe
    Up to 4.7 Years
    End point values
    Placebo Siltuximab
    Number of subjects analysed
    21
    22
    Units: Days
        median (full range (min-max))
    118.00 (56.0 to 565.0)
    125.50 (56.0 to 1021.0)
    No statistical analyses for this end point

    Secondary: Time to Worsening in the Brief Pain Inventory (BPI) Worst Item Scores

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    End point title
    Time to Worsening in the Brief Pain Inventory (BPI) Worst Item Scores
    End point description
    Time to worsening in BPI worst item is defined as time between randomization and first documentation of a worsening in BPI worst item. It has 2 domains reflecting pain severity and pain interference with domains of functioning and well-being. The selected item refers to “worst” pain patient has experienced over the past 24 hours. This item has been found to be most responsive to interference with key domains of functioning and well-being and may be used as a single item. Responses are provided on an 11-point numeric rating scale ranging from 0 “no pain” to 10 “pain as bad as you can imagine”. Responses are described as mild (1 to 4), moderate (5 to 6) and severe (7 to 10). Worsening in BPI worst item is defined as 2 points increase from baseline. ITT population included subjects who were randomly assigned to siltuximab or placebo treatment group based on an IVRS. Here, '99999' signifies that upper limit of CI was not estimable due to an insufficient number of events.
    End point type
    Secondary
    End point timeframe
    Up to 4.7 Years
    End point values
    Placebo Siltuximab
    Number of subjects analysed
    42
    43
    Units: Days
        median (confidence interval 95%)
    453.0 (277 to 99999)
    652.0 (226 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Subjects with Symptomatic Multiple Myeloma with Adverse Prognostic Features

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    End point title
    Number of Subjects with Symptomatic Multiple Myeloma with Adverse Prognostic Features
    End point description
    Number of subjects who progressed to symptomatic multiple myeloma with stage III of International Staging System (ISS) or abnormal cytogenetic findings were assessed. The ISS system consists of stage I: beta2-microglobulin < 3.5 milligram per liter (mg/L) and albumin >= 3.5 gram (g)/100 ml; stage II: neither stage I nor stage III and stage III: beta2-microglobulin >= 5.5 mg/L.
    End point type
    Secondary
    End point timeframe
    Up to 4.7 Years
    End point values
    Placebo Siltuximab
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: Subjects
    Notes
    [2] - Data was not collected and analyzed for this endpoint as per the change in planned analysis.
    [3] - Data was not collected and analyzed for this endpoint as per the change in planned analysis.
    No statistical analyses for this end point

    Secondary: Number of Subjects with Best Response to First Subsequent Multiple Myeloma Treatment

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    End point title
    Number of Subjects with Best Response to First Subsequent Multiple Myeloma Treatment
    End point description
    Best response to first subsequent anti-myeloma therapy was assessed by physician report at 6-month intervals and classified as: complete response (CR) (negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas and < 5% plasms cells (PCs) in bone marrow); stringent CR (CR + a normal FLC ratio, absence of clonal cells in bone marrow); near CR (< 5% PCs in a bone marrow aspirate, no increase in lytic bone lesions); very good partial response (VGPR) (serum and urine component detectable by immunofixation but not on electrophoresis, or >= 90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 hour); partial response (PR): >= 50 reduction of serum M-protein, reduction in 24-hour urinary M-protein by >=90 % or to < 200 mg/24 hours); minimal response (>=25% but <= 49% reduction of serum M-protein and reduction in urine M-protein by 50%-89%); stable disease (not meeting criteria for CR, VGPR, PR, or PD); PD; not evaluable and unknown.
    End point type
    Secondary
    End point timeframe
    Up to 4.7 Years
    End point values
    Placebo Siltuximab
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: Subjects
    Notes
    [4] - Data was not collected and analyzed for this endpoint as per the change in planned analysis.
    [5] - Data was not collected and analyzed for this endpoint as per the change in planned analysis.
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS is defined as the time between randomization and death due to any cause. ITT population included subjects who were randomly assigned to siltuximab or placebo treatment group based on an IVRS. Here, '99999' signifies that median and confidence interval was not estimable due to less number of events.
    End point type
    Secondary
    End point timeframe
    Up to 4.7 Years
    End point values
    Placebo Siltuximab
    Number of subjects analysed
    42
    43
    Units: Days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 4.7 Years
    Adverse event reporting additional description
    Safety analysis set included subjects who have received at least 1 administration of any study agent (siltuximab or placebo).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo as a 1-hour IV infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last subject).

    Reporting group title
    Siltuximab
    Reporting group description
    Subjects received 15 milligram per kilogram (mg/kg) of siltuximab as a 1-hour intravenous (IV) infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last subject).

    Serious adverse events
    Placebo Siltuximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 42 (30.95%)
    13 / 43 (30.23%)
         number of deaths (all causes)
    4
    3
         number of deaths resulting from adverse events
    Vascular disorders
    Ischaemia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Poor Venous Access
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon Cancer
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Back Injury
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint Dislocation
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Limb Fracture
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib Fracture
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Fracture
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Nasal Septum Deviation
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Facial Paresis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Eustachian Tube Disorder
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric Disorder
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis Acute
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Impairment
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastoiditis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis Media
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia Streptococcal
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Siltuximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 42 (100.00%)
    41 / 43 (95.35%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 42 (9.52%)
    1 / 43 (2.33%)
         occurrences all number
    4
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 42 (7.14%)
    8 / 43 (18.60%)
         occurrences all number
    7
    10
    Chest Pain
         subjects affected / exposed
    5 / 42 (11.90%)
    1 / 43 (2.33%)
         occurrences all number
    7
    1
    Fatigue
         subjects affected / exposed
    14 / 42 (33.33%)
    6 / 43 (13.95%)
         occurrences all number
    23
    9
    Influenza Like Illness
         subjects affected / exposed
    5 / 42 (11.90%)
    1 / 43 (2.33%)
         occurrences all number
    6
    1
    Oedema Peripheral
         subjects affected / exposed
    3 / 42 (7.14%)
    3 / 43 (6.98%)
         occurrences all number
    4
    3
    Pyrexia
         subjects affected / exposed
    6 / 42 (14.29%)
    3 / 43 (6.98%)
         occurrences all number
    8
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 42 (9.52%)
    0 / 43 (0.00%)
         occurrences all number
    4
    0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 42 (0.00%)
    4 / 43 (9.30%)
         occurrences all number
    0
    7
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    1 / 42 (2.38%)
    3 / 43 (6.98%)
         occurrences all number
    1
    3
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    4 / 42 (9.52%)
    1 / 43 (2.33%)
         occurrences all number
    4
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 42 (14.29%)
    6 / 43 (13.95%)
         occurrences all number
    6
    10
    Neutropenia
         subjects affected / exposed
    1 / 42 (2.38%)
    8 / 43 (18.60%)
         occurrences all number
    2
    42
    Thrombocytopenia
         subjects affected / exposed
    0 / 42 (0.00%)
    5 / 43 (11.63%)
         occurrences all number
    0
    5
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 42 (7.14%)
    3 / 43 (6.98%)
         occurrences all number
    6
    3
    Cough
         subjects affected / exposed
    8 / 42 (19.05%)
    8 / 43 (18.60%)
         occurrences all number
    17
    8
    Epistaxis
         subjects affected / exposed
    5 / 42 (11.90%)
    0 / 43 (0.00%)
         occurrences all number
    7
    0
    Oropharyngeal Pain
         subjects affected / exposed
    10 / 42 (23.81%)
    2 / 43 (4.65%)
         occurrences all number
    14
    2
    Rhinorrhoea
         subjects affected / exposed
    4 / 42 (9.52%)
    0 / 43 (0.00%)
         occurrences all number
    4
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 42 (14.29%)
    3 / 43 (6.98%)
         occurrences all number
    7
    3
    Headache
         subjects affected / exposed
    9 / 42 (21.43%)
    6 / 43 (13.95%)
         occurrences all number
    14
    12
    Sciatica
         subjects affected / exposed
    2 / 42 (4.76%)
    4 / 43 (9.30%)
         occurrences all number
    2
    4
    Syncope
         subjects affected / exposed
    1 / 42 (2.38%)
    3 / 43 (6.98%)
         occurrences all number
    1
    3
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    4 / 42 (9.52%)
    0 / 43 (0.00%)
         occurrences all number
    4
    0
    Abdominal Pain
         subjects affected / exposed
    6 / 42 (14.29%)
    3 / 43 (6.98%)
         occurrences all number
    9
    4
    Abdominal Pain Lower
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 43 (2.33%)
         occurrences all number
    3
    1
    Abdominal Pain Upper
         subjects affected / exposed
    4 / 42 (9.52%)
    2 / 43 (4.65%)
         occurrences all number
    4
    3
    Constipation
         subjects affected / exposed
    7 / 42 (16.67%)
    5 / 43 (11.63%)
         occurrences all number
    12
    7
    Diarrhoea
         subjects affected / exposed
    7 / 42 (16.67%)
    6 / 43 (13.95%)
         occurrences all number
    7
    7
    Stomatitis
         subjects affected / exposed
    3 / 42 (7.14%)
    2 / 43 (4.65%)
         occurrences all number
    3
    4
    Nausea
         subjects affected / exposed
    10 / 42 (23.81%)
    9 / 43 (20.93%)
         occurrences all number
    17
    15
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 42 (0.00%)
    6 / 43 (13.95%)
         occurrences all number
    0
    6
    Night Sweats
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 43 (0.00%)
         occurrences all number
    3
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 42 (26.19%)
    5 / 43 (11.63%)
         occurrences all number
    15
    7
    Back Pain
         subjects affected / exposed
    12 / 42 (28.57%)
    10 / 43 (23.26%)
         occurrences all number
    18
    10
    Muscle Spasms
         subjects affected / exposed
    5 / 42 (11.90%)
    0 / 43 (0.00%)
         occurrences all number
    11
    0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    9 / 42 (21.43%)
    5 / 43 (11.63%)
         occurrences all number
    9
    6
    Myalgia
         subjects affected / exposed
    3 / 42 (7.14%)
    2 / 43 (4.65%)
         occurrences all number
    4
    2
    Pain in Extremity
         subjects affected / exposed
    8 / 42 (19.05%)
    5 / 43 (11.63%)
         occurrences all number
    13
    7
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 42 (0.00%)
    4 / 43 (9.30%)
         occurrences all number
    0
    6
    Decreased Appetite
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 42 (7.14%)
    3 / 43 (6.98%)
         occurrences all number
    6
    4
    Herpes Zoster
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 43 (2.33%)
         occurrences all number
    4
    2
    Gastroenteritis
         subjects affected / exposed
    1 / 42 (2.38%)
    3 / 43 (6.98%)
         occurrences all number
    1
    3
    Nasopharyngitis
         subjects affected / exposed
    15 / 42 (35.71%)
    9 / 43 (20.93%)
         occurrences all number
    31
    20
    Oral Herpes
         subjects affected / exposed
    4 / 42 (9.52%)
    0 / 43 (0.00%)
         occurrences all number
    5
    0
    Pneumonia
         subjects affected / exposed
    1 / 42 (2.38%)
    3 / 43 (6.98%)
         occurrences all number
    1
    3
    Rhinitis
         subjects affected / exposed
    4 / 42 (9.52%)
    1 / 43 (2.33%)
         occurrences all number
    7
    1
    Sinusitis
         subjects affected / exposed
    3 / 42 (7.14%)
    3 / 43 (6.98%)
         occurrences all number
    5
    3
    Upper Respiratory Tract Infection
         subjects affected / exposed
    10 / 42 (23.81%)
    5 / 43 (11.63%)
         occurrences all number
    17
    11
    Urinary Tract Infection
         subjects affected / exposed
    3 / 42 (7.14%)
    3 / 43 (6.98%)
         occurrences all number
    7
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Feb 2012
    The overall reason for the amendment was to add a patient-reported outcome questionnaire (Non-Chemotherapy Anemia Symptom Scale [NCA-SS]), and to provide clarification on sections of the protocol, as specified below. In addition, an update to the company sponsorship information was required.
    25 Oct 2012
    The overall reason for the amendment was to broaden the high-risk SMM patient population by revising the inclusion criterion and the related stratification risk factor definition.
    15 May 2013
    The overall reason for the amendment was the duration of the study was substantially longer than planned because of slow recruitment. In order to evaluate if the study can achieve its objectives and to prevent subjects from being exposed to a potentially ineffective treatment, a formal futility analysis was incorporated.
    13 Jan 2014
    The overall reason for the amendment was after review of data from the futility analysis added per Amendment INT 3, the Steering Committee has recommended to continue the study and implement an additional interim futility analysis with progression event rate as an endpoint.
    13 Feb 2015
    The overall reason for the amendment was the accrual into the study was almost stopped due to a combination of changed clinical guidelines with respect to treatment of high-risk smoldering multiple myeloma (SMM) patients as well as the increased number of clinical studies within the indication. Given the longer recruitment time and thus total longer cumulative follow up time, timing of primary analysis has been moved forward, thereby making the interim analysis at 6 months redundant.
    09 May 2016
    The overall reason for the amendment was to ensure that ongoing subjects benefitted from siltuximab treatment can continue to receive siltuximab in an Open-Label Extension of the study.

    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.
    Siltuximab demonstrated positive trending toward 1-year PFS only in high risk SMM-group. Sponsor and Steering Committee decided not to further pursue clinical development of siltuximab for SMM and terminated study, and was considered as completed.
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