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    Clinical Trial Results:
    An open-label, long-term safety and efficacy study of ACZ885 (anti-interleukin-1β; monoclonal antibody) administered for at least 6 months in patients with the following cryopyrin-associated periodic syndromes: Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome, or Muckle-Wells Syndrome with overlapping symptoms of Neonatal Onset Multisystem Inflammatory Disease

    Summary
    EudraCT number
    2007-004367-22
    Trial protocol
    GB   DE   FR   ES   IT   BE   Outside EU/EEA  
    Global end of trial date
    29 Apr 2010

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    12 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CACZ885D2306
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00685373
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000060-PIP01-07
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Apr 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Apr 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of study was to assess the long-term safety and tolerability of canakinumab in subjects with the following cryopyrin associated periodic syndromes (CAPS): Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS) or MWS with overlapping symptoms of Neonatal Onset Multisystem Inflammatory Disease (NOMID).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed. Canakinumab dose was adjusted done during the course of the study as rescue medication. A rescue dose of 300 milligram (mg) subcutaneous (s.c.) (or 4 mg/kilogram (mg/kg) for subjects with a body weight less than or equal to (≤) 40 kg) by Day 8. Non responders by Day 15 were treated again with same dose as rescue medication and continued with maintenance dose of 600 mg s.c. (or 8 mg/kg for subjects ≤ 40 kg) every 8 weeks.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    19 May 2008
    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
    Spain: 5
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    United States: 32
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    France: 42
    Country: Number of subjects enrolled
    Germany: 46
    Country: Number of subjects enrolled
    India: 4
    Country: Number of subjects enrolled
    Italy: 14
    Worldwide total number of subjects
    166
    EEA total number of subjects
    125
    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)
    26
    Adolescents (12-17 years)
    21
    Adults (18-64 years)
    111
    From 65 to 84 years
    7
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 32 centres in 8 countries.

    Pre-assignment
    Screening details
    A total of 166 subjects were enrolled into the study.

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

    Arms
    Arm title
    Canakinumab
    Arm description
    Subjects received body-weight stratified dosage of canakinumab (2 mg/kg for subjects ≤ 40 kg or 150 mg for subjects more than (>) 40 kg) s.c. injection every 8 weeks. The dose was escalated to 4 mg/kg or 300 mg respectively at Day 8 if dose of canakinumab was not sufficient to achieve complete response by Day 15, as per investigator's discretion.
    Arm type
    Experimental

    Investigational medicinal product name
    Canakinumab
    Investigational medicinal product code
    ACZ885
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Canakinumab s.c. injection (2 mg/kg or 150 mg) was administered every 8 weeks.

    Number of subjects in period 1
    Canakinumab
    Started
    166
    Completed
    151
    Not completed
    15
         Consent withdrawn by subject
    5
         Adverse event, non-fatal
    3
         Subject’s condition no longer requires study drug
    1
         Lost to follow-up
    2
         'Unsatisfactory therapeutic effect '
    3
         Protocol deviation
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Canakinumab
    Reporting group description
    Subjects received body-weight stratified dosage of canakinumab (2 mg/kg for subjects ≤ 40 kg or 150 mg for subjects more than (>) 40 kg) s.c. injection every 8 weeks. The dose was escalated to 4 mg/kg or 300 mg respectively at Day 8 if dose of canakinumab was not sufficient to achieve complete response by Day 15, as per investigator's discretion.

    Reporting group values
    Canakinumab Total
    Number of subjects
    166 166
    Age categorical
    Units: Subjects
        Children (2-11 years)
    26 26
        Adolescents (12-17 years)
    21 21
        Adults (18-64 years)
    111 111
        From 65-84 years
    7 7
        85 years and over
    1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    30.9 ± 18.43 -
    Gender categorical
    Units: Subjects
        Female
    97 97
        Male
    69 69

    End points

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    End points reporting groups
    Reporting group title
    Canakinumab
    Reporting group description
    Subjects received body-weight stratified dosage of canakinumab (2 mg/kg for subjects ≤ 40 kg or 150 mg for subjects more than (>) 40 kg) s.c. injection every 8 weeks. The dose was escalated to 4 mg/kg or 300 mg respectively at Day 8 if dose of canakinumab was not sufficient to achieve complete response by Day 15, as per investigator's discretion.

    Primary: Number of subjects with adverse events (AEs) and serious adverse events (SAEs), discontinuation of study drug due to an AE, infections and infestations and injection site reactions

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    End point title
    Number of subjects with adverse events (AEs) and serious adverse events (SAEs), discontinuation of study drug due to an AE, infections and infestations and injection site reactions [1]
    End point description
    Adverse events (AEs) were defined as any unfavorable and unintended diagnosis, symptom, sign, syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events (SAEs) were defined as any untoward medical occurrences that result in death, are life threatening, require hospitalisation, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards. Discontinuation was defined as subjects with adverse events that lead to discontinuation of study drug. All infection relevant events were considered as infection by discretion of investigator. Injection site reaction involved pain, redness, swelling, induration, hemorrhage and itching. The analysis was performed in the safety set population defined as defined as subjects who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Day 1 up to Day 729
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive summary statistics was planned for this outcome measure.
    End point values
    Canakinumab
    Number of subjects analysed
    166
    Units: Number of subjects
        Adverse events
    150
        Serious adverse events
    18
        Discontinuation of study drug due to an AE
    4
        Infections and Infestations
    109
        Any Injection Site Reactions
    13
        Mild Injection Site Reactions
    11
        Moderate Injection Site Reactions
    2
    No statistical analyses for this end point

    Secondary: Percentage of subjects without disease relapse

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    End point title
    Percentage of subjects without disease relapse
    End point description
    Relapse was defined as a Physician’s Global Assessment of autoinflammatory disease activity score more minimal and either C reactive protein (CRP) and either Serum amyloid A (SAA) equal to or more than 30 mg/L, or Physician’s Global Assessment of autoinflammatory disease activity as score more than or equal to minimal and Physician’s global assessment of skin disease score as minimal Physician’s global assessment. Subjects were assessed based on Physician’s Global Assessment on 5-point scale for autoinflammatory disease activity as: 0 = None/absent; 1 = Minimal; 2 = Mild; 3 = Moderate; 4 = Severe.The analysis was performed in the safety set population.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 729
    End point values
    Canakinumab
    Number of subjects analysed
    141
    Units: Percentage of subjects
        number (not applicable)
    90.1
    No statistical analyses for this end point

    Secondary: Number of subjects who required canakinumab additional dose or dose frequency adjustment as assessed by investigator

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    End point title
    Number of subjects who required canakinumab additional dose or dose frequency adjustment as assessed by investigator
    End point description
    The number of subjects who required a dose adjustment of canakinumab or an administration frequency adjustment were defined as subjects who were not complete responders on Day 15 and treated with adjusted dose (canakinumab 300 mg or 4 mg/kg for subjects with less than 40 kg weight), continued with subsequent adjusted dose (canakinumab 600 mg or 8 mg/kg for subjects with less than 40 kg weight). Maintenance of response over time was determined by the Physician’s global assessment of autoinflammatory disease activity, assessment of skin disease and CRP and/or SAA. The analysis was performed in the safety set population.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 729
    End point values
    Canakinumab
    Number of subjects analysed
    166
    Units: Number of subjects
        Subjects with dose or dose frequency adjustments
    40
        Subjects with dose adjustments
    36
        Subjects with frequency adjustments
    19
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-canakinumab antibodies

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    End point title
    Number of subjects with anti-canakinumab antibodies
    End point description
    Immunogenicity assessment included determination of anti-canakinumab (ACZ885) antibodies in serum samples using Biacore system. The analysis was performed in the safety set population.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 729
    End point values
    Canakinumab
    Number of subjects analysed
    156
    Units: Number of subjects
    0
    No statistical analyses for this end point

    Secondary: Clearance from serum of canakinumab

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    End point title
    Clearance from serum of canakinumab
    End point description
    Clearance (CL) was defined as the total body clearance of canakinumab following an extravascular dose from the serum when the systemic bioavailability was unknown.The analysis was performed in the safety set population. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 8, Day 29, Day 57, Day 113, Day 169, Day 225, Day 281, Day 337, Day 393, Day 449, Day 505, Day 561, Day 617, Day 673 and Day 729
    End point values
    Canakinumab
    Number of subjects analysed
    163
    Units: Litre(s)/day
    arithmetic mean (standard deviation)
        Adult subjects >= 18 years (n=116)
    0.179 ± 0.084
        Pediatric subjects <18 years and >40 kg (n=18)
    0.18 ± 0.145
        Pediatric subjects <18 years and <= 40 kg (n=29)
    0.083 ± 0.033
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Canakinumab
    Reporting group description
    Subjects received body-weight stratified dosage of canakinumab (2 mg/kg for subjects ≤ 40 kg or 150 mg for subjects more than (>) 40 kg) s.c. injection every 8 weeks. The dose was escalated to 4 mg/kg or 300 mg respectively at Day 8 if dose of canakinumab was not sufficient to achieve complete response by Day 15, as per investigator's discretion.

    Serious adverse events
    Canakinumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 166 (10.84%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Hepatitis C antibody positive
         subjects affected / exposed
    1 / 166 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 166 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Drug exposure during pregnancy
         subjects affected / exposed
    1 / 166 (0.60%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Forearm fracture
         subjects affected / exposed
    1 / 166 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Muckle-Wells syndrome
         subjects affected / exposed
    1 / 166 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    2 / 166 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 166 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    1 / 166 (0.60%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nerve root compression
         subjects affected / exposed
    1 / 166 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    2 / 166 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Social circumstances
    Miscarriage of partner
         subjects affected / exposed
    1 / 166 (0.60%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Radicular cyst
         subjects affected / exposed
    1 / 166 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 166 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Nephrotic syndrome
         subjects affected / exposed
    1 / 166 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Tonsillitis
         subjects affected / exposed
    2 / 166 (1.20%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 166 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    1 / 166 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic tonsillitis
         subjects affected / exposed
    1 / 166 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 166 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 166 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 166 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    1 / 166 (0.60%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Canakinumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    124 / 166 (74.70%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    11 / 166 (6.63%)
         occurrences all number
    12
    Nervous system disorders
    Headache
         subjects affected / exposed
    33 / 166 (19.88%)
         occurrences all number
    58
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    18 / 166 (10.84%)
         occurrences all number
    36
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    16 / 166 (9.64%)
         occurrences all number
    18
    Nausea
         subjects affected / exposed
    11 / 166 (6.63%)
         occurrences all number
    13
    Diarrhoea
         subjects affected / exposed
    18 / 166 (10.84%)
         occurrences all number
    21
    Abdominal pain
         subjects affected / exposed
    13 / 166 (7.83%)
         occurrences all number
    14
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    16 / 166 (9.64%)
         occurrences all number
    23
    Oropharyngeal pain
         subjects affected / exposed
    14 / 166 (8.43%)
         occurrences all number
    16
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    24 / 166 (14.46%)
         occurrences all number
    30
    Back pain
         subjects affected / exposed
    12 / 166 (7.23%)
         occurrences all number
    18
    Pain in extremity
         subjects affected / exposed
    9 / 166 (5.42%)
         occurrences all number
    9
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    48 / 166 (28.92%)
         occurrences all number
    60
    Gastroenteritis
         subjects affected / exposed
    12 / 166 (7.23%)
         occurrences all number
    12
    Bronchitis
         subjects affected / exposed
    18 / 166 (10.84%)
         occurrences all number
    18
    Rhinitis
         subjects affected / exposed
    27 / 166 (16.27%)
         occurrences all number
    29
    Upper respiratory tract infection
         subjects affected / exposed
    17 / 166 (10.24%)
         occurrences all number
    22

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Feb 2008
    Subjects with severe renal insufficiency (Glomerular Filtration Rate (GFR) < 30 millilitre/minute/1.73 square metre) or planned liver transplantation would not undergo administration of a gadolinium contrast agent for the performance of a magnetic resonance imaging (MRI) evaluation.
    20 Feb 2009
    The age-range of subjects was lowered (3 years or younger), so as to allow for the inclusion of subjects with Neonatal Onset Multisystem Inflammatory Disease (canakinumab naive), and to update the sample size in the protocol.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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

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