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    Clinical Trial Results:
    A MULTICENTER, OPEN-LABEL, SINGLE ARM, LONG-TERM EXTENSION STUDY OF WA19926 TO DESCRIBE SAFETY DURING TREATMENT WITH TOCILIZUMAB IN PATIENTS WITH EARLY, MODERATE TO SEVERE RHEUMATOID ARTHRITIS

    Summary
    EudraCT number
    2011-006125-14
    Trial protocol
    HU  
    Global end of trial date
    18 Dec 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    16 Oct 2016
    First version publication date
    08 Jul 2016
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Revision to align public disclosures of outcome measures.

    Trial information

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    Trial identification
    Sponsor protocol code
    ML28146
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01649804
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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
    18 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Dec 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Dec 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective for this study was to evaluate the long term safety of tocilizumab therapy in all enrolled participants.
    Protection of trial subjects
    All study subjects were required to read and sign an informed consent form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Jul 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
    Hungary: 12
    Worldwide total number of subjects
    12
    EEA total number of subjects
    12
    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)
    11
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total number of 12 participants were enrolled in Hungary.

    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
    Tocilizumab
    Arm description
    Tocilizumab (RoActemra/Actemra) 8 milligram/kilogram (mg/kg) intravenously every 4 weeks for 104 weeks. Dose could be reduced due to safety reasons at any time during the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    RoActemra/Actemra
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tocilizumab (RoActemra/Actemra) 8 milligram/kilogram (mg/kg) intravenously every 4 weeks for 104 weeks. Dose could be reduced due to safety reasons at any time during the study.

    Number of subjects in period 1
    Tocilizumab
    Started
    12
    Completed
    4
    Not completed
    8
         Administrative/Other
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tocilizumab
    Reporting group description
    Tocilizumab (RoActemra/Actemra) 8 milligram/kilogram (mg/kg) intravenously every 4 weeks for 104 weeks. Dose could be reduced due to safety reasons at any time during the study.

    Reporting group values
    Tocilizumab Total
    Number of subjects
    12 12
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    51.25 ± 8.67 -
    Gender, Male/Female
    Units: participants
        Female
    8 8
        Male
    4 4

    End points

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    End points reporting groups
    Reporting group title
    Tocilizumab
    Reporting group description
    Tocilizumab (RoActemra/Actemra) 8 milligram/kilogram (mg/kg) intravenously every 4 weeks for 104 weeks. Dose could be reduced due to safety reasons at any time during the study.

    Primary: Percentage of Participants with Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs of Special Interest (AESIs)

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    End point title
    Percentage of Participants with Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs of Special Interest (AESIs) [1]
    End point description
    An AE was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. A SAE was any experience that: resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was medically significant. Adverse Events of Special Interest for this study were: Serious and/or medically significant infections; myocardial infarction/Acute coronary syndrome; Gastrointestinal perforation; Malignancies; Anaphylaxis/hypersensitivity reactions; Demyelinating disorders; Stroke and Serious and/or medically significant bleeding and hepatic events. Analysis population included all the enrolled participants in the study.
    End point type
    Primary
    End point timeframe
    End of Study (Week 104 or early withdrawal)
    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 analysis only.
    End point values
    Tocilizumab
    Number of subjects analysed
    12
    Units: percentage of participants
    number (not applicable)
        AEs
    75
        SAEs
    0
        AESI
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Remission, Low, Medium, and High Disease Activity, as Measured by Disease Activity Index 28 Erythrocyte Sedimentation Rate (DAS28-ESR)

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    End point title
    Number of Participants With Remission, Low, Medium, and High Disease Activity, as Measured by Disease Activity Index 28 Erythrocyte Sedimentation Rate (DAS28-ESR)
    End point description
    The DAS28 (ESR) score is a measure of the participant's disease activity. It is calculated using the tender joint count (28 joints), swollen joint count (28 joints), erythrocyte sedimentation rate (ESR) and general health status. The DAS28-ESR scale ranges from 0 to 10, where higher scores represent higher disease activity. DAS28 <=3.2 implied low disease activity, DAS >3.2 to 5.1 implied moderate disease activity, DAS >5.1 implied high disease activity, and DAS28 <2.6 = clinical remission. Analysis population included all the enrolled participants in the study.
    End point type
    Secondary
    End point timeframe
    Screening and End of Study (Week 104 or early withdrawal)
    End point values
    Tocilizumab
    Number of subjects analysed
    12
    Units: participants
    number (not applicable)
        Remission (Baseline)
    5
        Low Disease Activity (Baseline)
    1
        Moderate Disease Activity (Baseline)
    4
        High Disease Activity (Baseline)
    2
        Remission (End of Study)
    10
        Low Disease Activity (End of Study)
    1
        Moderate Disease Activity (End of Study)
    0
        High Disease Activity (End of Study)
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Remission, Low, Medium, and High Disease Activity, as Measured by Simplified Disease Activity Index (SDAI)

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    End point title
    Number of Participants With Remission, Low, Medium, and High Disease Activity, as Measured by Simplified Disease Activity Index (SDAI)
    End point description
    The SDAI was defined as the numerical sum of 5 outcome parameters: tender and swollen joint count (based on a 28-joint assessment), participant and physician global assessment of disease activity on a 100 millimeter (mm) Visual analogue scale (VAS) (VAS; 0 = no disease activity and 100 = worst disease activity) and level of C-reactive protein (CRP) (milligram per deciliter [mg/dl], normal < 1 mg/dl). SDAI total score = 0-86 where a higher score reflects worsening disease. SDAI <=3.3 indicates clinical remission, >3.4 to 11 = low disease activity, >11 to 26 = moderate disease activity, and >26 = high (or severe) disease activity. Analysis population included all the enrolled participants in the study.
    End point type
    Secondary
    End point timeframe
    Screening and End of Study (Week 104 or early withdrawal)
    End point values
    Tocilizumab
    Number of subjects analysed
    12
    Units: participants
    number (not applicable)
        Remission (Baseline)
    0
        Low Disease Activity (Baseline)
    6
        Moderate Disease Activity (Baseline)
    3
        High Disease Activity (Baseline)
    3
        Remission (End of Study)
    3
        Low Disease Activity (End of Study)
    7
        Moderate Disease Activity (End of Study)
    1
        High Disease Activity (End of Study)
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Decreased, Unchanged, and Increased Tender Joint Count (TJC)

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    End point title
    Number of Participants With Decreased, Unchanged, and Increased Tender Joint Count (TJC)
    End point description
    Tender joint count was performed by a skilled assessor, evaluating 68 joints for tenderness. Analysis population included all the evaluable participants for this outcome measure. "n" included all the participants analyzed on that particular time point.
    End point type
    Secondary
    End point timeframe
    Week 12 and Week 104
    End point values
    Tocilizumab
    Number of subjects analysed
    11
    Units: participants
    number (not applicable)
        Decreased (Week 12; n=11)
    5
        Unchanged (Week 12; n=11)
    4
        Increased (Week 12;n=11)
    2
        Decreased (Week 104;n=4)
    2
        Unchanged (Week 104;n=4)
    2
        Increased (Week 104;n=4)
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Decreased, Unchanged, and Increased Swollen Joint Count (SJC)

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    End point title
    Number of Participants With Decreased, Unchanged, and Increased Swollen Joint Count (SJC)
    End point description
    Swollen joint count was performed by a skilled assessor, evaluating 66 joints for swelling. Analysis population included all the evaluable participants for this outcome measure. "n" included all the participants analyzed on that particular time point.
    End point type
    Secondary
    End point timeframe
    Week 12 and Week 104
    End point values
    Tocilizumab
    Number of subjects analysed
    11
    Units: participants
    number (not applicable)
        Decreased (Week 12; n=11)
    3
        Unchanged (Week 12; n=11)
    7
        Increased (Week 12;n=11)
    1
        Decreased (Week 104;n=4)
    2
        Unchanged (Week 104;n=4)
    2
        Increased (Week 104;n=4)
    0
    No statistical analyses for this end point

    Secondary: Time to Rheumatoid Arthritis (RA) Flare

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    End point title
    Time to Rheumatoid Arthritis (RA) Flare
    End point description
    RA flare was defined as any worsening of the participant’s disease activity that in the opinion of the Investigator required treatment intensification beyond supportive therapy which included restarting of the study drug treatment. Time to RA flare was defined as the period of drug-free remission until documentation of RA flare. Drug-free remission was defined as clinical remission (based on DAS28-ESR < 2.6 and /or SDAI ≤ 3.3) for two consecutive assessment visits, followed by discontinuation of tocilizumab, at the Investigator's discretion, at the second assessment visit. Data were not analyzed as there were no participants who had achieved drug-free remission, per protocol definition.
    End point type
    Secondary
    End point timeframe
    End of Study (Week 104 or early withdrawal)
    End point values
    Tocilizumab
    Number of subjects analysed
    0 [2]
    Units: Weeks
        median (full range (min-max))
    ( to )
    Notes
    [2] - No participant had achieved clinical remission during the study hence data was not analyzed.
    No statistical analyses for this end point

    Secondary: Number of Participants With Decreased, Unchanged, and Increased Participants Global Assessment of Disease Activity

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    End point title
    Number of Participants With Decreased, Unchanged, and Increased Participants Global Assessment of Disease Activity
    End point description
    The participant global assessment of disease activity was measured using a 100 mm VAS ranging from 0=very good to 100=very bad. Analysis population included all the evaluable participants for this outcome measure. "n" included all the participants analyzed on that particular time point.
    End point type
    Secondary
    End point timeframe
    Week 12 and Week 104
    End point values
    Tocilizumab
    Number of subjects analysed
    11
    Units: participants
    number (not applicable)
        Decreased (Week 12; n=11)
    6
        Unchanged (Week 12; n=11)
    0
        Increased (Week 12;n=11)
    5
        Decreased (Week 104;n=4)
    2
        Unchanged (Week 104;n=4)
    0
        Increased (Week 104;n=4)
    2
    No statistical analyses for this end point

    Secondary: Number of Participants With Decreased, Unchanged, and Increased Participant Global assessment of Pain

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    End point title
    Number of Participants With Decreased, Unchanged, and Increased Participant Global assessment of Pain
    End point description
    A participant's overall assessment of pain on a VAS was assessed with a question concerning the amount of pain due to arthritis. Pain was assessed on a 100 mm VAS scale with a left-hand marker "no pain" (0 mm) or right-hand marker "extreme pain" (100 mm). Analysis population included all the evaluable participants for this outcome measure. "n" included all the participants analyzed on that particular time point.
    End point type
    Secondary
    End point timeframe
    Week 12 and Week 104
    End point values
    Tocilizumab
    Number of subjects analysed
    11
    Units: participants
    number (not applicable)
        Decreased (Week 12; n=11)
    7
        Unchanged (Week 12; n=11)
    4
        Increased (Week 12;n=11)
    0
        Decreased (Week 104;n=4)
    2
        Unchanged (Week 104;n=4)
    0
        Increased (Week 104;n=4)
    2
    No statistical analyses for this end point

    Secondary: Health Assessment Questionnaire Disability Index (HAQ-DI)

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    End point title
    Health Assessment Questionnaire Disability Index (HAQ-DI)
    End point description
    The Health Assessment Questionnaire Disability Index (HAQ-DI) is a participant-completed questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. Each item was scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores divided by the number of domains answered. Total possible scores range from 0 to 3, where 0=least difficulty, and 3=extreme difficulty. Analysis population included all the enrolled participants in the study.
    End point type
    Secondary
    End point timeframe
    End of Study (Week 104 or early withdrawal)
    End point values
    Tocilizumab
    Number of subjects analysed
    12
    Units: units on a scale
        arithmetic mean (standard deviation)
    1.18 ± 0.953
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    End of Study (Week 104 or early withdrawal)
    Adverse event reporting additional description
    An AE was any untoward medical occurrence in a study participant administered a pharmaceutical product, and which did not necessarily have a causal relationship with the treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    Tocilizumab
    Reporting group description
    Tocilizumab (RoActemra/Actemra) 8 mg/kg intravenously every 4 weeks for 104 weeks. Dose could be reduced due to safety reasons at any time during the study.

    Serious adverse events
    Tocilizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Tocilizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 12 (75.00%)
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Investigations
    White blood cell count decreased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    6
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Ranula
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Infections and infestations
    Otitis externa
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Otitis media
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Cystitis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Respiratory tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    5
    Influenza
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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