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    Clinical Trial Results:
    Flu-like Syndrome Inhibition Giving Anti-histaminic Therapy

    Summary
    EudraCT number
    2013-001055-12
    Trial protocol
    IT  
    Global end of trial date
    07 Jul 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Feb 2016
    First version publication date
    29 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BIIT0212
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, United States, 02142
    Public contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.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
    07 Jul 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this Phase IIIb, crossover, single-centre, randomized, placebo-controlled, double blind trial was evaluation of the efficacy of the administration of cetirizine 10 mg on flu-like syndrome (FLS) in patients with relapsing-remitting multiple sclerosis (RRMS) treated with interferon-β (IFN-β).
    Protection of trial subjects
    Written informed consent was obtained from each subject prior to evaluations being performed for eligibility. Subjects were given adequate time to review the information in the informed consent form and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study. Through the informed consent process each subject was made aware of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken. Any side effects or other health issues occurring during the study were followed up by the study doctor. Subjects were able to stop taking part in the study at any time without giving any reason.
    Background therapy
    All subjects in the study continued their treatment with IFN-β and any medications for FLS (standard of therapy), with stable dose and frequency. These drugs were dispensed to patients according to normal procedures of the Centre.
    Evidence for comparator
    -
    Actual start date of recruitment
    16 Sep 2013
    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
    Italy: 46
    Worldwide total number of subjects
    46
    EEA total number of subjects
    46
    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)
    46
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    This study included a 12-week screening period.

    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 / Cetirizine
    Arm description
    Subjects were randomized to a period of standard therapy plus placebo lasting 4 weeks followed by 4 weeks of standard therapy plus cetirizine 10 mg. If a subject was already taking drugs for the treatment of the FLS, such as acetaminophen or ibuprofen, he/she was asked to keep the dosage of such therapy stable as much as possible during the study period, always at the discretion of the investigator and in accordance with normal clinical practice.
    Arm type
    Experimental

    Investigational medicinal product name
    cetirizine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects took one capsule of cetirizine 10 mg one hour before injection of IFN-β. Dosage of cetirizine depended on the type of IFN-β used by the study subject (ie, the number of injections of IFN-β per week).

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects took one capsule of placebo one hour before injection of IFN-β.

    Arm title
    Cetirizine / Placebo
    Arm description
    Subjects were randomized to a period of standard therapy plus cetirizine 10 mg lasting 4 weeks followed by 4 weeks of standard therapy plus placebo. If a subject was already taking drugs for the treatment of the FLS, such as acetaminophen or ibuprofen, he/she was asked to keep the dosage of such therapy stable as much as possible during the study period, always at the discretion of the investigator and in accordance with normal clinical practice.
    Arm type
    Experimental

    Investigational medicinal product name
    cetirizine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects took one capsule of cetirizine 10 mg one hour before injection of IFN-β. Dosage of cetirizine depended on the type of IFN-β used by the study subject (ie, the number of injections of IFN-β per week).

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects took one capsule of placebo one hour before injection of IFN-β.

    Number of subjects in period 1 [1]
    Placebo / Cetirizine Cetirizine / Placebo
    Started
    23
    22
    Completed
    21
    20
    Not completed
    2
    2
         Consent withdrawn by subject
    2
    1
         Lost to follow-up
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 46 subjects were enrolled into the study; 1 subject was enrolled but not randomized.

    Baseline characteristics

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

    Reporting group values
    Overall Study Total
    Number of subjects
    45 45
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    45 45
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    39.1 ± 9.2 -
    Gender categorical
    Units: Subjects
        Female
    32 32
        Male
    13 13

    End points

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    End points reporting groups
    Reporting group title
    Placebo / Cetirizine
    Reporting group description
    Subjects were randomized to a period of standard therapy plus placebo lasting 4 weeks followed by 4 weeks of standard therapy plus cetirizine 10 mg. If a subject was already taking drugs for the treatment of the FLS, such as acetaminophen or ibuprofen, he/she was asked to keep the dosage of such therapy stable as much as possible during the study period, always at the discretion of the investigator and in accordance with normal clinical practice.

    Reporting group title
    Cetirizine / Placebo
    Reporting group description
    Subjects were randomized to a period of standard therapy plus cetirizine 10 mg lasting 4 weeks followed by 4 weeks of standard therapy plus placebo. If a subject was already taking drugs for the treatment of the FLS, such as acetaminophen or ibuprofen, he/she was asked to keep the dosage of such therapy stable as much as possible during the study period, always at the discretion of the investigator and in accordance with normal clinical practice.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intention to treat population: all randomized subjects who received at least one dose of cetirizine or one dose of placebo and have, for both products, at least one evaluation before and after taking the drug.

    Subject analysis set title
    Cetirizine
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intention to treat population: all randomized subjects who received at least one dose of cetirizine or one dose of placebo and have, for both products, at least one evaluation before and after taking the drug.

    Subject analysis set title
    Placebo: Baseline
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intention to treat population subjects taking placebo, assessed before injection.

    Subject analysis set title
    Placebo: 4/6 Hour
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intention to treat population subjects taking placebo, assessed after 4-6 hours post-injection.

    Subject analysis set title
    Placebo: 12/15 Hour
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intention to treat population subjects taking placebo, assessed after 12- 15 hours post-injection.

    Subject analysis set title
    Cetirizine: Baseline
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intention to treat population subjects taking cetirizine, assessed before injection.

    Subject analysis set title
    Cetirizine: 4/6 Hours
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intention to treat population subjects taking cetirizine, assessed after 4-6 hours post-injection.

    Subject analysis set title
    Cetirizine: 12/15 Hours
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intention to treat population subjects taking cetirizine, assessed after 12-15 hours post-injection.

    Primary: Mean Change in Subject Visual Analog Scale of Flu Like Symptoms (VAS-FLS)

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    End point title
    Mean Change in Subject Visual Analog Scale of Flu Like Symptoms (VAS-FLS) [1]
    End point description
    The mean change in the severity of subjective FLS, evaluated the subjective seriousness of the FLS as assessed by the subject on a visual analog scale (VAS-FLS). The VAS-FLS is 10 cm in length, where 0 = no discomfort due to FLS and 10 = maximum discomfort imaginable due to FLS. The values considered are the VAS scores collected 4 hours after the last injection after 4 weeks of treatment according to the treatment group (Placebo [A] or Cetirizine [B]). These values were then divided by the two sequences of randomization (AB vs BA) to allow assessment of the sequence effect.
    End point type
    Primary
    End point timeframe
    up to 8 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: P-value for placebo vs. cetirizine = 0.6029 (ANOVA; n = 39). Sequence x treatment p-value for placebo vs. cetirizine = 0.1279 (ANOVA; n = 39).
    End point values
    Placebo Cetirizine
    Number of subjects analysed
    39 [2]
    39 [3]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Sequence AB
    3.45 ± 3.09
    3.15 ± 2.95
        Sequence BA
    3.37 ± 2.35
    3.97 ± 2.58
        Total
    3.41 ± 2.71
    3.57 ± 2.76
    Notes
    [2] - Intention to treat population: three subjects were excluded due to missing data
    [3] - Intention to treat population: three subjects were excluded due to missing data
    No statistical analyses for this end point

    Secondary: Mean Change in the Symptom Score of FLS (FLS-S)

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    End point title
    Mean Change in the Symptom Score of FLS (FLS-S)
    End point description
    The mean change in severity of FLS (as assessed by the symptom score of FLS [FLS-S]) between the assessments before injection, after 4-6 hours after injection and after 12- 15 hours after injection during the entire study period. Subjects assigned a score to the presence and intensity of muscle pain, chills and weakness, each evaluated separately, according to the following scale: 0=absent; 1=mild, did not interfere with daily activities; 2=moderate, enough to interfere with daily activities; 3=severe, required bed rest. Body temperature was also recorded using the following scale: 0: <37.3° C; 1: ≥37.3° C and <37.8° C; 2: ≥37.8° C and <38.4° C; 3: ≥38.4° C. The scores of individual symptoms (muscle aches, chills, weakness and body temperature) were added together to get the FLS-S, which ranged between 0 (no symptoms) and 12 (worst symptoms). A change in the total score ≥2 points compared to the pre-injection score was considered positive for the presence of FLS.
    End point type
    Secondary
    End point timeframe
    up to 8 weeks
    End point values
    Placebo: Baseline Placebo: 4/6 Hour Placebo: 12/15 Hour Cetirizine: Baseline Cetirizine: 4/6 Hours Cetirizine: 12/15 Hours
    Number of subjects analysed
    41 [4]
    41 [5]
    41 [6]
    41 [7]
    41 [8]
    41 [9]
    Units: units on a scale
    arithmetic mean (standard deviation)
        First Week: Placebo - Cetirizine
    2 ± 2
    3.6 ± 2.8
    2.7 ± 2.2
    2.3 ± 2.7
    3.5 ± 2.8
    2.7 ± 2.8
        First Week: Cetirizine - Placebo
    1.7 ± 1.9
    3 ± 2.6
    3 ± 2.5
    2.3 ± 2.2
    3.8 ± 2.6
    3.6 ± 2.5
        First Week: Total
    1.8 ± 1.9
    3.3 ± 2.7
    2.8 ± 2.3
    2.3 ± 2.5
    3.6 ± 2.7
    3.1 ± 2.7
        Second Week: Placebo - Cetirizine
    1.8 ± 2.1
    3.7 ± 3
    3.1 ± 2.5
    2.4 ± 2.6
    3.1 ± 2.9
    2.6 ± 2.6
        Second Week: Cetirizine - Placebo
    2 ± 1.9
    3.2 ± 2.4
    3.2 ± 2.5
    2.4 ± 2.2
    3.7 ± 2.6
    3.3 ± 3
        Second Week: Total
    1.9 ± 2
    3.5 ± 2.7
    3.1 ± 2.5
    2.4 ± 2.4
    3.4 ± 2.7
    3 ± 2.7
        Third Week: Placebo - Cetirizine
    2.2 ± 2.3
    3.3 ± 2.9
    2.6 ± 2.4
    2 ± 2.2
    3 ± 3
    2.7 ± 2.6
        Third Week: Cetirizine - Placebo
    1.7 ± 1.8
    2.9 ± 2
    3 ± 2.6
    2.4 ± 2.5
    4 ± 2.7
    3.5 ± 2.9
        Third Week: Total
    2 ± 2.1
    3.1 ± 2.5
    2.8 ± 2.5
    2.2 ± 2.3
    3.5 ± 2.9
    3.1 ± 2.7
        Fourth Week: Placebo - Cetirizine
    2 ± 2.2
    3.3 ± 2.9
    2.7 ± 2.7
    2.3 ± 2.6
    3 ± 2.9
    2.6 ± 2.6
        Fourth Week: Cetirizine - Placebo
    2.1 ± 2.3
    3.3 ± 2.4
    3.4 ± 2.7
    2.3 ± 2.3
    4 ± 2.6
    3.5 ± 2.9
        Fourth Week: Total
    2 ± 2.2
    3.3 ± 2.6
    3 ± 2.7
    2.3 ± 2.4
    3.5 ± 2.7
    3 ± 2.7
    Notes
    [4] - Intention to treat population: one subject was excluded due to missing data
    [5] - Intention to treat population: one subject was excluded due to missing data
    [6] - Intention to treat population: one subject was excluded due to missing data
    [7] - Intention to treat population: one subject was excluded due to missing data
    [8] - Intention to treat population: one subject was excluded due to missing data
    [9] - Intention to treat population: one subject was excluded due to missing data
    No statistical analyses for this end point

    Secondary: Percentage of Subjects (Responders) With a Decrease of ≥ 2 FLS-S Compared With Pre-injection Values

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    End point title
    Percentage of Subjects (Responders) With a Decrease of ≥ 2 FLS-S Compared With Pre-injection Values
    End point description
    FLS-S scores recorded at baseline and after 4-6 hours from each injection were considered. Subjects for whom the score FLS-S was reduced by 2 or more units were defined as responders. Subjects with more than 1 weekly evaluation were considered responders if at least an evaluation of the difference of the score FLS-S between the value before the injection and the next 4-6 hours after injection was ≥ 2.
    End point type
    Secondary
    End point timeframe
    up to 8 weeks
    End point values
    Placebo Cetirizine
    Number of subjects analysed
    40 [10]
    40 [11]
    Units: percentage of subjects
    number (not applicable)
        Placebo - Cetirizine
    15
    20
        Cetirizine - Placebo
    10
    15
        Total
    25
    35
    Notes
    [10] - Intention to treat population: two subjects were excluded due to missing data
    [11] - Intention to treat population: two subjects were excluded due to missing data
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With an Increase of ≥ 2 FLS-S Compared to Pre-injection Values

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    End point title
    Percentage of Subjects With an Increase of ≥ 2 FLS-S Compared to Pre-injection Values
    End point description
    FLS incidence was defined as an increase of ≥ 2 FLS-S compared to the value before injection after 4-6 hours and after 12-15 hours during the entire study period.
    End point type
    Secondary
    End point timeframe
    up to 8 weeks
    End point values
    Placebo Cetirizine
    Number of subjects analysed
    40 [12]
    40 [13]
    Units: percentage of subjects
    number (not applicable)
        Placebo - Cetirizine
    75
    75
        Cetirizine - Placebo
    90
    85
        Total
    82.5
    80
    Notes
    [12] - Intention to treat population: two subjects were excluded due to missing data
    [13] - Intention to treat population: two subjects were excluded due to missing data
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug through the end of study (up to 8 weeks).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Placebo / Cetirizine: Period 1 (Treatment With Placebo)
    Reporting group description
    Subjects were randomized to a period of standard therapy plus placebo lasting 4 weeks (period 1) followed by 4 weeks of standard therapy plus cetirizine 10 mg (period 2). If a subject was already taking drugs for the treatment of the FLS, such as acetaminophen or ibuprofen, he/she was asked to keep the dosage of such therapy stable as much as possible during the study period, always at the discretion of the investigator and in accordance with normal clinical practice.

    Reporting group title
    Placebo / Cetirizine: Period 2 (Treatment With Cetirizine)
    Reporting group description
    Subjects were randomized to a period of standard therapy plus placebo lasting 4 weeks (period 1) followed by 4 weeks of standard therapy plus cetirizine 10 mg (period 2). If a subject was already taking drugs for the treatment of the FLS, such as acetaminophen or ibuprofen, he/she was asked to keep the dosage of such therapy stable as much as possible during the study period, always at the discretion of the investigator and in accordance with normal clinical practice.

    Reporting group title
    Cetirizine / Placebo: Period 1 (Treatment With Cetirizine)
    Reporting group description
    Subjects were randomized to a period of standard therapy plus cetirizine 10 mg (period 1) lasting 4 weeks followed by 4 weeks of standard therapy plus placebo (period 2). If a subject was already taking drugs for the treatment of the FLS, such as acetaminophen or ibuprofen, he/she was asked to keep the dosage of such therapy stable as much as possible during the study period, always at the discretion of the investigator and in accordance with normal clinical practice.

    Reporting group title
    Cetirizine / Placebo: Period 2 (Treatment With Placebo)
    Reporting group description
    Subjects were randomized to a period of standard therapy plus cetirizine 10 mg (period 1) lasting 4 weeks followed by 4 weeks of standard therapy plus placebo (period 2). If a subject was already taking drugs for the treatment of the FLS, such as acetaminophen or ibuprofen, he/she was asked to keep the dosage of such therapy stable as much as possible during the study period, always at the discretion of the investigator and in accordance with normal clinical practice.

    Serious adverse events
    Placebo / Cetirizine: Period 1 (Treatment With Placebo) Placebo / Cetirizine: Period 2 (Treatment With Cetirizine) Cetirizine / Placebo: Period 1 (Treatment With Cetirizine) Cetirizine / Placebo: Period 2 (Treatment With Placebo)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo / Cetirizine: Period 1 (Treatment With Placebo) Placebo / Cetirizine: Period 2 (Treatment With Cetirizine) Cetirizine / Placebo: Period 1 (Treatment With Cetirizine) Cetirizine / Placebo: Period 2 (Treatment With Placebo)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    0
    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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