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    Clinical Trial Results:
    Simplifying the Rabies Pre-exposure Vaccination

    Summary
    EudraCT number
    		 2011-001612-62
    Trial protocol
    		 BE  
    Global end of trial date
    12 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Oct 2018
    First version publication date
    31 Oct 2018
    Other versions
    Summary report(s)
    		 Publication_CID

    Trial information

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    Trial identification
    Sponsor protocol code
    ITMC0211
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01388985
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Institute of Tropical Medicine
    Sponsor organisation address
    Nationalestraat 155, Antwerpen, Belgium, 2000
    Public contact
    Yven Van Herrewege, Institute of Tropical Medicine Antwerp, 0032 3247 6557, yvanherrewege@itg.be
    Scientific contact
    Yven Van Herrewege, Institute of Tropical Medicine Antwerp, 0032 3247 6557,
    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
    06 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the clinical non-inferiority of an accelerated rabies vaccination schedule (of 2 two-sided intradermal injections on day 0 and 2 intradermal injections on day 7) to the standard schedule (of 3 one-side intradermal injections for pre-exposure immunization on day 0, day 7 and day 21 or 28) as assessed by "boostability" (% of subjects that have boostable rabies antibodies) after 1 to 3 years. Clinical non-inferiority is defined as a loss of no more than 10% of subjects that have boostable rabies antibody levels compared to standard treatment.
    Protection of trial subjects
    All subjects were asked to report any side effects or adverse events from the time of the injection until 7 days after. No severe pain and distress were expected during the injections.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Sep 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 498
    Worldwide total number of subjects
    498
    EEA total number of subjects
    498
    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)
    498
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at the Travel Clinic, Polyclinic department, in the Military Hospital Queen Astrid, Brussels. Subjects were recruited from the Belgian military settings (land deployment) before their departure on overseas deployment.

    Pre-assignment
    Screening details
    		 Inclusion: - ICF - age between 18 and 47 years - rabies seronegative - belgian soldiers or military students - prepared to follow study schedule Exclusion: - previous rabies vaccination - allergy to vaccine - immune depression or immuno depressant medication - intake of mefloquine - planned deployment to overseas area within 35 days

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1: One-month schedule
    Arm description
    		 Classic intradermal schedule with 1 injection (0,1 ml) (one site) on day 0, day 7 and day 28 respectively. Booster vaccination was done from 1 year after the first vaccination (day 365) on and before another deployment to rabies enzootic regions. If subjects were not deployed within the 3 years after the first rabies vaccination, booster vaccination was performed no later than 3 years after the first vaccination (day 1095 included).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rabipur
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection, Suspension for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    One intradermal injection (0.1ml) was given on three different days (day 0, day 7 and day 28 ). Booster vaccination was done from 1 year after the first vaccination (day 365) on and before another deployment to rabies enzootic regions. If subjects were not deployed within the 3 years after the first rabies vaccination, booster vaccination was performed no later than 3 years after the first vaccination (day 1095 included). Booster vaccination was done by one intradermal injection (0.1ml).

    Arm title
    		 Group 2: One-week schedule
    Arm description
    		 Accelerated intradermal schedule with 2 injections (0,1 ml) (each 2 separate injection sites) on day 0 and 2 injections (0.1ml) (separate sites) on day 7. Booster vaccination were done from 1 year after the first vaccination (day 365) on and before another deployment to rabies enzootic regions. If subjects were not deployed within the 3 years after the first rabies vaccination, booster vaccination was performed no later than 3 years after the first vaccination (day 1095 included).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rabipur
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection, Suspension for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    Primary vaccination: Two injections (0.1ml) were given on the same day (day 0 and day 7): one on each forearm. Booster vaccination was done from 1 year after the first vaccination (day 365) on and before another deployment to rabies enzootic regions. If subjects were not deployed within the 3 years after the first rabies vaccination, booster vaccination was performed no later than 3 years after the first vaccination (day 1095 included). Booster vaccination was done by one intradermal injection (0.1ml).

    Number of subjects in period 1
    		Group 1: One-month schedule Group 2: One-week schedule
    Started
    249
    249
    Completed
    200
    211
    Not completed
    49
    38
         Consent withdrawn by subject
    13
    4
         Subject unavailable (on mission)
    1
    -
         Death
    -
    1
         Subject unavailable (mission)
    -
    1
         Other
    -
    1
         Error of nurse
    5
    1
         Lost to follow-up
    30
    30

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1: One-month schedule
    Reporting group description
    		 Classic intradermal schedule with 1 injection (0,1 ml) (one site) on day 0, day 7 and day 28 respectively. Booster vaccination was done from 1 year after the first vaccination (day 365) on and before another deployment to rabies enzootic regions. If subjects were not deployed within the 3 years after the first rabies vaccination, booster vaccination was performed no later than 3 years after the first vaccination (day 1095 included).

    Reporting group title
    Group 2: One-week schedule
    Reporting group description
    		 Accelerated intradermal schedule with 2 injections (0,1 ml) (each 2 separate injection sites) on day 0 and 2 injections (0.1ml) (separate sites) on day 7. Booster vaccination were done from 1 year after the first vaccination (day 365) on and before another deployment to rabies enzootic regions. If subjects were not deployed within the 3 years after the first rabies vaccination, booster vaccination was performed no later than 3 years after the first vaccination (day 1095 included).

    Reporting group values
    		 Group 1: One-month schedule Group 2: One-week schedule Total
    Number of subjects
    		 249 249 498
    Age categorical
    Units: Subjects
        20 years or less
    		 11 17 28
        21-30
    		 138 136 274
        31-40
    		 71 60 131
        41-50
    		 29 35 64
        more than 50
    		 0 1 1
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 29 (24 to 35) 28 (23 to 34) -
    Gender categorical
    Units: Subjects
        Female
    		 12 8 20
        Male
    		 237 241 478
    Serology at baseline
    RFFIT serology value at baseline (before first vaccine injection).
    Units: Subjects
        0.5 IU/ml or less
    		 245 248 493
        more than 0.5 IU/ml
    		 4 1 5

    End points

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    End points reporting groups
    Reporting group title
    Group 1: One-month schedule
    Reporting group description
    		 Classic intradermal schedule with 1 injection (0,1 ml) (one site) on day 0, day 7 and day 28 respectively. Booster vaccination was done from 1 year after the first vaccination (day 365) on and before another deployment to rabies enzootic regions. If subjects were not deployed within the 3 years after the first rabies vaccination, booster vaccination was performed no later than 3 years after the first vaccination (day 1095 included).

    Reporting group title
    Group 2: One-week schedule
    Reporting group description
    		 Accelerated intradermal schedule with 2 injections (0,1 ml) (each 2 separate injection sites) on day 0 and 2 injections (0.1ml) (separate sites) on day 7. Booster vaccination were done from 1 year after the first vaccination (day 365) on and before another deployment to rabies enzootic regions. If subjects were not deployed within the 3 years after the first rabies vaccination, booster vaccination was performed no later than 3 years after the first vaccination (day 1095 included).

    Primary: Boostability (0.5 IU/ml or more) of the rabies antibodies after booster vaccination

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    End point title
    		 Boostability (0.5 IU/ml or more) of the rabies antibodies after booster vaccination
    End point description
    End point type
    Primary
    End point timeframe
    Assessed on day 7 after booster vaccination at year 1 to 3 after initial vaccination.
    End point values
    		 Group 1: One-month schedule Group 2: One-week schedule
    Number of subjects analysed
    185
    183
    Units: Subject counts
    185
    183
    Statistical analysis title
    		 Efficacy analysis
    Statistical analysis description
    The primary hypothesis will be assessed by calculating the two-sided 95% confidence interval (CI) for the difference in proportions of subjects boostable ("boostability rate") at 1 to 3 year. The CI will be calculated using Wilson's score method, pooled over the complete study population.
    Comparison groups
    Group 1: One-month schedule v Group 2: One-week schedule
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Proportion Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 2
    Notes
    [1] - - if the two-sided 95% CI for the difference in boostability rates (accelerated schedule - standard schedule) lies entirely above -10% then non-inferiority of the accelerated schedule is concluded; - if the 95% CI for the difference in boostability rates includes -10%, then non-inferiority cannot be established; - if the 95% CI for the difference in boostability rates lies entirely below ¬-10%, then the accelerated regimen is clinically inferior to the standard regimen.

    Secondary: Rabies serology of more than 0.5 IU/ml after primary vaccination

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    End point title
    		 Rabies serology of more than 0.5 IU/ml after primary vaccination
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed on day 35 after primary vaccination.
    End point values
    		 Group 1: One-month schedule Group 2: One-week schedule
    Number of subjects analysed
    231
    238
    Units: Subject Counts
    231
    238
    Statistical analysis title
    		 Efficacy analysis
    Statistical analysis description
    All secondary and tertiary endpoints are binary endpoints similar to the primary endpoint. They will be analyzed similarly to the primary endpoint by calculating differences in proportions and 95% CIs.
    Comparison groups
    Group 1: One-month schedule v Group 2: One-week schedule
    Number of subjects included in analysis
    469
    Analysis specification
    Post-hoc
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Proportion Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 2
    Notes
    [2] - No non-inferiority limits for the secondary endpoints are predefined, but the CIs will be interpreted in terms of clinical relevance of possible differences rather than statistical significance.

    Secondary: Rabies serology more than 10 IU/ml after primary vaccination

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    End point title
    		 Rabies serology more than 10 IU/ml after primary vaccination
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed on day 35 after primary vaccination and on day 7 after booster vaccination.
    End point values
    		 Group 1: One-month schedule Group 2: One-week schedule
    Number of subjects analysed
    231
    238
    Units: Subject Counts
    189
    167
    Statistical analysis title
    		 Efficacy analysis
    Statistical analysis description
    All secondary and tertiary endpoints are binary endpoints similar to the primary endpoint. They will be analyzed similarly to the primary endpoint by calculating differences in proportions and 95% CIs.
    Comparison groups
    Group 1: One-month schedule v Group 2: One-week schedule
    Number of subjects included in analysis
    469
    Analysis specification
    Post-hoc
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Difference
    Point estimate
    -12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19
         upper limit
    		 -4
    Notes
    [3] - No non-inferiority limits for the secondary endpoints are predefined, but the CIs will be interpreted in terms of clinical relevance of possible differences rather than statistical significance.

    Secondary: Adverse events and serious adverse events after primary and booster vaccinations

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    End point title
    		 Adverse events and serious adverse events after primary and booster vaccinations
    End point description
    End point type
    Secondary
    End point timeframe
    - Adverse events: within 7 days after initial and booster vaccinations. - Serious adverse events: within 28 days after initial and booster vaccinations.
    End point values
    		 Group 1: One-month schedule Group 2: One-week schedule
    Number of subjects analysed
    249
    249
    Units: number of subjects
        Any adverse event
    190
    190
        Possibly, probably or definitely drug-related AE
    173
    171
        Any Serious Adverse Event
    1
    2
        Local irritation of injection site
    164
    165
    Statistical analysis title
    		 Safety analyses
    Statistical analysis description
    All non-serious and serious adverse events will be grouped according to a pre-specified side-effect coding system and tabulated. The number of subjects experiencing any adverse event, any serious adverse event, and any drug-related serious adverse event will be compared between treatment groups using Fisher's exact test. Safety will be analyzed using the all-subjects-treated approach for the primary and booster vaccination periods separately.
    Comparison groups
    Group 1: One-month schedule v Group 2: One-week schedule
    Number of subjects included in analysis
    498
    Analysis specification
    Post-hoc
    Analysis type
    		 other [4]
    P-value
    		 = 1 [5]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [4] - The number of subjects experiencing any adverse event, any serious adverse event, and any drug-related serious adverse event will be compared between treatment groups using Fisher's exact test.
    [5] - adverse event: p-value=1 possibly, probably er definitely drug-related adverse event: p-value=0.92 serious adverse event: p-value=1 local irritation of injection sites: p-value=1 general discomfort related to injection sites: p-value=0.82

    Secondary: Rabies serology more than 10 IU/ml after booster vaccination

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    End point title
    		 Rabies serology more than 10 IU/ml after booster vaccination
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed at day 7 after booster vaccination.
    End point values
    		 Group 1: One-month schedule Group 2: One-week schedule
    Number of subjects analysed
    185
    183
    Units: Subject Counts
    154
    176
    Statistical analysis title
    		 Efficacy analysis
    Statistical analysis description
    All secondary and tertiary endpoints are binary endpoints similar to the primary endpoint. They will be analyzed similarly to the primary endpoint by calculating differences in proportions and 95% CIs.
    Comparison groups
    Group 1: One-month schedule v Group 2: One-week schedule
    Number of subjects included in analysis
    368
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    Method
    Parameter type
    		 Proportion difference
    Point estimate
    13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7
         upper limit
    		 19

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs occuring up to 7 days after each vaccination visit will be reported. All SAE’s occurring up to 28 days after each vaccination visit will be reported.
    Adverse event reporting additional description
    Persons will receive an adverse event report form: one during primary vaccination and one after booster vaccination. This form needs to be completed and returned to the investigator at the serology visit. All AEs will be reported on the source documents and in the eCRF. All SAEs will be reported to the sponsor using the SAE form.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Group 1: One-month schedule
    Reporting group description
    		 Classic intradermal schedule with 1 injection (0,1 ml) (one site) on day 0, day 7 and day 28 respectively. Booster vaccination was done from 1 year after the first vaccination (day 365) on and before another deployment to rabies enzootic regions. If subjects were not deployed within the 3 years after the first rabies vaccination, booster vaccination was performed no later than 3 years after the first vaccination (day 1095 included).

    Reporting group title
    Group 2: One-week schedule
    Reporting group description
    		 Accelerated intradermal schedule with 2 injections (0,1 ml) (each 2 separate injection sites) on day 0 and 2 injections (0.1ml) (separate sites) on day 7. Booster vaccination were done from 1 year after the first vaccination (day 365) on and before another deployment to rabies enzootic regions. If subjects were not deployed within the 3 years after the first rabies vaccination, booster vaccination was performed no later than 3 years after the first vaccination (day 1095 included).

    Serious adverse events
    		 Group 1: One-month schedule Group 2: One-week schedule
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 249 (0.40%)
    2 / 249 (0.80%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Hemianopia
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Oesophagitis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 249 (0.00%)
    2 / 249 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Group 1: One-month schedule Group 2: One-week schedule
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    156 / 249 (62.65%)
    134 / 249 (53.82%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 249 (0.40%)
         occurrences all number
    1
    1
    Hot flush
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences all number
    1
    0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Phlebitis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Suture insertion
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Tooth extraction
         subjects affected / exposed
    0 / 249 (0.00%)
    2 / 249 (0.80%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 249 (1.20%)
    5 / 249 (2.01%)
         occurrences all number
    3
    5
    Feeling hot
         subjects affected / exposed
    1 / 249 (0.40%)
    3 / 249 (1.20%)
         occurrences all number
    1
    3
    Induration
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Inflammation
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences all number
    1
    0
    Influenza like illness
         subjects affected / exposed
    15 / 249 (6.02%)
    11 / 249 (4.42%)
         occurrences all number
    15
    11
    Injection site erythema
         subjects affected / exposed
    130 / 249 (52.21%)
    131 / 249 (52.61%)
         occurrences all number
    130
    131
    Injection site haemorrhage
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 249 (0.00%)
         occurrences all number
    2
    0
    Injection site hypersensitivity
         subjects affected / exposed
    1 / 249 (0.40%)
    2 / 249 (0.80%)
         occurrences all number
    1
    2
    Injection site inflammation
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Injection site nodule
         subjects affected / exposed
    4 / 249 (1.61%)
    0 / 249 (0.00%)
         occurrences all number
    4
    0
    Injection site pain
         subjects affected / exposed
    14 / 249 (5.62%)
    17 / 249 (6.83%)
         occurrences all number
    14
    17
    Injection site pruritus
         subjects affected / exposed
    3 / 249 (1.20%)
    2 / 249 (0.80%)
         occurrences all number
    3
    2
    injection site swelling
         subjects affected / exposed
    43 / 249 (17.27%)
    67 / 249 (26.91%)
         occurrences all number
    43
    67
    Malaise
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences all number
    1
    0
    Pain
         subjects affected / exposed
    3 / 249 (1.20%)
    2 / 249 (0.80%)
         occurrences all number
    3
    2
    Pyrexia
         subjects affected / exposed
    6 / 249 (2.41%)
    2 / 249 (0.80%)
         occurrences all number
    6
    2
    Thirst
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 249 (0.00%)
         occurrences all number
    2
    0
    Dyspnoea
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences all number
    1
    0
    Respiratory disorder
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 249 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Fear
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 249 (0.80%)
    4 / 249 (1.61%)
         occurrences all number
    2
    4
    Frostbite
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Humerus fracture
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Meniscus injury
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Scratch
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Congenital, familial and genetic disorders
    Gilbert's syndrome
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    3 / 249 (1.20%)
    1 / 249 (0.40%)
         occurrences all number
    3
    1
    Dysgeusia
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    20 / 249 (8.03%)
    20 / 249 (8.03%)
         occurrences all number
    20
    20
    Syncope
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    6 / 249 (2.41%)
    2 / 249 (0.80%)
         occurrences all number
    6
    2
    Eye disorders
    Eye pain
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Photophobia
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 249 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    4 / 249 (1.61%)
    2 / 249 (0.80%)
         occurrences all number
    4
    2
    Nausea
         subjects affected / exposed
    6 / 249 (2.41%)
    0 / 249 (0.00%)
         occurrences all number
    6
    0
    Periodontitis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Stomatitis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences all number
    1
    0
    Toothache
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 249 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences all number
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 249 (0.00%)
    2 / 249 (0.80%)
         occurrences all number
    0
    2
    Pruritus
         subjects affected / exposed
    118 / 249 (47.39%)
    119 / 249 (47.79%)
         occurrences all number
    118
    119
    Rash
         subjects affected / exposed
    5 / 249 (2.01%)
    3 / 249 (1.20%)
         occurrences all number
    5
    3
    Skin exfoliation
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 249 (0.00%)
    2 / 249 (0.80%)
         occurrences all number
    0
    2
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences all number
    1
    0
    Hypothyroidism
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 249 (0.80%)
    3 / 249 (1.20%)
         occurrences all number
    2
    3
    Back pain
         subjects affected / exposed
    4 / 249 (1.61%)
    3 / 249 (1.20%)
         occurrences all number
    4
    3
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 249 (0.00%)
         occurrences all number
    2
    0
    Pain in extremity
         subjects affected / exposed
    4 / 249 (1.61%)
    4 / 249 (1.61%)
         occurrences all number
    4
    4
    Tendonitis
         subjects affected / exposed
    3 / 249 (1.20%)
    3 / 249 (1.20%)
         occurrences all number
    3
    3
    Torticollis
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    1 / 249 (0.40%)
    2 / 249 (0.80%)
         occurrences all number
    1
    2
    Bronchitis
         subjects affected / exposed
    5 / 249 (2.01%)
    1 / 249 (0.40%)
         occurrences all number
    5
    1
    Ear infection
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 249 (0.00%)
         occurrences all number
    2
    0
    Eye infection bacterial
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences all number
    1
    0
    Furuncle
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences all number
    1
    0
    Impetigo
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 249 (0.00%)
         occurrences all number
    2
    0
    Laryngitis
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 249 (0.00%)
         occurrences all number
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    5 / 249 (2.01%)
    4 / 249 (1.61%)
         occurrences all number
    5
    4
    Onychomycosis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 249 (0.00%)
         occurrences all number
    2
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    0
    1
    Rhinitis
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 249 (0.00%)
         occurrences all number
    2
    0
    Sinusitis
         subjects affected / exposed
    2 / 249 (0.80%)
    1 / 249 (0.40%)
         occurrences all number
    2
    1
    Tooth abscess
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences all number
    1
    0
    Tooth infection
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences all number
    1
    0
    Tracheitis
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 249 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Iron deficiency
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 249 (0.40%)
         occurrences all number
    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29939243
    For support, Contact us.
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    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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