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    Clinical Trial Results:
    A Phase 2a Randomized, Multi-center, Open-Label, Pharmacokinetic, and Dose Response Study of Asfotase Alfa in Adult Patients with Pediatric-Onset Hypophosphatasia (HPP)

    Summary
    EudraCT number
    2015-003131-35
    Trial protocol
    DE  
    Global end of trial date
    21 Jun 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Sep 2018
    First version publication date
    23 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AA-HPP-208
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02797821
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Alexion Pharmaceuticals, Inc
    Sponsor organisation address
    100 College Street, New Haven CT, United States,
    Public contact
    European Clinical Trial Information, Alexion Europe SAS, +33 147100606, clinicaltrials.eu@alexion.com
    Scientific contact
    European Clinical Trial Information, Alexion Europe SAS, +33 147100606, clinicaltrials.eu@alexion.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
    21 Jun 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Jun 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of asfotase alfa following administration of a range of dose regimens that encompasses the dose proven to be effective in children (in adult participants with pediatric-onset hypophosphatasia [HPP]).
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Feb 2016
    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
    Germany: 13
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    27
    EEA total number of subjects
    13
    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)
    24
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Twenty-seven participants were enrolled in this phase 2a study. Participants attended 4 study centres in 2 countries. The first participant was enrolled on 6 June 2016, and the last participant completed the study on 21 June 2017.

    Pre-assignment
    Screening details
    Participants with documented paediatric-onset HPP, defined as onset of first signs/symptoms of HPP prior to 18 years of age, were enrolled. Twenty-seven participants were randomised, 8 to the 0.5 milligram (mg)/kilogram (kg) cohort, 10 in the 2.0 mg/kg cohort, and 9 in the 3.0 mg/kg cohort. The first dose of asfotase alfa was given on Day 1, Week

    Pre-assignment period milestones
    Number of subjects started
    27
    Number of subjects completed
    27

    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
    Asfotase Alfa 0.5 mg/kg Dose
    Arm description
    Participants received 0.5 mg/kg of asfotase alfa administered subcutaneously (SC) 3 times a week from Weeks 3 through 9 following the initial single dose on Day 1 in Week 1.
    Arm type
    Active comparator

    Investigational medicinal product name
    Asfotase Alfa 0.5 mg/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    After the initial single dose of Asfotase Alfa 0.5 mg/kg on Day 1, 3 doses were administered each week.

    Arm title
    Asfotase Alfa 2.0 mg/kg Dose
    Arm description
    Participants received 2.0 mg/kg of asfotase alfa administered SC 3 times a week from Weeks 3 through 9 following the initial single dose on Day 1 in Week 1.
    Arm type
    Active comparator

    Investigational medicinal product name
    Asfotase Alfa 2.0 mg/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    After the initial single dose of Asfotase Alfa 2.0 mg/kg on Day 1, 3 doses were administered each week.

    Arm title
    Asfotase Alfa 3.0 mg/kg Dose
    Arm description
    Participants received 3.0 mg/kg of asfotase alfa administered SC 3 times a week from Weeks 3 through 9 following the initial single dose on Day 1 in Week 1.
    Arm type
    Active comparator

    Investigational medicinal product name
    Asfotase Alfa 3.0 mg/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    After the initial single dose of Asfotase Alfa 3.0 mg/kg on Day 1, 3 doses were administered each week.

    Number of subjects in period 1
    Asfotase Alfa 0.5 mg/kg Dose Asfotase Alfa 2.0 mg/kg Dose Asfotase Alfa 3.0 mg/kg Dose
    Started
    8
    10
    9
    Received at least 1 Dose of Study Drug
    8
    10
    9
    Completed
    8
    10
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Asfotase Alfa 0.5 mg/kg Dose
    Reporting group description
    Participants received 0.5 mg/kg of asfotase alfa administered subcutaneously (SC) 3 times a week from Weeks 3 through 9 following the initial single dose on Day 1 in Week 1.

    Reporting group title
    Asfotase Alfa 2.0 mg/kg Dose
    Reporting group description
    Participants received 2.0 mg/kg of asfotase alfa administered SC 3 times a week from Weeks 3 through 9 following the initial single dose on Day 1 in Week 1.

    Reporting group title
    Asfotase Alfa 3.0 mg/kg Dose
    Reporting group description
    Participants received 3.0 mg/kg of asfotase alfa administered SC 3 times a week from Weeks 3 through 9 following the initial single dose on Day 1 in Week 1.

    Reporting group values
    Asfotase Alfa 0.5 mg/kg Dose Asfotase Alfa 2.0 mg/kg Dose Asfotase Alfa 3.0 mg/kg Dose Total
    Number of subjects
    8 10 9 27
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    8 9 7 24
        From 65-84 years
    0 1 2 3
        85 years and over
    0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    41.5 ± 17.90 42.7 ± 16.77 50 ± 17.01 -
    Gender categorical
    Units: Subjects
        Female
    5 6 5 16
        Male
    3 4 4 11
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    0 0 0 0
        Non Hispanic or Latino
    8 10 9 27
        Unknown or Not Reported
    0 0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0
        Asian
    0 0 0 0
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    0 0 0 0
        White
    7 10 9 26
        More than one race
    1 0 0 1
        Unknown or Not Reported
    0 0 0 0
    Baseline Inorganic Pyrophosphate (PPi)
    Units: nanogram (ng)/millilitre (mL)
        arithmetic mean (standard deviation)
    5.4 ± 1.64 5.3 ± 1.22 5.0 ± 0.86 -
    Baseline Pyridoxal 5’-Phosphate (PLP)
    Units: nanogram (ng)/millilitre (mL)
        arithmetic mean (standard deviation)
    309.5 ± 349.16 382.1 ± 385.89 229.5 ± 321.43 -
    Subject analysis sets

    Subject analysis set title
    All participants
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomized participants

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All randomized participants who received ≥ 1 dose of study drug and had ≥ 1 pretreatment and ≥ 1 on-treatment PPi result.

    Subject analysis sets values
    All participants Full Analysis Set (FAS)
    Number of subjects
    27
    27
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    24
    24
        From 65-84 years
    3
    3
        85 years and over
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    44.8 ± 16.94
    44.8 ± 16.94
    Gender categorical
    Units: Subjects
        Female
    16
    16
        Male
    11
    11
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    0
    0
        Non Hispanic or Latino
    27
    27
        Unknown or Not Reported
    0
    0
    Race
    Units: Subjects
        American Indian or Alaska Native
    0
    0
        Asian
    0
    0
        Native Hawaiian or Other Pacific Islander
    0
    0
        Black or African American
    0
    0
        White
    26
    26
        More than one race
    1
    1
        Unknown or Not Reported
    0
    0
    Baseline Inorganic Pyrophosphate (PPi)
    Units: nanogram (ng)/millilitre (mL)
        arithmetic mean (standard deviation)
    5.2 ± 1.23
    5.2 ± 1.23
    Baseline Pyridoxal 5’-Phosphate (PLP)
    Units: nanogram (ng)/millilitre (mL)
        arithmetic mean (standard deviation)
    309.7 ± 346.99
    309.7 ± 346.99

    End points

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    End points reporting groups
    Reporting group title
    Asfotase Alfa 0.5 mg/kg Dose
    Reporting group description
    Participants received 0.5 mg/kg of asfotase alfa administered subcutaneously (SC) 3 times a week from Weeks 3 through 9 following the initial single dose on Day 1 in Week 1.

    Reporting group title
    Asfotase Alfa 2.0 mg/kg Dose
    Reporting group description
    Participants received 2.0 mg/kg of asfotase alfa administered SC 3 times a week from Weeks 3 through 9 following the initial single dose on Day 1 in Week 1.

    Reporting group title
    Asfotase Alfa 3.0 mg/kg Dose
    Reporting group description
    Participants received 3.0 mg/kg of asfotase alfa administered SC 3 times a week from Weeks 3 through 9 following the initial single dose on Day 1 in Week 1.

    Subject analysis set title
    All participants
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomized participants

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All randomized participants who received ≥ 1 dose of study drug and had ≥ 1 pretreatment and ≥ 1 on-treatment PPi result.

    Primary: Change In Plasma PPi From Baseline To Pre-3rd Dose At Week 9

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    End point title
    Change In Plasma PPi From Baseline To Pre-3rd Dose At Week 9
    End point description
    Plasma PPi concentrations were determined using a specific enzyme-catalyzed reaction with a radiolabelled marker in a 3-step process. Baseline plasma PPi values were calculated by averaging pre-dose values from samples collected during the Run-in Period at -168, -156, -24, -12, and 0 hours before Baseline. Week 9 plasma PPi values were calculated using blood samples collected before administration of the 3rd dose. The analysis was a restricted maximum likelihood (REML)-based repeated measures mixed model with treatment, visit, sex, Baseline PPi, Baseline weight group (≥ median versus < median), and study drug lot assignment as factors and an unstructured covariance structure for within-subject correlation. Per inclusion criteria, participants had to have had a Screening PPi concentration of ≥3.9 μM. Three participants (1 in each group) had Screening PPi concentrations of ≥3.9 micromolar (μM), but Baseline PPi values ranged between 3.5 to 3.8 μM.
    End point type
    Primary
    End point timeframe
    Baseline to Week 9
    End point values
    Asfotase Alfa 0.5 mg/kg Dose Asfotase Alfa 2.0 mg/kg Dose Asfotase Alfa 3.0 mg/kg Dose
    Number of subjects analysed
    8
    10
    8
    Units: μM
        least squares mean (standard error)
    -2.604 ± 0.2399
    -3.797 ± 0.1949
    -4.484 ± 0.2120
    Statistical analysis title
    Asfotase Alfa 0.5 mg/kg Dose, Asfotase Alfa 3.0 mg
    Statistical analysis description
    A fixed sequence testing procedure was performed to compare the 3.0 mg/kg cohort with the 0.5 mg/kg cohort first. The hypothesis testing for the second comparison of the 2.0 mg/kg cohort compared with the 0.5 mg/kg cohort was only performed if the null hypothesis was rejected for the previous comparison at a significance level of 0.05 (p-value <0.05). The primary endpoint was met if the null hypothesis was rejected for both comparisons at a significance level of 0.05 (both p-values <0.05).
    Comparison groups
    Asfotase Alfa 0.5 mg/kg Dose v Asfotase Alfa 3.0 mg/kg Dose
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001 [1]
    Method
    REML
    Parameter type
    Least Squares (LS) Means Difference
    Point estimate
    -1.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.544
         upper limit
    -1.216
    Notes
    [1] - REML-based repeated measures mixed model (treatment, visit, sex, Baseline PPi, Baseline weight group [≥median vs < median], and study drug lot assignment as factors) with an unstructured covariance structure for within-participant correlation.
    Statistical analysis title
    Asfotase Alfa 0.5 mg/kg Dose, Asfotase Alfa 2.0 mg
    Statistical analysis description
    A fixed sequence testing procedure was performed to compare the 3.0 mg/kg cohort with the 0.5 mg/kg cohort first. The hypothesis testing for the second comparison of the 2.0 mg/kg cohort compared with the 0.5 mg/kg cohort was only performed if the null hypothesis was rejected for the first comparison at a significance level of 0.05 (p-value <0.05). The primary endpoint was met if the null hypothesis was rejected for both comparisons at a significance level of 0.05 (both p-values <0.05).
    Comparison groups
    Asfotase Alfa 0.5 mg/kg Dose v Asfotase Alfa 2.0 mg/kg Dose
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0008 [2]
    Method
    Restricted maximum likelihood-based
    Parameter type
    LS Means Difference
    Point estimate
    -1.193
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.805
         upper limit
    -0.581
    Notes
    [2] - REML-based repeated measures mixed model (treatment, visit, sex, Baseline PPi, Baseline weight group [≥median vs < median], and study drug lot assignment as factors) with an unstructured covariance structure for within-participant correlation.

    Secondary: Change In Plasma PLP From Baseline To Pre-3rd Dose At Week 9

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    End point title
    Change In Plasma PLP From Baseline To Pre-3rd Dose At Week 9
    End point description
    Plasma PLP was quantified using tandem liquid chromatography/mass spectrometry. Baseline plasma PLP values were calculated by averaging the pre-dose PLP values from blood samples collected during the Run-in Period at -168, -156, -24, -12, and 0 hours before Baseline. Week 9 PLP values were calculated using blood samples collected before the administration of the 3rd dose. The analysis was a REML-based repeated measures mixed model with treatment, visit, sex, Baseline PPi, Baseline weight group (≥ median versus < median), and study drug lot assignment as factors and an unstructured covariance structure for within- subject correlation.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 9
    End point values
    Asfotase Alfa 0.5 mg/kg Dose Asfotase Alfa 2.0 mg/kg Dose Asfotase Alfa 3.0 mg/kg Dose
    Number of subjects analysed
    8
    10
    9
    Units: ng/mL
        least squares mean (standard error)
    -303.955 ± 9.4075
    -333.447 ± 8.1486
    -338.002 ± 8.5145
    Statistical analysis title
    Asfotase Alfa 0.5 mg/kg Dose, Asfotase Alfa 3.0 mg
    Comparison groups
    Asfotase Alfa 0.5 mg/kg Dose v Asfotase Alfa 3.0 mg/kg Dose
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0128 [3]
    Method
    REML
    Parameter type
    LS Means Difference
    Point estimate
    -34.047
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -60.171
         upper limit
    -7.922
    Notes
    [3] - REML-based repeated measures mixed model (treatment, visit, sex, Baseline PPi, Baseline weight group [≥ median versus < median], and study drug lot assignment as factors) with an unstructured covariance structure for within-participant correlation.
    Statistical analysis title
    Asfotase Alfa 0.5 mg/kg Dose, Asfotase Alfa 2.0 mg
    Comparison groups
    Asfotase Alfa 0.5 mg/kg Dose v Asfotase Alfa 2.0 mg/kg Dose
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0239 [4]
    Method
    REML
    Parameter type
    LS Means Difference
    Point estimate
    -29.492
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -54.723
         upper limit
    -4.261
    Notes
    [4] - REML-based repeated measures mixed model (treatment, visit, sex, Baseline PPi, Baseline weight group [≥ median versus < median], and study drug lot assignment as factors) with an unstructured covariance structure for within-participant correlation.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were monitored continuously throughout the study, from the run-in period through the safety follow-up call, which occurred 90 days after the last dose of study drug.
    Adverse event reporting additional description
    Results for AEs occurred in >5% of the overall Safety population. An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product, biologic, or medical device, which did not necessarily have a causal relationship with the asfotase alfa.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Asfotase Alfa 0.5 mg/kg Dose
    Reporting group description
    Participants received 0.5 mg/kg of asfotase alfa administered SC 3 times a week from Weeks 3 through 9 following the initial single dose on Day 1 in Week 1.

    Reporting group title
    Asfotase Alfa 2.0 mg/kg Dose
    Reporting group description
    Participants received 2.0 mg/kg of asfotase alfa administered SC 3 times a week 9 following the initial single dose on Day 1 in Week 1.

    Reporting group title
    Asfotase Alfa 3.0 mg/kg Dose
    Reporting group description
    Participants received 3.0 mg/kg of asfotase alfa administered SC 3 times a week from Weeks 3 through 9 following the initial single dose on Day 1 in Week 1.

    Serious adverse events
    Asfotase Alfa 0.5 mg/kg Dose Asfotase Alfa 2.0 mg/kg Dose Asfotase Alfa 3.0 mg/kg Dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Asfotase Alfa 0.5 mg/kg Dose Asfotase Alfa 2.0 mg/kg Dose Asfotase Alfa 3.0 mg/kg Dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    10 / 10 (100.00%)
    9 / 9 (100.00%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    3 / 9 (33.33%)
         occurrences all number
    0
    0
    5
    Laceration
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    1
    Head discomfort
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    1
    Headache
         subjects affected / exposed
    3 / 8 (37.50%)
    3 / 10 (30.00%)
    5 / 9 (55.56%)
         occurrences all number
    10
    9
    7
    Hypersomnia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    3
    1
    Paraesthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    4 / 9 (44.44%)
         occurrences all number
    0
    0
    10
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 8 (37.50%)
    4 / 10 (40.00%)
    3 / 9 (33.33%)
         occurrences all number
    9
    11
    5
    Feeling hot
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    1
    2
    Influenza like illness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    1
    Injection site bruising
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    1
    Injection site discomfort
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Injection site erythema
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 10 (30.00%)
    4 / 9 (44.44%)
         occurrences all number
    4
    4
    4
    Injection site haematoma
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    0
    Injection site pain
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 10 (10.00%)
    3 / 9 (33.33%)
         occurrences all number
    2
    2
    4
    Injection site reaction
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 10 (30.00%)
    4 / 9 (44.44%)
         occurrences all number
    4
    21
    68
    Pain
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 10 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    3
    2
    Peripheral swelling
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    3 / 9 (33.33%)
         occurrences all number
    0
    1
    3
    Insomnia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    2 / 9 (22.22%)
         occurrences all number
    1
    1
    2
    Restlessness
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Flatulence
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 10 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    3
    0
    Nausea
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 10 (10.00%)
    2 / 9 (22.22%)
         occurrences all number
    3
    2
    2
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 10 (30.00%)
    1 / 9 (11.11%)
         occurrences all number
    4
    7
    2
    Pruritus
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 8 (25.00%)
    4 / 10 (40.00%)
    5 / 9 (55.56%)
         occurrences all number
    13
    12
    15
    Back pain
         subjects affected / exposed
    4 / 8 (50.00%)
    1 / 10 (10.00%)
    2 / 9 (22.22%)
         occurrences all number
    13
    4
    2
    Bone pain
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 10 (30.00%)
    2 / 9 (22.22%)
         occurrences all number
    3
    3
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    3
    0
    2
    Myalgia
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    8
    0
    4
    Neck pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    3
    1
    Pain in extremity
         subjects affected / exposed
    4 / 8 (50.00%)
    5 / 10 (50.00%)
    4 / 9 (44.44%)
         occurrences all number
    17
    11
    10
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 10 (30.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    3
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    4 / 8 (50.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    4
    0
    0

    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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