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    Clinical Trial Results:
    A multi-centre, randomized, double-blind, placebo-controlled, dose range finding study to identify the optimal (i.e. safe and effective) dose of PURETHAL® Mites SCIT in patients with house dust mites-induced persistent allergic rhinitis/rhinoconjunctivitis.

    Summary
    EudraCT number
    		 2011-000393-61
    Trial protocol
    		 DE   AT   NL   ES   BE  
    Global end of trial date
    15 May 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Aug 2017
    First version publication date
    17 Aug 2017
    Other versions
    Summary report(s)
    		 CSR synopsis PM0037 EUdraCT

    Trial information

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    Trial identification
    Sponsor protocol code
    PM/0037
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    HAL Allergy
    Sponsor organisation address
    J.H. Oortweg 15-17, Leiden, Netherlands, NL-2333 CH
    Public contact
    Head Department of Clinical Development & Pharmacovigilance, HAL Allergy, +31 88 195 9000, pjdkam@hal-allergy.com
    Scientific contact
    Head Department of Clinical Development & Pharmacovigilance, HAL Allergy, +31 88 195 9000, pjdkam@hal-allergy.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
    31 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 May 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    15 May 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of the present study is to characterize the dose-response relationship of PURETHAL® Mites (PM) with a nasal provocation test in order to identify the optimal dose in terms of highest clinical efficacy and safety.
    Protection of trial subjects
    The trial is performed in accordance with GCP and with all applicable governmental regulations. Independent approval for the study conduct was obtained from the IECs. Informed consent was obtained from each subject participating in the trial after explanation of the aims, design, methods, benefits and potential hazards of the trial before any trial-specific procedures were performed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 28
    Country: Number of subjects enrolled
    Spain: 40
    Country: Number of subjects enrolled
    Austria: 10
    Country: Number of subjects enrolled
    Belgium: 30
    Country: Number of subjects enrolled
    Germany: 182
    Worldwide total number of subjects
    290
    EEA total number of subjects
    290
    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)
    290
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients visiting an outpatient clinic of a participating center fulfilling general in- and exclusion criteria, are informed about the study and requested to participate. Patient can also be recruited by means of advertisements. After their informed consent (IC) all inclusion and exclusion criteria were checked.

    Pre-assignment
    Screening details
    		 420 patients were screened, 130 were not randomized mainly because in- and/or exclusion criteria were not met. Diagnosis and main criteria for inclusion: Persistent rhinitis or rhinoconjunctivitis, with or without concomitant asthma, related to house dust mites, age ≥ 18 years and ≤ 60 years.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    Purethal Mites and matching placebo was delivered to the participating sites in clearly marked blinded vials. To fully ensure the blinding the injections were prepared by an independent medically trained person. This person prepared the syringe with the correct volume shortly before injection and covered it with tinfoil, subsequently the injection was performed by the investigator.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PM 6,667 AUeq/ml
    Arm description
    		 Active treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    PURETHAL Mites (PM)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    6,6667 AUeq/ml. Treatment started with an up-dosing phase lasting five weeks and six doses given at weekly intervals. After reaching the maintenance dose 10 monthly injections of 0.5 mL were administered. Dose: Weekly up-dosing of 0.05 mL, 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL. Followed by 4-weekly maintenance dose of 0.5 mL.

    Arm title
    		 PM 20,000 AUeq/ml
    Arm description
    		 Active treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    PURETHAL Mites (PM)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    20,000 AUeq/ml. Treatment started with an up-dosing phase lasting five weeks and six doses given at weekly intervals. After reaching the maintenance dose 10 monthly injections of 0.5 mL were administered. Dose: Weekly up-dosing of 0.05 mL, 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL. Followed by 4-weekly maintenance dose of 0.5 mL.

    Arm title
    		 PM 50,000 AUeq/ml
    Arm description
    		 Active treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    PURETHAL Mites (PM)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    50,000 AUeq/ml. Treatment started with an up-dosing phase lasting five weeks and six doses given at weekly intervals. After reaching the maintenance dose 10 monthly injections of 0.5 mL were administered. Dose: Weekly up-dosing of 0.05 mL, 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL. Followed by 4-weekly maintenance dose of 0.5 mL.

    Arm title
    		 PM 100,000 AUeq/ml
    Arm description
    		 Active treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    PURETHAL Mites (PM)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    100,000 AUeq/ml. Treatment started with an up-dosing phase lasting five weeks and six doses given at weekly intervals. After reaching the maintenance dose 10 monthly injections of 0.5 mL were administered. Dose: Weekly up-dosing of 0.05 mL, 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL. Followed by 4-weekly maintenance dose of 0.5 mL.

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0 AUeq/ml Treatment started with an up-dosing phase lasting five weeks and six doses given at weekly intervals. After reaching the maintenance dose 10 monthly injections of 0.5 mL were administered. Dose: Weekly up-dosing of 0.05 mL, 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL. Followed by 4-weekly maintenance dose of 0.5 mL.

    Number of subjects in period 1
    		PM 6,667 AUeq/ml PM 20,000 AUeq/ml PM 50,000 AUeq/ml PM 100,000 AUeq/ml Placebo
    Started
    57
    59
    59
    59
    56
    Maintenance dose 4
    47
    53
    49
    46
    50
    Completed
    47
    52
    46
    44
    47
    Not completed
    10
    7
    13
    15
    9
         Consent withdrawn by subject
    2
    1
    1
    -
    2
         Adverse event, non-fatal
    3
    1
    5
    7
    2
         Other reasons
    5
    5
    7
    8
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PM 6,667 AUeq/ml
    Reporting group description
    		 Active treatment

    Reporting group title
    PM 20,000 AUeq/ml
    Reporting group description
    		 Active treatment

    Reporting group title
    PM 50,000 AUeq/ml
    Reporting group description
    		 Active treatment

    Reporting group title
    PM 100,000 AUeq/ml
    Reporting group description
    		 Active treatment

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group values
    		 PM 6,667 AUeq/ml PM 20,000 AUeq/ml PM 50,000 AUeq/ml PM 100,000 AUeq/ml Placebo Total
    Number of subjects
    		 57 59 59 59 56 290
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 57 59 59 59 56 290
        From 65-84 years
    		 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 31.6 ± 9.2 32.1 ± 8.9 29.4 ± 8.9 30.5 ± 10.3 30.2 ± 10.1 -
    Gender categorical
    Units: Subjects
        Female
    		 30 25 30 35 28 148
        Male
    		 27 34 29 24 28 142

    End points

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    End points reporting groups
    Reporting group title
    PM 6,667 AUeq/ml
    Reporting group description
    		 Active treatment

    Reporting group title
    PM 20,000 AUeq/ml
    Reporting group description
    		 Active treatment

    Reporting group title
    PM 50,000 AUeq/ml
    Reporting group description
    		 Active treatment

    Reporting group title
    PM 100,000 AUeq/ml
    Reporting group description
    		 Active treatment

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Primary: Change from baseline in mean Lebel score

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    End point title
    		 Change from baseline in mean Lebel score
    End point description
    Change from baseline in mean Lebel score in the Titrated Nasal Provocation Test (TNPT) at the end of study in ITT population.
    End point type
    Primary
    End point timeframe
    At baseline and at end of study.
    End point values
    		 PM 6,667 AUeq/ml PM 20,000 AUeq/ml PM 50,000 AUeq/ml PM 100,000 AUeq/ml Placebo
    Number of subjects analysed
    57
    59
    59
    59
    56
    Units: Lebel score
        least squares mean (standard error)
    -2.28 ± 0.26
    -2.52 ± 0.25
    -2.57 ± 0.26
    -2.47 ± 0.27
    -1.74 ± 0.26
    Statistical analysis title
    		 Analysis of mean Lebel score: change from baseline
    Comparison groups
    PM 6,667 AUeq/ml v Placebo
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.14
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.26
         upper limit
    		 0.18
    Statistical analysis title
    		 Analysis of mean Lebel score: change from baseline
    Comparison groups
    Placebo v PM 20,000 AUeq/ml
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.04
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.44
         upper limit
    		 -0.04
    Statistical analysis title
    		 Analysis of mean Lebel score: change from baseline
    Comparison groups
    PM 50,000 AUeq/ml v Placebo
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.022
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.58
         upper limit
    		 -0.13
    Statistical analysis title
    		 Analysis of mean Lebel score: change from baseline
    Comparison groups
    Placebo v PM 100,000 AUeq/ml
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.049
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.47
         upper limit
    		 0

    Secondary: Change from baseline in mean Lebel score at maintenance visit 4

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    End point title
    		 Change from baseline in mean Lebel score at maintenance visit 4
    End point description
    Change from baseline in mean Lebel score in Titrated Nasal Provocation Test (TNPT) at Maintenance visit 4 in ITT population.
    End point type
    Secondary
    End point timeframe
    At baseline and at maintenance visit 4 (approximately 22 weeks after study start).
    End point values
    		 PM 6,667 AUeq/ml PM 20,000 AUeq/ml PM 50,000 AUeq/ml PM 100,000 AUeq/ml Placebo
    Number of subjects analysed
    47
    53
    49
    49
    45
    Units: Lebel score
        least squares mean (standard error)
    -1.43 ± 0.3
    -1.47 ± 0.28
    -1.83 ± 0.29
    -1.47 ± 0.3
    -1.42 ± 0.29
    Statistical analysis title
    		 Analysis of mean Lebel score at visit 4
    Comparison groups
    Placebo v PM 6,667 AUeq/ml
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.999
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Analysis of mean Lebel score at visit 4
    Comparison groups
    Placebo v PM 20,000 AUeq/ml
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9014
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Analysis of mean Lebel score at visit 4
    Comparison groups
    Placebo v PM 50,000 AUeq/ml
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3238
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Analysis of mean Lebel score at visit 4
    Comparison groups
    Placebo v PM 100,000 AUeq/ml
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9194
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Frequency counts of change in mean Lebel score in TNPT (EOS - baseline)

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    End point title
    		 Frequency counts of change in mean Lebel score in TNPT (EOS - baseline)
    End point description
    Frequency counts of change in mean Lebel score in titrated nasal provocation test (TNPT) between EOS and baseline (worsened, unchanged, improved) per treatment arm in ITT population.
    End point type
    Secondary
    End point timeframe
    At baseline and at end of study.
    End point values
    		 PM 6,667 AUeq/ml PM 20,000 AUeq/ml PM 50,000 AUeq/ml PM 100,000 AUeq/ml Placebo
    Number of subjects analysed
    47
    52
    46
    44
    47
    Units: Change in mean Lebel score in TNPT (n)
    number (not applicable)
        Worsened
    6
    6
    4
    3
    7
        Unchanged
    2
    4
    2
    1
    4
        Improved
    39
    42
    40
    40
    36
    No statistical analyses for this end point

    Secondary: Change from baseline in Peak Nasal Inspiratory Flow at the end of study

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    End point title
    		 Change from baseline in Peak Nasal Inspiratory Flow at the end of study
    End point description
    The change from baseline of mean of Peak Nasal Inspiratory Flow (PNIF) at end of study in the ITT population.
    End point type
    Secondary
    End point timeframe
    At baseline and at end of study.
    End point values
    		 PM 6,667 AUeq/ml PM 20,000 AUeq/ml PM 50,000 AUeq/ml PM 100,000 AUeq/ml Placebo
    Number of subjects analysed
    47
    52
    46
    44
    47
    Units: L/min
        least squares mean (standard error)
    26.3 ± 5.9
    30.7 ± 5.8
    35.2 ± 6.1
    30.3 ± 6.1
    28.5 ± 5.9
    Statistical analysis title
    		 Analysis of change from baseline of PNIF
    Comparison groups
    Placebo v PM 6,667 AUeq/ml
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.01
         upper limit
    		 14.61
    Statistical analysis title
    		 Analysis of change from baseline of PNIF
    Comparison groups
    Placebo v PM 20,000 AUeq/ml
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.788
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.4
         upper limit
    		 18.8
    Statistical analysis title
    		 Analysis of change from baseline of PNIF
    Comparison groups
    Placebo v PM 50,000 AUeq/ml
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.432
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.3
         upper limit
    		 23.7
    Statistical analysis title
    		 Analysis of change from baseline of PNIF
    Comparison groups
    Placebo v PM 100,000 AUeq/ml
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.828
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.2
         upper limit
    		 18.6

    Secondary: Serum specific immunoglobulins EOS - baseline

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    End point title
    		 Serum specific immunoglobulins EOS - baseline [1]
    End point description
    Difference of active group vs. placebo of the change from baseline of serum specific immunoglobulins (in ITT population): ssIgG4 D. pteronyssinus, ssIgG4 D. farinae, ssIgG4 nDer p 1, ssIgG4 rDer p 2, ssIgG nDer p 1, ssIgG rDer p 2, ssIgE D.pteronyssinus, ssIgE nDer p 1, ssIgE rDer p 2. IgG levels were measured in mg/L, IgG4 levels were measured in µg/L, IgE levels were measured in KU/L.
    End point type
    Secondary
    End point timeframe
    At baseline and end of study.
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No values were reported for the placebo treatment group because the presented values include the difference of LS means of the active treatment groups compared to placebo treatment group.
    End point values
    		 PM 6,667 AUeq/ml PM 20,000 AUeq/ml PM 50,000 AUeq/ml PM 100,000 AUeq/ml
    Number of subjects analysed
    57
    59
    59
    59
    Units: concentration
    least squares mean (standard error)
        ssIgG4 D. pteronyssinus (µg/L)
    377.3 ± 441.1
    806.6 ± 434.6
    1945.7 ± 444.1
    4213.6 ± 455.4
        ssIgG4 D. farinae (µg/L)
    426.8 ± 493
    907.3 ± 485.6
    2492.8 ± 495.1
    4512.5 ± 508.3
        ssIgG4 nDer p 1 (µg/L)
    268.1 ± 317.9
    531.9 ± 310.9
    1237.5 ± 138.8
    3256.6 ± 327.3
        ssIgG4 rDer p 2 (µg/L)
    254 ± 140.3
    489.6 ± 139.3
    1005.6 ± 139
    1267.4 ± 146.2
        ssIgG nDer p 1 (mg/L)
    0.34 ± 0.17
    0.57 ± 0.17
    1.34 ± 0.17
    2.34 ± 0.17
        ssIgG rDer p 2 (mg/L)
    0.2 ± 0.17
    0.47 ± 0.16
    1 ± 0.16
    1.2 ± 0.17
        ssIgE D. pteronyssinus (KU/L)
    -2.1 ± 6.5
    -7.9 ± 6.4
    -2.5 ± 6.6
    2.1 ± 6.7
        ssIgE nDer p 1 (KU/L)
    1 ± 2.9
    -1.5 ± 2.8
    1.3 ± 2.9
    7.7 ± 2.9
        ssIgE rDer p 2 (KU/L)
    -2.7 ± 2.9
    -3.1 ± 2.8
    3.7 ± 2.9
    1.1 ± 3
    No statistical analyses for this end point

    Secondary: Average adjusted symptom score

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    End point title
    		 Average adjusted symptom score
    End point description
    Change from baseline of average adjusted symptom score (AAdSS) at the end of study in ITT population.
    End point type
    Secondary
    End point timeframe
    At baseline and end of study.
    End point values
    		 PM 6,667 AUeq/ml PM 20,000 AUeq/ml PM 50,000 AUeq/ml PM 100,000 AUeq/ml Placebo
    Number of subjects analysed
    46
    52
    47
    44
    48
    Units: AadSS
        least squares mean (standard error)
    -3 ± 0.3
    -2.7 ± 0.3
    -2.6 ± 0.3
    -3 ± 0.3
    -2.6 ± 0.3
    Statistical analysis title
    		 Analysis of change from baseline of AAdSS
    Comparison groups
    Placebo v PM 6,667 AUeq/ml
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.999
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.22
         upper limit
    		 0.58
    Statistical analysis title
    		 Analysis of change from baseline of AAdSS
    Comparison groups
    Placebo v PM 20,000 AUeq/ml
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.97
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 0.86
    Statistical analysis title
    		 Analysis of change from baseline of AAdSS
    Comparison groups
    Placebo v PM 50,000 AUeq/ml
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.958
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.88
         upper limit
    		 0.92
    Statistical analysis title
    		 Analysis of change from baseline of AAdSS
    Comparison groups
    Placebo v PM 100,000 AUeq/ml
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.473
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.23
         upper limit
    		 0.57

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected throughout the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.2
    Reporting groups
    Reporting group title
    PM 6,667 AUeq/ml
    Reporting group description
    		 Active treatment

    Reporting group title
    PM 20,000 AUeq/ml
    Reporting group description
    		 Active treatment

    Reporting group title
    PM 50,000 AUeq/ml
    Reporting group description
    		 Active treatment

    Reporting group title
    PM 100,000 AUeq/ml
    Reporting group description
    		 Active treatment

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 PM 6,667 AUeq/ml PM 20,000 AUeq/ml PM 50,000 AUeq/ml PM 100,000 AUeq/ml Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 59 (1.69%)
    3 / 59 (5.08%)
    3 / 59 (5.08%)
    2 / 56 (3.57%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Lower limb fracture
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    jaw fracture
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hip surgery
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    1 / 59 (1.69%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mammoplasty
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Status epilepticus
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 59 (1.69%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    syncope
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 59 (1.69%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    1 / 59 (1.69%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injection site nodule
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    1 / 59 (1.69%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Hiatus hernia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 59 (1.69%)
    1 / 59 (1.69%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 59 (1.69%)
    0 / 59 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    arthralgia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Tonsillitis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 59 (1.69%)
    1 / 59 (1.69%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 PM 6,667 AUeq/ml PM 20,000 AUeq/ml PM 50,000 AUeq/ml PM 100,000 AUeq/ml Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 57 (87.72%)
    54 / 59 (91.53%)
    53 / 59 (89.83%)
    56 / 59 (94.92%)
    50 / 56 (89.29%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    17 / 57 (29.82%)
    22 / 59 (37.29%)
    20 / 59 (33.90%)
    20 / 59 (33.90%)
    15 / 56 (26.79%)
         occurrences all number
    23
    44
    36
    72
    49
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    18 / 57 (31.58%)
    23 / 59 (38.98%)
    23 / 59 (38.98%)
    34 / 59 (57.63%)
    1 / 56 (1.79%)
         occurrences all number
    41
    68
    83
    142
    1
    injection site pain
         subjects affected / exposed
    5 / 57 (8.77%)
    11 / 59 (18.64%)
    3 / 59 (5.08%)
    8 / 59 (13.56%)
    3 / 56 (5.36%)
         occurrences all number
    12
    18
    9
    13
    6
    Injection site pruritus
         subjects affected / exposed
    17 / 57 (29.82%)
    26 / 59 (44.07%)
    15 / 59 (25.42%)
    18 / 59 (30.51%)
    2 / 56 (3.57%)
         occurrences all number
    52
    73
    56
    88
    3
    Injection site swelling
         subjects affected / exposed
    17 / 57 (29.82%)
    26 / 59 (44.07%)
    31 / 59 (52.54%)
    36 / 59 (61.02%)
    0 / 56 (0.00%)
         occurrences all number
    51
    72
    112
    155
    0
    injection site warmth
         subjects affected / exposed
    3 / 57 (5.26%)
    3 / 59 (5.08%)
    2 / 59 (3.39%)
    9 / 59 (15.25%)
    0 / 56 (0.00%)
         occurrences all number
    8
    4
    2
    58
    0
    nasopharyngitis
         subjects affected / exposed
    19 / 57 (33.33%)
    22 / 59 (37.29%)
    19 / 59 (32.20%)
    24 / 59 (40.68%)
    19 / 56 (33.93%)
         occurrences all number
    23
    27
    27
    32
    28
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    5 / 57 (8.77%)
    3 / 59 (5.08%)
    3 / 59 (5.08%)
    7 / 59 (11.86%)
    4 / 56 (7.14%)
         occurrences all number
    6
    5
    3
    9
    6
    Eye disorders
    Eye pruritus
         subjects affected / exposed
    3 / 57 (5.26%)
    3 / 59 (5.08%)
    2 / 59 (3.39%)
    5 / 59 (8.47%)
    2 / 56 (3.57%)
         occurrences all number
    5
    6
    2
    6
    2
    Lacrimation increased
         subjects affected / exposed
    3 / 57 (5.26%)
    5 / 59 (8.47%)
    3 / 59 (5.08%)
    6 / 59 (10.17%)
    2 / 56 (3.57%)
         occurrences all number
    8
    16
    4
    11
    6
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    3 / 57 (5.26%)
    3 / 59 (5.08%)
    4 / 59 (6.78%)
    4 / 59 (6.78%)
    3 / 56 (5.36%)
         occurrences all number
    3
    3
    4
    5
    7
    Sneezing
         subjects affected / exposed
    5 / 57 (8.77%)
    6 / 59 (10.17%)
    2 / 59 (3.39%)
    5 / 59 (8.47%)
    3 / 56 (5.36%)
         occurrences all number
    8
    19
    10
    6
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jun 2012
    The following changes were implemented in the clinical trial protocol: • To adapt the symptom and medication score to the Adjusted Symptom Score • To give a justification for the use of the PNIF measurement.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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

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