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    Clinical Trial Results:
    A phase 2, randomised, double-blind, placebo-controlled, crossover study to evaluate the effects of a topical pentosan polysulphate sodium (PPS) formulation in subjects with seasonal allergic rhinitis

    Summary
    EudraCT number
    2016-003341-28
    Trial protocol
    SE  
    Global end of trial date
    22 Mar 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    07 Apr 2018
    First version publication date
    07 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PARA_003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Paradigm Biopharmaceuticals
    Sponsor organisation address
    Level 2, 517 Flinders Lane, Melbourne, Australia,
    Public contact
    Claire Kaufman, Chief Operations Officer, Paradigm Biopharmaceuticals, +61 413 421 160, ckaufman@paradigmbiopharma.com
    Scientific contact
    Claire Kaufman, Chief Operations Officer, Paradigm Biopharmaceuticals, +61 413 421 160, ckaufman@paradigmbiopharma.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
    17 Nov 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to assess the effect of a topical Pentosan polysulphate sodium formulation on post-challenge nasal symptoms using an allergen challenge model in subjects with seasonal allergic rhinitis.
    Protection of trial subjects
    Subjects attended a follow-up visit 1 to 2 weeks after the last day of the second treatment period. Additional physical and nasal examinations and measurements of vital signs could be performed if clinically indicated.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    21 Nov 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
    Sweden: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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)
    40
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    All subjects were recruited at a single site. Informed consent and screening were on the same day. The first subject provided informed consent and was screened on 21 November 2016. The last subject provided informed consent and was screened on 18 January 2017.

    Pre-assignment
    Screening details
    Forty-five (45) subjects were screened, of whom 40 were randomized to one of the two treatment arms. There were 5 screening failures, all of which were because exclusion criterion #13 (APTT value outside the normal range at screening) was met.

    Period 1
    Period 1 title
    Baseline period (screening to day -1)
    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
    The Sponsor was also blinded to treatment arm allocation.

    Arms
    Arm title
    Baseline period
    Arm description
    All enrolled subjects
    Arm type
    No intervention

    Investigational medicinal product name
    Pentosan polysulphate sodium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Intranasal use
    Dosage and administration details
    Pentosan polysulphate sodium was provided in a 20 mL silicone lined class 1 glass bottle, closed with a cartridge pump system nasal pump device. NOTE: Pentosan polysulphate sodium was not administered during the baseline period.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Intranasal use
    Dosage and administration details
    The placebo formulation consisted of the Pentosan polysulphate sodium formulation vehicle, adjusted to isotonicity with NaCl. Placebo was provided in a 20 mL silicone lined class 1 glass bottle, closed with a cartridge pump system nasal pump device. NOTE: Placebo was not administered during the baseline period.

    Number of subjects in period 1
    Baseline period
    Started
    40
    Completed
    40
    Period 2
    Period 2 title
    Treatment period (days 1 to 14)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    The Sponsor was also blinded to treatment arm allocation. The placebo and formulations were identical in appearance and nasal feel. The study site was given envelopes (one per subject) containing each subject's treatment allocation. These envelopes were held in a secure location. In a medical emergency requiring knowledge of the study drug, the envelope for that subject could be opened to determine their treatment allocation (while maintaining the blinding for all other subjects).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Pentosan polysulphate sodium then Placebo
    Arm description
    Subjects received Pentosan polysulphate sodium (80 mg/day) during treatment period 1 and Placebo during treatment period 2. Subjects received IMP using 2 sprays per nostril twice daily. Nasal symptoms and PNIF ( Peak Nasal Inspiratory Flow) were assessed before each dose. During the last 7 days of each treatment period, an individualised allergen challenge was administered after the morning dose of IMP. Nasal symptoms were assessed 10 minutes after the allergen challenge.
    Arm type
    Experimental and Placebo

    Investigational medicinal product name
    Pentosan polysulphate sodium
    Investigational medicinal product code
    Other name
    PPS, Rhinosul®
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Intranasal use
    Dosage and administration details
    Pentosan polysulphate sodium was provided in a 20 mL silicone lined class 1 glass bottle, closed with a cartridge pump system nasal pump device. Subjects received Pentosan polysulphate sodium as 2 equal daily doses for 14 days. They self-administered Pentosan polysulphate sodium each morning and evening. For each morning or evening dose, subjects administered 1 spray (100 µL) of Pentosan polysulphate sodium to each nostril, waited 2 minutes, and then administered a second spray to each nostril. The concentration of Pentosan polysulphate sodium was 100 mg/mL and the total dose per day was 80 mg.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Intranasal use
    Dosage and administration details
    The placebo formulation consisted of the Pentosan polysulphate sodium formulation vehicle, adjusted to isotonicity with NaCl. Placebo was provided in a 20 mL silicone lined class 1 glass bottle, closed with a cartridge pump system nasal pump device. Subjects received Placebo for 14 days. They self-administered Placebo each morning and evening. For each morning or evening dose, subjects administered 1 spray (100 µL) of Placebo to each nostril, waited 2 minutes, and then administered a second spray to each nostril.

    Arm title
    Placebo then Pentosan polysulphate sodium
    Arm description
    Subjects received Placebo during treatment period 1 and Pentosan polysulphate sodium (80 mg/day) during treatment period 2. Subjects received IMP using 2 sprays per nostril twice daily. Nasal symptoms and PNIF ( Peak Nasal Inspiratory Flow) were assessed before each dose. During the last 7 days of each treatment period, an individualised allergen challenge was administered after the morning dose of IMP. Nasal symptoms were assessed 10 minutes after the allergen challenge.
    Arm type
    Experimental and Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Intranasal use
    Dosage and administration details
    See description for Pentosan polysulphate sodium then Placebo arm

    Investigational medicinal product name
    Pentosan polysulphate sodium
    Investigational medicinal product code
    Other name
    PPS, Rhinosul®
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Intranasal use
    Dosage and administration details
    See description for Pentosan polysulphate sodium then Placebo arm

    Number of subjects in period 2
    Pentosan polysulphate sodium then Placebo Placebo then Pentosan polysulphate sodium
    Started
    20
    20
    Completed
    19
    20
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline period
    Reporting group description
    All enrolled subjects

    Reporting group values
    Baseline period Total
    Number of subjects
    40 40
    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)
    40 40
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    25.8 ± 4.8 -
    Gender categorical
    Units: Subjects
        Female
    8 8
        Male
    32 32
    Ethnicity
    Units: Subjects
        Asian
    1 1
        Black
    1 1
        White
    38 38
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    74.9 ± 13.0 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    179.2 ± 9.4 -
    Subject analysis sets

    Subject analysis set title
    PPROT, Pentosan polysulphate sodium
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Pentosan polysulphate sodium data for all randomised subjects who (i) were deemed to have no major protocol violations that could interfere with the primary objective of the study and (ii) took at least 22 of 28 full doses of the study drug, including all 3 morning doses and the first 2 evening doses during the last 3 days of allergen challenge (treatment days 12 to 14), according to the diary cards, during both treatment periods

    Subject analysis set title
    PPROT, Placebo
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Placebo data for all randomised subjects who (i) were deemed to have no major protocol violations that could interfere with the primary objective of the study and (ii) took at least 22 of 28 full doses of the study drug, including all 3 morning doses and the first 2 evening doses during the last 3 days of allergen challenge (treatment days 12 to 14), according to the diary cards, during both treatment periods

    Subject analysis set title
    FAS, Pentosan polysulphate sodium
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Pentosan polysulphate sodium data for all randomised subjects who (i) took at least 1 dose of study drug, (ii) received at least 1 allergen challenge and (iii) had at least 1 post-baseline assessment of any efficacy variable

    Subject analysis set title
    FAS, Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Placebo data for all randomised subjects who (i) took at least 1 dose of study drug, (ii) received at least 1 allergen challenge and (iii) had at least 1 post-baseline assessment of any efficacy variable

    Subject analysis set title
    Safety Set, Pentosan polysulphate sodium then Placebo arm
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomised subjects in the Pentosan polysulphate sodium then Placebo arm who received at least 1 dose of study drug

    Subject analysis set title
    Safety Set, Placebo then Pentosan polysulphate sodium arm
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomised subjects in the Placebo then Pentosan polysulphate sodium arm who received at least 1 dose of study drug

    Subject analysis sets values
    PPROT, Pentosan polysulphate sodium PPROT, Placebo FAS, Pentosan polysulphate sodium FAS, Placebo Safety Set, Pentosan polysulphate sodium then Placebo arm Safety Set, Placebo then Pentosan polysulphate sodium arm
    Number of subjects
    37
    37
    40
    40
    20
    20
    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)
    37
    37
    40
    40
    20
    20
        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)
    25.7 ± 4.8
    25.7 ± 4.8
    25.8 ± 4.8
    25.8 ± 4.8
    25.7 ± 3.6
    25.9 ± 5.8
    Gender categorical
    Units: Subjects
        Female
    8
    8
    8
    8
    3
    5
        Male
    29
    29
    32
    32
    17
    15
    Ethnicity
    Units: Subjects
        Asian
    1
    1
    1
    1
    1
    0
        Black
    1
    1
    1
    1
    1
    0
        White
    35
    35
    38
    38
    18
    20
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    74.8 ± 13.4
    74.8 ± 13.4
    74.9 ± 13.0
    74.9 ± 13.0
    77.2 ± 14.2
    72.7 ± 11.5
    Height
    Units: cm
        arithmetic mean (standard deviation)
    178.1 ± 8.9
    178.1 ± 8.9
    179.2 ± 9.4
    179.2 ± 9.4
    179.4 ± 9.1
    178.9 ± 9.9

    End points

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    End points reporting groups
    Reporting group title
    Baseline period
    Reporting group description
    All enrolled subjects
    Reporting group title
    Pentosan polysulphate sodium then Placebo
    Reporting group description
    Subjects received Pentosan polysulphate sodium (80 mg/day) during treatment period 1 and Placebo during treatment period 2. Subjects received IMP using 2 sprays per nostril twice daily. Nasal symptoms and PNIF ( Peak Nasal Inspiratory Flow) were assessed before each dose. During the last 7 days of each treatment period, an individualised allergen challenge was administered after the morning dose of IMP. Nasal symptoms were assessed 10 minutes after the allergen challenge.

    Reporting group title
    Placebo then Pentosan polysulphate sodium
    Reporting group description
    Subjects received Placebo during treatment period 1 and Pentosan polysulphate sodium (80 mg/day) during treatment period 2. Subjects received IMP using 2 sprays per nostril twice daily. Nasal symptoms and PNIF ( Peak Nasal Inspiratory Flow) were assessed before each dose. During the last 7 days of each treatment period, an individualised allergen challenge was administered after the morning dose of IMP. Nasal symptoms were assessed 10 minutes after the allergen challenge.

    Subject analysis set title
    PPROT, Pentosan polysulphate sodium
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Pentosan polysulphate sodium data for all randomised subjects who (i) were deemed to have no major protocol violations that could interfere with the primary objective of the study and (ii) took at least 22 of 28 full doses of the study drug, including all 3 morning doses and the first 2 evening doses during the last 3 days of allergen challenge (treatment days 12 to 14), according to the diary cards, during both treatment periods

    Subject analysis set title
    PPROT, Placebo
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Placebo data for all randomised subjects who (i) were deemed to have no major protocol violations that could interfere with the primary objective of the study and (ii) took at least 22 of 28 full doses of the study drug, including all 3 morning doses and the first 2 evening doses during the last 3 days of allergen challenge (treatment days 12 to 14), according to the diary cards, during both treatment periods

    Subject analysis set title
    FAS, Pentosan polysulphate sodium
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Pentosan polysulphate sodium data for all randomised subjects who (i) took at least 1 dose of study drug, (ii) received at least 1 allergen challenge and (iii) had at least 1 post-baseline assessment of any efficacy variable

    Subject analysis set title
    FAS, Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Placebo data for all randomised subjects who (i) took at least 1 dose of study drug, (ii) received at least 1 allergen challenge and (iii) had at least 1 post-baseline assessment of any efficacy variable

    Subject analysis set title
    Safety Set, Pentosan polysulphate sodium then Placebo arm
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomised subjects in the Pentosan polysulphate sodium then Placebo arm who received at least 1 dose of study drug

    Subject analysis set title
    Safety Set, Placebo then Pentosan polysulphate sodium arm
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomised subjects in the Placebo then Pentosan polysulphate sodium arm who received at least 1 dose of study drug

    Primary: Mean post-challenge TNSS over the last 3 days of allergen challenge

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    End point title
    Mean post-challenge TNSS over the last 3 days of allergen challenge
    End point description
    Nasal symptoms were monitored approximately 10 minutes after allergen challenge. TNSS (total nasal symptom score) was calculated as the sum of the scores for the following nasal symptoms, each scored on a scale from 1 to 3: (i) nasal secretion, (ii) nasal congestion and (iii) sneezing or nasal itching (whichever was more severe). TNSS has a value of 0 to 9.
    End point type
    Primary
    End point timeframe
    Last 3 days of allergen challenge (treatment days 12 to 14)
    End point values
    PPROT, Pentosan polysulphate sodium PPROT, Placebo FAS, Pentosan polysulphate sodium FAS, Placebo
    Number of subjects analysed
    37
    37
    40
    39
    Units: no units
        arithmetic mean (standard deviation)
    5.3 ± 1.7
    5.1 ± 1.6
    5.1 ± 1.7
    5.1 ± 1.6
    Statistical analysis title
    ANOVA, PPROT
    Statistical analysis description
    ANOVA model with subject, treatment period and treatment as fixed effects
    Comparison groups
    PPROT, Pentosan polysulphate sodium v PPROT, Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.5759 [2]
    Method
    ANOVA
    Confidence interval
    Notes
    [1] - Comparison of Pentosan polysulphate sodium versus Placebo in the 37 subjects with data for both Pentosan polysulphate sodium and Placebo. Note: Number of subjects included in analysis = 37.
    [2] - Not significant
    Statistical analysis title
    ANOVA, FAS
    Statistical analysis description
    ANOVA model with subject, treatment period and treatment as fixed effects
    Comparison groups
    FAS, Pentosan polysulphate sodium v FAS, Placebo
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.6083 [4]
    Method
    ANOVA
    Confidence interval
    Notes
    [3] - Comparison of Pentosan polysulphate sodium versus Placebo in the 39 subjects with data for both Pentosan polysulphate sodium and Placebo. Note: Number of subjects included in analysis = 39.
    [4] - Not significant

    Secondary: Mean morning TNSS over the last 3 days of allergen challenge

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    End point title
    Mean morning TNSS over the last 3 days of allergen challenge
    End point description
    Nasal symptoms were monitored within 30 minutes of waking. TNSS was calculated as the sum of the scores for (i) nasal secretion, (ii) nasal congestion and (iii) sneezing or nasal itching (whichever was more severe).
    End point type
    Secondary
    End point timeframe
    Last 3 days of allergen challenge (treatment days 12 to 14)
    End point values
    PPROT, Pentosan polysulphate sodium PPROT, Placebo FAS, Pentosan polysulphate sodium FAS, Placebo
    Number of subjects analysed
    37
    37
    40
    39
    Units: no units
        arithmetic mean (standard deviation)
    1.55 ± 1.18
    1.52 ± 1.34
    1.55 ± 1.18
    1.59 ± 1.48
    Statistical analysis title
    ANOVA, PPROT
    Statistical analysis description
    ANOVA model with subject, treatment period and treatment as fixed effects
    Comparison groups
    PPROT, Pentosan polysulphate sodium v PPROT, Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    = 0.8953 [6]
    Method
    ANOVA
    Confidence interval
    Notes
    [5] - Comparison of Pentosan polysulphate sodium versus Placebo in the 37 subjects with data for both Pentosan polysulphate sodium and Placebo. Note: Number of subjects included in analysis = 37.
    [6] - Not significant
    Statistical analysis title
    ANOVA, FAS
    Statistical analysis description
    ANOVA model with subject, treatment period and treatment as fixed effects
    Comparison groups
    FAS, Pentosan polysulphate sodium v FAS, Placebo
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.7166 [8]
    Method
    ANOVA
    Confidence interval
    Notes
    [7] - Comparison of Pentosan polysulphate sodium versus Placebo in the 39 subjects with data for both Pentosan polysulphate sodium and Placebo. Note: Number of subjects included in analysis = 39.
    [8] - Not significant

    Secondary: Mean evening TNSS over the last 3 days of allergen challenge

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    End point title
    Mean evening TNSS over the last 3 days of allergen challenge
    End point description
    Nasal symptoms were monitored between 20:00 and 24:00. TNSS was calculated as the sum of the scores for (i) nasal secretion, (ii) nasal congestion and (iii) sneezing or nasal itching (whichever was more severe).
    End point type
    Secondary
    End point timeframe
    Last 3 days of allergen challenge (treatment days 12 to 14)
    End point values
    PPROT, Pentosan polysulphate sodium PPROT, Placebo FAS, Pentosan polysulphate sodium FAS, Placebo
    Number of subjects analysed
    37
    37
    40
    39
    Units: no units
        arithmetic mean (standard deviation)
    1.76 ± 1.41
    1.40 ± 1.46
    1.79 ± 1.38
    1.48 ± 1.62
    Statistical analysis title
    ANOVA, PPROT
    Statistical analysis description
    ANOVA model with subject, treatment period and treatment as fixed effects
    Comparison groups
    PPROT, Pentosan polysulphate sodium v PPROT, Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.1526 [10]
    Method
    ANOVA
    Confidence interval
    Notes
    [9] - Comparison of Pentosan polysulphate sodium versus Placebo in the 37 subjects with data for both Pentosan polysulphate sodium and Placebo. Note: Number of subjects included in analysis = 37.
    [10] - Not significant
    Statistical analysis title
    ANOVA, FAS
    Statistical analysis description
    ANOVA model with subject, treatment period and treatment as fixed effects
    Comparison groups
    FAS, Pentosan polysulphate sodium v FAS, Placebo
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.2075 [12]
    Method
    ANOVA
    Confidence interval
    Notes
    [11] - Comparison of Pentosan polysulphate sodium versus Placebo in the 39 subjects with data for both Pentosan polysulphate sodium and Placebo. Note: Number of subjects included in analysis = 39.
    [12] - Not significant

    Secondary: Mean post-challenge PNIF over the last 3 days of allergen challenge

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    End point title
    Mean post-challenge PNIF over the last 3 days of allergen challenge
    End point description
    Subjects measured PNIF (peak nasal inspiratory flow) using a flow meter equipped with a facial mask immediately after post-allergen challenge monitoring of nasal symptoms. Subjects recorded 3 PNIF measurements, the highest of which was used in the analyses.
    End point type
    Secondary
    End point timeframe
    Last 3 days of allergen challenge (treatment days 12 to 14)
    End point values
    PPROT, Pentosan polysulphate sodium PPROT, Placebo FAS, Pentosan polysulphate sodium FAS, Placebo
    Number of subjects analysed
    37
    37
    40
    39
    Units: L/min
        arithmetic mean (standard deviation)
    133.2 ± 42.8
    136.4 ± 36.9
    131.3 ± 42.6
    135.7 ± 36.8
    Statistical analysis title
    ANOVA, PPROT
    Statistical analysis description
    ANOVA model with subject, treatment period and treatment as fixed effects
    Comparison groups
    PPROT, Placebo v PPROT, Pentosan polysulphate sodium
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    superiority [13]
    P-value
    = 0.3467 [14]
    Method
    ANOVA
    Confidence interval
    Notes
    [13] - Comparison of Pentosan polysulphate sodium versus Placebo in the 37 subjects with data for both Pentosan polysulphate sodium and Placebo. Note: Number of subjects included in analysis = 37.
    [14] - Not significant
    Statistical analysis title
    ANOVA, FAS
    Statistical analysis description
    ANOVA model with subject, treatment period and treatment as fixed effects
    Comparison groups
    FAS, Pentosan polysulphate sodium v FAS, Placebo
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    = 0.2687 [16]
    Method
    ANOVA
    Confidence interval
    Notes
    [15] - Comparison of Pentosan polysulphate sodium versus Placebo in the 39 subjects with data for both Pentosan polysulphate sodium and Placebo. Note: Number of subjects included in analysis = 39.
    [16] - Not significant

    Secondary: Mean morning PNIF over the last 3 days of allergen challenge

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    End point title
    Mean morning PNIF over the last 3 days of allergen challenge
    End point description
    Subjects measured PNIF immediately after morning monitoring of nasal symptoms. Subjects recorded 3 PNIF measurements, the highest of which was used in the analyses.
    End point type
    Secondary
    End point timeframe
    Last 3 days of allergen challenge (treatment days 12 to 14)
    End point values
    PPROT, Pentosan polysulphate sodium PPROT, Placebo FAS, Pentosan polysulphate sodium FAS, Placebo
    Number of subjects analysed
    37
    37
    40
    39
    Units: L/min
        arithmetic mean (standard deviation)
    155.41 ± 39.00
    156.49 ± 37.43
    152.17 ± 41.21
    155.38 ± 39.11
    Statistical analysis title
    ANOVA, PPROT
    Statistical analysis description
    ANOVA model with subject, treatment period and treatment as fixed effects
    Comparison groups
    PPROT, Placebo v PPROT, Pentosan polysulphate sodium
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    superiority [17]
    P-value
    = 0.7048 [18]
    Method
    ANOVA
    Confidence interval
    Notes
    [17] - Comparison of Pentosan polysulphate sodium versus Placebo in the 37 subjects with data for both Pentosan polysulphate sodium and Placebo. Note: Number of subjects included in analysis = 37.
    [18] - Not significant
    Statistical analysis title
    ANOVA, FAS
    Statistical analysis description
    ANOVA model with subject, treatment period and treatment as fixed effects
    Comparison groups
    FAS, Placebo v FAS, Pentosan polysulphate sodium
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    = 0.5238 [20]
    Method
    ANOVA
    Confidence interval
    Notes
    [19] - Comparison of Pentosan polysulphate sodium versus Placebo in the 39 subjects with data for both Pentosan polysulphate sodium and Placebo. Note: Number of subjects included in analysis = 39.
    [20] - Not significant

    Secondary: Mean evening PNIF over the last 3 days of allergen challenge

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    End point title
    Mean evening PNIF over the last 3 days of allergen challenge
    End point description
    Subjects measured PNIF immediately after evening monitoring of nasal symptoms. Subjects recorded 3 PNIF measurements, the highest of which was used in the analyses.
    End point type
    Secondary
    End point timeframe
    Last 3 days of allergen challenge (treatment days 12 to 14)
    End point values
    PPROT, Pentosan polysulphate sodium PPROT, Placebo FAS, Pentosan polysulphate sodium FAS, Placebo
    Number of subjects analysed
    37
    37
    40
    39
    Units: L/min
        arithmetic mean (standard deviation)
    159.23 ± 37.93
    169.23 ± 42.12
    156.46 ± 39.34
    167.31 ± 43.10
    Statistical analysis title
    ANOVA, PPROT
    Statistical analysis description
    ANOVA model with subject, treatment period and treatment as fixed effects
    Comparison groups
    PPROT, Placebo v PPROT, Pentosan polysulphate sodium
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    superiority [21]
    P-value
    = 0.0262 [22]
    Method
    ANOVA
    Confidence interval
    Notes
    [21] - Comparison of Pentosan polysulphate sodium versus Placebo in the 37 subjects with data for both Pentosan polysulphate sodium and Placebo. Note: Number of subjects included in analysis = 37.
    [22] - Significant difference in favour of Placebo
    Statistical analysis title
    ANOVA, FAS
    Statistical analysis description
    ANOVA model with subject, treatment period and treatment as fixed effects
    Comparison groups
    FAS, Placebo v FAS, Pentosan polysulphate sodium
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    superiority [23]
    P-value
    = 0.0177 [24]
    Method
    ANOVA
    Confidence interval
    Notes
    [23] - Comparison of Pentosan polysulphate sodium versus Placebo in the 39 subjects with data for both Pentosan polysulphate sodium and Placebo. Note: Number of subjects included in analysis = 39.
    [24] - Significant difference in favour of Placebo

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing of informed consent at Visit 1 (screening) to completion of the final study visit
    Adverse event reporting additional description
    AEs elicited with non-leading questions or directly observed or spontaneously volunteered by subjects were reported. Subjects were asked to telephone the study site to report any AEs that occurred in the week following Visit 1, and to record AEs occurring between visits on diary cards.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Pentosan polysulphate sodium treatment
    Reporting group description
    Adverse events that occurred in the Safety Set in relation to Pentosan polysulphate sodium treatment

    Reporting group title
    Placebo treatment
    Reporting group description
    Adverse events that occurred in the Safety Set in relation to Placebo treatment

    Serious adverse events
    Pentosan polysulphate sodium treatment Placebo treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 39 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Head injury
    Additional description: Subject was hit by a car when cycling during treatment period 1 (Pentosan polysulphate sodium). He sustained a head injury, was hospitalised and discontinued the study. The Investigator judged no causal relationship with study treatment,
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Pentosan polysulphate sodium treatment Placebo treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 40 (80.00%)
    24 / 39 (61.54%)
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    27 / 40 (67.50%)
    8 / 39 (20.51%)
         occurrences all number
    52
    13
    Nasal crusting
         subjects affected / exposed
    11 / 40 (27.50%)
    6 / 39 (15.38%)
         occurrences all number
    12
    6
    Nasal discomfort
         subjects affected / exposed
    8 / 40 (20.00%)
    3 / 39 (7.69%)
         occurrences all number
    9
    3
    Nasal dryness
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Nasal pruritus
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 39 (0.00%)
         occurrences all number
    2
    0
    Nasal septum disorder
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Nasal ulcer
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Rhinalgia
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 39 (5.13%)
         occurrences all number
    1
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 40 (0.00%)
    3 / 39 (7.69%)
         occurrences all number
    0
    3
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    2
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 40 (5.00%)
    7 / 39 (17.95%)
         occurrences all number
    2
    7

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Mar 2017
    A preliminary review of blinded data (prior to finalisation of the statistical analysis plan and database lock) revealed that 15/40 subjects would be excluded from the per-protocol set, as defined in the study protocol, because they failed to take “all 6 doses [of IMP] during the last 3 days of allergen challenge (treatment days 12 to 14; according to the diary cards), during both treatment periods”. With one exception, all subjects who failed to take all of these 6 doses of IMP failed to take the very last dose and only that dose. This last dose was scheduled to be taken after the final assessments (of nasal symptoms and peak nasal inspiratory flow) on the last day of the treatment period. Therefore, failure to take the final evening dose had no implications for the efficacy analyses. To increase the validity of the efficacy analyses, which use the per-protocol set as the primary analysis population, the per-protocol set was redefined as: "All randomised subjects who (i) are deemed to have no major protocol violations that could interfere with the primary objective of this study and (ii) took at least 22 of the 28 doses of the study medication, including all 3 morning doses and the first 2 evening doses during the last 3 days of allergen challenge (treatment days 12 to 14) according to the diary cards, during both treatment periods." NOTE: The actual date of the amendment is 24 April 2017 (i.e. after 22 March 2017, the global end of trial date).

    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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