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    Clinical Trial Results:
    Demonstration of therapeutic equivalence/non-inferiority as well as early onset of action of the novel water-soluble budesonide nasal spray (Budesolv) compared with marketed Rhinocort® aqua 64 in patients suffering from grass pollen induced allergic rhinitis/rhinoconjunctivitis with or without controlled asthma.

    Summary
    EudraCT number
    		 2018-001324-19
    Trial protocol
    		 AT  
    Global end of trial date
    05 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 May 2021
    First version publication date
    23 May 2021
    Other versions
    Summary report(s)
    		 Fast effectiveness of solubilized low-dose budesonide nasal spray in allergic rhinitis

    Trial information

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    Trial identification
    Sponsor protocol code
    BDS_18_01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03755557
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Marinomed Biotech AG
    Sponsor organisation address
    Hovengasse 25, Korneuburg, Austria, 2100
    Public contact
    Project manager, Marinomed Biotech AG, +43 1250774460, andreas.goessl@marinomed.com
    Scientific contact
    Project manager, Marinomed Biotech AG, +43 1250774460, andreas.goessl@marinomed.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
    20 Nov 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial is to demonstrate therapeutic equivalence/non-inferiority between Budesolv 10 and Rhinocort® aqua 64, a marketed comparator containing the same compound (budesonide), in patients suffering from grass pollen induced allergic rhinitis/rhinoconjunctivitis with or without controlled asthma on day 8 of treatment.
    Protection of trial subjects
    This study was performed in compliance with the ICH E6 Guideline for Good Clinical Practice, the principles that have their origin in the Declaration of Helsinki and local laws and regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Sep 2018
    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
    Austria: 83
    Worldwide total number of subjects
    83
    EEA total number of subjects
    83
    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)
    83
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited from one study site in Austria.

    Pre-assignment
    Screening details
    		 Patients were screened for appropriate allergic response. A Total Nasal Symptom Score (TNSS) of at least 6 points out of 12 within the first two hours in the grass pollen challenge chamber was required to be included into the study.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Rhinocort aqua 64
    Arm description
    		 Rhinocort aqua 64 nasal spray - budesonide suspension 83 subjects were randomised. 8 subjects were lost to follow up.75 subjects completed the trial per protocol.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rhinocort aqua 64 nasal spray
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, suspension
    Routes of administration
    Intranasal use
    Dosage and administration details
    once daily 2 puffs per nostil; for 8 days

    Arm title
    		 Budesolv 10 micrograms
    Arm description
    		 Budesolv nasal spray, solution, 200mg/ml budesonide 83 subjects were randomised. 8 subjects were lost to follow up.75 subjects completed the trial per protocol.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Budesonide 10 micrograms, nasal spray
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Intranasal use
    Dosage and administration details
    once daily two puffs per nostril; for 8 days

    Arm title
    		 Placebo nasal spray
    Arm description
    		 Matching Placebo to Budesolv 10 nasal spray 83 subjects were randomised. 8 subjects were lost to follow up.75 subjects completed the trial per protocol.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo nasal spray
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Intranasal use
    Dosage and administration details
    once daily two puffs per nostril; for 8 days

    Number of subjects in period 1
    		Rhinocort aqua 64 Budesolv 10 micrograms Placebo nasal spray
    Started
    75
    75
    75
    wash-out 1
    75
    75
    75
    wash-out 2
    75
    75
    75
    Completed
    75
    75
    75

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rhinocort aqua 64
    Reporting group description
    		 Rhinocort aqua 64 nasal spray - budesonide suspension 83 subjects were randomised. 8 subjects were lost to follow up.75 subjects completed the trial per protocol.

    Reporting group title
    Budesolv 10 micrograms
    Reporting group description
    		 Budesolv nasal spray, solution, 200mg/ml budesonide 83 subjects were randomised. 8 subjects were lost to follow up.75 subjects completed the trial per protocol.

    Reporting group title
    Placebo nasal spray
    Reporting group description
    		 Matching Placebo to Budesolv 10 nasal spray 83 subjects were randomised. 8 subjects were lost to follow up.75 subjects completed the trial per protocol.

    Reporting group values
    		 Rhinocort aqua 64 Budesolv 10 micrograms Placebo nasal spray Total
    Number of subjects
    		 75 75 75 75
    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)
    		 75 75 75 75
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 31 (20 to 61) 31 (20 to 61) 31 (20 to 61) -
    Gender categorical
    Units: Subjects
        Female
    		 45 45 45 45
        Male
    		 30 30 30 30
    Subject analysis sets

    Subject analysis set title
    Non-inferiority assessment on Day 8
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    In the randomised placebo controlled cross-over non-inferiority trial efficacy analysis was done on day 8 of treatment

    Subject analysis set title
    Early onset of action on day 1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    In the randomised placebo controlled cross-over trial early onset of action was measured after initial single treatment.

    Subject analysis sets values
    		 Non-inferiority assessment on Day 8 Early onset of action on day 1
    Number of subjects
    75
    78
    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)
    75
    78
        From 65-84 years
    0
    0
        85 years and over
    0
    0
    Age continuous
    Units: years
        median (full range (min-max))
    31 (20 to 61)
    31 (20 to 61)
    Gender categorical
    Units: Subjects
        Female
    44
    46
        Male
    31
    32

    End points

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    End points reporting groups
    Reporting group title
    Rhinocort aqua 64
    Reporting group description
    		 Rhinocort aqua 64 nasal spray - budesonide suspension 83 subjects were randomised. 8 subjects were lost to follow up.75 subjects completed the trial per protocol.

    Reporting group title
    Budesolv 10 micrograms
    Reporting group description
    		 Budesolv nasal spray, solution, 200mg/ml budesonide 83 subjects were randomised. 8 subjects were lost to follow up.75 subjects completed the trial per protocol.

    Reporting group title
    Placebo nasal spray
    Reporting group description
    		 Matching Placebo to Budesolv 10 nasal spray 83 subjects were randomised. 8 subjects were lost to follow up.75 subjects completed the trial per protocol.

    Subject analysis set title
    Non-inferiority assessment on Day 8
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    In the randomised placebo controlled cross-over non-inferiority trial efficacy analysis was done on day 8 of treatment

    Subject analysis set title
    Early onset of action on day 1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    In the randomised placebo controlled cross-over trial early onset of action was measured after initial single treatment.

    Primary: Total nasal symptom score

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    End point title
    		 Total nasal symptom score [1]
    End point description
    The TNSS was the sum of the symptoms “nasal congestion”, “rhinorrhea”, “itchy nose” and “sneezing”. Each individual symptom was scored on a 4-point categorical scale from 0-3 (where “0”= none, “1”=mild, “2”=moderate, “3”=severe).
    End point type
    Primary
    End point timeframe
    Mean 2-6 h assessed on day 8
    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: Due to the cross-over setting and the non-inferiority assessment statistics for all the arms in the baseline period can not be indicated. Please refer to the uploaded publication to see the study setting and the results.
    End point values
    		 Rhinocort aqua 64 Budesolv 10 micrograms
    Number of subjects analysed
    75
    75
    Units: TNSS points
        arithmetic mean (confidence interval 95%)
    5.05 (4.41 to 5.68)
    4.98 (4.39 to 5.57)
    Statistical analysis title
    		 Non-inferiority Rhinocort/Budesolv
    Statistical analysis description
    As it is not foreseen to enter such a complex trial setting, we uploaded already published results in Clinical Experimental Allergy 2020. The total number of subjects analysed were 75 but as this is a cross-over trail the subjects analysed below are featuring as 150 as the number of subjects adds up on selecting the two arms that are being compared.
    Comparison groups
    Rhinocort aqua 64 v Budesolv 10 micrograms
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.15
    Notes
    [2] - A 95% confidence interval was calculated for the mean difference between the two active treatments. Non-inferiority could be stated if the upper limit of the confidence interval did not exceed mean reference plus 15%. The upper limit of the 95% confidence interval of the individual differences (Rhinocort® aqua 64 – Budesolv 10) was 0.64. Mean sum of scores (Budesolv) + 0.64 is 5.62. This value is below 5.80 ([mean Rhinocort® aqua 64] +15%). Non-inferiority was shown.

    Secondary: Active anterior rhinomanometry

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    End point title
    		 Active anterior rhinomanometry [3]
    End point description
    Active anterior rhinomanometry was measured as objective parameter to support recorded subjective symptoms scores. Non-inferiority margin: Mean of active control (Rhinocort® aqua 64) - 15% = 319.0 Non-inferiority margin*: Lower 95% confidence interval of active control (Rhinocort® aqua 64) - 15% = 331.8. Mean difference (Rhinocort® aqua 64 – Budesolv 10) was -8.58 ± 116.60. The lower limit of the 95% confidence interval of the difference was -35.41. Mean sum of scores of test treatment (Budesolv 10, 383.87) -35.41 is 348.46, and thus falls above both margins (319.0 and 331.8). Hence, non-inferiority was shown for Nasal Airflow measured by rhinomanometry.
    End point type
    Secondary
    End point timeframe
    mean 2-6h on day 8
    Notes
    [3] - 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: Due to the cross-over setting and the non-inferiority assessment statistics for all the arms in the baseline period can not be indicated. Please refer to the uploaded publication to see the study setting and the results.
    End point values
    		 Rhinocort aqua 64 Budesolv 10 micrograms
    Number of subjects analysed
    75
    75
    Units: ml/sec
        arithmetic mean (confidence interval 95%)
    375.29 (337.51 to 413.06)
    383.87 (345.64 to 422.10)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported during the whole study period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Budesolv 10 micrograms
    Reporting group description
    		 Budesonide 10 nasal spray

    Reporting group title
    Rhinocort aqua 64
    Reporting group description
    		 Rhinocort nasal spray

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo nasal spray

    Serious adverse events
    		 Budesolv 10 micrograms Rhinocort aqua 64 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 78 (0.00%)
    0 / 78 (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
    		 Budesolv 10 micrograms Rhinocort aqua 64 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 78 (23.08%)
    15 / 78 (19.23%)
    18 / 78 (23.08%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 78 (3.85%)
    2 / 78 (2.56%)
    3 / 78 (3.85%)
         occurrences all number
    8
    8
    8
    Migraine
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 78 (0.00%)
    0 / 78 (0.00%)
         occurrences all number
    1
    1
    1
    Immune system disorders
    Allergy to animal
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 78 (0.00%)
    0 / 78 (0.00%)
         occurrences all number
    2
    2
    2
    Drug hypersensitivity
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 78 (1.28%)
    0 / 78 (0.00%)
         occurrences all number
    1
    1
    1
    Hypersensitivity
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 78 (1.28%)
    2 / 78 (2.56%)
         occurrences all number
    4
    4
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 78 (1.28%)
    1 / 78 (1.28%)
         occurrences all number
    3
    3
    3
    Dysphonia
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 78 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    1
    1
    1
    Epistaxis
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 78 (1.28%)
    0 / 78 (0.00%)
         occurrences all number
    4
    4
    4
    Nasal congestion
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 78 (0.00%)
    2 / 78 (2.56%)
         occurrences all number
    2
    2
    2
    Nasal discomfort
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 78 (0.00%)
    2 / 78 (2.56%)
         occurrences all number
    2
    2
    2
    Nasal pruritus
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 78 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    1
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 78 (2.56%)
    0 / 78 (0.00%)
         occurrences all number
    2
    2
    2
    Throat irritation
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 78 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    1
    1
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 78 (2.56%)
    1 / 78 (1.28%)
         occurrences all number
    4
    4
    4
    Pain in extremity
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 78 (1.28%)
    0 / 78 (0.00%)
         occurrences all number
    1
    1
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 78 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    1
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 78 (3.85%)
    4 / 78 (5.13%)
    3 / 78 (3.85%)
         occurrences all number
    10
    10
    10
    Tonsillitis
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 78 (0.00%)
    0 / 78 (0.00%)
         occurrences all number
    2
    2
    2

    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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    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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