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    Clinical Trial Results:
    A 24-Week Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study Evaluating the Efficacy and Safety of Intranasal Administration of 186 and 372 μg of OPN-375 Twice a Day (BID) in Subjects with Chronic Sinusitis With or Without the Presence of Nasal Polyps

    Summary
    EudraCT number
    		 2019-000368-12
    Trial protocol
    		 GB   BG  
    Global end of trial date
    19 Jan 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Apr 2023
    First version publication date
    01 Apr 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    OPN-FLU-CS-3205
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND: 110089
    Sponsors
    Sponsor organisation name
    OptiNose US, Inc.
    Sponsor organisation address
    1020 Stony Hill Road, Suite 300, Yardley, PA, United States, 19067
    Public contact
    Global Clinical Operations, OptiNose US, Inc., john.messina@optinose.com
    Scientific contact
    Global Clinical Operations, OptiNose US, Inc., john.messina@optinose.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
    19 Jan 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Jan 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jan 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to compare the efficacy of intranasal administration of twice-daily doses of 186 and 372 μg of OPN-375 (fluticasone propionate) with placebo in subjects with chronic sinusitis using the following co-primary endpoints: • change from baseline in symptoms as measured by a composite score of nasal symptoms (CSNS): congestion, facial pain or pressure sensation, and nasal discharge (anterior and/or posterior) at the end of Week 4 and • change from baseline to Week 24/Early Termination (ET) in the average percent of the volume opacified (APOV) in the ethmoid and maxillary sinuses
    Protection of trial subjects
    Subjects will be informed that they are free to withdraw from study treatment and/or the study at any time at their own request without prejudice to their future medical care, or that they may be withdrawn at any time at the discretion of the investigator or Sponsor for safety, nonadherence to protocol requirements, or administrative reasons (eg, termination of study by Sponsor). Subjects wishing to withdraw from study treatment will be strongly encouraged to continue in the study and have all scheduled study procedures performed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Nov 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
    Russian Federation: 24
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    United States: 183
    Country: Number of subjects enrolled
    Poland: 90
    Country: Number of subjects enrolled
    Sweden: 8
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Bulgaria: 7
    Country: Number of subjects enrolled
    Georgia: 2
    Worldwide total number of subjects
    332
    EEA total number of subjects
    105
    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)
    277
    From 65 to 84 years
    54
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was carried out in subjects with chronic sinusitis with or without nasal polyps.

    Pre-assignment
    Screening details
    		 Subjects who met eligibility criteria at screening were dispensed a single-blind kit containing 2 placebo units marked “1” and “2” for use during the 7- to 21-day. Subjects self-administered 1 spray per nostril each morning and evening. Symptoms were assessed to ensure symptom eligibility criteria and a CT scan was obtained if necessary.

    Pre-assignment period milestones
    Number of subjects started
    		 556 [1]
    Number of subjects completed
    		 332

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Not eligible for study treatment: 224
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 224 subjects failed screening and were never enrolled into the study
    Period 1
    Period 1 title
    Double-blind Treatment Phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo nasal spray, 1 or 2 sprays per nostril twice daily
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    1 or 2 sprays per nostril twice daily

    Arm title
    		 OPN-375 (186 μg BID)
    Arm description
    		 OPN-375 1 spray per nostril (186 μg) twice daily (BID)
    Arm type
    		 Experimental

    Investigational medicinal product name
    OPN-375
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    1 spray per nostril (186 μg per dose)

    Arm title
    		 OPN-375 (372 μg BID)
    Arm description
    		 OPN-375 2 sprays per nostril (372 μg) twice daily (BID)
    Arm type
    		 Experimental

    Investigational medicinal product name
    OPN-375
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    2 sprays per nostril (372 μg per dose)

    Number of subjects in period 1
    		Placebo OPN-375 (186 μg BID) OPN-375 (372 μg BID)
    Started
    112
    111
    109
    Completed
    96
    102
    101
    Not completed
    16
    9
    8
         Consent withdrawn by subject
    1
    -
    1
         Adverse event, non-fatal
    3
    2
    2
         Not specified
    -
    2
    2
         Lost to follow-up
    2
    1
    1
         Lack of efficacy
    9
    4
    2
         Protocol deviation
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo nasal spray, 1 or 2 sprays per nostril twice daily

    Reporting group title
    OPN-375 (186 μg BID)
    Reporting group description
    		 OPN-375 1 spray per nostril (186 μg) twice daily (BID)

    Reporting group title
    OPN-375 (372 μg BID)
    Reporting group description
    		 OPN-375 2 sprays per nostril (372 μg) twice daily (BID)

    Reporting group values
    		 Placebo OPN-375 (186 μg BID) OPN-375 (372 μg BID) Total
    Number of subjects
    		 112 111 109 332
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 89 95 93 277
        From 65-84 years
    		 23 16 15 54
        85 years and over
    		 0 0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 49.2 ( 15.26 ) 48.4 ( 13.85 ) 49.6 ( 13.49 ) -
    Gender categorical
    Units: Subjects
        Female
    		 51 47 43 141
        Male
    		 61 64 66 191
    Race
    Units: Subjects
        White
    		 101 99 99 299
        American Indian or Alaska Native
    		 0 1 0 1
        Black or African American
    		 6 10 4 20
        Asian
    		 4 1 5 10
        Other
    		 1 0 1 2
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 8 1 9 18
        Not Hispanic or Latino
    		 104 110 100 314
    Previous or current diagnosis of nasal polyps
    Units: Subjects
        Yes
    		 78 78 77 233
        No
    		 34 33 32 99
    Number of acute sinusitis exacerbations treated with an antibiotic or oral steroids in last year
    Units: Subjects
        0 acute sinusitis exacerbations
    		 50 48 49 147
        1 acute sinusitis exacerbation
    		 22 23 29 74
        2 acute sinusitis exacerbations
    		 17 15 11 43
        3 acute sinusitis exacerbations
    		 14 13 9 36
        4 acute sinusitis exacerbations
    		 5 9 9 23
        5 acute sinusitis exacerbations
    		 2 2 1 5
        6 acute sinusitis exacerbations
    		 2 0 1 3
        7 acute sinusitis exacerbations
    		 0 1 0 1
    Nasal Polyp (Subgroups for Analyses in the Full Analysis Set)
    Units: Subjects
        Present
    		 69 69 67 205
        Absent
    		 41 41 40 122
        Not part of the Full Analysis Set
    		 2 1 2 5
    Prior Sinus Surgery (Subgroups for Analyses in the Full Analysis Set)
    Prior Sinus Surgery only counts any ethmoidectomy or maxillary antrostomy.
    Units: Subjects
        Yes
    		 44 51 42 137
        No
    		 66 59 65 190
        Not part of the Full Analysis Set
    		 2 1 2 5
    Weight
    Units: kilogram
        arithmetic mean (standard deviation)
    		 84.04 ( 21.610 ) 82.74 ( 20.882 ) 83.78 ( 18.803 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo nasal spray, 1 or 2 sprays per nostril twice daily

    Reporting group title
    OPN-375 (186 μg BID)
    Reporting group description
    		 OPN-375 1 spray per nostril (186 μg) twice daily (BID)

    Reporting group title
    OPN-375 (372 μg BID)
    Reporting group description
    		 OPN-375 2 sprays per nostril (372 μg) twice daily (BID)

    Primary: Change from Baseline to Week 4 in the 7-Day Average of Instantaneous Morning Composite Symptom Score

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    End point title
    		 Change from Baseline to Week 4 in the 7-Day Average of Instantaneous Morning Composite Symptom Score
    End point description
    LS = least squares. CSS = composite symptom score. -9999 = not applicable 0000 = not applicable
    End point type
    Primary
    End point timeframe
    Baseline to Week 4.
    End point values
    		 Placebo OPN-375 (186 μg BID) OPN-375 (372 μg BID)
    Number of subjects analysed
    110
    110
    107
    Units: LS Mean Change from Baseline in CSS
    least squares mean (confidence interval 95%)
        LS Mean Change (from baseline)
    -0.62 (-9999 to 0000)
    -1.58 (-9999 to 0000)
    -1.60 (-9999 to 0000)
        LS Mean Difference (active minus placebo)
    0000 (0000 to 0000)
    -0.97 (-1.41 to -0.52)
    -0.98 (-1.43 to -0.54)
    Statistical analysis title
    		 P-value versus Placebo
    Statistical analysis description
    P-value versus Placebo of OPN-375 (186 μg BID) and P-value versus Placebo of OPN-375 (372 μg BID). Inferential statistics are based on a linear mixed model for repeated measures (MMRM) including categorical effects for previous sinus surgery, nasal polyp status, treatment, week (2, 4), treatment-by-week interaction, and continuous covariate: baseline 7-day average score, with baseline score-by-week interaction.
    Comparison groups
    OPN-375 (186 μg BID) v OPN-375 (372 μg BID) v Placebo
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 MMRM
    Confidence interval

    Primary: Change from Baseline to Week 24/ET in APOV in Ethmoid and Maxillary Sinuses Combined

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    End point title
    		 Change from Baseline to Week 24/ET in APOV in Ethmoid and Maxillary Sinuses Combined
    End point description
    ET = early termination. APOV = average of the percentages of opacified volume. LS = least squares. -9999 = not applicable. 9999 = not applicable.
    End point type
    Primary
    End point timeframe
    Baseline to Week 24.
    End point values
    		 Placebo OPN-375 (186 μg BID) OPN-375 (372 μg BID)
    Number of subjects analysed
    110
    110
    107
    Units: LS Mean Change from Baseline
    least squares mean (confidence interval 95%)
        LS Mean Change (from baseline)
    -1.60 (-9999 to 9999)
    -5.58 (-9999 to 9999)
    -6.20 (-9999 to 9999)
        LS Mean Difference (active minus placebo)
    9999 (-9999 to 9999)
    -3.98 (-7.86 to -0.09)
    -4.59 (-8.41 to -0.78)
    Statistical analysis title
    		 P-value versus Placebo for OPN-375 (186 μg BID)
    Statistical analysis description
    Inferential statistics are based on multiple imputation of a linear analysis of covariance (ANCOVA) model including categorical effects for nasal polyp status, previous sinus surgery, treatment, and continuous baseline value as covariate.
    Comparison groups
    OPN-375 (186 μg BID) v Placebo
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.045
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 P-value versus Placebo for OPN-375 (372 μg BID)
    Comparison groups
    Placebo v OPN-375 (372 μg BID)
    Number of subjects included in analysis
    217
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.018
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [1] - Inferential statistics are based on multiple imputation of a linear analysis of covariance (ANCOVA) model including categorical effects for nasal polyp status, previous sinus surgery, treatment, and continuous baseline value as covariate.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Pretreatment (Screening/Run-in) period to end of treatment (Week 24)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 All enrolled/randomized subjects who received at least 1 dose of placebo

    Reporting group title
    OPN-375 186 μg
    Reporting group description
    		 All enrolled/randomized subjects who received at least 1 dose of randomized study treatment (186 μg twice daily).

    Reporting group title
    OPN-375 372 μg
    Reporting group description
    		 All enrolled/randomized subjects who received at least 1 dose of randomized study treatment (372 μg twice daily).

    Serious adverse events
    		 Placebo OPN-375 186 μg OPN-375 372 μg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 112 (2.68%)
    1 / 111 (0.90%)
    2 / 109 (1.83%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adenomyosis
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Alcoholic pancreatitis
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 112 (1.79%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1.5%
    Non-serious adverse events
    		 Placebo OPN-375 186 μg OPN-375 372 μg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    58 / 112 (51.79%)
    57 / 111 (51.35%)
    52 / 109 (47.71%)
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    0 / 112 (0.00%)
    2 / 111 (1.80%)
    0 / 109 (0.00%)
         occurrences all number
    0
    2
    0
    Injury, poisoning and procedural complications
    Vaccination complication
         subjects affected / exposed
    3 / 112 (2.68%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences all number
    3
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 112 (0.00%)
    2 / 111 (1.80%)
    1 / 109 (0.92%)
         occurrences all number
    0
    2
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 112 (0.89%)
    2 / 111 (1.80%)
    3 / 109 (2.75%)
         occurrences all number
    2
    2
    4
    Dizziness
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 111 (0.00%)
    3 / 109 (2.75%)
         occurrences all number
    0
    0
    3
    Parosmia
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 111 (0.00%)
    2 / 109 (1.83%)
         occurrences all number
    1
    0
    4
    Sinus headache
         subjects affected / exposed
    2 / 112 (1.79%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences all number
    2
    0
    0
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    0 / 112 (0.00%)
    2 / 111 (1.80%)
    0 / 109 (0.00%)
         occurrences all number
    0
    2
    0
    Eye disorders
    Cataract nuclear
         subjects affected / exposed
    0 / 112 (0.00%)
    5 / 111 (4.50%)
    4 / 109 (3.67%)
         occurrences all number
    0
    5
    4
    Cataract cortical
         subjects affected / exposed
    1 / 112 (0.89%)
    6 / 111 (5.41%)
    2 / 109 (1.83%)
         occurrences all number
    1
    6
    3
    Cataract subcapsular
         subjects affected / exposed
    2 / 112 (1.79%)
    1 / 111 (0.90%)
    1 / 109 (0.92%)
         occurrences all number
    2
    1
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 112 (1.79%)
    1 / 111 (0.90%)
    2 / 109 (1.83%)
         occurrences all number
    2
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 112 (0.89%)
    5 / 111 (4.50%)
    13 / 109 (11.93%)
         occurrences all number
    1
    8
    15
    Asthma
         subjects affected / exposed
    1 / 112 (0.89%)
    5 / 111 (4.50%)
    4 / 109 (3.67%)
         occurrences all number
    2
    6
    4
    Nasal polyps
    Additional description: One subject reported an AE of “nasal polyps exacerbation” which was coded to the MedDRA preferred term of “nasal polyps".
         subjects affected / exposed
    8 / 112 (7.14%)
    4 / 111 (3.60%)
    2 / 109 (1.83%)
         occurrences all number
    10
    4
    2
    Nasal congestion
         subjects affected / exposed
    5 / 112 (4.46%)
    1 / 111 (0.90%)
    2 / 109 (1.83%)
         occurrences all number
    6
    1
    4
    Nasal mucosal erosion
         subjects affected / exposed
    0 / 112 (0.00%)
    2 / 111 (1.80%)
    1 / 109 (0.92%)
         occurrences all number
    0
    2
    1
    Haemoptysis
         subjects affected / exposed
    0 / 112 (0.00%)
    2 / 111 (1.80%)
    0 / 109 (0.00%)
         occurrences all number
    0
    3
    0
    Oropharyngeal pain
         subjects affected / exposed
    2 / 112 (1.79%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences all number
    2
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 112 (0.00%)
    2 / 111 (1.80%)
    0 / 109 (0.00%)
         occurrences all number
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 111 (0.00%)
    3 / 109 (2.75%)
         occurrences all number
    0
    0
    4
    Back pain
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 111 (0.00%)
    2 / 109 (1.83%)
         occurrences all number
    0
    0
    2
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    9 / 112 (8.04%)
    7 / 111 (6.31%)
    6 / 109 (5.50%)
         occurrences all number
    14
    7
    6
    Nasopharyngitis
         subjects affected / exposed
    3 / 112 (2.68%)
    6 / 111 (5.41%)
    3 / 109 (2.75%)
         occurrences all number
    3
    6
    3
    Acute sinusitis
         subjects affected / exposed
    4 / 112 (3.57%)
    5 / 111 (4.50%)
    2 / 109 (1.83%)
         occurrences all number
    4
    6
    2
    COVID-19
         subjects affected / exposed
    6 / 112 (5.36%)
    2 / 111 (1.80%)
    5 / 109 (4.59%)
         occurrences all number
    6
    2
    5
    Chronic sinusitis
    Additional description: All AEs that coded to the MedDRA preferred term of “chronic sinusitis” experienced a CRS exacerbation.
         subjects affected / exposed
    7 / 112 (6.25%)
    5 / 111 (4.50%)
    1 / 109 (0.92%)
         occurrences all number
    8
    5
    2
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 112 (2.68%)
    3 / 111 (2.70%)
    1 / 109 (0.92%)
         occurrences all number
    4
    3
    1
    Influenza
         subjects affected / exposed
    0 / 112 (0.00%)
    3 / 111 (2.70%)
    0 / 109 (0.00%)
         occurrences all number
    0
    3
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 112 (2.68%)
    1 / 111 (0.90%)
    1 / 109 (0.92%)
         occurrences all number
    3
    1
    1
    Otitis media
         subjects affected / exposed
    0 / 112 (0.00%)
    2 / 111 (1.80%)
    0 / 109 (0.00%)
         occurrences all number
    0
    2
    0
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 112 (1.79%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences all number
    2
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Feb 2019
    Required subjects to administer 2 sprays per nostril for each dose of randomized study treatment; identified the co-primary endpoint related to nasal symptoms as the CSNS (“CSS” in all reports including this CSR); extended the single-blind run-in period from 14 to 21 days; modified inclusion/exclusion criteria; added assessments of NP grading to Weeks 4, 12, and 24; added IOP >21 mmHg, nasal septal perforation, and new onset or worsening of cataracts to withdrawal criteria; and provided additional details/clarifications for primary and IAs.
    05 Dec 2019
    Modified inclusion/exclusion criteria; added a biomarker substudy (no analysis done due to low number of participating subjects); revised the endpoint related to sinus volume occupied by disease from evaluating “each” maxillary and ethmoid sinus occupied by disease to evaluating the “worst” maxillary and “worst” ethmoid sinus; and added an assessment of the impact of treatment on subjects approved for surgery who no longer elect to undergo surgery.
    15 Jun 2020
    Amendments 3 (15 June 2022) and 4 (21 August 2020): Modified the protocol in reaction to the COVID-19 pandemic. Most notably, nasal endoscopy and associated polyp grading were removed from Visits 3 and 5; ocular examinations were removed; and subjects were allowed to delay the Week 24 Visit in case of COVID-19 or any upper respiratory infection and continue taking study drug until they could have the Week 24 Visit. Also, remote visits were allowed as needed and provisions were made for completing PROs remotely.
    21 Aug 2020
    Amendments 3 (15 June 2022) and 4 (21 August 2020): Modified the protocol in reaction to the COVID-19 pandemic. Most notably, nasal endoscopy and associated polyp grading were removed from Visits 3 and 5; ocular examinations were removed; and subjects were allowed to delay the Week 24 Visit in case of COVID-19 or any upper respiratory infection and continue taking study drug until they could have the Week 24 Visit. Also, remote visits were allowed as needed and provisions were made for completing PROs remotely.
    23 Jul 2021
    Modified key secondary and other secondary objectives/endpoints by moving SF-36 MCS and PCS endpoints from key secondary to other secondary; added key secondary objectives/endpoints to be analyzed using pooled data from Studies 3205 and 3206; and updated sample size text.
    07 Jan 2022
    Modified key secondary and other secondary objectives/endpoints by moving SNOT-22 total score from key secondary to other secondary; moving SNOT22 and PSQI endpoints to be analyzed using pooled data from Studies 3205 and 3206 from key secondary to other secondary; and adding CSS total score and frequency of acute exacerbations of chronic sinusitis (both analyzed using pooled data from Studies 3205 and 3206) in subjects who were using a standard nasal steroid at study entry to key secondary objectives. Other changes were removal of the biomarker substudy, updates of statistical methods to reflect the changes in key and other secondary objectives/endpoints, and modifications/clarifications to poor score assignments for various endpoints in case of intercurrent events and sensitivity analyses for the APOV co-primary endpoint.

    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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