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    Clinical Trial Results:
    Double-blind placebo-controlled proof-of-concept trial to demonstrate the anti-viral efficacy of different doses of azelastine in COVID-19 positive patients.

    Summary
    EudraCT number
    		 2020-005544-34
    Trial protocol
    		 DE  
    Global end of trial date
    26 Jun 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2022
    First version publication date
    13 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CARVIN
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ursapharm Arzneimittel GmbH
    Sponsor organisation address
    Industriestraße 35, Saarbrücken, Germany, 66129
    Public contact
    Dr. Peter Meiser, Leitung Med.-Wiss., Ursapharm Arzneimittel GmbH, peter.meiser@ursapharm.de
    Scientific contact
    Dr. Peter Meiser, Leitung Med.-Wiss., Ursapharm Arzneimittel GmbH, peter.meiser@ursapharm.de
    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
    01 Jun 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 May 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to assess the first data on efficacy of azelastine nasal spray in SARS-CoV-2 infected patients with regards to virus load in nasopharyngeal swabs.
    Protection of trial subjects
    Symptomatic treatments for COVID-19 (e.g., analgesic drugs) have been allowed, but the following concomitant medications and procedures that might would have interfered with the clinical results werw prohibited from one months before Day 1 of the trial to Day 11: - Any nasalia including nasal lavage fluids - Any concurrent antihistamine therapies
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Mar 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 90
    Worldwide total number of subjects
    90
    EEA total number of subjects
    90
    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)
    90
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from March 2021 until May 2021 using newspaper advertisments and information flyers in COVID testing centres.

    Pre-assignment
    Screening details
    		 Main Inclusion criteria Patients aged from 18 - 60 years, having the diagnosis of SARS-CoV-2 infection documented by a positive PCR test (patients do not need to suffer from COVID-19 symptoms) Main Exclusion criteria Patients requiring hospitalization, No enrolment permitted if COVID-19 testing was performed more than 48 hours ago

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active 1
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    0.1 % Azelastine nasal spray
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Nasal use
    Dosage and administration details
    1 puff per nostril, three times daily

    Arm title
    		 Active 2
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    0.02% Azelastine nasal spray
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Nasal use
    Dosage and administration details
    1 puff per nostril, three times daily

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Nasal use
    Dosage and administration details
    1 puff per nostril, three times daily

    Number of subjects in period 1
    		Active 1 Active 2 Placebo
    Started
    29
    31
    30
    Completed
    29
    31
    30

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Active 1
    Reporting group description
    		 -

    Reporting group title
    Active 2
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Active 1 Active 2 Placebo Total
    Number of subjects
    		 29 31 30 90
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Patients were aged 18 - 60 years
    Units: years
        arithmetic mean (standard deviation)
    		 37.66 ( 12.96 ) 33.81 ( 12.90 ) 35.67 ( 13.12 ) -
    Gender categorical
    Male or female patients were enrolled in this trial.
    Units: Subjects
        Female
    		 15 16 15 46
        Male
    		 14 15 15 44
    Subject analysis sets

    Subject analysis set title
    safety population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    safety population (baseline characteristics, adverse events)

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT population: all randomized patients who met key eligibility and evaluability criteria. This dataset was defined by the existence of evaluable viral load measurements at Day 1 (baseline) and at Day 11 or at the early termination visit, respectively.

    Subject analysis sets values
    		 safety population ITT population
    Number of subjects
    90
    81
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Patients were aged 18 - 60 years
    Units: years
        arithmetic mean (standard deviation)
    35.67 ( 12.94 )
    35.67 ( 12.94 )
    Gender categorical
    Male or female patients were enrolled in this trial.
    Units: Subjects
        Female
    46
    46
        Male
    44
    44

    End points

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    End points reporting groups
    Reporting group title
    Active 1
    Reporting group description
    		 -

    Reporting group title
    Active 2
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    safety population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    safety population (baseline characteristics, adverse events)

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT population: all randomized patients who met key eligibility and evaluability criteria. This dataset was defined by the existence of evaluable viral load measurements at Day 1 (baseline) and at Day 11 or at the early termination visit, respectively.

    Primary: Efficacy of the treatment with azelastine (PCR E gene)

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    End point title
    		 Efficacy of the treatment with azelastine (PCR E gene)
    End point description
    Primary endpoint of the efficacy of azelastine nasal spray in COVID-positive patients is the baseline adjusted course of the median of virus load in nasopharyngeal swabs of the three treatment groups at any of the six timepoints after baseline (PCR performed on E gene).
    End point type
    Primary
    End point timeframe
    day 1 to day 11
    End point values
    		 Active 1 Active 2 Placebo
    Number of subjects analysed
    27
    28
    26
    Units: quantitative viral load cp/ml
        median (standard deviation)
    -5.48 ( 2.29 )
    -5.81 ( 2.29 )
    -5.18 ( 2.00 )
    Statistical analysis title
    		 Decrease quantitive viral load (E gene)
    Comparison groups
    Active 1 v Active 2 v Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05 [1]
    Method
    		 t-test, 1-sided
    Confidence interval
    Notes
    [1] - overall statistical tests: Kruskal Wallis test Pairwise comparisons were performed by Mann Whitney U test. Due to Bonferroni correction statistically significance level was p<0.0167.

    Primary: Efficacy of the treatment with azelastine (PCR ORF gene)

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    End point title
    		 Efficacy of the treatment with azelastine (PCR ORF gene)
    End point description
    Primary endpoint of the efficacy of azelastine nasal spray in COVID-positive patients is the baseline adjusted course of the median of virus load in nasopharyngeal swabs of the three treatment groups at any of the six timepoints after baseline (PCR performed on ORF gene).
    End point type
    Primary
    End point timeframe
    day 1 to day 11
    End point values
    		 Active 1 Active 2 Placebo
    Number of subjects analysed
    27
    28
    26
    Units: quantitative viral load cp/ml
        median (standard deviation)
    -4.45 ( 2.26 )
    -4.02 ( 2.01 )
    -3.79 ( 1.61 )
    Statistical analysis title
    		 Decrease quantitative viral load (ORF gene)
    Comparison groups
    Active 1 v Active 2 v Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05 [2]
    Method
    		 t-test, 1-sided
    Confidence interval
    Notes
    [2] - overall statistical test: Kruskal Wallis test Pairwise comparison performed by Mann Whitney U test. Due to Bonferroni correction statistically significance level was p<0.0167.

    Secondary: 10-fold decrease in virus load

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    End point title
    		 10-fold decrease in virus load
    End point description
    Proportion of patients who show a 10-fold decrease in virus load of SARS-CoV-2 within 3 days of treatment
    End point type
    Secondary
    End point timeframe
    day 1 to day 4
    End point values
    		 Active 1 Active 2 Placebo
    Number of subjects analysed
    27
    28
    26
    Units: Percentage
        10-fold decrease in viral load
    70
    59
    62
    No statistical analyses for this end point

    Secondary: change in sum symptom score

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    End point title
    		 change in sum symptom score
    End point description
    The change in symptom severity (anosmia, ageusia, fever, cough, sore throat, shortness of breath, coryza, general weakness, headache, aching limbs, loss of appetite, pneumonia, nausea, abdominal pain, vomiting, diarrhoea, conjunctivitis, rash, lymph node swelling, apathy, somnolence) from baseline presented as total symptom score.
    End point type
    Secondary
    End point timeframe
    day 1 to day 11
    End point values
    		 Active 1 Active 2 Placebo
    Number of subjects analysed
    27
    28
    26
    Units: sum score
    geometric mean (standard deviation)
        sum symptom score
    -12.74 ( 10.74 )
    -8.38 ( 9.42 )
    -11.12 ( 9.45 )
    No statistical analyses for this end point

    Secondary: Patient state (WHO COVID-19 status)

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    End point title
    		 Patient state (WHO COVID-19 status)
    End point description
    The change in patient state using a 11-category ordinal score as proposed by the WHO [A minimal common outcome measure set for COVID-19 clinical research. Lancet Infect Dis 2020; 20:e192-97]. The investigator will assess the patient state as uninfected: no viral RNA detected (0); ambulatory mild disease: asymptomatic, viral RNA detected (1), OR symptomatic; independent (2); OR symptomatic; assistance needed (3); hospitalized moderate disease: hospitalized, no oxygen therapy* (4); OR hospitalized; oxygen by mask or nasal prongs (5); hospitalized severe disease: hospitalized; oxygen by NIV or high-flow (6), OR intubation and mechanical ventilation, pO2/FiO2 >= 150 or SpO2/FiO2 >= 200 (7) OR mechanical ventilation or vasopressors pO2/FiO2 < 150 (SpO2/FiO2 < 200 (8); OR mechanical ventilation pO2/FiO2 < 150 and vasopressors, dialysis, or ECMO (9); Dead: Dead (10). (*if hospitalised for isolation only, record status as for ambulatory patient.)
    End point type
    Secondary
    End point timeframe
    day 1 to day 60
    End point values
    		 Active 1 Active 2 Placebo
    Number of subjects analysed
    29
    31
    30
    Units: 11-category ordinal score
        patient status (WHO COVID-19 status)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: change in Quality of Life (SF-36)

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    End point title
    		 change in Quality of Life (SF-36)
    End point description
    The change in quality of life as assessed by the SF-36 generic quality of life questionnaire.
    End point type
    Secondary
    End point timeframe
    day 1 to day 11
    End point values
    		 Active 1 Active 2 Placebo
    Number of subjects analysed
    27
    28
    26
    Units: sum score
    median (standard deviation)
        SF-36 sum score (physical parameters)
    5.73 ( 9.63 )
    -0.46 ( 10.58 )
    3.97 ( 8.20 )
        SF-36 sum score (mental parameters)
    0.16 ( 9.93 )
    -2.43 ( 9.21 )
    5.12 ( 10.47 )
    No statistical analyses for this end point

    Secondary: Safety

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    End point title
    		 Safety
    End point description
    Occurance of Adverse Events
    End point type
    Secondary
    End point timeframe
    D1 - D60
    End point values
    		 Active 1 Active 2 Placebo
    Number of subjects analysed
    29
    31
    30
    Units: AEs
    16
    13
    12
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    D1 - D60 overall trial
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Active 1
    Reporting group description
    		 -

    Reporting group title
    Active 2
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Active 1 Active 2 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Active 1 Active 2 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 29 (55.17%)
    13 / 31 (41.94%)
    22 / 30 (73.33%)
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    loss of smell
         subjects affected / exposed
    2 / 29 (6.90%)
    3 / 31 (9.68%)
    1 / 30 (3.33%)
         occurrences all number
    2
    3
    1
    loss of taste
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    sleepiness
         subjects affected / exposed
    3 / 29 (10.34%)
    5 / 31 (16.13%)
    5 / 30 (16.67%)
         occurrences all number
    3
    5
    5
    taste bitter
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    1
    nasal mucosa swelling
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    nasal sinus blockage
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    nose bleed
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    sinus pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    dry nasal mucosa
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    common cold
         subjects affected / exposed
    4 / 29 (13.79%)
    3 / 31 (9.68%)
    5 / 30 (16.67%)
         occurrences all number
    4
    3
    5
    Conjunctivitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 31 (0.00%)
    4 / 30 (13.33%)
         occurrences all number
    1
    0
    4
    Rhinitis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Mar 2021
    Increase in the compensation for expenses of study subjects due to increased time spent on the reporting of patient-reported outcome
    26 Apr 2021
    Involvement of an additional trial site

    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
    For support, Contact us.
    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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