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    Clinical Trial Results:
    A prospective, active-controlled, randomized, open label, single-center, multiple dose, two-period crossover clinical trial to assess the efficacy, safety and pharmacokinetics of a budesonide inhalation solution (AQ001S) compared to a budesonide inhalation suspension (comparator) in adults with mild asthma

    Summary
    EudraCT number
    		 2019-002849-38
    Trial protocol
    		 BE  
    Global end of trial date
    21 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Mar 2024
    First version publication date
    10 Mar 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AQ-PRO-005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aquilon Pharmaceuticals SA
    Sponsor organisation address
    Quai de la Boverie, 59, Liège, Belgium, 4020
    Public contact
    Clinical Operations, Aquilon Pharmaceuticals, 32 042292800, nait@aquilonpharma.com
    Scientific contact
    Clinical Operations, Aquilon Pharmaceuticals, 32 042292800, nait@aquilonpharma.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
    07 Sep 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Dec 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Dec 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the clinical trial were: - to compare the efficacy, i.e. the bronchoprotection, of AQ001S 0.125 mg/mL with the comparator - to assess the safety of AQ001S 0.125 mg/mL Based on the results of the non-clinical data, it was hypothesized that AQ001S 0.125 mg/mL would show a higher efficacy in treating asthma than the comparator used at the same dose.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and in compliance with all International Conference on Harmonisation (ICH), Good Clinical Practice (GCP) guidelines and the Belgian regulations. Each subject was given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the study and it was ensured that the informed consent form was signed and dated before any study specific procedure was performed. Opportunity was given to ask questions and subjects were allowed time to consider the information provided. Subjects were also notified that they were free to discontinue from the study at any time. Written informed consent was obtained from all subjects prior to initiation of the study. Trial subjects were monitored at baseline and daily throughout the trial by the study nurse and monthly by the study investigator. As-needed reliever medication (only short-acting beta2-agonist containing medication) were allowed.
    Background therapy
    		 Relevant treatment (prior/current medications, including all prescription/non-prescription medications) received by the subject within 3 months prior the screening visit were recorded. After a pre-trial visit, the study plan foresaw a wash out period of min. 60 days for subjects under inhaled corticosteroids.
    Evidence for comparator
    		 The comparator Budesonide TEVA is indicated for patients with bronchial asthma, who require maintenance treatment with inhaled glucocorticosteroids, for control of the underlying airways inflammation. It is a liquid suspension of budesonide for nebulization. Budesonide is an inhaled corticosteroid approved since 1981 for the treatment of asthma.
    Actual start date of recruitment
    23 Jul 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
    Belgium: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    23
    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)
    23
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were screened within 7 days prior to randomization from an asthma clinical center in Belgium. Subjects were to be aged 18 years to 65 years and have a documented clinical diagnosis of stable, persistent asthma for at least 3 months. Following all screening procedures, patients who satisfied eligibility criteria were randomized.

    Pre-assignment
    Screening details
    		 Screening included informed consent process, demographic data, review of exclusion criteria, medical and surgical history, respiratory and asthma history, medication history including respiratory medication, physical and clinical examination (ECG, spirometry, vital signs, laboratory tests, urine pregnancy test for females of reproductive age).

    Pre-assignment period milestones
    Number of subjects started
    		 24 [1]
    Number of subjects completed
    		 23

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    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: 24 patients were screened and signed informed consent. Among them, one subject withdraw his consent after the screening visit and was then not randomized. Only 23 subjects were randomized and received study medications.
    Period 1
    Period 1 title
    Cross-over by sequence (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    As this was an open-label study, no blinding procedure was used.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sequence A: AQ001S - Comparator
    Arm description
    		 AQ001S budesonide solution was administered for 29 (+2) days once daily (treatment period 1). Following a wash-out period of 14 (+2) days, the comparator Budesonide TEVA suspension was administered for 29 (+2) days once daily (treatment period 2).
    Arm type
    		 Experimental

    Investigational medicinal product name
    AQ001S 0.125 mg/mL
    Investigational medicinal product code
    Other name
    Budesonide 0.125 mg/mL inhalation solution
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Both products were administered by inhalation with a standard jet nebulizer using the same strength i.e. 0.125 mg budesonide/mL, according to the following administration scheme: - 0.25 mg budesonide administration (2mL) at day 0 of each treatment period - 0.125 mg budesonide daily administration (1mL) for 28 days per treatment period.

    Investigational medicinal product name
    Active comparator
    Investigational medicinal product code
    Other name
    Budesonide TEVA 0.125 mg/mL inhalation suspension
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Both products were administered by inhalation with a standard jet nebulizer using the same strength i.e. 0.125 mg budesonide/mL, according to the following administration scheme: - 0.25 mg budesonide administration (2mL) at day 0 of each treatment period - 0.125 mg budesonide daily administration (1mL) for 28 days per treatment period.

    Arm title
    		 Sequence B: Comparator - AQ001S
    Arm description
    		 Comparator Budesonide TEVA suspension was administered for 29 (+2) days once daily (treatment period 1). Following a washout period of 14 (+2) days, AQ001S budesonide solution was administered for 29 (+2) days once daily (treatment period 2).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Active comparator
    Investigational medicinal product code
    Other name
    Budesonide TEVA 0.125 mg/mL inhalation suspension
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Both products were administered by inhalation with a standard jet nebulizer using the same strength i.e. 0.125 mg budesonide/mL, according to the following administration scheme: - 0.25 mg budesonide administration (2mL) at day 0 of each treatment period - 0.125 mg budesonide daily administration (1mL) for 28 days per treatment period.

    Investigational medicinal product name
    AQ001S 0.125 mg/mL
    Investigational medicinal product code
    Other name
    Budesonide 0.125 mg/mL inhalation solution
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Both products were administered by inhalation with a standard jet nebulizer using the same strength, i.e., 0.125 mg budesonide/mL, according to the following administration scheme: - 0.25 mg budesonide administration (2 mL) at D0 of each treatment period. - 0.125 mg budesonide daily administration (1 mL) for 28 days per treatment period.

    Number of subjects in period 1
    		Sequence A: AQ001S - Comparator Sequence B: Comparator - AQ001S
    Started
    11
    12
    Completed
    11
    11
    Not completed
    0
    1
         Pregnancy
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sequence A: AQ001S - Comparator
    Reporting group description
    		 AQ001S budesonide solution was administered for 29 (+2) days once daily (treatment period 1). Following a wash-out period of 14 (+2) days, the comparator Budesonide TEVA suspension was administered for 29 (+2) days once daily (treatment period 2).

    Reporting group title
    Sequence B: Comparator - AQ001S
    Reporting group description
    		 Comparator Budesonide TEVA suspension was administered for 29 (+2) days once daily (treatment period 1). Following a washout period of 14 (+2) days, AQ001S budesonide solution was administered for 29 (+2) days once daily (treatment period 2).

    Reporting group values
    		 Sequence A: AQ001S - Comparator Sequence B: Comparator - AQ001S Total
    Number of subjects
    		 11 12 23
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 11 12 23
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
        Adults
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.3 ± 11.2 29.1 ± 9.9 -
    Gender categorical
    Units: Subjects
        Female
    		 4 8 12
        Male
    		 7 4 11
    Subject analysis sets

    Subject analysis set title
    AQ001S - efficacy population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The efficacy population encompasses all subjects that completed both treatment periods and for which the primary efficacy parameter PC20 was available at baseline (Visit 1) and after both treatment periods (Visit 2 and Visit 4).

    Subject analysis set title
    Comparator - efficacy population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The efficacy population encompasses all subjects that completed both treatment periods and for which the primary efficacy parameter PC20 was available at baseline (Visit 1) and after both treatment periods (Visit 2 and Visit 4).

    Subject analysis set title
    AQ001S - safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population includes all randomized subjects who received at least one dose of AQ001S 0.125 mg/ml.

    Subject analysis set title
    Comparator - safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population includes all randomized subjects who received at least one dose of the comparator Budesonide TEVA.

    Subject analysis sets values
    		 AQ001S - efficacy population Comparator - efficacy population AQ001S - safety population Comparator - safety population
    Number of subjects
    22
    22
    23
    23
    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)
    22
    22
    23
    23
        From 65-84 years
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
        Adults
    0
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    Sequence A: AQ001S - Comparator
    Reporting group description
    		 AQ001S budesonide solution was administered for 29 (+2) days once daily (treatment period 1). Following a wash-out period of 14 (+2) days, the comparator Budesonide TEVA suspension was administered for 29 (+2) days once daily (treatment period 2).

    Reporting group title
    Sequence B: Comparator - AQ001S
    Reporting group description
    		 Comparator Budesonide TEVA suspension was administered for 29 (+2) days once daily (treatment period 1). Following a washout period of 14 (+2) days, AQ001S budesonide solution was administered for 29 (+2) days once daily (treatment period 2).

    Subject analysis set title
    AQ001S - efficacy population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The efficacy population encompasses all subjects that completed both treatment periods and for which the primary efficacy parameter PC20 was available at baseline (Visit 1) and after both treatment periods (Visit 2 and Visit 4).

    Subject analysis set title
    Comparator - efficacy population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The efficacy population encompasses all subjects that completed both treatment periods and for which the primary efficacy parameter PC20 was available at baseline (Visit 1) and after both treatment periods (Visit 2 and Visit 4).

    Subject analysis set title
    AQ001S - safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population includes all randomized subjects who received at least one dose of AQ001S 0.125 mg/ml.

    Subject analysis set title
    Comparator - safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population includes all randomized subjects who received at least one dose of the comparator Budesonide TEVA.

    Primary: Change from baseline in PC20 after each treatment period

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    End point title
    		 Change from baseline in PC20 after each treatment period
    End point description
    Bronchoprotection was asssessed by PC20, as determined by methacholine challenge test. The primary efficacy endpoint were the change from baseline (visit 1) in PC20 after each treatment period.
    End point type
    Primary
    End point timeframe
    visit 1 (randomization/baseline) - visit 2 (end of treatment period 1) - visit 4 (end of treatment period 2)
    End point values
    		 AQ001S - efficacy population Comparator - efficacy population
    Number of subjects analysed
    22
    22
    Units: mg/mL
        arithmetic mean (confidence interval 95%)
    3.7 (0.9 to 6.5)
    1.2 (-0.7 to 3.0)
    Statistical analysis title
    		 AQ001S vs Comparator
    Statistical analysis description
    The primary efficacy endpoint is the change from baseline in PC20 after each treatment period (baseline is defined at Visit 1). For primary efficacy analysis, the mean PC20 changes from baseline between AQ001S 0.125 mg/ml and the comparator were compared by analysis of covariance (ANCOVA) for crossover design. A p-value was calculated for the difference of the parameter between AQ001S 0.125 mg/ml and comparator. Additionally, an adjusted 95%-CI for the mean difference was obtained by the ANCOVA
    Comparison groups
    AQ001S - efficacy population v Comparator - efficacy population
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.000813 [2]
    Method
    		 ANCOVA
    Parameter type
    		 difference/ratio of least square means
    Point estimate
    180.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 106.42
         upper limit
    		 306.48
    Notes
    [1] - in a cross-over design, groups examined should not be added. The number N = 44 (subject in this analysis) is an innate error of the EudraCT database system. Actual number of subjects in the analysis is 22.
    [2] - The difference/ratio of Least Square means [95%-CI] between the treatments was 180.60 [106.42; 306.48]. The p-value of 0.000813 for the difference of PC20 between AQ001S and Budesonide TEVA is significant showing a better bronchoprotection of AQ001S.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    adverse events/serious adverse events were recorded from the time the subjects signed the informed consent until the last study visit.
    Adverse event reporting additional description
    Treatment-emergent adverse events are reported and defined as AEs that started or worsened in severity on or after the first dose of study medication. The safety population was used to evaluate AEs. The safety population included all randomized subjects who received at least one dose of the study medication (AQ001S or comparator budesonide TEVA).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    AQ001S - safety population
    Reporting group description
    		 -

    Reporting group title
    Budesonide TEVA - safety population
    Reporting group description
    		 -

    Serious adverse events
    		 AQ001S - safety population Budesonide TEVA - safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 AQ001S - safety population Budesonide TEVA - safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 23 (21.74%)
    2 / 23 (8.70%)
    Injury, poisoning and procedural complications
    Contusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Limb injury
    Additional description: right thumb wound
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 23 (4.35%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Toothache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthmatic crisis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Dyspnoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
    Additional description: shoulder pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 23 (4.35%)
         occurrences all number
    1
    2
    Infections and infestations
    COVID-19 pneumonia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 23 (4.35%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Aug 2020
    After IEC review (Comité d’Ethique Hospitalo-Facultaire Universitaire de Liège) dated 24 March 2020 of the original CTA and subsequent CTA withdrawal, amendment 1 was resubmitted with the following substantial modifications: - Removal of CT scans and related FRI endpoints - Emphasis on the primary efficacy parameter, e.g. PC20, explaining the need for this assessment at Visits 1 (baseline), Visit 2 (end of first treatment period) and Visit 4 (end of second treatment period) - Addition of HIV and COVID-19 infections as exclusion criterion - Add of assessment of COVID-19 symptoms in physical and clinical examination

    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.
    No limitations or caveat are reported for this trial.
    For support, Contact us.
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