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    Clinical Trial Results:
    A Double Blind, Multicentre, Randomised, Placebo-Controlled, 3-Way Cross-Over Study To Evaluate The Effect Of A Triple Combination Of Beclometasone Dipropionate And Formoterol Fumarate Plus Glycopyrronium (CHF5993) And A Dual Combination Of Beclometasone Dipropionate Plus Formoterol Fumarate (CHF1535) Both Administered Via pMDI On Lung Hyperinflation And Exercise Endurance Time In Subjects With Chronic Obstructive Pulmonary Disease (COPD).

    Summary
    EudraCT number
    		 2020-004718-36
    Trial protocol
    		 DE   HU   PL  
    Global end of trial date
    24 Feb 2023

    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

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLI-05993AA1-17
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici S.p.A
    Sponsor organisation address
    via Palermo, 26/A, PARMA, Italy, 43122
    Public contact
    Clinical Trial Transparency, Chiesi Farmaceutici S.p.A, clinicaltrials_info@chiesi.com
    Scientific contact
    Clinical Trial Transparency, Chiesi Farmaceutici S.p.A, clinicaltrials_info@chiesi.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
    03 Nov 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Feb 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of triple (CHF5993 100/6/10 μg) and dual (CHF1535 100/6 μg) ICS-containing combinations, both administered via pMDI, on exercise tolerance, lung hyperinflation and physical activity. A placebo-controlled design was selected to evaluate the effect of CHF5993 and CHF1535 on clinical parameters associated with cardiopulmonary exercise testing and to allow quantification of the response to study treatments.
    Protection of trial subjects
    The clinical study was performed in accordance with the principles that have their origin in the Declaration of Helsinki, and with local regulations. The study was carried out in accordance with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) notes for guidance on Good Clinical Practice (GCP) (ICH E6 Version 2). The samples were collected by qualified and well-trained healthcare professionals, investigators insured a close follow-up of safety signals, and that everything has been done to reduce the burden of study procedures (e.g. low volume of blood collection, no painful procedures, etc.).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Oct 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
    Poland: 73
    Country: Number of subjects enrolled
    Germany: 105
    Country: Number of subjects enrolled
    Hungary: 3
    Worldwide total number of subjects
    181
    EEA total number of subjects
    181
    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)
    77
    From 65 to 84 years
    104
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 181 subjects were enrolled, of whom 106 were randomised into one of the 6 treatment sequences. Of the 106 randomised subjects, all received at least 1 dose of study treatment.

    Pre-assignment
    Screening details
    		 The screening visit (V1, Week -1) was planned to assess the eligibility of subjects and obtain ICF signature if not done at the pre-screening visit. All inclusion/exclusion criteria, presented in the CSR synopsis, were assessed.

    Period 1
    Period 1 title
    Treatment Period 1, Period 2, Period 3 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject, Monitor, Data analyst
    Blinding implementation details
    The double-blind randomisation ensured that no systematic bias affected the treatment sequence allocation and subject/Investigator perceptions of the study treatments. The IRT system was used to assign all kits in order to have an inventory control and subject dosing tracking. The randomisation list was not available to subjects, Investigators, monitors or employees of the centre involved in the management of the clinical study before unblinding of the data, except in case of emergency.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment Sequence 1: BDP/FF/G // BDP/FF // Placebo
    Arm description
    		 The treatment sequence 1 BDP/FF/G // BDP/FF // Placebo consists of: - First treatment period with CHF5993 (BDP/FF/G pMDI 100/6/10 μg), 2 inhalations twice daily (BID); - Second treatment period with CHF1535 (BDP/FF pMDI 100/6 μg), 2 inhalations twice daily (BID); - Third treatment period with CHF5993 Placebo, 2 inhalations twice daily (BID). 17 subjects were randomized into this treatment sequence and completed the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CHF5993 (BDP/FF/G pMDI 100/6/10 μg), CHF1535 (BDP/FF pMDI 100/6 μg)
    Investigational medicinal product code
    Other name
    TRIMBOW® - CHF5993, FOSTER® - CHF1535
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    CHF5993 [TRIMBOW®, fixed combination of beclometasone dipropionate (BDP) 100 μg, plus formoterol fumarate (FF) 6 μg, plus glycopyrronium (G) 10 μg] and CHF1535 [FOSTER®, fixed combination of BDP 100 μg, plus FF 6 μg] are drug pressurised inhaler. They were given twice daily (BID), 2 inhalations (in the morning and in the evening). The total daily doses (TDD) administered are: - BDP/FF/G 400/24/40 µg for CHF5993 [TRIMBOW®]; - BDP/FF 400/24 µg for CHF1535 [FOSTER®]. The reference product is CHF5993 placebo, a drug pressurised inhaler. It was given twice daily (BID), 2 inhalations.

    Arm title
    		 Treatment Sequence 2: BDP/FF/G // Placebo // BDP/FF
    Arm description
    		 The treatment sequence 2 BDP/FF/G // Placebo // BDP/FF consists of: - First treatment period with CHF5993 (BDP/FF/G pMDI 100/6/10 μg), 2 inhalations twice daily (BID); - Second treatment period with CHF5993 Placebo, 2 inhalations twice daily (BID); - Third treatment period with CHF1535 (BDP/FF pMDI 100/6 μg), 2 inhalations twice daily (BID). 17 subjects were randomized into this treatment sequence, of whom 14 completed the study. 3 subjects discontinued for recording adverse events.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CHF5993 (BDP/FF/G pMDI 100/6/10 μg), CHF1535 (BDP/FF pMDI 100/6 μg)
    Investigational medicinal product code
    Other name
    TRIMBOW® - CHF5993, FOSTER® - CHF1535
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    CHF5993 [TRIMBOW®, fixed combination of beclometasone dipropionate (BDP) 100 μg, plus formoterol fumarate (FF) 6 μg, plus glycopyrronium (G) 10 μg] and CHF1535 [FOSTER®, fixed combination of BDP 100 μg, plus FF 6 μg] are drug pressurised inhaler. They were given twice daily (BID), 2 inhalations (in the morning and in the evening). The total daily doses (TDD) administered are: - BDP/FF/G 400/24/40 µg for CHF5993 [TRIMBOW®]; - BDP/FF 400/24 µg for CHF1535 [FOSTER®]. The reference product is CHF5993 placebo, a drug pressurised inhaler. It was given twice daily (BID), 2 inhalations.

    Arm title
    		 Treatment Sequence 3: BDP/FF // BDP/FF/G // Placebo
    Arm description
    		 The treatment sequence 3 BDP/FF // BDP/FF/G // Placebo consists of: - First treatment period with CHF1535 (BDP/FF pMDI 100/6 μg), 2 inhalations twice daily (BID); - Second treatment period with CHF5993 (BDP/FF/G pMDI 100/6/10 μg), 2 inhalations twice daily (BID); - Third treatment period with CHF5993 Placebo, 2 inhalations twice daily (BID). 18 subjects were randomized into this treatment sequence and completed the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CHF5993 (BDP/FF/G pMDI 100/6/10 μg), CHF1535 (BDP/FF pMDI 100/6 μg)
    Investigational medicinal product code
    Other name
    TRIMBOW® - CHF5993, FOSTER® - CHF1535
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    CHF5993 [TRIMBOW®, fixed combination of beclometasone dipropionate (BDP) 100 μg, plus formoterol fumarate (FF) 6 μg, plus glycopyrronium (G) 10 μg] and CHF1535 (FOSTER®, fixed combination of BDP 100 μg, plus FF 6 μg) are drug pressurised inhaler. They were given twice daily (BID), 2 inhalations (in the morning and in the evening). The total daily doses (TDD) administered are: - BDP/FF/G 400/24/40 µg for CHF5993 [TRIMBOW®]; - BDP/FF 400/24 µg for CHF1535 [FOSTER®]. The reference product is CHF5993 placebo, a drug pressurised inhaler. It was given twice daily (BID), 2 inhalations.

    Arm title
    		 Treatment Sequence 4: BDP/FF // Placebo // BDP/FF/G
    Arm description
    		 The treatment sequence 4 BDP/FF // Placebo // BDP/FF/G consists of: - First treatment period with CHF1535 (BDP/FF pMDI 100/6 μg), 2 inhalations twice daily (BID); - Second treatment period with CHF5993 Placebo, 2 inhalations twice daily (BID); - Third treatment period with CHF5993 (BDP/FF/G pMDI 100/6/10 μg), 2 inhalations twice daily (BID). 17 subjects were randomized into this treatment sequence, of whom 15 completed the study. 2 subjects discontinued for recording adverse events and COPD exacerbation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CHF5993 (BDP/FF/G pMDI 100/6/10 μg), CHF1535 (BDP/FF pMDI 100/6 μg)
    Investigational medicinal product code
    Other name
    TRIMBOW® - CHF5993, FOSTER® - CHF1535
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    CHF5993 [TRIMBOW®, fixed combination of beclometasone dipropionate (BDP) 100 μg, plus formoterol fumarate (FF) 6 μg, plus glycopyrronium (G) 10 μg] and CHF1535 (FOSTER®, fixed combination of BDP 100 μg, plus FF 6 μg) are drug pressurised inhaler. They were given twice daily (BID), 2 inhalations (in the morning and in the evening). The total daily doses (TDD) administered are: - BDP/FF/G 400/24/40 µg for CHF5993 [TRIMBOW®]; - BDP/FF 400/24 µg for CHF1535 [FOSTER®]. The reference product is CHF5993 placebo, a drug pressurised inhaler. It was given twice daily (BID), 2 inhalations.

    Arm title
    		 Treatment Sequence 5: Placebo // BDP/FF/G // BDP/FF
    Arm description
    		 The treatment sequence 5 Placebo // BDP/FF/G // BDP/FF consists of: - First treatment period with CHF5993 Placebo, 2 inhalations twice daily (BID); - Second treatment period with CHF5993 (BDP/FF/G pMDI 100/6/10 μg), 2 inhalations twice daily (BID); - Third treatment period with CHF1535 (BDP/FF pMDI 100/6 μg), 2 inhalations twice daily (BID). 18 subjects were randomized into this treatment sequence, of whom 15 completed the study. 3 subjects discontinued for recording adverse events and for consent withdrawal.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CHF5993 (BDP/FF/G pMDI 100/6/10 μg), CHF1535 (BDP/FF pMDI 100/6 μg)
    Investigational medicinal product code
    Other name
    TRIMBOW® - CHF5993, FOSTER® - CHF1535
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    CHF5993 [TRIMBOW®, fixed combination of beclometasone dipropionate (BDP) 100 μg, plus formoterol fumarate (FF) 6 μg, plus glycopyrronium (G) 10 μg] and CHF1535 (FOSTER®, fixed combination of BDP 100 μg, plus FF 6 μg) are drug pressurised inhaler. They were given twice daily (BID), 2 inhalations (in the morning and in the evening). The total daily doses (TDD) administered are: - BDP/FF/G 400/24/40 µg for CHF5993 [TRIMBOW®]; - BDP/FF 400/24 µg for CHF1535 [FOSTER®]. The reference product is CHF5993 placebo, a drug pressurised inhaler. It was given twice daily (BID), 2 inhalations.

    Arm title
    		 Treatment Sequence 6: Placebo // BDP/FF // BDP/FF/G
    Arm description
    		 The treatment sequence 6 Placebo // BDP/FF // BDP/FF/G consists of: - First treatment period with CHF5993 Placebo, 2 inhalations twice daily (BID); - Second treatment period with CHF1535 (BDP/FF pMDI 100/6 μg), 2 inhalations twice daily (BID); - Third treatment period with CHF5993 (BDP/FF/G pMDI 100/6/10 μg), 2 inhalations twice daily (BID). 19 subjects were randomized into this treatment sequence, of whom 16 completed the study. 3 subjects discontinued for recording adverse events and COPD exacerbation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CHF5993 (BDP/FF/G pMDI 100/6/10 μg), CHF1535 (BDP/FF pMDI 100/6 μg)
    Investigational medicinal product code
    Other name
    TRIMBOW® - CHF5993, FOSTER® - CHF1535
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    CHF5993 [TRIMBOW®, fixed combination of beclometasone dipropionate (BDP) 100 μg, plus formoterol fumarate (FF) 6 μg, plus glycopyrronium (G) 10 μg] and CHF1535 (FOSTER®, fixed combination of BDP 100 μg, plus FF 6 μg) are drug pressurised inhaler. They were given twice daily (BID), 2 inhalations (in the morning and in the evening). The total daily doses (TDD) administered are: - BDP/FF/G 400/24/40 µg for CHF5993 [TRIMBOW®]; - BDP/FF 400/24 µg for CHF1535 [FOSTER®]. The reference product is CHF5993 placebo, a drug pressurised inhaler. It was given twice daily (BID), 2 inhalations.

    Number of subjects in period 1 [1]
    		Treatment Sequence 1: BDP/FF/G // BDP/FF // Placebo Treatment Sequence 2: BDP/FF/G // Placebo // BDP/FF Treatment Sequence 3: BDP/FF // BDP/FF/G // Placebo Treatment Sequence 4: BDP/FF // Placebo // BDP/FF/G Treatment Sequence 5: Placebo // BDP/FF/G // BDP/FF Treatment Sequence 6: Placebo // BDP/FF // BDP/FF/G
    Started
    17
    17
    18
    17
    18
    19
    Completed
    17
    14
    18
    15
    15
    16
    Not completed
    0
    3
    0
    2
    3
    3
         Consent withdrawn by subject
    -
    -
    -
    -
    1
    -
         Adverse event, non-fatal
    -
    3
    -
    1
    2
    2
         COPD Exacerbation
    -
    -
    -
    1
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 181 subjects were enrolled, of whom 106 were randomised into one of the 6 treatment sequences. Of the 106 randomised subjects, all received at least 1 dose of study treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Sequence 1: BDP/FF/G // BDP/FF // Placebo
    Reporting group description
    		 The treatment sequence 1 BDP/FF/G // BDP/FF // Placebo consists of: - First treatment period with CHF5993 (BDP/FF/G pMDI 100/6/10 μg), 2 inhalations twice daily (BID); - Second treatment period with CHF1535 (BDP/FF pMDI 100/6 μg), 2 inhalations twice daily (BID); - Third treatment period with CHF5993 Placebo, 2 inhalations twice daily (BID). 17 subjects were randomized into this treatment sequence and completed the study.

    Reporting group title
    Treatment Sequence 2: BDP/FF/G // Placebo // BDP/FF
    Reporting group description
    		 The treatment sequence 2 BDP/FF/G // Placebo // BDP/FF consists of: - First treatment period with CHF5993 (BDP/FF/G pMDI 100/6/10 μg), 2 inhalations twice daily (BID); - Second treatment period with CHF5993 Placebo, 2 inhalations twice daily (BID); - Third treatment period with CHF1535 (BDP/FF pMDI 100/6 μg), 2 inhalations twice daily (BID). 17 subjects were randomized into this treatment sequence, of whom 14 completed the study. 3 subjects discontinued for recording adverse events.

    Reporting group title
    Treatment Sequence 3: BDP/FF // BDP/FF/G // Placebo
    Reporting group description
    		 The treatment sequence 3 BDP/FF // BDP/FF/G // Placebo consists of: - First treatment period with CHF1535 (BDP/FF pMDI 100/6 μg), 2 inhalations twice daily (BID); - Second treatment period with CHF5993 (BDP/FF/G pMDI 100/6/10 μg), 2 inhalations twice daily (BID); - Third treatment period with CHF5993 Placebo, 2 inhalations twice daily (BID). 18 subjects were randomized into this treatment sequence and completed the study.

    Reporting group title
    Treatment Sequence 4: BDP/FF // Placebo // BDP/FF/G
    Reporting group description
    		 The treatment sequence 4 BDP/FF // Placebo // BDP/FF/G consists of: - First treatment period with CHF1535 (BDP/FF pMDI 100/6 μg), 2 inhalations twice daily (BID); - Second treatment period with CHF5993 Placebo, 2 inhalations twice daily (BID); - Third treatment period with CHF5993 (BDP/FF/G pMDI 100/6/10 μg), 2 inhalations twice daily (BID). 17 subjects were randomized into this treatment sequence, of whom 15 completed the study. 2 subjects discontinued for recording adverse events and COPD exacerbation.

    Reporting group title
    Treatment Sequence 5: Placebo // BDP/FF/G // BDP/FF
    Reporting group description
    		 The treatment sequence 5 Placebo // BDP/FF/G // BDP/FF consists of: - First treatment period with CHF5993 Placebo, 2 inhalations twice daily (BID); - Second treatment period with CHF5993 (BDP/FF/G pMDI 100/6/10 μg), 2 inhalations twice daily (BID); - Third treatment period with CHF1535 (BDP/FF pMDI 100/6 μg), 2 inhalations twice daily (BID). 18 subjects were randomized into this treatment sequence, of whom 15 completed the study. 3 subjects discontinued for recording adverse events and for consent withdrawal.

    Reporting group title
    Treatment Sequence 6: Placebo // BDP/FF // BDP/FF/G
    Reporting group description
    		 The treatment sequence 6 Placebo // BDP/FF // BDP/FF/G consists of: - First treatment period with CHF5993 Placebo, 2 inhalations twice daily (BID); - Second treatment period with CHF1535 (BDP/FF pMDI 100/6 μg), 2 inhalations twice daily (BID); - Third treatment period with CHF5993 (BDP/FF/G pMDI 100/6/10 μg), 2 inhalations twice daily (BID). 19 subjects were randomized into this treatment sequence, of whom 16 completed the study. 3 subjects discontinued for recording adverse events and COPD exacerbation.

    Reporting group values
    		 Treatment Sequence 1: BDP/FF/G // BDP/FF // Placebo Treatment Sequence 2: BDP/FF/G // Placebo // BDP/FF Treatment Sequence 3: BDP/FF // BDP/FF/G // Placebo Treatment Sequence 4: BDP/FF // Placebo // BDP/FF/G Treatment Sequence 5: Placebo // BDP/FF/G // BDP/FF Treatment Sequence 6: Placebo // BDP/FF // BDP/FF/G Total
    Number of subjects
    		 17 17 18 17 18 19 106
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 6 8 9 9 8 11 51
        From 65-84 years
    		 11 9 9 8 10 8 55
        85 years and over
    		 0 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 67.1 ( 7.8 ) 66.2 ( 7.6 ) 64.8 ( 6.5 ) 65.6 ( 7.0 ) 65.1 ( 9.5 ) 63.6 ( 4.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 4 3 7 10 8 40
        Male
    		 9 13 15 10 8 11 66
    Race
    Units: Subjects
        White
    		 17 17 18 17 18 19 106
        Asian
    		 0 0 0 0 0 0 0
        Black or African American
    		 0 0 0 0 0 0 0
        Other
    		 0 0 0 0 0 0 0
    Smoking Status
    Units: Subjects
        Ex-smoker
    		 10 8 6 6 7 10 47
        Current smoker
    		 7 9 12 11 11 9 59
    Weight
    Units: Kg
        arithmetic mean (standard deviation)
    		 74.06 ( 18.97 ) 76.02 ( 11.19 ) 87.23 ( 15.44 ) 82.42 ( 13.47 ) 77.61 ( 16.11 ) 84.58 ( 18.94 ) -
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 25.58 ( 4.62 ) 25.66 ( 2.99 ) 28.44 ( 4.90 ) 27.78 ( 3.42 ) 26.75 ( 4.21 ) 28.36 ( 5.09 ) -

    End points

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    End points reporting groups
    Reporting group title
    Treatment Sequence 1: BDP/FF/G // BDP/FF // Placebo
    Reporting group description
    		 The treatment sequence 1 BDP/FF/G // BDP/FF // Placebo consists of: - First treatment period with CHF5993 (BDP/FF/G pMDI 100/6/10 μg), 2 inhalations twice daily (BID); - Second treatment period with CHF1535 (BDP/FF pMDI 100/6 μg), 2 inhalations twice daily (BID); - Third treatment period with CHF5993 Placebo, 2 inhalations twice daily (BID). 17 subjects were randomized into this treatment sequence and completed the study.

    Reporting group title
    Treatment Sequence 2: BDP/FF/G // Placebo // BDP/FF
    Reporting group description
    		 The treatment sequence 2 BDP/FF/G // Placebo // BDP/FF consists of: - First treatment period with CHF5993 (BDP/FF/G pMDI 100/6/10 μg), 2 inhalations twice daily (BID); - Second treatment period with CHF5993 Placebo, 2 inhalations twice daily (BID); - Third treatment period with CHF1535 (BDP/FF pMDI 100/6 μg), 2 inhalations twice daily (BID). 17 subjects were randomized into this treatment sequence, of whom 14 completed the study. 3 subjects discontinued for recording adverse events.

    Reporting group title
    Treatment Sequence 3: BDP/FF // BDP/FF/G // Placebo
    Reporting group description
    		 The treatment sequence 3 BDP/FF // BDP/FF/G // Placebo consists of: - First treatment period with CHF1535 (BDP/FF pMDI 100/6 μg), 2 inhalations twice daily (BID); - Second treatment period with CHF5993 (BDP/FF/G pMDI 100/6/10 μg), 2 inhalations twice daily (BID); - Third treatment period with CHF5993 Placebo, 2 inhalations twice daily (BID). 18 subjects were randomized into this treatment sequence and completed the study.

    Reporting group title
    Treatment Sequence 4: BDP/FF // Placebo // BDP/FF/G
    Reporting group description
    		 The treatment sequence 4 BDP/FF // Placebo // BDP/FF/G consists of: - First treatment period with CHF1535 (BDP/FF pMDI 100/6 μg), 2 inhalations twice daily (BID); - Second treatment period with CHF5993 Placebo, 2 inhalations twice daily (BID); - Third treatment period with CHF5993 (BDP/FF/G pMDI 100/6/10 μg), 2 inhalations twice daily (BID). 17 subjects were randomized into this treatment sequence, of whom 15 completed the study. 2 subjects discontinued for recording adverse events and COPD exacerbation.

    Reporting group title
    Treatment Sequence 5: Placebo // BDP/FF/G // BDP/FF
    Reporting group description
    		 The treatment sequence 5 Placebo // BDP/FF/G // BDP/FF consists of: - First treatment period with CHF5993 Placebo, 2 inhalations twice daily (BID); - Second treatment period with CHF5993 (BDP/FF/G pMDI 100/6/10 μg), 2 inhalations twice daily (BID); - Third treatment period with CHF1535 (BDP/FF pMDI 100/6 μg), 2 inhalations twice daily (BID). 18 subjects were randomized into this treatment sequence, of whom 15 completed the study. 3 subjects discontinued for recording adverse events and for consent withdrawal.

    Reporting group title
    Treatment Sequence 6: Placebo // BDP/FF // BDP/FF/G
    Reporting group description
    		 The treatment sequence 6 Placebo // BDP/FF // BDP/FF/G consists of: - First treatment period with CHF5993 Placebo, 2 inhalations twice daily (BID); - Second treatment period with CHF1535 (BDP/FF pMDI 100/6 μg), 2 inhalations twice daily (BID); - Third treatment period with CHF5993 (BDP/FF/G pMDI 100/6/10 μg), 2 inhalations twice daily (BID). 19 subjects were randomized into this treatment sequence, of whom 16 completed the study. 3 subjects discontinued for recording adverse events and COPD exacerbation.

    Subject analysis set title
    BDP/FF/G
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects who took CHF5993 (BDP/FF/G pMDI 100/6/10 μg), 2 inhalations BID via pMDI (in the morning and in the evening).

    Subject analysis set title
    BDP/FF
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects who took CHF1535 (BDP/FF pMDI 100/6 μg) 2 inhalations BID via pMDI (in the morning and in the evening).

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects who took CHF5993 Placebo, 2 inhalations BID via pMDI.

    Primary: CHF5993 (BDP/FF/G) vs. Placebo - Change from baseline in 2h post-dose IC after 3 weeks of treatment

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    End point title
    		 CHF5993 (BDP/FF/G) vs. Placebo - Change from baseline in 2h post-dose IC after 3 weeks of treatment
    End point description
    This primary efficacy variable was analysed on the ITT population using a linear mixed model. The model included treatment and period as fixed effects, baseline value of the current treatment period and baseline value averaged across all the treatment periods as covariates, and subject as a random effect.
    End point type
    Primary
    End point timeframe
    Baseline value was defined as the pre-dose IC value collected at the beginning of each treatment period (i.e., V2, V4 and V6).
    End point values
    		 BDP/FF/G Placebo
    Number of subjects analysed
    91 [1]
    89 [2]
    Units: score
        arithmetic mean (standard deviation)
    0.383 ( 0.323 )
    -0.024 ( 0.284 )
    Notes
    [1] - Number of subjects with available data/Number of subjects in the ITT set: 91/99
    [2] - Number of subjects with available data/Number of subjects in the ITT set: 89/105
    Statistical analysis title
    		 Change from baseline in 2h post-dose at week 3
    Statistical analysis description
    An unstructured covariance matrix was assumed, and the Kenward-Roger adjustment was used for the degrees of freedom. The adjusted means in each treatment group, the adjusted mean difference between treatments and their 95% CIs after 3 weeks of treatment were estimated by the model. Data are presented as adjusted mean differences with their 95% two-sided Confidence Intervals, and p value.
    Comparison groups
    BDP/FF/G v Placebo
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    0.315
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 0.38

    Primary: CHF1535 (BDP/FF) vs. Placebo - Change from baseline in 2h post-dose IC after 3 weeks of treatment

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    End point title
    		 CHF1535 (BDP/FF) vs. Placebo - Change from baseline in 2h post-dose IC after 3 weeks of treatment
    End point description
    This primary efficacy variable was analysed on the ITT population using a linear mixed model. The model included treatment and period as fixed effects, baseline value of the current treatment period and baseline value averaged across all the treatment periods as covariates, and subject as a random effect.
    End point type
    Primary
    End point timeframe
    Baseline value was defined as the pre-dose IC value collected at the beginning of each treatment period (i.e., V2, V4 and V6).
    End point values
    		 BDP/FF Placebo
    Number of subjects analysed
    91 [3]
    89 [4]
    Units: score
        arithmetic mean (standard deviation)
    0.203 ( 0.275 )
    -0.024 ( 0.284 )
    Notes
    [3] - Number of subjects with available data/Number of subjects in the ITT set: 91/99
    [4] - Number of subjects with available data/Number of subjects in the ITT set: 89/105
    Statistical analysis title
    		 Change from baseline in 2h post-dose at week 3
    Statistical analysis description
    An unstructured covariance matrix was assumed, and the Kenward-Roger adjustment was used for the degrees of freedom. The adjusted means in each treatment group, the adjusted mean difference between treatments and their 95% CIs after 3 weeks of treatment were estimated by the model. Data are presented as adjusted mean differences with their 95% two-sided Confidence Intervals, and p value.
    Comparison groups
    BDP/FF v Placebo
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    0.223
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 0.285

    Secondary: CHF5993 (BDP/FF/G) vs. Placebo - Change from baseline in IC at isotime after 3 weeks of treatment

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    End point title
    		 CHF5993 (BDP/FF/G) vs. Placebo - Change from baseline in IC at isotime after 3 weeks of treatment
    End point description
    Key-secondary variables were analysed using a linear model including treatment and period as fixed effects, baseline value of the current treatment period and baseline value averaged across all the treatment periods as covariates, and subject as a random effect.
    End point type
    Secondary
    End point timeframe
    The baseline IC value was collected at isotime at the beginning of each treatment period [V2, V4 and V6].
    End point values
    		 BDP/FF/G Placebo
    Number of subjects analysed
    92 [5]
    92 [6]
    Units: score
        arithmetic mean (standard deviation)
    0.266 ( 0.522 )
    -0.027 ( 0.435 )
    Notes
    [5] - Number of subjects with available data/Number of subjects in the ITT set: 92/99
    [6] - Number of subjects with available data/Number of subjects in the ITT set: 92/105
    Statistical analysis title
    		 Change from baseline in IC at isotime at week 3
    Statistical analysis description
    An unstructured covariance matrix was assumed, and the Kenward-Roger adjustment was used for the degrees of freedom. Data are presented as adjusted mean differences with their 95% two-sided Confidence Intervals, and p value.
    Comparison groups
    BDP/FF/G v Placebo
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Linear Model
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    0.245
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.147
         upper limit
    		 0.342

    Secondary: CHF1535 (BDP/FF) vs. Placebo - Change from baseline in IC at isotime after 3 weeks of treatment

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    End point title
    		 CHF1535 (BDP/FF) vs. Placebo - Change from baseline in IC at isotime after 3 weeks of treatment
    End point description
    Key-secondary variables were analysed using a linear model including treatment and period as fixed effects, baseline value of the current treatment period and baseline value averaged across all the treatment periods as covariates, and subject as a random effect.
    End point type
    Secondary
    End point timeframe
    The baseline IC value was collected at isotime at the beginning of each treatment period [V2, V4 and V6].
    End point values
    		 BDP/FF Placebo
    Number of subjects analysed
    95 [7]
    92 [8]
    Units: score
        arithmetic mean (standard deviation)
    0.126 ( 0.560 )
    -0.027 ( 0.435 )
    Notes
    [7] - Number of subjects with available data/Number of subjects in the ITT set: 95/99
    [8] - Number of subjects with available data/Number of subjects in the ITT set: 92/105
    Statistical analysis title
    		 Change from baseline in IC at isotime at week 3
    Statistical analysis description
    An unstructured covariance matrix was assumed, and the Kenward-Roger adjustment was used for the degrees of freedom. Data are presented as adjusted mean differences with their 95% two-sided Confidence Intervals, and p value.
    Comparison groups
    BDP/FF v Placebo
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.053
    Method
    		 Linear Model
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    0.096
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.001
         upper limit
    		 0.193

    Secondary: CHF5993 (BDP/FF/G) vs. Placebo - Change from baseline in 2h post-dose EET after 3 weeks of treatment

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    End point title
    		 CHF5993 (BDP/FF/G) vs. Placebo - Change from baseline in 2h post-dose EET after 3 weeks of treatment
    End point description
    Key-secondary variables were analysed using a linear model including treatment and period as fixed effects, baseline value of the current treatment period and baseline value averaged across all the treatment periods as covariates, and subject as a random effect.
    End point type
    Secondary
    End point timeframe
    The baseline EET value was collected at the beginning of each treatment period [V2, V4 and V6].
    End point values
    		 BDP/FF/G Placebo
    Number of subjects analysed
    95 [9]
    95 [10]
    Units: seconds
        arithmetic mean (standard deviation)
    67.0 ( 184.7 )
    0.3 ( 149.6 )
    Notes
    [9] - Number of subjects with available data/Number of subjects in the ITT set: 95/99
    [10] - Number of subjects with available data/Number of subjects in the ITT set: 95/105
    Statistical analysis title
    		 Change from baseline in 2h post-dose EET at week 3
    Statistical analysis description
    An unstructured covariance matrix was assumed, and the Kenward-Roger adjustment was used for the degrees of freedom. Data are presented as adjusted mean differences with their 95% two-sided Confidence Intervals, and p value.
    Comparison groups
    BDP/FF/G v Placebo
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Linear Model
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    69.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 32.88
         upper limit
    		 105.51

    Secondary: CHF1535 (BDP/FF) vs. Placebo - Change from baseline in 2h post-dose EET after 3 weeks of treatment

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    End point title
    		 CHF1535 (BDP/FF) vs. Placebo - Change from baseline in 2h post-dose EET after 3 weeks of treatment
    End point description
    Key-secondary variables were analysed using a linear model including treatment and period as fixed effects, baseline value of the current treatment period and baseline value averaged across all the treatment periods as covariates, and subject as a random effect.
    End point type
    Secondary
    End point timeframe
    The baseline EET value was collected at the beginning of each treatment period [V2, V4 and V6].
    End point values
    		 BDP/FF Placebo
    Number of subjects analysed
    96 [11]
    95 [12]
    Units: seconds
        arithmetic mean (standard deviation)
    46.4 ( 149.5 )
    0.3 ( 149.6 )
    Notes
    [11] - Number of subjects with available data/Number of subjects in the ITT set: 96/99
    [12] - Number of subjects with available data/Number of subjects in the ITT set: 95/105
    Statistical analysis title
    		 Change from baseline in 2h post-dose EET at week 3
    Statistical analysis description
    An unstructured covariance matrix was assumed, and the Kenward-Roger adjustment was used for the degrees of freedom. Data are presented as adjusted mean differences with their 95% two-sided Confidence Intervals, and p value.
    Comparison groups
    BDP/FF v Placebo
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Linear Model
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    70.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 33.57
         upper limit
    		 106.56

    Other pre-specified: CHF5993 (BDP/FF/G) vs. Placebo - Change from baseline in pre-dose morning FEV1 after 3 weeks of treatment

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    End point title
    		 CHF5993 (BDP/FF/G) vs. Placebo - Change from baseline in pre-dose morning FEV1 after 3 weeks of treatment
    End point description
    The exploratory variable was analysed on the ITT population using a linear mixed model similar as the one used for the primary efficacy analysis, including the FEV1 baseline value of the current treatment period and baseline value averaged across all the treatment periods as covariates.
    End point type
    Other pre-specified
    End point timeframe
    Baseline value was defined as the FEV1 value collected at the beginning of each treatment period.
    End point values
    		 BDP/FF/G Placebo
    Number of subjects analysed
    98 [13]
    102 [14]
    Units: L
        arithmetic mean (standard deviation)
    0.178 ( 0.199 )
    -0.058 ( 0.206 )
    Notes
    [13] - Number of subjects with available data/Number of subjects in the ITT set: 98/99
    [14] - Number of subjects with available data/Number of subjects in the ITT set: 102/105
    Statistical analysis title
    		 Change from baseline in pre-dose FEV1 at week 3
    Statistical analysis description
    Data are presented as adjusted mean differences with their 95% two-sided Confidence Intervals, and p value.
    Comparison groups
    BDP/FF/G v Placebo
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 0.25

    Other pre-specified: CHF1535 (BDP/FF) vs. Placebo - Change from baseline in pre-dose morning FEV1 after 3 weeks of treatment

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    End point title
    		 CHF1535 (BDP/FF) vs. Placebo - Change from baseline in pre-dose morning FEV1 after 3 weeks of treatment
    End point description
    The exploratory variable was analysed on the ITT population using a linear mixed model similar as the one used for the primary efficacy analysis, including the FEV1 baseline value of the current treatment period and baseline value averaged across all the treatment periods as covariates.
    End point type
    Other pre-specified
    End point timeframe
    Baseline value was defined as the FEV1 value collected at the beginning of each treatment period.
    End point values
    		 BDP/FF Placebo
    Number of subjects analysed
    98 [15]
    102 [16]
    Units: L
        arithmetic mean (standard deviation)
    0.047 ( 0.188 )
    -0.085 ( 0.206 )
    Notes
    [15] - Number of subjects with available data/Number of subjects in the ITT set: 98/99
    [16] - Number of subjects with available data/Number of subjects in the ITT set: 102/105
    Statistical analysis title
    		 Change from baseline in pre-dose FEV1 at week 3
    Statistical analysis description
    Data are presented as adjusted mean differences with their 95% two-sided Confidence Intervals, and p value.
    Comparison groups
    Placebo v BDP/FF
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.07
         upper limit
    		 0.15

    Other pre-specified: CHF5993 (BDP/FF/G) vs. CHF1535 (BDP/FF) - Change from baseline in pre-dose morning FEV1 after 3 weeks of treatment

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    End point title
    		 CHF5993 (BDP/FF/G) vs. CHF1535 (BDP/FF) - Change from baseline in pre-dose morning FEV1 after 3 weeks of treatment
    End point description
    The exploratory variable was analysed on the ITT population using a linear mixed model similar as the one used for the primary efficacy analysis, including the FEV1 baseline value of the current treatment period and baseline value averaged across all the treatment periods as covariates.
    End point type
    Other pre-specified
    End point timeframe
    Baseline value was defined as the FEV1 value collected at the beginning of each treatment period.
    End point values
    		 BDP/FF/G BDP/FF
    Number of subjects analysed
    98 [17]
    98 [18]
    Units: L
        arithmetic mean (standard deviation)
    0.178 ( 0.199 )
    0.047 ( 0.188 )
    Notes
    [17] - Number of subjects with available data/Number of subjects in the ITT set: 98/99
    [18] - Number of subjects with available data/Number of subjects in the ITT set: 98/99
    Statistical analysis title
    		 Change from baseline in pre-dose FEV1 at week 3
    Statistical analysis description
    Data are presented as adjusted mean differences with their 95% two-sided Confidence Intervals, and p value.
    Comparison groups
    BDP/FF/G v BDP/FF
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.06
         upper limit
    		 0.14

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Safety analyses were conducted in the Safety population that included 106 subjects overall. Treatment-emergent adverse events (TEAE), defined as AEs starting on or after time of first study drug intake, were displayed.
    Adverse event reporting additional description
    All AEs are reported by System Organ Class and Preferred Term and are coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 24.0.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    BDP/FF/G
    Reporting group description
    		 CHF5993 (BDP/FF/G pMDI 100/6/10 μg), 2 inhalations BID via pMDI (in the morning and in the evening).

    Reporting group title
    BDP/FF
    Reporting group description
    		 CHF1535 (BDP/FF pMDI 100/6 μg) 2 inhalations BID via pMDI (in the morning and in the evening).

    Reporting group title
    Placebo
    Reporting group description
    		 CHF5993 Placebo, 2 inhalations BID via pMDI.

    Serious adverse events
    		 BDP/FF/G BDP/FF Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 99 (0.00%)
    0 / 105 (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: 0%
    Non-serious adverse events
    		 BDP/FF/G BDP/FF Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 99 (27.27%)
    25 / 99 (25.25%)
    20 / 105 (19.05%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Oral haemangioma
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 99 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    1
    0
    0
    Vascular disorders
    Blood pressure fluctuation
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 99 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    1
    0
    0
    Hypertension
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 99 (1.01%)
    0 / 105 (0.00%)
         occurrences all number
    1
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 99 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    1
    0
    0
    Sensation of foreign body
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 99 (1.01%)
    0 / 105 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 99 (0.00%)
    4 / 105 (3.81%)
         occurrences all number
    0
    0
    4
    Cough
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 99 (1.01%)
    0 / 105 (0.00%)
         occurrences all number
    1
    1
    0
    Dysphonia
         subjects affected / exposed
    1 / 99 (1.01%)
    3 / 99 (3.03%)
    0 / 105 (0.00%)
         occurrences all number
    1
    3
    0
    Dyspnoea
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 99 (0.00%)
    2 / 105 (1.90%)
         occurrences all number
    0
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    1 / 99 (1.01%)
    2 / 99 (2.02%)
    0 / 105 (0.00%)
         occurrences all number
    1
    2
    0
    Productive cough
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 99 (0.00%)
    1 / 105 (0.95%)
         occurrences all number
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 99 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    1
    0
    0
    Sputum increased
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 99 (1.01%)
    0 / 105 (0.00%)
         occurrences all number
    0
    1
    0
    Throat irritation
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 99 (1.01%)
    0 / 105 (0.00%)
         occurrences all number
    1
    1
    0
    Psychiatric disorders
    Middle insomnia
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 99 (1.01%)
    0 / 105 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    White blood cell count increased
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 99 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 99 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    1
    0
    0
    Foot fracture
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 99 (1.01%)
    0 / 105 (0.00%)
         occurrences all number
    0
    1
    0
    Sternal fracture
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 99 (1.01%)
    0 / 105 (0.00%)
         occurrences all number
    0
    1
    0
    Vaccination complication
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 99 (0.00%)
    1 / 105 (0.95%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 99 (0.00%)
    1 / 105 (0.95%)
         occurrences all number
    2
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 99 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    1
    0
    0
    Vertigo
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 99 (0.00%)
    1 / 105 (0.95%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 99 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 99 (1.01%)
    0 / 105 (0.00%)
         occurrences all number
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 99 (1.01%)
    2 / 99 (2.02%)
    2 / 105 (1.90%)
         occurrences all number
    1
    2
    2
    Dyspepsia
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 99 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    1
    0
    0
    Food poisoning
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 99 (1.01%)
    0 / 105 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    0 / 99 (0.00%)
    2 / 99 (2.02%)
    1 / 105 (0.95%)
         occurrences all number
    0
    2
    1
    Toothache
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 99 (0.00%)
    1 / 105 (0.95%)
         occurrences all number
    0
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 99 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 99 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 99 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    1
    0
    0
    Hand dermatitis
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 99 (1.01%)
    0 / 105 (0.00%)
         occurrences all number
    0
    1
    0
    Skin irritation
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 99 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 99 (2.02%)
    2 / 99 (2.02%)
    2 / 105 (1.90%)
         occurrences all number
    2
    2
    2
    Back pain
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 99 (1.01%)
    1 / 105 (0.95%)
         occurrences all number
    0
    1
    1
    Haemarthrosis
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 99 (0.00%)
    1 / 105 (0.95%)
         occurrences all number
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 99 (1.01%)
    0 / 105 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 99 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    1
    0
    0
    COVID-19
         subjects affected / exposed
    0 / 99 (0.00%)
    3 / 99 (3.03%)
    4 / 105 (3.81%)
         occurrences all number
    0
    3
    4
    Conjunctivitis
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 99 (1.01%)
    0 / 105 (0.00%)
         occurrences all number
    0
    1
    0
    Cystitis
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 99 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    2
    0
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 99 (1.01%)
    1 / 105 (0.95%)
         occurrences all number
    0
    1
    1
    Furuncle
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 99 (0.00%)
    1 / 105 (0.95%)
         occurrences all number
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    4 / 99 (4.04%)
    3 / 99 (3.03%)
    3 / 105 (2.86%)
         occurrences all number
    4
    3
    3
    Oral candidiasis
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 99 (1.01%)
    0 / 105 (0.00%)
         occurrences all number
    0
    1
    0
    Paronychia
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 99 (0.00%)
    1 / 105 (0.95%)
         occurrences all number
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 99 (1.01%)
    0 / 105 (0.00%)
         occurrences all number
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 99 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 99 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    1
    0
    0

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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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