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    Clinical Trial Results:
    The efficacy and safety of new formulation of combination of fluticasone propionate / salmeterol (125μg / 25μg) in MDI HFA inhaler compared with the reference drug at a dose of 500μg / 50μg in DPI (dry powder inhaler) type disc in patients with chronic asthma

    Summary
    EudraCT number
    		 2017-000735-14
    Trial protocol
    		 PL  
    Global end of trial date
    27 Feb 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Mar 2021
    First version publication date
    04 Mar 2021
    Other versions
    Summary report(s)
    		 Study Summary

    Trial information

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    Trial identification
    Sponsor protocol code
    L-A/2017/COM/01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    LEK-AM Sp. z o.o.
    Sponsor organisation address
    ul. Ostrzykowizna 14A, Zakroczym, Poland, 05-170
    Public contact
    Deputy General Manager, QAH Sp. z o.o. Sp. k., +48 426563048, mateusz.jastrzebski@qah.pl
    Scientific contact
    Deputy General Manager, QAH Sp. z o.o. Sp. k., +48 426563048, mateusz.jastrzebski@qah.pl
    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
    27 Feb 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To prove non-inferiority in terms of efficacy and safety of new formulation of combination of fluticasone propionate / salmeterol (125μg / 25μg) in MDI HFA inhaler applied two puffs twice daily compared with the reference drug at a dose of 500μg / 50μg in DPI (dry powder inhaler) type disc applied one puff twice daily in patients with chronic asthma. Primary endpoint of the trial: avarage morning PEF during 12-week treatment period (change from Week1 to Week12)
    Protection of trial subjects
    All patients were informed in details on the study procedures and their rights, all expressed in written their consent to participate in the trial. Due to the study design no further protection procedures were needed.
    Background therapy
    		 All subjects were randomised to one of two study arms. During the study period subjects receive therapies due to their comorbidities (mostly: hypertension, diabetes mellitus, other respiratory conditions, gastrointestinal diseases).
    Evidence for comparator
    		 The comparator used in the study contains the same molecules as the investigated drug, but at different doses. Additionally, they are administered from a different type of inhaler (DPI) that generates larger diameter particles and reaches the upper level of the respiratory tract. Administering a combination of fluticasone propionate and salmeterol from the DPI inhaler has been the standard way of administering these drugs so far.
    Actual start date of recruitment
    15 Jan 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 231
    Worldwide total number of subjects
    231
    EEA total number of subjects
    231
    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)
    199
    From 65 to 84 years
    32
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited in one large University Hospital (Allergology Department) and 12 outpatient clinics. The first patient was recruited in March 2018, the last one in October 2019.

    Pre-assignment
    Screening details
    		 Patient screening was conducted according to the study inclusion criteria. At the screening visit laboratory tests were performed, and the patient was instructed on how to use the peak flow meter and recorded its indications in the patient's diary. During the screening visit, the current treatment of the patient did not change.

    Period 1
    Period 1 title
    Overall Trial
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Comboterol
    Arm description
    		 Subjects randomized to be treated with investigated drug - Comboterol. Comboterol is a combination of salmeterol and fluticasone propionate inhaled using the MDI HFA inhaler. The investigated group will receive COMBOTEROL (25 µg / 125 µg) administered in the MDI HFA inhaler two doses twice a aday.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comboterol 25 µg / 125 µg
    Investigational medicinal product code
    R03AK06
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Comboterol, 25 µg + 125 µg (salmeterol + fluticasone propionate) / inhalation dose, inhalation aerosol, suspension - two doses twice a day.

    Arm title
    		 Seretide 500
    Arm description
    		 Seretide Disk 500, 50 µg + 500 µg (salmeterol + fluticasone propionate) / inhalation dose, inhalation powder. Seretide is a combination of salmeterol and fluticasone propionate inhaled using the DPI-Disk inhaler. It is a multi dose, flow dependent, medium resistance inhaler. Its optimal inspiratory flow is 30-60 l / min. At a flow of 30 liters, 80% of the dose reaches the patient's mouth from the inhaler. The pulmonary deposition of this inhaler is 11.9-16.6%
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Seretide Dysk 500
    Investigational medicinal product code
    R03AK06
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Seretide Disk 500, 50 µg + 500 µg (salmeterol + fluticasone propionate) / inhalation dose, inhalation powder - twice a day, one dose each

    Number of subjects in period 1
    		Comboterol Seretide 500
    Started
    117
    114
    Completed
    111
    110
    Not completed
    6
    4
         Consent withdrawn by subject
    2
    1
         Adverse event, non-fatal
    2
    3
         Lost to follow-up
    2
    -
    Period 2
    Period 2 title
    Overall Trial
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Comboterol
    Arm description
    		 Subjects randomized to be treated with investigated drug - Comboterol. Comboterol is a combination of salmeterol and fluticasone propionate inhaled using the MDI HFA inhaler. The investigated group will receive COMBOTEROL (25 µg / 125 µg) administered in the MDI HFA inhaler two doses twice a aday.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comboterol 25 µg / 125 µg
    Investigational medicinal product code
    R03AK06
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Comboterol, 25 µg + 125 µg (salmeterol + fluticasone propionate) / inhalation dose, inhalation aerosol, suspension - two doses twice a day.

    Arm title
    		 Seretide 500
    Arm description
    		 Seretide Disk 500, 50 µg + 500 µg (salmeterol + fluticasone propionate) / inhalation dose, inhalation powder. Seretide is a combination of salmeterol and fluticasone propionate inhaled using the DPI-Disk inhaler. It is a multi dose, flow dependent, medium resistance inhaler. Its optimal inspiratory flow is 30-60 l / min. At a flow of 30 liters, 80% of the dose reaches the patient's mouth from the inhaler. The pulmonary deposition of this inhaler is 11.9-16.6%
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Seretide Dysk 500
    Investigational medicinal product code
    R03AK06
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Seretide Disk 500, 50 µg + 500 µg (salmeterol + fluticasone propionate) / inhalation dose, inhalation powder - twice a day, one dose each

    Number of subjects in period 2
    		Comboterol Seretide 500
    Started
    117
    114
    Completed
    111
    110
    Not completed
    6
    4
         Consent withdrawn by subject
    2
    1
         Adverse event, non-fatal
    2
    3
         Lost to follow-up
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 231 231
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 199 199
        From 65-84 years
    		 32 32
    Age continuous
    Units: years
        median (standard deviation)
    		 49.5 ± 12.2 -
    Gender categorical
    Units: Subjects
        Female
    		 138 138
        Male
    		 93 93

    End points

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    End points reporting groups
    Reporting group title
    Comboterol
    Reporting group description
    		 Subjects randomized to be treated with investigated drug - Comboterol. Comboterol is a combination of salmeterol and fluticasone propionate inhaled using the MDI HFA inhaler. The investigated group will receive COMBOTEROL (25 µg / 125 µg) administered in the MDI HFA inhaler two doses twice a aday.

    Reporting group title
    Seretide 500
    Reporting group description
    		 Seretide Disk 500, 50 µg + 500 µg (salmeterol + fluticasone propionate) / inhalation dose, inhalation powder. Seretide is a combination of salmeterol and fluticasone propionate inhaled using the DPI-Disk inhaler. It is a multi dose, flow dependent, medium resistance inhaler. Its optimal inspiratory flow is 30-60 l / min. At a flow of 30 liters, 80% of the dose reaches the patient's mouth from the inhaler. The pulmonary deposition of this inhaler is 11.9-16.6%
    Reporting group title
    Comboterol
    Reporting group description
    		 Subjects randomized to be treated with investigated drug - Comboterol. Comboterol is a combination of salmeterol and fluticasone propionate inhaled using the MDI HFA inhaler. The investigated group will receive COMBOTEROL (25 µg / 125 µg) administered in the MDI HFA inhaler two doses twice a aday.

    Reporting group title
    Seretide 500
    Reporting group description
    		 Seretide Disk 500, 50 µg + 500 µg (salmeterol + fluticasone propionate) / inhalation dose, inhalation powder. Seretide is a combination of salmeterol and fluticasone propionate inhaled using the DPI-Disk inhaler. It is a multi dose, flow dependent, medium resistance inhaler. Its optimal inspiratory flow is 30-60 l / min. At a flow of 30 liters, 80% of the dose reaches the patient's mouth from the inhaler. The pulmonary deposition of this inhaler is 11.9-16.6%

    Primary: Mean morning PEF change

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    End point title
    		 Mean morning PEF change
    End point description
    End point type
    Primary
    End point timeframe
    Mean change in morning PEF over the 12-week treatment period. The baseline value will be calculated as the average of the 14 days of the screening period. The average PEF for visit 4 will be calculated from the last 14 days before the visit.
    End point values
    		 Comboterol Seretide 500 Comboterol Seretide 500
    Number of subjects analysed
    117
    114
    111
    110
    Units: l/s
        median (confidence interval 95%)
    6.2 (5.8 to 6.5)
    6.0 (5.7 to 6.4)
    6.6 (6.2 to 7.1)
    6.9 (6.4 to 7.3)
    Attachments
    		 Untitled (Filename: COMBO_PEF.png)
    Statistical analysis title
    		 Final
    Statistical analysis description
    The results were analyzed with StatSoft Statistica 13 (StatSoft, Poland). To detect a 15 l/min difference in the morning PEF value between the two treatment groups (standard deviation [SD]=45 l/min, significance level 5%, power 80%), we used a sample size of 110 patients for each group. The patients’ characteristics were compared using the chi-squared or Fisher’s exact two-tailed test for discrete variables, or the Student’s t-test for continuous variables.
    Comparison groups
    Comboterol v Seretide 500
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 ≤ 0.05
    Method
    		 ANOVA
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: Asthma Control Test ACT

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    End point title
    		 Asthma Control Test ACT
    End point description
    End point type
    Secondary
    End point timeframe
    ACT change was measured based on the comparison of initial completion at Visit I and final observation at Visit IV.
    End point values
    		 Comboterol Seretide 500 Comboterol Seretide 500
    Number of subjects analysed
    117
    114
    111
    110
    Units: number
        number (confidence interval 95%)
    18.7 (17.9 to 19.4)
    18.7 (17.9 to 19.4)
    20.7 (20.1 to 21.4)
    20.5 (19.9 to 21.2)
    Attachments
    		 Untitled (Filename: COMBO_ACT.png)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events were collected after subject entry through the whole study participation of each study subject.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    MDI 250
    Reporting group description
    		 -

    Reporting group title
    DPI 500
    Reporting group description
    		 -

    Serious adverse events
    		 MDI 250 DPI 500
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 114 (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: 5%
    Non-serious adverse events
    		 MDI 250 DPI 500
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    102 / 117 (87.18%)
    104 / 114 (91.23%)
    Cardiac disorders
    ECG deviations
         subjects affected / exposed
    8 / 117 (6.84%)
    10 / 114 (8.77%)
         occurrences all number
    8
    10
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 117 (1.71%)
    2 / 114 (1.75%)
         occurrences all number
    2
    2
    Blood and lymphatic system disorders
    Laboratory tests abnormalities
         subjects affected / exposed
    95 / 117 (81.20%)
    99 / 114 (86.84%)
         occurrences all number
    145
    145
    Respiratory, thoracic and mediastinal disorders
    Hoarseness
         subjects affected / exposed
    0 / 117 (0.00%)
    5 / 114 (4.39%)
         occurrences all number
    0
    5
    Infections and infestations
    Cold
         subjects affected / exposed
    5 / 117 (4.27%)
    5 / 114 (4.39%)
         occurrences all number
    5
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33276251
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