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    Clinical Trial Results:
    A pharmacodynamic, randomised, single dose, cross-over study to compare the bronchodilator effect of a new formulation of Tiotropium DPI versus Spiriva® 18 μg Handihaler®

    Summary
    EudraCT number
    		 2019-004095-19
    Trial protocol
    		 BG  
    Global end of trial date
    21 Oct 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Jul 2021
    First version publication date
    12 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TIO-II-19-1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Laboratoires SMB S.A.
    Sponsor organisation address
    26-28 rue de la pastorale, brussels, Belgium, 1080
    Public contact
    Clinical Trial Department, Laboratoires SMB S.A., +32 24114828, DptClinique@smb.be
    Scientific contact
    Clinical Trial Department, Laboratoires SMB S.A., +32 24114828, DptClinique@smb.be
    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
    12 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Oct 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Objective - To assess the non-inferiority between Tiotropium DPI capsule 8.8μg and Spiriva® 18μg Handihaler® by measurement of the bronchodilating effect
    Protection of trial subjects
    The trial was conducted in compliance with the protocol, with the ICH Harmonised Tripartite Guideline, Guideline for Good Clinical Practice, Step 5 (CPMP/ICH/135/95) (1), the applicable regulatory requirement(s) based on EU Directive 2001/20/EC (2) and EU GCP Directive (2005/28/EC) (3), and the Declaration of Helsinki (World Medical Association) in its revised edition (Brazil, 2013)
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Jun 2020
    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
    North Macedonia: 6
    Country: Number of subjects enrolled
    Bulgaria: 60
    Worldwide total number of subjects
    66
    EEA total number of subjects
    60
    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)
    33
    From 65 to 84 years
    33
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The patients were screened within 21 days prior to the randomization. Following all screening procedures, patients who satisfied all of the inclusion/exclusion criteria were randomized. The patients visited the clinic 4 times + one telephone follow-up call. Each visit was separated by a wash-out period of at least 3 days with a maximum of 14 days

    Pre-assignment
    Screening details
    		 Obtain a signed informed consent form/Obtain demographic data/Record COPD history/review of prior and concomitant médications/Perform a measurement of pulmonary function/review of the inclusion and exclusion criteria/Perform a 12-lead ECG+Vital sign+laboratory tests/Dispensation of rescue medication

    Period 1
    Period 1 title
    Cross-over phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    This study was partly blinded. The blind was maintained only for the two doses of SMB tiotropium DPI formulations.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 SMB Tiotropium 8.8µg
    Arm description
    		 SMB Tiotropium 8.8 µg DPI, one capsule a day taken by inhalation via the Vertical-Haler®, containing 10.59 µg of tiotropium bromide anhydrous (equivalent to 8.8 µg of tiotropium base)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Inhalation use
    Dosage and administration details
    SMB Tiotropium 8.8 µg DPI, one capsule a day taken by inhalation via the Vertical-Haler®, containing 10.59 µg of tiotropium bromide anhydrous (equivalent to 8.8 µg of tiotropium base)

    Arm title
    		 SMB Tiotropim 2.2µg
    Arm description
    		 SMB tiotropium 2.2 µg DPI, one capsule a day taken by inhalation via the Vertical-Haler®, containing 2.64 µg of tiotropium bromide anhydrous (equivalent to 2.2 µg of tiotropium base)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Inhalation use
    Dosage and administration details
    SMB tiotropium 2.2 µg DPI, one capsule a day taken by inhalation via the Vertical-Haler®, containing 2.64 µg of tiotropium bromide anhydrous (equivalent to 2.2 µg of tiotropium base)

    Arm title
    		 Spiriva Handihaler 18µg
    Arm description
    		 Spiriva® Handihaler® 18 µg, one inhalation via the Handihaler®, each inhalation containing 22.5 µg of tiotropium bromide monohydrate (equivalent to 18 μg of tiotropium base)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Inhalation use
    Dosage and administration details
    Spiriva® Handihaler® 18 µg, one inhalation via the Handihaler®, each inhalation containing 22.5 µg of tiotropium bromide monohydrate (equivalent to 18 μg of tiotropium base)

    Number of subjects in period 1
    		SMB Tiotropium 8.8µg SMB Tiotropim 2.2µg Spiriva Handihaler 18µg
    Started
    66
    66
    66
    Completed
    63
    63
    63
    Not completed
    3
    3
    3
         Consent withdrawn by subject
    2
    2
    2
         Adverse event, non-fatal
    1
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cross-over phase
    Reporting group description
    		 Sixty-six subjects were included and randomized into 6 sequences groups. All randomized subjects took at least one unit of the study drugs. Three subjects prematurely withdrew from the study and 63 (95.5% of the randomized subjects) completed the study.

    Reporting group values
    		 Cross-over phase Total
    Number of subjects
    		 66 66
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 33 33
        From 65-84 years
    		 33 33
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.1 ( 7.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 17 17
        Male
    		 49 49

    End points

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    End points reporting groups
    Reporting group title
    SMB Tiotropium 8.8µg
    Reporting group description
    		 SMB Tiotropium 8.8 µg DPI, one capsule a day taken by inhalation via the Vertical-Haler®, containing 10.59 µg of tiotropium bromide anhydrous (equivalent to 8.8 µg of tiotropium base)

    Reporting group title
    SMB Tiotropim 2.2µg
    Reporting group description
    		 SMB tiotropium 2.2 µg DPI, one capsule a day taken by inhalation via the Vertical-Haler®, containing 2.64 µg of tiotropium bromide anhydrous (equivalent to 2.2 µg of tiotropium base)

    Reporting group title
    Spiriva Handihaler 18µg
    Reporting group description
    		 Spiriva® Handihaler® 18 µg, one inhalation via the Handihaler®, each inhalation containing 22.5 µg of tiotropium bromide monohydrate (equivalent to 18 μg of tiotropium base)

    Primary: Trough FEV1 response

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    End point title
    		 Trough FEV1 response
    End point description
    The bronchodilating effect was evaluated by the trough FEV1 response defined as the change in FEV1 from baseline to FEV1 24h post-dose measurement.
    End point type
    Primary
    End point timeframe
    Visit 2, visit 3 and visit 4
    End point values
    		 SMB Tiotropium 8.8µg SMB Tiotropim 2.2µg Spiriva Handihaler 18µg
    Number of subjects analysed
    63
    63
    63
    Units: L/sec
        arithmetic mean (standard deviation)
    0.091 ( 0.169 )
    0.068 ( 0.168 )
    0.075 ( 0.193 )
    Statistical analysis title
    		 Primary efficacy endpoint analysis
    Statistical analysis description
    The bronchodilating effect will be evaluated by the trough FEV1 response. Trough FEV1 response will be compared between IMPs using a mixed model with sequence, period and IMP as fixed effects, patient within sequence as random effect and period-specific baseline as covariate. LS means will be derived from the model and contrasts between IMP will be calculated. The lower bound of the 95% CI of the contrast between treatments will be compared to the non-inferiority threshold of -0.100 L
    Comparison groups
    SMB Tiotropium 8.8µg v Spiriva Handihaler 18µg
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.596
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.015
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.041
         upper limit
    		 0.07
    Statistical analysis title
    		 Secondary endpoint analysis (Tio 2.2 vs Tio 8.8)
    Statistical analysis description
    Secondary criteria will be analysed using mixed models for cross-over designs. All IMPs will be compared without reference to a non-inferiority threshold. Estimates of the variable and their standard error will be calculated for each IMP Contrast between all IMPs will be computed and compared to 0. P-value and 95% confidence interval of each difference will be presented without adjustment for multiple comparisons.
    Comparison groups
    SMB Tiotropium 8.8µg v SMB Tiotropim 2.2µg
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.467
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.035
         upper limit
    		 0.076
    Statistical analysis title
    		 Secondary endpoint analysis (Tio 2.2 vs Spiriva)
    Comparison groups
    SMB Tiotropim 2.2µg v Spiriva Handihaler 18µg
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.844
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.005
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.061

    Secondary: Baseline-adjusted AUC of FEV1 from 0 to 24h

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    End point title
    		 Baseline-adjusted AUC of FEV1 from 0 to 24h
    End point description
    End point type
    Secondary
    End point timeframe
    Visit 2, visit3 and visit 4
    End point values
    		 SMB Tiotropium 8.8µg SMB Tiotropim 2.2µg Spiriva Handihaler 18µg
    Number of subjects analysed
    63
    63
    63
    Units: L/sec*h
        arithmetic mean (standard deviation)
    3.637 ( 3.425 )
    3.216 ( 3.428 )
    3.457 ( 4.090 )
    Statistical analysis title
    		 Secondary endpoint analysis (Tio 2.2 vs Tio 8.8)
    Comparison groups
    SMB Tiotropium 8.8µg v SMB Tiotropim 2.2µg
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.428
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.377
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.562
         upper limit
    		 1.316
    Statistical analysis title
    		 Secondary endpoint analysis (Tio 2.2 vs Spiriva)
    Comparison groups
    Spiriva Handihaler 18µg v SMB Tiotropim 2.2µg
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.705
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.179
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.756
         upper limit
    		 1.113
    Statistical analysis title
    		 Secondary endpoint analysis (Tio 8.8 vs Spiriva)
    Comparison groups
    SMB Tiotropium 8.8µg v Spiriva Handihaler 18µg
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.677
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.198
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.743
         upper limit
    		 1.14

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Visit 1 to visit 4
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    SMB Tiotropium 8.8µg
    Reporting group description
    		 SMB Tiotropium 8.8 µg DPI, one capsule a day taken by inhalation via the Vertical-Haler®, containing 10.59 µg of tiotropium bromide anhydrous (equivalent to 8.8 µg of tiotropium base)

    Reporting group title
    SMB Tiotropim 2.2µg
    Reporting group description
    		 SMB tiotropium 2.2 µg DPI, one capsule a day taken by inhalation via the Vertical-Haler®, containing 2.64 µg of tiotropium bromide anhydrous (equivalent to 2.2 µg of tiotropium base)

    Reporting group title
    Spiriva Handihaler 18µg
    Reporting group description
    		 Spiriva® Handihaler® 18 µg, one inhalation via the Handihaler®, each inhalation containing 22.5 µg of tiotropium bromide monohydrate (equivalent to 18 μg of tiotropium base)

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No non-serious adverse events superior to the defined threshold (5%) were reported in this study.
    Serious adverse events
    		 SMB Tiotropium 8.8µg SMB Tiotropim 2.2µg Spiriva Handihaler 18µg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 63 (1.59%)
    0 / 63 (0.00%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    0
    1
    0
    Cardiac disorders
    ARRHYTHMIA
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 63 (1.59%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SMB Tiotropium 8.8µg SMB Tiotropim 2.2µg Spiriva Handihaler 18µg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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