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    Clinical Trial Results:
    A study to test the combination of tiotropium and olodaterol using the Respimat® inhaler in people with chronic obstructive pulmonary disease (COPD) who have different abilities to inhale

    Summary
    EudraCT number
    		 2019-001719-21
    Trial protocol
    		 DE  
    Global end of trial date
    20 Sep 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    03 Nov 2021
    First version publication date
    29 Sep 2021
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    1237-0095
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04223843
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Straße 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.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
    06 Nov 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Sep 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Sep 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This trial was designed to demonstrate the efficacy of inhaled tiotropium + olodaterol 5 μg/5 μg (referred to as T+O) via Respimat® on lung function in patients with moderate to severe COPD with optimal and sub-optimal peak inspiratory flow rate (PIFR).
    Protection of trial subjects
    Prior to the initiation of any trial-related procedure, all patients were informed about the trial verbally and in writing by the investigator. The patient was allowed sufficient time to consider participation in the trial and to ask questions concerning the details of the trial. Each patient signed and dated an ICF according to the local regulatory and legal requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Jan 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
    United States: 208
    Country: Number of subjects enrolled
    Germany: 121
    Worldwide total number of subjects
    329
    EEA total number of subjects
    121
    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)
    161
    From 65 to 84 years
    167
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 A randomised, double-blind, placebo-controlled trial to demonstrate the efficacy of 5µg/5µg inhaled tiotropium + olodateral (Tio+Olo) via Respimat® on lung function in patients with moderate to severe chronic obstructive pulmonary disease (COPD) with optimal and sub-obtimal peak inspiratory flow rate (PIFR).

    Pre-assignment
    Screening details
    		 Only patients that met all inclusion and none of the exclusion criteria were included in this trial. Prior to the initiation of any trial-related procedure, all patients were informed about the trial verbally and in writing by the investigator. Patients signed and dated an Informed Consent Form according to local regulatory and legal requirements.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Patients, investigators, and everyone involved in trial conduct or analysis or with any other interest in this double-blind trial was to remain blinded with regard to the randomised treatment assignments until after database lock. Access to the randomisation code was kept restricted until its release for analysis.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tio+Olo (5μg/5μg) - Sub-optimal PIFR
    Arm description
    		 A fixed dose combination of 5 microgram (μg)/5μg (two times 2.5µg/2.5µg) tiotropium + olodaterol (Tio+Olo) inhalation solution was administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (<60 Liter(L)/minute (min)) over a 4-week treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium + Olodaterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Oral use
    Dosage and administration details
    A fixed dose combination of 5 micorgram (μg)/5μg (two times 2.5µg/2.5µg) tiotropium + olodaterol (Tio+Olo) inhalation solution was administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (<60 Liter(L)/minute (min)) over a 4-week treatment period.

    Arm title
    		 Matching Placebo - Sub-optimal PIFR
    Arm description
    		 2 inhalation solutions of matching placebo were administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (<60 L/min) over a 4-week treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Oral use
    Dosage and administration details
    2 inhalation solutions of matching placebo were administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (<60 L/min) over a 4-week treatment period.

    Arm title
    		 Tio+Olo (5μg/5μg ) - Optimal PIFR
    Arm description
    		 A fixed dose combination of 5μg/5μg (two times 2.5µg/2.5µg) tiotropium + olodaterol (Tio+Olo) inhalation solution was administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (≥60 L/min) over a 4-week treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium + Olodaterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Oral use
    Dosage and administration details
    A fixed dose combination of 5μg/5μg (two times 2.5µg/2.5µg) tiotropium + olodaterol (Tio+Olo) inhalation solution was administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (≥60 L/min) over a 4-week treatment period.

    Arm title
    		 Matching Placebo - Optimal PIFR
    Arm description
    		 2 inhalation solutions of matching placebo were administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with optimal peak inspiratory flow rate (PIFR) (≥60 L/min) over a 4-week treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Oral use
    Dosage and administration details
    2 inhalation solutions of matching placebo were administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with optimal peak inspiratory flow rate (PIFR) (≥60 L/min) over a 4-week treatment period.

    Number of subjects in period 1 [1]
    		Tio+Olo (5μg/5μg) - Sub-optimal PIFR Matching Placebo - Sub-optimal PIFR Tio+Olo (5μg/5μg ) - Optimal PIFR Matching Placebo - Optimal PIFR
    Started
    55
    55
    51
    52
    Completed
    55
    55
    51
    52
    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: 329 patients were enrolled worldwide, whereof 213 were included in the trial.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tio+Olo (5μg/5μg) - Sub-optimal PIFR
    Reporting group description
    		 A fixed dose combination of 5 microgram (μg)/5μg (two times 2.5µg/2.5µg) tiotropium + olodaterol (Tio+Olo) inhalation solution was administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (<60 Liter(L)/minute (min)) over a 4-week treatment period.

    Reporting group title
    Matching Placebo - Sub-optimal PIFR
    Reporting group description
    		 2 inhalation solutions of matching placebo were administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (<60 L/min) over a 4-week treatment period.

    Reporting group title
    Tio+Olo (5μg/5μg ) - Optimal PIFR
    Reporting group description
    		 A fixed dose combination of 5μg/5μg (two times 2.5µg/2.5µg) tiotropium + olodaterol (Tio+Olo) inhalation solution was administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (≥60 L/min) over a 4-week treatment period.

    Reporting group title
    Matching Placebo - Optimal PIFR
    Reporting group description
    		 2 inhalation solutions of matching placebo were administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with optimal peak inspiratory flow rate (PIFR) (≥60 L/min) over a 4-week treatment period.

    Reporting group values
    		 Tio+Olo (5μg/5μg) - Sub-optimal PIFR Matching Placebo - Sub-optimal PIFR Tio+Olo (5μg/5μg ) - Optimal PIFR Matching Placebo - Optimal PIFR Total
    Number of subjects
    		 55 55 51 52 213
    Age categorical
    Treated Set (TS): This patient set included all randomised patients who were dispensed trial medication and were documented to have taken any dose of trial medication. The TS was used for demographics and baseline disease characteristics, concomitant theraphies, treatment exposure, and safety analysis.
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 29 23 30 24 106
        From 65-84 years
    		 25 32 21 28 106
        85 years and over
    		 1 0 0 0 1
    Age Continuous
    Treated Set (TS): This patient set included all randomised patients who were dispensed trial medication and were documented to have taken any dose of trial medication. The TS was used for demographics and baseline disease characteristics, concomitant theraphies, treatment exposure, and safety analysis.
    Units: years
        arithmetic mean (standard deviation)
    		 64 ( 9.79 ) 67.05 ( 7.54 ) 62.80 ( 7.48 ) 65.88 ( 7.43 ) -
    Sex: Female, Male
    Treated Set (TS): This patient set included all randomised patients who were dispensed trial medication and were documented to have taken any dose of trial medication. The TS was used for demographics and baseline disease characteristics, concomitant theraphies, treatment exposure, and safety analysis.
    Units: Participants
        Female
    		 28 37 24 20 109
        Male
    		 27 18 27 32 104
    Race (NIH/OMB)
    Treated Set (TS): This patient set included all randomised patients who were dispensed trial medication and were documented to have taken any dose of trial medication. The TS was used for demographics and baseline disease characteristics, concomitant theraphies, treatment exposure, and safety analysis.
    Units: Subjects
        American Indian or Alaska Native
    		 2 1 0 0 3
        Asian
    		 0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 2 3 1 0 6
        White
    		 51 51 50 51 203
        More than one race
    		 0 0 0 1 1
        Unknown or Not Reported
    		 0 0 0 0 0
    Forced Expiratory Volume in one second (FEV1) area under the curve from 0 to 3 hours (AUC0-3h)
    FEV1 AUC0-3 at baseline. The baseline FEV1 value will be the measurement made prior to the first dosing at Visit 2. The area under the curve (AUC) is calculated as the area under the curve from 0 to 3 hours at baseline using the trapezoidal rule, divided by 3 hours to report in liters. Full Analysis Set (FAS): This patient set was nested within the TS and included all patients who had a baseline and at least 1 post-baseline measurement for at least 1 efficacy endpoint. Only patients with available data for this endpoint were included.
    Units: Liter (L)
        arithmetic mean (standard deviation)
    		 1.224 ( 0.060 ) 1.277 ( 0.079 ) 1.388 ( 0.070 ) 1.523 ( 0.074 ) -

    End points

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    End points reporting groups
    Reporting group title
    Tio+Olo (5μg/5μg) - Sub-optimal PIFR
    Reporting group description
    		 A fixed dose combination of 5 microgram (μg)/5μg (two times 2.5µg/2.5µg) tiotropium + olodaterol (Tio+Olo) inhalation solution was administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (<60 Liter(L)/minute (min)) over a 4-week treatment period.

    Reporting group title
    Matching Placebo - Sub-optimal PIFR
    Reporting group description
    		 2 inhalation solutions of matching placebo were administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (<60 L/min) over a 4-week treatment period.

    Reporting group title
    Tio+Olo (5μg/5μg ) - Optimal PIFR
    Reporting group description
    		 A fixed dose combination of 5μg/5μg (two times 2.5µg/2.5µg) tiotropium + olodaterol (Tio+Olo) inhalation solution was administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (≥60 L/min) over a 4-week treatment period.

    Reporting group title
    Matching Placebo - Optimal PIFR
    Reporting group description
    		 2 inhalation solutions of matching placebo were administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with optimal peak inspiratory flow rate (PIFR) (≥60 L/min) over a 4-week treatment period.

    Primary: Change from baseline in Forced Expiratory Volume in one second (FEV1) area under the curve from 0 to 3 hours (AUC0-3h) after 4 weeks of treatment

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    End point title
    		 Change from baseline in Forced Expiratory Volume in one second (FEV1) area under the curve from 0 to 3 hours (AUC0-3h) after 4 weeks of treatment
    End point description
    FEV1 AUC0-3h was calculated as the area under the FEV1-time curve from 0 to 3h post-dose using the trapezoidal rule, divided by the duration (3h) to report in liters. Mean is adjusted mean. A hierarchical testing procedure was used to test the primary endpoint. Each of the tests wer considered confirmatory only if all previous tests were successful. Full Analysis Set (FAS): This patient set was nested within the treated set and included all patients who had a baseline and at least 1 post-baseline measurement for at least 1 efficacy endpoint. Only patients with non-missing endpoint results were included.
    End point type
    Primary
    End point timeframe
    At baseline and at week 4: 10 minutes (min) prior and 5 min, 15 min, 30 min and 1 hour (h), 2h and 3h after drug intake, respectively.
    End point values
    		 Tio+Olo (5μg/5μg) - Sub-optimal PIFR Matching Placebo - Sub-optimal PIFR Tio+Olo (5μg/5μg ) - Optimal PIFR Matching Placebo - Optimal PIFR
    Number of subjects analysed
    43 [1]
    47 [2]
    44 [3]
    47 [4]
    Units: Liter (L)
        arithmetic mean (standard error)
    0.250 ( 0.033 )
    -0.086 ( 0.031 )
    0.333 ( 0.032 )
    0.012 ( 0.031 )
    Notes
    [1] - FAS
    [2] - FAS
    [3] - FAS
    [4] - FAS
    Statistical analysis title
    		 Comparison FEV1 AUC0-3h change from baseline
    Statistical analysis description
    H0: There is no difference in the mean FEV1 AUC0-3h change from baseline between Tio+Olo and matching placebo.
    Comparison groups
    Tio+Olo (5μg/5μg) - Sub-optimal PIFR v Matching Placebo - Sub-optimal PIFR
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference of adjusted means
    Point estimate
    0.336
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.246
         upper limit
    		 0.425
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.045
    Statistical analysis title
    		 Comparison FEV1 AUC0-3 change from baseline
    Statistical analysis description
    H0: There is no difference in the mean FEV1 AUC0-3h change from baseline between Tio+Olo and matching placebo.
    Comparison groups
    Tio+Olo (5μg/5μg ) - Optimal PIFR v Matching Placebo - Optimal PIFR
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference of adjusted means
    Point estimate
    0.321
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.233
         upper limit
    		 0.409
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.044

    Secondary: Change from baseline in trough Forced Expiratory Volume in one second (FEV1) after 4 weeks of treatment

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    End point title
    		 Change from baseline in trough Forced Expiratory Volume in one second (FEV1) after 4 weeks of treatment
    End point description
    Change from baseline in trough Forced Expiratory Volume in one second (FEV1) after 4 weeks of treatment. FAS: This patient set was nested within the TS and included all patients who had a baseline and at least 1 post-baseline measurement for at least 1 efficacy endpoint. Only patients with non-missing endpoint results were included.
    End point type
    Secondary
    End point timeframe
    At baseline and at week 4.
    End point values
    		 Tio+Olo (5μg/5μg) - Sub-optimal PIFR Matching Placebo - Sub-optimal PIFR Tio+Olo (5μg/5μg ) - Optimal PIFR Matching Placebo - Optimal PIFR
    Number of subjects analysed
    50 [5]
    52 [6]
    47 [7]
    50 [8]
    Units: Liter
        arithmetic mean (standard error)
    0.095 ( 0.031 )
    -0.106 ( 0.030 )
    0.177 ( 0.030 )
    -0.040 ( 0.029 )
    Notes
    [5] - FAS
    [6] - FAS
    [7] - FAS
    [8] - FAS
    Statistical analysis title
    		 Comparison trough FEV1 change from baseline
    Statistical analysis description
    H0: There is no difference in the mean trough FEV1 change from baseline between Tio+Olo and matching placebo.
    Comparison groups
    Tio+Olo (5μg/5μg) - Sub-optimal PIFR v Matching Placebo - Sub-optimal PIFR
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference of adjusted means
    Point estimate
    0.201
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.117
         upper limit
    		 0.286
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.043
    Statistical analysis title
    		 Comparison trough FEV1 change from baseline
    Statistical analysis description
    H0: There is no difference in the mean trough FEV1 change from baseline between Tio+Olo and matching placebo.
    Comparison groups
    Tio+Olo (5μg/5μg ) - Optimal PIFR v Matching Placebo - Optimal PIFR
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference of adjusted means
    Point estimate
    0.217
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.135
         upper limit
    		 0.299
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.041

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From first intake of trial medication until last trial medication intake plus 21 days (residual effect period), up to 50 days.
    Adverse event reporting additional description
    Treated Set: This patient set included all randomised patients who were dispensed trial medication and were documented to have taken any dose of trial medication. Adverse events were summarized by treatment group (Tio/Olo vs. Placebo), as defined in the statistical analysis plan.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    5μg/5μg Tio+Olo - Overall
    Reporting group description
    		 A fixed dose combination (FDC) of 5μg/5μg (two times 2.5µg/2.5µg) tiotropium + olodaterol (Tio+Olo) inhalation solution was administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) over a 4-week treatment period. Overall group included patients with both, sub-optimal (<60 L/min) peak inspiratory flow rate (PIFR) and optimal (≥60 L/min) peak inspiratory flow rate (PIFR).

    Reporting group title
    Matching Placebo - Overall
    Reporting group description
    		 2 inhalation solutions of matching placebo were administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) over a 4-week treatment period. Overall group included patients with both, sub-optimal (<60 L/min) peak inspiratory flow rate (PIFR) and optimal (≥60 L/min) peak inspiratory flow rate (PIFR).

    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 were reported.
    Serious adverse events
    		 5μg/5μg Tio+Olo - Overall Matching Placebo - Overall
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 106 (1.89%)
    1 / 107 (0.93%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Endometrial cancer
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 5μg/5μg Tio+Olo - Overall Matching Placebo - Overall
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 107 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Dec 2019
    In this revision of the trial protocol, the stipulation to perform in-home PIFR measurements at high resistance was removed to reduce the complexity of patient procedures at home; associated text was updated. Text and flow chart footnotes were clarified or corrected to ensure alignment across trial-procedure descriptions within the document.
    28 Jan 2020
    In this revision of the trial protocol, exclusion criterion 21 was broadened to exclude patients with eGFR measuring <50 mL/min/1.73 m2; the flowchart was updated in line with this addition. Exclusion criterion 1 was updated to refer to local SmPC/USPI to provide additional guidance regarding exclusions. More precise criteria for discontinuation of trial medication were added, specifically trial medication was to be discontinued if paradoxical bronchospasm, allergic reaction, or 2 or more eye symptoms occurred. Finally, it was clarified that triple combination therapies containing ICS were restricted and that their use was not permitted within 6 months of trial entry, nor at any point during the trial itself.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    16 Mar 2020
    Due to the current COVID-19 pandemic, the recruitment of new subjects was temporarily discontinued. Ongoing, randomised patients were managed per Trial Protocol.
    23 Jun 2020

    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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