Clinical Trial Results:
A Phase III, randomised, double-blind, placebo-controlled, parallel group study to determine the effect of 12 weeks treatment of orally inhaled tiotropium + olodaterol fixed dose combination (2.5/5 µg, 5/5 µg) delivered by the Respimat® Inhaler, on exercise endurance time during constant work rate cycle ergometry in patients with Chronic Obstructive Pulmonary Disease (COPD) (TorractoTM)
Due to a system error, the data reported in v1 is not correct and has been removed from public view.
Summary
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EudraCT number |
2011-004253-11 |
Trial protocol |
FI DE HU ES IE IT GB |
Global end of trial date |
26 Sep 2013
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Results information
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Results version number |
v2(current) |
This version publication date |
23 Jul 2016
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First version publication date |
26 Jul 2015
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Other versions |
v1 (removed from public view) |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
1237.15
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01525615 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Boehringer Ingelheim
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Sponsor organisation address |
Binger Strasse 173 , Ingelheim am Rhein , Germany, 55216
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Public contact |
QRPE Processes and Systems Coordination
Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 800 243 0127 , clintriage.rdg@boehringer-ingelheim.com
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Scientific contact |
QRPE Processes and Systems Coordination
Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 800 243 0127 , clintriage.rdg@boehringer-ingelheim.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
06 Nov 2013
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
26 Sep 2013
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Global end of trial reached? |
Yes
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Global end of trial date |
26 Sep 2013
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of this study is to compare the effects of orally inhaled tiotropium + olodaterol fixed dose combination (2.5/5 µg; 5/5 µg) with placebo on exercise tolerance after 12 weeks of treatment in patients with COPD. Exercise tolerance will be assessed by measurement of symptom-limited endurance time during constant work rate cycle ergometry at 75% Wcap (Maximal Work Capacity).
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Protection of trial subjects |
Only subjects that met all the study inclusion and none of the exclusion criteria were entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required.
An individual patient could be withdrawn from the clinical trial prior to completion if any of the following criteria apply:
1. The patient was no longer able to participate for medical reasons (e.g. pregnancy, surgery, adverse events, or other diseases).
2. Administrative reasons (protocol violations, persistent non-compliance).
3. Decision by Boehringer Ingelheim to discontinue a specific patient (e.g. in case of SAEs)
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
12 Mar 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 50
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Country: Number of subjects enrolled |
United Kingdom: 73
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Country: Number of subjects enrolled |
Finland: 24
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Country: Number of subjects enrolled |
France: 22
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Country: Number of subjects enrolled |
Germany: 76
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Country: Number of subjects enrolled |
Hungary: 76
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Country: Number of subjects enrolled |
Italy: 43
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Country: Number of subjects enrolled |
Argentina: 31
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Country: Number of subjects enrolled |
Canada: 56
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Country: Number of subjects enrolled |
United States: 93
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Worldwide total number of subjects |
544
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EEA total number of subjects |
364
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
313
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From 65 to 84 years |
231
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
All subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that they (the subjects) met all strictly implemented inclusion/exclusion criteria. Subjects were not randomised to trial treatment if any one of the specific entry criteria were violated. | ||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Treatment period (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst | ||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | ||||||||||||||||||||||||||||||||||||
Arm description |
Once daily 2 puffs, solution for inhalation Respimat placebo to tiotropium+olodaterol during the 12-week treatment period: comparator | ||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation solution
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Routes of administration |
Inhalation use
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Dosage and administration details |
Matching placebo
During the 12-week treatment period, patients were to inhale 2 actuations from the
RESPIMAT Inhaler, once a day, in the morning.
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Arm title
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Tio+Olo 2.5 / 5.0 μg | ||||||||||||||||||||||||||||||||||||
Arm description |
Oral inhalation of fixed dose combination (FDC) of Tiotropium (Tio) 2.5 μg and Olodaterol (Olo) 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning during the 12-week treatment period. | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Tiotropium/Olodaterol FDC
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation solution
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Routes of administration |
Inhalation use
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Dosage and administration details |
2.5 μg tiotropium / 5 μg olodaterol (1.25 μg + 2.5 μg per actuation, respectively)
During the 12-week treatment period, patients were to inhale 2 actuations from the
RESPIMAT Inhaler, once a day, in the morning.
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Arm title
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Tio+Olo 5.0 / 5.0 μg | ||||||||||||||||||||||||||||||||||||
Arm description |
Oral inhalation of FDC of Tiotropium (Tio) 5 μg and Olodaterol (Olo) 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning during the 12-week treatment period. | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Tiotropium/Olodaterol FDC
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation solution
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Routes of administration |
Inhalation use
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Dosage and administration details |
5 μg tiotropium / 5 μg olodaterol (2.5 μg each per actuation)
During the 12-week treatment period, patients were to inhale 2 actuations from the
RESPIMAT Inhaler, once a day, in the morning.
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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: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication. |
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Once daily 2 puffs, solution for inhalation Respimat placebo to tiotropium+olodaterol during the 12-week treatment period: comparator | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Tio+Olo 2.5 / 5.0 μg
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Reporting group description |
Oral inhalation of fixed dose combination (FDC) of Tiotropium (Tio) 2.5 μg and Olodaterol (Olo) 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning during the 12-week treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Tio+Olo 5.0 / 5.0 μg
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Reporting group description |
Oral inhalation of FDC of Tiotropium (Tio) 5 μg and Olodaterol (Olo) 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning during the 12-week treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Once daily 2 puffs, solution for inhalation Respimat placebo to tiotropium+olodaterol during the 12-week treatment period: comparator | ||
Reporting group title |
Tio+Olo 2.5 / 5.0 μg
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Reporting group description |
Oral inhalation of fixed dose combination (FDC) of Tiotropium (Tio) 2.5 μg and Olodaterol (Olo) 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning during the 12-week treatment period. | ||
Reporting group title |
Tio+Olo 5.0 / 5.0 μg
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Reporting group description |
Oral inhalation of FDC of Tiotropium (Tio) 5 μg and Olodaterol (Olo) 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning during the 12-week treatment period. |
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End point title |
Adjusted mean endurance time (sec) during constant work rate cycle ergometry (CWRCE) after 12 weeks | ||||||||||||||||
End point description |
Primary endpoint was endurance time during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 12 weeks of treatment.The endurance time in seconds was transformed using log10 scale to correct skewness in endurance time on original scale and then the MMRM model was fitted to the log10-transformed data and the least square means and SEs were obtained. To present the results in a way easier for interpretation, the least square mean from the MMRM fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate for the log10 of geometric mean and the corresponding SE was transformed using delta method to get the corresponding SEs of the geometric mean.
Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
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End point type |
Primary
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End point timeframe |
12 weeks
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Notes [1] - Full analysis set (FAS) [2] - FAS [3] - FAS |
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Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Treatment ratio between Tio+Olo 5.0/5.0 and placebo. This treatment comparison is the first one in the alpha-protected hierarchical testing chain.
Tio+Olo 5.0/5.0 is numerator and placebo is denominator.
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Comparison groups |
Placebo v Tio+Olo 5.0 / 5.0 μg
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Number of subjects included in analysis |
256
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Analysis specification |
Pre-specified
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Analysis type |
superiority [4] | ||||||||||||||||
P-value |
= 0.0209 [5] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
Treatment ratio | ||||||||||||||||
Point estimate |
1.138
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
1.02 | ||||||||||||||||
upper limit |
1.269 | ||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.063
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Notes [4] - Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was calculated using the delta method. [5] - Mixed effects Model Repeated Measures (MMRM) with fixed effects of treatment, test day, treatment by test day interaction, log10 (baseline endurance time), log10 (baseline endurance time) by test day interaction, and patient as a random effect. |
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Statistical analysis title |
Tio+Olo 2.5 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Treatment ratio between Tio+Olo 2.5/5.0 and placebo. This treatment comparison is the second one in the alpha-protected hierarchical testing chain. Since the p-value for this treatment comparison is >0.05, the hierarchical testing chain is broken and all of the following hypothesis tests in this hierarchical chain are considered as descriptive only.
Tio+Olo 2.5/5.0 is numerator and placebo is denominator.
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Comparison groups |
Placebo v Tio+Olo 2.5 / 5.0 μg
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Number of subjects included in analysis |
250
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Analysis specification |
Pre-specified
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Analysis type |
superiority [6] | ||||||||||||||||
P-value |
= 0.1419 [7] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
Treatment ratio | ||||||||||||||||
Point estimate |
1.086
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.973 | ||||||||||||||||
upper limit |
1.213 | ||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.061
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Notes [6] - Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was calculated using the delta method. [7] - MMRM for log10 (endurance time [s]) with fixed effects of treatment, test day, treatment by test day interaction, log10 (baseline endurance time [s]), log10 (baseline endurance time [s]) by test day interaction and patient as a random effect. |
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Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg | ||||||||||||||||
Statistical analysis description |
Treatment ratio between Tio+Olo 5.0/5.0 and Tio+Olo 2.5/5.0. This treatment comparison is not included in the alpha-protected hierarchical testing chain.
Tio+Olo 5.0/5.0 is numerator and Tio+Olo 2.5/5.0 is denominator.
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Comparison groups |
Tio+Olo 2.5 / 5.0 μg v Tio+Olo 5.0 / 5.0 μg
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Number of subjects included in analysis |
264
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Analysis specification |
Pre-specified
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Analysis type |
superiority [8] | ||||||||||||||||
P-value |
= 0.397 [9] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
Treatment ratio | ||||||||||||||||
Point estimate |
1.047
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.941 | ||||||||||||||||
upper limit |
1.166 | ||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.057
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Notes [8] - Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was calculated using the delta method. [9] - MMRM for log10 (endurance time [s]) with fixed effects of treatment, test day, treatment by test day interaction, log10 (baseline endurance time [s]), log10 (baseline endurance time [s]) by test day interaction and patient as a random effect. |
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End point title |
Adjusted mean endurance time (sec) during endurance shuttle walk test (ESWT) after 12 weeks | ||||||||||||||||
End point description |
Key secondary endpoint was endurance time during endurance shuttle walk test to symptom limitation at 85% of predicted maximum oxygen consumption (VO2) peak after 12 weeks of treatment.The endurance time in seconds was transformed using log10 scale to correct skewness in endurance time on original scale & then MMRM model was fitted to the log10-transformed data &the least square means &SEs were obtained.To present the results in a way easier for interpretation, least square mean from the MMRM fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate for the log10 of geometric mean & the corresponding SE was transformed using delta method to get the corresponding SEs of the geometric mean.
Endurance shuttle walk test (ESWT) substudy set: It includes all patients in the TS who had given informed consent for participating in the ESWT substudy &had a baseline and at least one postbaseline measurement during ESWT before or at Week 12.
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End point type |
Secondary
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End point timeframe |
12 weeks
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Notes [10] - ESWT substudy set [11] - ESWT substudy set [12] - ESWT substudy set |
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Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Treatment ratio between Tio+Olo 5.0/5.0 and placebo. Since the hierarchical testing chain has been broken, even though this treatment comparison is included as the 3rd one in the alpha-protected hierarchical testing chain, this hypothesis test is descriptive only.
Tio+Olo 5.0/5.0 is the numerator and placebo is the denominator.
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Comparison groups |
Placebo v Tio+Olo 5.0 / 5.0 μg
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Number of subjects included in analysis |
109
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Analysis specification |
Pre-specified
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Analysis type |
superiority [13] | ||||||||||||||||
P-value |
= 0.0552 [14] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
Treatment ratio | ||||||||||||||||
Point estimate |
1.209
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.996 | ||||||||||||||||
upper limit |
1.467 | ||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.119
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Notes [13] - Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was calculated using the delta method. [14] - MMRM for log10 (endurance time [s]) with fixed effects of treatment, test day, treatment by test day interaction, log10 (baseline endurance time [s]), log10 (baseline endurance time [s]) by test day interaction and patient as a random effect. |
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Statistical analysis title |
Tio+Olo 2.5 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Treatment ratio between Tio+Olo 2.5/5.0 and placebo.
Tio+Olo 2.5/5.0 is the numerator and placebo is the denominator. The hypothesis test is descriptive only.
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Comparison groups |
Placebo v Tio+Olo 2.5 / 5.0 μg
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Number of subjects included in analysis |
106
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Analysis specification |
Pre-specified
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Analysis type |
superiority [15] | ||||||||||||||||
P-value |
= 0.0562 [16] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
Treatment ratio | ||||||||||||||||
Point estimate |
1.211
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.995 | ||||||||||||||||
upper limit |
1.475 | ||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.121
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Notes [15] - Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was calculated using the delta method. [16] - MMRM for log10 (endurance time [s]) with fixed effects of treatment, test day, treatment by test day interaction, log10 (baseline endurance time [s]), log10 (baseline endurance time [s]) by test day interaction and patient as a random effect. |
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Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg | ||||||||||||||||
Statistical analysis description |
Treatment ratio between Tio+Olo 5.0/5.0 and Tio+Olo 2.5/5.0. This treatment comparison is not included in the alpha-protected hierarchical testing chain. The hypothesis test is descriptive only.
Tio+Olo 5.0/5.0 is the numerator and Tio+Olo 2.5/5.0 is the denominator.
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Comparison groups |
Tio+Olo 2.5 / 5.0 μg v Tio+Olo 5.0 / 5.0 μg
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Number of subjects included in analysis |
115
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Analysis specification |
Pre-specified
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Analysis type |
superiority [17] | ||||||||||||||||
P-value |
= 0.9822 [18] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
Treatment ratio | ||||||||||||||||
Point estimate |
0.998
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.826 | ||||||||||||||||
upper limit |
1.205 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.095
|
||||||||||||||||
Notes [17] - Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was calculated using the delta method. [18] - MMRM for log10 (endurance time [s]) with fixed effects of treatment, test day, treatment by test day interaction, log10 (baseline endurance time [s]), log10 (baseline endurance time [s]) by test day interaction andpatient as a random effect. |
|
|||||||||||||||||
End point title |
Adjusted mean inspiratory capacity (L) at pre-exercise after 12 weeks | ||||||||||||||||
End point description |
Secondary endpoint was inspiratory capacity (IC) before constant work rate cycle ergometry to symptom limitation at 75% maximal work capacity (Wcap) after 12 weeks of treatment.
Full analysis set (FAS): This patient set included all patients in the TS who had a baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
12 weeks
|
||||||||||||||||
|
|||||||||||||||||
Notes [19] - FAS [20] - FAS [21] - FAS |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 5.0 / 5.0 minus Placebo.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Placebo v Tio+Olo 5.0 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
252
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [22] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
0.234
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.133 | ||||||||||||||||
upper limit |
0.336 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.052
|
||||||||||||||||
Notes [22] - MMRM for inspiratory capacity with fixed effects of treatment, test day, treatment by test day interaction, baseline inspiratory capacity, baseline inspiratory capacity by test day interaction and patient as a random effect. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 2.5 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 2.5 / 5.0 minus Placebo.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Placebo v Tio+Olo 2.5 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [23] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
0.207
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.105 | ||||||||||||||||
upper limit |
0.309 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.052
|
||||||||||||||||
Notes [23] - MMRM for inspiratory capacity with fixed effects of treatment, test day, treatment by test day interaction, baseline inspiratory capacity, baseline inspiratory capacity by test day interaction and patient as a random effect. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 5.0 / 5.0 minus Tio+Olo 2.5 / 5.0.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Tio+Olo 5.0 / 5.0 μg v Tio+Olo 2.5 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
261
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.5892 [24] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
0.027
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-0.072 | ||||||||||||||||
upper limit |
0.126 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.05
|
||||||||||||||||
Notes [24] - MMRM for inspiratory capacity with fixed effects of treatment, test day, treatment by test day interaction, baseline inspiratory capacity, baseline inspiratory capacity by test day interaction and patient as a random effect. |
|
|||||||||||||||||
End point title |
Adjusted mean endurance time (sec) during constant work rate cycle ergometry (CWRCE) on Day 1 | ||||||||||||||||
End point description |
Secondary endpoint was endurance time during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity on Day 1. Analysis of covariance model on log10 transformed data. Adjusted means are back transformed to report in original units as geometric mean. Standard errors (SEs) are calculated using the delta method.
The V4 set included all patients in the TS who had evaluable measurements of endurance time at Baseline (Visit 3) and at Visit 4 (Day 1) during CWRCE. Patients were assigned to the Visit 4 set after implementation of data handling rules that set measurements to missing.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Day 1
|
||||||||||||||||
|
|||||||||||||||||
Notes [25] - Visit 4 (V4) set [26] - V4 set [27] - V4 set |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Treatment ratio between Tio+Olo 5.0/5.0 and placebo.
Tio+Olo 5.0/5.0 is numerator and placebo is denominator.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Placebo v Tio+Olo 5.0 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
157
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.0245 [28] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
Treatment ratio | ||||||||||||||||
Point estimate |
1.126
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
1.015 | ||||||||||||||||
upper limit |
1.248 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.059
|
||||||||||||||||
Notes [28] - ANCOVA model for log10 (endurance time [s]) with categorical effects of treatment and (log10-transformed) baseline as continuous covariate. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 2.5 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Treatment ratio between Tio+Olo 2.5/5.0 and placebo.
Tio+Olo 2.5/5.0 is numerator and placebo is denominator.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Placebo v Tio+Olo 2.5 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
154
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.0655 [29] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
Treatment ratio | ||||||||||||||||
Point estimate |
1.103
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.994 | ||||||||||||||||
upper limit |
1.223 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.058
|
||||||||||||||||
Notes [29] - ANCOVA model for log10 (endurance time [s]) with categorical effects of treatment and (log10-transformed) baseline as continuous covariate. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg | ||||||||||||||||
Statistical analysis description |
Treatment ratio between Tio+Olo 5.0/5.0 and Tio+Olo 2.5/5.0.
Tio+Olo 5.0/5.0 is numerator and Tio+Olo 2.5/5.0 is denominator.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Tio+Olo 5.0 / 5.0 μg v Tio+Olo 2.5 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
157
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.6912 [30] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
Treatment ratio | ||||||||||||||||
Point estimate |
1.021
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.921 | ||||||||||||||||
upper limit |
1.132 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.053
|
||||||||||||||||
Notes [30] - ANCOVA model for log10 (endurance time [s]) with categorical effects of treatment and (log10-transformed) baseline as continuous covariate. |
|
|||||||||||||||||
End point title |
Adjusted mean endurance time (sec) during constant work rate cycle ergometry (CWRCE) after 6 weeks treatment | ||||||||||||||||
End point description |
Secondary endpoint was endurance time during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 6 weeks of treatment. The endurance time in seconds was transformed using log10 scale to correct skewness in endurance time on original scale and then the MMRM model was fitted to the log10-transformed data and the least square means and SEs were obtained. To present the results in a way easier for interpretation, the least square mean from the MMRM fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate for the log10 of geometric mean and the corresponding SE was transformed using delta method to get the corresponding SEs of the geometric mean.
Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
6 weeks
|
||||||||||||||||
|
|||||||||||||||||
Notes [31] - FAS [32] - FAS [33] - FAS |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Treatment ratio between Tio+Olo 5.0/5.0 and placebo. Hypothesis test is descriptive.
Tio+Olo 5.0/5.0 is numerator and placebo is denominator.
|
||||||||||||||||
Comparison groups |
Placebo v Tio+Olo 5.0 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
256
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [34] | ||||||||||||||||
P-value |
= 0.0002 [35] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
Treatment ratio | ||||||||||||||||
Point estimate |
1.229
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
1.103 | ||||||||||||||||
upper limit |
1.37 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.068
|
||||||||||||||||
Notes [34] - Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was calculated using the delta method. [35] - MMRM for log10 (endurance time [s]) with fixed effects of treatment, test day, treatment by test day interaction, log10 (baseline endurance time [s]), log10 (baseline endurance time [s]) by test day interaction and patient as a random effect. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 2.5 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Treatment ratio between Tio+Olo 2.5/5.0 and placebo. Hypothesis test is descriptive.
Tio+Olo 2.5/5.0 is numerator and placebo is denominator.
|
||||||||||||||||
Comparison groups |
Placebo v Tio+Olo 2.5 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
250
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [36] | ||||||||||||||||
P-value |
= 0.0004 [37] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
Treatment ratio | ||||||||||||||||
Point estimate |
1.221
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
1.095 | ||||||||||||||||
upper limit |
1.362 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.068
|
||||||||||||||||
Notes [36] - Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was calculated using the delta method. [37] - MMRM for log10 (endurance time [s]) with fixed effects of treatment, test day, treatment by test day interaction, log10 (baseline endurance time [s]), log10 (baseline endurance time [s]) by test day interaction and patient as a random effect. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg | ||||||||||||||||
Statistical analysis description |
Treatment ratio between Tio+Olo 5.0/5.0 and Tio+Olo 2.5/5.0. Hypothesis test is descriptive.
Tio+Olo 5.0/5.0 is numerator and Tio+Olo 2.5/5.0 is denominator.
|
||||||||||||||||
Comparison groups |
Tio+Olo 5.0 / 5.0 μg v Tio+Olo 2.5 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
264
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [38] | ||||||||||||||||
P-value |
= 0.9062 [39] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
Treatment ratio | ||||||||||||||||
Point estimate |
1.006
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.905 | ||||||||||||||||
upper limit |
1.12 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.055
|
||||||||||||||||
Notes [38] - Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was calculated using the delta method. [39] - MMRM for log10 (endurance time [s]) with fixed effects of treatment, test day, treatment by test day interaction, log10 (baseline endurance time [s]), log10 (baseline endurance time [s]) by test day interaction and patient as a random effect. |
|
|||||||||||||||||
End point title |
Adjusted mean inspiratory capacity (L) at pre-exercise on Day 1 | ||||||||||||||||
End point description |
Secondary endpoint was pre-exercise inspiratory capacity (IC) on Day 1.
The V4 set included all patients in the TS who had evaluable measurements of endurance time at Baseline (Visit 3) and at Visit 4 (Day 1) during CWRCE. Patients were assigned to the Visit 4 set after implementation of data handling rules that set measurements to missing.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Day 1
|
||||||||||||||||
|
|||||||||||||||||
Notes [40] - V4 set [41] - V4 set [42] - V4 set |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 5.0 / 5.0 minus Placebo.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Placebo v Tio+Olo 5.0 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
151
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.0049 [43] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
0.165
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.051 | ||||||||||||||||
upper limit |
0.279 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.058
|
||||||||||||||||
Notes [43] - ANCOVA model for inspiratory capacity (liters) with categorical effect of treatment and baseline as continuous covariate. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 2.5 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 2.5 / 5.0 minus Placebo.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Tio+Olo 2.5 / 5.0 μg v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
152
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.0006 [44] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
0.202
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.088 | ||||||||||||||||
upper limit |
0.316 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.058
|
||||||||||||||||
Notes [44] - ANCOVA model for inspiratory capacity (liters) with categorical effect of treatment and baseline as continuous covariate. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 5.0 / 5.0 minus Tio+Olo 2.5 / 5.0.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Tio+Olo 2.5 / 5.0 μg v Tio+Olo 5.0 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
153
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.5162 [45] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
-0.037
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-0.151 | ||||||||||||||||
upper limit |
0.076 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.058
|
||||||||||||||||
Notes [45] - ANCOVA model for inspiratory capacity (liters) with categorical effect of treatment and baseline as continuous covariate. |
|
|||||||||||||||||
End point title |
Adjusted mean inspiratory capacity (L) at pre-exercise after 6 weeks | ||||||||||||||||
End point description |
Secondary endpoint was pre-exercise inspiratory capacity (IC) after 6 weeks of treatment.
Full analysis set (FAS): This patient set included all patients in the TS who had a baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
6 weeks
|
||||||||||||||||
|
|||||||||||||||||
Notes [46] - FAS [47] - FAS [48] - FAS |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 5.0 / 5.0 minus Placebo.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Placebo v Tio+Olo 5.0 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
252
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [49] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
0.225
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.124 | ||||||||||||||||
upper limit |
0.326 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.051
|
||||||||||||||||
Notes [49] - MMRM for inspiratory capacity with fixed effects of treatment, test day, treatment by test day interaction, baseline inspiratory capacity, baseline inspiratory capacity by test day interaction and patient as a random effect. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 2.5 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 2.5 / 5.0 minus Placebo.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Placebo v Tio+Olo 2.5 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
247
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.0003 [50] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
0.187
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.086 | ||||||||||||||||
upper limit |
0.288 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.052
|
||||||||||||||||
Notes [50] - MMRM for inspiratory capacity with fixed effects of treatment, test day, treatment by test day interaction, baseline inspiratory capacity, baseline inspiratory capacity by test day interaction and patient as a random effect. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 5.0 / 5.0 minus Tio+Olo 2.5 / 5.0.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Tio+Olo 2.5 / 5.0 μg v Tio+Olo 5.0 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
261
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.4541 [51] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
0.038
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-0.061 | ||||||||||||||||
upper limit |
0.137 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.05
|
||||||||||||||||
Notes [51] - MMRM for inspiratory capacity with fixed effects of treatment, test day, treatment by test day interaction, baseline inspiratory capacity, baseline inspiratory capacity by test day interaction and patient as a random effect. |
|
|||||||||||||||||
End point title |
Adjusted mean slope of the intensity of breathing discomfort on Day 1 | ||||||||||||||||
End point description |
Secondary endpoint was the slope of the intensity of breathing discomfort during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 1 day of treatment. The intensity of breathing discomfort was rated on the Borg Scale with categories from 0 (nothing at all) to 10 (maximal). The slope of the intensity of breathing discomfort was defined as the Borg scale value of breathing discomfort at the end of exercise minus the Borg scale value of breathing discomfort at pre-exercise divided by the endurance time. A decrease in slope indicates slowing down in decline in breathing, i.e., favorable results.
The V4 set included all patients in the TS who had evaluable measurements of endurance time at Baseline (Visit 3) and at Visit 4 (Day 1) during CWRCE. Patients were assigned to the Visit 4 set after implementation of data handling rules that set measurements to missing.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Day 1
|
||||||||||||||||
|
|||||||||||||||||
Notes [52] - V4 set [53] - V4 set [54] - V4 set |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 5.0 / 5.0 minus Placebo.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Placebo v Tio+Olo 5.0 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
156
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.0468 [55] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
-0.002
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-0.004 | ||||||||||||||||
upper limit |
0 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.001
|
||||||||||||||||
Notes [55] - ANCOVA model for mean slope of the intensity of breathing discomfort with categorical effect of treatment and baseline as continuous covariate. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 2.5 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 2.5 / 5.0 minus Placebo.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Placebo v Tio+Olo 2.5 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
153
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.018 [56] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
-0.002
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-0.005 | ||||||||||||||||
upper limit |
0 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.001
|
||||||||||||||||
Notes [56] - ANCOVA model for mean slope of the intensity of breathing discomfort with categorical effect of treatment and baseline as continuous covariate. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 5.0 / 5.0 minus Tio+Olo 2.5 / 5.0.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Tio+Olo 5.0 / 5.0 μg v Tio+Olo 2.5 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
157
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.6856 [57] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
0
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-0.002 | ||||||||||||||||
upper limit |
0.002 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.001
|
||||||||||||||||
Notes [57] - ANCOVA model for mean slope of the intensity of breathing discomfort with categorical effect of treatment and baseline as continuous covariate. |
|
|||||||||||||||||
End point title |
Adjusted mean slope of the intensity of breathing discomfort after week 6 | ||||||||||||||||
End point description |
Secondary endpoint was the slope of the intensity of breathing discomfort during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 6 weeks of treatment. The intensity of breathing discomfort was rated on the Borg Scale with categories from 0 (nothing at all) to 10 (maximal). The slope of the intensity of breathing discomfort was defined as the Borg scale value of breathing discomfort at the end of exercise minus the Borg scale value of breathing discomfort at pre-exercise divided by the endurance time. A decrease in slope indicates favorable results.
Full analysis set (FAS): This patient set included all patients in the TS who had a baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
6 weeks
|
||||||||||||||||
|
|||||||||||||||||
Notes [58] - FAS [59] - FAS [60] - FAS |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 5.0 / 5.0 minus Placebo.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Placebo v Tio+Olo 5.0 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
255
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.0081 [61] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
-0.003
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-0.005 | ||||||||||||||||
upper limit |
-0.001 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.001
|
||||||||||||||||
Notes [61] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 2.5 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 2.5 / 5.0 minus Placebo.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Placebo v Tio+Olo 2.5 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
249
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.0099 [62] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
-0.003
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-0.005 | ||||||||||||||||
upper limit |
-0.001 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.001
|
||||||||||||||||
Notes [62] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 5.0 / 5.0 minus Tio+Olo 2.5 / 5.0.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Tio+Olo 5.0 / 5.0 μg v Tio+Olo 2.5 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
264
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.9626 [63] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
0
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-0.002 | ||||||||||||||||
upper limit |
0.002 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.001
|
||||||||||||||||
Notes [63] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect. |
|
|||||||||||||||||
End point title |
Adjusted mean slope of the intensity of breathing discomfort after week 12 | ||||||||||||||||
End point description |
Secondary endpoint was the slope of the intensity of breathing discomfort during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 12 weeks of treatment. The intensity of breathing discomfort was rated on the Borg Scale with categories from 0 (nothing at all) to 10 (maximal). The slope of the intensity of breathing discomfort was defined as the Borg scale value of breathing discomfort at the end of exercise minus the Borg scale value of breathing discomfort at pre-exercise divided by the endurance time. A decrease in slope indicates favorable results.
Full analysis set (FAS): This patient set included all patients in the TS who had a baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
12 weeks
|
||||||||||||||||
|
|||||||||||||||||
Notes [64] - FAS [65] - FAS [66] - FAS |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 5.0 / 5.0 minus Placebo.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Placebo v Tio+Olo 5.0 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
255
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.0598 [67] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
-0.002
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-0.004 | ||||||||||||||||
upper limit |
0 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.001
|
||||||||||||||||
Notes [67] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 2.5 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 2.5 / 5.0 minus Placebo.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Placebo v Tio+Olo 2.5 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
249
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.0218 [68] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
-0.003
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-0.005 | ||||||||||||||||
upper limit |
0 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.001
|
||||||||||||||||
Notes [68] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 5.0 / 5.0 minus Tio+Olo 2.5 / 5.0.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Tio+Olo 5.0 / 5.0 μg v Tio+Olo 2.5 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
264
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.6549 [69] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
0
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-0.002 | ||||||||||||||||
upper limit |
0.003 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.001
|
||||||||||||||||
Notes [69] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect. |
|
|||||||||||||||||
End point title |
Adjusted mean 1-hour post-dose Forced Expiratory Volume in one second (FEV1) (L) on Day 1 | ||||||||||||||||
End point description |
Secondary endpoint was adjusted mean 1-hour post-dose Forced Expiratory Volume in one second (FEV1) observed on Day 1.
Full analysis set (FAS): This patient set included all patients in the TS who had a baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Day 1
|
||||||||||||||||
|
|||||||||||||||||
Notes [70] - FAS [71] - FAS [72] - FAS |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 5.0 / 5.0 minus Placebo.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Placebo v Tio+Olo 5.0 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
256
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [73] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
0.17
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.116 | ||||||||||||||||
upper limit |
0.224 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.028
|
||||||||||||||||
Notes [73] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 2.5 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 2.5 / 5.0 minus Placebo.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Placebo v Tio+Olo 2.5 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
250
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [74] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
0.184
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.129 | ||||||||||||||||
upper limit |
0.239 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.028
|
||||||||||||||||
Notes [74] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 5.0 / 5.0 minus Tio+Olo 2.5 / 5.0.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Tio+Olo 5.0 / 5.0 μg v Tio+Olo 2.5 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
264
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.6105 [75] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
-0.014
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-0.067 | ||||||||||||||||
upper limit |
0.04 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.027
|
||||||||||||||||
Notes [75] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect. |
|
|||||||||||||||||
End point title |
Adjusted mean 1-hour post-dose Forced Expiratory Volume in one second (FEV1) (L) after 6 weeks | ||||||||||||||||
End point description |
Secondary endpoint was adjusted mean 1-hour post-dose Forced Expiratory Volume in one second (FEV1) observed after 6 weeks of treatment.
Full analysis set (FAS): This patient set included all patients in the TS who had a baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
6 weeks
|
||||||||||||||||
|
|||||||||||||||||
Notes [76] - FAS [77] - FAS [78] - FAS |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 5.0 / 5.0 minus Placebo.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Placebo v Tio+Olo 5.0 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
256
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [79] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
0.246
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.192 | ||||||||||||||||
upper limit |
0.3 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.028
|
||||||||||||||||
Notes [79] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 2.5 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 2.5 / 5.0 minus Placebo.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Placebo v Tio+Olo 2.5 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
250
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [80] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
0.273
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.218 | ||||||||||||||||
upper limit |
0.328 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.028
|
||||||||||||||||
Notes [80] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 5.0 / 5.0 minus Tio+Olo 2.5 / 5.0.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Tio+Olo 5.0 / 5.0 μg v Tio+Olo 2.5 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
264
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.3236 [81] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
-0.027
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-0.08 | ||||||||||||||||
upper limit |
0.027 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.027
|
||||||||||||||||
Notes [81] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect. |
|
|||||||||||||||||
End point title |
Adjusted mean 1-hour post-dose Forced Expiratory Volume in one second (FEV1) (L) after 12 weeks | ||||||||||||||||
End point description |
Secondary endpoint was adjusted mean 1-hour post-dose Forced Expiratory Volume in one second (FEV1) observed after 12 weeks of treatment.
Full analysis set (FAS): This patient set included all patients in the TS who had a baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
12 weeks
|
||||||||||||||||
|
|||||||||||||||||
Notes [82] - FAS [83] - FAS [84] - FAS |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 5.0 / 5.0 minus Placebo.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Placebo v Tio+Olo 5.0 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
256
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [85] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
0.251
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.196 | ||||||||||||||||
upper limit |
0.305 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.028
|
||||||||||||||||
Notes [85] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 2.5 / 5.0 µg versus Placebo | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 2.5/ 5.0 minus Placebo.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Placebo v Tio+Olo 2.5 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
250
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [86] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
0.257
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.202 | ||||||||||||||||
upper limit |
0.312 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.028
|
||||||||||||||||
Notes [86] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect. |
|||||||||||||||||
Statistical analysis title |
Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg | ||||||||||||||||
Statistical analysis description |
Difference calculated as Tio+Olo 5.0 / 5.0 minus Tio+Olo 2.5 / 5.0.
The hypothesis test is descriptive only.
|
||||||||||||||||
Comparison groups |
Tio+Olo 5.0 / 5.0 μg v Tio+Olo 2.5 / 5.0 μg
|
||||||||||||||||
Number of subjects included in analysis |
264
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.8156 [87] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
LSMean Difference-Final Values | ||||||||||||||||
Point estimate |
-0.006
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-0.06 | ||||||||||||||||
upper limit |
0.047 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.027
|
||||||||||||||||
Notes [87] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect. |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
142 days
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
All adverse events, occurring during the course of the clinical trial (i.e. from signing the informed consent onwards throughout the 12 week treatment period and the 21-day follow up period) were to be collected, documented, and reported to the sponsor on the appropriate electronic case report form / serious adverse event reporting forms.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Once daily 2 puffs, solution for inhalation Respimat placebo to tiotropium+olodaterol during the 12-week treatment period: comparator | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Tio+Olo 5.0 / 5.0 µg
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Oral inhalation of FDC of Tiotropium (Tio) 5 μg and Olodaterol (Olo) 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning during the 12-week treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Tio+Olo 2.5 / 5.0 µg
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Oral inhalation of fixed dose combination (FDC) of Tiotropium (Tio) 2.5 μg and Olodaterol (Olo) 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning during the 12-week treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
15 Mar 2012 |
Additional guidance was provided for premature withdrawal, if the patient forgot to take study medication within the specified time window, regarding concomitant medications, and regarding the rescheduling of visits. As a recommendation of local authorities to restrict the trial population to Gold Stage II and III, the inclusion criteria were restricted to patients with a post-bronchodilator 30% ≤FEV1 <80% of predicted normal. A clarification was added that patients had to remain clinically stable for 3 weeks prior to the randomisation visit. For safety reasons, patients with chronic respiratory failure were excluded from the trial. Individual withdrawal criteria were defined. In alignment with the statistical section the list of ‘other endpoints’ was changed to refer to ‘secondary endpoints’. A specification that SAEs needed to be reported until 21 days after the last administration of study medication was added and a list of ‘always serious‘ AEs was included to comply with a new BI internal procedure. For consistency with the recovery phase after cycle ergometry, the IC-maneuver was included in the recovery phase after shuttle walking at sites using the Oxycon Mobile. The procedure of measuring IC was clarified. Administrative changes, minor corrections and further
clarifications were introduced. |
||
22 Oct 2012 |
The procedure for clinical evaluation of drug-induced liver injury was specified to implement a new BI guideline to comply with the FDA guidance for industry ‘Drug-Induced Liver Injury: Premarketing Clinical Evaluation’. As part of the reporting procedure of drug-induced liver injury, protocol-specific significant events were introduced. The period during which a pregnancy test after end of treatment was to be performed was specified. It was specified that mortality adjudication and SAE adjudication was to be performed separately and that vital signs were to be taken prior to each PFT. Clarifications regarding the use of PDE4-inhibitors and on medication restrictions prior to exercise testing were added. The definition of moderate COPD exacerbations was corrected. A clarification was added that more detailed information on exercise testing, equipment and calibration requirements was available in a Manual of Procedures. Administrative changes, minor corrections and further clarifications were introduced. |
||
25 Jun 2013 |
The description and categorisation of secondary and other endpoints was changed for the following reasons: Since this was a parallel-group trial, isotime was based on only one treatment. This change resulted in treatment comparisons at isotime to be based on different time points. Therefore, endpoints defined at isotime were regarded as less precise and important for treatment comparisons than planned in the original protocol and were relegated to other endpoints. In addition, slope of the intensity of breathing discomfort was used as a measure of the improvement of breathing discomfort during exercise and was added as one of the secondary efficacy endpoints. To be consistent with other exercise trials in the 1237.P1 project, the list of secondary efficacy endpoints was shortened. |
||
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 |