Clinical Trial Results:
A pharmacodynamic, randomised, single dose, cross-over study to compare the bronchodilator effect of a new formulation of Tiotropium DPI versus Spiriva® 18 μg Handihaler®
Summary
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EudraCT number |
2019-004095-19 |
Trial protocol |
BG |
Global end of trial date |
21 Oct 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
12 Jul 2021
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First version publication date |
12 Jul 2021
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Other versions |
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 |
TIO-II-19-1
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Laboratoires SMB S.A.
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Sponsor organisation address |
26-28 rue de la pastorale, brussels, Belgium, 1080
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Public contact |
Clinical Trial Department, Laboratoires SMB S.A., +32 24114828, DptClinique@smb.be
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Scientific contact |
Clinical Trial Department, Laboratoires SMB S.A., +32 24114828, DptClinique@smb.be
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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 |
12 Mar 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
21 Oct 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
21 Oct 2020
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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 |
Primary Objective
- To assess the non-inferiority between Tiotropium DPI capsule 8.8μg and Spiriva® 18μg Handihaler® by measurement of the bronchodilating effect
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Protection of trial subjects |
The trial was conducted in compliance with the protocol, with the ICH Harmonised Tripartite Guideline, Guideline for Good Clinical Practice, Step 5 (CPMP/ICH/135/95) (1), the applicable regulatory requirement(s) based on EU Directive 2001/20/EC (2) and EU GCP Directive (2005/28/EC) (3), and the Declaration of Helsinki (World Medical Association) in its revised edition (Brazil, 2013)
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 Jun 2020
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Bulgaria: 60
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Country: Number of subjects enrolled |
North Macedonia: 6
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Worldwide total number of subjects |
66
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EEA total number of subjects |
60
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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) |
33
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From 65 to 84 years |
33
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85 years and over |
0
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Recruitment
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Recruitment details |
The patients were screened within 21 days prior to the randomization. Following all screening procedures, patients who satisfied all of the inclusion/exclusion criteria were randomized. The patients visited the clinic 4 times + one telephone follow-up call. Each visit was separated by a wash-out period of at least 3 days with a maximum of 14 days | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
Obtain a signed informed consent form/Obtain demographic data/Record COPD history/review of prior and concomitant médications/Perform a measurement of pulmonary function/review of the inclusion and exclusion criteria/Perform a 12-lead ECG+Vital sign+laboratory tests/Dispensation of rescue medication | ||||||||||||||||||||||||
Period 1
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Period 1 title |
Cross-over phase (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 | ||||||||||||||||||||||||
Blinding implementation details |
This study was partly blinded. The blind was maintained only for the two doses of SMB tiotropium DPI formulations.
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Arms
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Are arms mutually exclusive |
No
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Arm title
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SMB Tiotropium 8.8µg | ||||||||||||||||||||||||
Arm description |
SMB Tiotropium 8.8 µg DPI, one capsule a day taken by inhalation via the Vertical-Haler®, containing 10.59 µg of tiotropium bromide anhydrous (equivalent to 8.8 µg of tiotropium base) | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Tiotropium
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Inhalation use
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Dosage and administration details |
SMB Tiotropium 8.8 µg DPI, one capsule a day taken by inhalation via the Vertical-Haler®, containing 10.59 µg of tiotropium bromide anhydrous (equivalent to 8.8 µg of tiotropium base)
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Arm title
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SMB Tiotropim 2.2µg | ||||||||||||||||||||||||
Arm description |
SMB tiotropium 2.2 µg DPI, one capsule a day taken by inhalation via the Vertical-Haler®, containing 2.64 µg of tiotropium bromide anhydrous (equivalent to 2.2 µg of tiotropium base) | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Tiotropium
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Inhalation use
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Dosage and administration details |
SMB tiotropium 2.2 µg DPI, one capsule a day taken by inhalation via the Vertical-Haler®, containing 2.64 µg of tiotropium bromide anhydrous (equivalent to 2.2 µg of tiotropium base)
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Arm title
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Spiriva Handihaler 18µg | ||||||||||||||||||||||||
Arm description |
Spiriva® Handihaler® 18 µg, one inhalation via the Handihaler®, each inhalation containing 22.5 µg of tiotropium bromide monohydrate (equivalent to 18 μg of tiotropium base) | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
Tiotropium
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Inhalation use
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Dosage and administration details |
Spiriva® Handihaler® 18 µg, one inhalation via the Handihaler®, each inhalation containing 22.5 µg of tiotropium bromide monohydrate (equivalent to 18 μg of tiotropium base)
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Baseline characteristics reporting groups
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Reporting group title |
Cross-over phase
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Reporting group description |
Sixty-six subjects were included and randomized into 6 sequences groups. All randomized subjects took at least one unit of the study drugs. Three subjects prematurely withdrew from the study and 63 (95.5% of the randomized subjects) completed the study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
SMB Tiotropium 8.8µg
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Reporting group description |
SMB Tiotropium 8.8 µg DPI, one capsule a day taken by inhalation via the Vertical-Haler®, containing 10.59 µg of tiotropium bromide anhydrous (equivalent to 8.8 µg of tiotropium base) | ||
Reporting group title |
SMB Tiotropim 2.2µg
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Reporting group description |
SMB tiotropium 2.2 µg DPI, one capsule a day taken by inhalation via the Vertical-Haler®, containing 2.64 µg of tiotropium bromide anhydrous (equivalent to 2.2 µg of tiotropium base) | ||
Reporting group title |
Spiriva Handihaler 18µg
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Reporting group description |
Spiriva® Handihaler® 18 µg, one inhalation via the Handihaler®, each inhalation containing 22.5 µg of tiotropium bromide monohydrate (equivalent to 18 μg of tiotropium base) |
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End point title |
Trough FEV1 response | ||||||||||||||||
End point description |
The bronchodilating effect was evaluated by the trough FEV1 response defined as the change in FEV1 from baseline to FEV1 24h post-dose measurement.
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End point type |
Primary
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End point timeframe |
Visit 2, visit 3 and visit 4
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Statistical analysis title |
Primary efficacy endpoint analysis | ||||||||||||||||
Statistical analysis description |
The bronchodilating effect will be evaluated by the trough FEV1 response. Trough FEV1 response will be compared between IMPs using a mixed model with sequence, period and IMP as fixed effects, patient within sequence as random effect and period-specific baseline as covariate. LS means will be derived from the model and contrasts between IMP will be calculated. The lower bound of the 95% CI of the contrast between treatments will be compared to the non-inferiority threshold of -0.100 L
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Comparison groups |
SMB Tiotropium 8.8µg v Spiriva Handihaler 18µg
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Number of subjects included in analysis |
126
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||||||
P-value |
= 0.596 | ||||||||||||||||
Method |
ANOVA | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
0.015
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.041 | ||||||||||||||||
upper limit |
0.07 | ||||||||||||||||
Statistical analysis title |
Secondary endpoint analysis (Tio 2.2 vs Tio 8.8) | ||||||||||||||||
Statistical analysis description |
Secondary criteria will be analysed using mixed models for cross-over designs. All IMPs will be compared without reference to a non-inferiority threshold. Estimates of the variable and their standard error will be calculated for each IMP Contrast between all IMPs will be computed and compared to 0. P-value and 95% confidence interval of each difference will be presented without adjustment for multiple comparisons.
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Comparison groups |
SMB Tiotropium 8.8µg v SMB Tiotropim 2.2µg
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Number of subjects included in analysis |
126
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||
P-value |
= 0.467 | ||||||||||||||||
Method |
ANOVA | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
0.02
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.035 | ||||||||||||||||
upper limit |
0.076 | ||||||||||||||||
Statistical analysis title |
Secondary endpoint analysis (Tio 2.2 vs Spiriva) | ||||||||||||||||
Comparison groups |
SMB Tiotropim 2.2µg v Spiriva Handihaler 18µg
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Number of subjects included in analysis |
126
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||
P-value |
= 0.844 | ||||||||||||||||
Method |
ANOVA | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
0.005
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.05 | ||||||||||||||||
upper limit |
0.061 |
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End point title |
Baseline-adjusted AUC of FEV1 from 0 to 24h | ||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Visit 2, visit3 and visit 4
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Statistical analysis title |
Secondary endpoint analysis (Tio 2.2 vs Tio 8.8) | ||||||||||||||||
Comparison groups |
SMB Tiotropium 8.8µg v SMB Tiotropim 2.2µg
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Number of subjects included in analysis |
126
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||
P-value |
= 0.428 | ||||||||||||||||
Method |
ANOVA | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
0.377
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.562 | ||||||||||||||||
upper limit |
1.316 | ||||||||||||||||
Statistical analysis title |
Secondary endpoint analysis (Tio 2.2 vs Spiriva) | ||||||||||||||||
Comparison groups |
Spiriva Handihaler 18µg v SMB Tiotropim 2.2µg
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Number of subjects included in analysis |
126
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||
P-value |
= 0.705 | ||||||||||||||||
Method |
ANOVA | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
0.179
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.756 | ||||||||||||||||
upper limit |
1.113 | ||||||||||||||||
Statistical analysis title |
Secondary endpoint analysis (Tio 8.8 vs Spiriva) | ||||||||||||||||
Comparison groups |
SMB Tiotropium 8.8µg v Spiriva Handihaler 18µg
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Number of subjects included in analysis |
126
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||
P-value |
= 0.677 | ||||||||||||||||
Method |
ANOVA | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
0.198
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.743 | ||||||||||||||||
upper limit |
1.14 |
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Adverse events information [1]
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Timeframe for reporting adverse events |
Visit 1 to visit 4
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||
Dictionary version |
22.1
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Reporting groups
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Reporting group title |
SMB Tiotropium 8.8µg
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Reporting group description |
SMB Tiotropium 8.8 µg DPI, one capsule a day taken by inhalation via the Vertical-Haler®, containing 10.59 µg of tiotropium bromide anhydrous (equivalent to 8.8 µg of tiotropium base) | ||||||||||||||||||||||||||||||||||||||||
Reporting group title |
SMB Tiotropim 2.2µg
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Reporting group description |
SMB tiotropium 2.2 µg DPI, one capsule a day taken by inhalation via the Vertical-Haler®, containing 2.64 µg of tiotropium bromide anhydrous (equivalent to 2.2 µg of tiotropium base) | ||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Spiriva Handihaler 18µg
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Reporting group description |
Spiriva® Handihaler® 18 µg, one inhalation via the Handihaler®, each inhalation containing 22.5 µg of tiotropium bromide monohydrate (equivalent to 18 μg of tiotropium base) | ||||||||||||||||||||||||||||||||||||||||
Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: No non-serious adverse events superior to the defined threshold (5%) were reported in this study. |
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |