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Fixed Dose Combination Versus Free Combination of Tiotropium and Olodaterol in COPD

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ClinicalTrials.gov Identifier: NCT02683109
Recruitment Status : Completed
First Posted : February 17, 2016
Results First Posted : August 17, 2018
Last Update Posted : August 17, 2018
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Pulmonary Disease, Chronic Obstructive
Interventions Drug: FDC of tiotropium + olodaterol
Drug: Placebo
Drug: Tiotropium
Drug: Olodaterol
Enrollment 221
Recruitment Details Definition: Open-Label Treated Set (OLTS): This patient set includes all patients who signed the informed consent and were dispensed open-label study medication during the run-in period prior to randomisation and were documented to have taken any dose of this medication.
Pre-assignment Details Definition: Randomised Set (RS): This patient set is nested within the OLTS and includes all patients who signed the informed consent form and were also randomised, regardless of whether the patient was treated with study medication or not.
Arm/Group Title T+O 5/5 T 5/O 5
Hide Arm/Group Description

The subjects were administered Tiotropium (T) + Olodaterol (O) Fixed Dose Combination (FDC) solution for inhalation 2.5 μg/2.5 μg per actuation, 2 inhalations orally once daily via RESPIMAT® inhaler.

Placebo matching Tiotropium solution was administered 2 inhalations once daily via RESPIMAT® inhaler.

The subjects were administered Tiotropium solution for inhalation, 2.5 μg per actuation + Olodaterol solution for inhalation, 2.5 μg per actuation as a free combination. Two inhalations were administered once daily (a.m. dosing) via RESPIMAT® inhaler for both Tiotropium and Olodaterol.
Period Title: Overall Study
Started 110 111
Completed 109 111
Not Completed 1 0
Reason Not Completed
Adverse Event             1             0
Arm/Group Title T+O 5/5 T 5/O 5 Total
Hide Arm/Group Description

The subjects were administered Tiotropium (T) + Olodaterol (O) Fixed Dose Combination (FDC) solution for inhalation 2.5 μg/2.5 μg per actuation, 2 inhalations orally once daily via RESPIMAT® inhaler.

Placebo matching Tiotropium solution was administered 2 inhalations once daily via RESPIMAT® inhaler.

The subjects were administered Tiotropium solution for inhalation, 2.5 μg per actuation + Olodaterol solution for inhalation, 2.5 μg per actuation as a free combination. Two inhalations were administered once daily (a.m. dosing) via RESPIMAT® inhaler for both Tiotropium and Olodaterol. Total of all reporting groups
Overall Number of Baseline Participants 110 111 221
Hide Baseline Analysis Population Description
Treated set [TS]: This patient set is nested within the RS and includes all patients who were dispensed study medication and were documented to have taken any dose of study medication.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 110 participants 111 participants 221 participants
66.5  (7.1) 66.5  (6.4) 66.5  (6.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 110 participants 111 participants 221 participants
Female
33
  30.0%
30
  27.0%
63
  28.5%
Male
77
  70.0%
81
  73.0%
158
  71.5%
1.Primary Outcome
Title Trough Forced Expiratory Volume in 1 Second (FEV1) (in Liter) After 28 Days of Treatment
Hide Description

This outcome measure presents FEV1 after 28 days of treatment (measurement on Day 29). Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), and was measured at 24 hours (+/- 10 minutes) after trial medication administration at Visit 5.

The FEV1 measurement at Visit 4, which was 24 hours after the last open-label run-in treatment intake and 15 minutes before the first double-blind study drug intake was the baseline measurement.

Time Frame Day 29
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS): This patient set is nested within the TS and includes patients who had a baseline measurement and at least one post-baseline measurement for the primary endpoint.
Arm/Group Title T+O 5/5 T 5/O 5
Hide Arm/Group Description:

The subjects were administered Tiotropium (T) + Olodaterol (O) Fixed Dose Combination (FDC) solution for inhalation 2.5 μg/2.5 μg per actuation, 2 inhalations orally once daily via RESPIMAT® inhaler.

Placebo matching Tiotropium solution was administered 2 inhalations once daily via RESPIMAT® inhaler.

The subjects were administered Tiotropium solution for inhalation, 2.5 μg per actuation + Olodaterol solution for inhalation, 2.5 μg per actuation as a free combination. Two inhalations were administered once daily (a.m. dosing) via RESPIMAT® inhaler for both Tiotropium and Olodaterol.
Overall Number of Participants Analyzed 108 108
Mean (Standard Error)
Unit of Measure: Liter
1.422  (0.016) 1.399  (0.016)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection T+O 5/5, T 5/O 5
Comments The primary analysis was conducted using an Analysis of Covariance [ANCOVA] model including treatment as fixed categorical effect and baseline as continuous covariate.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Non-inferiority of the Tio+Olo FDC versus the Tio/Olo free combination was tested at the one-sided α-level of 0.025 using a non-inferiority margin of 0.1 L.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted mean
Estimated Value 0.024
Confidence Interval (2-Sided) 95%
-0.020 to 0.067
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.022
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Trough Forced Vital Capacity (FVC) (in Liter) After 28 Days of Treatment
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This outcome measure presents trough FVC after 28 days of treatment (measurement on Day 29).

The FVC measurement at Visit 4, which was 24 hours after the last open-label run-in treatment intake and 15 minutes before the first double-blind study drug intake was the baseline measurement for FVC.

Time Frame Day 29
Hide Outcome Measure Data
Hide Analysis Population Description
FAS.
Arm/Group Title T+O 5/5 T 5/O 5
Hide Arm/Group Description:

The subjects were administered Tiotropium (T) + Olodaterol (O) Fixed Dose Combination (FDC) solution for inhalation 2.5 μg/2.5 μg per actuation, 2 inhalations orally once daily via RESPIMAT® inhaler.

Placebo matching Tiotropium solution was administered 2 inhalations once daily via RESPIMAT® inhaler.

The subjects were administered Tiotropium solution for inhalation, 2.5 μg per actuation + Olodaterol solution for inhalation, 2.5 μg per actuation as a free combination. Two inhalations were administered once daily (a.m. dosing) via RESPIMAT® inhaler for both Tiotropium and Olodaterol.
Overall Number of Participants Analyzed 108 108
Mean (Standard Error)
Unit of Measure: Liter
3.126  (0.024) 3.121  (0.024)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection T+O 5/5, T 5/O 5
Comments The secondary analysis was conducted using an ANCOVA model including treatment as fixed categorical effect and baseline as continuous covariate.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8648
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted mean
Estimated Value 0.006
Confidence Interval (2-Sided) 95%
-0.061 to 0.073
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.034
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Chronic Obstructive Pulmonary Disease (COPD) Assessment Test™ (CAT) Score on Day 28
Hide Description

This outcome measure presents COPD assessment test score on Day 28. The COPD Assessment Test™ is a short 8-item questionnaire for assessment and monitoring of COPD health status in routine practice. Its scale is 0-40 (high score = poor health).

The CAT measurement on Visit 4 prior to the first dose of double-blind study drug was the baseline for CAT.

Time Frame Day 28
Hide Outcome Measure Data
Hide Analysis Population Description
FAS. One patient in the T 5/O 5 free combination group had missing data for the CAT questionnaire.
Arm/Group Title T+O 5/5 T 5/O 5
Hide Arm/Group Description:

The subjects were administered Tiotropium (T) + Olodaterol (O) Fixed Dose Combination (FDC) solution for inhalation 2.5 μg/2.5 μg per actuation, 2 inhalations orally once daily via RESPIMAT® inhaler.

Placebo matching Tiotropium solution was administered 2 inhalations once daily via RESPIMAT® inhaler.

The subjects were administered Tiotropium solution for inhalation, 2.5 μg per actuation + Olodaterol solution for inhalation, 2.5 μg per actuation as a free combination. Two inhalations were administered once daily (a.m. dosing) via RESPIMAT® inhaler for both Tiotropium and Olodaterol.
Overall Number of Participants Analyzed 108 107
Mean (Standard Error)
Unit of Measure: Score on scale
15.423  (0.377) 15.750  (0.379)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection T+O 5/5, T 5/O 5
Comments The secondary analysis was conducted using an ANCOVA model including treatment as fixed categorical effect and baseline as continuous covariate.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5420
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted mean
Estimated Value -0.327
Confidence Interval (2-Sided) 95%
-1.384 to 0.729
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.536
Estimation Comments [Not Specified]
Time Frame From first drug administration until 28 days after last drug administration, up to 49 days.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title T+O 5/5 T 5/O 5 Total
Hide Arm/Group Description

The subjects were administered Tiotropium (T) + Olodaterol (O) Fixed Dose Combination (FDC) solution for inhalation 2.5 μg/2.5 μg per actuation, 2 inhalations orally once daily via RESPIMAT® inhaler.

Placebo matching Tiotropium solution was administered 2 inhalations once daily via RESPIMAT® inhaler.

The subjects were administered Tiotropium solution for inhalation, 2.5 μg per actuation + Olodaterol solution for inhalation, 2.5 μg per actuation as a free combination. Two inhalations were administered once daily (a.m. dosing) via RESPIMAT® inhaler for both Tiotropium and Olodaterol. The total number of subjects who were administered T+O 5/5 or T 5/O 5.
All-Cause Mortality
T+O 5/5 T 5/O 5 Total
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
T+O 5/5 T 5/O 5 Total
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/110 (0.91%)   2/111 (1.80%)   3/221 (1.36%) 
Cardiac disorders       
Cardiac failure  1  1/110 (0.91%)  0/111 (0.00%)  1/221 (0.45%) 
Left ventricular failure  1  0/110 (0.00%)  1/111 (0.90%)  1/221 (0.45%) 
Vascular disorders       
Deep vein thrombosis  1  0/110 (0.00%)  1/111 (0.90%)  1/221 (0.45%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 19.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
T+O 5/5 T 5/O 5 Total
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   9/110 (8.18%)   9/111 (8.11%)   18/221 (8.14%) 
Respiratory, thoracic and mediastinal disorders       
Chronic obstructive pulmonary disease  1  9/110 (8.18%)  9/111 (8.11%)  18/221 (8.14%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 19.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI’s intellectual property rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Boehringer Ingelheim, Call Center
Organization: Boehringer Ingelheim
Phone: 1800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Layout table for additonal information
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02683109     History of Changes
Other Study ID Numbers: 1237.49
2015-003879-29 ( EudraCT Number )
First Submitted: February 12, 2016
First Posted: February 17, 2016
Results First Submitted: December 7, 2017
Results First Posted: August 17, 2018
Last Update Posted: August 17, 2018