Characterization of 24-hour Lung Function Profiles of Inhaled Tiotropium + Olodaterol Fixed Dose Combination in Patients Suffering From Chronic Obstructive Pulmonary Disease

Randomised, Double-blind, Placebo-controlled, 6 Treatment, 4 Period, Incomplete Cross-over Trial to Characterise the 24-hour Lung Function Profiles of Tiotropium + Olodaterol Fixed Dose Combination (2.5/5 µg, 5/5 µg), Tiotropium (2.5 µg, 5 µg) and Olodaterol (5 µg) (Oral Inhalation, Delivered by the Respimat® Inhaler) After 6 Weeks Once Daily Treatment in Patients With Chronic Obstructive Pulmonary Disease (COPD) [VIVACITOTM]

The primary objective of the trial is to determine the 24-hour FEV1-time profile of tiotropium + olodaterol FDC, administered once daily by the RESPIMAT Inhaler after 6 weeks of treatment.

Study Overview

• Status: Completed
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Device: Respimat; Drug: olodaterol; Drug: tiotropium; Drug: tiotropium; Drug: tiotropium + olodaterol; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 219
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Genk, Belgium
    • 1237.20.32203 Boehringer Ingelheim Investigational Site
  • Gent, Belgium
    • 1237.20.32201 Boehringer Ingelheim Investigational Site
  • Jambes, Belgium
    • 1237.20.32204 Boehringer Ingelheim Investigational Site
• Canada
  • Quebec, Canada
    • 1237.20.02202 Boehringer Ingelheim Investigational Site
  • Quebec
    • Sherbrooke, Quebec, Canada
      • 1237.20.02201 Boehringer Ingelheim Investigational Site
• Denmark
  • Hvidovre, Denmark
    • 1237.20.45002 Boehringer Ingelheim Investigational Site
  • Odense C, Denmark
    • 1237.20.45003 Boehringer Ingelheim Investigational Site
  • Silkeborg, Denmark
    • 1237.20.45001 Boehringer Ingelheim Investigational Site
• Germany
  • Berlin, Germany
    • 1237.20.49205 Boehringer Ingelheim Investigational Site
  • Großhansdorf, Germany
    • 1237.20.49204 Boehringer Ingelheim Investigational Site
  • Hamburg, Germany
    • 1237.20.49203 Boehringer Ingelheim Investigational Site
  • Hamburg, Germany
    • 1237.20.49206 Boehringer Ingelheim Investigational Site
  • Mannheim, Germany
    • 1237.20.49201 Boehringer Ingelheim Investigational Site
  • Mönchengladbach, Germany
    • 1237.20.49207 Boehringer Ingelheim Investigational Site
  • Wiesbaden, Germany
    • 1237.20.49202 Boehringer Ingelheim Investigational Site
• Hungary
  • Gödöllö, Hungary
    • 1237.20.36202 Boehringer Ingelheim Investigational Site
  • Komarom, Hungary
    • 1237.20.36204 Boehringer Ingelheim Investigational Site
  • Pecs, Hungary
    • 1237.20.36203 Boehringer Ingelheim Investigational Site
  • Szarvas, Hungary
    • 1237.20.36201 Boehringer Ingelheim Investigational Site
  • Szazhalombatta, Hungary
    • 1237.20.36205 Boehringer Ingelheim Investigational Site
• Netherlands
  • Almelo, Netherlands
    • 1237.20.31205 Boehringer Ingelheim Investigational Site
  • Breda, Netherlands
    • 1237.20.31202 Boehringer Ingelheim Investigational Site
  • Heerlen, Netherlands
    • 1237.20.31201 Boehringer Ingelheim Investigational Site
  • Hengelo, Netherlands
    • 1237.20.31204 Boehringer Ingelheim Investigational Site
  • Zutphen, Netherlands
    • 1237.20.31203 Boehringer Ingelheim Investigational Site
• United States
  • Alabama
    • Jasper, Alabama, United States
      • 1237.20.1204 Boehringer Ingelheim Investigational Site
  • South Carolina
    • Easley, South Carolina, United States
      • 1237.20.1203 Boehringer Ingelheim Investigational Site
    • Greenville, South Carolina, United States
      • 1237.20.1201 Boehringer Ingelheim Investigational Site
    • Spartanburg, South Carolina, United States
      • 1237.20.1202 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Diagnosis of chronic obstructive pulmonary disease
2. Relatively stable airway obstruction with a post-bronchodilator FEV1< 80% of predicted normal and a post-bronchodilator FEV1/FVC <70%
3. Male or female patients, 40 years of age or older
4. Smoking history of more than 10 pack years
5. Ability to perform technically acceptable pulmonary function tests and maintain records
6. Ability to inhale medication in a competent manner from the RESPIMAT Inhaler and from a metered dose inhaler (MDI)

Exclusion criteria:

1. significant disease other than COPD
2. clinically relevant abnormal lab values
3. history of asthma
4. diagnosis of thyrotoxicosis
5. diagnosis of paroxysmal tachycardia
6. history of myocardial infarction
7. unstable or life-threatening cardiac arrhythmia
8. Hospitalization for heart failure within the past year
9. known active tuberculosis
10. malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years
11. history of life-threatening pulmonary obstruction
12. history of cystic fibrosis
13. clinically evident bronchiectasis
14. history of significant alcohol or drug abuse
15. history of thoracotomy with pulmonary resection
16. oral or patch ß-adrenergics
17. oral corticosteroid medication at unstable doses
18. regular use daytime oxygen therapy for more than one hour per day
19. Pulmonary rehabilitation program in the six weeks prior to the screening visit
20. Investigational drug within one month or six half lives (whichever is greater) prior to screening visit
21. Known hypersensitivity to ß-adrenergic drugs, BAC, EDTA
22. Pregnant or nursing women
23. Women of childbearing potential not using a highly effective method of birth control
24. Patients who have previously been randomised in this study or are currently participating in another study
25. Patients who are unable to comply with pulmonary medication restrictions prior to randomisation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: tiotropium+olodaterol FDC low dose; tiotropium+olodaterol FDC low dose; 2 inhalations once daily (a.m. dosing)	Device: Respimat; Respimat inhaler; Drug: tiotropium + olodaterol; low dose + one dose only
EXPERIMENTAL: tiotropium+olodaterol FDC high dose; tiotropium+olodaterol FDC high dose; 2 inhalations once daily (a.m. dosing)	Device: Respimat; Respimat inhaler; Drug: tiotropium + olodaterol; low dose + one dose only
ACTIVE_COMPARATOR: tiotropium low dose; tiotropium low dose; 2 inhalations once daily (a.m. dosing)	Device: Respimat; Respimat inhaler; Drug: tiotropium; low dose; Drug: tiotropium; high dose
ACTIVE_COMPARATOR: tiotropium high dose; tiotropium high dose; 2 inhalations once daily (a.m. dosing)	Device: Respimat; Respimat inhaler; Drug: tiotropium; low dose; Drug: tiotropium; high dose
ACTIVE_COMPARATOR: olodaterol; one dose only; 2 inhalations once daily (a.m. dosing)	Device: Respimat; Respimat inhaler; Drug: olodaterol; one dose only
PLACEBO_COMPARATOR: placebo; 2 inhalations once daily (a.m. dosing)	Device: Respimat; Respimat inhaler; Drug: Placebo; placebo matching tiotropium+olodaterol FDC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forced Expiratory Volume in 1 Second (FEV1) AUC0-24h Response [L] After 6 Weeks Treatment.	Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatement-time curve from 0 to 24 h post-dose, using the trapezoidal rule, divided by the duration (24 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.	day 1 and week 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
FEV1 AUC0-12h Response [L] After 6 Weeks Treatment.	Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatement-time curve from 0 to 12 h post-dose, using the trapezoidal rule, divided by the duration (12h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.	day 1 and week 6
FEV1 AUC12-24h Response [L] After 6 Weeks Treatment.	Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatement-time curve from 12 to 24 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.	day 1 and week 6
Trough FEV1 Response [L] After 6 Weeks Treatment.	Trough Forced Expiratory Volume in 1 second (FEV1) response after 6 weeks treatment period. The trough was defined as the mean of the 23 h and 23 h50 min measurements and Response was defined as the change from patient baseline. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.	day 1 and week 6
Peak(0-3h) FEV1 Response [L] After 6 Weeks Treatment.	Peak (0-3h) Forced Expiratory Volume in 1 second (FEV1) response. The peak was defined as the maximum value measured within the first 3 h post dosing and response was defined as the change from patient baseline. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.	day 1 and week 6
FVC AUC0-24h Response [L] After 6 Weeks Treatment.	Area under the Forced Vital Capacity (FVC) after 6 weeks treatment period-time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.	day 1 and week 6
FVC AUC0-12h Response [L] After 6 Weeks Treatment.	Area under the Forced Vital Capacity (FVC) after 6 weeks treatment period-time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.	day 1 and week 6
FVC AUC12-24h Response [L] After 6 Weeks Treatment.	Area under the Forced Vital Capacity (FVC) after 6 weeks treatment period-time curve from 12 to 24 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.	day 1 and week 6
Trough FVC Response [L] After 6 Weeks Treatment.	Trough Forced Vital Capacity (FVC) response after 6 weeks treatment period. The trough was defined as the mean of the 23 h and 23 h50 min measurements and response was defined as the change from patient baseline. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.	day1 and week 6
Peak (0-3h) FVC Response [L] After 6 Weeks Treatment.	Peak (0-3h) Forced Vital Capacity (FVC) responses after 6 weeks treatment. Peak was defined as the maximum value measured within the first 3 h post dosing and response was defined as the change from patient baseline. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.	day 1 and week 6

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Beeh KM, Westerman J, Kirsten AM, Hebert J, Gronke L, Hamilton A, Tetzlaff K, Derom E. The 24-h lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination in chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2015 Jun;32:53-9. doi: 10.1016/j.pupt.2015.04.002. Epub 2015 May 6.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (ACTUAL): August 1, 2013
• Study Completion (ACTUAL): August 1, 2013

Study Registration Dates

• First Submitted: March 19, 2012
• First Submitted That Met QC Criteria: March 20, 2012
• First Posted (ESTIMATE): March 21, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): July 16, 2015
• Last Update Submitted That Met QC Criteria: June 19, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Tiotropium Bromide; Olodaterol
• Other Study ID Numbers: 1237.20; 2011-004710-42 (EUDRACT_NUMBER: EudraCT)