Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The overall objective of this study is to assess efficacy and safety of 12 weeks, once daily, orally inhaled co-administration of olodaterol 5 µg (delivered by the Respimat® Inhaler) and tiotropium (delivered by the Handihaler® as Spiriva Handihaler®), compared to tiotropium (Spiriva Handihaler®) monotherapy on lung function in patients with COPD.
Interventions
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. All patients must sign an informed consent consistent with International Conference on Harmonization-Good Clinical Practice (ICH-GCP) guidelines prior to participation in the trial, which includes medication washout and restrictions. 2. All patients must have a diagnosis of chronic obstructive pulmonary disease and must meet the following spirometric criteria: Patients must have a relatively stable airway obstruction with a post-bronchodilator FEV1 ≥ 30 % and \< 80% of predicted normal and a post-bronchodilator FEV1/FVC \<70% at Visit 1. 3. Male or female patients, 40 years of age or older. 4. Patients must be current or ex-smokers with a smoking history of more than 10 pack years 5. Patients must be able to: perform technically acceptable pulmonary function tests, and maintain records(paper diary). 6. Patients must be able to inhale medication in a competent manner from the Respimat Inhaler as well as the Handihaler.
Exclusion criteria
1. Patients with a significant disease other than COPD; a significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the study, (ii) influence the results of the study, or (iii) cause concern regarding the patients ability to participate in the study. 2. Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis; all patients with an AST \>x2 ULN, ALT \>x2 ULN, bilirubin \>x2 ULN or creatinine \>x2 ULN will be excluded regardless of clinical condition (a repeat laboratory evaluation will not be conducted in these patients). 3. Patients with a history of asthma. For patients with allergic rhinitis or atopy, source documentation is required to verify that the patient does not have asthma. If a patient has a total blood eosinophil count ≥600/mm3, source documentation is required to verify that the increased eosinophil count is related to a non-asthmatic condition. 4. A diagnosis of thyrotoxicosis (due to the known class side effect profile of ß2-agonists). 5. A diagnosis of paroxysmal tachycardia (\>100 beats per minute) (due to the known class side effect profile of ß2-agonists). 6. A history of myocardial infarction within 1 year of screening visit (Visit 1). 7. Unstable or life-threatening cardiac arrhythmia. 8. Hospitalization for heart failure within the past year. 9. Known active tuberculosis. 10. A malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years (patients with treated basal cell carcinoma are allowed). 11. A history of life-threatening pulmonary obstruction. 12. A history of cystic fibrosis. 13. Clinically evident bronchiectasis. 14. A history of significant alcohol or drug abuse. 15. Patients who have undergone thoracotomy with pulmonary resection (patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1). 16. Patients being treated with oral or patch ß-adrenergics. 17. Patients being treated with oral corticosteroid medication at unstable doses (i.e., less than six weeks on a stable dose) or at doses in excess of the equivalent of 10 mg of prednisone per day or 20 mg every other day. 18. Patients who regularly use daytime oxygen therapy for more than one hour per day and in the investigators opinion will be unable to abstain from the use of oxygen therapy during clinic visits. 19. Patients who have completed a pulmonary rehabilitation program in the six weeks prior to the screening visit (Visit 1) or patients who are currently in a pulmonary rehabilitation program. 20. Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to screening visit (Visit 1). 21. Patients with known hypersensitivity to ß-adrenergic drugs, BAC, EDTA, or any other component of the Respimat® inhalation solution. 22. Patients with known hypersensitivity to anticholinergic drugs, lactose, or any other components of the HandiHaler®. 23. Pregnant or nursing women. 24. Women of childbearing potential not using a highly effective method of birth control\*. Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation, or post-menopausal for at least two years. \* as per ICH M3(R2) a highly effective method of birth control is defined as those which result in a low failure rate (i.e. less than 1% per year). 25. Patients who have previously been randomised in this study or are currently participating in another study. 26. Patients who are unable to comply with pulmonary medication restrictions prior to randomisation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| FEV1 AUC0-3h Response at 12 Weeks; Defined as Change From Baseline to Week 12 | baseline and 12 weeks | FEV1 (Forced expiratory volume in 1 second) AUC0-3h (area under the curve) response at 12 weeks; defined as change from baseline to Week 12. AUC was standardized by dividing by time unit. |
| Trough FEV1 Response at 12 Weeks; Defined as Change From Baseline to Week 12 | baseline and 12 weeks | Trough FEV1 (Forced expiratory volume in 1 second) response at 12 weeks; defined as change from baseline to Week 12 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak FEV1 Response at 12 Weeks - Defined as Change From Baseline | baseline and 12 weeks | Peak FEV1 (Forced Expiratory Volume in 1 second) response at 12 Weeks - defined as change from baseline. All p-values for these measures are only descriptive. |
| FVC AUC0-3h Response at 12 Weeks; Defined as Change From Baseline | baseline and 12 Weeks | Forced Vital Capacity (FVC) AUC0-3h response at 12 weeks - defined as change from baseline. AUC was standardized by dividing by time unit. |
| Peak FVC Response at 12 Weeks; Defined as Change From Baseline | baseline and 12 weeks | Peak FVC response at 12 weeks - defined as change from baseline. |
| Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | over 12 weeks | Rescue medication usage - mean weekly rescue usage (total daily). The baseline for the rescue use was the mean of the observations during the last week of the baseline period. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol metered dose inhaler (MDI) (100 μg per puff) was provided as rescue medication . Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary. Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline. Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (555) |
| Rescue Medication Usage - Percentage of Rescue Free Days | over 12 weeks | Rescue medication usage - the percentage of rescue free days. The percentage of rescue free days is defined as: number of rescue free days divided by total exposure, multiplied by 100%. The baseline for the number of rescue-free days was defined as the number of rescue-free days observed during the last week of the baseline period (i.e., the 7 days prior to administration of the first dose of randomized treatment). Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline. Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (552) |
| Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | over 12 weeks | Rescue medication usage - Mean weekly rescue usage during daytime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary. Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline. Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (555) |
| Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | over 12 weeks | Rescue medication usage - Mean weekly rescue usage during nighttime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary. Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline. Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (555) |
| Trough FVC Response at 12 Weeks; Defined as Change From Baseline | baseline and 12 weeks | Trough Forced Vital Capacity (FVC) response at 12 weeks- defined as change from baseline. |
| Saint George Respiratory Questionnaire - (Total Score) Based on Combined 1222.51 and 1222.52 Data | 12 weeks | The Saint George Respiratory Questionnaire (SGRQ) is designed to measure health impairment in patients with asthma and chronic obstructive pulmonary disease (COPD). It is divided into two parts. Part I produces the Symptoms score (several scales), and Part II the Activity and Impacts scores \[dichotomous (true/false) except last question (4-point Likert scale)\]. A Total score is also produced with scores ranging from 0 to 100, with higher scores indicating more limitations. Since the SGRQ analysis is based on the combined data from both this study and protocol 1222.51 (NCT01694771), only combined SGRQ results will be included in the latest clinical trial report. Hence there will only be one SGRQ analysis from both studies, which will not appear in the first clinical trial report. For this same reason, another covariate - study - will also be included in the MMRM for SGRQ analysis. The combined data for this outcome measure was pre-specified in both protocols. |
Countries
United States
Participant flow
Pre-assignment details
1137 patients were entered and randomized to treatment and 1135 patients were treated with study medication.
Participants by arm
| Arm | Count |
|---|---|
| Olodaterol (5μg) and Tiotropium (18μg) 2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered
Olodaterol: One dose
Tiotropium: Marketed dose | 566 |
| Placebo and Tiotropium (18μg) 2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning
Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning | 569 |
| Total | 1,135 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 21 | 11 |
| Overall Study | Lack of Efficacy | 2 | 3 |
| Overall Study | Lost to Follow-up | 2 | 5 |
| Overall Study | Other reason prematurely discontinued | 5 | 3 |
| Overall Study | Protocol Violation | 9 | 3 |
| Overall Study | Withdrawal by Subject | 4 | 6 |
Baseline characteristics
| Characteristic | Olodaterol (5μg) and Tiotropium (18μg) | Placebo and Tiotropium (18μg) | Total |
|---|---|---|---|
| Age, Continuous | 64.6 years STANDARD_DEVIATION 9 | 63.6 years STANDARD_DEVIATION 8.9 | 64.1 years STANDARD_DEVIATION 9 |
| Sex: Female, Male Female | 261 Participants | 266 Participants | 527 Participants |
| Sex: Female, Male Male | 305 Participants | 303 Participants | 608 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 48 / 566 | 44 / 569 |
| serious Total, serious adverse events | 24 / 566 | 27 / 569 |
Outcome results
Primary
FEV1 AUC0-3h Response at 12 Weeks; Defined as Change From Baseline to Week 12
FEV1 (Forced expiratory volume in 1 second) AUC0-3h (area under the curve) response at 12 weeks; defined as change from baseline to Week 12. AUC was standardized by dividing by time unit.
Time frame: baseline and 12 weeks
Population: Full analysis set (FAS) with last observation carried forward (LOCF) imputation at 12 weeks. FAS included all patients in the treated set who had both baseline and at least one post-baseline measurement at or before 12 weeks for any of the co-primary efficacy variables
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olodaterol (5μg) and Tiotropium (18μg) | FEV1 AUC0-3h Response at 12 Weeks; Defined as Change From Baseline to Week 12 | 0.297 Area Under the Curve (L) (standardized) | Standard Error 0.01 |
| Placebo and Tiotropium (18μg) | FEV1 AUC0-3h Response at 12 Weeks; Defined as Change From Baseline to Week 12 | 0.191 Area Under the Curve (L) (standardized) | Standard Error 0.01 |
Comparison: Results are from an mixed model repeated measure (MMRM) model. Fixed effects include treatment, visit, treatment by visit interaction, baseline and baseline by visit interaction. Patient is considered random and an unstructured covariance structure was used. Number of patients contributing to models: Tio+Placebo (566), Tio+Olo 5ug (563).p-value: <0.000195% CI: [0.078, 0.135]Mixed Model Repeated Measure
Primary
Trough FEV1 Response at 12 Weeks; Defined as Change From Baseline to Week 12
Trough FEV1 (Forced expiratory volume in 1 second) response at 12 weeks; defined as change from baseline to Week 12
Time frame: baseline and 12 weeks
Population: Full Analysis set (FAS) with last observation carried forward (LOCF) imputation at 12 weeks.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olodaterol (5μg) and Tiotropium (18μg) | Trough FEV1 Response at 12 Weeks; Defined as Change From Baseline to Week 12 | 0.175 L | Standard Error 0.009 |
| Placebo and Tiotropium (18μg) | Trough FEV1 Response at 12 Weeks; Defined as Change From Baseline to Week 12 | 0.135 L | Standard Error 0.009 |
Comparison: Results are from an MMRM model. Fixed effects include treatment, visit, treatment by visit interaction, baseline and baseline by visit interaction. Patient is considered random and an unstructured covariance structure was used. Number of patients contributing to models: Tio+Placebo (555), Tio+Olo 5ug (550).p-value: 0.002995% CI: [0.014, 0.065]Mixed Model Repeated Measure
Secondary
FVC AUC0-3h Response at 12 Weeks; Defined as Change From Baseline
Forced Vital Capacity (FVC) AUC0-3h response at 12 weeks - defined as change from baseline. AUC was standardized by dividing by time unit.
Time frame: baseline and 12 Weeks
Population: Full analysis set (FAS) with last observation carried forward (LOCF) imputation at 12 weeks.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olodaterol (5μg) and Tiotropium (18μg) | FVC AUC0-3h Response at 12 Weeks; Defined as Change From Baseline | 0.424 L | Standard Error 0.017 |
| Placebo and Tiotropium (18μg) | FVC AUC0-3h Response at 12 Weeks; Defined as Change From Baseline | 0.306 L | Standard Error 0.017 |
Comparison: Results are from an MMRM model. Fixed effects include treatment, visit, treatment by visit interaction, baseline and baseline by visit interaction. Patient is considered random and an unstructured covariance structure was used.~Number of patients contributing to models: Tio+Placebo (566), Tio+Olo 5ug (563).p-value: <0.000195% CI: [0.072, 0.164]Mixed Model Repeated Measure
Secondary
Peak FEV1 Response at 12 Weeks - Defined as Change From Baseline
Peak FEV1 (Forced Expiratory Volume in 1 second) response at 12 Weeks - defined as change from baseline. All p-values for these measures are only descriptive.
Time frame: baseline and 12 weeks
Population: Full analysis set (FAS) with last observation carried forward (LOCF) imputation at 12 weeks.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olodaterol (5μg) and Tiotropium (18μg) | Peak FEV1 Response at 12 Weeks - Defined as Change From Baseline | 0.371 L | Standard Error 0.011 |
| Placebo and Tiotropium (18μg) | Peak FEV1 Response at 12 Weeks - Defined as Change From Baseline | 0.271 L | Standard Error 0.011 |
Comparison: Results are from an MMRM model. Fixed effects include treatment, visit, treatment by visit interaction, baseline and baseline by visit interaction. Patient is considered random and an unstructured covariance structure was used.~Number of patients contributing to models: Tio+Placebo (566), Tio+Olo 5ug (563).p-value: <0.000195% CI: [0.071, 0.129]Mixed Model Repeated Measure
Secondary
Peak FVC Response at 12 Weeks; Defined as Change From Baseline
Peak FVC response at 12 weeks - defined as change from baseline.
Time frame: baseline and 12 weeks
Population: Full analysis set (FAS) with last observation carried forward (LOCF) imputation at 12 weeks.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olodaterol (5μg) and Tiotropium (18μg) | Peak FVC Response at 12 Weeks; Defined as Change From Baseline | 0.562 L | Standard Error 0.017 |
| Placebo and Tiotropium (18μg) | Peak FVC Response at 12 Weeks; Defined as Change From Baseline | 0.457 L | Standard Error 0.017 |
Comparison: Results are from an MMRM model. Fixed effects include treatment, visit, treatment by visit interaction, baseline and baseline by visit interaction. Patient is considered random and an unstructured covariance structure was used.~Number of patients contributing to models: Tio+Placebo (566), Tio+Olo 5ug (563).p-value: <0.000195% CI: [0.057, 0.152]Mixed Model Repeated Measure
Secondary
Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime)
Rescue medication usage - Mean weekly rescue usage during daytime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary. Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline. Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (555)
Time frame: over 12 weeks
Population: Full analysis set (FAS) with last observation carried forward (LOCF) imputation
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 1 | 0.406 number of puffs | Standard Error 0.025 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 2 | 0.421 number of puffs | Standard Error 0.027 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 3 | 0.407 number of puffs | Standard Error 0.03 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 4 | 0.408 number of puffs | Standard Error 0.031 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 5 | 0.375 number of puffs | Standard Error 0.03 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 6 | 0.378 number of puffs | Standard Error 0.03 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 7 | 0.403 number of puffs | Standard Error 0.033 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 8 | 0.417 number of puffs | Standard Error 0.033 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 9 | 0.396 number of puffs | Standard Error 0.033 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 10 | 0.392 number of puffs | Standard Error 0.032 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 11 | 0.383 number of puffs | Standard Error 0.031 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 12 | 0.393 number of puffs | Standard Error 0.032 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 11 | 0.482 number of puffs | Standard Error 0.031 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 1 | 0.437 number of puffs | Standard Error 0.025 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 7 | 0.499 number of puffs | Standard Error 0.032 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 2 | 0.466 number of puffs | Standard Error 0.027 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 10 | 0.480 number of puffs | Standard Error 0.031 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 3 | 0.459 number of puffs | Standard Error 0.03 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 8 | 0.482 number of puffs | Standard Error 0.033 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 4 | 0.479 number of puffs | Standard Error 0.031 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 12 | 0.483 number of puffs | Standard Error 0.032 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 5 | 0.479 number of puffs | Standard Error 0.03 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 9 | 0.487 number of puffs | Standard Error 0.032 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Week 6 | 0.491 number of puffs | Standard Error 0.03 |
Comparison: Week 12 - Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline.~Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (555).p-value: 0.046795% CI: [-0.178, -0.001]ANCOVA
Secondary
Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime)
Rescue medication usage - Mean weekly rescue usage during nighttime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary. Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline. Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (555)
Time frame: over 12 weeks
Population: Full analysis set (FAS) with last observation carried forward (LOCF) imputation
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 1 | 1.222 number of puffs | Standard Error 0.055 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 2 | 1.232 number of puffs | Standard Error 0.058 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 3 | 1.229 number of puffs | Standard Error 0.062 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 4 | 1.239 number of puffs | Standard Error 0.064 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 5 | 1.177 number of puffs | Standard Error 0.065 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 6 | 1.148 number of puffs | Standard Error 0.065 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 7 | 1.139 number of puffs | Standard Error 0.065 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 8 | 1.173 number of puffs | Standard Error 0.067 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 9 | 1.125 number of puffs | Standard Error 0.065 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 10 | 1.108 number of puffs | Standard Error 0.066 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 11 | 1.104 number of puffs | Standard Error 0.067 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 12 | 1.143 number of puffs | Standard Error 0.067 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 11 | 1.630 number of puffs | Standard Error 0.066 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 1 | 1.633 number of puffs | Standard Error 0.055 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 7 | 1.641 number of puffs | Standard Error 0.064 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 2 | 1.677 number of puffs | Standard Error 0.058 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 10 | 1.630 number of puffs | Standard Error 0.065 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 3 | 1.707 number of puffs | Standard Error 0.062 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 8 | 1.628 number of puffs | Standard Error 0.066 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 4 | 1.709 number of puffs | Standard Error 0.064 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 12 | 1.625 number of puffs | Standard Error 0.066 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 5 | 1.710 number of puffs | Standard Error 0.064 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 9 | 1.636 number of puffs | Standard Error 0.065 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Week 6 | 1.692 number of puffs | Standard Error 0.064 |
Comparison: Week 12 - Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline.~Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (555).p-value: <0.000195% CI: [-0.668, -0.298]ANCOVA
Secondary
Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily)
Rescue medication usage - mean weekly rescue usage (total daily). The baseline for the rescue use was the mean of the observations during the last week of the baseline period. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol metered dose inhaler (MDI) (100 μg per puff) was provided as rescue medication . Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary. Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline. Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (555)
Time frame: over 12 weeks
Population: Full analysis set (FAS) with last observation carried forward (LOCF) imputation
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 1 | 1.627 usage (total daily) number of puffs | Standard Error 0.066 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 2 | 1.652 usage (total daily) number of puffs | Standard Error 0.072 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 3 | 1.635 usage (total daily) number of puffs | Standard Error 0.078 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 4 | 1.647 usage (total daily) number of puffs | Standard Error 0.081 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 5 | 1.551 usage (total daily) number of puffs | Standard Error 0.081 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 6 | 1.523 usage (total daily) number of puffs | Standard Error 0.081 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 7 | 1.540 usage (total daily) number of puffs | Standard Error 0.083 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 8 | 1.586 usage (total daily) number of puffs | Standard Error 0.085 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 9 | 1.519 usage (total daily) number of puffs | Standard Error 0.083 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 10 | 1.499 usage (total daily) number of puffs | Standard Error 0.082 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 11 | 1.484 usage (total daily) number of puffs | Standard Error 0.083 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 12 | 1.535 usage (total daily) number of puffs | Standard Error 0.084 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 11 | 2.107 usage (total daily) number of puffs | Standard Error 0.082 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 1 | 2.072 usage (total daily) number of puffs | Standard Error 0.066 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 7 | 2.138 usage (total daily) number of puffs | Standard Error 0.082 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 2 | 2.145 usage (total daily) number of puffs | Standard Error 0.072 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 10 | 2.103 usage (total daily) number of puffs | Standard Error 0.081 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 3 | 2.167 usage (total daily) number of puffs | Standard Error 0.078 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 8 | 2.107 usage (total daily) number of puffs | Standard Error 0.084 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 4 | 2.189 usage (total daily) number of puffs | Standard Error 0.08 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 12 | 2.103 usage (total daily) number of puffs | Standard Error 0.083 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 5 | 2.183 usage (total daily) number of puffs | Standard Error 0.08 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 9 | 2.121 usage (total daily) number of puffs | Standard Error 0.082 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Week 6 | 2.179 usage (total daily) number of puffs | Standard Error 0.08 |
Comparison: Week 12 - Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline.~Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (555).p-value: <0.000195% CI: [-0.8, -0.336]ANCOVA
Secondary
Rescue Medication Usage - Percentage of Rescue Free Days
Rescue medication usage - the percentage of rescue free days. The percentage of rescue free days is defined as: number of rescue free days divided by total exposure, multiplied by 100%. The baseline for the number of rescue-free days was defined as the number of rescue-free days observed during the last week of the baseline period (i.e., the 7 days prior to administration of the first dose of randomized treatment). Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline. Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (552)
Time frame: over 12 weeks
Population: Full analysis set (FAS) with last observation carried forward (LOCF) imputation
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 1 | 53.207 percentage of days | Standard Error 1.481 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 2 | 54.249 percentage of days | Standard Error 48.64 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 3 | 54.820 percentage of days | Standard Error 1.536 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 4 | 60.761 percentage of days | Standard Error 1.388 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 5 | 60.154 percentage of days | Standard Error 1.55 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 6 | 59.707 percentage of days | Standard Error 1.572 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 7 | 59.493 percentage of days | Standard Error 1.598 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 8 | 59.021 percentage of days | Standard Error 1.634 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 9 | 60.524 percentage of days | Standard Error 1.636 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 10 | 60.216 percentage of days | Standard Error 1.636 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 11 | 59.650 percentage of days | Standard Error 1.636 |
| Olodaterol (5μg) and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 12 | 62.327 percentage of days | Standard Error 1.525 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 11 | 51.604 percentage of days | Standard Error 1.616 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 1 | 48.583 percentage of days | Standard Error 1.472 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 7 | 50.164 percentage of days | Standard Error 1.594 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 2 | 48.640 percentage of days | Standard Error 1.477 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 10 | 51.634 percentage of days | Standard Error 1.616 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 3 | 49.865 percentage of days | Standard Error 1.528 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 8 | 51.017 percentage of days | Standard Error 1.626 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 4 | 55.969 percentage of days | Standard Error 1.378 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 12 | 55.090 percentage of days | Standard Error 1.508 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 5 | 51.840 percentage of days | Standard Error 1.549 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 9 | 51.273 percentage of days | Standard Error 1.62 |
| Placebo and Tiotropium (18μg) | Rescue Medication Usage - Percentage of Rescue Free Days | Week 6 | 49.001 percentage of days | Standard Error 1.568 |
Comparison: Week 12: Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline.~Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (552).p-value: 0.000895% CI: [3.028, 11.446]ANCOVA
Secondary
Saint George Respiratory Questionnaire - (Total Score) Based on Combined 1222.51 and 1222.52 Data
The Saint George Respiratory Questionnaire (SGRQ) is designed to measure health impairment in patients with asthma and chronic obstructive pulmonary disease (COPD). It is divided into two parts. Part I produces the Symptoms score (several scales), and Part II the Activity and Impacts scores \[dichotomous (true/false) except last question (4-point Likert scale)\]. A Total score is also produced with scores ranging from 0 to 100, with higher scores indicating more limitations. Since the SGRQ analysis is based on the combined data from both this study and protocol 1222.51 (NCT01694771), only combined SGRQ results will be included in the latest clinical trial report. Hence there will only be one SGRQ analysis from both studies, which will not appear in the first clinical trial report. For this same reason, another covariate - study - will also be included in the MMRM for SGRQ analysis. The combined data for this outcome measure was pre-specified in both protocols.
Time frame: 12 weeks
Population: FAS with last observation carried forward (LOCF) imputation (combined data from twin studies 1222.51 and 1222.52). Number of patients contributing to models: Tio+Placebo (1055), Tio+Olo 5ug (1039).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olodaterol (5μg) and Tiotropium (18μg) | Saint George Respiratory Questionnaire - (Total Score) Based on Combined 1222.51 and 1222.52 Data | 41.204 units on a scale (total score) | Standard Error 0.327 |
| Placebo and Tiotropium (18μg) | Saint George Respiratory Questionnaire - (Total Score) Based on Combined 1222.51 and 1222.52 Data | 43.059 units on a scale (total score) | Standard Error 0.325 |
Comparison: Results are from ANCOVA model. Fixed effects include study, treatment and baseline.~Number of patients contributing to models: Tio+Placebo (1055), Tio+Olo 5ug (1039).p-value: <0.000195% CI: [-2.757, -0.951]ANCOVA
Secondary
Trough FVC Response at 12 Weeks; Defined as Change From Baseline
Trough Forced Vital Capacity (FVC) response at 12 weeks- defined as change from baseline.
Time frame: baseline and 12 weeks
Population: Full analysis set (FAS) with last observation carried forward (LOCF) imputation
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olodaterol (5μg) and Tiotropium (18μg) | Trough FVC Response at 12 Weeks; Defined as Change From Baseline | 0.269 L | Standard Error 0.015 |
| Placebo and Tiotropium (18μg) | Trough FVC Response at 12 Weeks; Defined as Change From Baseline | 0.235 L | Standard Error 0.015 |
Comparison: Results are from an MMRM model. Fixed effects include treatment, visit, treatment by visit interaction, baseline and baseline by visit interaction. Patient is considered random and an unstructured covariance structure was used.~Number of patients contributing to models: Tio+Placebo (555), Tio+Olo 5ug (550).p-value: 0.115695% CI: [-0.008, 0.076]Mixed Model Repeated Measure