Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The primary objective of this pragmatic study is to compare the time to first moderate or severe COPD exacerbation in patients, not controlled on their current therapy, randomized to Stiolto Respimat versus triple therapy over 12 months of treatment The secondary objectives of this study include: 1. To compare the annual rate of moderate or severe COPD exacerbations for patients on Stiolto Respimat with patients on triple therapy. 2. To compare the time to first severe COPD exacerbation in both treatment arms. 3. To compare the annual rate of severe COPD exacerbations in both treatment arms. 4. To compare the proportion of patients with moderate or severe COPD exacerbations in both treatment arms.
Interventions
DRUGStiolto Respimat
Duration - 12 months
DRUGICS (Inhaled Corticosteroid) (Triple therapy)
Duration - 12 months
DRUGLABA (Long-Acting Beta Agonist) (Triple therapy)
Duration - 12 months
DRUGLAMA (Long-Acting Muscarinic Antagonist) (Triple therapy)
Duration - 12 months
Sponsors
Carelon Research
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* COPD diagnosis as defined by the study physician * Currently on one of the following maintenance therapies: * LAMA monotherapy * LABA monotherapy * ICS/LABA (FDC) * Physician determination that patient is not controlled on current pharmacotherapy * Adult patient 40 years of age or older at time of study enrollment * Willingness and ability to understand and provide documented Informed Consent Form (ICF) and Health Insurance Portability and Accountability Act (HIPAA) Authorization Form prior to commencement of any study required assessments, either directly or through Legally Authorized Representative.
Exclusion criteria
* Currently on LAMA/LABA (free or FDC) or triple therapy (ICS plus LABA plus LAMA) * Contraindication to any study medications (LAMA, LABA or ICS) * Documented diagnosis of current asthma * Pregnant or nursing women * Women of childbearing potential are not restricted in this trial, however it is expected that the investigator will assess the risks and benefits of the assigned treatment as per the product label(s) and discuss this with any women of childbearing potential prior to providing the patient with the prescription for the assigned treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Over the 12 Month Study Period | Baseline till end of study, up to 12 months. | Time to first moderate or severe chronic obstructive (COPD) exacerbation over 12 months of treatment pulmonary disease. Moderate exacerbation was a patient receiving an exacerbation-related prescription such as oral corticosteroid (prednisone or prednisolone) and/or antibiotic, but not requiring hospitalization. Severe exacerbation was a patient requiring hospitalization or emergency room visit due to COPD (ICD-9-491.21 or ICD-10-J44.1). Median survival time as well as 95% confidence interval was calculated using Kaplan-Meier curves. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annual Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations | Baseline till end of study, up to 12 months. | Annual rate of moderate or severe chronic obstructive pulmonary disease (COPD) exacerbations. Moderate exacerbation was a patient receiving an exacerbation-related prescription such as oral corticosteroid (prednisone or prednisolone) and/or antibiotic, but not requiring hospitalization. Severe exacerbation was a patient requiring hospitalization or emergency room visit due to COPD (ICD-9-491.21 or ICD-10-J44.1). Annual rate analysis utilized a negative binomial model with fixed effect of treatment (Stiolto Respimat versus triple therapy), logarithm of observational time as offset, and baseline prior ICS was used as a covariate. |
| Time to First Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Over 12 Months of Treatment Pulmonary Disease | Baseline till end of study, up to 12 months. | Time to first severe chronic obstructive (COPD) exacerbation over 12 months of treatment pulmonary disease. Moderate exacerbation was a patient receiving an exacerbation-related prescription such as oral corticosteroid (prednisone or prednisolone) and/or antibiotic, but not requiring hospitalization. Severe exacerbation was a patient requiring hospitalization or emergency room visit due to COPD (ICD-9-491.21 or ICD-10-J44.1). Median survival time as well as 95% confidence interval was calculated using Kaplan-Meier curves. |
| Annual Rate of Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations | Baseline till end of study, up to 12 months. | Annual rate of severe chronic obstructive pulmonary disease (COPD) exacerbations. Severe exacerbation was a patient requiring hospitalization or emergency room visit due to COPD (ICD-9-491.21 or ICD-10-J44.1). Annual rate analysis utilized a negative binomial model with fixed effect of treatment (Stiolto Respimat versus triple therapy), logarithm of observational time as offset, and baseline prior ICS was used as a covariate. |
| Number of Patients With Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Over the 12 Month Observation Period | 12 months after baseline. | Number of patients with moderate or severe chronic obstructive pulmonary disease (COPD) exacerbations over the 12 month observation period. Moderate exacerbation was a patient receiving an exacerbation-related prescription such as oral corticosteroid (prednisone or prednisolone) and/or antibiotic, but not requiring hospitalization. Severe exacerbation was a patient requiring hospitalization or emergency room visit due to COPD (ICD-9-491.21 or ICD-10-J44.1). |
Countries
United States
Participant flow
Recruitment details
This was a pragmatic randomized open label active controlled parallel group design trial conducted in a real-world, community-based practice setting. Participants were on long-acting muscarinic antagonist (LAMA), long-acting beta agonist (LABA) or Inhaled Corticosteroid (ICS)/LABA for COPD, but were determined by their physician to not be controlled on their current therapy. Subjects were randomized to either Stiolto Respimat or ICS plus LABA plus LAMA (triple therapy) for the study.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Stiolto® Respimat® Patients with chronic obstructive pulmonary disease (COPD) who were on long-acting muscarinic antagonist (LAMA) or long-acting beta agonist (LABA) or inhaled corticosteroid (ICS)/LABA maintenance therapy, and whose treatment was not controlled on the medication regimen as determined by the physician.
Patients started the following Stiolto® Respimat® treatment: Fixed dose of 2.5 micrograms (mcg) tiotropium and 2.5 mcg olodaterol (Stiolto® Respimat®) per actuation were inhaled twice daily (tiotropium/olodaterol daily dosage: 5/5 mcg). Patients were followed for 12 months regardless of treatment switching or discontinuing study treatment. | 356 |
| ICS Plus LABA Plus LAMA (Triple Therapy) Patients with chronic obstructive pulmonary disease (COPD) who were on long-acting muscarinic antagonist (LAMA) or long-acting beta agonist (LABA) or inhaled corticosteroid (ICS)/LABA maintenance therapy, and whose treatment was not controlled on the medication regimen as determined by the physician.
Patients started the following ICS plus LABA plus LAMA (triple therapy) treatment made up of the combination of any approved drugs that their physician chooses.Triple Therapy (ICS + LABA + LAMA) was inhaled with dose as prescribed by physicians per label for selected medications. Patients were followed for 12 months regardless of treatment switching or discontinuing study treatment. | 358 |
| Total | 714 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 12 | 12 |
| Overall Study | Did not want to take medication | 1 | 0 |
| Overall Study | Entered into Electronic Data Capture in error | 0 | 1 |
| Overall Study | Incorrectly randomized | 16 | 6 |
| Overall Study | Lost to Follow-up | 13 | 9 |
| Overall Study | missing end of study form, could not definitely count as completion or discontinuation | 0 | 1 |
| Overall Study | Physician Decision | 0 | 3 |
| Overall Study | Protocol Violation | 2 | 0 |
| Overall Study | Site closed | 2 | 3 |
| Overall Study | Subject could not afford medication | 0 | 1 |
| Overall Study | Subject transferred to another facility | 0 | 1 |
| Overall Study | Switched back to previous medication | 1 | 0 |
| Overall Study | Withdrawal by Subject | 23 | 19 |
Baseline characteristics
| Characteristic | Stiolto® Respimat® | ICS Plus LABA Plus LAMA (Triple Therapy) | Total |
|---|---|---|---|
| Age, Continuous | 69.0 years STANDARD_DEVIATION 9.32 | 69.9 years STANDARD_DEVIATION 9.81 | 69.5 years STANDARD_DEVIATION 9.57 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants | 20 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 329 Participants | 334 Participants | 663 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 4 Participants | 11 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 6 Participants | 7 Participants | 13 Participants |
| Race/Ethnicity, Customized Black or African American | 42 Participants | 38 Participants | 80 Participants |
| Race/Ethnicity, Customized Missing | 6 Participants | 3 Participants | 9 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 9 Participants | 9 Participants | 18 Participants |
| Race/Ethnicity, Customized White or Caucasian | 292 Participants | 300 Participants | 592 Participants |
| Sex/Gender, Customized Female | 169 Participants | 181 Participants | 350 Participants |
| Sex/Gender, Customized Male | 181 Participants | 174 Participants | 355 Participants |
| Sex/Gender, Customized Missing | 6 Participants | 3 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 12 / 356 | 12 / 358 |
| other Total, other adverse events | 0 / 325 | 0 / 318 |
| serious Total, serious adverse events | 56 / 325 | 45 / 318 |
Outcome results
Primary
Time to First Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Over the 12 Month Study Period
Time to first moderate or severe chronic obstructive (COPD) exacerbation over 12 months of treatment pulmonary disease. Moderate exacerbation was a patient receiving an exacerbation-related prescription such as oral corticosteroid (prednisone or prednisolone) and/or antibiotic, but not requiring hospitalization. Severe exacerbation was a patient requiring hospitalization or emergency room visit due to COPD (ICD-9-491.21 or ICD-10-J44.1). Median survival time as well as 95% confidence interval was calculated using Kaplan-Meier curves.
Time frame: Baseline till end of study, up to 12 months.
Population: Intent to Treat (ITT) Population: The ITT population will include all randomized patients allocated to their original randomized treatment group, even if they switched or discontinued study treatment. Only patients with non missing ICS baseline values were included. Due to investigator error, 5 patients in each group received the prescription for the wrong treatment. These subjects were included in the actual treatment, not the randomized treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stiolto® Respimat® | Time to First Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Over the 12 Month Study Period | NA Months |
| ICS Plus LABA Plus LAMA (Triple Therapy) | Time to First Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Over the 12 Month Study Period | NA Months |
95% CI: [0.87, 1.72]
Secondary
Annual Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations
Annual rate of moderate or severe chronic obstructive pulmonary disease (COPD) exacerbations. Moderate exacerbation was a patient receiving an exacerbation-related prescription such as oral corticosteroid (prednisone or prednisolone) and/or antibiotic, but not requiring hospitalization. Severe exacerbation was a patient requiring hospitalization or emergency room visit due to COPD (ICD-9-491.21 or ICD-10-J44.1). Annual rate analysis utilized a negative binomial model with fixed effect of treatment (Stiolto Respimat versus triple therapy), logarithm of observational time as offset, and baseline prior ICS was used as a covariate.
Time frame: Baseline till end of study, up to 12 months.
Population: Intent to Treat (ITT) Population: The ITT population will include all randomized patients allocated to their original randomized treatment group, even if they switched or discontinued study treatment. Only patients with non missing ICS baseline values were included. Due to investigator error, 5 patients in each group received the prescription for the wrong treatment. These subjects were included in the actual treatment, not the randomized treatment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Stiolto® Respimat® | Annual Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations | 0.36 Exacerbations per participant per year |
| ICS Plus LABA Plus LAMA (Triple Therapy) | Annual Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations | 0.26 Exacerbations per participant per year |
95% CI: [0.97, 2.04]
Secondary
Annual Rate of Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations
Annual rate of severe chronic obstructive pulmonary disease (COPD) exacerbations. Severe exacerbation was a patient requiring hospitalization or emergency room visit due to COPD (ICD-9-491.21 or ICD-10-J44.1). Annual rate analysis utilized a negative binomial model with fixed effect of treatment (Stiolto Respimat versus triple therapy), logarithm of observational time as offset, and baseline prior ICS was used as a covariate.
Time frame: Baseline till end of study, up to 12 months.
Population: Intent to Treat (ITT) Population: The ITT population will include all randomized patients allocated to their original randomized treatment group, even if they switched or discontinued study treatment. Only patients with non missing ICS baseline values were included. Due to investigator error, 5 patients in each group received the prescription for the wrong treatment. These subjects were included in the actual treatment, not the randomized treatment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Stiolto® Respimat® | Annual Rate of Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations | 0.07 Exacerbations per participant per year |
| ICS Plus LABA Plus LAMA (Triple Therapy) | Annual Rate of Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations | 0.07 Exacerbations per participant per year |
95% CI: [0.58, 2.01]
Secondary
Number of Patients With Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Over the 12 Month Observation Period
Number of patients with moderate or severe chronic obstructive pulmonary disease (COPD) exacerbations over the 12 month observation period. Moderate exacerbation was a patient receiving an exacerbation-related prescription such as oral corticosteroid (prednisone or prednisolone) and/or antibiotic, but not requiring hospitalization. Severe exacerbation was a patient requiring hospitalization or emergency room visit due to COPD (ICD-9-491.21 or ICD-10-J44.1).
Time frame: 12 months after baseline.
Population: Intent to Treat (ITT) Population: The ITT population will include all randomized patients allocated to their original randomized treatment group, even if they switched or discontinued study treatment. Only patients with non missing ICS baseline values were included. Due to investigator error, 5 patients in each group received the prescription for the wrong treatment. These subjects were included in the actual treatment, not the randomized treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stiolto® Respimat® | Number of Patients With Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Over the 12 Month Observation Period | 73 Participants |
| ICS Plus LABA Plus LAMA (Triple Therapy) | Number of Patients With Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Over the 12 Month Observation Period | 62 Participants |
Comparison: A Cochran-Mantel-Haenszel (CMH) model with baseline ICS prior use as stratum was used to estimate the Risk Ratio (RR) (Stiolto Respimat versus triple therapy) of moderate or severe COPD exacerbations along with 95% CI.95% CI: [0.89, 1.64]
Comparison: A Cochran-Mantel-Haenszel (CMH) model with baseline ICS prior use as stratum was used to estimate the Risk Difference (Stiolto Respimat versus triple therapy) of moderate or severe COPD exacerbations along with 95% CI.95% CI: [-0.022, 0.094]
Secondary
Time to First Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Over 12 Months of Treatment Pulmonary Disease
Time to first severe chronic obstructive (COPD) exacerbation over 12 months of treatment pulmonary disease. Moderate exacerbation was a patient receiving an exacerbation-related prescription such as oral corticosteroid (prednisone or prednisolone) and/or antibiotic, but not requiring hospitalization. Severe exacerbation was a patient requiring hospitalization or emergency room visit due to COPD (ICD-9-491.21 or ICD-10-J44.1). Median survival time as well as 95% confidence interval was calculated using Kaplan-Meier curves.
Time frame: Baseline till end of study, up to 12 months.
Population: Intent to Treat (ITT) Population: The ITT population will include all randomized patients allocated to their original randomized treatment group, even if they switched or discontinued study treatment. Only patients with non missing ICS baseline values were included. Due to investigator error, 5 patients in each group received the prescription for the wrong treatment. These subjects were included in the actual treatment, not the randomized treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stiolto® Respimat® | Time to First Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Over 12 Months of Treatment Pulmonary Disease | NA Months |
| ICS Plus LABA Plus LAMA (Triple Therapy) | Time to First Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Over 12 Months of Treatment Pulmonary Disease | NA Months |
95% CI: [0.62, 2]