Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The real world study aims to assess effectiveness and safety profile between tiotropium/olodaterol (Tio/Olo) and inhaled corticosteroids(ICS) / Long-acting β2-agonists (LABA) in patients with chronic obstructive pulmonary disease (COPD) in Taiwan. The data used in this study will come from the Taiwan National Health Insurance (NHI) claims data between 2014 and 2019.
Interventions
DRUGTiotropium (Tio)
Tiotropium (Tio)
Inhaled corticosteroids (ICS)
DRUGOlodaterol (Olo)
Olodaterol (Olo)
Long-acting β2-agonists (LABA)
Sponsors
Boehringer Ingelheim
Study design
Observational model
COHORT
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. At least one prescriptions for Tiotropium/Olodaterol (Tio/Olo) combined inhaler or Long-acting ß2 agonist / Inhaled Corticosteroids (LABA/ICS) combined inhaler between 1st January 2014 and 31st December 2019. 1. The first dispensing of either Tio/Olo or LABA/ICS combined inhaler will be defined as the index date; 2. For the main analyses, only fixed dose combination (FDC) inhalers will be included. 2. Aged ≥ 40 years on the index date (in a sensitivity analysis we will only include patients aged ≥ 55 years on the index date); 3. At least one diagnosis of chronic obstructive pulmonary disease (COPD) at any time prior to or on the index date; 4. At least one year of continuous medical and health insurance plan prior to the index date will be required to allow for a look-back period for the covariates and identification of new use of the study drugs; 5. At least one record in the health insurance system database
Exclusion criteria
1. Any use of Tio/Olo, ICS/LABA, or ICS/LABA/ Long-acting muscarinic antagonists (LAMA) in free or fixed form for one year prior to the index date; 2. Individuals with asthma, allergic rhinitis, lung cancer, interstitial lung disease, or lung transplant identified at any time prior to the index date (in a sensitivity analysis we will include patients with asthma);
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Event First Moderate or Severe COPD Exacerbations After Index Date | From the index date (the first dispensing of either Tio/Olo or ICS/LABA combined inhaler) until first event, up to 6 years. | Number of subjects with event first moderate or severe COPD exacerbations after index date. The first dispensing of either Tio/Olo or ICS/LABA combined inhaler was defined as the index date. Definition of moderate or severe COPD exacerbation: 1. Moderate exacerbation was defined as an outpatient visit with a diagnosis code for COPD in any field and a prescription for an oral corticosteroid or an antibiotic for respiratory infections 2. Severe exacerbation was defined as a hospitalization or emergency room visit with a primary diagnosis for COPD |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Event Triple Therapy Escalation After Index Date | From the index date (The first dispensing of either Tio/Olo or ICS/LABA combined inhaler) until first event, up to 6 years. | Number of subjects with event triple therapy escalation, defined as any LAMA/ICS/LABA fixed dose combination or any concurrent use for 30 consecutive days of the following: 1. any LAMA/LABA fixed dose combination + any ICS single formulation 2. any LAMA single formulation + any ICS/LABA fixed dose combination 3. any LAMA single formulation + any LABA single formulation + any ICS single formulation The event date was the 30th day after initiation of triple therapy. |
| Incidence Rate of Triple Therapy Initiation | From the index date (The first dispensing of either Tio/Olo or ICS/LABA combined inhaler) until first event, up to 6 years. | Incidence rate of triple therapy initiation (first event per patient). Triple therapy escalation, defined as any LAMA/ICS/LABA fixed dose combination or any concurrent use for 30 consecutive days of the following: 1. any LAMA/LABA fixed dose combination + any ICS single formulation 2. any LAMA single formulation + any ICS/LABA fixed dose combination 3. any LAMA single formulation + any LABA single formulation + any ICS single formulation Incidence rate calculated as (total number of patients in the cohort experiencing an event of interest for the first time during the given time period) / (total person-time at risk from current use of treatment of cohort during the given period). |
| Number of Subjects With Event First Hospitalization for Community-acquired Pneumonia After Entry | From the index date (The first dispensing of either Tio/Olo or ICS/LABA combined inhaler) until first event, up to 6 years. | Number of subjects with event the first hospitalization for community-acquired pneumonia after initiation of study drug. |
| Annualized Rate of Prescriptions of Rescue Medications After the Index Date | From the index date (The first dispensing of either Tio/Olo or ICS/LABA combined inhaler) until first event, up to 6 years. | Annualized rate of prescriptions of rescue medications after the index date. Rescue medications were defined as free or combination use of short-acting beta-agonist (SABA) or short-acting muscarinic antagonist (SAMA) or SABA/SAMA. Annualized rates were calculated for each cohort as follows: (total number of events in the cohort during the given time period) / (total person-year at risk from current use of treatment of cohort during the given period). |
| Annualized Rate of COPD Exacerbations After Index Date | From the index date (The first dispensing of either Tio/Olo or ICS/LABA combined inhaler) until first event, up to 6 years. | Annualized rate of moderate or severe COPD exacerbation after the index date. Annualized rate is calculated as follows: number of moderate or severe COPD exacerbations/total patient year at risk=number of exacerbations per patient year. Definitions of moderate or severe COPD exacerbation were: 1. Moderate exacerbation was defined as an outpatient visit with a diagnosis code for COPD in any field + a prescription for an oral corticosteroid or an antibiotic for respiratory infections, prescriptions within 30 days of each other were considered as continuation of the initial exacerbation. 2. Severe exacerbation was defined as a hospitalization or emergency room visit with a primary diagnosis for COPD; hospitalizations or emergency room visits within 30 days of each other were considered as continuation of the initial exacerbation. |
Countries
China
Participant flow
Recruitment details
This was a real-world study to assess effectiveness and safety profiles between tiotropium/olodaterol (Tio/Olo) and Inhaled Corticosteroids (ICS) + Long-acting ß2 agonists (LABA). Data sources included Taiwan National Health Insurance (NHI), Taiwan Cancer Registry (TCR) and Taiwan Mortality Data.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated. Only subjects that met all inclusion and none of the exclusion criteria were included in the study.
Participants by arm
| Arm | Count |
|---|---|
| Tiotropium + Olodaterol Cohort - Propensity Score Matched Subjects who initiated Tiotropium + Olodaterol between 1st January 2014 and 31st December 2019 according to data from the Taiwan National Health Insurance (NHI), Taiwan Cancer Registry (TCR) and Taiwan Mortality Data.
Subjects were 1:1 propensity score matched to the ICS + LABA cohort. The two groups were comparable with regards to year of treatment initiation, season of treatment initiation, prior treatment for Chronic Obstructive Pulmonary Disease (COPD), use of respiratory drugs of interest, frequency and severity of COPD exacerbation, prevalence of major comorbidity, Charlson Comorbidity Index, and concomitant medications. | 3,752 |
| Inhaled Corticosteroids (ICS) + Long-acting ß2 Agonists (LABA) Cohort - Propensity Score Matched Subjects who initiated Inhaled Corticosteroids (ICS) + Long-acting ß2 agonists (LABA) between 1st January 2014 and 31st December 2019 according to data from the Taiwan National Health Insurance (NHI), Taiwan Cancer Registry (TCR) and Taiwan Mortality Data.
Subjects were 1:1 propensity score matched to the Tiotropium + Olodaterol cohort. The two groups were comparable with regards to year of treatment initiation, season of treatment initiation, prior treatment for Chronic Obstructive Pulmonary Disease (COPD), use of respiratory drugs of interest, frequency and severity of COPD exacerbation, prevalence of major comorbidity, Charlson Comorbidity Index, and concomitant medications. | 3,752 |
| Total | 7,504 |
Baseline characteristics
| Characteristic | Tiotropium + Olodaterol Cohort - Propensity Score Matched | Inhaled Corticosteroids (ICS) + Long-acting ß2 Agonists (LABA) Cohort - Propensity Score Matched | Total |
|---|---|---|---|
| Age, Continuous | 72 years STANDARD_DEVIATION 12.19 | 72 years STANDARD_DEVIATION 12.76 | 72 years STANDARD_DEVIATION 12.48 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 451 Participants | 458 Participants | 909 Participants |
| Sex: Female, Male Male | 3301 Participants | 3294 Participants | 6595 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Number of Subjects With Event First Moderate or Severe COPD Exacerbations After Index Date
Number of subjects with event first moderate or severe COPD exacerbations after index date. The first dispensing of either Tio/Olo or ICS/LABA combined inhaler was defined as the index date. Definition of moderate or severe COPD exacerbation: 1. Moderate exacerbation was defined as an outpatient visit with a diagnosis code for COPD in any field and a prescription for an oral corticosteroid or an antibiotic for respiratory infections 2. Severe exacerbation was defined as a hospitalization or emergency room visit with a primary diagnosis for COPD
Time frame: From the index date (the first dispensing of either Tio/Olo or ICS/LABA combined inhaler) until first event, up to 6 years.
Population: Propensity score matched cohorts: Subjects were 1:1 propensity score matched between cohorts. The two groups were comparable with regards to year of treatment initiation, season of treatment initiation, prior treatment for Chronic Obstructive Pulmonary Disease (COPD), use of respiratory drugs of interest, frequency and severity of COPD exacerbation, prevalence of major comorbidity, Charlson Comorbidity Index, and concomitant medications.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tiotropium + Olodaterol Cohort - Propensity Score Matched | Number of Subjects With Event First Moderate or Severe COPD Exacerbations After Index Date | 424 Participants |
| Inhaled Corticosteroids (ICS) + Long-acting ß2 Agonists (LABA) Cohort - Propensity Score Matched | Number of Subjects With Event First Moderate or Severe COPD Exacerbations After Index Date | 375 Participants |
Comparison: Univariate proportional hazards regression was used to compare the time to event (first moderate or severe COPD exacerbations) between the two treatment groups. In the event that there were baseline covariates with unequal distribution between the treatment groups, defined as absolute standardized difference larger than 0.1, the covariate(s) were included in a multiple regression model in addition to the exposure status (Tio/Olo or ICS/LABA).95% CI: [0.87, 1.15]
Secondary
Annualized Rate of COPD Exacerbations After Index Date
Annualized rate of moderate or severe COPD exacerbation after the index date. Annualized rate is calculated as follows: number of moderate or severe COPD exacerbations/total patient year at risk=number of exacerbations per patient year. Definitions of moderate or severe COPD exacerbation were: 1. Moderate exacerbation was defined as an outpatient visit with a diagnosis code for COPD in any field + a prescription for an oral corticosteroid or an antibiotic for respiratory infections, prescriptions within 30 days of each other were considered as continuation of the initial exacerbation. 2. Severe exacerbation was defined as a hospitalization or emergency room visit with a primary diagnosis for COPD; hospitalizations or emergency room visits within 30 days of each other were considered as continuation of the initial exacerbation.
Time frame: From the index date (The first dispensing of either Tio/Olo or ICS/LABA combined inhaler) until first event, up to 6 years.
Population: Propensity score matched cohorts: Subjects were 1:1 propensity score matched between cohorts. The two groups were comparable with regards to year of treatment initiation, season of treatment initiation, prior treatment for Chronic Obstructive Pulmonary Disease (COPD), use of respiratory drugs of interest, frequency and severity of COPD exacerbation, prevalence of major comorbidity, Charlson Comorbidity Index, and concomitant medications.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tiotropium + Olodaterol Cohort - Propensity Score Matched | Annualized Rate of COPD Exacerbations After Index Date | 0.36 Events (exacerbations) per Person-year |
| Inhaled Corticosteroids (ICS) + Long-acting ß2 Agonists (LABA) Cohort - Propensity Score Matched | Annualized Rate of COPD Exacerbations After Index Date | 0.37 Events (exacerbations) per Person-year |
Comparison: The rate ratio of Tio+Olo - exposed group relative to LABA/ICS group, along with 95% CIs were derived using a univariate negative binomial model. In the event that there are baseline covariates with unequal distribution between the treatment groups, defined as absolute standardized difference larger than 0.1, the covariate(s) will be included in a multiple regression model in addition to the exposure status (Tio/Olo or LABA/ICS).95% CI: [0.87, 1.18]
Secondary
Annualized Rate of Prescriptions of Rescue Medications After the Index Date
Annualized rate of prescriptions of rescue medications after the index date. Rescue medications were defined as free or combination use of short-acting beta-agonist (SABA) or short-acting muscarinic antagonist (SAMA) or SABA/SAMA. Annualized rates were calculated for each cohort as follows: (total number of events in the cohort during the given time period) / (total person-year at risk from current use of treatment of cohort during the given period).
Time frame: From the index date (The first dispensing of either Tio/Olo or ICS/LABA combined inhaler) until first event, up to 6 years.
Population: Propensity score matched cohorts: Subjects were 1:1 propensity score matched between cohorts. The two groups were comparable with regards to year of treatment initiation, season of treatment initiation, prior treatment for Chronic Obstructive Pulmonary Disease (COPD), use of respiratory drugs of interest, frequency and severity of COPD exacerbation, prevalence of major comorbidity, Charlson Comorbidity Index, and concomitant medications.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tiotropium + Olodaterol Cohort - Propensity Score Matched | Annualized Rate of Prescriptions of Rescue Medications After the Index Date | 0.86 Events (prescriptions) per Person-year |
| Inhaled Corticosteroids (ICS) + Long-acting ß2 Agonists (LABA) Cohort - Propensity Score Matched | Annualized Rate of Prescriptions of Rescue Medications After the Index Date | 1.03 Events (prescriptions) per Person-year |
Comparison: The rate ratio of Tio+Olo - exposed group relative to LABA/ICS group, along with 95% CIs were derived using a univariate negative binomial model. In the event that there are baseline covariates with unequal distribution between the treatment groups, defined as absolute standardized difference larger than 0.1, the covariate(s) will be included in a multiple regression model in addition to the exposure status (Tio/Olo or LABA/ICS).95% CI: [0.81, 1.03]
Secondary
Incidence Rate of Triple Therapy Initiation
Incidence rate of triple therapy initiation (first event per patient). Triple therapy escalation, defined as any LAMA/ICS/LABA fixed dose combination or any concurrent use for 30 consecutive days of the following: 1. any LAMA/LABA fixed dose combination + any ICS single formulation 2. any LAMA single formulation + any ICS/LABA fixed dose combination 3. any LAMA single formulation + any LABA single formulation + any ICS single formulation Incidence rate calculated as (total number of patients in the cohort experiencing an event of interest for the first time during the given time period) / (total person-time at risk from current use of treatment of cohort during the given period).
Time frame: From the index date (The first dispensing of either Tio/Olo or ICS/LABA combined inhaler) until first event, up to 6 years.
Population: Propensity score matched cohorts: Subjects were 1:1 propensity score matched between cohorts. The two groups were comparable with regards to year of treatment initiation, season of treatment initiation, prior treatment for Chronic Obstructive Pulmonary Disease (COPD), use of respiratory drugs of interest, frequency and severity of COPD exacerbation, prevalence of major comorbidity, Charlson Comorbidity Index, and concomitant medications.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tiotropium + Olodaterol Cohort - Propensity Score Matched | Incidence Rate of Triple Therapy Initiation | 76.2 Events(escalations per 1000 person years |
| Inhaled Corticosteroids (ICS) + Long-acting ß2 Agonists (LABA) Cohort - Propensity Score Matched | Incidence Rate of Triple Therapy Initiation | 114.2 Events(escalations per 1000 person years |
Comparison: The rate ratio of Tio+Olo - exposed group relative to LABA/ICS group, along with 95% CIs were derived using a univariate negative binomial model. In the event that there are baseline covariates with unequal distribution between the treatment groups, defined as absolute standardized difference larger than 0.1, the covariate(s) will be included in a multiple regression model in addition to the exposure status (Tio/Olo or LABA/ICS).95% CI: [-60.1, -15.8]
Comparison: The rate ratio of Tio+Olo - exposed group relative to LABA/ICS group, along with 95% CIs were derived using a univariate negative binomial model. In the event that there are baseline covariates with unequal distribution between the treatment groups, defined as absolute standardized difference larger than 0.1, the covariate(s) will be included in a multiple regression model in addition to the exposure status (Tio/Olo or LABA/ICS).95% CI: [0.51, 0.85]
Secondary
Number of Subjects With Event First Hospitalization for Community-acquired Pneumonia After Entry
Number of subjects with event the first hospitalization for community-acquired pneumonia after initiation of study drug.
Time frame: From the index date (The first dispensing of either Tio/Olo or ICS/LABA combined inhaler) until first event, up to 6 years.
Population: Propensity score matched cohorts: Subjects were 1:1 propensity score matched between cohorts. The two groups were comparable with regards to year of treatment initiation, season of treatment initiation, prior treatment for Chronic Obstructive Pulmonary Disease (COPD), use of respiratory drugs of interest, frequency and severity of COPD exacerbation, prevalence of major comorbidity, Charlson Comorbidity Index, and concomitant medications.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tiotropium + Olodaterol Cohort - Propensity Score Matched | Number of Subjects With Event First Hospitalization for Community-acquired Pneumonia After Entry | 11 Participants |
| Inhaled Corticosteroids (ICS) + Long-acting ß2 Agonists (LABA) Cohort - Propensity Score Matched | Number of Subjects With Event First Hospitalization for Community-acquired Pneumonia After Entry | 11 Participants |
Comparison: Univariate proportional hazards regression was used to compare the time to event (first hospitalization for community-acquired pneumonia after initiation of study drug) between the two treatment groups. In the event that there were baseline covariates with unequal distribution between the treatment groups, defined as absolute standardized difference larger than 0.1, the covariate(s) were included in a multiple regression model in addition to the exposure status (Tio/Olo or ICS/LABA).95% CI: [0.36, 1.93]
Secondary
Number of Subjects With Event Triple Therapy Escalation After Index Date
Number of subjects with event triple therapy escalation, defined as any LAMA/ICS/LABA fixed dose combination or any concurrent use for 30 consecutive days of the following: 1. any LAMA/LABA fixed dose combination + any ICS single formulation 2. any LAMA single formulation + any ICS/LABA fixed dose combination 3. any LAMA single formulation + any LABA single formulation + any ICS single formulation The event date was the 30th day after initiation of triple therapy.
Time frame: From the index date (The first dispensing of either Tio/Olo or ICS/LABA combined inhaler) until first event, up to 6 years.
Population: Propensity score matched cohorts: Subjects were 1:1 propensity score matched between cohorts. The two groups were comparable with regards to year of treatment initiation, season of treatment initiation, prior treatment for Chronic Obstructive Pulmonary Disease (COPD), use of respiratory drugs of interest, frequency and severity of COPD exacerbation, prevalence of major comorbidity, Charlson Comorbidity Index, and concomitant medications.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tiotropium + Olodaterol Cohort - Propensity Score Matched | Number of Subjects With Event Triple Therapy Escalation After Index Date | 122 Participants |
| Inhaled Corticosteroids (ICS) + Long-acting ß2 Agonists (LABA) Cohort - Propensity Score Matched | Number of Subjects With Event Triple Therapy Escalation After Index Date | 153 Participants |
Comparison: Univariate proportional hazards regression was used to compare the time to event (triple therapy escalation) between the two treatment groups. In the event that there were baseline covariates with unequal distribution between the treatment groups, defined as absolute standardized difference larger than 0.1, the covariate(s) were included in a multiple regression model in addition to the exposure status (Tio/Olo or ICS/LABA).95% CI: [0.53, 0.85]