Comparative Effectiveness and Safety of Tiotropium and Olodaterol in Comparison to LABA/ICS

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04138758
• Collaborator: (none)
• Enrollment: 42,953
• Location: 1
• Actual Duration (Days): 3
• Patients Per Site Per Month: 435794

Study Details

Study Description

Brief Summary

The primary objective is to compare the effectiveness of maintenance therapy initiation with the combination treatment Tiotropium and Olodaterol (Olo+Tio) compared with LABA/ICS combination in COPD as the time to the first COPD exacerbation.

Secondary objectives are to compare patients treated with Tio+Olo and patients treated with LABA/ ICS combination.

Condition or Disease	Intervention/Treatment	Phase
COPD	Drug: Tiotropium bromide + Olodaterol; Drug: LABA/ICS

Study Design

• Study Type: Observational
• Actual Enrollment: 42953 participants
• Observational Model: Cohort
• Time Perspective: Retrospective
• Official Title: Effectiveness and Safety of Maintenance Treatment With Combination of Tiotropium and Olodaterol in Comparison to Maintenance Treatment With a Combination of Inhaled Corticosteroids and Long-acting β2 Agonists in COPD Patients
• Actual Study Start Date: Nov 1, 2019
• Actual Primary Completion Date: Nov 4, 2019
• Actual Study Completion Date: Nov 4, 2019

Arms and Interventions

Arm	Intervention/Treatment
Patients initiating Tiotropium+Olodaterol therapy	Drug: Tiotropium bromide + Olodaterol; Tiotropium bromide + Olodaterol
Patients initiating Long-acting beta agonist/inhaled corticosteroid therapy	Drug: LABA/ICS; Long-acting beta2-agonist and Inhaled corticosteroids (LABA and ICS)

Outcome Measures

Primary Outcome Measures

1. Incidence Rate of Chronic Obstructive Pulmonary Disease (COPD) Exacerbation [From cohort entry (index date) until the occurrence of a hospitalization for COPD (severe exacerbation), ED visit for COPD or prescription of an antibiotic and oral corticosteroid on the same day (moderate exacerbation). Up to one year after cohort entry.]

   Incidence rate of Chronic Obstructive Pulmonary Disease (COPD) exacerbation after cohort entry. The event was defined as follows: Severe exacerbation: Hospitalization with a principal discharge diagnosis of COPD. or Moderate exacerbation: An emergency department (ED) visit with a discharge diagnosis of COPD, or, an antibiotic for a respiratory condition dispensed the same day as an oral corticosteroid.

Secondary Outcome Measures

1. Incidence Rate of First Hospitalization for Community-acquired Pneumonia [From cohort entry (index date) until the occurrence of first hospitalization for community-acquired pneumonia (serious pneumonia). Up to one year after cohort entry.]

   Incidence rate of first hospitalization for community-acquired pneumonia (serious pneumonia). Pneumonia was defined using ICD-9-CM diagnoses and ICD-10 diagnosis codes.

2. Incidence Rate of the First Date of a Pharmacy Dispensing Indicating Escalation (Original Case Definition) to Triple Therapy [From cohort entry (index date) until the escalation, up to one year after cohort entry.]

   Incidence rate of the first date of a pharmacy dispensing indicating escalation to triple therapy, (i.e., addition of Inhaled Corticosteroids to Tiotropium and Olodaterol or a Long-acting Muscarinic Antagonists to long-acting beta agonist / inhaled corticosteroid therapy).

3. Incidence Rate of the First Date of a Pharmacy Dispensing Indicating Escalation (Alternative Case Definition) to Triple Therapy [From cohort entry (index date) until the escalation, up to one year after cohort entry.]

   Incidence rate of the first date of a pharmacy dispensing indicating escalation to triple therapy. Based on feedback from clinical experts during review of study results, an alternative post-hoc definition was also assessed in which initiation of any treatment including simultaneous LABA (long-acting beta agonist) /LAMA (Long-acting Muscarinic Antagonists) /ICS (inhaled corticosteroid therapy) use in free or fixed combination was counted as an outcome.

4. Incidence Rate of Any Element of a Composite Outcome Including Exacerbation, Hospitalization for Pneumonia, or Escalation (Original Case Definition) to Triple Therapy [From cohort entry (index date) until exacerbation, hospitalization (for community-acquired pneumonia) or escalation, up to one year after cohort entry.]

   Incidence rate of any element of a composite outcome including exacerbation, hospitalization for pneumonia, or escalation (original case definition) to triple therapy. Exacerbation was defined as follows: Severe exacerbation: Hospitalization with a principal discharge diagnosis of COPD. Moderate exacerbation: An emergency department (ED) visit with a discharge diagnosis of COPD, or, an antibiotic for a respiratory condition dispensed the same day as an oral corticosteroid. Pneumonia was defined using ICD-9-CM diagnoses and ICD-10 diagnosis codes. Escalation was defined as the addition of Inhaled Corticosteroids to Tiotropium and Olodaterol or a Long-acting Muscarinic Antagonists to long-acting beta agonist / inhaled corticosteroid therapy.

5. Incidence Rate of Any Element of a Composite Outcome Including Exacerbation, Hospitalization for Pneumonia, or Escalation (Alternative Case Definition) to Triple Therapy [From cohort entry (index date) until exacerbation, hospitalization (for community-acquired pneumonia) or escalation, up to one year after cohort entry.]

   Incidence rate of any element of a composite outcome including exacerbation, hospitalization for pneumonia, or escalation (alternative case definition) to triple therapy. Exacerbation was defined as follows: Severe exacerbation: Hospitalization with a principal discharge diagnosis of COPD. Moderate exacerbation: An emergency department (ED) visit with a discharge diagnosis of COPD, or, an antibiotic for a respiratory condition dispensed the same day as an oral corticosteroid. Pneumonia was defined using ICD-9-CM diagnoses and ICD-10 diagnosis codes. Escalation was defined as the initiation of any treatment including simultaneous LABA (long-acting beta agonist) /LAMA (Long-acting Muscarinic Antagonists) /ICS (inhaled corticosteroid therapy) use in free or fixed combination.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. At least one prescription for Tio+Olo combined inhaler or a LABA/ICS combined inhaler between 1 January 2013 and 31 March 2019.

2. The first dispensing of either Tio+Olo or LABA/ICS combined inhaler will be defined as the index date.

3. For the main analyses, only fixed dose combination (FDC) inhalers will be included. Sensitivity analyses will also accept free combinations of LABA/ICS.

4. At least one diagnosis of COPD at any time prior to the index date.

5. At least one year of continuous medical and pharmacy health plan eligibility prior to the index date will be required to allow a baseline period for the covariates and identification of new use of the study drugs.

Exclusion Criteria:

1. To increase the likelihood of a true diagnosis of COPD, we will exclude:

2. All patients less than 40 years of age on the index date, and

3. All patients with a diagnosis of asthma in the year prior to the index date

4. To limit the population to those without severe lung compromise outside of COPD, we will exclude individuals with lung cancer, interstitial lung disease, or lung transplant identified at any time prior to the index date

5. To restrict the cohort to new users of Tio+Olo or LABA/ICS, we will exclude any individual with use of either Tio+Olo, LABA/ICS, or LABA/LAMA/ICS combination therapy in free or fixed form for at least one year prior to the index date.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	HealthCore, Inc.	Watertown	Massachusetts	United States	02472

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 19, 2020

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT04138758
• Other Study ID Numbers: 1237-0093
• First Posted: Oct 24, 2019
• Last Update Posted: Nov 15, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Bromides; Tiotropium Bromide; Olodaterol

Study Results

Participant Flow

Recruitment Details	In this cohort study, administrative data from the HealthCore Integrated Research Database (US, HIRD, Jan 2013 - March 2019) were used to identify and compare new users of Tio+Olo (Tiotropium and Olodaterol) with new users of LABA/ICS (Long-acting Beta2-Agonists/Inhaled Corticosteroids) combination therapy with respect to safety and effectiveness.
Pre-assignment Detail	Only subjects that met all inclusion and none of the exclusion criteria were included. two cohorts (Initiators of Tiotropium + Olodaterol and patients receiving Long-acting beta agonist / inhaled corticosteroid) were established. The cohorts after propensity score matching were used for the analyses

Arm/Group Title	Tiotropium + Olodaterol	Long-acting Beta Agonist / Inhaled Corticosteroid Therapy
Arm/Group Description	Cohort of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from administrative data from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated fixed dose combination (FDC) inhaler treatment of Tiotropium and Olodaterol, with the first prescription defined as the index date. Following the index date participants were followed for up to one year.	Cohort of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from administrative data from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated long-acting beta agonist / inhaled corticosteroid therapy, with the first prescription defined as the index date. Following the index date participants were followed for up to one year.
Period Title: Overall Study
STARTED	2600	40353
COMPLETED	2600	40353
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Tiotropium + Olodaterol	Long-acting Beta Agonist / Inhaled Corticosteroid Therapy	Total
Arm/Group Description	Cohort of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from administrative data from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated fixed dose combination (FDC) inhaler treatment of Tiotropium and Olodaterol, with the first prescription defined as the index date. Following the index date participants were followed for up to one year.	Cohort of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from administrative data from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated long-acting beta agonist / inhaled corticosteroid therapy, with the first prescription defined as the index date. Following the index date participants were followed for up to one year.	Total of all reporting groups
Overall Participants	2600	40353	42953
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65 (10.3)	64.8 (11.5)	64.81 (11.4)
Sex: Female, Male (Count of Participants)
Female	1415 54.4%	21994 54.5%	23409 54.5%
Male	1185 45.6%	18359 45.5%	19544 45.5%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%

Outcome Measures

1. Primary Outcome

Title	Incidence Rate of Chronic Obstructive Pulmonary Disease (COPD) Exacerbation
Description	Incidence rate of Chronic Obstructive Pulmonary Disease (COPD) exacerbation after cohort entry. The event was defined as follows: Severe exacerbation: Hospitalization with a principal discharge diagnosis of COPD. or Moderate exacerbation: An emergency department (ED) visit with a discharge diagnosis of COPD, or, an antibiotic for a respiratory condition dispensed the same day as an oral corticosteroid.
Time Frame	From cohort entry (index date) until the occurrence of a hospitalization for COPD (severe exacerbation), ED visit for COPD or prescription of an antibiotic and oral corticosteroid on the same day (moderate exacerbation). Up to one year after cohort entry.

Outcome Measure Data

Analysis Population Description

Propensity score weighted populations of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated fixed dose combination (FDC) inhaler treatment of Tiotropium and Olodaterol or long-acting beta agonist / inhaled corticosteroid therapy.

Arm/Group Title	Tiotropium + Olodaterol	Long-acting Beta Agonist / Inhaled Corticosteroid Therapy
Arm/Group Description	Cohort of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from administrative data from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated fixed dose combination (FDC) inhaler treatment of Tiotropium and Olodaterol, with the first prescription defined as the index date. Following the index date participants were followed for up to one year.	Cohort of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from administrative data from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated long-acting beta agonist / inhaled corticosteroid therapy, with the first prescription defined as the index date. Following the index date participants were followed for up to one year.
Measure Participants	2600	40353
Number (95% Confidence Interval) [Events per 1,000 Person-days]	1.63	2.43

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium + Olodaterol, Long-acting Beta Agonist / Inhaled Corticosteroid Therapy
	Comments	Cox proportional hazard regression models were used to assess the effect of Tiotropium + Olodaterol combination versus the Long-acting beta agonist / inhaled corticosteroid therapy combination on the risk of a first COPD exacerbation.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.68 to 0.85
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratio lower than 1 favors Tiotropium + Olodaterol.

2. Secondary Outcome

Title	Incidence Rate of First Hospitalization for Community-acquired Pneumonia
Description	Incidence rate of first hospitalization for community-acquired pneumonia (serious pneumonia). Pneumonia was defined using ICD-9-CM diagnoses and ICD-10 diagnosis codes.
Time Frame	From cohort entry (index date) until the occurrence of first hospitalization for community-acquired pneumonia (serious pneumonia). Up to one year after cohort entry.

Outcome Measure Data

Analysis Population Description

Propensity score weighted populations of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated fixed dose combination (FDC) inhaler treatment of Tiotropium and Olodaterol or long-acting beta agonist / inhaled corticosteroid therapy.

Arm/Group Title	Tiotropium + Olodaterol	Long-acting Beta Agonist / Inhaled Corticosteroid Therapy
Arm/Group Description	Cohort of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from administrative data from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated fixed dose combination (FDC) inhaler treatment of Tiotropium and Olodaterol, with the first prescription defined as the index date. Following the index date participants were followed for up to one year.	Cohort of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from administrative data from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated long-acting beta agonist / inhaled corticosteroid therapy, with the first prescription defined as the index date. Following the index date participants were followed for up to one year.
Measure Participants	2600	40353
Number (95% Confidence Interval) [events per 1,000 Person-days]	0.23	0.34

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium + Olodaterol, Long-acting Beta Agonist / Inhaled Corticosteroid Therapy
	Comments	Cox proportional hazard regression models were used to assess the effect of Tiotropium + Olodaterol combination versus the Long-acting beta agonist / inhaled corticosteroid therapy combination on the risk of first hospitalization for community-acquired pneumonia.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.57 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratio lower than 1 favors Tiotropium + Olodaterol.

3. Secondary Outcome

Title	Incidence Rate of the First Date of a Pharmacy Dispensing Indicating Escalation (Original Case Definition) to Triple Therapy
Description	Incidence rate of the first date of a pharmacy dispensing indicating escalation to triple therapy, (i.e., addition of Inhaled Corticosteroids to Tiotropium and Olodaterol or a Long-acting Muscarinic Antagonists to long-acting beta agonist / inhaled corticosteroid therapy).
Time Frame	From cohort entry (index date) until the escalation, up to one year after cohort entry.

Outcome Measure Data

Analysis Population Description

Propensity score weighted populations of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated fixed dose combination (FDC) inhaler treatment of Tiotropium and Olodaterol or long-acting beta agonist / inhaled corticosteroid therapy.

Arm/Group Title	Tiotropium + Olodaterol	Long-acting Beta Agonist / Inhaled Corticosteroid Therapy
Arm/Group Description	Cohort of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from administrative data from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated fixed dose combination (FDC) inhaler treatment of Tiotropium and Olodaterol, with the first prescription defined as the index date. Following the index date participants were followed for up to one year.	Cohort of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from administrative data from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated long-acting beta agonist / inhaled corticosteroid therapy, with the first prescription defined as the index date. Following the index date participants were followed for up to one year.
Measure Participants	2600	40353
Number (95% Confidence Interval) [events per 1,000 Person-days]	0.54	2.90

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium + Olodaterol, Long-acting Beta Agonist / Inhaled Corticosteroid Therapy
	Comments
	Type of Statistical Test	Other
	Comments	Cox proportional hazard regression models were used to assess the effect of Tiotropium + Olodaterol combination versus the Long-acting beta agonist / inhaled corticosteroid therapy combination on the risk of escalation.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.23
	Confidence Interval	(2-Sided) 95%; 0.19 to 0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratio lower than 1 favors Tiotropium + Olodaterol.

4. Secondary Outcome

Title	Incidence Rate of the First Date of a Pharmacy Dispensing Indicating Escalation (Alternative Case Definition) to Triple Therapy
Description	Incidence rate of the first date of a pharmacy dispensing indicating escalation to triple therapy. Based on feedback from clinical experts during review of study results, an alternative post-hoc definition was also assessed in which initiation of any treatment including simultaneous LABA (long-acting beta agonist) /LAMA (Long-acting Muscarinic Antagonists) /ICS (inhaled corticosteroid therapy) use in free or fixed combination was counted as an outcome.
Time Frame	From cohort entry (index date) until the escalation, up to one year after cohort entry.

Outcome Measure Data

Analysis Population Description

Propensity score weighted populations of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated fixed dose combination (FDC) inhaler treatment of Tiotropium and Olodaterol or long-acting beta agonist / inhaled corticosteroid therapy.

Arm/Group Title	Tiotropium + Olodaterol	Long-acting Beta Agonist / Inhaled Corticosteroid Therapy
Arm/Group Description	Cohort of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from administrative data from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated fixed dose combination (FDC) inhaler treatment of Tiotropium and Olodaterol, with the first prescription defined as the index date. Following the index date participants were followed for up to one year.	Cohort of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from administrative data from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated long-acting beta agonist / inhaled corticosteroid therapy, with the first prescription defined as the index date. Following the index date participants were followed for up to one year.
Measure Participants	2600	40353
Number (95% Confidence Interval) [events per 1,000 Person-days]	0.57	3.14

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium + Olodaterol, Long-acting Beta Agonist / Inhaled Corticosteroid Therapy
	Comments	Cox proportional hazard regression models were used to assess the effect of Tiotropium + Olodaterol combination versus the Long-acting beta agonist / inhaled corticosteroid therapy combination on the risk of escalation.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.22
	Confidence Interval	(2-Sided) 95%; 0.19 to 0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratio lower than 1 favors Tiotropium + Olodaterol.

5. Secondary Outcome

Title	Incidence Rate of Any Element of a Composite Outcome Including Exacerbation, Hospitalization for Pneumonia, or Escalation (Original Case Definition) to Triple Therapy
Description	Incidence rate of any element of a composite outcome including exacerbation, hospitalization for pneumonia, or escalation (original case definition) to triple therapy. Exacerbation was defined as follows: Severe exacerbation: Hospitalization with a principal discharge diagnosis of COPD. Moderate exacerbation: An emergency department (ED) visit with a discharge diagnosis of COPD, or, an antibiotic for a respiratory condition dispensed the same day as an oral corticosteroid. Pneumonia was defined using ICD-9-CM diagnoses and ICD-10 diagnosis codes. Escalation was defined as the addition of Inhaled Corticosteroids to Tiotropium and Olodaterol or a Long-acting Muscarinic Antagonists to long-acting beta agonist / inhaled corticosteroid therapy.
Time Frame	From cohort entry (index date) until exacerbation, hospitalization (for community-acquired pneumonia) or escalation, up to one year after cohort entry.

Outcome Measure Data

Analysis Population Description

Propensity score weighted populations of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated fixed dose combination (FDC) inhaler treatment of Tiotropium and Olodaterol or long-acting beta agonist / inhaled corticosteroid therapy.

Arm/Group Title	Tiotropium + Olodaterol	Long-acting Beta Agonist / Inhaled Corticosteroid Therapy
Arm/Group Description	Cohort of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from administrative data from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated fixed dose combination (FDC) inhaler treatment of Tiotropium and Olodaterol, with the first prescription defined as the index date. Following the index date participants were followed for up to one year.	Cohort of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from administrative data from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated long-acting beta agonist / inhaled corticosteroid therapy, with the first prescription defined as the index date. Following the index date participants were followed for up to one year.
Measure Participants	2600	40353
Number (95% Confidence Interval) [events per 1,000 Person-days]	2.14	5.45

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium + Olodaterol, Long-acting Beta Agonist / Inhaled Corticosteroid Therapy
	Comments	Cox proportional hazard regression models were used to assess the effect of Tiotropium + Olodaterol combination versus the Long-acting beta agonist / inhaled corticosteroid therapy combination on the risk of any element of a composite outcome including exacerbation, hospitalization for pneumonia, or escalation.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.46
	Confidence Interval	(2-Sided) 95%; 0.42 to 0.51
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratio lower than 1 favors Tiotropium + Olodaterol.

6. Secondary Outcome

Title	Incidence Rate of Any Element of a Composite Outcome Including Exacerbation, Hospitalization for Pneumonia, or Escalation (Alternative Case Definition) to Triple Therapy
Description	Incidence rate of any element of a composite outcome including exacerbation, hospitalization for pneumonia, or escalation (alternative case definition) to triple therapy. Exacerbation was defined as follows: Severe exacerbation: Hospitalization with a principal discharge diagnosis of COPD. Moderate exacerbation: An emergency department (ED) visit with a discharge diagnosis of COPD, or, an antibiotic for a respiratory condition dispensed the same day as an oral corticosteroid. Pneumonia was defined using ICD-9-CM diagnoses and ICD-10 diagnosis codes. Escalation was defined as the initiation of any treatment including simultaneous LABA (long-acting beta agonist) /LAMA (Long-acting Muscarinic Antagonists) /ICS (inhaled corticosteroid therapy) use in free or fixed combination.
Time Frame	From cohort entry (index date) until exacerbation, hospitalization (for community-acquired pneumonia) or escalation, up to one year after cohort entry.

Outcome Measure Data

Analysis Population Description

Propensity score weighted populations of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated fixed dose combination (FDC) inhaler treatment of Tiotropium and Olodaterol or long-acting beta agonist / inhaled corticosteroid therapy.

Arm/Group Title	Tiotropium + Olodaterol	Long-acting Beta Agonist / Inhaled Corticosteroid Therapy
Arm/Group Description	Cohort of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from administrative data from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated fixed dose combination (FDC) inhaler treatment of Tiotropium and Olodaterol, with the first prescription defined as the index date. Following the index date participants were followed for up to one year.	Cohort of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from administrative data from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated long-acting beta agonist / inhaled corticosteroid therapy, with the first prescription defined as the index date. Following the index date participants were followed for up to one year.
Measure Participants	2600	40353
Number (95% Confidence Interval) [events per 1,000 Person-days]	2.16	5.67

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium + Olodaterol, Long-acting Beta Agonist / Inhaled Corticosteroid Therapy
	Comments	Cox proportional hazard regression models were used to assess the effect of Tiotropium + Olodaterol combination versus the Long-acting beta agonist / inhaled corticosteroid therapy combination on the risk of any element of a composite outcome including exacerbation, hospitalization for pneumonia, or escalation.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.45
	Confidence Interval	(2-Sided) 95%; 0.41 to 0.49
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratio lower than 1 favors Tiotropium + Olodaterol.

Adverse Events

Adverse Event Reporting Description	As this is a non-interventional study with secondary use of data retrieved from a US health claims database, safety monitoring and safety reporting on an individual case level is not applicable. Total number of participants at risk is 0 since adverse events were not planned to be collected and reported for this study.
Arm/Group Title	Tiotropium + Olodaterol		Long-acting Beta Agonist / Inhaled Corticosteroid Therapy
Arm/Group Description	Cohort of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from administrative data from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated fixed dose combination (FDC) inhaler treatment of Tiotropium and Olodaterol, with the first prescription defined as the index date. Following the index date participants were followed for up to one year.		Cohort of patients with Chronic Obstructive Pulmonary Disease (COPD) derived from administrative data from the HealthCore Integrated Research Database (HIRD, January 2013 - March 2019), who initiated long-acting beta agonist / inhaled corticosteroid therapy, with the first prescription defined as the index date. Following the index date participants were followed for up to one year.
All Cause Mortality
	Tiotropium + Olodaterol		Long-acting Beta Agonist / Inhaled Corticosteroid Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Serious Adverse Events
	Tiotropium + Olodaterol		Long-acting Beta Agonist / Inhaled Corticosteroid Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Tiotropium + Olodaterol		Long-acting Beta Agonist / Inhaled Corticosteroid Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.