Effectiveness of Triple Therapy in COPD

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03724877
• Collaborator: (none)
• Enrollment: 8,853
• Location: 1
• Actual Duration (Days): 2
• Patients Per Site Per Month: 134731.6

Study Details

Study Description

Brief Summary

To assess the effectiveness of maintenance treatment of Chronic obstructive pulmonary disease (COPD) with the Long-acting beta2-agonist - long-acting muscarinic antagonists-inhaled corticosteroids (LABA-LAMA-ICS) combination with a LABA-LAMA combination on the risk of COPD exacerbation and the safety on the incidence of community acquired pneumonia.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: Long-acting beta2-agonist-long-acting muscarinic antagonists-inhaled corticosteroids(LABA-LAMA-ICS); Drug: Long-acting beta2-agonist-inhaled corticosteroids-long-acting muscarinic antagonists (LABA-LAMA)

Study Design

• Study Type: Observational
• Actual Enrollment: 8853 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Comparative Effectiveness of Triple Therapy in COPD: A New-user Cohort Study
• Actual Study Start Date: Nov 10, 2018
• Actual Primary Completion Date: Nov 12, 2018
• Actual Study Completion Date: Nov 12, 2018

Arms and Interventions

Arm	Intervention/Treatment
Subjects with Chronic obstructive pulmonary disease (COPD)	Drug: Long-acting beta2-agonist-long-acting muscarinic antagonists-inhaled corticosteroids(LABA-LAMA-ICS); (LABA-LAMA-ICS); Drug: Long-acting beta2-agonist-inhaled corticosteroids-long-acting muscarinic antagonists (LABA-LAMA); (LABA-LAMA)

Outcome Measures

Primary Outcome Measures

1. Number of Participants Hospitalised With Severe Exacerbation [1 year]

   The primary outcome event for effectiveness was the first COPD exacerbation to occur after cohort entry. The event was defined as a hospitalization with a primary diagnosis of COPD (severe exacerbation) is presented.

2. Number of Participants Hospitalised With Moderate Exacerbation [1 year]

   The primary outcome event for effectiveness was the first COPD exacerbation to occur after cohort entry. The event was defined as a hospitalization with the prescription of an oral corticosteroid, namely prednisolone (moderate exacerbation) is presented.

3. Number of Participants Hospitalised With Community-acquired Pneumonia (Serious Pneumonia) [1 year]

   The primary outcome event for safety was the occurrence of the first hospitalization for community-acquired pneumonia (serious pneumonia).

Secondary Outcome Measures

1. The Rate of COPD Exacerbations Over the One-year Follow-up [1 year]

   This outcome was based on the number of hospitalizations and on the number of courses of treatment with an oral corticosteroid. A gap of at least 30 days between treatment courses was required to consider the exacerbations as separate events.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• New users of long-acting bronchodilators, Long-acting beta2-agonist (LABA) and long-acting muscarinic antagonists (LAMA) on the same date or of LABA, LAMA and inhaled corticosteroids (ICS), either as a fixed-dose combination (LABA-ICS) or free combination, on the same date between January 2002 and December 2016.

• Diagnosis of Chronic obstructive pulmonary disease (COPD) prior to first maintenance inhaler and age ≥ 55 years at first maintenance inhaler.

Exclusion Criteria:

• Less than one year of medical history information prior to the date of combined treatment initiation (study cohort entry)

• Asthma diagnosis prior to study cohort entry

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Practice Research Datalink	London		United Kingdom	E14 4PU

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 23, 2018

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT03724877
• Other Study ID Numbers: 1237-0078
• First Posted: Oct 30, 2018
• Last Update Posted: Dec 3, 2019
• Last Verified: Nov 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Additional relevant MeSH terms: Pulmonary Disease, Chronic Obstructive; Cholinergic Agents; Muscarinic Antagonists

Study Results

Participant Flow

Recruitment Details	Base cohort consisted participants with ChronicObstructivePulmonaryDisease(COPD) who subsequently received at least one prescription for a long-acting bronchodilator, either Long-Acting Beta2-Agonist(LABA) or long-acting MuscarinicAntagonists(LAMA), or for inhaled corticosteroid(ICS), alone or in combination, from 1January2002 until 31December2015.
Pre-assignment Detail	Population-based incident new-user cohort design with high-dimensional time-conditional propensity score matching. The study cohort was formed from the base cohort using an incident new-user cohort design with time-conditional propensity scores.

Arm/Group Title	LABA-LAMA-ICS	LABA-LAMA
Arm/Group Description	The participants with COPD initiating treatment with LABA-LAMA-ICS combination as three or two inhalers on the same day were included in this group. Participants were followed for up to one year from the cohort entry date, the date of death, 31 March 2016, or the end of coverage in the practice, whichever occurred first.	The participants with COPD with their first concurrent prescriptions of a LAMA and LABA (no ICS) as two inhalers on the same day included in this group were matched on high-dimensional propensity score with patients initiating treatment with LABA-LAMA-ICS combination as three or two inhalers on the same day. Participants were followed for up to one year from the cohort entry date, the date of death, 31 March 2016, or the end of coverage in the practice, whichever occurred first.
Period Title: Overall Study
STARTED	6921	1932
COMPLETED	6921	1932
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	LABA-LAMA-ICS	LABA-LAMA	Total
Arm/Group Description	The participants with COPD initiating treatment with LABA-LAMA-ICS combination as three or two inhalers on the same day were included in this group. Participants were followed for up to one year from the cohort entry date, the date of death, 31 March 2016, or the end of coverage in the practice, whichever occurred first.	The participants with COPD with their first concurrent prescriptions of a LAMA and LABA (no ICS) as two inhalers on the same day included in this group were matched on high-dimensional propensity score with patients initiating treatment with LABA-LAMA-ICS combination as three or two inhalers on the same day. Participants were followed for up to one year from the cohort entry date, the date of death, 31 March 2016, or the end of coverage in the practice, whichever occurred first.	Total of all reporting groups
Overall Participants	6921	1932	8853
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	71.9 (8.5)	71.6 (8.5)	71.8 (8.5)
Sex: Female, Male (Count of Participants)
Female	2619 37.8%	746 38.6%	3365 38%
Male	4302 62.2%	1186 61.4%	5488 62%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Hospitalised With Severe Exacerbation
Description	The primary outcome event for effectiveness was the first COPD exacerbation to occur after cohort entry. The event was defined as a hospitalization with a primary diagnosis of COPD (severe exacerbation) is presented.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The main analysis was on matched patients. The cohort of initiators of LAMA-LABA-ICS and their propensity score-matched initiators of LAMA-LABA.

Arm/Group Title	LABA-LAMA-ICS	LABA-LAMA
Arm/Group Description	The participants with COPD initiating treatment with LABA-LAMA-ICS combination as three or two inhalers on the same day were included in this group. Participants were followed for up to one year from the cohort entry date, the date of death, 31 March 2016, or the end of coverage in the practice, whichever occurred first.	The participants with COPD with their first concurrent prescriptions of a LAMA and LABA (no ICS) as two inhalers on the same day included in this group were matched on high-dimensional propensity score with patients initiating treatment with LABA-LAMA-ICS combination as three or two inhalers on the same day. Participants were followed for up to one year from the cohort entry date, the date of death, 31 March 2016, or the end of coverage in the practice, whichever occurred first.
Measure Participants	6921	1932
Count of Participants [Participants]	3074 44.4%	630 32.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LABA-LAMA-ICS, LABA-LAMA
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted hazard ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.79 to 1.38
	Parameter Dispersion	Type: Value:
	Estimation Comments	After matching on high-dimensional propensity scores, sex prior severe exacerbation, prior maintenance treatment and calendar time, adjusted further for the deciles of propensity score and percent predicted forced expiratory volume1 (FEV1).

2. Primary Outcome

Title	Number of Participants Hospitalised With Moderate Exacerbation
Description	The primary outcome event for effectiveness was the first COPD exacerbation to occur after cohort entry. The event was defined as a hospitalization with the prescription of an oral corticosteroid, namely prednisolone (moderate exacerbation) is presented.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The main analysis was on matched patients. The cohort of initiators of LAMA-LABA-ICS and their propensity score-matched initiators of LAMA-LABA.

Arm/Group Title	LABA-LAMA-ICS	LABA-LAMA
Arm/Group Description	The participants with COPD initiating treatment with LABA-LAMA-ICS combination as three or two inhalers on the same day were included in this group. Participants were followed for up to one year from the cohort entry date, the date of death, 31 March 2016, or the end of coverage in the practice, whichever occurred first.	The participants with COPD with their first concurrent prescriptions of a LAMA and LABA (no ICS) as two inhalers on the same day included in this group were matched on high-dimensional propensity score with patients initiating treatment with LABA-LAMA-ICS combination as three or two inhalers on the same day. Participants were followed for up to one year from the cohort entry date, the date of death, 31 March 2016, or the end of coverage in the practice, whichever occurred first.
Measure Participants	6921	1932
Count of Participants [Participants]	2487 35.9%	542 28.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LABA-LAMA-ICS, LABA-LAMA
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted HR
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.87 to 1.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	After matching on high-dimensional propensity scores, sex prior severe exacerbation, prior maintenance treatment and calendar time, adjusted further for the deciles of propensity score and percent predicted FEV1.

3. Primary Outcome

Title	Number of Participants Hospitalised With Community-acquired Pneumonia (Serious Pneumonia)
Description	The primary outcome event for safety was the occurrence of the first hospitalization for community-acquired pneumonia (serious pneumonia).
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The main analysis was on matched patients. The cohort of initiators of LAMA-LABA-ICS and their propensity score-matched initiators of LAMA-LABA.

Arm/Group Title	LABA-LAMA-ICS	LABA-LAMA
Arm/Group Description	The participants with COPD initiating treatment with LABA-LAMA-ICS combination as three or two inhalers on the same day were included in this group. Participants were followed for up to one year from the cohort entry date, the date of death, 31 March 2016, or the end of coverage in the practice, whichever occurred first.	The participants with COPD with their first concurrent prescriptions of a LAMA and LABA (no ICS) as two inhalers on the same day included in this group were matched on high-dimensional propensity score with patients initiating treatment with LABA-LAMA-ICS combination as three or two inhalers on the same day. Participants were followed for up to one year from the cohort entry date, the date of death, 31 March 2016, or the end of coverage in the practice, whichever occurred first.
Measure Participants	6921	1932
Count of Participants [Participants]	3099 44.8%	634 32.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LABA-LAMA-ICS, LABA-LAMA
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted HR
	Estimated Value	1.46
	Confidence Interval	(2-Sided) 95%; 1.03 to 2.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	After matching on high-dimensional propensity scores, sex prior severe exacerbation, prior maintenance treatment and calendar time, adjusted further for the deciles of propensity score and percent predicted FEV1.

4. Secondary Outcome

Title	The Rate of COPD Exacerbations Over the One-year Follow-up
Description	This outcome was based on the number of hospitalizations and on the number of courses of treatment with an oral corticosteroid. A gap of at least 30 days between treatment courses was required to consider the exacerbations as separate events.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The main analysis was on matched patients. The cohort of initiators of LAMA-LABA-ICS and their propensity score-matched initiators of LAMA-LABA.

Arm/Group Title	LABA-LAMA-ICS	LABA-LAMA
Arm/Group Description	The participants with COPD initiating treatment with LABA-LAMA-ICS combination as three or two inhalers on the same day were included in this group. Participants were followed for up to one year from the cohort entry date, the date of death, 31 March 2016, or the end of coverage in the practice, whichever occurred first.	The participants with COPD with their first concurrent prescriptions of a LAMA and LABA (no ICS) as two inhalers on the same day included in this group were matched on high-dimensional propensity score with patients initiating treatment with LABA-LAMA-ICS combination as three or two inhalers on the same day. Participants were followed for up to one year from the cohort entry date, the date of death, 31 March 2016, or the end of coverage in the practice, whichever occurred first.
Measure Participants	6921	1932
Moderate/ sever exacerbation	94.4	89.3
Severe exacerbation	13.4	11.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LABA-LAMA-ICS, LABA-LAMA
	Comments	Moderate/ sever exacerbation
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted rate ratio
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.83 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	After matching on high-dimensional propensity scores, sex prior severe exacerbation, prior maintenance treatment and calendar time, adjusted further for the deciles of propensity score and percent predicted FEV1.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LABA-LAMA-ICS, LABA-LAMA
	Comments	Severe exacerbation
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted rate ratio
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.70 to 1.28
	Parameter Dispersion	Type: Value:
	Estimation Comments	After matching on high-dimensional propensity scores, sex prior severe exacerbation, prior maintenance treatment and calendar time, adjusted further for the deciles of propensity score and percent predicted FEV1.

Adverse Events

Time Frame	Adverse event information was not applicable for this study.
Adverse Event Reporting Description	This was an observational study and was not designed to assess adverse event; therefore safety reporting was not applicable for this study. Adverse Events were not monitored/assessed.
Arm/Group Title	LABA-LAMA-ICS		LABA-LAMA
Arm/Group Description	The participants with COPD initiating treatment with LABA-LAMA-ICS combination as three or two inhalers on the same day were included in this group. Participants were followed for up to one year from the cohort entry date, the date of death, 31 March 2016, or the end of coverage in the practice, whichever occurred first.		The participants with COPD with their first concurrent prescriptions of a LAMA and LABA (no ICS) as two inhalers on the same day included in this group were matched on high-dimensional propensity score with patients initiating treatment with LABA-LAMA-ICS combination as three or two inhalers on the same day. Participants were followed for up to one year from the cohort entry date, the date of death, 31 March 2016, or the end of coverage in the practice, whichever occurred first.
All Cause Mortality
	LABA-LAMA-ICS		LABA-LAMA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Serious Adverse Events
	LABA-LAMA-ICS		LABA-LAMA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	LABA-LAMA-ICS		LABA-LAMA
	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.