The ENERGITO® 2 Study Compares 2 Inhaled Medicines for Chronic Obstructive Pulmonary Disease (COPD). One Medicine is a Combination of Tiotropium and Olodaterol (Stiolto®) Taken Using the Respimat® Inhaler and the Other Medicine is a Combination of Fluticasone and Salmeterol Taken Using the Diskus

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03240575
• Collaborator: (none)
• Enrollment: 302
• Locations: 45
• Arms: 2
• Actual Duration (Months): 20.7
• Patients Per Site: 6.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The primary objective of the trial is to show superiority in lung function of once daily (2 inhalations) treatment with orally inhaled tiotropium+olodaterol fixed dose combination to twice daily (one inhalation) treatment with fluticasone propionate+salmeterol fixed dose combination over 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD).

A Digital Health (DH) exploratory study has been integrated into the main study as a site specific study. The DH exploratory study will be performed at a single site; the site is also participating in the main study. The DH exploratory study site will enter (randomize) approximately 20 patients (subjects) (in addition to the patients to be enrolled in the main study at this site). The patients enrolled in the DH exploratory study are not considered to be part of the main study (i.e. data collected in the DH exploratory study will be analyzed separately from the data collected in the main study).

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: Tiotropium; Drug: Olodaterol; Drug: Fluticasone propionate; Drug: Salmeterol	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 302 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Double-dummy, Active-controlled, Multi-center, Parallel Group Study to Show the Superiority in Lung Function of 12 Weeks Once Daily Treatment With Orally Inhaled Tiotropium+Olodaterol Fixed Dose Combination Delivered by the Respimat® Inhaler vs. 12 Weeks Twice Daily Treatment With Fluticasone Propionate+Salmeterol Fixed Dose Combination Delivered by the Diskus® in Patients With Chronic Obstructive Pulmonary Disease (COPD) [ENERGITO® 2]
• Actual Study Start Date: Aug 14, 2017
• Actual Primary Completion Date: Apr 8, 2019
• Actual Study Completion Date: May 6, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tiotropium + Olodaterol fixed dose combination	Drug: Tiotropium; Fixed Dose Combination; Other Names: INSPIOLTO, SPIOLTO, STIOLTO, VAHELVA, YANIMO ; Drug: Olodaterol; Fixed Dose Combination; Other Names: INSPIOLTO, SPIOLTO, STIOLTO, VAHELVA, YANIMO
Active Comparator: Fluticasone propionate + Salmeterol fixed dose combination	Drug: Fluticasone propionate; Fixed Dose Combination; Drug: Salmeterol; Fixed Dose Combination

Outcome Measures

Primary Outcome Measures

1. Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 to 24 Hours (AUC0-24) Response (Change From Baseline) [L] After 12 Weeks of Treatment [1 hours (h) and 10 minutes (min) before first dose at day1 of weeks 1 for baseline.10 min before and 30 min, 1 h, 2h, 3h, 4h, 6h, 8h, 10h, 11h 50min, 12h 30 min, 13h, 14h, 22h, 23h, and 24h post morning dose at week 12.]

   Forced Expiratory Volume in one second (FEV1) Area under the Curve from 0 to 24 hours (AUC0-24) response (change from baseline) [L] after 12 weeks of treatment. FEV1 AUC0-24 was calculated as the area under the FEV1-time curve from 0-24 hours post-dose using the trapezoidal rule, divided by the duration (24 hours) and reported in liters. FEV1 AUC0-24 response (change from baseline) was defined as FEV1 AUC0-24 mius baseline FEV1.

Secondary Outcome Measures

1. Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 to 12 Hours (AUC0-12) Response (Change From Baseline) [L] After 12 Weeks of Treatment [1 hours (h) and 10 minutes (min) before first dose at day1 of weeks 1 for baseline. 10 min before and 30 min, 1 h, 2h, 3h, 4h, 6h, 8h, 10h, 11h 50min post morning dose at week 12.]

   Forced Expiratory Volume in one second (FEV1) Area under the Curve from 0 to 12 hours (AUC0-12) response (change from baseline) [L] after 12 weeks of treatment. FEV1 AUC0-12 was calculated as the area under the FEV1-time curve from 0-12 hours post-dose using the trapezoidal rule, divided by the duration (12 hours) and reported in liters. FEV1 AUC0-12 response (change from baseline) was defined as FEV1 AUC0-12 minus baseline FEV1.

2. Trough Forced Expiratory Volume in One Second (FEV1) Response (Change From Baseline) [L] After 12 Weeks Treatment [At 23 h and 24 h post dose at baseline and at 23h and 24 h post dose at week 12.]

   Trough Forced Expiratory Volume in one second (FEV1) response (change from baseline) [L] after 12 weeks treatment. Trough FEV1 was defined as the mean of the FEV1 value measured at 23 hours and at 24 hours after the trial medication administration. Through FEV1 response (change from baseline) was defined as trough FEV1 minus baseline FEV1.

3. Peak 0-3 Hours Forced Expiratory Volume in One Second (FEV1) Response (Change From Baseline) [L] After 12 Weeks Treatment [30 minutes, 1 h, 2h and 3h post dose at baseline and week 12.]

   Peak 0-3 hours Forced Expiratory Volume in one second (FEV1) response (change from baseline) [L] after 12 weeks treatment. Peak 0-3h was defined as the maximum value measured within the first three hours post doing.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• All patients must sign an informed consent consistent with FDA regulations prior to participation in the trial, which includes medication washout and restrictions.

• All patients must have a diagnosis of chronic obstructive pulmonary disease and must meet the following spirometric criteria:

-- Patients with a post-bronchodilator 30% ≤ Forced Expiratory Volume in one second (FEV1) <80% of predicted normal (European Coal and Steel Community( ECSC)); and a post-bronchodilator FEV1/Forced Vital Capacity (FVC) <70% at Visit 1

• Male or female patients, 40 years of age or older.

• Patients must be current or ex-smokers with a smoking history of more than 10 pack years. Patients who have never smoked cigarettes must be excluded.

• Patients must be able to perform, according to investigator's judgment, all trial related procedures including:

• Technically acceptable pulmonary function tests (spirometry)

• Completion of study questionnaires

• Patients must be able to inhale medication in a competent manner (in the opinion of the investigator) from the Respimat® and Diskus® inhalers and from a metered dose inhaler (MDI).

Exclusion Criteria:

• Patients with a significant disease other than Chronic Obstructive Pulmonary Disease (COPD); a significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the study, (ii) influence the results of the study, or (iii) cause concern regarding the patient's ability to participate in the study.

• Patients who have had a COPD exacerbation that required treatment with antibiotics, systemic steroids (oral or intravenous) or hospitalization in the last 3 months prior to Visit 1 and/or between Visit 1 and Visit 2.

• Patients with a history of asthma. For patients with allergic rhinitis or atopy, source documentation is required to verify that the patient does not have asthma. If a patient has a total blood eosinophil count ≥ 600/mm3, source documentation is required to verify that the increased eosinophil count is related to a nonasthmatic condition.

Patients with any of the following conditions:

• A diagnosis of thyrotoxicosis (due to the known class side effect profile of ß2-agonists).

• A diagnosis of paroxysmal tachycardia (>100 beats per minute) (due to the known class side effect profile of ß2-agonists).

• A history of myocardial infarction within 1 year of screening visit (Visit 1).

• Unstable or life-threatening cardiac arrhythmia.

• Hospitalization for heart failure within the past year.

• Known active tuberculosis.

• A malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years (patients with treated basal cell carcinoma are allowed).

• A history of life-threatening pulmonary obstruction.

• A history of cystic fibrosis.

• Clinically evident bronchiectasis.

• A history of significant alcohol or drug abuse.

• Patients who have undergone thoracotomy with pulmonary resection (patients with a history of thoracotomy for other reasons should be evaluated as per the first exclusion criterion).

• Patients being treated with oral or patch β-adrenergics.

• Patients being treated with oral corticosteroid medication within 6 weeks prior to Visit 1.

• Patients who regularly use daytime oxygen therapy for more than one hour per day and in the investigator's opinion will be unable to abstain from the use of oxygen therapy during clinic visits.

• Patients who have completed a pulmonary rehabilitation program in the six weeks prior to the screening visit (Visit 1) or patients who are currently in a pulmonary rehabilitation program.

• Patients who have taken an investigational drug within one month, six half-lives or within the wash out period (whichever is greater) prior to screening visit (Visit 1).

• Patients with known hypersensitivity to β-adrenergic drugs, BAC, EDTA, or any other component of the Respimat® inhalation solution. In addition, patients with known hypersensitivity to Lactose monohydrate (which contains milk proteins).

• Pregnant or nursing women.

• Women of childbearing potential not using a method of birth control classified at least as "acceptable". Female patients will be considered to be of childbearing potential unless surgically sterilized by hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or post-menopausal (defined as no menses for 12 months without an alternative medical cause). Tubal ligation is NOT a method of permanent sterilisation.

• Patients who have previously been randomized in this study or are currently participating in another study.

• Patients who are unable to comply with pulmonary medication restrictions prior to randomization.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Jasper Summit Research, LLC	Jasper	Alabama	United States	35501
2	Clinical Trial Connection	Flagstaff	Arizona	United States	86001
3	California Research Medical Group, Inc.	Fullerton	California	United States	92835
4	Allergy and Asthma Specialists Medical Group	Huntington Beach	California	United States	92647
5	California Medical Research Associates Inc.	Northridge	California	United States	91324
6	IMMUNOe Research Centers	Centennial	Colorado	United States	80112
7	Clinical Research of West Florida, Inc.	Clearwater	Florida	United States	33765
8	Bioclinica Research	Orlando	Florida	United States	32806
9	IMIC, Inc	Palmetto Bay	Florida	United States	33157
10	Clinical Research of West Florida, Inc.	Tampa	Florida	United States	33603
11	Duluth Biomedical Research	Duluth	Georgia	United States	30096
12	DC Pulmonary Medicine	Marietta	Georgia	United States	30060
13	New Orleans Center for Clinical Research	New Orleans	Louisiana	United States	70119
14	Johns Hopkins Hospital	Baltimore	Maryland	United States	21224
15	Pulmonary Rsrch Inst of SE MI	Farmington Hills	Michigan	United States	48336
16	Minnesota Lung Center and Sleep Institute	Edina	Minnesota	United States	55435
17	Clinical Research Institute Inc	Minneapolis	Minnesota	United States	55402
18	Minnesota Lung Center	Woodbury	Minnesota	United States	55125
19	The Clinical Research Center, LLC	Saint Louis	Missouri	United States	63141
20	Northwell Health	New Hyde Park	New York	United States	11040
21	Gastonia Pharmaceutical Research, LLC	Gastonia	North Carolina	United States	28054
22	Hendersonville Pharmaceutical Research	Hendersonville	North Carolina	United States	28739
23	North Carolina Clinical Research	Raleigh	North Carolina	United States	27607
24	Southeastern Research Center	Winston-Salem	North Carolina	United States	27103
25	Bernstein Clinical Rsrch Ctr	Cincinnati	Ohio	United States	45231
26	Aventiv Research Inc.	Columbus	Ohio	United States	43213
27	Aventiv Research Inc.	Dublin	Ohio	United States	43016
28	OK Clinical Research, LLC	Edmond	Oklahoma	United States	73034
29	IPS Research Company	Oklahoma City	Oklahoma	United States	73103
30	Arcuri Clinical Research, LLC	Philadelphia	Pennsylvania	United States	19142
31	Lowcountry Lung and Critical Care	Charleston	South Carolina	United States	29406
32	VitaLink Research - Easley	Easley	South Carolina	United States	29640
33	VitaLink Research -Gaffney	Gaffney	South Carolina	United States	29340
34	VitaLink Research	Greenville	South Carolina	United States	29615
35	Vita Link Research- Rock Hill	Rock Hill	South Carolina	United States	29732
36	South Carolina Pharma Rsrch	Spartanburg	South Carolina	United States	29303
37	Spartanburg Medical Research	Spartanburg	South Carolina	United States	29303
38	Centex Studies, Inc.	Houston	Texas	United States	77058
39	Advanced Clinical Research Associates	Plano	Texas	United States	75093
40	Sherman Clinical Research	Sherman	Texas	United States	75092
41	DM Clinical Research	Tomball	Texas	United States	77375
42	Pulmonary Associates of Richmond, Inc.	Richmond	Virginia	United States	23225
43	Pulmonary Associates of Richmond, Inc.	Richmond	Virginia	United States	23229
44	MultiCare Institute for Research and Innovation	Tacoma	Washington	United States	98405
45	Morgantown Pulmonary ClinRsrch	Morgantown	West Virginia	United States	26505

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

None specified.

Study Documents (Full-Text)

• Statistical Analysis Plan - May 14, 2018
• Study Protocol - Mar 6, 2018

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT03240575
• Other Study ID Numbers: 1237-0063
• First Posted: Aug 7, 2017
• Last Update Posted: Apr 16, 2020
• Last Verified: Apr 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Fluticasone; Xhance; Tiotropium Bromide; Salmeterol Xinafoate; Olodaterol

Study Results

Participant Flow

Recruitment Details	The study compares treatment tiotropium+olodaterol (5μg/5μg) once daily FDC to Fluticasone propionate+Salmeterol (250μg/50μg) twice daily FDC over 12 weeks in patients with COPD. A Digital Health (DH)-study has been integrated a site specific study. The patients enrolled in the DH-study are not considered to be part of the main study.
Pre-assignment Detail	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 non of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

Arm/Group Title	Tiotropium+Olodaterol (5μg/5μg) - Main Study	Fluticasone Propionate+Salmeterol (500μg/100μg) - Main Study	Tiotropium+Olodaterol (5μg/5μg) - DH-study	Fluticasone Propionate+Salmeterol (500μg/100μg) - DH-study
Arm/Group Description	2 inhalations of fixed dose combination (FDC) of 2.5 microgram (μg) tiotropium and 2.5μg olodaterol (T+O) (total 5μg/5μg) were administered orally once daily in the morning via RESPIMAT inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the main study were not eligible to participate in the DH study.	2 inhalations of fixed dose combination (FDC) of 250μg fluticasone propionate and 50μg salmeterol (F+S) (total 500μg/100μg) were administered orally twice daily in the morning and in the evening (12h after morning dose) via Diskus inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the main study were not eligible to participate in the DH study.	2 inhalations of fixed dose combination (FDC) of 2.5 microgram (μg) tiotropium and 2.5μg olodaterol (T+O) (total 5μg/5μg) were administered orally once daily in the morning via RESPIMAT inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the DH study were not eligible to participate in the main study.	2 inhalations of fixed dose combination (FDC) of 250μg fluticasone propionate and 50μg salmeterol (F+S) (total 500μg/100μg) were administered orally twice daily in the morning and in the evening (12h after morning dose) via Diskus inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the DH study were not eligible to participate in the main study.
Period Title: Overall Study
STARTED	146	145	6	5
COMPLETED	144	131	6	3
NOT COMPLETED	2	14	0	2

Baseline Characteristics

Arm/Group Title	Tiotropium+Olodaterol (5μg/5μg) - Main Study	Fluticasone Propionate+Salmeterol (500μg/100μg) - Main Study	Tiotropium+Olodaterol (5μg/5μg) - DH-study	Fluticasone Propionate+Salmeterol (500μg/100μg) - DH-study	Total
Arm/Group Description	2 inhalations of fixed dose combination (FDC) of 2.5 microgram (μg) tiotropium and 2.5μg olodaterol (T+O) (total 5μg/5μg) were administered orally once daily in the morning via RESPIMAT inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the main study were not eligible to participate in the DH study.	2 inhalations of fixed dose combination (FDC) of 250μg fluticasone propionate and 50μg salmeterol (F+S) (total 500μg/100μg) were administered orally twice daily in the morning and in the evening (12h after morning dose) via Diskus inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the main study were not eligible to participate in the DH study.	2 inhalations of fixed dose combination (FDC) of 2.5 microgram (μg) tiotropium and 2.5μg olodaterol (T+O) (total 5μg/5μg) were administered orally once daily in the morning via RESPIMAT inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the DH study were not eligible to participate in the main study.	2 inhalations of fixed dose combination (FDC) of 250μg fluticasone propionate and 50μg salmeterol (F+S) (total 500μg/100μg) were administered orally twice daily in the morning and in the evening (12h after morning dose) via Diskus inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the DH study were not eligible to participate in the main study.	Total of all reporting groups
Overall Participants	146	145	6	5	302
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.95 (8.32)	64.74 (7.33)	71.00 (4.77)	60.00 (4.58)	63.44 (7.81)
Sex: Female, Male (Count of Participants)
Female	72 49.3%	62 42.8%	1 16.7%	4 80%	139 46%
Male	74 50.7%	83 57.2%	5 83.3%	1 20%	163 54%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 1.4%	2 1.4%	0 0%	0 0%	4 1.3%
Not Hispanic or Latino	144 98.6%	143 98.6%	6 100%	5 100%	298 98.7%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	1 0.7%	0 0%	0 0%	1 0.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	14 9.6%	16 11%	0 0%	0 0%	30 9.9%
White	132 90.4%	127 87.6%	6 100%	5 100%	270 89.4%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 0.7%	0 0%	0 0%	1 0.3%

Outcome Measures

1. Primary Outcome

Title	Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 to 24 Hours (AUC0-24) Response (Change From Baseline) [L] After 12 Weeks of Treatment
Description	Forced Expiratory Volume in one second (FEV1) Area under the Curve from 0 to 24 hours (AUC0-24) response (change from baseline) [L] after 12 weeks of treatment. FEV1 AUC0-24 was calculated as the area under the FEV1-time curve from 0-24 hours post-dose using the trapezoidal rule, divided by the duration (24 hours) and reported in liters. FEV1 AUC0-24 response (change from baseline) was defined as FEV1 AUC0-24 mius baseline FEV1.
Time Frame	1 hours (h) and 10 minutes (min) before first dose at day1 of weeks 1 for baseline.10 min before and 30 min, 1 h, 2h, 3h, 4h, 6h, 8h, 10h, 11h 50min, 12h 30 min, 13h, 14h, 22h, 23h, and 24h post morning dose at week 12.

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): FAS included all patients in the TS who had baseline and at least one post-baseline measurement for at least one efficacy parameter. The Mixed-effects model repeated measurement (MMRM) model defined the participants who contributed to the model.

Arm/Group Title	Tiotropium+Olodaterol (5μg/5μg) - Main Study	Fluticasone Propionate+Salmeterol (500μg/100μg) - Main Study	Tiotropium+Olodaterol (5μg/5μg) - DH-study	Fluticasone Propionate+Salmeterol (500μg/100μg) - DH-study
Arm/Group Description	2 inhalations of fixed dose combination (FDC) of 2.5 microgram (μg) tiotropium and 2.5μg olodaterol (T+O) (total 5μg/5μg) were administered orally once daily in the morning via RESPIMAT inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the main study were not eligible to participate in the DH study.	2 inhalations of fixed dose combination (FDC) of 250μg fluticasone propionate and 50μg salmeterol (F+S) (total 500μg/100μg) were administered orally twice daily in the morning and in the evening (12h after morning dose) via Diskus inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the main study were not eligible to participate in the DH study.	2 inhalations of fixed dose combination (FDC) of 2.5 microgram (μg) tiotropium and 2.5μg olodaterol (T+O) (total 5μg/5μg) were administered orally once daily in the morning via RESPIMAT inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the DH study were not eligible to participate in the main study.	2 inhalations of fixed dose combination (FDC) of 250μg fluticasone propionate and 50μg salmeterol (F+S) (total 500μg/100μg) were administered orally twice daily in the morning and in the evening (12h after morning dose) via Diskus inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the DH study were not eligible to participate in the main study.
Measure Participants	145	138	6	4
Mean (Standard Error) [Litre*hours (L*h)]	0.174 (0.019)	0.122 (0.019)	NA (NA)	NA (NA)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium+Olodaterol (5μg/5μg) - Main Study, Fluticasone Propionate+Salmeterol (500μg/100μg) - Main Study
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0543
	Comments
	Method	Mixed-effects model repeated measures
	Comments	Treatment, visit and treatment by visit interaction as fixed effects, and baseline as well as baseline by visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.052
	Confidence Interval	(2-Sided) 95%; -0.001 to 0.105
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.027
	Estimation Comments

2. Secondary Outcome

Title	Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 to 12 Hours (AUC0-12) Response (Change From Baseline) [L] After 12 Weeks of Treatment
Description	Forced Expiratory Volume in one second (FEV1) Area under the Curve from 0 to 12 hours (AUC0-12) response (change from baseline) [L] after 12 weeks of treatment. FEV1 AUC0-12 was calculated as the area under the FEV1-time curve from 0-12 hours post-dose using the trapezoidal rule, divided by the duration (12 hours) and reported in liters. FEV1 AUC0-12 response (change from baseline) was defined as FEV1 AUC0-12 minus baseline FEV1.
Time Frame	1 hours (h) and 10 minutes (min) before first dose at day1 of weeks 1 for baseline. 10 min before and 30 min, 1 h, 2h, 3h, 4h, 6h, 8h, 10h, 11h 50min post morning dose at week 12.

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): FAS included all patients in the TS who had baseline and at least one post-baseline measurement for at least one efficacy parameter. The Mixed-effects model repeated measurement (MMRM) model defined the participants who contributed to the model.

Arm/Group Title	Tiotropium+Olodaterol (5μg/5μg) - Main Study	Fluticasone Propionate+Salmeterol (500μg/100μg) - Main Study	Tiotropium+Olodaterol (5μg/5μg) - DH-study	Fluticasone Propionate+Salmeterol (500μg/100μg) - DH-study
Arm/Group Description	2 inhalations of fixed dose combination (FDC) of 2.5 microgram (μg) tiotropium and 2.5μg olodaterol (T+O) (total 5μg/5μg) were administered orally once daily in the morning via RESPIMAT inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the main study were not eligible to participate in the DH study.	2 inhalations of fixed dose combination (FDC) of 250μg fluticasone propionate and 50μg salmeterol (F+S) (total 500μg/100μg) were administered orally twice daily in the morning and in the evening (12h after morning dose) via Diskus inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the main study were not eligible to participate in the DH study.	2 inhalations of fixed dose combination (FDC) of 2.5 microgram (μg) tiotropium and 2.5μg olodaterol (T+O) (total 5μg/5μg) were administered orally once daily in the morning via RESPIMAT inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the DH study were not eligible to participate in the main study.	2 inhalations of fixed dose combination (FDC) of 250μg fluticasone propionate and 50μg salmeterol (F+S) (total 500μg/100μg) were administered orally twice daily in the morning and in the evening (12h after morning dose) via Diskus inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the DH study were not eligible to participate in the main study.
Measure Participants	145	138	6	3
Mean (Standard Error) [Litre*hours (L*h)]	0.237 (0.019)	0.147 (0.020)	NA (NA)	NA (NA)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium+Olodaterol (5μg/5μg) - Main Study, Fluticasone Propionate+Salmeterol (500μg/100μg) - Main Study
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0011
	Comments
	Method	Mixed-effects model repeated measures
	Comments	Treatment, visit and treatment by visit interaction as fixed effects, and baseline as well as baseline by visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.090
	Confidence Interval	(2-Sided) 95%; 0.037 to 0.144
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.027
	Estimation Comments

3. Secondary Outcome

Title	Trough Forced Expiratory Volume in One Second (FEV1) Response (Change From Baseline) [L] After 12 Weeks Treatment
Description	Trough Forced Expiratory Volume in one second (FEV1) response (change from baseline) [L] after 12 weeks treatment. Trough FEV1 was defined as the mean of the FEV1 value measured at 23 hours and at 24 hours after the trial medication administration. Through FEV1 response (change from baseline) was defined as trough FEV1 minus baseline FEV1.
Time Frame	At 23 h and 24 h post dose at baseline and at 23h and 24 h post dose at week 12.

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): FAS included all patients in the TS who had baseline and at least one post-baseline measurement for at least one efficacy parameter. The Mixed-effects model repeated measurement (MMRM) model defined the participants who contributed to the model.

Arm/Group Title	Tiotropium+Olodaterol (5μg/5μg) - Main Study	Fluticasone Propionate+Salmeterol (500μg/100μg) - Main Study	Tiotropium+Olodaterol (5μg/5μg) - DH-study	Fluticasone Propionate+Salmeterol (500μg/100μg) - DH-study
Arm/Group Description	2 inhalations of fixed dose combination (FDC) of 2.5 microgram (μg) tiotropium and 2.5μg olodaterol (T+O) (total 5μg/5μg) were administered orally once daily in the morning via RESPIMAT inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the main study were not eligible to participate in the DH study.	2 inhalations of fixed dose combination (FDC) of 250μg fluticasone propionate and 50μg salmeterol (F+S) (total 500μg/100μg) were administered orally twice daily in the morning and in the evening (12h after morning dose) via Diskus inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the main study were not eligible to participate in the DH study.	2 inhalations of fixed dose combination (FDC) of 2.5 microgram (μg) tiotropium and 2.5μg olodaterol (T+O) (total 5μg/5μg) were administered orally once daily in the morning via RESPIMAT inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the DH study were not eligible to participate in the main study.	2 inhalations of fixed dose combination (FDC) of 250μg fluticasone propionate and 50μg salmeterol (F+S) (total 500μg/100μg) were administered orally twice daily in the morning and in the evening (12h after morning dose) via Diskus inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the DH study were not eligible to participate in the main study.
Measure Participants	145	138	6	3
Mean (Standard Error) [Litre (L)]	0.118 (0.019)	0.114 (0.019)	NA (NA)	NA (NA)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium+Olodaterol (5μg/5μg) - Main Study, Fluticasone Propionate+Salmeterol (500μg/100μg) - Main Study
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8593
	Comments
	Method	Mixed-effects model repeated measures
	Comments	Treatment, visit and treatment by visit interaction as fixed effects, and baseline as well as baseline by visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.005
	Confidence Interval	(2-Sided) 95%; -0.048 to 0.058
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.027
	Estimation Comments

4. Secondary Outcome

Title	Peak 0-3 Hours Forced Expiratory Volume in One Second (FEV1) Response (Change From Baseline) [L] After 12 Weeks Treatment
Description	Peak 0-3 hours Forced Expiratory Volume in one second (FEV1) response (change from baseline) [L] after 12 weeks treatment. Peak 0-3h was defined as the maximum value measured within the first three hours post doing.
Time Frame	30 minutes, 1 h, 2h and 3h post dose at baseline and week 12.

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): FAS included all patients in the TS who had baseline and at least one post-baseline measurement for at least one efficacy parameter. The Mixed-effects model repeated measurement (MMRM) model defined the participants who contributed to the model.

Arm/Group Title	Tiotropium+Olodaterol (5μg/5μg) - Main Study	Fluticasone Propionate+Salmeterol (500μg/100μg) - Main Study	Tiotropium+Olodaterol (5μg/5μg) - DH-study	Fluticasone Propionate+Salmeterol (500μg/100μg) - DH-study
Arm/Group Description	2 inhalations of fixed dose combination (FDC) of 2.5 microgram (μg) tiotropium and 2.5μg olodaterol (T+O) (total 5μg/5μg) were administered orally once daily in the morning via RESPIMAT inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the main study were not eligible to participate in the DH study.	2 inhalations of fixed dose combination (FDC) of 250μg fluticasone propionate and 50μg salmeterol (F+S) (total 500μg/100μg) were administered orally twice daily in the morning and in the evening (12h after morning dose) via Diskus inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the main study were not eligible to participate in the DH study.	2 inhalations of fixed dose combination (FDC) of 2.5 microgram (μg) tiotropium and 2.5μg olodaterol (T+O) (total 5μg/5μg) were administered orally once daily in the morning via RESPIMAT inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the DH study were not eligible to participate in the main study.	2 inhalations of fixed dose combination (FDC) of 250μg fluticasone propionate and 50μg salmeterol (F+S) (total 500μg/100μg) were administered orally twice daily in the morning and in the evening (12h after morning dose) via Diskus inhaler over a treatment period of 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients enrolled in the DH study were not eligible to participate in the main study.
Measure Participants	144	138	6	3
Mean (Standard Error) [Litre (L)]	0.341 (0.021)	0.243 (0.021)	NA (NA)	NA (NA)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium+Olodaterol (5μg/5μg) - Main Study, Fluticasone Propionate+Salmeterol (500μg/100μg) - Main Study
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0010
	Comments
	Method	Mixed-effects model repeated measures
	Comments	Treatment, visit and treatment by visit interaction as fixed effects, and baseline as well as baseline by visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.098
	Confidence Interval	(2-Sided) 95%; 0.040 to 0.156
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.029
	Estimation Comments

Adverse Events

Time Frame	From screening visit (28 days before treatment start) until end of follow up period (up to 105 days).
Adverse Event Reporting Description	Safety analysis is reported for TS of both studies. Participants of each particular treatment arm in main and DH-study were combined in one particular treatment arm for adverse event reporting.
Arm/Group Title	Tiotropium+Olodaterol (5μg/5μg)		Fluticasone Propionate+Salmeterol (500μg/100μg)
Arm/Group Description	Once daily treatment of orally inhaled tiotropium + olodaterol (T+O) (5μg/5μg) fixed dose combination (FDC) over 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients from Main and DH-study combined.		Twice daily treatment of orally inhaled fluticasone propionate + salmeterol (F+S) (250μg/50μg) fixed dose combination (FDC) over 12 weeks in patients with Chronic Obstructive Pulmonary Disease (COPD). Patients from Main and DH-study combined.
All Cause Mortality
	Tiotropium+Olodaterol (5μg/5μg)		Fluticasone Propionate+Salmeterol (500μg/100μg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/152 (0%)		0/150 (0%)
Serious Adverse Events
	Tiotropium+Olodaterol (5μg/5μg)		Fluticasone Propionate+Salmeterol (500μg/100μg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/152 (3.9%)		3/150 (2%)
Cardiac disorders
Acute myocardial infarction	1/152 (0.7%)		0/150 (0%)
Stress cardiomyopathy	1/152 (0.7%)		0/150 (0%)
Infections and infestations
Pneumonia	1/152 (0.7%)		0/150 (0%)
Sepsis	1/152 (0.7%)		0/150 (0%)
Injury, poisoning and procedural complications
Fall	0/152 (0%)		1/150 (0.7%)
Upper limb fracture	0/152 (0%)		1/150 (0.7%)
Musculoskeletal and connective tissue disorders
Cervical spinal stenosis	1/152 (0.7%)		0/150 (0%)
Intervertebral disc compression	1/152 (0.7%)		0/150 (0%)
Muscle spasms	1/152 (0.7%)		0/150 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/152 (0.7%)		0/150 (0%)
Squamous cell carcinoma of the oral cavity	0/152 (0%)		1/150 (0.7%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/152 (0.7%)		0/150 (0%)
Chronic obstructive pulmonary disease	3/152 (2%)		1/150 (0.7%)
Respiratory failure	1/152 (0.7%)		0/150 (0%)
Other (Not Including Serious) Adverse Events
	Tiotropium+Olodaterol (5μg/5μg)		Fluticasone Propionate+Salmeterol (500μg/100μg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/152 (5.3%)		15/150 (10%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	8/152 (5.3%)		15/150 (10%)

Limitations/Caveats

The objectives of the DH-study were exploratory. The DH-study aimed to gather information and experience about the feasibility of a remote trial in this indication, and was not designed to support treatment comparisons.

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.