A Study to Test the Combination of Tiotropium and Olodaterol Using the Respimat® Inhaler in People With Chronic Obstructive Pulmonary Disease (COPD) Who Have Different Abilities to Inhale

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04223843
• Collaborator: (none)
• Enrollment: 213
• Locations: 26
• Arms: 2
• Actual Duration (Months): 8.7
• Patients Per Site: 8.2
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

To demonstrate the efficacy of inhaled tiotropium + olodaterol via Respimat® on lung function in patients with moderate to severe Chronic Obstructive Pulmonary Disease (COPD) with optimal and sub-optimal Peak Inspiratory Flow Rate (PIFR). Disease severity (moderate to severe) is based on the Global Initiative for Chronic Lung Disease (GOLD) guidelines (GOLD 2 - 3)

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: Tiotropium + olodaterol; Drug: Placebo	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 213 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled, Multi-center, Parallel Group Study to Compare the Efficacy of Inhaled Tiotropium + Olodaterol, Fixed Dose Combination (5 mcg/5mcg) vs. Placebo Delivered by Respimat Inhaler in Patients With Moderate to Severe COPD, Stratified by Peak Inspiratory Flow Rate [TRONARTO].
• Actual Study Start Date: Jan 8, 2020
• Actual Primary Completion Date: Sep 7, 2020
• Actual Study Completion Date: Sep 29, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Active Arm Tiotropium + Olodaterol Fixed Dose Combination (FDC) via Respimat	Drug: Tiotropium + olodaterol; Oral Inhalation
Placebo Comparator: Placebo Arm Matching placebo via Respimat	Drug: Placebo; Oral Inhalation

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 to 3 Hours (AUC0-3h) After 4 Weeks of Treatment. [At baseline and at week 4: 10 minutes (min) prior and 5 min, 15 min, 30 min and 1 hour (h), 2h and 3h after drug administration, respectively.]

   FEV1 AUC0-3h was calculated as the area under the FEV1-time curve from 0 to 3h post-dose using the trapezoidal rule, divided by the duration (3h) to report in liters. Mean is adjusted mean. A hierarchical testing procedure was used to test the primary endpoint. Each of the tests were considered confirmatory only if all previous tests were successful.

Secondary Outcome Measures

1. Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) After 4 Weeks of Treatment [At baseline and at week 4.]

   Change from baseline in trough Forced Expiratory Volume in one second (FEV1) after 4 weeks of treatment.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Signed and dated written informed consent in accordance with International Council on Harmonisation Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial.

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

• All patients must have a diagnosis of chronic obstructive pulmonary disease and must meet the following spirometric criteria: patients with a post-bronchodilator Forced Expiratory Volume in one second (FEV1) >30% and <80% of predicted normal (European Coal and Steel Community (ECSC), [R94-1408]); and a postbronchodilator FEV1/ Functional Residual Capacity (FVC) <70%, at the screening visit.

• Patients must be current or ex-smokers with a smoking history of more than 10 pack years

• Patients should meet the peak inspiratory flow rate criteria (optimal or sub-optimal) at the time of randomization depending on which strata is available for inclusion in the study.

• Women of childbearing potential must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information.

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

• Technically acceptable pulmonary function tests (spirometry)

• Use of In-Check DIAL G16 device to measure peak inspiratory flow rate.

• Inhale medication in a competent manner (in the opinion of the investigator) from the Respimat® device

• Perform technically acceptable body plethysmography measurements. This is applicable only to patients who will consent to the optional trial procedure at the selected sites.

Exclusion Criteria:

• Patients with a significant disease other than chronic obstructive pulmonary disease; a significant disease defined as a disease which, in the opinion of the investigator, and referring to the warnings to be observed as quoted in the locally applicable SmPC or prescribing information, could (i) put the patient at risk because of participation in the trial, (ii) influence the results of the trial, or (iii) cause concern regarding the patient's ability to participate in the trial.

• Patients who have had a chronic obstructive pulmonary disease exacerbation that required treatment with antibiotics, systemic steroids (oral or intravenous) or hospitalization in the 6 weeks prior to screening visit or during the screening period.

• Patients who experienced two or more moderate chronic obstructive pulmonary disease exacerbations (exacerbation that required treatment with antibiotics and/or oral corticosteroids), or one or more exacerbation leading to hospitalization within a year prior to visit 1.

• 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.

• Patients taking inhaled corticosteroids (including combinations, e.g. inhaled corticosteroids / Long-Acting β2-agonist) in the 6 months prior to screening visit.

• Patients being treated with oral corticosteroid medication due to reasons other than chronic obstructive pulmonary disease exacerbation within 6 weeks prior to the screening visit.

• Patients who have completed a pulmonary rehabilitation program in the 6 weeks prior to screening visit or patients who are currently in a pulmonary rehabilitation program.

• Further criteria apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	SEC Lung	Andalusia	Alabama	United States	36420
2	Jasper Summit Research, LLC	Jasper	Alabama	United States	35501
3	Meris Clinical Research	Brandon	Florida	United States	33511
4	Clinical Research of West Florida, Inc.	Clearwater	Florida	United States	33765
5	Clinical Research Specialists LLC	Kissimmee	Florida	United States	34746
6	Clinical Research of West Florida, Inc.	Tampa	Florida	United States	33606
7	Best Clinical Trials, LLC	New Orleans	Louisiana	United States	70115
8	Infinity Medical Research	North Dartmouth	Massachusetts	United States	02747
9	Pulmonary Rsrch Inst of SE MI	Farmington Hills	Michigan	United States	48152
10	Minnesota Lung Center and Sleep Institute	Edina	Minnesota	United States	55435
11	Minnesota Lung Center	Woodbury	Minnesota	United States	55125
12	Valley Regional Hospital	Claremont	New Hampshire	United States	03743
13	CHEAR Center LLC	Bronx	New York	United States	10455
14	North Carolina Clinical Research	Raleigh	North Carolina	United States	27607
15	Southeastern Research Center	Winston-Salem	North Carolina	United States	27103
16	Bernstein Clinical Rsrch Ctr	Cincinnati	Ohio	United States	45231
17	Lowcountry Lung and Critical Care	Charleston	South Carolina	United States	29406
18	Carolina Medical Research	Clinton	South Carolina	United States	29325
19	VitaLink Research -Gaffney	Gaffney	South Carolina	United States	29340
20	Vitalink Research - Spartansburg	Spartanburg	South Carolina	United States	29303
21	Diagnostics Research Group	San Antonio	Texas	United States	78229
22	Klinische Forschung Berlin GbR	Berlin		Germany	10787
23	IKF Pneumologie GmbH & Co. KG	Frankfurt		Germany	60596
24	Pneumologisches Forschungsinstitut an der LungenClinic Grosshansdorf GmbH	Grosshansdorf		Germany	22927
25	Hamburger Institut für Therapieforschung GmbH (HIT)	Hamburg		Germany	20354
26	KLB Gesundheitsforschung Lübeck GmbH	Lübeck		Germany	23552

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jan 28, 2020
• Statistical Analysis Plan - Sep 29, 2020

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT04223843
• Other Study ID Numbers: 1237-0095; 2019-001719-21
• First Posted: Jan 10, 2020
• Last Update Posted: Nov 18, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Lung Diseases; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Olodaterol

Study Results

Participant Flow

Recruitment Details	A randomised, double-blind, placebo-controlled trial to demonstrate the efficacy of 5µg/5µg inhaled tiotropium + olodaterol (Tio+Olo) via Respimat® on lung function in patients with moderate to severe chronic obstructive pulmonary disease (COPD) with optimal and sub-optimal peak inspiratory flow rate (PIFR).
Pre-assignment Detail	Only patients that met all inclusion and none of the exclusion criteria were included in this trial. Prior to the initiation of any trial-related procedure, all patients were informed about the trial verbally and in writing by the investigator. Each patient signed and dated an Informed Consent Form (ICF) according to the local regulatory and legal requirements.

Arm/Group Title	Tio+Olo (5μg/5μg) - Sub-optimal PIFR	Matching Placebo - Sub-optimal PIFR	Tio+Olo (5μg/5μg ) - Optimal PIFR	Matching Placebo - Optimal PIFR
Arm/Group Description	A fixed dose combination of 5 microgram (μg)/5μg (two times 2.5µg/2.5µg) tiotropium + olodaterol (Tio+Olo) inhalation solution was administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (<60 Liter(L)/minute (min)) over a 4-week treatment period.	2 inhalation solutions of matching placebo were administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (<60 L/min) over a 4-week treatment period.	A fixed dose combination of 5μg/5μg (two times 2.5µg/2.5µg) tiotropium + olodaterol (Tio+Olo) inhalation solution was administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (≥60 L/min) over a 4-week treatment period.	2 inhalation solutions of matching placebo were administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with optimal peak inspiratory flow rate (PIFR) (≥60 L/min) over a 4-week treatment period.
Period Title: Overall Study
STARTED	55	55	51	52
COMPLETED	55	55	51	52
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Tio+Olo (5μg/5μg) - Sub-optimal PIFR	Matching Placebo - Sub-optimal PIFR	Tio+Olo (5μg/5μg ) - Optimal PIFR	Matching Placebo - Optimal PIFR	Total
Arm/Group Description	A fixed dose combination of 5 microgram (μg)/5μg (two times 2.5µg/2.5µg) tiotropium + olodaterol (Tio+Olo) inhalation solution was administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (<60 Liter(L)/minute (min)) over a 4-week treatment period.	2 inhalation solutions of matching placebo were administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (<60 L/min) over a 4-week treatment period.	A fixed dose combination of 5μg/5μg (two times 2.5µg/2.5µg) tiotropium + olodaterol (Tio+Olo) inhalation solution was administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (≥60 L/min) over a 4-week treatment period.	2 inhalation solutions of matching placebo were administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with optimal peak inspiratory flow rate (PIFR) (≥60 L/min) over a 4-week treatment period.	Total of all reporting groups
Overall Participants	55	55	51	52	213
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	64 (9.79)	67.05 (7.54)	62.80 (7.48)	65.88 (7.43)	64.96 (8.25)
Sex: Female, Male (Count of Participants)
Female	28 50.9%	37 67.3%	24 47.1%	20 38.5%	109 51.2%
Male	27 49.1%	18 32.7%	27 52.9%	32 61.5%	104 48.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 3.6%	1 1.8%	0 0%	0 0%	3 1.4%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	2 3.6%	3 5.5%	1 2%	0 0%	6 2.8%
White	51 92.7%	51 92.7%	50 98%	51 98.1%	203 95.3%
More than one race	0 0%	0 0%	0 0%	1 1.9%	1 0.5%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Forced Expiratory Volume in one second (FEV1) area under the curve from 0 to 3 hours (AUC0-3h) (Liter (L)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Liter (L)]	1.224 (0.060)	1.277 (0.079)	1.388 (0.070)	1.523 (0.074)	1.324 (0.467)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 to 3 Hours (AUC0-3h) After 4 Weeks of Treatment.
Description	FEV1 AUC0-3h was calculated as the area under the FEV1-time curve from 0 to 3h post-dose using the trapezoidal rule, divided by the duration (3h) to report in liters. Mean is adjusted mean. A hierarchical testing procedure was used to test the primary endpoint. Each of the tests were considered confirmatory only if all previous tests were successful.
Time Frame	At baseline and at week 4: 10 minutes (min) prior and 5 min, 15 min, 30 min and 1 hour (h), 2h and 3h after drug administration, respectively.

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): This patient set was nested within the TS and included all patients who had a baseline and at least 1 post-baseline measurement for at least 1 efficacy endpoint. Only patients with non-missing endpoint results were included.

Arm/Group Title	Tio+Olo (5μg/5μg) - Sub-optimal PIFR	Matching Placebo - Sub-optimal PIFR	Tio+Olo (5μg/5μg ) - Optimal PIFR	Matching Placebo - Optimal PIFR
Arm/Group Description	A fixed dose combination of 5 microgram (μg)/5μg (two times 2.5µg/2.5µg) tiotropium + olodaterol (Tio+Olo) inhalation solution was administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (<60 Liter(L)/minute (min)) over a 4-week treatment period.	2 inhalation solutions of matching placebo were administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (<60 L/min) over a 4-week treatment period.	A fixed dose combination of 5μg/5μg (two times 2.5µg/2.5µg) tiotropium + olodaterol (Tio+Olo) inhalation solution was administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (≥60 L/min) over a 4-week treatment period.	2 inhalation solutions of matching placebo were administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with optimal peak inspiratory flow rate (PIFR) (≥60 L/min) over a 4-week treatment period.
Measure Participants	43	47	44	47
Mean (Standard Error) [Liter (L)]	0.250 (0.033)	-0.086 (0.031)	0.333 (0.032)	0.012 (0.031)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo (5μg/5μg) - Sub-optimal PIFR, Matching Placebo - Sub-optimal PIFR
	Comments	H0: There is no difference in the mean FEV1 AUC0-3 change from baseline between Tio+Olo and matching placebo.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	Model included fixed categorical effects of treatment and the fixed continous effect of baseline FEV1 AUC0-3.
Method of Estimation	Estimation Parameter	Difference of adjusted means
	Estimated Value	0.336
	Confidence Interval	(2-Sided) 95%; 0.246 to 0.425
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.045
	Estimation Comments	Difference = (Tio+Olo) - (Placebo)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo (5μg/5μg ) - Optimal PIFR, Matching Placebo - Optimal PIFR
	Comments	H0: There is no difference in the mean FEV1 AUC0-3h change from baseline between Tio+Olo and matching placebo.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	Model included the fixed categorical effect of treatment and the fixed continuous effect of baseline FEV1 AUC0-3h.
Method of Estimation	Estimation Parameter	Difference of adjusted means
	Estimated Value	0.321
	Confidence Interval	(2-Sided) 95%; 0.233 to 0.409
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.044
	Estimation Comments	Difference = (Tio+Olo) - (Placebo)

2. Secondary Outcome

Title	Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) After 4 Weeks of Treatment
Description	Change from baseline in trough Forced Expiratory Volume in one second (FEV1) after 4 weeks of treatment.
Time Frame	At baseline and at week 4.

Outcome Measure Data

Analysis Population Description

FAS: This patient set was nested within the TS and included all patients who had a baseline and at least 1 post-baseline measurement for at least 1 efficacy endpoint. Only patients with non-missing endpoint results were included.

Arm/Group Title	Tio+Olo (5μg/5μg) - Sub-optimal PIFR	Matching Placebo - Sub-optimal PIFR	Tio+Olo (5μg/5μg ) - Optimal PIFR	Matching Placebo - Optimal PIFR
Arm/Group Description	A fixed dose combination of 5 microgram (μg)/5μg (two times 2.5µg/2.5µg) tiotropium + olodaterol (Tio+Olo) inhalation solution was administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (<60 Liter(L)/minute (min)) over a 4-week treatment period.	2 inhalation solutions of matching placebo were administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (<60 L/min) over a 4-week treatment period.	A fixed dose combination of 5μg/5μg (two times 2.5µg/2.5µg) tiotropium + olodaterol (Tio+Olo) inhalation solution was administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (≥60 L/min) over a 4-week treatment period.	2 inhalation solutions of matching placebo were administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with optimal peak inspiratory flow rate (PIFR) (≥60 L/min) over a 4-week treatment period.
Measure Participants	50	52	47	50
Mean (Standard Error) [Liter]	0.095 (0.031)	-0.106 (0.030)	0.177 (0.030)	-0.040 (0.029)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo (5μg/5μg) - Sub-optimal PIFR, Matching Placebo - Sub-optimal PIFR
	Comments	H0: There is no difference in the mean trough FEV1 change from baseline between Tio+Olo and matching placebo.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed model with repeated measures including fixed categorial effect of treatment at each visit and fixed continuous effect of baseline at each visit.
Method of Estimation	Estimation Parameter	Difference of adjusted means
	Estimated Value	0.201
	Confidence Interval	(2-Sided) 95%; 0.117 to 0.286
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.043
	Estimation Comments	Difference = (Tio+Olo) - (Placebo)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tio+Olo (5μg/5μg ) - Optimal PIFR, Matching Placebo - Optimal PIFR
	Comments	H0: There is no difference in the mean trough FEV1 change from baseline between Tio+Olo and matching placebo.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed model with repeated measures including fixed categorial effect of treatment at each visit and fixed continuous effect of baseline at each visit.
Method of Estimation	Estimation Parameter	Difference of adjusted means
	Estimated Value	0.217
	Confidence Interval	(2-Sided) 95%; 0.135 to 0.299
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.041
	Estimation Comments	Difference = (Tio+Olo) - (Placebo)

Adverse Events

Time Frame	From first intake of trial medication until last trial medication intake plus 21 days (residual effect period), up to 50 days.
Adverse Event Reporting Description	Treated Set: This patient set included all randomised patients who were dispensed trial medication and were documented to have taken any dose of trial medication. Adverse events were summarized by treatment group (Tio/Olo vs. Placebo), as defined in the statistical analysis plan.
Arm/Group Title	5μg/5μg Tio+Olo - Overall		Matching Placebo - Overall
Arm/Group Description	A fixed dose combination (FDC) of 5μg/5μg (two times 2.5µg/2.5µg) tiotropium + olodaterol (Tio+Olo) inhalation solution was administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) over a 4-week treatment period. Overall group included patients with both, sub-optimal (<60 L/min) peak inspiratory flow rate (PIFR) and optimal (≥60 L/min) peak inspiratory flow rate (PIFR).		2 inhalation solutions of matching placebo were administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) over a 4-week treatment period. Overall group included patients with both, sub-optimal (<60 L/min) peak inspiratory flow rate (PIFR) and optimal (≥60 L/min) peak inspiratory flow rate (PIFR).
All Cause Mortality
	5μg/5μg Tio+Olo - Overall		Matching Placebo - Overall
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/106 (0%)		0/107 (0%)
Serious Adverse Events
	5μg/5μg Tio+Olo - Overall		Matching Placebo - Overall
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/106 (1.9%)		1/107 (0.9%)
Infections and infestations
Gastroenteritis	1/106 (0.9%)		0/107 (0%)
Necrotising fasciitis	0/106 (0%)		1/107 (0.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Endometrial cancer	1/106 (0.9%)		0/107 (0%)
Renal and urinary disorders
Acute kidney injury	0/106 (0%)		1/107 (0.9%)
Other (Not Including Serious) Adverse Events
	5μg/5μg Tio+Olo - Overall		Matching Placebo - Overall
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/106 (0%)		0/107 (0%)

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.