Evaluation of Tiotropium 2.5 and 5 mcg Once Daily Delivered Via the Respimat® Inhaler Compared to Placebo and Salmeterol HydroFluoroAlkane (HFA) Metered Dose Inhaler (MDI) (50 mcg Twice Daily) in Patient With Moderate Persistent Asthma I

This study has been completed.

Sponsor:

Collaborator:

Pfizer

Information provided by (Responsible Party):

Boehringer Ingelheim

ClinicalTrials.gov Identifier:

NCT01172808

First received: July 26, 2010

Last updated: June 3, 2014

Last verified: January 2014

History of Changes

Results First Received: October 25, 2013

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double-Blind; Primary Purpose: Treatment
Condition:	Asthma
Interventions:	Drug: Placebo Drug: tiotropium Respimat® low dose Drug: tiotropium Respimat® high dose Drug: 50 mcg salmeterol HFA MDI

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
There was 1 patient in the TIO R5 group randomized but not treated.

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Participant Flow: Overall Study

	Placebo	Tio R2.5	Tio R5	Salmeterol
STARTED	269 ^[1]	262 ^[1]	264 ^[1]	275 ^[1]
COMPLETED	248	249	241	260
NOT COMPLETED	21	13	23	15
Adverse Event	8	4	8	3
Lack of Efficacy	1	0	0	0
Protocol Violation	2	2	2	0
Lost to Follow-up	0	1	1	3
Withdrawal by Subject	4	1	3	2
Other	6	5	9	7

^[1]	Entered and Treated

Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Treated Set (TS) - all randomised patients who received at least 1 dose of randomised trial medication.

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Total	Total of all reporting groups

Baseline Measures

	Placebo	Tio R2.5	Tio R5	Salmeterol	Total
Overall Participants Analyzed [Units: Participants]	269	262	264	275	1070

Age [Units: Years] Mean (Standard Deviation)	42.5 (13.1)	43.7 (13.1)	44.4 (12.6)	42.6 (12.6)	43.3 (12.9)

Gender [Units: Participants]
Female	166	156	154	159	635
Male	103	106	110	116	435

Outcome Measures

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1. Primary:

Peak FEV1 Within 3 Hours Post-dose Response [ Time Frame: 24 weeks ]

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2. Primary:

Trough FEV1 Response [ Time Frame: 24 weeks ]

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3. Primary:

The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808) [ Time Frame: 24 weeks ]

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4. Secondary:

Peak FVC Within 3 Hours Post-dose Response [ Time Frame: 24 weeks ]

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5. Secondary:

Trough FVC Response [ Time Frame: 24 weeks ]

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6. Secondary:

FEV1 Area Under Curve 0-3 Hours (AUC0-3h) Response [ Time Frame: 24 weeks ]

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7. Secondary:

FVC Area Under Curve 0-3 Hours (AUC0-3h) Response [ Time Frame: 24 weeks ]

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8. Secondary:

Trough PEF Response [ Time Frame: 24 weeks ]

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9. Secondary:

Total Asthma Quality of Life Questionnaire (AQLQs)) Score [ Time Frame: 24 weeks ]

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10. Secondary:

Total Asthma Control Questionnaire (ACQ) Score at the End of the 24-week Treatment Period [ Time Frame: 24 weeks ]

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11. Secondary:

The Responder Rate as Assessed by the ACQ [ Time Frame: 24 weeks ]

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12. Secondary:

Mean Pre-dose Morning PEF (PEF a.m.) Based on the Weekly Mean Response at Week 24 [ Time Frame: Baseline and last 7 days before week 24 visit ]

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13. Secondary:

Mean Pre-dose Evening PEF (PEF p.m.) Based on the Weekly Mean Response at Week 24 [ Time Frame: Baseline and last 7 days before week 24 visit ]

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14. Secondary:

PEF Variability [ Time Frame: Last 7 days before week 24 visit ]

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15. Secondary:

Mean Pre-dose Morning FEV1 (FEV1 a.m.) Based on the Weekly Mean Response at Week 24 [ Time Frame: Baseline and last 7 days before week 24 visit ]

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16. Secondary:

Mean Pre-dose Evening FEV1 (FEV1 p.m.) Based on the Weekly Mean Response at Week 24 [ Time Frame: Baseline and last 7 days before week 24 visit ]

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17. Secondary:

Mean Number of Puffs of Rescue Medication During the Entire 24-h Day Based on the Weekly Mean Response at Week 24 [ Time Frame: Baseline and last 7 days before week 24 visit ]

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18. Secondary:

Asthma Symptom-free Days Based on the Weekly Mean Response at Week 24 [ Time Frame: Baseline and last 7 days before week 24 visit ]

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19. Secondary:

Time to First Severe Asthma Exacerbation From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808) [ Time Frame: 24 weeks ]

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20. Secondary:

Time to First Asthma Exacerbation From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808) [ Time Frame: 24 weeks ]

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Serious Adverse Events

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Time Frame	24 weeks
Additional Description	No text entered.

Reporting Groups

	Description
Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Serious Adverse Events

	Placebo	Tio R2.5	Tio R5	Salmeterol
Total, Serious Adverse Events
# participants affected / at risk	10/269 (3.72%)	5/262 (1.91%)	4/264 (1.52%)	7/275 (2.55%)
Cardiac disorders
Acute myocardial infarction ^† 1
# participants affected / at risk	1/269 (0.37%)	0/262 (0.00%)	0/264 (0.00%)	0/275 (0.00%)
Atrial fibrillation ^† 1
# participants affected / at risk	0/269 (0.00%)	1/262 (0.38%)	0/264 (0.00%)	0/275 (0.00%)
Coronary artery disease ^† 1
# participants affected / at risk	1/269 (0.37%)	0/262 (0.00%)	0/264 (0.00%)	0/275 (0.00%)
Myocardial infarction ^† 1
# participants affected / at risk	0/269 (0.00%)	1/262 (0.38%)	0/264 (0.00%)	0/275 (0.00%)
Eye disorders
Vitreous haemorrhage ^† 1
# participants affected / at risk	1/269 (0.37%)	0/262 (0.00%)	0/264 (0.00%)	0/275 (0.00%)
Gastrointestinal disorders
Duodenal obstruction ^† 1
# participants affected / at risk	1/269 (0.37%)	0/262 (0.00%)	0/264 (0.00%)	0/275 (0.00%)
Hepatobiliary disorders
Cholelithiasis ^† 1
# participants affected / at risk	0/269 (0.00%)	0/262 (0.00%)	1/264 (0.38%)	0/275 (0.00%)
Infections and infestations
Appendicitis ^† 1
# participants affected / at risk	1/269 (0.37%)	0/262 (0.00%)	0/264 (0.00%)	0/275 (0.00%)
Chikungunya virus infection ^† 1
# participants affected / at risk	1/269 (0.37%)	0/262 (0.00%)	0/264 (0.00%)	0/275 (0.00%)
Gastroenteritis ^† 1
# participants affected / at risk	0/269 (0.00%)	1/262 (0.38%)	0/264 (0.00%)	1/275 (0.36%)
Peritonsillar abscess ^† 1
# participants affected / at risk	1/269 (0.37%)	0/262 (0.00%)	0/264 (0.00%)	0/275 (0.00%)
Pneumonia ^† 1
# participants affected / at risk	0/269 (0.00%)	1/262 (0.38%)	0/264 (0.00%)	0/275 (0.00%)
Pyelonephritis ^† 1
# participants affected / at risk	0/269 (0.00%)	0/262 (0.00%)	0/264 (0.00%)	1/275 (0.36%)
Urinary tract infection ^† 1
# participants affected / at risk	0/269 (0.00%)	0/262 (0.00%)	0/264 (0.00%)	1/275 (0.36%)
Injury, poisoning and procedural complications
Post procedural bile leak ^† 1
# participants affected / at risk	1/269 (0.37%)	0/262 (0.00%)	0/264 (0.00%)	0/275 (0.00%)
Metabolism and nutrition disorders
Dehydration ^† 1
# participants affected / at risk	1/269 (0.37%)	0/262 (0.00%)	0/264 (0.00%)	0/275 (0.00%)
Musculoskeletal and connective tissue disorders
Osteoarthritis ^† 1
# participants affected / at risk	1/269 (0.37%)	0/262 (0.00%)	0/264 (0.00%)	0/275 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign salivary gland neoplasm ^† 1
# participants affected / at risk	0/269 (0.00%)	0/262 (0.00%)	1/264 (0.38%)	0/275 (0.00%)
Gastrointestinal tract adenoma ^† 1
# participants affected / at risk	1/269 (0.37%)	0/262 (0.00%)	0/264 (0.00%)	0/275 (0.00%)
Nervous system disorders
Cerebrovascular accident ^† 1
# participants affected / at risk	2/269 (0.74%)	0/262 (0.00%)	0/264 (0.00%)	1/275 (0.36%)
Intracranial haematoma ^† 1
# participants affected / at risk	0/269 (0.00%)	0/262 (0.00%)	0/264 (0.00%)	1/275 (0.36%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous ^† 1
# participants affected / at risk	1/269 (0.37%)	0/262 (0.00%)	0/264 (0.00%)	0/275 (0.00%)
Abortion spontaneous complete ^† 1
# participants affected / at risk	0/269 (0.00%)	0/262 (0.00%)	0/264 (0.00%)	1/275 (0.36%)
Reproductive system and breast disorders
Cervical dysplasia ^† 1
# participants affected / at risk	0/269 (0.00%)	0/262 (0.00%)	1/264 (0.38%)	0/275 (0.00%)
Respiratory, thoracic and mediastinal disorders
Asthma ^† 1
# participants affected / at risk	1/269 (0.37%)	0/262 (0.00%)	0/264 (0.00%)	1/275 (0.36%)
Haemoptysis ^† 1
# participants affected / at risk	0/269 (0.00%)	1/262 (0.38%)	0/264 (0.00%)	0/275 (0.00%)
Pulmonary embolism ^† 1
# participants affected / at risk	0/269 (0.00%)	0/262 (0.00%)	0/264 (0.00%)	1/275 (0.36%)
Surgical and medical procedures
Abortion induced ^† 1
# participants affected / at risk	0/269 (0.00%)	0/262 (0.00%)	1/264 (0.38%)	0/275 (0.00%)
Vascular disorders
Deep vein thrombosis ^† 1
# participants affected / at risk	0/269 (0.00%)	0/262 (0.00%)	0/264 (0.00%)	1/275 (0.36%)
Hypertension ^† 1
# participants affected / at risk	0/269 (0.00%)	1/262 (0.38%)	0/264 (0.00%)	0/275 (0.00%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MEDDRA 15.1

Other Adverse Events

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Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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More Information

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Certain Agreements:

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.

Results Point of Contact:

Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim Pharmaceuticals
phone: 1-800-243-0127
e-mail: clintriage.rdg@boehringer-ingelheim.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kerstjens HA, Casale TB, Bleecker ER, Meltzer EO, Pizzichini E, Schmidt O, Engel M, Bour L, Verkleij CB, Moroni-Zentgraf P, Bateman ED. Tiotropium or salmeterol as add-on therapy to inhaled corticosteroids for patients with moderate symptomatic asthma: two replicate, double-blind, placebo-controlled, parallel-group, active-comparator, randomised trials. Lancet Respir Med. 2015 May;3(5):367-76. doi: 10.1016/S2213-2600(15)00031-4. Epub 2015 Feb 12.

Responsible Party:	Boehringer Ingelheim
ClinicalTrials.gov Identifier:	NCT01172808 History of Changes
Other Study ID Numbers:	205.418 2009-018004-18 ( EudraCT Number: EudraCT )
Study First Received:	July 26, 2010
Results First Received:	October 25, 2013
Last Updated:	June 3, 2014

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