Clinical trial NCT01172821: 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 II
Official title: A Phase III Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution Delivered Via Respimat® Inhaler (2.5 and 5 µg Once Daily) Compared With Placebo and Salmeterol HFA MDI (50 µg Twice Daily) Over 24 Weeks in Moderate Persistent Asthma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Asthma
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
Collaborators: name: Pfizer
First posted: 2010-07-30
Enrollment: 1032
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The aim of this trial is to evaluate the efficacy and safety of 2.5 and 5 mcg tiotropium over a 24-week treatment period as compared to placebo and salmeterol (50 mcg twice daily). Tiotropium inhalation solution delivered by the Respimat® inhaler will be examined on top of maintenance treatment with inhaled corticosteroid controller medication in patients with moderate persistent asthma. Efficacy and safety will be assessed by measuring effects on lung function, effects on asthma exacerbations, effects on quality of life, effects on asthma control, effects on health care resource utilisation, and number of adverse events.


Eligibility criteria: Inclusion criteria:

1. All patients must sign and date an Informed Consent Form consistent with International Conference on Harmonisation - Good Clinical Practice (ICH-GCP) guidelines and local legislation prior to participation in the trial (i.e. prior to any trial procedures, including any pre-trial washout of medications and medication restrictions for pulmonary function test at Visit 1).
2. Male or female patients aged at least 18 years but not more than 75 years.
3. All patients must have at least a 3 month history of asthma at the time of enrolment into the trial. The diagnosis should be confirmed at Visit 1 by fulfilling inclusion criterion 5.
4. The initial diagnosis of asthma must have been made before the patient's age of 40.
5. The diagnosis of asthma has to be confirmed at Visit 1 with a bronchodilator reversibility (15 minutes after 400 mcg salbutamol (albuterol)) resulting in a Forced Expiratory Volume in one second (FEV1) increase of at least 12% and at least 200mL.
6. All patients must have been on maintenance treatment with a medium, stable dose of inhaled corticosteroids for at least for 4 weeks prior to Visit 1. 7. All patients must be symptomatic at Visit 1 (screening) and prior to randomisation at Visit 2 as defined by an Asthma Control Questionnaire (ACQ) mean score of at least 1.5.

8. All patients must have a pre-bronchodilator FEV1 at least 60% and less than or equal to 90% of predicted normal at Visit 1.

9. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ± 30%.

10. Patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment (Visit 0) and who have a smoking history of less than 10 pack years.

11. Patients must be able to use the Respimat® inhaler and metered dose inhaler correctly.

12. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of electronic diary/peak flow meter.

Exclusion criteria:

1. Patients with a significant disease other than asthma. 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 trial, or (ii) influence the results of the trial, or (iii) cause concern regarding the patient's ability to participate in the trial.
2. Patients with a clinically relevant abnormal screening (Visit 1) haematology or blood chemistry if the abnormality defines a significant disease as defined in exclusion criterion 1.
3. Patients with a recent history (i.e. six months or less) of myocardial infarction.
4. Patients who have been hospitalised for cardiac failure during the past year.
5. Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year.
6. Patients with lung diseases other than asthma (e.g. Chronic Obstructive Pulmonary Disease (COPD)).
7. Patients with known active tuberculosis.
8. Patients with malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years. Patients with treated basal cell carcinoma are allowed.
9. Patients who have undergone thoracotomy with pulmonary resection. Patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion no. 1.
10. Patients with significant alcohol or drug abuse within the past two years.
11. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to Visit 1 (screening).
12. Patients with known hypersensitivity to anticholinergic drugs, benzalkonium chloride (BAC), ethylenediamineteraacetic acid (EDTA), salmeterol xinafoate or any other components of the study medication delivery systems.
13. Pregnant or nursing woman.
14. Women of childbearing potential not using a highly effective method of birth control.
15. Patients who have taken an investigational drug within four weeks prior to Visit 1.
16. Patients who have been treated with beta-blocker medication within four weeks prior to Visit 1 and/or during the screening period. Topical cardio-selective beta-blocker eye medications for non-narrow angle glaucoma are allowed.
17. Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva®) within four weeks prior to Visit 1 and/or during the screening period.
18. Patients who have been treated with oral or patch beta-adrenergics within four weeks prior to Visit 1 and/or during the Screening period.
19. Patients who have been treated with oral corticosteroids within four weeks prior to Visit 1 and/or during the screening period.
20. Patients who have been treated with anti-IgE antibodies, e.g. omalizumab (Xolair®), within 6 months prior to Visit 1 and/or during the screening period.
21. Patients who have been treated with cromone within two weeks prior to Visit 1 and/or during the screening period.
22. Patients who have been treated with methylxanthines or phosphodiesterase 4 inhibitors within two weeks prior to Visit 1 and/or during the screening period.
23. Patients who have been treated with other non-approved and according to international guidelines not recommended "experimental" drugs for routine asthma therapy within four weeks prior to Visit 1 and/or during the screening period.
24. Patients with any asthma exacerbation or any respiratory tract infection iin the four weeks prior to Visit 1 and/or during the screening period.
25. Patients who have previously been randomised in this trial or in the respective twin trial (205.418) or are currently participating in another trial.

Primary outcomes:
measure: Peak FEV1 Within 3 Hours Post-dose Response
timeFrame: 24 weeks
measure: Trough FEV1 Response
timeFrame: 24 weeks
measure: The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821)
timeFrame: 24 weeks
Secondary outcomes:
measure: Peak FVC Within 3 Hours Post-dose Response
timeFrame: 24 weeks
measure: Trough FVC Response
timeFrame: 24 weeks
measure: FEV1 Area Under Curve 0-3 Hours (AUC0-3h) Response
timeFrame: 24 weeks
measure: FVC Area Under Curve 0-3 Hours (AUC0-3h) Response
timeFrame: 24 weeks
measure: Trough PEF Response
timeFrame: 24 weeks
measure: Total Asthma Quality of Life Questionnaire (AQLQs)) Score
timeFrame: 24 weeks
measure: Total Asthma Control Questionnaire (ACQ) Score
timeFrame: 24 weeks
measure: The Responder Rate as Assessed by the ACQ
timeFrame: 24 weeks
measure: Mean Pre-dose Morning PEF (PEF a.m.) Based on the Weekly Mean Response at Week 24
timeFrame: Baseline and last 7 days before week 24 visit
measure: Mean Pre-dose Evening PEF (PEF p.m.) Based on the Weekly Mean Response at Week 24
timeFrame: Baseline and last 7 days before week 24 visit
measure: PEF Variability
timeFrame: Last 7 days before week 24 visit
measure: Mean Pre-dose Morning FEV1 (FEV1 a.m.) Based on the Weekly Mean Response at Week 24
timeFrame: Baseline and last 7 days before week 24 visit
measure: Mean Pre-dose Evening FEV1 (FEV1 p.m.) Based on the Weekly Mean Response at Week 24
timeFrame: Baseline and last 7 days before week 24 visit
measure: Mean Number of Puffs of Rescue Medication During the Entire 24-h Day Based on the Weekly Mean Response at Week 24
timeFrame: Baseline and last 7 days before week 24 visit
measure: Asthma Symptom-free Days Based on the Weekly Mean Response at Week 24
timeFrame: Baseline and last 7 days before week 24 visit
measure: Time to First Severe Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821)
timeFrame: 24 weeks
measure: Time to First Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821)
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: 205.419.01058 Boehringer Ingelheim Investigational Site
state: California
city: Stockton
country: United States
facility: 205.419.01053 Boehringer Ingelheim Investigational Site
state: California
city: Centennial
country: United States
facility: 205.419.01061 Boehringer Ingelheim Investigational Site
state: Colorado
city: Denver
country: United States
facility: 205.419.01066 Boehringer Ingelheim Investigational Site
state: Colorado
city: Panama City
country: United States
facility: 205.419.01064 Boehringer Ingelheim Investigational Site
state: Florida
city: Winter Park
country: United States
facility: 205.419.01060 Boehringer Ingelheim Investigational Site
state: Florida
city: Novi
country: United States
facility: 205.419.01068 Boehringer Ingelheim Investigational Site
state: Michigan
city: Plymouth
country: United States
facility: 205.419.01054 Boehringer Ingelheim Investigational Site
state: Minnesota
city: St. Louis
country: United States
facility: 205.419.01062 Boehringer Ingelheim Investigational Site
state: Missouri
city: Bozeman
country: United States
facility: 205.419.01070 Boehringer Ingelheim Investigational Site
state: Montana
city: Skillman
country: United States
facility: 205.419.01067 Boehringer Ingelheim Investigational Site
state: New Jersey
city: Raleigh
country: United States
facility: 205.419.01071 Boehringer Ingelheim Investigational Site
state: North Carolina
city: Cincinnati
country: United States
facility: 205.419.01055 Boehringer Ingelheim Investigational Site
state: Ohio
city: Portland
country: United States
facility: 205.419.01065 Boehringer Ingelheim Investigational Site
state: Oregon
city: Greenville
country: United States
facility: 205.419.01069 Boehringer Ingelheim Investigational Site
state: South Carolina
city: Union
country: United States
facility: 205.419.01056 Boehringer Ingelheim Investigational Site
state: South Carolina
city: El Paso
country: United States
facility: 205.419.01063 Boehringer Ingelheim Investigational Site
state: Texas
city: San Antonio
country: United States
facility: 205.419.01051 Boehringer Ingelheim Investigational Site
state: Texas
city: Florianopolis
country: Brazil
facility: 205.419.55053 Boehringer Ingelheim Investigational Site
city: Porto Alegre
country: Brazil
facility: 205.419.55054 Boehringer Ingelheim Investigational Site
city: Sao Paulo
country: Brazil
facility: 205.419.55052 Boehringer Ingelheim Investigational Site
city: Sao Paulo
country: Brazil
facility: 205.419.55055 Boehringer Ingelheim Investigational Site
city: Chengdu
country: China
facility: 205.419.86061 Boehringer Ingelheim Investigational Site
city: Chongqing
country: China
facility: 205.419.86053 Boehringer Ingelheim Investigational Site
city: Guangzhou
country: China
facility: 205.419.86056 Boehringer Ingelheim Investigational Site
city: Guangzhou
country: China
facility: 205.419.86062 Boehringer Ingelheim Investigational Site
city: Haikou
country: China
facility: 205.419.86054 Boehringer Ingelheim Investigational Site
city: Kunming
country: China
facility: 205.419.86059 Boehringer Ingelheim Investigational Site
city: Nanchang
country: China
facility: 205.419.86058 Boehringer Ingelheim Investigational Site
city: Nanjing
country: China
facility: 205.419.86064 Boehringer Ingelheim Investigational Site
city: Shanghai
country: China
facility: 205.419.86051 Boehringer Ingelheim Investigational Site
city: Shanghai
country: China
facility: 205.419.86052 Boehringer Ingelheim Investigational Site
city: Shanghai
country: China
facility: 205.419.86055 Boehringer Ingelheim Investigational Site
city: Shanghai
country: China
facility: 205.419.86066 Boehringer Ingelheim Investigational Site
city: Xi'An
country: China
facility: 205.419.86057 Boehringer Ingelheim Investigational Site
city: Xi'An
country: China
facility: 205.419.86065 Boehringer Ingelheim Investigational Site
city: Xuzhou
country: China
facility: 205.419.86063 Boehringer Ingelheim Investigational Site
city: Yangzhou
country: China
facility: 205.419.86067 Boehringer Ingelheim Investigational Site
city: Yinchuan
country: China
facility: 205.419.86068 Boehringer Ingelheim Investigational Site
city: Bogota
country: Colombia
facility: 205.419.57051 Boehringer Ingelheim Investigational Site
city: Bogota
country: Colombia
facility: 205.419.57052 Boehringer Ingelheim Investigational Site
city: Bogota
country: Colombia
facility: 205.419.57053 Boehringer Ingelheim Investigational Site
city: Medelin
country: Colombia
facility: 205.419.57054 Boehringer Ingelheim Investigational Site
city: Bamberg
country: Germany
facility: 205.419.49061 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 205.419.49051 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 205.419.49052 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 205.419.49062 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 205.419.49063 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 205.419.49064 Boehringer Ingelheim Investigational Site
city: Frankfurt
country: Germany
facility: 205.419.49054 Boehringer Ingelheim Investigational Site
city: Hamburg
country: Germany
facility: 205.419.49058 Boehringer Ingelheim Investigational Site
city: Koblenz
country: Germany
facility: 205.419.49057 Boehringer Ingelheim Investigational Site
city: Lübeck
country: Germany
facility: 205.419.49056 Boehringer Ingelheim Investigational Site
city: Rüdersdorf
country: Germany
facility: 205.419.49059 Boehringer Ingelheim Investigational Site
city: Wiesbaden
country: Germany
facility: 205.419.49053 Boehringer Ingelheim Investigational Site
city: Witten
country: Germany
facility: 205.419.49055 Boehringer Ingelheim Investigational Site
city: Ahmedabad
country: India
facility: 205.419.91057 Boehringer Ingelheim Investigational Site
city: Coimbatore
country: India
facility: 205.419.91056 Boehringer Ingelheim Investigational Site
city: Hyderabad
country: India
facility: 205.419.91055 Boehringer Ingelheim Investigational Site
city: Jaipur
country: India
facility: 205.419.91051 Boehringer Ingelheim Investigational Site
city: Jaipur
country: India
facility: 205.419.91058 Boehringer Ingelheim Investigational Site
city: Mumbai
country: India
facility: 205.419.91054 Boehringer Ingelheim Investigational Site
city: Mysore
country: India
facility: 205.419.91059 Boehringer Ingelheim Investigational Site
city: Nagpur
country: India
facility: 205.419.91053 Boehringer Ingelheim Investigational Site
city: Aira, Kagoshima
country: Japan
facility: 205.419.81085 Boehringer Ingelheim Investigational Site
city: Chuo-ku, Tokyo
country: Japan
facility: 205.419.81062 Boehringer Ingelheim Investigational Site
city: Fukuoka, Fukuoka
country: Japan
facility: 205.419.81073 Boehringer Ingelheim Investigational Site
city: Fukuoka, Fukuoka
country: Japan
facility: 205.419.81074 Boehringer Ingelheim Investigational Site
city: Fukuyama, Hiroshima
country: Japan
facility: 205.419.81072 Boehringer Ingelheim Investigational Site
city: Habikino, Osaka
country: Japan
facility: 205.419.81069 Boehringer Ingelheim Investigational Site
city: Hiroshima, Hiroshima
country: Japan
facility: 205.419.81071 Boehringer Ingelheim Investigational Site
city: Itabashi-ku, Tokyo
country: Japan
facility: 205.419.81058 Boehringer Ingelheim Investigational Site
city: Iwata, Shizuoka
country: Japan
facility: 205.419.81064 Boehringer Ingelheim Investigational Site
city: Kanazawa, Ishikawa
country: Japan
facility: 205.419.81063 Boehringer Ingelheim Investigational Site
city: Kishiwada, Osaka
country: Japan
facility: 205.419.81054 Boehringer Ingelheim Investigational Site
city: Kitakyushu, Fukuoka
country: Japan
facility: 205.419.81075 Boehringer Ingelheim Investigational Site
city: Kobe, Hyogo
country: Japan
facility: 205.419.81070 Boehringer Ingelheim Investigational Site
city: Koto-ku, Tokyo
country: Japan
facility: 205.419.81061 Boehringer Ingelheim Investigational Site
city: Kyoto, Kyoto
country: Japan
facility: 205.419.81067 Boehringer Ingelheim Investigational Site
city: Matsusaka, Mie
country: Japan
facility: 205.419.81080 Boehringer Ingelheim Investigational Site
city: Meguro-ku, Tokyo
country: Japan
facility: 205.419.81081 Boehringer Ingelheim Investigational Site
city: Minato-ku, Tokyo
country: Japan
facility: 205.419.81060 Boehringer Ingelheim Investigational Site
city: Minato-ku, Tokyo
country: Japan
facility: 205.419.81077 Boehringer Ingelheim Investigational Site
city: Morioka, Iwate
country: Japan
facility: 205.419.81056 Boehringer Ingelheim Investigational Site
city: Naka-gun, Ibaraki
country: Japan
facility: 205.419.81055 Boehringer Ingelheim Investigational Site
city: Nakano-ku,Tokyo
country: Japan
facility: 205.419.81078 Boehringer Ingelheim Investigational Site
city: Oita,Oita
country: Japan
facility: 205.419.81084 Boehringer Ingelheim Investigational Site
city: Osaka-Sayama, Osaka
country: Japan
facility: 205.419.81068 Boehringer Ingelheim Investigational Site
city: Sapporo, Hokkaido
country: Japan
facility: 205.419.81053 Boehringer Ingelheim Investigational Site
city: Sendai, Miyagi
country: Japan
facility: 205.419.81057 Boehringer Ingelheim Investigational Site
city: Seto, Aichi
country: Japan
facility: 205.419.81059 Boehringer Ingelheim Investigational Site
city: Shinagawa-ku, Tokyo
country: Japan
facility: 205.419.81082 Boehringer Ingelheim Investigational Site
city: Shizuoka, Shizuoka
country: Japan
facility: 205.419.81065 Boehringer Ingelheim Investigational Site
city: Toyota, Aichi
country: Japan
facility: 205.419.81066 Boehringer Ingelheim Investigational Site
city: Urasoe, Okinawa
country: Japan
facility: 205.419.81051 Boehringer Ingelheim Investigational Site
city: Urasoe, Okinawa
country: Japan
facility: 205.419.81052 Boehringer Ingelheim Investigational Site
city: Urasoe, Okinawa
country: Japan
facility: 205.419.81076 Boehringer Ingelheim Investigational Site
city: Yokohama, Kanagawa
country: Japan
facility: 205.419.81083 Boehringer Ingelheim Investigational Site
city: Yotsukaido, Chiba
country: Japan
facility: 205.419.81079 Boehringer Ingelheim Investigational Site
city: Mexico City
country: Mexico
facility: 205.419.52051 Boehringer Ingelheim Investigational Site
city: Mexico City
country: Mexico
facility: 205.419.52052 Boehringer Ingelheim Investigational Site
city: Monterrey
country: Mexico
facility: 205.419.52053 Boehringer Ingelheim Investigational Site
city: Lima
country: Peru
facility: 205.419.51051 Boehringer Ingelheim Investigational Site
city: Lima
country: Peru
facility: 205.419.51052 Boehringer Ingelheim Investigational Site
city: Lima
country: Peru
facility: 205.419.51053 Boehringer Ingelheim Investigational Site
city: Lima
country: Peru
facility: 205.419.51054 Boehringer Ingelheim Investigational Site
city: Lima
country: Peru
facility: 205.419.51055 Boehringer Ingelheim Investigational Site
city: Bialystok
country: Poland
facility: 205.419.48052 Boehringer Ingelheim Investigational Site
city: Bydgoszcz
country: Poland
facility: 205.419.48054 Boehringer Ingelheim Investigational Site
city: Gorzow Wielkopolski
country: Poland
facility: 205.419.48055 Boehringer Ingelheim Investigational Site
city: Krakow
country: Poland
facility: 205.419.48051 Boehringer Ingelheim Investigational Site
city: Poznan
country: Poland
facility: 205.419.48057 Boehringer Ingelheim Investigational Site
city: Sopot
country: Poland
facility: 205.419.48058 Boehringer Ingelheim Investigational Site
city: Wloszczowa
country: Poland
facility: 205.419.48053 Boehringer Ingelheim Investigational Site
city: Wroclaw
country: Poland
facility: 205.419.48056 Boehringer Ingelheim Investigational Site
city: Brasov
country: Romania
facility: 205.419.40055 Boehringer Ingelheim Investigational Site
city: Brasov
country: Romania
facility: 205.419.40056 Boehringer Ingelheim Investigational Site
city: Bucharest
country: Romania
facility: 205.419.40052 Boehringer Ingelheim Investigational Site
city: Bucharest
country: Romania
facility: 205.419.40053 Boehringer Ingelheim Investigational Site
city: Bucharest
country: Romania
facility: 205.419.40054 Boehringer Ingelheim Investigational Site
city: Bucharest
country: Romania
facility: 205.419.40058 Boehringer Ingelheim Investigational Site
city: Bucharest
country: Romania
facility: 205.419.40060 Boehringer Ingelheim Investigational Site
city: Bucuresti
country: Romania
facility: 205.419.40051 Boehringer Ingelheim Investigational Site
city: Constanta
country: Romania
facility: 205.419.40059 Boehringer Ingelheim Investigational Site
city: Iasi
country: Romania
facility: 205.419.40057 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Halpin DMG, Hamelmann EH, Frith PA, Moroni-Zentgraf PM, van Hecke B, Unseld A, Kerstjens HAM, Szefler SJ. Comparative Responses in Lung Function Measurements with Tiotropium in Adolescents and Adults, and Across Asthma Severities: A Post Hoc Analysis. Pulm Ther. 2020 Jun;6(1):131-140. doi: 10.1007/s41030-020-00113-w. Epub 2020 Mar 16.
citation: Casale TB, Aalbers R, Bleecker ER, Meltzer EO, Zaremba-Pechmann L, de la Hoz A, Kerstjens HAM. Tiotropium Respimat(R) add-on therapy to inhaled corticosteroids in patients with symptomatic asthma improves clinical outcomes regardless of baseline characteristics. Respir Med. 2019 Oct-Nov;158:97-109. doi: 10.1016/j.rmed.2019.09.014. Epub 2019 Sep 30.
citation: Halpin DMG, Meltzer EO, Pisternick-Ruf W, Moroni-Zentgraf P, Engel M, Zaremba-Pechmann L, Casale T, FitzGerald JM. Peak expiratory flow as an endpoint for clinical trials in asthma: a comparison with FEV1. Respir Res. 2019 Jul 18;20(1):159. doi: 10.1186/s12931-019-1119-6.
citation: Casale TB, Bateman ED, Vandewalker M, Virchow JC, Schmidt H, Engel M, Moroni-Zentgraf P, Kerstjens HAM. Tiotropium Respimat Add-on Is Efficacious in Symptomatic Asthma, Independent of T2 Phenotype. J Allergy Clin Immunol Pract. 2018 May-Jun;6(3):923-935.e9. doi: 10.1016/j.jaip.2017.08.037. Epub 2017 Nov 22.
citation: 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.