Clinical trial NCT01172808: 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
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: 1071
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 (205.419) 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 205.419 (NCT01172821) and the Present 205.418 (NCT01172808)
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 at the End of the 24-week Treatment Period
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 205.419 (NCT01172821) and the Present 205.418 (NCT01172808)
timeFrame: 24 weeks
measure: Time to First Asthma Exacerbation From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808)
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Huntington Beach
country: United States
facility: 205.418.01020 Boehringer Ingelheim Investigational Site
state: California
city: Mission Viejo
country: United States
facility: 205.418.01002 Boehringer Ingelheim Investigational Site
state: California
city: San Diego
country: United States
facility: 205.418.01014 Boehringer Ingelheim Investigational Site
state: California
city: Wheat Ridge
country: United States
facility: 205.418.01011 Boehringer Ingelheim Investigational Site
state: Colorado
city: Coeur d'Alene
country: United States
facility: 205.418.01004 Boehringer Ingelheim Investigational Site
state: Idaho
city: Normal
country: United States
facility: 205.418.01017 Boehringer Ingelheim Investigational Site
state: Illinois
city: South Bend
country: United States
facility: 205.418.01008 Boehringer Ingelheim Investigational Site
state: Indiana
city: Baltimore
country: United States
facility: 205.418.01012 Boehringer Ingelheim Investigational Site
state: Maryland
city: North Dartmouth
country: United States
facility: 205.418.01013 Boehringer Ingelheim Investigational Site
state: Massachusetts
city: North Dartmouth
country: United States
facility: 205.418.01015 Boehringer Ingelheim Investigational Site
state: Massachusetts
city: Minneapolis
country: United States
facility: 205.418.01009 Boehringer Ingelheim Investigational Site
state: Minnesota
city: Bellevue
country: United States
facility: 205.418.01006 Boehringer Ingelheim Investigational Site
state: Nebraska
city: Boys Town
country: United States
facility: 205.418.01016 Boehringer Ingelheim Investigational Site
state: Nebraska
city: Omaha
country: United States
facility: 205.418.01003 Boehringer Ingelheim Investigational Site
state: Nebraska
city: Winston-Salem
country: United States
facility: 205.418.01021 Boehringer Ingelheim Investigational Site
state: North Carolina
city: Oklahoma City
country: United States
facility: 205.418.01018 Boehringer Ingelheim Investigational Site
state: Oklahoma
city: Charleston
country: United States
facility: 205.418.01005 Boehringer Ingelheim Investigational Site
state: South Carolina
city: Easely
country: United States
facility: 205.418.01010 Boehringer Ingelheim Investigational Site
state: South Carolina
city: Dallas
country: United States
facility: 205.418.01007 Boehringer Ingelheim Investigational Site
state: Texas
city: Seattle
country: United States
facility: 205.418.01019 Boehringer Ingelheim Investigational Site
state: Washington
city: Tacoma
country: United States
facility: 205.418.01001 Boehringer Ingelheim Investigational Site
state: Washington
city: Juiz de Fora
country: Brazil
facility: 205.418.55002 Boehringer Ingelheim Investigational Site
city: Porto Alegre
country: Brazil
facility: 205.418.55001 Boehringer Ingelheim Investigational Site
city: Porto Alegre
country: Brazil
facility: 205.418.55004 Boehringer Ingelheim Investigational Site
city: Porto Alegre
country: Brazil
facility: 205.418.55005 Boehringer Ingelheim Investigational Site
city: Rio de Janeiro - RJ
country: Brazil
facility: 205.418.55003 Boehringer Ingelheim Investigational Site
city: Beijing
country: China
facility: 205.418.86001 Boehringer Ingelheim Investigational Site
city: Beijing
country: China
facility: 205.418.86005 Boehringer Ingelheim Investigational Site
city: Beijing
country: China
facility: 205.418.86007 Boehringer Ingelheim Investigational Site
city: Beijing
country: China
facility: 205.418.86012 Boehringer Ingelheim Investigational Site
city: Changsha
country: China
facility: 205.418.86014 Boehringer Ingelheim Investigational Site
city: Chengdu
country: China
facility: 205.418.86011 Boehringer Ingelheim Investigational Site
city: Chengdu
country: China
facility: 205.418.86015 Boehringer Ingelheim Investigational Site
city: Chongqing
country: China
facility: 205.418.86003 Boehringer Ingelheim Investigational Site
city: Guangzhou
country: China
facility: 205.418.86010 Boehringer Ingelheim Investigational Site
city: Kunming
country: China
facility: 205.418.86013 Boehringer Ingelheim Investigational Site
city: Qingdao
country: China
facility: 205.418.86008 Boehringer Ingelheim Investigational Site
city: Shanghai
country: China
facility: 205.418.86002 Boehringer Ingelheim Investigational Site
city: Shenyang
country: China
facility: 205.418.86004 Boehringer Ingelheim Investigational Site
city: Shenyang
country: China
facility: 205.418.86009 Boehringer Ingelheim Investigational Site
city: Xi'An
country: China
facility: 205.418.86006 Boehringer Ingelheim Investigational Site
city: Guatelama City
country: Guatemala
facility: 205.418.50203 Boehringer Ingelheim Investigational Site
city: Guatelmala city
country: Guatemala
facility: 205.418.50204 Boehringer Ingelheim Investigational Site
city: Guatelmala City
country: Guatemala
facility: 205.418.50205 Boehringer Ingelheim Investigational Site
city: Guatemala City
country: Guatemala
facility: 205.418.50201 Boehringer Ingelheim Investigational Site
city: Guatemala city
country: Guatemala
facility: 205.418.50202 Boehringer Ingelheim Investigational Site
city: Banglore
country: India
facility: 205.418.91008 Boehringer Ingelheim Investigational Site
city: Chennai
country: India
facility: 205.418.91005 Boehringer Ingelheim Investigational Site
city: Coimbatore
country: India
facility: 205.418.91004 Boehringer Ingelheim Investigational Site
city: Coimbatore
country: India
facility: 205.418.91006 Boehringer Ingelheim Investigational Site
city: Hyderabad
country: India
facility: 205.418.91003 Boehringer Ingelheim Investigational Site
city: Jaipur
country: India
facility: 205.418.91009 Boehringer Ingelheim Investigational Site
city: Nagpur
country: India
facility: 205.418.91002 Boehringer Ingelheim Investigational Site
city: Pune
country: India
facility: 205.418.91007 Boehringer Ingelheim Investigational Site
city: Pune
country: India
facility: 205.418.91010 Boehringer Ingelheim Investigational Site
city: Adachi-ku, Tokyo
country: Japan
facility: 205.418.81018 Boehringer Ingelheim Investigational Site
city: Ako, Hyogo
country: Japan
facility: 205.418.81030 Boehringer Ingelheim Investigational Site
city: Chiyoda-ku, Tokyo
country: Japan
facility: 205.418.81001 Boehringer Ingelheim Investigational Site
city: Chuo-ku, Tokyo
country: Japan
facility: 205.418.81005 Boehringer Ingelheim Investigational Site
city: Chuo-ku, Tokyo
country: Japan
facility: 205.418.81025 Boehringer Ingelheim Investigational Site
city: Fujioka, Gunma
country: Japan
facility: 205.418.81015 Boehringer Ingelheim Investigational Site
city: Himeji, Hyogo
country: Japan
facility: 205.418.81023 Boehringer Ingelheim Investigational Site
city: Hitachi, Ibaraki
country: Japan
facility: 205.418.81007 Boehringer Ingelheim Investigational Site
city: Iwamizawa, Hokkaido
country: Japan
facility: 205.418.81009 Boehringer Ingelheim Investigational Site
city: Kanazawa, Ishikawa
country: Japan
facility: 205.418.81028 Boehringer Ingelheim Investigational Site
city: Kitakami, Iwate
country: Japan
facility: 205.418.81011 Boehringer Ingelheim Investigational Site
city: Kitakami, Iwate
country: Japan
facility: 205.418.81012 Boehringer Ingelheim Investigational Site
city: Koga, Ibaraki
country: Japan
facility: 205.418.81031 Boehringer Ingelheim Investigational Site
city: Koganei, Tokyo
country: Japan
facility: 205.418.81016 Boehringer Ingelheim Investigational Site
city: Komaki, Aichi
country: Japan
facility: 205.418.81006 Boehringer Ingelheim Investigational Site
city: Kunitachi, Tokyo
country: Japan
facility: 205.418.81002 Boehringer Ingelheim Investigational Site
city: Mito, Ibaraki
country: Japan
facility: 205.418.81004 Boehringer Ingelheim Investigational Site
city: Osaka, Osaka
country: Japan
facility: 205.418.81032 Boehringer Ingelheim Investigational Site
city: Ota-ku, Tokyo
country: Japan
facility: 205.418.81019 Boehringer Ingelheim Investigational Site
city: Sapporo, Hokkaido
country: Japan
facility: 205.418.81008 Boehringer Ingelheim Investigational Site
city: Sendai, Miyagi
country: Japan
facility: 205.418.81013 Boehringer Ingelheim Investigational Site
city: Sendai, Miyagi
country: Japan
facility: 205.418.81014 Boehringer Ingelheim Investigational Site
city: Setagaya-ku, Tokyo
country: Japan
facility: 205.418.81026 Boehringer Ingelheim Investigational Site
city: Takasaki, Gunma
country: Japan
facility: 205.418.81024 Boehringer Ingelheim Investigational Site
city: Tomakomai, Hokkaido
country: Japan
facility: 205.418.81010 Boehringer Ingelheim Investigational Site
city: Toshima-ku, Tokyo
country: Japan
facility: 205.418.81003 Boehringer Ingelheim Investigational Site
city: Toshima-ku, Tokyo
country: Japan
facility: 205.418.81017 Boehringer Ingelheim Investigational Site
city: Yao, Osaka
country: Japan
facility: 205.418.81022 Boehringer Ingelheim Investigational Site
city: Yokohama, Kanagawa
country: Japan
facility: 205.418.81020 Boehringer Ingelheim Investigational Site
city: Yokohama, Kanagawa
country: Japan
facility: 205.418.81021 Boehringer Ingelheim Investigational Site
city: Daugavpils
country: Latvia
facility: 205.418.37004 Boehringer Ingelheim Investigational Site
city: Preili
country: Latvia
facility: 205.418.37008 Boehringer Ingelheim Investigational Site
city: Riga
country: Latvia
facility: 205.418.37001 Boehringer Ingelheim Investigational Site
city: Riga
country: Latvia
facility: 205.418.37002 Boehringer Ingelheim Investigational Site
city: Riga
country: Latvia
facility: 205.418.37005 Boehringer Ingelheim Investigational Site
city: Riga
country: Latvia
facility: 205.418.37006 Boehringer Ingelheim Investigational Site
city: Riga
country: Latvia
facility: 205.418.37007 Boehringer Ingelheim Investigational Site
city: Riga
country: Latvia
facility: 205.418.37009 Boehringer Ingelheim Investigational Site
city: Ventspils
country: Latvia
facility: 205.418.37003 Boehringer Ingelheim Investigational Site
city: Monterrey
country: Mexico
facility: 205.418.52002 Boehringer Ingelheim Investigational Site
city: Zapopan
country: Mexico
facility: 205.418.52003 Boehringer Ingelheim Investigational Site
city: Zona Río
country: Mexico
facility: 205.418.52001 Boehringer Ingelheim Investigational Site
city: Callao
country: Peru
facility: 205.418.51003 Boehringer Ingelheim Investigational Site
city: Lima
country: Peru
facility: 205.418.51001 Boehringer Ingelheim Investigational Site
city: Lima
country: Peru
facility: 205.418.51002 Boehringer Ingelheim Investigational Site
city: Krakow
country: Poland
facility: 205.418.48006 Boehringer Ingelheim Investigational Site
city: Lodz
country: Poland
facility: 205.418.48001 Boehringer Ingelheim Investigational Site
city: Lodz
country: Poland
facility: 205.418.48005 Boehringer Ingelheim Investigational Site
city: Ostrow Wielkopolska
country: Poland
facility: 205.418.48002 Boehringer Ingelheim Investigational Site
city: Poznan
country: Poland
facility: 205.418.48004 Boehringer Ingelheim Investigational Site
city: Tczew
country: Poland
facility: 205.418.48003 Boehringer Ingelheim Investigational Site
city: Gatchina (Leningradskaya oblast)
country: Russian Federation
facility: 205.418.07007 Boehringer Ingelheim Investigational Site
city: Moscow
country: Russian Federation
facility: 205.418.07004 Boehringer Ingelheim Investigational Site
city: Moscow
country: Russian Federation
facility: 205.418.07005 Boehringer Ingelheim Investigational Site
city: Moscow
country: Russian Federation
facility: 205.418.07006 Boehringer Ingelheim Investigational Site
city: Moscow
country: Russian Federation
facility: 205.418.07008 Boehringer Ingelheim Investigational Site
city: St. Petersburg
country: Russian Federation
facility: 205.418.07001 Boehringer Ingelheim Investigational Site
city: St. Petersburg
country: Russian Federation
facility: 205.418.07002 Boehringer Ingelheim Investigational Site
city: St. Petersburg
country: Russian Federation
facility: 205.418.07003 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.