Clinical trial NCT01316380: Efficacy and Safety of 2 Doses of Tiotropium Via Respimat in Adult Patients With Mild Persistent Asthma
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 ug and 5 ug Once Daily) Compared to Placebo Over 12 Weeks in Mild Persistent Asthma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Asthma
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
Collaborators: name: Pfizer
First posted: 2011-03-16
Enrollment: 465
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 compared to placebo over 12 week treatment period. Tiotropium inhalation solution will be delivered via Respimat inhaler and will be examined on top of maintenance inhaled corticosteroid treatment in patients with mild persistent asthma. Efficacy and safety will be assessed by measuring the effects on lung functions, effects on lung exacerbations, effects on asthma control and numbers 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 18 years or more at Visit 0 and 75 years or less at Visit 0.

   All patients must have
3. at least a 3 months history of asthma at the time of enrolment into the trial. The initial diagnosis of asthma must have been made before the patient's age of 40;
4. a pre-bronchodilator Forced Expiratory Volume in 1 second (FEV1)= 60% predicted and = 90% of predicted normal at Visit 1. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ± 30%.
5. Patient's diagnosis of asthma has to be confirmed at Visit 1 with a bronchodilator reversibility (within 10 minutes pre and 15-30 minutes after 400 µg salbutamol/albuterol) resulting in a FEV1 increase of = 12% and = 200mL. If this is not achieved the reversibility test may be repeated once within two weeks.
6. All patients must be symptomatic despite their current maintenance treatment with low doses of inhaled corticosteroids.
7. All patients must be symptomatic at Visit 1 (screening) and Visit 2 as defined by an Asthma Control Questionnaire (ACQ) mean score of = 1.5.
8. All patients must have been on maintenance treatment with a low, stable dose of inhaled corticosteroids for at least 4 weeks prior to Visit 1.
9. Patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment and who have a smoking history of less than 10 pack years ((see Appendix 10.3 for calculation).
10. Patients must be able to use the Respimat® inhaler correctly.
11. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of the e-Diary/peak flow meter (e-Diary-compliance of at least 80% is required; refer to Section 6.2.1 for instructions).
12. Patients taking a chronic pulmonary medication allowed by the study protocol must be willing to continue this therapy for the entire duration of the study (exception: times of acute disease deterioration).

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) 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 number 1.
3. Patients requiring more than 10 puffs of rescue medication (salbutamol/albuterol MDI) per 24 hours on 2 consecutive days during the screening period.
4. Patients with a recent history (i.e. six months or less) of Acute Coronary Syndrome (STEMI, Non-STEMI and Unstable Angina Pectoris).
5. Patients who have been hospitalised for cardiac failure during the past year.
6. Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year.
7. Patients with lung diseases other than asthma (e.g. COPD).
8. Patients with known active tuberculosis.
9. 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.
10. 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.
11. Patients with significant alcohol or drug abuse on Investigator's assessment within the past two years.
12. 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).
13. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the tiotropium inhalation solution.
14. Pregnant or nursing woman, including female patients with positive beta-HCG test at Visit 1.
15. Female patients of child-bearing potential not using highly effective method of birth control As defined in ICH (M3).
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 oral or patch beta-adrenergics, systemic, i.e. oral or intravenous corticosteroids, 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 depot corticosteroids within six months prior to Visit 1 and/or during the screening period.
19. Patients who have ever been treated with anti-IgE antibodies.
20. Patients who have been treated with leukotriene modifiers, systemic anticholinergics, cromolyn sodium or nedocromil sodium and methylxanthines or phosphodiesterase 4 inhibitors within two weeks prior to Visit 1 and/or during the screening period.
21. Patients who have been treated with inhaled long acting beta adrenergics and long acting beta adrenergics combination products within four weeks prior to Visit 0 and/or during the screening period.
22. Patients who have taken an investigational drug within four weeks or six half lives whichever is greater prior to Visit 1.
23. Patients who have been treated with other non-approved and according to international guidelines not recommended, experimental drugs for routine asthma therapy (e.g. TNFalpha blockers, methotrexate, cyclosporin) within four weeks prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2).
24. Patients with any asthma exacerbation or any respiratory tract infection in the four weeks prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2).
25. Current participation in another trial.

Primary outcomes:
measure: Peak Forced Expiratory Volume in 1 Second (FEV1) Response Within 3 Hours Post Dosing (0-3h) After a Treatment Period of 12 Weeks.
timeFrame: Baseline and 12 weeks
Secondary outcomes:
measure: Trough FEV1 Response Determined After a Treatment Period of 12 Weeks.
timeFrame: Baseline and 12 weeks
measure: Peak (Within 3 Hours Post-dosing) Forced Vital Capacity (FVC) Response at the End of the 12-week Treatment Period.
timeFrame: Baseline and 12 weeks
measure: FEV1 Area Under the Curve (AUC0-3h) Response at the End of the 12-week Treatment Period.
timeFrame: Baseline and 12 weeks
measure: FVC (AUC0-3h) Response at the End of the 12-week Treatment Period.
timeFrame: Baseline and 12 weeks
measure: Asthma Control Questionnaire (ACQ) Responder After 12 Weeks of Treatment
timeFrame: 12 weeks
measure: Time to First Severe Asthma Exacerbation During the 12-week Treatment.
timeFrame: 12 weeks
measure: Time to First Asthma Exacerbation During the 12-week Treatment.
timeFrame: 12 weeks
measure: Use of Rescue Medication During 24h Period
timeFrame: Baseline and 12 weeks
measure: Use of Rescue Medication During Daytime
timeFrame: Baseline and 12 weeks
measure: Use of Rescue Medication During Nighttime
timeFrame: Baseline and 12 weeks
Other outcomes:
Locations:
city: Capital Federal
country: Argentina
facility: 205.442.54002 Boehringer Ingelheim Investigational Site
city: Capital Federal
country: Argentina
facility: 205.442.54005 Boehringer Ingelheim Investigational Site
city: Florencio Varela
country: Argentina
facility: 205.442.54003 Boehringer Ingelheim Investigational Site
city: Linz
country: Austria
facility: 205.442.43002 Boehringer Ingelheim Investigational Site
city: Schlüsslberg
country: Austria
facility: 205.442.43003 Boehringer Ingelheim Investigational Site
city: Wels
country: Austria
facility: 205.442.43001 Boehringer Ingelheim Investigational Site
city: Rijeka
country: Croatia
facility: 205.442.38502 Boehringer Ingelheim Investigational Site
city: Split
country: Croatia
facility: 205.442.38501 Boehringer Ingelheim Investigational Site
city: Split
country: Croatia
facility: 205.442.38503 Boehringer Ingelheim Investigational Site
city: Zagreb
country: Croatia
facility: 205.442.38504 Boehringer Ingelheim Investigational Site
city: Kohtla-Järve
country: Estonia
facility: 205.442.37203 Boehringer Ingelheim Investigational Site
city: Rakvere
country: Estonia
facility: 205.442.37201 Boehringer Ingelheim Investigational Site
city: Tartu
country: Estonia
facility: 205.442.37202 Boehringer Ingelheim Investigational Site
city: Guatemala
country: Guatemala
facility: 205.442.50203 Boehringer Ingelheim Investigational Site
city: Guatemala
country: Guatemala
facility: 205.442.50204 Boehringer Ingelheim Investigational Site
city: Nivel Guatemala
country: Guatemala
facility: 205.442.50201 Boehringer Ingelheim Investigational Site
city: Nivel Guatemala
country: Guatemala
facility: 205.442.50202 Boehringer Ingelheim Investigational Site
city: Vila hermosa I
country: Guatemala
facility: 205.442.50205 Boehringer Ingelheim Investigational Site
city: Budapest
country: Hungary
facility: 205.442.36007 Boehringer Ingelheim Investigational Site
city: Cegled
country: Hungary
facility: 205.442.36003 Boehringer Ingelheim Investigational Site
city: Gödöllö
country: Hungary
facility: 205.442.36002 Boehringer Ingelheim Investigational Site
city: Komarom
country: Hungary
facility: 205.442.36004 Boehringer Ingelheim Investigational Site
city: Pecs
country: Hungary
facility: 205.442.36006 Boehringer Ingelheim Investigational Site
city: Szarvas
country: Hungary
facility: 205.442.36001 Boehringer Ingelheim Investigational Site
city: Szazhalombatta
country: Hungary
facility: 205.442.36005 Boehringer Ingelheim Investigational Site
city: Ahmedabad
country: India
facility: 205.442.91011 Boehringer Ingelheim Investigational Site
city: Bangalore
country: India
facility: 205.442.91005 Boehringer Ingelheim Investigational Site
city: Banglore
country: India
facility: 205.442.91009 Boehringer Ingelheim Investigational Site
city: Coimbatore
country: India
facility: 205.442.91002 Boehringer Ingelheim Investigational Site
city: Coimbatore
country: India
facility: 205.442.91003 Boehringer Ingelheim Investigational Site
city: Coimbatore
country: India
facility: 205.442.91004 Boehringer Ingelheim Investigational Site
city: Hyderabad
country: India
facility: 205.442.91008 Boehringer Ingelheim Investigational Site
city: Jaipur
country: India
facility: 205.442.91007 Boehringer Ingelheim Investigational Site
city: Nagpur
country: India
facility: 205.442.91001 Boehringer Ingelheim Investigational Site
city: Pune
country: India
facility: 205.442.91006 Boehringer Ingelheim Investigational Site
city: Acquaviva delle Fonti (BA)
country: Italy
facility: 205.442.39007 Boehringer Ingelheim Investigational Site
city: Cagliari
country: Italy
facility: 205.442.39006 Boehringer Ingelheim Investigational Site
city: Chieti
country: Italy
facility: 205.442.39003 Boehringer Ingelheim Investigational Site
city: Pisa
country: Italy
facility: 205.442.39001 Boehringer Ingelheim Investigational Site
city: Cheongju-si
country: Korea, Republic of
facility: 205.442.82006 Boehringer Ingelheim Investigational Site
city: Gangwon-do
country: Korea, Republic of
facility: 205.442.82002 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 205.442.82001 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 205.442.82003 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 205.442.82004 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 205.442.82005 Boehringer Ingelheim Investigational Site
city: Baldone
country: Latvia
facility: 205.442.37101 Boehringer Ingelheim Investigational Site
city: Daugavpils
country: Latvia
facility: 205.442.37103 Boehringer Ingelheim Investigational Site
city: Daugavpils
country: Latvia
facility: 205.442.37104 Boehringer Ingelheim Investigational Site
city: Talsi
country: Latvia
facility: 205.442.37102 Boehringer Ingelheim Investigational Site
city: Gizycko
country: Poland
facility: 205.442.48003 Boehringer Ingelheim Investigational Site
city: Gorzow Wielkopolski
country: Poland
facility: 205.442.48002 Boehringer Ingelheim Investigational Site
city: Krakow
country: Poland
facility: 205.442.48005 Boehringer Ingelheim Investigational Site
city: Ostrow Wielkopolska
country: Poland
facility: 205.442.48004 Boehringer Ingelheim Investigational Site
city: Poznan
country: Poland
facility: 205.442.48001 Boehringer Ingelheim Investigational Site
city: Bardejov
country: Slovakia
facility: 205.442.42105 Boehringer Ingelheim Investigational Site
city: Humenne
country: Slovakia
facility: 205.442.42107 Boehringer Ingelheim Investigational Site
city: Kosice
country: Slovakia
facility: 205.442.42104 Boehringer Ingelheim Investigational Site
city: Nitra
country: Slovakia
facility: 205.442.42102 Boehringer Ingelheim Investigational Site
city: Nove Zamky
country: Slovakia
facility: 205.442.42101 Boehringer Ingelheim Investigational Site
city: Poprad
country: Slovakia
facility: 205.442.42108 Boehringer Ingelheim Investigational Site
city: Spisska Nova Ves
country: Slovakia
facility: 205.442.42106 Boehringer Ingelheim Investigational Site
city: Topolcany
country: Slovakia
facility: 205.442.42103 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: 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: Paggiaro P, Halpin DM, Buhl R, Engel M, Zubek VB, Blahova Z, Moroni-Zentgraf P, Pizzichini E. The Effect of Tiotropium in Symptomatic Asthma Despite Low- to Medium-Dose Inhaled Corticosteroids: A Randomized Controlled Trial. J Allergy Clin Immunol Pract. 2016 Jan-Feb;4(1):104-13.e2. doi: 10.1016/j.jaip.2015.08.017. Epub 2015 Nov 7.