Clinical trial NCT01257230: Efficacy and Safety of 2 Doses of Tiotropium Via Respimat Compared to Placebo in Adolescents With Moderate Persistent Asthma
Official title: A Phase III, Randomised, Double Blind, Placebo-controlled, Parallel Group Study to Assess the Efficacy and Safety Over 48 Weeks of Orally Inhaled Tiotropium Bromide (2.5 and 5 µg Once Daily ) Delivered by the Respimat® Inhaler in Adolescents (12 to 17 Years Old) With 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: 2010-12-09
Enrollment: 398
Sex: ALL
Minimum age (years): 12
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The aim of the study is to evaluate efficacy and safety of a 48-week treatment with two doses of tiotropium bromide compared to placebo in adolescent patients with moderate persistent asthma. Efficacy and safety will be assessed by measuring lung function parameters and evaluating the effects on asthma exacerbations, on Quality of life, on health care resource utilisation an on the number of adverse events.


Eligibility criteria: Inclusion criteria:

1. All patients and their parents (or legally accepted caregiver) must sign and date an informed consent consistent with ICH-GCP guidelines and local legislation prior to participation in the trial.
2. Male or female patients between 12 and 17 years of age.
3. All patients must have at least a 3 months history of asthma at the time of enrolment into the trial. The diagnosis of asthma has to be confirmed at visit 1 with a bronchodilator reversibility test.
4. All patients must have been on maintenance treatment with inhaled corticosteroids at a stable medium dose for at least 4 weeks before Visit 1.
5. All patients must be symptomatic (partly controlled) at Visit 1 (screening) and at randomisation defined by an Asthma Control Questionnaire (ACQ) mean score of more than or equal to 1.5.
6. All patients must have a pre-bronchodilator FEV1 more than or equal to 60% and less than or equal to 90% of predicted normal at Visit 1. Variation of absolute FEV1 values of Visit 1 as compared to Visit 2 must be within ± 30%.
7. All patients must have an increase in FEV1 of equal or above 12% and 200 mL after 400 µg salbutamol (albuterol) at Visit 1. If patients in the lower age range (e.g., 12 to 14 year olds) exhibit a very small total lung volume, positive reversibility testing might be based solely on the relative (12%) post-bronchodilator response.
8. All patients should be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment.
9. Patients should be able to use the Respimat® inhaler correctly.
10. Patients must be able to perform all trial related procedures including technically acceptable spirometric manoeuvres.

Exclusion criteria:

1. Patients with a significant disease other than asthma.
2. Patients with clinically relevant abnormal screening haematology or blood chemistry
3. Patients with a history of congenital or acquired heart disease, and/or have been hospitalised for cardiac syncope or failure during the past year.
4. Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year.
5. Patients with malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years.
6. Patients with lung diseases other than asthma (e.g. Cystic Fibrosis). In case of ex-premature infants, a history of significant bronchopulmonary dysplasia will be regarded as exclusion criterion.
7. Patients with known active tuberculosis.
8. Patients with significant alcohol or drug abuse within the past two years.
9. Patients who have undergone thoracotomy with pulmonary resection.
10. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to the screening visit (Visit 1).
11. Patients with known hypersensitivity to anticholinergic drugs, Benzalkonium chloride (BAC), Ethylenediaminetetraacetic acis (EDTA) or any other components of the tiotropium inhalation solution.
12. Pregnant or nursing adolescent female patients
13. Sexually active female patients of child-bearing potential not using a highly effective method of birth control.
14. Patients who have taken an investigational drug within 4 weeks prior to Visit 1.
15. Patients who have been treated with long-acting anticholinergics (e.g. tiotropium -Spiriva) within four weeks prior to screening (Visit 1).
16. Patients who are unable to comply with pulmonary medication restrictions prior to randomisation.
17. Patients who have been treated with Anti-IgE treatment (Omalizumab Xolair) within the last 6 months prior to screening.
18. Patients who have been treated with systemic (oral or intravenous) corticosteroids within 4 weeks prior to screening (Visit 1).
19. Patients who have been treated with long-acting theophylline preparations within 2 weeks prior to screening (Visit 1) or during the run-in period
20. Patients who have been treated with other non-approved and according to international guidelines not recommended ¿experimental¿ drugs for routine asthma therapy.
21. Patients with any acute asthma exacerbation or respiratory tract infection in the 4 weeks prior to Visit 1.
22. Patients requiring 10 or more puffs of rescue medication (salbutamol/albuterol) per day on more than 2 consecutive days during the run-in period.
23. Patients who have previously been randomised in this trial or are currently participating in another study.
24. Patients who are being treated with oral beta-blocker medication.
25. Patients with a known narrow-angle glaucoma, or any other disease where anticholinergic treatment is contraindicated.
26. Patients with renal impairment, as defined by a creatinine clearance less than 50 mL/min/1.73 m2 Body Surface Area as calculated by Schwartz formula.

Primary outcomes:
measure: FEV1 peak0-3 Change From Baseline
timeFrame: Baseline and 24 weeks
Secondary outcomes:
measure: Trough FEV1 Change From Baseline
timeFrame: Baseline and 24 weeks
measure: FVC peak0-3 Change From Baseline
timeFrame: Baseline and 24 weeks
measure: Trough FVC Change From Baseline
timeFrame: Baseline and 24 weeks
measure: FEV1 AUC (0-3h) Change From Baseline
timeFrame: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 24 weeks
measure: FVC AUC (0-3h) Change From Baseline
timeFrame: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 24 weeks
measure: FEF25-75 Change From Baseline
timeFrame: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 24 weeks
measure: Use of PRN Rescue Medication During the Daytime
timeFrame: Baseline and Week 24
measure: Use of PRN Rescue Medication During the Night-time
timeFrame: Baseline and week 24
measure: Use of PRN Rescue Medication During the Day
timeFrame: Baseline and week 24
measure: Control of Asthma as Assessed by ACQ Total Score
timeFrame: Baseline and week 24
measure: ACQ Total Score Responders
timeFrame: Week 24
measure: Control of Asthma as Assessed by ACQ6
timeFrame: Baseline and week 24
measure: ACQ6 Responders
timeFrame: Week 24
measure: Time to First Severe Asthma Exacerbation During the 48 Week Treatment Period
timeFrame: 48 weeks
measure: Time to First Asthma Exacerbation During the 48 Week Treatment Period
timeFrame: Week 48
Other outcomes:
Locations:
city: Plymouth
country: United States
facility: 205.444.01004 Boehringer Ingelheim Investigational Site
state: Minnesota
city: Columbia
country: United States
facility: 205.444.01005 Boehringer Ingelheim Investigational Site
state: Missouri
city: Cincinnati
country: United States
facility: 205.444.01001 Boehringer Ingelheim Investigational Site
state: Ohio
city: Oklahoma City
country: United States
facility: 205.444.01014 Boehringer Ingelheim Investigational Site
state: Oklahoma
city: Charleston
country: United States
facility: 205.444.01002 Boehringer Ingelheim Investigational Site
state: South Carolina
city: Charleston
country: United States
facility: 205.444.01012 Boehringer Ingelheim Investigational Site
state: South Carolina
city: El Paso
country: United States
facility: 205.444.01013 Boehringer Ingelheim Investigational Site
state: Texas
city: South Burlington
country: United States
facility: 205.444.01003 Boehringer Ingelheim Investigational Site
state: Vermont
city: Santiago
country: Chile
facility: 205.444.56002 Boehringer Ingelheim Investigational Site
city: Viña del Mar
country: Chile
facility: 205.444.56001 Boehringer Ingelheim Investigational Site
city: Viña del Mar
country: Chile
facility: 205.444.56003 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 205.444.49007 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 205.444.49008 Boehringer Ingelheim Investigational Site
city: Bochum
country: Germany
facility: 205.444.49001 Boehringer Ingelheim Investigational Site
city: Ettenheim
country: Germany
facility: 205.444.49003 Boehringer Ingelheim Investigational Site
city: Koblenz
country: Germany
facility: 205.444.49006 Boehringer Ingelheim Investigational Site
city: Rosenheim
country: Germany
facility: 205.444.49005 Boehringer Ingelheim Investigational Site
city: Ajka
country: Hungary
facility: 205.444.36007 Boehringer Ingelheim Investigational Site
city: Budapest
country: Hungary
facility: 205.444.36005 Boehringer Ingelheim Investigational Site
city: Budapest
country: Hungary
facility: 205.444.36008 Boehringer Ingelheim Investigational Site
city: Kaposvar
country: Hungary
facility: 205.444.36006 Boehringer Ingelheim Investigational Site
city: Miskolc
country: Hungary
facility: 205.444.36001 Boehringer Ingelheim Investigational Site
city: Mosdos
country: Hungary
facility: 205.444.36002 Boehringer Ingelheim Investigational Site
city: Szeged
country: Hungary
facility: 205.444.36003 Boehringer Ingelheim Investigational Site
city: Szigetbecse
country: Hungary
facility: 205.444.36004 Boehringer Ingelheim Investigational Site
city: Ancona
country: Italy
facility: 205.444.39001 Boehringer Ingelheim Investigational Site
city: Bolzano
country: Italy
facility: 205.444.39003 Boehringer Ingelheim Investigational Site
city: Verona
country: Italy
facility: 205.444.39002 Boehringer Ingelheim Investigational Site
city: Guri
country: Korea, Republic of
facility: 205.444.82003 Boehringer Ingelheim Investigational Site
city: Incheon
country: Korea, Republic of
facility: 205.444.82006 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 205.444.82001 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 205.444.82004 Boehringer Ingelheim Investigational Site
city: Baldone
country: Latvia
facility: 205.444.37101 Boehringer Ingelheim Investigational Site
city: Balvi
country: Latvia
facility: 205.444.37107 Boehringer Ingelheim Investigational Site
city: Ogre
country: Latvia
facility: 205.444.37102 Boehringer Ingelheim Investigational Site
city: Rezekne
country: Latvia
facility: 205.444.37105 Boehringer Ingelheim Investigational Site
city: Riga
country: Latvia
facility: 205.444.37106 Boehringer Ingelheim Investigational Site
city: Talsi
country: Latvia
facility: 205.444.37103 Boehringer Ingelheim Investigational Site
city: Tukums
country: Latvia
facility: 205.444.37104 Boehringer Ingelheim Investigational Site
city: Guadalajara
country: Mexico
facility: 205.444.52002 Boehringer Ingelheim Investigational Site
city: Hermosillo
country: Mexico
facility: 205.444.52001 Boehringer Ingelheim Investigational Site
city: Monterrey
country: Mexico
facility: 205.444.52003 Boehringer Ingelheim Investigational Site
city: Moscow
country: Russian Federation
facility: 205.444.70003 Boehringer Ingelheim Investigational Site
city: St. Petersburg
country: Russian Federation
facility: 205.444.70002 Boehringer Ingelheim Investigational Site
city: St. Petersburg
country: Russian Federation
facility: 205.444.70004 Boehringer Ingelheim Investigational Site
city: St. Petersburg
country: Russian Federation
facility: 205.444.70005 Boehringer Ingelheim Investigational Site
city: St. Petersburg
country: Russian Federation
facility: 205.444.70006 Boehringer Ingelheim Investigational Site
city: Yaroslavl
country: Russian Federation
facility: 205.444.70001 Boehringer Ingelheim Investigational Site
city: Kosice
country: Slovakia
facility: 205.444.42104 Boehringer Ingelheim Investigational Site
city: Martin
country: Slovakia
facility: 205.444.42106 Boehringer Ingelheim Investigational Site
city: Nitra
country: Slovakia
facility: 205.444.42101 Boehringer Ingelheim Investigational Site
city: Roznava
country: Slovakia
facility: 205.444.42105 Boehringer Ingelheim Investigational Site
city: Esplugues del Llobregat
country: Spain
facility: 205.444.34007 Boehringer Ingelheim Investigational Site
city: Madrid
country: Spain
facility: 205.444.34001 Boehringer Ingelheim Investigational Site
city: Majadahonda (Madrid)
country: Spain
facility: 205.444.34004 Boehringer Ingelheim Investigational Site
city: Marbella
country: Spain
facility: 205.444.34005 Boehringer Ingelheim Investigational Site
city: Sabdadell
country: Spain
facility: 205.444.34006 Boehringer Ingelheim Investigational Site
city: Valencia
country: Spain
facility: 205.444.34008 Boehringer Ingelheim Investigational Site
city: Dnipropetrovsk
country: Ukraine
facility: 205.444.38008 Boehringer Ingelheim Investigational Site
city: Donetsk
country: Ukraine
facility: 205.444.38002 Boehringer Ingelheim Investigational Site
city: Kharkiv
country: Ukraine
facility: 205.444.38005 Boehringer Ingelheim Investigational Site
city: Kiev
country: Ukraine
facility: 205.444.38003 Boehringer Ingelheim Investigational Site
city: Kiev
country: Ukraine
facility: 205.444.38004 Boehringer Ingelheim Investigational Site
city: Lviv
country: Ukraine
facility: 205.444.38001 Boehringer Ingelheim Investigational Site
city: Zaporizhya
country: Ukraine
facility: 205.444.38010 Boehringer Ingelheim Investigational Site
city: Zaporizhzhya
country: Ukraine
facility: 205.444.38009 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: Hamelmann E, Bateman ED, Vogelberg C, Szefler SJ, Vandewalker M, Moroni-Zentgraf P, Avis M, Unseld A, Engel M, Boner AL. Tiotropium add-on therapy in adolescents with moderate asthma: A 1-year randomized controlled trial. J Allergy Clin Immunol. 2016 Aug;138(2):441-450.e8. doi: 10.1016/j.jaci.2016.01.011. Epub 2016 Mar 5.