Efficacy and Safety of 2 Doses of Tiotropium Via Respimat Compared to Placebo in Adolescents With Moderate Persistent Asthma

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.

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.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: placebo Respimat; Drug: tiotropium Respimat low dose; Drug: tiotropium Respimat high dose

• Study Type: Interventional
• Enrollment (Actual): 398
• Phase: Phase 3

Contacts and Locations

Study Locations

• Chile
  • Santiago, Chile
    • 205.444.56002 Boehringer Ingelheim Investigational Site
  • Viña del Mar, Chile
    • 205.444.56001 Boehringer Ingelheim Investigational Site
  • Viña del Mar, Chile
    • 205.444.56003 Boehringer Ingelheim Investigational Site
• Germany
  • Berlin, Germany
    • 205.444.49007 Boehringer Ingelheim Investigational Site
  • Berlin, Germany
    • 205.444.49008 Boehringer Ingelheim Investigational Site
  • Bochum, Germany
    • 205.444.49001 Boehringer Ingelheim Investigational Site
  • Ettenheim, Germany
    • 205.444.49003 Boehringer Ingelheim Investigational Site
  • Koblenz, Germany
    • 205.444.49006 Boehringer Ingelheim Investigational Site
  • Rosenheim, Germany
    • 205.444.49005 Boehringer Ingelheim Investigational Site
• Hungary
  • Ajka, Hungary
    • 205.444.36007 Boehringer Ingelheim Investigational Site
  • Budapest, Hungary
    • 205.444.36005 Boehringer Ingelheim Investigational Site
  • Budapest, Hungary
    • 205.444.36008 Boehringer Ingelheim Investigational Site
  • Kaposvar, Hungary
    • 205.444.36006 Boehringer Ingelheim Investigational Site
  • Miskolc, Hungary
    • 205.444.36001 Boehringer Ingelheim Investigational Site
  • Mosdos, Hungary
    • 205.444.36002 Boehringer Ingelheim Investigational Site
  • Szeged, Hungary
    • 205.444.36003 Boehringer Ingelheim Investigational Site
  • Szigetbecse, Hungary
    • 205.444.36004 Boehringer Ingelheim Investigational Site
• Italy
  • Ancona, Italy
    • 205.444.39001 Boehringer Ingelheim Investigational Site
  • Bolzano, Italy
    • 205.444.39003 Boehringer Ingelheim Investigational Site
  • Verona, Italy
    • 205.444.39002 Boehringer Ingelheim Investigational Site
• Korea, Republic of
  • Guri, Korea, Republic of
    • 205.444.82003 Boehringer Ingelheim Investigational Site
  • Incheon, Korea, Republic of
    • 205.444.82006 Boehringer Ingelheim Investigational Site
  • Seoul, Korea, Republic of
    • 205.444.82001 Boehringer Ingelheim Investigational Site
  • Seoul, Korea, Republic of
    • 205.444.82004 Boehringer Ingelheim Investigational Site
• Latvia
  • Baldone, Latvia
    • 205.444.37101 Boehringer Ingelheim Investigational Site
  • Balvi, Latvia
    • 205.444.37107 Boehringer Ingelheim Investigational Site
  • Ogre, Latvia
    • 205.444.37102 Boehringer Ingelheim Investigational Site
  • Rezekne, Latvia
    • 205.444.37105 Boehringer Ingelheim Investigational Site
  • Riga, Latvia
    • 205.444.37106 Boehringer Ingelheim Investigational Site
  • Talsi, Latvia
    • 205.444.37103 Boehringer Ingelheim Investigational Site
  • Tukums, Latvia
    • 205.444.37104 Boehringer Ingelheim Investigational Site
• Mexico
  • Guadalajara, Mexico
    • 205.444.52002 Boehringer Ingelheim Investigational Site
  • Hermosillo, Mexico
    • 205.444.52001 Boehringer Ingelheim Investigational Site
  • Monterrey, Mexico
    • 205.444.52003 Boehringer Ingelheim Investigational Site
• Russian Federation
  • Moscow, Russian Federation
    • 205.444.70003 Boehringer Ingelheim Investigational Site
  • St. Petersburg, Russian Federation
    • 205.444.70002 Boehringer Ingelheim Investigational Site
  • St. Petersburg, Russian Federation
    • 205.444.70004 Boehringer Ingelheim Investigational Site
  • St. Petersburg, Russian Federation
    • 205.444.70005 Boehringer Ingelheim Investigational Site
  • St. Petersburg, Russian Federation
    • 205.444.70006 Boehringer Ingelheim Investigational Site
  • Yaroslavl, Russian Federation
    • 205.444.70001 Boehringer Ingelheim Investigational Site
• Slovakia
  • Kosice, Slovakia
    • 205.444.42104 Boehringer Ingelheim Investigational Site
  • Martin, Slovakia
    • 205.444.42106 Boehringer Ingelheim Investigational Site
  • Nitra, Slovakia
    • 205.444.42101 Boehringer Ingelheim Investigational Site
  • Roznava, Slovakia
    • 205.444.42105 Boehringer Ingelheim Investigational Site
• Spain
  • Esplugues del Llobregat, Spain
    • 205.444.34007 Boehringer Ingelheim Investigational Site
  • Madrid, Spain
    • 205.444.34001 Boehringer Ingelheim Investigational Site
  • Majadahonda (Madrid), Spain
    • 205.444.34004 Boehringer Ingelheim Investigational Site
  • Marbella, Spain
    • 205.444.34005 Boehringer Ingelheim Investigational Site
  • Sabdadell, Spain
    • 205.444.34006 Boehringer Ingelheim Investigational Site
  • Valencia, Spain
    • 205.444.34008 Boehringer Ingelheim Investigational Site
• Ukraine
  • Dnipropetrovsk, Ukraine
    • 205.444.38008 Boehringer Ingelheim Investigational Site
  • Donetsk, Ukraine
    • 205.444.38002 Boehringer Ingelheim Investigational Site
  • Kharkiv, Ukraine
    • 205.444.38005 Boehringer Ingelheim Investigational Site
  • Kiev, Ukraine
    • 205.444.38003 Boehringer Ingelheim Investigational Site
  • Kiev, Ukraine
    • 205.444.38004 Boehringer Ingelheim Investigational Site
  • Lviv, Ukraine
    • 205.444.38001 Boehringer Ingelheim Investigational Site
  • Zaporizhya, Ukraine
    • 205.444.38010 Boehringer Ingelheim Investigational Site
  • Zaporizhzhya, Ukraine
    • 205.444.38009 Boehringer Ingelheim Investigational Site
• United States
  • Minnesota
    • Plymouth, Minnesota, United States
      • 205.444.01004 Boehringer Ingelheim Investigational Site
  • Missouri
    • Columbia, Missouri, United States
      • 205.444.01005 Boehringer Ingelheim Investigational Site
  • Ohio
    • Cincinnati, Ohio, United States
      • 205.444.01001 Boehringer Ingelheim Investigational Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
      • 205.444.01014 Boehringer Ingelheim Investigational Site
  • South Carolina
    • Charleston, South Carolina, United States
      • 205.444.01002 Boehringer Ingelheim Investigational Site
    • Charleston, South Carolina, United States
      • 205.444.01012 Boehringer Ingelheim Investigational Site
  • Texas
    • El Paso, Texas, United States
      • 205.444.01013 Boehringer Ingelheim Investigational Site
  • Vermont
    • South Burlington, Vermont, United States
      • 205.444.01003 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 17 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: placebo; once daily, delivered with Respimat inhaler	Drug: placebo Respimat; placebo representing comparator
EXPERIMENTAL: tiotropium low dose; once daily, delivered with Respimat inhaler	Drug: tiotropium Respimat low dose; IMP
EXPERIMENTAL: tiotropium high dose; once daily, delivered with Respimat inhaler	Drug: tiotropium Respimat high dose; IMP

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
FEV1 peak0-3 Change From Baseline	Change from baseline in peak Forced expiratory volume in 1 second within the first 3 hours post dosing (FEV1 peak0-3) measured at week 24. Note, the measured values presented are actually adjusted means.	Baseline and 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Trough FEV1 Change From Baseline	Change from baseline in Trough (pre-dose) Forced expiratory volume in 1 second (FEV1) measured at week 24. The measured values presented are actually adjusted means.	Baseline and 24 weeks
FVC peak0-3 Change From Baseline	Change from baseline in Maximum forced vital capacity (FVC) measured within the first 3 h after administration of trial medication (FVC peak0-3h) after 24 weeks of treatment. The measured values presented are actually adjusted means.	Baseline and 24 weeks
Trough FVC Change From Baseline	Change from baseline of Trough (pre-dose) forced vital capacity (FVC) measured 10 min before the administration of trial medication after 24 weeks of treatment. The measured values presented are actually adjusted means..	Baseline and 24 weeks
FEV1 AUC (0-3h) Change From Baseline	Change from baseline of area under the curve (AUC) from 0 to 3 h for FEV1 (FEV1 AUC 0-3h) after 24 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h). The measured values presented are actually adjusted means.	Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 24 weeks
FVC AUC (0-3h) Change From Baseline	Change from baseline of area under the curve (AUC) from 0 to 3 h for FVC (FVC AUC0-3h) after 24 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h). The measured values presented are actually adjusted means.	Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 24 weeks
FEF25-75 Change From Baseline	Change from baseline in mean forced expiratory flow between 25% and 75% of the FVC (FEF25-75%), also known as maximum mid-expiratory flow, at individual time points after 24 weeks of treatment. The measured values presented are actually adjusted means.	Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 24 weeks
Use of PRN Rescue Medication During the Daytime	Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the daytime based on the weekly mean at week 24. The measured values presented are actually adjusted means.	Baseline and Week 24
Use of PRN Rescue Medication During the Night-time	Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the night-time based on the weekly mean at week 24. The measured values presented are actually adjusted means.	Baseline and week 24
Use of PRN Rescue Medication During the Day	Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the day (24 hour period) based on the weekly mean at week 24. The measured values presented are actually adjusted means.	Baseline and week 24
Control of Asthma as Assessed by ACQ Total Score	Change from baseline in Asthma Control Questionnaire (ACQ) total score measured at week 24. The ACQ is a scale containing 7 questions, each question has a 7-point scale which ranges from 0 to 6; a score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ total score was calculated as the mean of the responses to all 7 questions. The measured values presented are actually adjusted means.	Baseline and week 24
ACQ Total Score Responders	Responder rates based on the ACQ total score after 24 weeks of treatment. Analysis was performed using the following categories and definitions: responder (change from trial baseline ≤-0.5), no change (-0.5 <change from trial baseline <0.5) and worsening (change from trial baseline ≥0.5) The ACQ is a scale containing 7 questions, each question has a 7-point scale which ranges from 0 to 6; a score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment.	Week 24
Control of Asthma as Assessed by ACQ6	Change from baseline in AQC6 score at week 24. The ACQ6 score is calculated as the mean of the responses to the first 6 questions of the ACQ. The ACQ is a scale containing 7 questions, each question has a 7-point scale which ranges from 0 to 6; a score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. The measured values presented are actually adjusted means.	Baseline and week 24
ACQ6 Responders	Responder rates based on the ACQ6 after 24 weeks of treatment. Analysis was performed using the following categories and definitions: responder (change from trial baseline ≤-0.5), no change (-0.5 <change from trial baseline <0.5) and worsening (change from trial baseline ≥0.5) The ACQ6 score is calculated as the mean of the responses to the first 6 questions of the ACQ. The ACQ is a scale containing 7 questions, each question has a 7-point scale which ranges from 0 to 6; a score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment.	Week 24
Time to First Severe Asthma Exacerbation During the 48 Week Treatment Period	The median time to first severe asthma exacerbation was not calculable, so the number of patients who experienced a severe asthma exacerbation are presented for the measured values. A severe asthma exacerbation was defined as a subgroup of all asthma exacerbations that required treatment with systemic corticosteroid for at least 3 days.	48 weeks
Time to First Asthma Exacerbation During the 48 Week Treatment Period	The median time to first asthma exacerbation was not calculable, so the number of patients who experienced an asthma exacerbation are presented for the measured values.	Week 48

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim
• Collaborators: Pfizer

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (ACTUAL): December 1, 2013
• Study Completion (ACTUAL): December 1, 2013

Study Registration Dates

• First Submitted: December 6, 2010
• First Submitted That Met QC Criteria: December 8, 2010
• First Posted (ESTIMATE): December 9, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): September 5, 2014
• Last Update Submitted That Met QC Criteria: August 27, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Tiotropium Bromide
• Other Study ID Numbers: 205.444; 2010-021093-11 (EUDRACT_NUMBER: EudraCT)