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

A Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution Delivered Via Respimat® Inhaler (2.5 mcg and 5 mcg Once Daily) Over 12 Weeks as add-on Controller Therapy on Top of Usual Care in Adolescents (12 to 17 Years Old) With Severe Persistent Asthma

The overall purpose of the trial is to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 mcg and 5 mcg once daily) over 12 weeks, compared to placebo, as add-on controller therapy on top of usual care in adolescents (12 to 17 years old) with severe persistent asthma.

The primary objective of the trial is to demonstrate superiority of tiotropium (5 mcg and possibly 2.5 mcg once daily in the evening) over placebo with regard to the primary pulmonary function endpoint after 12 weeks of treatment.

Secondary objectives are to evaluate efficacy of tiotropium with regard to other endpoints, and to evaluate the safety of tiotropium, compared to placebo, as add-on controller therapy on top of usual care in this patient population.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 392
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Capital Federal, Argentina
    • 205.456.54002 Boehringer Ingelheim Investigational Site
  • Capital Federal, Argentina
    • 205.456.54006 Boehringer Ingelheim Investigational Site
  • Capital Federal, Argentina
    • 205.456.54008 Boehringer Ingelheim Investigational Site
  • Florencio Varela, Argentina
    • 205.456.54003 Boehringer Ingelheim Investigational Site
  • Mendoza, Argentina
    • 205.456.54005 Boehringer Ingelheim Investigational Site
  • San Miguel de Tucuman, Argentina
    • 205.456.54009 Boehringer Ingelheim Investigational Site
  • San Miguel de Tucumán, Argentina
    • 205.456.54004 Boehringer Ingelheim Investigational Site
• Australia
  • Victoria
    • Parkville, Victoria, Australia
      • 205.456.61002 Boehringer Ingelheim Investigational Site
  • Western Australia
    • Perth, Western Australia, Australia
      • 205.456.61001 Boehringer Ingelheim Investigational Site
• Bulgaria
  • Plovdiv, Bulgaria
    • 205.456.35902 Boehringer Ingelheim Investigational Site
  • Ruse, Bulgaria
    • 205.456.35901 Boehringer Ingelheim Investigational Site
  • Sofia, Bulgaria
    • 205.456.35903 Boehringer Ingelheim Investigational Site
• Germany
  • Berlin, Germany
    • 205.456.49008 Boehringer Ingelheim Investigational Site
  • Bochum, Germany
    • 205.456.49001 Boehringer Ingelheim Investigational Site
  • Frankfurt, Germany
    • 205.456.49004 Boehringer Ingelheim Investigational Site
  • Kehl, Germany
    • 205.456.49005 Boehringer Ingelheim Investigational Site
  • Koblenz, Germany
    • 205.456.49003 Boehringer Ingelheim Investigational Site
  • Mainz, Germany
    • 205.456.49010 Boehringer Ingelheim Investigational Site
  • Neu-Isenburg, Germany
    • 205.456.49007 Boehringer Ingelheim Investigational Site
  • Wesel, Germany
    • 205.456.49002 Boehringer Ingelheim Investigational Site
• Guatemala
  • Guatemala City, Guatemala
    • 205.456.50201 Boehringer Ingelheim Investigational Site
  • Guatemala City, Guatemala
    • 205.456.50203 Boehringer Ingelheim Investigational Site
  • Guatemala City, Guatemala
    • 205.456.50204 Boehringer Ingelheim Investigational Site
  • Guatemala City, Guatemala
    • 205.456.50205 Boehringer Ingelheim Investigational Site
• Hungary
  • Budapest, Hungary
    • 205.456.36005 Boehringer Ingelheim Investigational Site
  • Debrecen, Hungary
    • 205.456.36002 Boehringer Ingelheim Investigational Site
  • Gyula, Hungary
    • 205.456.36004 Boehringer Ingelheim Investigational Site
  • Miskolc, Hungary
    • 205.456.36001 Boehringer Ingelheim Investigational Site
  • Mosdos, Hungary
    • 205.456.36007 Boehringer Ingelheim Investigational Site
  • Nagyatad, Hungary
    • 205.456.36006 Boehringer Ingelheim Investigational Site
• Israel
  • Holon, Israel
    • 205.456.97205 Boehringer Ingelheim Investigational Site
  • Petach Tikva, Israel
    • 205.456.97203 Boehringer Ingelheim Investigational Site
  • Safed, Israel
    • 205.456.97201 Boehringer Ingelheim Investigational Site
• Latvia
  • Baldone, Latvia
    • 205.456.37101 Boehringer Ingelheim Investigational Site
  • Balvi, Latvia
    • 205.456.37104 Boehringer Ingelheim Investigational Site
  • Rezekne, Latvia
    • 205.456.37103 Boehringer Ingelheim Investigational Site
  • Riga, Latvia
    • 205.456.37102 Boehringer Ingelheim Investigational Site
  • Talsi, Latvia
    • 205.456.37105 Boehringer Ingelheim Investigational Site
• Mexico
  • Hermosillo Sonora, Mexico
    • 205.456.52001 Boehringer Ingelheim Investigational Site
  • Monterrey, Mexico
    • 205.456.52002 Boehringer Ingelheim Investigational Site
  • Monterrey, Mexico
    • 205.456.52003 Boehringer Ingelheim Investigational Site
  • Nuevo León, Mexico
    • 205.456.52004 Boehringer Ingelheim Investigational Site
• Philippines
  • Quezon City, Philippines
    • 205.456.09001 Boehringer Ingelheim Investigational Site
  • Quezon City, Philippines
    • 205.456.09002 Boehringer Ingelheim Investigational Site
• Portugal
  • Coimbra, Portugal
    • 205.456.35105 Boehringer Ingelheim Investigational Site
  • Lisboa, Portugal
    • 205.456.35101 Boehringer Ingelheim Investigational Site
  • Lisboa, Portugal
    • 205.456.35102 Boehringer Ingelheim Investigational Site
  • Lisboa, Portugal
    • 205.456.35104 Boehringer Ingelheim Investigational Site
  • Porto, Portugal
    • 205.456.35103 Boehringer Ingelheim Investigational Site
• South Africa
  • Cape Town, South Africa
    • 205.456.27001 Boehringer Ingelheim Investigational Site
  • Durban, South Africa
    • 205.456.27002 Boehringer Ingelheim Investigational Site
• Ukraine
  • Dnipropetrovsk, Ukraine
    • 205.456.38006 Boehringer Ingelheim Investigational Site
  • Kharkiv, Ukraine
    • 205.456.38004 Boehringer Ingelheim Investigational Site
  • Kiev, Ukraine
    • 205.456.38003 Boehringer Ingelheim Investigational Site
  • Kriviy Rig, Ukraine
    • 205.456.38010 Boehringer Ingelheim Investigational Site
  • Kyiv, Ukraine
    • 205.456.38009 Boehringer Ingelheim Investigational Site
  • Lviv, Ukraine
    • 205.456.38001 Boehringer Ingelheim Investigational Site
  • Lviv, Ukraine
    • 205.456.38007 Boehringer Ingelheim Investigational Site
  • Uzhgorod, Ukraine
    • 205.456.38005 Boehringer Ingelheim Investigational Site
  • Vinnytsya, Ukraine
    • 205.456.38008 Boehringer Ingelheim Investigational Site
  • Zaporizhzhya, Ukraine
    • 205.456.38002 Boehringer Ingelheim Investigational Site
• United States
  • California
    • Stockton, California, United States
      • 205.456.01004 Boehringer Ingelheim Investigational Site
  • Illinois
    • Normal, Illinois, United States
      • 205.456.01008 Boehringer Ingelheim Investigational Site
  • Maryland
    • Baltimore, Maryland, United States
      • 205.456.01003 Boehringer Ingelheim Investigational Site
  • Missouri
    • Columbia, Missouri, United States
      • 205.456.01007 Boehringer Ingelheim Investigational Site
  • Nebraska
    • Bellevue, Nebraska, United States
      • 205.456.01002 Boehringer Ingelheim Investigational Site
  • New York
    • Rockville Centre, New York, United States
      • 205.456.01001 Boehringer Ingelheim Investigational Site
  • Ohio
    • Cincinnati, Ohio, United States
      • 205.456.01005 Boehringer Ingelheim Investigational Site
  • South Carolina
    • Summerville, South Carolina, United States
      • 205.456.01006 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 parent(s) (or legally accepted representative) must sign and date respectively an informed assent and an informed consent consistent with International Conference on Harmonisation - Harmonised Tripartite Guideline for Good Clinical Practice (ICH-GCP) guidelines and local legislation prior to the patient's participation in the trial. A separate informed consent/assent is required for pharmacogenomic sampling.
2. Male or female patients between 12 and 17 years of age (at date of informed consent/assent).
3. All patients must have at least a 3-month history of asthma at the time of enrolment into the trial.
4. All patients must have been on maintenance treatment with an inhaled corticosteroid either at stable high dose in combination with another controller medication, OR at stable medium dose in combination with two other controller medications, for at least 4 weeks before Visit 1.
5. 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 = 1.5.
6. All patients must have a pre-bronchodilator Forced Expiratory Volume in 1 second (FEV1) = 60% and = 90% of predicted normal at Visit 1.
7. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator, considered as 100%) as compared to Visit 2 (pre-dose) must be within ± 30%.
8. All patients must confirm the diagnosis of asthma by bronchodilator reversibility at Visit 1, resulting in an increase in FEV1 of = 12% and = 200 mL 15 to 30 minutes after 400 µg salbutamol (albuterol). If patients in the lower age range (e.g. 12 to 14 year old patients) exhibit a very small total lung volume, positive reversibility testing might be based solely on the relative (=12%) post-bronchodilator response.
9. All patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment.
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 spirometric manoeuvres according to American Thoracic Society/ European Respiratory Society (ATS/ERS) standards and use of the electronic diary/peak flow meter (diary compliance of at least 80% is required).

Exclusion criteria:

1. Significant disease other than asthma.
2. Abnormal haematology or blood chemistry.
3. History of heart disease, and/or hospitalised for cardiac syncope or failure.
4. Any unstable or life-threatening or requiring intervention or cardiac arrhythmia.
5. Malignancy for which the patient has undergone resection, radiation therapy or chemotherapy.
6. Active tuberculosis.
7. Alcohol or drug abuse.
8. Thoracotomy with pulmonary resection.
9. Pulmonary rehabilitation program.
10. Hypersensitivity to anticholinergic drugs, or any components of the study medication delivery system.
11. Pregnant or nursing adolescent female patients.
12. Female patients of child-bearing potential not using a highly effective method of birth control.
13. Investigational drug within four weeks or six half lives prior to Visit 1.
14. Long-acting anticholinergics within four weeks prior to Visit 1.
15. Systemic corticosteroids at a high dose or at a not stable low dose within four weeks prior to Visit 1.
16. Leukotriene modifiers if not stabilised for at least four weeks prior to Visit 1.
17. Long-acting theophylline preparations if not stabilised for at least two weeks prior to Visit 1.
18. Anti Immunoglobulin E (Anti-IgE) treatment if not stabilised for at least six months prior to Visit 1.
19. Cromones if not stabilised within four weeks prior to Visit 1.
20. Oral beta-blocker medication within four weeks prior to Visit 1.
21. Systemic oral or i.v. or s.c. beta-adrenergics within four weeks prior to Visit 1.
22. Other non-approved and according to international guidelines not recommended experimental drugs for routine asthma therapy within four weeks prior to Visit 1.
23. Any acute asthma exacerbation or respiratory tract infection in the four weeks prior to Visit 1and/or in the four weeks prior to Visit 2. In case of an asthma deterioration occurring in the four weeks prior to Visit 1 and/or in the four weeks prior to Visit 2, the visit must be postponed.
24. Randomised in this trial or currently participating in another trial.
25. Narrow-angle glaucoma, or any other disease where anticholinergic treatment is contraindicated.
26. Moderate to severe renal impairment.
27. Patients requiring 10 or more puffs of rescue medication per day on more than 2 consecutive days in the four weeks prior to Visit 1 and/or in the four weeks prior to Visit 2. In case of an asthma deterioration occurring in the four weeks prior to Visit 1 and/or in the four weeks prior to Visit 2, the visit must be postponed.

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
EXPERIMENTAL: B	Drug: tiotropium high dose; 2 actuations once daily
EXPERIMENTAL: A	Drug: tiotropium low dose; 2 actuations once daily
PLACEBO_COMPARATOR: C	Drug: placebo; 2 actuations once daily

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 12. Measured values presented are actually adjusted means.	Baseline and 12 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 12. Measured values presented are actually adjusted means.	Baseline and 12 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 12. Measured values presented are actually adjusted means.	Baseline and 12 weeks
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 12. Measured values presented are actually adjusted means	Baseline and 12 weeks
FVC peak0-3 Change From Baseline	Change from baseline in Maximum forced vital capacity (FVC) measured within the first 3 hours after administration of trial medication (FVC peak0-3h) after 12 weeks of treatment. The measured values presented are actually adjusted means.	Baseline and 12 weeks
FEV1 AUC (0-3h) Change From Baseline	Change from baseline of area under the curve (AUC) from 0 to 3 hours for FEV1 (FEV1 AUC 0-3h) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h). 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 12 weeks
FVC AUC (0-3h) Change From Baseline	Change from baseline of area under the curve (AUC) from 0 to 3 hours for FVC (Forced vital capacity) (FVC AUC0-3h) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h). 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 12 weeks
Control of Asthma as Assessed by ACQ6 Score.	Change from baseline in Asthma Control Questionnaire (ACQ) 6 score measured at week 12 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. ACQ6 score is calculated as the mean of the responses to the first 6 questions of the ACQ6. The measured values presented are actually adjusted means.	Baseline and 12 weeks
ACQ6 Score Responders	Responder rates based on the ACQ6 score after 12 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. ACQ6 is calculated as the mean of the responses to the first 6 questions of the ACQ6. No statistical testing was performed on ACQ6 responders.	12 weeks
Control of Asthma as Assessed by ACQ Total Score	Change from baseline in Asthma Control Questionnaire (ACQ) total score measured at week 12. 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 is calculated as the mean of the responses to all 7 questions. The measured values presented are actually adjusted means.	Baseline and 12 weeks
ACQ Total Score Responders	Responder rates based on the ACQ total score after 12 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) No statistical testing was performed for ACQ total score responders. 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.	12 weeks
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 12. The measured values presented are actually adjusted means.	Baseline and 12 weeks
Time to First Severe Asthma Exacerbation During the 12-week Treatment Period.	Time in days to first severe asthma exacerbation during the 12 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 an initiation of treatment with systemic corticosteroids for at least 3 days or, in case of ongoing and pre-existing systemic corticosteroid therapy, requiring at least doubling of previous daily doses of systemic corticosteroids for at least 3 days.	12 weeks
Analysis of Time to First Asthma Exacerbation During the 12 Week Treatment Period.	Time in days to first asthma exacerbation during the 12 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.	12 weeks
Clinically Relevant Abnormalities for Physical Examination, ECG, Vital Signs and Laboratory Tests	Clinically relevant abnormalities for physical examination, ECG, vital signs and laboratory tests. New abnormal findings or worsening of baseline conditions were reported as adverse events.	From first drug administration until 30 days after last drug intake, up to 142 days

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim
• Collaborators: Pfizer

Publications and helpful links

General Publications

• 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, Bernstein JA, Vandewalker M, Moroni-Zentgraf P, Verri D, Unseld A, Engel M, Boner AL. A randomised controlled trial of tiotropium in adolescents with severe symptomatic asthma. Eur Respir J. 2017 Jan 11;49(1):1601100. doi: 10.1183/13993003.01100-2016. Print 2017 Jan.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (ACTUAL): October 1, 2013
• Study Completion (ACTUAL): October 1, 2013

Study Registration Dates

• First Submitted: January 13, 2011
• First Submitted That Met QC Criteria: January 13, 2011
• First Posted (ESTIMATE): January 17, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): October 20, 2014
• Last Update Submitted That Met QC Criteria: October 14, 2014
• Last Verified: October 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: 205.456; 2010-021778-13 (EUDRACT_NUMBER: EudraCT)