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

Asthma Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01257230
• Other study ID #: 205.444
• Secondary ID: 2010-021093-11
• Status: Completed
• Phase: Phase 3
• First received: December 6, 2010
• Last updated: August 27, 2014
• Start date: December 2010
• Est. completion date: December 2013

Study information

• Verified date: August 2014
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Chile: Instituto de Salud Pública de ChileGermany: Federal Institute for Drugs and Medical DevicesHungary: National Institute of PharmacyItaly: Ethics CommitteeLatvia: State Agency of MedicinesMexico: Federal Commission for Protection Against Health RisksRussia: Pharmacological Committee, Ministry of HealthSlovakia: State Institute for Drug ControlSouth Korea: Ministry of Food and Drug Safety (MFDS)Spain: Spanish Agency of MedicinesUkraine: State Pharmacological Center - Ministry of HealthUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 398
• Est. completion date: December 2013
• Est. primary completion date: December 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 12 Years to 17 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Asthma

Intervention

Drug:
• tiotropium Respimat low dose
IMP
• placebo Respimat
placebo representing comparator
• tiotropium Respimat high dose
IMP

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Boehringer Ingelheim	Pfizer

Countries where clinical trial is conducted

United States,  Chile,  Germany,  Hungary,  Italy,  Korea, Republic of,  Latvia,  Mexico,  Russian Federation,  Slovakia,  Spain,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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 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	No
Secondary	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	No
Secondary	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 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	No
Secondary	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	No
Secondary	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	No