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

Asthma Clinical Trial

Official title:

A Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution (2.5 mcg and 5 mcg) Delivered Via Respimat® Inhaler Once Daily in the Evening Over 12 Weeks as add-on Controller Therapy on Top of Usual Care in Children (6 to 11 Years Old) With Severe Persistent Asthma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01634152
• Other study ID #: 205.446
• Secondary ID: 2011-001777-43
• Status: Completed
• Phase: Phase 3
• First received: July 3, 2012
• Last updated: December 22, 2015
• Start date: July 2012
• Est. completion date: May 2015

Study information

• Verified date: December 2015
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Argentina: Admin Nacional de Medicamentos, Alimentos Tecnologia MedicaAustralia: Human Research Ethics CommitteeBelgium: Federal Agency for Medicinal and Health ProductsBrazil: Ministry of HealthCanada: Health CanadaCzech Republic: State Institute for Drug ControlGermany: Federal Institute for Drugs and Medical DevicesGuatemala: Ministry of Public Health and Social AssistanceHungary: National Institute of PharmacyLatvia: State Agency of MedicinesLithuania: State Medicine Control Agency - Ministry of HealthPoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsRomania: National Medicines AgencyRussia: Pharmacological Committee, Ministry of HealthSlovakia: State Institute for Drug ControlUkraine: State Pharmacological Center - Ministry of HealthUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The overall purpose of the trial is to evaluate efficacy and safety of tiotropium inhalation solution (2.5 mcg and 5 mcg) delivered via Respimat® inhaler once daily in the evening over 12 weeks, compared to placebo, as add-on controller therapy on top of usual care in children (6 to 11 years old) with severe persistent asthma.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 401
• Est. completion date: May 2015
• Est. primary completion date: May 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 6 Years to 11 Years

Eligibility

Inclusion criteria:

Inclusion criteria are:

1. All patients' parent(s) (or legal guardian) must sign and date an informed consent prior to participation in the trial. In addition, an informed assent suitable for this age group has to be obtained from patients. A separate informed consent/assent is required for pharmacogenomic sampling.

2. Male or female patients between 6 and 11 years of age.

3. All patients must have at least a 6-month history of asthma.

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 (partly controlled) at Visit 1 and prior to randomisation at Visit 2 as defined by an Asthma Control Questionnaire (ACQ-IA) mean score >= 1.5.

6. All patients must have a pre-bronchodilator forced expiratory volume in one 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% 15 to 30 minutes after 200 mcg salbutamol/albuterol.

9. Patients must be able to use the Respimat inhaler correctly.

10. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of electronic diary/peak flow meter (diary compliance of at least 80% is required).

Exclusion criteria:

Exclusion criteria are:

1. Patients with a significant disease other than asthma.

2. Patients with a clinically relevant abnormal haematology or blood chemistry at screening.

3. Patients with a history of congenital or acquired heart disease, or patients who 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 a malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years.

6. Patients with known active tuberculosis.

7. Patients who have undergone thoracotomy with pulmonary resection.

8. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the six weeks prior to Visit 1.

9. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the inhalation solution used with the Respimat inhaler.

10. Pregnant or nursing female patients, including postmenarchal girls with a positive urine pregnancy test at Visit 1.

11. Postmenarchal girls of child-bearing potential not using a highly effective method of birth control.

12. Patients who have been treated with systemic corticosteroids within four weeks prior to Visit 1.

13. Patients who have been treated with systemic beta-adrenergics within four weeks prior to Visit 1.

14. Patients who have been treated with oral beta-blocker medication within four weeks prior to Visit 1 and/or during the screening period.

15. Patients who have been treated with inhaled long-acting anticholinergics or systemic anticholinergic treatment within four weeks prior to Visit 1 and/or during the screening period, or who have been treated with inhaled short-acting anticholinergics within two weeks prior to Visit 1.

16. Patients who have been treated with short-acting theophylline preparations within two weeks prior to Visit 1.

17. Patients who have been treated with non-approved and according to international guidelines not recommended experimental drugs for routine asthma therapy within four weeks prior to Visit 1 and/or during the screening period.

18. Patients who have taken an investigational drug within six half lives according to the investigator's information, or four weeks (whichever is greater) prior to Visit 1 and/or during the screening period.

19. Patients who have previously been randomised in this trial or are currently participating in another trial.

20. Patients with any acute asthma exacerbation or respiratory tract infection 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.

21. Patients requiring six or more puffs of rescue medication per day on more than two 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.

22. Patients who are unable to comply with medication restrictions prior to Visit 1 and/or prior to Visit 2.

23. Patients with a known narrow-angle glaucoma, or any other disease where anticholinergic treatment is contraindicated.

24. Patients with moderate to severe renal impairment, as defined by a creatinine clearance <50 mL/min/1.73 m2 BSA, as tiotropium is a predominantly renally excreted drug.

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:
• Placebo
2 actuations once daily in the evening
• Tiotropium low dose mcg
2 actuations once daily in the evening
• Tiotropium high dose
2 actuations once daily in the evening

Locations

Country	Name	City	State
Argentina	205.446.54006 Boehringer Ingelheim Investigational Site	Buenos Aires
Argentina	205.446.54002 Boehringer Ingelheim Investigational Site	Capital Federal
Argentina	205.446.54003 Boehringer Ingelheim Investigational Site	Capital Federal
Argentina	205.446.54008 Boehringer Ingelheim Investigational Site	Capital Federal
Argentina	205.446.54005 Boehringer Ingelheim Investigational Site	Mar del Plata
Argentina	205.446.54004 Boehringer Ingelheim Investigational Site	Mendoza
Argentina	205.446.54007 Boehringer Ingelheim Investigational Site	San Miguel de Tucuman
Australia	205.446.61003 Boehringer Ingelheim Investigational Site	Herston	Queensland
Australia	205.446.61001 Boehringer Ingelheim Investigational Site	Perth	Western Australia
Belgium	205.446.32004 Boehringer Ingelheim Investigational Site	Antwerpen
Belgium	205.446.32005 Boehringer Ingelheim Investigational Site	Brugge
Belgium	205.446.32006 Boehringer Ingelheim Investigational Site	Namur
Brazil	205.446.55001 Boehringer Ingelheim Investigational Site	Curitiba
Brazil	205.446.55007 Boehringer Ingelheim Investigational Site	Goiânia
Brazil	205.446.55006 Boehringer Ingelheim Investigational Site	Porto Alegre
Brazil	205.446.55002 Boehringer Ingelheim Investigational Site	Sao Paulo
Brazil	205.446.55003 Boehringer Ingelheim Investigational Site	Sao Paulo
Brazil	205.446.55004 Boehringer Ingelheim Investigational Site	Sao Paulo
Brazil	205.446.55005 Boehringer Ingelheim Investigational Site	Sao Paulo
Canada	205.446.02003 Boehringer Ingelheim Investigational Site	London	Ontario
Canada	205.446.02001 Boehringer Ingelheim Investigational Site	Sherbrooke	Quebec
Czech Republic	205.446.42005 Boehringer Ingelheim Investigational Site	Jablonec nad Nisou
Czech Republic	205.446.42001 Boehringer Ingelheim Investigational Site	Jihlava
Czech Republic	205.446.42002 Boehringer Ingelheim Investigational Site	Prague
Czech Republic	205.446.42004 Boehringer Ingelheim Investigational Site	Prague
Germany	205.446.49012 Boehringer Ingelheim Investigational Site	Berlin
Germany	205.446.49015 Boehringer Ingelheim Investigational Site	Berlin
Germany	205.446.49001 Boehringer Ingelheim Investigational Site	Bochum
Germany	205.446.49007 Boehringer Ingelheim Investigational Site	Dresden
Germany	205.446.49003 Boehringer Ingelheim Investigational Site	Frankfurt
Germany	205.446.49009 Boehringer Ingelheim Investigational Site	Koblenz
Germany	205.446.49014 Boehringer Ingelheim Investigational Site	Marburg
Germany	205.446.49011 Boehringer Ingelheim Investigational Site	Mönchengladbach
Guatemala	205.446.50201 Boehringer Ingelheim Investigational Site	Guatemala
Guatemala	205.446.50202 Boehringer Ingelheim Investigational Site	Guatemala
Guatemala	205.446.50203 Boehringer Ingelheim Investigational Site	Guatemala
Guatemala	205.446.50204 Boehringer Ingelheim Investigational Site	Guatemala
Hungary	205.446.36002 Boehringer Ingelheim Investigational Site	Ajka
Hungary	205.446.36001 Boehringer Ingelheim Investigational Site	Budapest
Hungary	205.446.36003 Boehringer Ingelheim Investigational Site	Nagyatad
Hungary	205.446.36004 Boehringer Ingelheim Investigational Site	Szeged
Latvia	205.446.37105 Boehringer Ingelheim Investigational Site	Baldone
Latvia	205.446.37104 Boehringer Ingelheim Investigational Site	Balvi
Latvia	205.446.37108 Boehringer Ingelheim Investigational Site	Daugavpils
Latvia	205.446.37107 Boehringer Ingelheim Investigational Site	Jekabpils
Latvia	205.446.37101 Boehringer Ingelheim Investigational Site	Ogre
Latvia	205.446.37106 Boehringer Ingelheim Investigational Site	Rezekne
Latvia	205.446.37102 Boehringer Ingelheim Investigational Site	Riga
Latvia	205.446.37103 Boehringer Ingelheim Investigational Site	Riga
Lithuania	205.446.37004 Boehringer Ingelheim Investigational Site	Siauliai
Lithuania	205.446.37003 Boehringer Ingelheim Investigational Site	Taurage
Lithuania	205.446.37002 Boehringer Ingelheim Investigational Site	Utena
Lithuania	205.446.37001 Boehringer Ingelheim Investigational Site	Vilnius
Poland	205.446.48004 Boehringer Ingelheim Investigational Site	Bialystok
Poland	205.446.48002 Boehringer Ingelheim Investigational Site	Lodz
Poland	205.446.48001 Boehringer Ingelheim Investigational Site	Lublin
Poland	205.446.48003 Boehringer Ingelheim Investigational Site	Tarnow
Romania	205.446.40002 Boehringer Ingelheim Investigational Site	Bucharest
Russian Federation	205.446.70002 Boehringer Ingelheim Investigational Site	Moscow
Russian Federation	205.446.70005 Boehringer Ingelheim Investigational Site	Moscow
Russian Federation	205.446.70007 Boehringer Ingelheim Investigational Site	Moscow
Russian Federation	205.446.70011 Boehringer Ingelheim Investigational Site	Moscow
Russian Federation	205.446.70012 Boehringer Ingelheim Investigational Site	Novosibirsk
Russian Federation	205.446.70001 Boehringer Ingelheim Investigational Site	St. Petersburg
Russian Federation	205.446.70003 Boehringer Ingelheim Investigational Site	St. Petersburg
Russian Federation	205.446.70004 Boehringer Ingelheim Investigational Site	St. Petersburg
Russian Federation	205.446.70010 Boehringer Ingelheim Investigational Site	St. Petersburg
Russian Federation	205.446.70009 Boehringer Ingelheim Investigational Site	Yaroslavl
Slovakia	205.446.42101 Boehringer Ingelheim Investigational Site	Kosice
Slovakia	205.446.42103 Boehringer Ingelheim Investigational Site	Presov
Slovakia	205.446.42102 Boehringer Ingelheim Investigational Site	Spisska Nova Ves
Ukraine	205.446.38013 Boehringer Ingelheim Investigational Site	Chernivtsi
Ukraine	205.446.38002 Boehringer Ingelheim Investigational Site	Dnipropetrovsk
Ukraine	205.446.38003 Boehringer Ingelheim Investigational Site	Dnipropetrovsk
Ukraine	205.446.38005 Boehringer Ingelheim Investigational Site	Donetsk
Ukraine	205.446.38012 Boehringer Ingelheim Investigational Site	Donetsk
Ukraine	205.446.38009 Boehringer Ingelheim Investigational Site	Kharkiv
Ukraine	205.446.38004 Boehringer Ingelheim Investigational Site	Kiev
Ukraine	205.446.38006 Boehringer Ingelheim Investigational Site	Kriviy Rig
Ukraine	205.446.38001 Boehringer Ingelheim Investigational Site	Lviv
Ukraine	205.446.38014 Boehringer Ingelheim Investigational Site	Odesa
Ukraine	205.446.38010 Boehringer Ingelheim Investigational Site	Vinnytsya
Ukraine	205.446.38011 Boehringer Ingelheim Investigational Site	Zaporizhya
Ukraine	205.446.38008 Boehringer Ingelheim Investigational Site	Zaporizhzhya
United States	205.446.01012 Boehringer Ingelheim Investigational Site	Arlington	Texas
United States	205.446.01004 Boehringer Ingelheim Investigational Site	Charleston	South Carolina
United States	205.446.01005 Boehringer Ingelheim Investigational Site	Cincinnati	Ohio
United States	205.446.01009 Boehringer Ingelheim Investigational Site	Columbia	Missouri
United States	205.446.01011 Boehringer Ingelheim Investigational Site	Denver	Colorado
United States	205.446.01002 Boehringer Ingelheim Investigational Site	North Charleston	South Carolina
United States	205.446.01003 Boehringer Ingelheim Investigational Site	North Dartmouth	Massachusetts
United States	205.446.01010 Boehringer Ingelheim Investigational Site	Oklahoma City	Oklahoma
United States	205.446.01014 Boehringer Ingelheim Investigational Site	Rolling Hills Estates	California
United States	205.446.01013 Boehringer Ingelheim Investigational Site	San Antonio	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Boehringer Ingelheim	Pfizer

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Brazil,  Canada,  Czech Republic,  Germany,  Guatemala,  Hungary,  Latvia,  Lithuania,  Poland,  Romania,  Russian Federation,  Slovakia,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	FEV1 Peak(0-3h) Change From Baseline	Change from baseline in peak forced expiratory volume in 1 second within the first 3 hours post dosing (FEV1 peak(0-3h)) measured at week 12.; Measured values presented are actually adjusted means.	Baseline and 12 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 12.; Measured values presented are actually adjusted means.	Baseline and 12 weeks	No
Secondary	FVC Peak(0-3h) Change From Baseline	Change from baseline in Maximum forced vital capacity (FVC) measured within the first 3 hours after administration of trial medication (FVC peak(0-3h)) after 12 weeks of treatment.; The measured values presented are actually adjusted means.	Baseline and 12 weeks	No
Secondary	Trough FVC Change From Baseline	Change from baseline in Trough (pre-dose) FVC measured at week 12.; Measured values presented are actually adjusted means.	Baseline and 12 weeks	No
Secondary	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	No
Secondary	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 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	No
Secondary	FEV1 Change From Baseline at Each Individual Timepoint	Forced expiratory volume in one second (FEV1) change from baseline at each individual timepoint.; 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 12 weeks	No
Secondary	FVC Change From Baseline at Each Individual Timepoint	FVC change from baseline at each individual timepoint.; 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 12 weeks	No
Secondary	Control of Asthma as Assessed by ACQ-IA Total Score	Change from baseline in Interviewer-Administered Asthma Control Questionnaire (ACQ-IA) total score measured at week 12.; The ACQ-IA 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-IA 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	No
Secondary	ACQ-IA Total Score Responders	Responder categories based on the ACQ-IA 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 The ACQ-IA 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	No
Secondary	Use of PRN Rescue Medication Per Day	Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used per day (24 hour period) based on the weekly mean at week 12.; The measured values presented are actually adjusted means.	Baseline and 12 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 12.; Measured values presented are actually adjusted means.	Baseline and 12 weeks	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 12.; Measured values presented are actually adjusted means	Baseline and 12 weeks	No
Secondary	Peak Expiratory Flow (PEF) a.m. Change From Baseline	Change from baseline in the morning (a.m.) peak expiratory flow based on the weekly mean at week 12.; Measured values presented are actually adjusted means.	Baseline and 12 weeks	No
Secondary	Peak Expiratory Flow (PEF) p.m. Change From Baseline	Change from baseline in the evening (p.m.) peak expiratory flow based on the weekly mean at week 12.; Measured values presented are actually adjusted means.	Baseline and 12 weeks	No
Secondary	Peak Expiratory Flow (PEF) Variability Change From Baseline	Change from baseline in the peak expiratory flow variability based on the weekly mean at week 12.; Measured values presented are actually adjusted means.	Baseline and 12 weeks	No
Secondary	FEV1 a.m. Change From Baseline	Change from baseline in morning (a.m.) FEV1 based on the weekly mean at week 12.; Measured values presented are actually adjusted means.	Baseline and 12 weeks	No
Secondary	FEV1 p.m. Change From Baseline	Change from baseline in evening (p.m.) FEV1 based on the weekly mean at week 12.; Measured values presented are actually adjusted means.	Baseline and 12 weeks	No
Secondary	Change From Baseline in Nighttime Awakenings	Change from baseline in nighttime awakenings based on the weekly mean at week 12.; Nighttime awakenings was assessed by the question "Did you wake up during the night due to your asthma?" from the e-diary. Scores range from 1 (did not wake up) to 5 (was awake all night).; Measured values presented are actually adjusted means.	Baseline and 12 weeks	No
Secondary	Change From Baseline in Morning Asthma Symptoms	Change from baseline in morning asthma symptoms based on the weekly mean at week 12.; Morning asthma symptoms was assessed by the question "how were your asthma symptoms this morning?" from the e-diary. Scores range from 1 (no asthma symptoms) to 5 (very severe asthma symptoms).; Measured values presented are actually adjusted means.	Baseline and 12 weeks	No
Secondary	Change From Baseline in Daytime Asthma Symptoms	Change from baseline in daytime asthma symptoms based on the weekly mean at week 12.; Daytime asthma symptoms was assessed by the question "how were your asthma symptoms during the day?" from the e-diary. Scores range from 1 (no asthma symptoms) to 5 (very severe asthma symptoms).; Measured values presented are actually adjusted means.	Baseline and 12 weeks	No
Secondary	Change From Baseline in Daytime Activity Limitations	Change from baseline in daytime activity limitations based on the weekly mean at week 12.; Daytime activity limitations was assessed by the question "how limited were you in your activities today because of your asthma?" from the e-diary. Scores range from 1 (not limited) to 5 (totally limited).; Measured values presented are actually adjusted means.	Baseline and 12 weeks	No
Secondary	Change From Baseline in Daytime Experiences of Shortness of Breath	Change from baseline in daytime experiences of shortness of breath based on the weekly mean at week 12.; Daytime experiences of shortness of breath was assessed by the question "how much shortness of breath did you experience during the day" from the e-diary. Scores range from 1 (none) to 5 (a very great deal).; Measured values presented are actually adjusted means.	Baseline and 12 weeks	No
Secondary	Change From Baseline in Daytime Experiences of Wheeze or Cough	Change from baseline in daytime experiences of wheeze or cough based on the weekly mean at week 12.; Daytime experiences of wheeze or cough was assessed by the question "did you experience wheeze or cough during the day?" from the e-diary. Scores range from 1 (not at all) to 5 (all the time).; Measured values presented are actually adjusted means.	Baseline and 12 weeks	No
Secondary	Change From Baseline in Asthma Symptom-free Days	Change from baseline in asthma symptom-free days based on the weekly mean at week 12.; A day was considered as an asthma symptom-free day if there were no symptoms reported via the e-Diary and no use of rescue medication reported via the eDiary during that day.; Measured values presented are actually adjusted means.	Baseline and 12 weeks	No

External Links

•   Link