Efficacy and Safety of 2 Doses of Tiotropium Respimat Compared to Placebo in Adolescents 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 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01277523
• Other study ID #: 205.456
• Secondary ID: 2010-021778-13
• Status: Completed
• Phase: Phase 3
• First received: January 13, 2011
• Last updated: October 14, 2014
• Start date: January 2011
• Est. completion date: October 2013

Study information

• Verified date: October 2014
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Argentina: Admin Nacional de Medicamentos, Alimentos Tecnologia MedicaAustralia: Human Research Ethics CommitteeBulgaria: Bulgarian Drug AgencyGermany: Federal Institute for Drugs and Medical DevicesGuatemala: Ministry of Public Health and Social AssistanceHungary: National Institute of PharmacyIsrael: Israeli Health Ministry Pharmaceutical AdministrationLatvia: State Agency of MedicinesMexico: Federal Commission for Sanitary Risks ProtectionPhilippines: Bureau of Food and DrugsPortugal: National Pharmacy and Medicines InstituteSouth Africa: Medicines Control CouncilUkraine: 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 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 392
• Est. completion date: October 2013
• Est. primary completion date: October 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 12 Years to 17 Years

Eligibility

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 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 high dose
2 actuations once daily
• placebo
2 actuations once daily
• tiotropium low dose
2 actuations once daily

Locations

Country	Name	City	State
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	Capital Federal
Argentina	205.456.54003 Boehringer Ingelheim Investigational Site	Florencio Varela
Argentina	205.456.54005 Boehringer Ingelheim Investigational Site	Mendoza
Argentina	205.456.54009 Boehringer Ingelheim Investigational Site	San Miguel de Tucuman
Argentina	205.456.54004 Boehringer Ingelheim Investigational Site	San Miguel de Tucumán
Australia	205.456.61002 Boehringer Ingelheim Investigational Site	Parkville	Victoria
Australia	205.456.61001 Boehringer Ingelheim Investigational Site	Perth	Western Australia
Bulgaria	205.456.35902 Boehringer Ingelheim Investigational Site	Plovdiv
Bulgaria	205.456.35901 Boehringer Ingelheim Investigational Site	Ruse
Bulgaria	205.456.35903 Boehringer Ingelheim Investigational Site	Sofia
Germany	205.456.49008 Boehringer Ingelheim Investigational Site	Berlin
Germany	205.456.49001 Boehringer Ingelheim Investigational Site	Bochum
Germany	205.456.49004 Boehringer Ingelheim Investigational Site	Frankfurt
Germany	205.456.49005 Boehringer Ingelheim Investigational Site	Kehl
Germany	205.456.49003 Boehringer Ingelheim Investigational Site	Koblenz
Germany	205.456.49010 Boehringer Ingelheim Investigational Site	Mainz
Germany	205.456.49007 Boehringer Ingelheim Investigational Site	Neu-Isenburg
Germany	205.456.49002 Boehringer Ingelheim Investigational Site	Wesel
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	Guatemala City
Hungary	205.456.36005 Boehringer Ingelheim Investigational Site	Budapest
Hungary	205.456.36002 Boehringer Ingelheim Investigational Site	Debrecen
Hungary	205.456.36004 Boehringer Ingelheim Investigational Site	Gyula
Hungary	205.456.36001 Boehringer Ingelheim Investigational Site	Miskolc
Hungary	205.456.36007 Boehringer Ingelheim Investigational Site	Mosdos
Hungary	205.456.36006 Boehringer Ingelheim Investigational Site	Nagyatad
Israel	205.456.97205 Boehringer Ingelheim Investigational Site	Holon
Israel	205.456.97203 Boehringer Ingelheim Investigational Site	Petach Tikva
Israel	205.456.97201 Boehringer Ingelheim Investigational Site	Safed
Latvia	205.456.37101 Boehringer Ingelheim Investigational Site	Baldone
Latvia	205.456.37104 Boehringer Ingelheim Investigational Site	Balvi
Latvia	205.456.37103 Boehringer Ingelheim Investigational Site	Rezekne
Latvia	205.456.37102 Boehringer Ingelheim Investigational Site	Riga
Latvia	205.456.37105 Boehringer Ingelheim Investigational Site	Talsi
Mexico	205.456.52001 Boehringer Ingelheim Investigational Site	Hermosillo Sonora
Mexico	205.456.52002 Boehringer Ingelheim Investigational Site	Monterrey
Mexico	205.456.52003 Boehringer Ingelheim Investigational Site	Monterrey
Mexico	205.456.52004 Boehringer Ingelheim Investigational Site	Nuevo León
Philippines	205.456.09001 Boehringer Ingelheim Investigational Site	Quezon City
Philippines	205.456.09002 Boehringer Ingelheim Investigational Site	Quezon City
Portugal	205.456.35105 Boehringer Ingelheim Investigational Site	Coimbra
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	Lisboa
Portugal	205.456.35103 Boehringer Ingelheim Investigational Site	Porto
South Africa	205.456.27001 Boehringer Ingelheim Investigational Site	Cape Town
South Africa	205.456.27002 Boehringer Ingelheim Investigational Site	Durban
Ukraine	205.456.38006 Boehringer Ingelheim Investigational Site	Dnipropetrovsk
Ukraine	205.456.38004 Boehringer Ingelheim Investigational Site	Kharkiv
Ukraine	205.456.38003 Boehringer Ingelheim Investigational Site	Kiev
Ukraine	205.456.38010 Boehringer Ingelheim Investigational Site	Kriviy Rig
Ukraine	205.456.38009 Boehringer Ingelheim Investigational Site	Kyiv
Ukraine	205.456.38001 Boehringer Ingelheim Investigational Site	Lviv
Ukraine	205.456.38007 Boehringer Ingelheim Investigational Site	Lviv
Ukraine	205.456.38005 Boehringer Ingelheim Investigational Site	Uzhgorod
Ukraine	205.456.38008 Boehringer Ingelheim Investigational Site	Vinnytsya
Ukraine	205.456.38002 Boehringer Ingelheim Investigational Site	Zaporizhzhya
United States	205.456.01003 Boehringer Ingelheim Investigational Site	Baltimore	Maryland
United States	205.456.01002 Boehringer Ingelheim Investigational Site	Bellevue	Nebraska
United States	205.456.01005 Boehringer Ingelheim Investigational Site	Cincinnati	Ohio
United States	205.456.01007 Boehringer Ingelheim Investigational Site	Columbia	Missouri
United States	205.456.01008 Boehringer Ingelheim Investigational Site	Normal	Illinois
United States	205.456.01001 Boehringer Ingelheim Investigational Site	Rockville Centre	New York
United States	205.456.01004 Boehringer Ingelheim Investigational Site	Stockton	California
United States	205.456.01006 Boehringer Ingelheim Investigational Site	Summerville	South Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Boehringer Ingelheim	Pfizer

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Bulgaria,  Germany,  Guatemala,  Hungary,  Israel,  Latvia,  Mexico,  Philippines,  Portugal,  South Africa,  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 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 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	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 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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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 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	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 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	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	No
Secondary	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	No
Secondary	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	No

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