Clinical trial NCT01277523: Efficacy and Safety of 2 Doses of Tiotropium Respimat Compared to Placebo in Adolescents With Severe Persistent Asthma
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Asthma
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
Collaborators: name: Pfizer
First posted: 2011-01-17
Enrollment: 392
Sex: ALL
Minimum age (years): 12
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: FEV1 peak0-3 Change From Baseline
timeFrame: Baseline and 12 weeks
Secondary outcomes:
measure: Trough FEV1 Change From Baseline
timeFrame: Baseline and 12 weeks
measure: FVC peak0-3 Change From Baseline
timeFrame: Baseline and 12 weeks
measure: FEV1 AUC (0-3h) Change From Baseline
timeFrame: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks
measure: FVC AUC (0-3h) Change From Baseline
timeFrame: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks
measure: Control of Asthma as Assessed by ACQ6 Score.
timeFrame: Baseline and 12 weeks
measure: ACQ6 Score Responders
timeFrame: 12 weeks
measure: Control of Asthma as Assessed by ACQ Total Score
timeFrame: Baseline and 12 weeks
measure: ACQ Total Score Responders
timeFrame: 12 weeks
measure: Use of PRN Rescue Medication During the Day
timeFrame: Baseline and 12 weeks
measure: Use of PRN Rescue Medication During the Daytime
timeFrame: Baseline and 12 weeks
measure: Use of PRN Rescue Medication During the Night-time
timeFrame: Baseline and 12 weeks
measure: Time to First Severe Asthma Exacerbation During the 12-week Treatment Period.
timeFrame: 12 weeks
measure: Analysis of Time to First Asthma Exacerbation During the 12 Week Treatment Period.
timeFrame: 12 weeks
measure: Clinically Relevant Abnormalities for Physical Examination, ECG, Vital Signs and Laboratory Tests
timeFrame: From first drug administration until 30 days after last drug intake, up to 142 days
Other outcomes:
Locations:
city: Stockton
country: United States
facility: 205.456.01004 Boehringer Ingelheim Investigational Site
state: California
city: Normal
country: United States
facility: 205.456.01008 Boehringer Ingelheim Investigational Site
state: Illinois
city: Baltimore
country: United States
facility: 205.456.01003 Boehringer Ingelheim Investigational Site
state: Maryland
city: Columbia
country: United States
facility: 205.456.01007 Boehringer Ingelheim Investigational Site
state: Missouri
city: Bellevue
country: United States
facility: 205.456.01002 Boehringer Ingelheim Investigational Site
state: Nebraska
city: Rockville Centre
country: United States
facility: 205.456.01001 Boehringer Ingelheim Investigational Site
state: New York
city: Cincinnati
country: United States
facility: 205.456.01005 Boehringer Ingelheim Investigational Site
state: Ohio
city: Summerville
country: United States
facility: 205.456.01006 Boehringer Ingelheim Investigational Site
state: South Carolina
city: Capital Federal
country: Argentina
facility: 205.456.54002 Boehringer Ingelheim Investigational Site
city: Capital Federal
country: Argentina
facility: 205.456.54006 Boehringer Ingelheim Investigational Site
city: Capital Federal
country: Argentina
facility: 205.456.54008 Boehringer Ingelheim Investigational Site
city: Florencio Varela
country: Argentina
facility: 205.456.54003 Boehringer Ingelheim Investigational Site
city: Mendoza
country: Argentina
facility: 205.456.54005 Boehringer Ingelheim Investigational Site
city: San Miguel de Tucuman
country: Argentina
facility: 205.456.54009 Boehringer Ingelheim Investigational Site
city: San Miguel de Tucumán
country: Argentina
facility: 205.456.54004 Boehringer Ingelheim Investigational Site
city: Parkville
country: Australia
facility: 205.456.61002 Boehringer Ingelheim Investigational Site
state: Victoria
city: Perth
country: Australia
facility: 205.456.61001 Boehringer Ingelheim Investigational Site
state: Western Australia
city: Plovdiv
country: Bulgaria
facility: 205.456.35902 Boehringer Ingelheim Investigational Site
city: Ruse
country: Bulgaria
facility: 205.456.35901 Boehringer Ingelheim Investigational Site
city: Sofia
country: Bulgaria
facility: 205.456.35903 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 205.456.49008 Boehringer Ingelheim Investigational Site
city: Bochum
country: Germany
facility: 205.456.49001 Boehringer Ingelheim Investigational Site
city: Frankfurt
country: Germany
facility: 205.456.49004 Boehringer Ingelheim Investigational Site
city: Kehl
country: Germany
facility: 205.456.49005 Boehringer Ingelheim Investigational Site
city: Koblenz
country: Germany
facility: 205.456.49003 Boehringer Ingelheim Investigational Site
city: Mainz
country: Germany
facility: 205.456.49010 Boehringer Ingelheim Investigational Site
city: Neu-Isenburg
country: Germany
facility: 205.456.49007 Boehringer Ingelheim Investigational Site
city: Wesel
country: Germany
facility: 205.456.49002 Boehringer Ingelheim Investigational Site
city: Guatemala City
country: Guatemala
facility: 205.456.50201 Boehringer Ingelheim Investigational Site
city: Guatemala City
country: Guatemala
facility: 205.456.50203 Boehringer Ingelheim Investigational Site
city: Guatemala City
country: Guatemala
facility: 205.456.50204 Boehringer Ingelheim Investigational Site
city: Guatemala City
country: Guatemala
facility: 205.456.50205 Boehringer Ingelheim Investigational Site
city: Budapest
country: Hungary
facility: 205.456.36005 Boehringer Ingelheim Investigational Site
city: Debrecen
country: Hungary
facility: 205.456.36002 Boehringer Ingelheim Investigational Site
city: Gyula
country: Hungary
facility: 205.456.36004 Boehringer Ingelheim Investigational Site
city: Miskolc
country: Hungary
facility: 205.456.36001 Boehringer Ingelheim Investigational Site
city: Mosdos
country: Hungary
facility: 205.456.36007 Boehringer Ingelheim Investigational Site
city: Nagyatad
country: Hungary
facility: 205.456.36006 Boehringer Ingelheim Investigational Site
city: Holon
country: Israel
facility: 205.456.97205 Boehringer Ingelheim Investigational Site
city: Petach Tikva
country: Israel
facility: 205.456.97203 Boehringer Ingelheim Investigational Site
city: Safed
country: Israel
facility: 205.456.97201 Boehringer Ingelheim Investigational Site
city: Baldone
country: Latvia
facility: 205.456.37101 Boehringer Ingelheim Investigational Site
city: Balvi
country: Latvia
facility: 205.456.37104 Boehringer Ingelheim Investigational Site
city: Rezekne
country: Latvia
facility: 205.456.37103 Boehringer Ingelheim Investigational Site
city: Riga
country: Latvia
facility: 205.456.37102 Boehringer Ingelheim Investigational Site
city: Talsi
country: Latvia
facility: 205.456.37105 Boehringer Ingelheim Investigational Site
city: Hermosillo Sonora
country: Mexico
facility: 205.456.52001 Boehringer Ingelheim Investigational Site
city: Monterrey
country: Mexico
facility: 205.456.52002 Boehringer Ingelheim Investigational Site
city: Monterrey
country: Mexico
facility: 205.456.52003 Boehringer Ingelheim Investigational Site
city: Nuevo León
country: Mexico
facility: 205.456.52004 Boehringer Ingelheim Investigational Site
city: Quezon City
country: Philippines
facility: 205.456.09001 Boehringer Ingelheim Investigational Site
city: Quezon City
country: Philippines
facility: 205.456.09002 Boehringer Ingelheim Investigational Site
city: Coimbra
country: Portugal
facility: 205.456.35105 Boehringer Ingelheim Investigational Site
city: Lisboa
country: Portugal
facility: 205.456.35101 Boehringer Ingelheim Investigational Site
city: Lisboa
country: Portugal
facility: 205.456.35102 Boehringer Ingelheim Investigational Site
city: Lisboa
country: Portugal
facility: 205.456.35104 Boehringer Ingelheim Investigational Site
city: Porto
country: Portugal
facility: 205.456.35103 Boehringer Ingelheim Investigational Site
city: Cape Town
country: South Africa
facility: 205.456.27001 Boehringer Ingelheim Investigational Site
city: Durban
country: South Africa
facility: 205.456.27002 Boehringer Ingelheim Investigational Site
city: Dnipropetrovsk
country: Ukraine
facility: 205.456.38006 Boehringer Ingelheim Investigational Site
city: Kharkiv
country: Ukraine
facility: 205.456.38004 Boehringer Ingelheim Investigational Site
city: Kiev
country: Ukraine
facility: 205.456.38003 Boehringer Ingelheim Investigational Site
city: Kriviy Rig
country: Ukraine
facility: 205.456.38010 Boehringer Ingelheim Investigational Site
city: Kyiv
country: Ukraine
facility: 205.456.38009 Boehringer Ingelheim Investigational Site
city: Lviv
country: Ukraine
facility: 205.456.38001 Boehringer Ingelheim Investigational Site
city: Lviv
country: Ukraine
facility: 205.456.38007 Boehringer Ingelheim Investigational Site
city: Uzhgorod
country: Ukraine
facility: 205.456.38005 Boehringer Ingelheim Investigational Site
city: Vinnytsya
country: Ukraine
facility: 205.456.38008 Boehringer Ingelheim Investigational Site
city: Zaporizhzhya
country: Ukraine
facility: 205.456.38002 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.