Please note that IPD sharing statement and summary results sections will be added to the ANZCTR form in the coming weeks in order to comply with the updated WHO Trial Registration Data Set.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01277523




Trial ID
NCT01277523
Ethics application status
Date submitted
13/01/2011
Date registered
13/01/2011
Date last updated
14/10/2014

Titles & IDs
Public title
Efficacy and Safety of 2 Doses of Tiotropium Respimat Compared to Placebo in Adolescents With Severe Persistent Asthma
Scientific 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
Secondary ID [1] 0 0
2010-021778-13
Secondary ID [2] 0 0
205.456
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Asthma 0 0
Condition category
Condition code
Respiratory 0 0 0 0
Asthma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - tiotropium high dose
Treatment: Drugs - placebo
Treatment: Drugs - tiotropium low dose

Experimental: A -

Experimental: B -

Placebo Comparator: C -


Treatment: Drugs: tiotropium high dose
2 actuations once daily

Treatment: Drugs: placebo
2 actuations once daily

Treatment: Drugs: tiotropium low dose
2 actuations once daily

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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.
Timepoint [1] 0 0
Baseline and 12 weeks
Secondary outcome [1] 0 0
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.
Timepoint [1] 0 0
Baseline and 12 weeks
Secondary outcome [2] 0 0
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.
Timepoint [2] 0 0
Baseline and 12 weeks
Secondary outcome [3] 0 0
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.
Timepoint [3] 0 0
Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks
Secondary outcome [4] 0 0
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.
Timepoint [4] 0 0
Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks
Secondary outcome [5] 0 0
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.
Timepoint [5] 0 0
Baseline and 12 weeks
Secondary outcome [6] 0 0
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.
Timepoint [6] 0 0
12 weeks
Secondary outcome [7] 0 0
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.
Timepoint [7] 0 0
Baseline and 12 weeks
Secondary outcome [8] 0 0
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.
Timepoint [8] 0 0
12 weeks
Secondary outcome [9] 0 0
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.
Timepoint [9] 0 0
Baseline and 12 weeks
Secondary outcome [10] 0 0
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.
Timepoint [10] 0 0
Baseline and 12 weeks
Secondary outcome [11] 0 0
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
Timepoint [11] 0 0
Baseline and 12 weeks
Secondary outcome [12] 0 0
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.
Timepoint [12] 0 0
12 weeks
Secondary outcome [13] 0 0
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.
Timepoint [13] 0 0
12 weeks
Secondary outcome [14] 0 0
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.
Timepoint [14] 0 0
From first drug administration until 30 days after last drug intake, up to 142 days

Eligibility
Key inclusion 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).
Minimum age
12 Years
Maximum age
17 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC,WA
Recruitment hospital [1] 0 0
205.456.61002 Boehringer Ingelheim Investigational Site - Parkville
Recruitment hospital [2] 0 0
205.456.61001 Boehringer Ingelheim Investigational Site - Perth
Recruitment postcode(s) [1] 0 0
- Parkville
Recruitment postcode(s) [2] 0 0
- Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Illinois
Country [3] 0 0
United States of America
State/province [3] 0 0
Maryland
Country [4] 0 0
United States of America
State/province [4] 0 0
Missouri
Country [5] 0 0
United States of America
State/province [5] 0 0
Nebraska
Country [6] 0 0
United States of America
State/province [6] 0 0
New York
Country [7] 0 0
United States of America
State/province [7] 0 0
Ohio
Country [8] 0 0
United States of America
State/province [8] 0 0
South Carolina
Country [9] 0 0
Argentina
State/province [9] 0 0
Capital Federal
Country [10] 0 0
Argentina
State/province [10] 0 0
Florencio Varela
Country [11] 0 0
Argentina
State/province [11] 0 0
Mendoza
Country [12] 0 0
Argentina
State/province [12] 0 0
San Miguel de Tucuman
Country [13] 0 0
Argentina
State/province [13] 0 0
San Miguel de Tucumán
Country [14] 0 0
Bulgaria
State/province [14] 0 0
Plovdiv
Country [15] 0 0
Bulgaria
State/province [15] 0 0
Ruse
Country [16] 0 0
Bulgaria
State/province [16] 0 0
Sofia
Country [17] 0 0
Germany
State/province [17] 0 0
Berlin
Country [18] 0 0
Germany
State/province [18] 0 0
Bochum
Country [19] 0 0
Germany
State/province [19] 0 0
Frankfurt
Country [20] 0 0
Germany
State/province [20] 0 0
Kehl
Country [21] 0 0
Germany
State/province [21] 0 0
Koblenz
Country [22] 0 0
Germany
State/province [22] 0 0
Mainz
Country [23] 0 0
Germany
State/province [23] 0 0
Neu-Isenburg
Country [24] 0 0
Germany
State/province [24] 0 0
Wesel
Country [25] 0 0
Guatemala
State/province [25] 0 0
Guatemala City
Country [26] 0 0
Hungary
State/province [26] 0 0
Budapest
Country [27] 0 0
Hungary
State/province [27] 0 0
Debrecen
Country [28] 0 0
Hungary
State/province [28] 0 0
Gyula
Country [29] 0 0
Hungary
State/province [29] 0 0
Miskolc
Country [30] 0 0
Hungary
State/province [30] 0 0
Mosdos
Country [31] 0 0
Hungary
State/province [31] 0 0
Nagyatad
Country [32] 0 0
Israel
State/province [32] 0 0
Holon
Country [33] 0 0
Israel
State/province [33] 0 0
Petach Tikva
Country [34] 0 0
Israel
State/province [34] 0 0
Safed
Country [35] 0 0
Latvia
State/province [35] 0 0
Baldone
Country [36] 0 0
Latvia
State/province [36] 0 0
Balvi
Country [37] 0 0
Latvia
State/province [37] 0 0
Rezekne
Country [38] 0 0
Latvia
State/province [38] 0 0
Riga
Country [39] 0 0
Latvia
State/province [39] 0 0
Talsi
Country [40] 0 0
Mexico
State/province [40] 0 0
Hermosillo Sonora
Country [41] 0 0
Mexico
State/province [41] 0 0
Monterrey
Country [42] 0 0
Mexico
State/province [42] 0 0
Nuevo León
Country [43] 0 0
Philippines
State/province [43] 0 0
Quezon City
Country [44] 0 0
Portugal
State/province [44] 0 0
Coimbra
Country [45] 0 0
Portugal
State/province [45] 0 0
Lisboa
Country [46] 0 0
Portugal
State/province [46] 0 0
Porto
Country [47] 0 0
South Africa
State/province [47] 0 0
Cape Town
Country [48] 0 0
South Africa
State/province [48] 0 0
Durban
Country [49] 0 0
Ukraine
State/province [49] 0 0
Dnipropetrovsk
Country [50] 0 0
Ukraine
State/province [50] 0 0
Kharkiv
Country [51] 0 0
Ukraine
State/province [51] 0 0
Kiev
Country [52] 0 0
Ukraine
State/province [52] 0 0
Kriviy Rig
Country [53] 0 0
Ukraine
State/province [53] 0 0
Kyiv
Country [54] 0 0
Ukraine
State/province [54] 0 0
Lviv
Country [55] 0 0
Ukraine
State/province [55] 0 0
Uzhgorod
Country [56] 0 0
Ukraine
State/province [56] 0 0
Vinnytsya
Country [57] 0 0
Ukraine
State/province [57] 0 0
Zaporizhzhya

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Boehringer Ingelheim
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Pfizer
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT01277523
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Boehringer Ingelheim
Address 0 0
Boehringer Ingelheim
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries