Efficacy and Safety of 2 Doses of Tiotropium Respimat Compared to Placebo in Adolescents With Severe Persistent Asthma
Condition: Asthma
MeSH terms: Asthma
Intervention: tiotropium high dose; placebo; tiotropium low dose
Intervention description: 2 actuations once daily; 2 actuations once daily; 2 actuations once daily
Intervention MeSH terms: Tiotropium Bromide
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Enrollment: 392.0
Sex: All
Minimum age: 12 Years
Maximum age: 17 Years
Healthy volunteers: No

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.