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

This study has been completed.
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01277523
First received: January 13, 2011
Last updated: October 14, 2014
Last verified: October 2014
  Purpose

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.


Condition Intervention Phase
Asthma
Drug: tiotropium high dose
Drug: placebo
Drug: tiotropium low dose
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double-Blind
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • FEV1 peak0-3 Change From Baseline [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]

    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.



Secondary Outcome Measures:
  • Trough FEV1 Change From Baseline [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]

    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.


  • FVC peak0-3 Change From Baseline [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]

    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.


  • FEV1 AUC (0-3h) Change From Baseline [ Time Frame: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks ] [ Designated as safety issue: No ]

    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.


  • FVC AUC (0-3h) Change From Baseline [ Time Frame: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks ] [ Designated as safety issue: No ]

    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.


  • Control of Asthma as Assessed by ACQ6 Score. [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]

    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.


  • ACQ6 Score Responders [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

    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.


  • Control of Asthma as Assessed by ACQ Total Score [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]

    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.


  • ACQ Total Score Responders [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

    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.


  • Use of PRN Rescue Medication During the Day [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]

    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.


  • Use of PRN Rescue Medication During the Daytime [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]

    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.


  • Use of PRN Rescue Medication During the Night-time [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]

    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


  • Time to First Severe Asthma Exacerbation During the 12-week Treatment Period. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

    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.


  • Analysis of Time to First Asthma Exacerbation During the 12 Week Treatment Period. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    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.

  • Clinically Relevant Abnormalities for Physical Examination, ECG, Vital Signs and Laboratory Tests [ Time Frame: From first drug administration until 30 days after last drug intake, up to 142 days ] [ Designated as safety issue: No ]
    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.


Enrollment: 392
Study Start Date: January 2011
Study Completion Date: October 2013
Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A Drug: tiotropium low dose
2 actuations once daily
Experimental: B Drug: tiotropium high dose
2 actuations once daily
Placebo Comparator: C Drug: placebo
2 actuations once daily

  Eligibility

Ages Eligible for Study:   12 Years to 17 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01277523

  Show 69 Study Locations
Sponsors and Collaborators
Boehringer Ingelheim
Pfizer
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

Additional Information:
No publications provided

Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01277523     History of Changes
Other Study ID Numbers: 205.456, 2010-021778-13
Study First Received: January 13, 2011
Results First Received: October 14, 2014
Last Updated: October 14, 2014
Health Authority: Argentina: Admin Nacional de Medicamentos, Alimentos Tecnologia Medica
Australia: Human Research Ethics Committee
Bulgaria: Bulgarian Drug Agency
Germany: Federal Institute for Drugs and Medical Devices
Guatemala: Ministry of Public Health and Social Assistance
Hungary: National Institute of Pharmacy
Israel: Israeli Health Ministry Pharmaceutical Administration
Latvia: State Agency of Medicines
Mexico: Federal Commission for Sanitary Risks Protection
Philippines: Bureau of Food and Drugs
Portugal: National Pharmacy and Medicines Institute
South Africa: Medicines Control Council
Ukraine: State Pharmacological Center - Ministry of Health
United States: Food and Drug Administration

Additional relevant MeSH terms:
Asthma
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Tiotropium
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Asthmatic Agents
Respiratory System Agents
Therapeutic Uses
Parasympatholytics
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on October 19, 2014