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

This study has been completed.
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01634152
First received: July 3, 2012
Last updated: December 22, 2015
Last verified: December 2015
  Purpose
The overall purpose of the trial is to evaluate efficacy and safety of tiotropium inhalation solution (2.5 mcg and 5 mcg) delivered via Respimat® inhaler once daily in the evening over 12 weeks, compared to placebo, as add-on controller therapy on top of usual care in children (6 to 11 years old) with severe persistent asthma.

Condition Intervention Phase
Asthma
Drug: Placebo
Drug: Tiotropium low dose mcg
Drug: Tiotropium high 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 (2.5 mcg and 5 mcg) Delivered Via Respimat® Inhaler Once Daily in the Evening Over 12 Weeks as add-on Controller Therapy on Top of Usual Care in Children (6 to 11 Years Old) With Severe Persistent Asthma

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • FEV1 Peak(0-3h) 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 peak(0-3h)) 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 Peak(0-3h) 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 peak(0-3h)) after 12 weeks of treatment.

    The measured values presented are actually adjusted means.


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

    Change from baseline in Trough (pre-dose) FVC measured at week 12.

    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 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.


  • FEV1 Change From Baseline at Each Individual Timepoint [ 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 ]

    Forced expiratory volume in one second (FEV1) change from baseline at each individual timepoint.

    The measured values presented are actually adjusted means.


  • FVC Change From Baseline at Each Individual Timepoint [ 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 ]

    FVC change from baseline at each individual timepoint.

    The measured values presented are actually adjusted means.


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

    Change from baseline in Interviewer-Administered Asthma Control Questionnaire (ACQ-IA) total score measured at week 12.

    The ACQ-IA 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-IA total score is calculated as the mean of the responses to all 7 questions.

    The measured values presented are actually adjusted means.


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

    Responder categories based on the ACQ-IA 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-IA total score responders.

    The ACQ-IA 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 Per 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 per 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


  • Peak Expiratory Flow (PEF) a.m. Change From Baseline [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]

    Change from baseline in the morning (a.m.) peak expiratory flow based on the weekly mean at week 12.

    Measured values presented are actually adjusted means.


  • Peak Expiratory Flow (PEF) p.m. Change From Baseline [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]

    Change from baseline in the evening (p.m.) peak expiratory flow based on the weekly mean at week 12.

    Measured values presented are actually adjusted means.


  • Peak Expiratory Flow (PEF) Variability Change From Baseline [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]

    Change from baseline in the peak expiratory flow variability based on the weekly mean at week 12.

    Measured values presented are actually adjusted means.


  • FEV1 a.m. Change From Baseline [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]

    Change from baseline in morning (a.m.) FEV1 based on the weekly mean at week 12.

    Measured values presented are actually adjusted means.


  • FEV1 p.m. Change From Baseline [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]

    Change from baseline in evening (p.m.) FEV1 based on the weekly mean at week 12.

    Measured values presented are actually adjusted means.


  • Change From Baseline in Nighttime Awakenings [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]

    Change from baseline in nighttime awakenings based on the weekly mean at week 12.

    Nighttime awakenings was assessed by the question "Did you wake up during the night due to your asthma?" from the e-diary. Scores range from 1 (did not wake up) to 5 (was awake all night).

    Measured values presented are actually adjusted means.


  • Change From Baseline in Morning Asthma Symptoms [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]

    Change from baseline in morning asthma symptoms based on the weekly mean at week 12.

    Morning asthma symptoms was assessed by the question "how were your asthma symptoms this morning?" from the e-diary. Scores range from 1 (no asthma symptoms) to 5 (very severe asthma symptoms).

    Measured values presented are actually adjusted means.


  • Change From Baseline in Daytime Asthma Symptoms [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]

    Change from baseline in daytime asthma symptoms based on the weekly mean at week 12.

    Daytime asthma symptoms was assessed by the question "how were your asthma symptoms during the day?" from the e-diary. Scores range from 1 (no asthma symptoms) to 5 (very severe asthma symptoms).

    Measured values presented are actually adjusted means.


  • Change From Baseline in Daytime Activity Limitations [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]

    Change from baseline in daytime activity limitations based on the weekly mean at week 12.

    Daytime activity limitations was assessed by the question "how limited were you in your activities today because of your asthma?" from the e-diary. Scores range from 1 (not limited) to 5 (totally limited).

    Measured values presented are actually adjusted means.


  • Change From Baseline in Daytime Experiences of Shortness of Breath [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]

    Change from baseline in daytime experiences of shortness of breath based on the weekly mean at week 12.

    Daytime experiences of shortness of breath was assessed by the question "how much shortness of breath did you experience during the day" from the e-diary. Scores range from 1 (none) to 5 (a very great deal).

    Measured values presented are actually adjusted means.


  • Change From Baseline in Daytime Experiences of Wheeze or Cough [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]

    Change from baseline in daytime experiences of wheeze or cough based on the weekly mean at week 12.

    Daytime experiences of wheeze or cough was assessed by the question "did you experience wheeze or cough during the day?" from the e-diary. Scores range from 1 (not at all) to 5 (all the time).

    Measured values presented are actually adjusted means.


  • Change From Baseline in Asthma Symptom-free Days [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]

    Change from baseline in asthma symptom-free days based on the weekly mean at week 12.

    A day was considered as an asthma symptom-free day if there were no symptoms reported via the e-Diary and no use of rescue medication reported via the eDiary during that day.

    Measured values presented are actually adjusted means.



Enrollment: 401
Study Start Date: July 2012
Study Completion Date: May 2015
Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo QD Drug: Placebo
2 actuations once daily in the evening
Experimental: Tiotropium low dose QD Drug: Tiotropium low dose mcg
2 actuations once daily in the evening
Experimental: Tiotropium medium dose QD Drug: Tiotropium high dose
2 actuations once daily in the evening

  Eligibility

Ages Eligible for Study:   6 Years to 11 Years   (Child)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

Inclusion criteria are:

  1. All patients' parent(s) (or legal guardian) must sign and date an informed consent prior to participation in the trial. In addition, an informed assent suitable for this age group has to be obtained from patients. A separate informed consent/assent is required for pharmacogenomic sampling.
  2. Male or female patients between 6 and 11 years of age.
  3. All patients must have at least a 6-month history of asthma.
  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 (partly controlled) at Visit 1 and prior to randomisation at Visit 2 as defined by an Asthma Control Questionnaire (ACQ-IA) mean score >= 1.5.
  6. All patients must have a pre-bronchodilator forced expiratory volume in one 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% 15 to 30 minutes after 200 mcg salbutamol/albuterol.
  9. Patients must be able to use the Respimat inhaler correctly.
  10. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of electronic diary/peak flow meter (diary compliance of at least 80% is required).

Exclusion criteria:

Exclusion criteria are:

  1. Patients with a significant disease other than asthma.
  2. Patients with a clinically relevant abnormal haematology or blood chemistry at screening.
  3. Patients with a history of congenital or acquired heart disease, or patients who have been hospitalised for cardiac syncope or failure during the past year.
  4. Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year.
  5. Patients with a malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years.
  6. Patients with known active tuberculosis.
  7. Patients who have undergone thoracotomy with pulmonary resection.
  8. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the six weeks prior to Visit 1.
  9. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the inhalation solution used with the Respimat inhaler.
  10. Pregnant or nursing female patients, including postmenarchal girls with a positive urine pregnancy test at Visit 1.
  11. Postmenarchal girls of child-bearing potential not using a highly effective method of birth control.
  12. Patients who have been treated with systemic corticosteroids within four weeks prior to Visit 1.
  13. Patients who have been treated with systemic beta-adrenergics within four weeks prior to Visit 1.
  14. Patients who have been treated with oral beta-blocker medication within four weeks prior to Visit 1 and/or during the screening period.
  15. Patients who have been treated with inhaled long-acting anticholinergics or systemic anticholinergic treatment within four weeks prior to Visit 1 and/or during the screening period, or who have been treated with inhaled short-acting anticholinergics within two weeks prior to Visit 1.
  16. Patients who have been treated with short-acting theophylline preparations within two weeks prior to Visit 1.
  17. Patients who have been treated with non-approved and according to international guidelines not recommended experimental drugs for routine asthma therapy within four weeks prior to Visit 1 and/or during the screening period.
  18. Patients who have taken an investigational drug within six half lives according to the investigator's information, or four weeks (whichever is greater) prior to Visit 1 and/or during the screening period.
  19. Patients who have previously been randomised in this trial or are currently participating in another trial.
  20. Patients with any acute asthma exacerbation or respiratory tract infection 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.
  21. Patients requiring six or more puffs of rescue medication per day on more than two 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.
  22. Patients who are unable to comply with medication restrictions prior to Visit 1 and/or prior to Visit 2.
  23. Patients with a known narrow-angle glaucoma, or any other disease where anticholinergic treatment is contraindicated.
  24. Patients with moderate to severe renal impairment, as defined by a creatinine clearance <50 mL/min/1.73 m2 BSA, as tiotropium is a predominantly renally excreted drug.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01634152

  Show 94 Study Locations
Sponsors and Collaborators
Boehringer Ingelheim
Pfizer
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

Additional Information:
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01634152     History of Changes
Other Study ID Numbers: 205.446  2011-001777-43 
Study First Received: July 3, 2012
Results First Received: November 17, 2015
Last Updated: December 22, 2015
Health Authority: Argentina: Admin Nacional de Medicamentos, Alimentos Tecnologia Medica
Australia: Human Research Ethics Committee
Belgium: Federal Agency for Medicinal and Health Products
Brazil: Ministry of Health
Canada: Health Canada
Czech Republic: State Institute for Drug Control
Germany: Federal Institute for Drugs and Medical Devices
Guatemala: Ministry of Public Health and Social Assistance
Hungary: National Institute of Pharmacy
Latvia: State Agency of Medicines
Lithuania: State Medicine Control Agency - Ministry of Health
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Romania: National Medicines Agency
Russia: Pharmacological Committee, Ministry of Health
Slovakia: State Institute for Drug Control
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 Bromide
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Parasympatholytics
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 24, 2016