Evaluation of Tiotropium 2.5 and 5 mcg Once Daily Delivered Via the Respimat® Inhaler Compared to Placebo in 1 to 5 Year Old Patients With Persistent Asthma

• ClinicalTrials.gov Identifier: NCT01634113
• Recruitment Status: Completed
• First Posted: July 6, 2012
• Results First Posted: June 23, 2015
• Last Update Posted: June 23, 2015
• Sponsor: Boehringer Ingelheim
• Collaborator: Pfizer
• Information provided by (Responsible Party): Boehringer Ingelheim

Tracking Information

• First Submitted Date: April 16, 2012
• First Posted Date: July 6, 2012
• Results First Submitted Date: June 3, 2015
• Results First Posted Date: June 23, 2015
• Last Update Posted Date: June 23, 2015
• Study Start Date: July 2012
• Actual Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 3, 2015)

• Weekly Mean Combined Daytime Asthma Symptom Score [ Time Frame: Baseline and 12 weeks ]
  Change from baseline in the weekly mean combined daytime asthma symptom score as assessed by the Paediatric Asthma Caregivers Diary (PACD) in the last week of the 12 week treatment period. The PACD is a diary designed to evaluate daily asthma symptoms in children aged 2-5 years. The diary consists of three questions to be answered each morning, when the child wakes up, and seven questions to be answered each evening, right after the child goes to bed for the night. A week was defined as 7 days. The combined daytime score is the average of scores from questions 4 - 7 in the diary which are questions regarding severity of cough, wheezing, trouble breathing and interference with activities, scores for each question range from 0 (best) to 5 (worst). The week 12 weekly mean is the mean of the responses for each day averaged over the 7 days in week 12, so combined daytime asthma symptom scores also range from 0 (best) to 5 (worst). The measured values presented are adjusted means.
• FEV1 Peak (0-3h) Change From Baseline [ Time Frame: 10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12 ]
  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

Original Primary Outcome Measures (submitted: July 3, 2012)

• Combined daytime asthma symptom score [ Time Frame: 12 weeks ]
• Peak Forced Expiratory Volume in one second (FEV1 Peak0-3h) response within 3 hours post afternoon dosing (only for 5 yr olds capable of providing technically acceptable Pulmonary Function Tests (PFTs)) [ Time Frame: 12 weeks ]

Current Secondary Outcome Measures (submitted: June 3, 2015)

• Weekly Mean Overnight Asthma Symptom Score Response [ Time Frame: Baseline and 12 weeks ]
  Change from baseline in the weekly mean overnight asthma symptom score response as assessed by the PACD in the last week of the 12 week treatment period. The overnight score is the score from the following question in the PACD, "How much did your child cough last night after your child was put to bed for the night until he/she awoke this morning?". This endpoint was determined only for patients with 2 or more nights with symptoms per week during the baseline period. In this case, the baseline period is the 7 days used to derive the baseline value. A patient has a night with symptoms if the question was answered with scores 1, 2, 3, 4 or 5 or the patient received β-Agonist at least one time since he/she went to bed. A week was defined as 7 days. Scores range from 0 (best) to 4 (worst), a value of 5 indicates severity of symptoms is unknown. The measured values presented are adjusted means
• Weekly Percentage of Days Without Asthma Symptoms [ Time Frame: 12 weeks ]
  Weekly Percentage of days without asthma symptoms at week 12. A day without asthma symptoms was defined as a day during which the patient experienced no asthma symptoms, did not use rescue medication (salbutamol/albuterol) and had no asthma exacerbation/worsening requiring systemic corticosteroids, or unscheduled visits to a doctor's office, emergency department, or hospital. A week was defined as 7 days. The measured values presented are adjusted means
• Weekly Percentage of Days With Use of Salbutamol (Albuterol) Rescue Medication [ Time Frame: 12 weeks ]
  Weekly percentage of days with use of salbutamol (albuterol) rescue medication at week 12. A week was defined as 7 days.
• Weekly Mean Nighttime Awakenings Due to Asthma Symptoms [ Time Frame: Baseline and 12 weeks ]
  Change from baseline in the weekly mean nighttime awakenings due to asthma symptoms as assessed by the PACD, in the last week of the 12 week treatment period. The weekly mean was calculated as the average of the weekly scores for the question "Did your child wake up during the night due to his/her asthma?" The question was answered on a 5-point verbal rating scale, with scores ranging from 1 (did not wake up) to 5 (was awake all night). A week was defined as 7 days. The measured values presented are adjusted means
• Trough FEV1 Change From Baseline [ Time Frame: Baseline and 12 weeks ]
  Change from baseline in Trough (pre-dose) Forced expiratory volume in 1 second (FEV1) measured at week 12.
• FEV1 AUC (0-3h) Change From Baseline [ Time Frame: 10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12 ]
  Change from baseline of area under the curve (AUC) from 0 to 3 h 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).
• FVC Peak (0-3h) Change From Baseline [ Time Frame: 10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12 ]
  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.
• Trough FVC Change From Baseline [ Time Frame: Baseline and 12 weeks ]
  Change from baseline of trough (pre-dose) forced vital capacity (FVC) measured 10 min before the administration of trial medication after 12 weeks of treatment.
• FVC AUC (0-3h) Change From Baseline [ Time Frame: 10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12 ]
  Change from baseline of area under the curve (AUC) from 0 to 3 h for FVC (FVC AUC0-3h) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h).
• Individual FEV1 Measurements [ Time Frame: Baseline and 12 weeks ]
  Change from baseline in individual FEV1 measurements at each timepoint after 12 weeks
• Individual FVC Measurements [ Time Frame: Baseline and 12 weeks ]
  Change from baseline in individual FVC measurements at each timepoint after 12 weeks

Original Secondary Outcome Measures (submitted: July 3, 2012)

• Vital signs [ Time Frame: 0-12 weeks ]
• All adverse events [ Time Frame: 0-12 weeks ]
• Amount of tiotropium that is eliminated unchanged in urine from the time point t1 to time point t2 [ Time Frame: Day 1 and 12 weeks ]
• Fraction of tiotropium dose excreted unchanged in urine from the time point t1 to time point t2 [ Time Frame: Day 1 and 12 weeks ]
• Overnight asthma symptom score [ Time Frame: 12 weeks ]
• Percentage of days without asthma symptoms during the 12-week treatment period [ Time Frame: 0-12 weeks ]
• Percentage of days with use of salbutamol (albuterol) rescue medication [ Time Frame: 0-12 weeks ]
• Nighttime awakenings due to asthma symptoms [ Time Frame: 12 weeks ]
• Trough FEV1 response (only for 5 yr olds capable of providing technically acceptable PFTs) [ Time Frame: 12 weeks ]
• Forced Vital Capacity (FVC) Peak0-3h response and trough FVC response (only for 5 yr olds capable of providing technically acceptable PFTs) [ Time Frame: 12 weeks ]
• FEV1 (AUC0-3h) response and FVC (AUC0-3h) response (only for 5 yr olds capable of providing technically acceptable PFTs) [ Time Frame: 12 weeks ]
• Individual FEV1 and FVC measurements (response) (only for 5 yr olds capable of providing technically acceptable PFTs) [ Time Frame: 12 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Evaluation of Tiotropium 2.5 and 5 mcg Once Daily Delivered Via the Respimat® Inhaler Compared to Placebo in 1 to 5 Year Old Patients With Persistent Asthma
• Official Title: A Phase II/III, Randomised, Double-blind, Placebo-controlled, Parallel Group Trial to Evaluate Safety and Efficacy of Tiotropium Inhalation Solution (2.5 µg and 5 µg) Administered Once Daily in the Afternoon Via Respimat® Inhaler for 12 Weeks in Patients 1 to 5 Years Old With Persistent Asthma
• Brief Summary: The primary objective of this trial is to evaluate the safety and efficacy of two doses of tiotropium inhalation solution delivered via the Respimat® inhaler once daily in the afternoon in patients (1 to 5 years old) with persistent asthma on top of inhaled corticosteroid (ICS) treatment.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double; Primary Purpose: Treatment
• Condition: Asthma

Intervention

• Drug: tiotropium-bromide
  IMP
• Drug: placebo
  placebo matching tiotropium

Study Arms

• Experimental: tiotropium low dose
  Once daily, delivered with Respimat® inhaler
  Intervention: Drug: tiotropium-bromide
• Experimental: tiotropium high dose
  Once daily, delivered with Respimat® inhaler
  Intervention: Drug: tiotropium-bromide
• Placebo Comparator: placebo
  Once daily, delivered with Respimat® inhaler
  Intervention: Drug: placebo

Publications *

• Wachtel H, Nagel M, Engel M, El Azzi G, Sharma A, Suggett J. In vitro and clinical characterization of the valved holding chamber AeroChamber Plus(R) Flow-Vu(R) for administrating tiotropium Respimat(R) in 1-5-year-old children with persistent asthmatic symptoms. Respir Med. 2018 Apr;137:181-190. doi: 10.1016/j.rmed.2018.03.010. Epub 2018 Mar 7.
• Vrijlandt EJLE, El Azzi G, Vandewalker M, Rupp N, Harper T, Graham L, Szefler SJ, Moroni-Zentgraf P, Sharma A, Vulcu SD, Sigmund R, Chawes B, Engel M, Bisgaard H. Safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2018 Feb;6(2):127-137. doi: 10.1016/S2213-2600(18)30012-2. Epub 2018 Jan 18.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 3, 2012): 102
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: December 2014
• Actual Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria:

1. All patients' parents (or legal guardians) must sign and date an informed consent consistent with ICH-GCP guidelines and local legislation prior to participation in the trial. Where appropriate, participants should assent to enroll in the study.
2. Male or female patients between 1 and 5 years of age.
3. By a physician documented (at least 6 month) history of persistent asthma symptoms, including (but not limited to) wheezing, cough, and/or shortness of breath. (persistent = need for inhalation corticosteroid maintenance therapy to control asthma symptoms)
4. For patients aged 5 years and capable of performing technically acceptable Pulmonary Function tests (PFTs): documented impaired lung function (i.e. pre-bronchodilator Forced Expiratory Volume in 1 second (FEV1) is smaller or equal to 90% of predicted normal).
5. All patients must have been on maintenance treatment with an inhaled corticosteroid at stable dose, either as mono treatment or in combination with another controller medication, for at least 4 weeks before Visit 1.
6. All patients must be symptomatic (partly controlled) as defined by the Global Initiative for Asthma (GINA) guideline for children aged 5 years and younger in the week prior to Visit 1 (screening) and in the week prior to randomisation (Visit 2).

Further inclusion criteria apply.

Exclusion criteria:

1. Patients with a significant disease other than asthma.
2. Patients with clinically relevant abnormal screening haematology or blood chemistry will be excluded if the abnormality defines a significant disease as defined in exclusion criterion 1.
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, including cardiac arrhythmia requiring intervention (e.g. pacemaker implantation) 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.
6. Patients with clinically significant lung diseases other than asthma.
7. Alternative causes (other causes than asthma) that can lead to respiratory symptoms of wheeze, cough and shortness of breath.
8. Patients with known active tuberculosis.
9. Patients who have undergone thoracotomy with pulmonary resection.
10. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to the screening visit (Visit 1).

Further exclusion criteria apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Year to 5 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Finland, Germany, Korea, Republic of, Latvia, Lithuania, Malaysia, Netherlands, Philippines, Ukraine, United States
• Removed Location Countries: Peru

Administrative Information

• NCT Number: NCT01634113
• Other Study ID Numbers: 205.443; 2011-005512-28 ( EudraCT Number: EudraCT )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Boehringer Ingelheim
• Original Responsible Party: Same as current
• Current Study Sponsor: Boehringer Ingelheim
• Original Study Sponsor: Same as current
• Collaborators: Pfizer

Investigators

• Study Chair: Boehringer Ingelheim; Boehringer Ingelheim

• PRS Account: Boehringer Ingelheim
• Verification Date: June 2015