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

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

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.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: tiotropium-bromide; Drug: placebo

• Study Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Antwerpen, Belgium
    • 205.443.01004 Boehringer Ingelheim Investigational Site
  • Brussel, Belgium
    • 205.443.01002 Boehringer Ingelheim Investigational Site
  • Edegem, Belgium
    • 205.443.01001 Boehringer Ingelheim Investigational Site
• Finland
  • Helsinki, Finland
    • 205.443.02002 Boehringer Ingelheim Investigational Site
  • Turku, Finland
    • 205.443.02003 Boehringer Ingelheim Investigational Site
• Germany
  • Berlin, Germany
    • 205.443.03003 Boehringer Ingelheim Investigational Site
  • Bochum, Germany
    • 205.443.03001 Boehringer Ingelheim Investigational Site
  • Ettenheim, Germany
    • 205.443.03002 Boehringer Ingelheim Investigational Site
  • Frankfurt, Germany
    • 205.443.03010 Boehringer Ingelheim Investigational Site
• Korea, Republic of
  • Guri, Korea, Republic of
    • 205.443.82003 Boehringer Ingelheim Investigational Site
  • Incheon, Korea, Republic of
    • 205.443.82002 Boehringer Ingelheim Investigational Site
  • Seoul, Korea, Republic of
    • 205.443.82001 Boehringer Ingelheim Investigational Site
• Latvia
  • Balvi, Latvia
    • 205.443.05001 Boehringer Ingelheim Investigational Site
  • Rezekne, Latvia
    • 205.443.05003 Boehringer Ingelheim Investigational Site
  • Riga, Latvia
    • 205.443.05002 Boehringer Ingelheim Investigational Site
• Lithuania
  • Vilnius, Lithuania
    • 205.443.06002 Boehringer Ingelheim Investigational Site
  • Vilnius, Lithuania
    • 205.443.06003 Boehringer Ingelheim Investigational Site
• Malaysia
  • Kelantan, Malaysia
    • 205.443.10002 Boehringer Ingelheim Investigational Site
  • Kuala Lumpur, Malaysia
    • 205.443.10001 Boehringer Ingelheim Investigational Site
  • Pahang, Malaysia
    • 205.443.10003 Boehringer Ingelheim Investigational Site
• Netherlands
  • Breda, Netherlands
    • 205.443.04003 Boehringer Ingelheim Investigational Site
  • Groningen, Netherlands
    • 205.443.04001 Boehringer Ingelheim Investigational Site
• Philippines
  • Quezon City, Philippines
    • 205.443.09001 Boehringer Ingelheim Investigational Site
  • Quezon City, Philippines
    • 205.443.09002 Boehringer Ingelheim Investigational Site
• Ukraine
  • Dnipropetrovsk, Ukraine
    • 205.443.07003 Boehringer Ingelheim Investigational Site
  • Donetsk, Ukraine
    • 205.443.07002 Boehringer Ingelheim Investigational Site
  • Vinnytsya, Ukraine
    • 205.443.07005 Boehringer Ingelheim Investigational Site
  • Zaporizhya, Ukraine
    • 205.443.07004 Boehringer Ingelheim Investigational Site
  • Zaporizhzhya, Ukraine
    • 205.443.07001 Boehringer Ingelheim Investigational Site
• United States
  • Missouri
    • Columbia, Missouri, United States
      • 205.443.12003 Boehringer Ingelheim Investigational Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
      • 205.443.12005 Boehringer Ingelheim Investigational Site
  • South Carolina
    • Charleston, South Carolina, United States
      • 205.443.12006 Boehringer Ingelheim Investigational Site
    • Summerville, South Carolina, United States
      • 205.443.12004 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 5 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: tiotropium low dose; Once daily, delivered with Respimat® inhaler	Drug: tiotropium-bromide; IMP
EXPERIMENTAL: tiotropium high dose; Once daily, delivered with Respimat® inhaler	Drug: tiotropium-bromide; IMP
PLACEBO_COMPARATOR: placebo; Once daily, delivered with Respimat® inhaler	Drug: placebo; placebo matching tiotropium

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weekly Mean Combined Daytime Asthma Symptom Score	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.	Baseline and 12 weeks
FEV1 Peak (0-3h) Change From Baseline	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	10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weekly Mean Overnight Asthma Symptom Score Response	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	Baseline and 12 weeks
Weekly Percentage of Days Without Asthma Symptoms	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	12 weeks
Weekly Percentage of Days With Use of Salbutamol (Albuterol) Rescue Medication	Weekly percentage of days with use of salbutamol (albuterol) rescue medication at week 12. A week was defined as 7 days.	12 weeks
Weekly Mean Nighttime Awakenings Due to Asthma Symptoms	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	Baseline and 12 weeks
Trough FEV1 Change From Baseline	Change from baseline in Trough (pre-dose) Forced expiratory volume in 1 second (FEV1) measured at week 12.	Baseline and 12 weeks
FEV1 AUC (0-3h) Change From Baseline	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).	10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12
FVC Peak (0-3h) Change From Baseline	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.	10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12
Trough FVC Change From Baseline	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.	Baseline and 12 weeks
FVC AUC (0-3h) Change From Baseline	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).	10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12
Individual FEV1 Measurements	Change from baseline in individual FEV1 measurements at each timepoint after 12 weeks	Baseline and 12 weeks
Individual FVC Measurements	Change from baseline in individual FVC measurements at each timepoint after 12 weeks	Baseline and 12 weeks

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim
• Collaborators: Pfizer

Publications and helpful links

General 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.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (ACTUAL): December 1, 2014
• Study Completion (ACTUAL): December 1, 2014

Study Registration Dates

• First Submitted: April 16, 2012
• First Submitted That Met QC Criteria: July 3, 2012
• First Posted (ESTIMATE): July 6, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): June 23, 2015
• Last Update Submitted That Met QC Criteria: June 3, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Anticonvulsants; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Tiotropium Bromide; Bromides
• Other Study ID Numbers: 205.443; 2011-005512-28 (EUDRACT_NUMBER: EudraCT)