Efficacy and Safety of 3 Doses of Tiotropium Compared to Placebo in Adolescents (12 to 17 Yrs) With Moderate Asthma

• ClinicalTrials.gov Identifier: NCT01122680
• Recruitment Status: Completed
• First Posted: May 13, 2010
• Results First Posted: June 27, 2012
• Last Update Posted: May 16, 2014
• Sponsor: Boehringer Ingelheim
• Collaborator: Pfizer
• Information provided by (Responsible Party): Boehringer Ingelheim

Tracking Information

• First Submitted Date: May 11, 2010
• First Posted Date: May 13, 2010
• Results First Submitted Date: April 10, 2012
• Results First Posted Date: June 27, 2012
• Last Update Posted Date: May 16, 2014
• Study Start Date: May 2010
• Actual Primary Completion Date: April 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 23, 2012)

Forced Expiratory Volume (FEV1) Peak (0-3h) Response [ Time Frame: Baseline and 4 weeks ]

The FEV1 peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FEV1 measured within the first 3 hours post dosing and the FEV1 baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

• Original Primary Outcome Measures (submitted: May 11, 2010): Forced expiratory volume in 1 second (FEV1) peak (0-3h), i.e. the maximum FEV1 measured within 3 hours post dosing [ Time Frame: end of each 4-week treatment period ]

Current Secondary Outcome Measures (submitted: May 23, 2012)

• Trough FEV1 Response [ Time Frame: Baseline and 4 weeks ]
  The trough FEV1 is defined as the pre-dose FEV1 measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
• FEV1 Area Under the Curve From 0 to 3 h (AUC0-3h) Response [ Time Frame: Baseline and 4 weeks ]
  FEV1 (AUC0-3h) will be calculated as the area under the curve from 0 to 3hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
• FEV1 Individual Measurements Response at Each Time-point [ Time Frame: Baseline and 4 weeks (10 min pre-dose, 30 min, 1,2,3 hours post-dose) ]
  Individual FEV1 measurements at each time-point ("personal best"). Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
• Forced Vital Capacity (FVC) Peak (0-3h) Response [ Time Frame: Baseline and 4 weeks ]
  The FVC peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FVC measured within the first 3 hours post dosing and the FVC baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
• FVC Trough Response [ Time Frame: Baseline and 4 weeks ]
  The trough FVC response is defined as the pre-dose FVC measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
• FVC Area Under the Curve From 0 to 3 h (AUC0-3h) Response [ Time Frame: Baseline and 4 weeks ]
  FVC (AUC0-3h) will be calculated as the area under the curve from 0 to 3hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
• FVC Individual Measurements at Each Time-point [ Time Frame: Baseline and 4 weeks (10 min pre-dose, 30 min, 1,2,3 hours post-dose) ]
  Individual FVC measurements at each time-point ("personal best"). Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
• Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point [ Time Frame: Baseline and 4 weeks (10 min pre-dose, 30 min, 1,2,3 hours post-dose) ]
  FEF 25-75% is the mean forced expiratory flow between 25% and 75% of the FVC determined at the end of the 4-week treatment period. This is often referred to as the maximum midexpiratory flow. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
• Mean Morning Peak Expiratory Flow (PEF) Response [ Time Frame: Baseline and 4 weeks ]
  Mean morning PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
• Mean Evening PEF Response [ Time Frame: Baseline and 4 weeks ]
  Mean evening PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
• Change From Baseline in the Number of Puffs of Rescue Medication Per Day [ Time Frame: Baseline and 4 weeks ]
  Mean number of inhalations (puffs) of unscheduled rescue salbutamol therapy during whole day. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
• Control of Asthma as Assessed by Asthma Control Questionnaire (ACQ) [ Time Frame: 4 weeks ]
  ACQ is a questionnaire consisting of a seven point Likert scale ranging from 0 to 6, whereby 0 represents good control and 6 represents poor control of asthma. The scale describes the frequency and severity of asthma symptoms. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
• Change From Baseline in Mean Number of Nighttime Awakenings [ Time Frame: Baseline and last week of treatment (week 4) ]
  Mean number of nighttime awakenings due to asthma symptoms as assessed by patients eDiary incorporated in the AM3® device. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

Original Secondary Outcome Measures (submitted: May 11, 2010)

• Subset of patients with 24-hour pulmonary function testing: FEV1 (AUC0-14h), FEV1 (AUC0-24h), FEV1 (AUC14-24h), FVC (AUC0-14h), FVC (AUC0-24h), and FVC (AUC14-24h) [ Time Frame: once during the trial, after 4 weeks of randomised treatment, at Visit, 3, 4, or 5 ]
• All adverse events [ Time Frame: 19 weeks plus 30 days ]
• Vital signs (blood pressure and heart rate) in conjunction with spirometry pre-dose and up to 3 hours post dosing [ Time Frame: end of each 4-week treatment period ]
• Pharmacokinetic evaluation of primary exposure parameters, e.g. Area under the curve (AUC) and Cmax, and evaluation of secondary parameters, e.g. CL/F, Vz/F and t1/2. PK parameters will be assessed after acute and chronic dosing. [ Time Frame: first treatment period ]
• Trough forced expiratory volume in 1 second (FEV1) [ Time Frame: end of each 4-week treatment period ]
• Forced Vital Capacity peak within 3 hours post-dosing (FVC 0-3h) and trough FVC [ Time Frame: end of each 4-week treatment period ]
• FEV1 (AUC 0-3h) and FVC (AUC 0-3h) [ Time Frame: end of each 4-week treatment period ]
• Individual FEV1 and FVC measurements [ Time Frame: end of each 4-week treatment period ]
• Mean forced expiratory flow between 25% and 75% of the FVC (FEF 25-75%) [ Time Frame: end of each 4-week treatment period ]
• Peak Expiratory Flow (PEF) a.m./p.m. (home assessment) [ Time Frame: last week of each period of randomised treatment ]
• Use of p.r.n. rescue medication [ Time Frame: last week of each period of randomised treatment ]
• Asthma Control Questionnaire (ACQ) [ Time Frame: end of each 4-week treatment period ]
• Night time awakenings due to asthma symptoms as assessed by patient's eDiary (home assessment) [ Time Frame: last week of each period of randomised treatment ]

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

Descriptive Information

• Brief Title: Efficacy and Safety of 3 Doses of Tiotropium Compared to Placebo in Adolescents (12 to 17 Yrs) With Moderate Asthma
• Official Title: A Phase II Randomised, Double-blind, Placebo-controlled, Incomplete Crossover Trial With 4-week Treatment Periods to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution (Doses of 1.25 µg, 2.5 µg and 5 µg) Delivered Via Respimat® Inhaler Once Daily in the Evening in Adolescents (12 to 17 Yrs Old) With Moderate Persistent Asthma
• Brief Summary: The primary objective of this trial is to evaluate the efficacy and safety of tiotropium 1.25 mcg (2 actuations of 0.625 mcg), tiotropium 2.5 mcg (2 actuations of 1.25 mcg) and tiotropium 5 mcg (2 actuations of 2.5 mcg) once daily in the evening delivered by the Respimat inhaler in adolescents (12 to 17 yrs) with moderate persistent asthma, compared to placebo and on top of maintenance therapy with an inhaled corticosteroid controller medication. It is a randomised, double-blind, placebo-controlled Phase II trial with incomplete cross-over design. Patients need to be still symptomatic, i. e. not fully controlled with their maintenance treatment.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Double; Primary Purpose: Treatment
• Condition: Asthma

Intervention

• Drug: Tiotropium bromide
  inhalation solution, dose of 1.25 mcg (2 puffs of 0.625 mcg)
• Drug: tiotropium bromide
  inhalation solution, dose of 2.5 mcg (2 puffs of 1.25 mcg)
• Drug: tiotropium bromide
  inhalation solution, dose of 5 mcg (2 puffs of 2.5 mcg)
• Drug: Placebo
  placebo inhalation solution

Study Arms

• Experimental: Treatment A
  patients inhale 2 puffs (dose of 1.25 mcg) once daily in the evening via Respimat inhaler
  Intervention: Drug: Tiotropium bromide
• Experimental: Treatment C
  patients inhale 2 puffs (dose of 5 mcg) once daily in the evening via Respimat inhaler
  Intervention: Drug: tiotropium bromide
• Placebo Comparator: Placebo
  patients inhale 2 puffs of placebo matching tiotropium once daily in the evening via Respimat inhaler
  Intervention: Drug: Placebo
• Experimental: Treatment B
  patients inhale 2 puffs (dose of 2.5 mcg) once daily in the evening via Respimat inhaler
  Intervention: Drug: tiotropium bromide

• Publications *: Vogelberg C, Engel M, Moroni-Zentgraf P, Leonaviciute-Klimantaviciene M, Sigmund R, Downie J, Nething K, Vevere V, Vandewalker M. Tiotropium in asthmatic adolescents symptomatic despite inhaled corticosteroids: a randomised dose-ranging study. Respir Med. 2014 Sep;108(9):1268-76. doi: 10.1016/j.rmed.2014.06.011. Epub 2014 Jul 17.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 4, 2011): 105
• Original Estimated Enrollment (submitted: May 11, 2010): 92
• Study Completion Date: Not Provided
• Actual Primary Completion Date: April 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria:

1. All patients and legally accepted caregiver(s) must sign and date an Informed Consent form consistent with Good Clinical Practice (GCP) guidelines of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and local legislation prior to participation in the trial.
2. Male or female patients between 12 and 17 years of age.
3. All patients must have at least a 3 months history of asthma and fulfill the diagnostic criteria of moderate persistent asthma, according to the current Global Initiative for Asthma (GINA) guidelines at the time of enrolment into the trial.
4. All patients must have been on maintenance treatment with inhaled corticosteroids at a stable medium dose for at least 4 weeks before Visit 1.
5. All patients must be symptomatic (partly controlled) at Visit 1 (screening) and prior to randomisation at Visit 2 as defined by an Asthma Control Questionnaire (ACQ) mean score of equal or above 1.5.
6. All patients must have a pre-bronchodilator FEV1 above 60% and less than or equal 90% of predicted normal at Visit 1. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ± 30%.
7. All patients must have an increase in FEV1 of equal or above 12% and 200 mL 15 min. after 400 mcg salbutamol (albuterol) at Visit 1. If patients in the lower age range (e.g., 12 to 14 year olds) exhibit a very small total lung volume, positive reversibility testing might be based solely on the relative (12%) post-bronchodilator response.
8. All patients should be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment.
9. Patients should be able to use the Respimat® inhaler correctly.
10. Patients must be able to perform all trial related procedures including technically acceptable spirometric manoeuvres, according to American Thoracic Society (ATS) standards and the use of the electronic diary/peak flow meter.

Exclusion criteria:

1. Patients with a significant disease other than asthma.
2. Patients with a history of congenital or acquired heart disease, and/or have been hospitalised for cardiac syncope or failure during the past year.
3. Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention (e. g. pacemaker implantation) or a change in drug therapy within the past year.
4. Patients with malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years.
5. Patients with lung diseases other than asthma, e.g. cystic fibrosis (CF). In case of ex-premature infants, a history of significant bronchopulmonary dysplasia (BPD) will be regarded as exclusion criterion
6. Patients with significant alcohol or drug abuse within the past two years.
7. Patients with known hypersensitivity to anticholinergic drugs, benzalkonium chloride (BAC), ethylenediaminetetraacetic acid (EDTA) or any other components of the tiotropium inhalation solution.
8. Pregnant or nursing adolescent female patients, including female patients with a positive Beta HCG (serum pregnancy) testing at screening (visit 1).
9. Sexually active female patients of child-bearing potential not using a highly effective method of birth control.
10. Patients with a known narrow-angle glaucoma, or any other disease where anticholinergic treatment is contraindicated.
11. Patients with renal impairment, as defined by a creatinine clearance less than 50 mL/min/1.73 m2 body surface area (BSA) as calculated by Schwartz Formula.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany, Latvia, Lithuania, Slovenia, United States

Administrative Information

• NCT Number: NCT01122680
• Other Study ID Numbers: 205.424; 2009-017745-55 ( EudraCT Number: EudraCT )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Boehringer Ingelheim
• Study Sponsor: Boehringer Ingelheim
• Collaborators: Pfizer

Investigators

• Study Chair: Boehringer Ingelheim; Boehringer Ingelheim

• PRS Account: Boehringer Ingelheim
• Verification Date: July 2012