Tiotropium Bromide in Cystic Fibrosis

Study Overview
=================
Brief Summary
-----------------
To date, there have been no formal clinical studies completed using tiotropium in CF patients. While there is a large body of evidence demonstrating the efficacy and safety of tiotropium in patients with Chronic Obstructive Pulmonary Disease (COPD), relatively little is known about its efficacy and safety in patients with a diagnosis of cystic fibrosis. Therefore, Boehringer Ingelheim proposed to profile the long acting anticholinergic tiotropium and to generate adequate clinical data for use as a bronchodilator in paediatric and adult CF. The phase III trial (205.438) is a part of the approved Paediatric Investigation Plan (PIP) agreed for Spiriva® Respimat® in Cystic Fibrosis.

Official Title
-----------------
A Randomised, Double-blind, Placebo-controlled Parallel-group Trial to Confirm the Efficacy After 12 Weeks and the Safety of Tiotropium 5 Mcg Administered Once Daily Via the Respimat® Device in Patients With Cystic Fibrosis.

Conditions
-----------------
Cystic Fibrosis

Intervention / Treatment
-----------------
* Drug: tiotropium Respimat® inhaler
* Drug: Placebo Respimat® inhaler


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Patients with a documented diagnosis of Cystic Fibrosis (CF) (positive sweat chloride >=60 mEq/liter, by pilocarpine iontophoresis) and/or a genotype with two identifiable mutations. Male or female patients (children less than 12 years and adolescents >12 years). Patients >=5 years of age must be able to perform acceptable spirometric maneuvers, according to the American Thoracic Society (ATS) standards. Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) >25% of predicted values. Pre-bronchodilator FEV1 at Visit 2 must be within 15% of FEV1 at Visit 1. No evidence of respiratory tract infection and no pulmonary exacerbation requiring use of intravenous/oral/inhaled antibiotics, or oral corticosteroids within 2 weeks of screening. The patient or the patient's legally acceptable representative must be able to give informed consent. Patients who are on a cycling TOBI® regimen must have completed at least 2 cycles every other month TOBI® administration prior to the screening visit. Patients who are on daily inhaled antibiotic use must be stabilized for at least 6 weeks prior to Visit 1 (screening). Patients having previously participated in study 205.339 can also be selected. Exclusion criteria: Patients with a known hypersensitivity to study drug Patients who have participated in another study with an Investigational drug within one month preceding the screening visit. Patients who are currently participating in another trial. Observational studies are allowed. Permission should be obtained from sponsor of other study. Patients with known relevant substance abuse, including alcohol or drug abuse. Adolescent and adult female patients who are pregnant or lactating, including females who have a positive serum pregnancy test at screening. Female patients of child bearing potential who are not using a medically approved form of contraception. Clinically significant disease or medical condition other than CF or CF-related conditions that, in the opinion of the Investigator, would compromise the safety of the patient or the quality of the data. Patients with diabetes may participate if their disease is under good control prior to screening.
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: tiotropium<br>2 inhalations once daily delivered with Respimat® inhaler | Drug: tiotropium Respimat® inhaler<br>* to evaluate safety and efficacy tiotropium delivered with Respimat® inhaler compared to placebo.<br>|
| Placebo Comparator: placebo<br>2 inhalations once daily delivered with Respimat® inhaler | Drug: Placebo Respimat® inhaler<br>* patient to receive placebo matching active drug once daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve 0-4 Hours (AUC0-4h) Response | Mixed Model Repeated Measurement (MMRM) results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (<= 11, >=12), baseline and baseline-by-visit interaction. FEV1 AUC0-4h was normalised for time and was calculated using the trapezoidal rule divided by the observation time (4 h). | 30 minutes (min) before first dosing of study drug (defined as baseline), at 1 hour (h), 2 h , 3 h, and 4 h post dosing at day 1 and at 30 min before dosing, at 1 hour, 2 h , 3 h, and 4 h post dosing after 12 weeks. | 
| Trough FEV1 Response | MMRM results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. Trough FEV1 was defined as the pre-dose FEV1 measured just prior to the administration of randomised treatment. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (<= 11, >=12), baseline and baseline-by-visit interaction. | Baseline and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced Vital Capacity (FVC) Area Under the Curve 0-4 Hours (AUC0-4h) Response | MMRM results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (<= 11, >=12), baseline and baseline-by-visit interaction. FVC AUC0-4h was normalised for time and was calculated using the trapezoidal rule divided by the observation time (4 h). | 30 minutes (min) before first dosing of study drug (defined as baseline), at 1 hour (h), 2 h , 3 h, and 4 h post dosing at day 1 and at 30 min before dosing, at 1 hour, 2 h , 3 h, and 4 h post dosing after 12 weeks. | 
| Trough FVC Response | MMRM results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. Trough FCV was defined as the pre-dose FVC measured just prior to the administration of randomised treatment. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (<= 11, >=12), baseline and baseline-by-visit interaction. | Baseline and 12 weeks | 
| Pre-bronchodilator Forced Expiratory Flow Between 25 Percent and 75 Percent of the FVC (FEF25-75) Response | MMRM results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. FEF25-75 is also known as maximum mid-expiratory flow and was measured before bronchodilator (salbutamol) use. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (<= 11, >=12), baseline and baseline-by-visit interaction. | Baseline and 12 weeks | 
| Percentage of Participants With at Least 1 Pulmonary Exacerbation During Double-blind Treatment | Selected questions from the Respiratory and Systemic Symptoms Questionnaire (RSSQ), the investigator assessment of physical findings and pulmonary function, and the use of intravenous antibiotics as a concomitant therapy were used to determine if a cystic fibrosis-related pulmonary exacerbation had occurred. | 12 weeks | 
| Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Different format of CFQ-R are used depending of the patients' age. Adolescent and adult format of CFQ-R is used for patients of 14 years and older, for younger children a parent version and a children format is used. In case parent and children questionnaires were filled out, the children questionnaire is taken into account. Scores were calculated for each domain of the CFQ-R which are presented separately. A score of 100 corresponds to the highest quality of life possible, whereas a score of 0 corresponds to the lowest quality of life possible. Increasing score indicates better health. | Baseline and 12 weeks |