Tiotropium Bromide in Cystic Fibrosis

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Cystic Fibrosis	Drug: tiotropium Respimat® inhaler; Drug: Placebo Respimat® inhaler	Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	464 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double
Primary Purpose:	Treatment
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.
Study Start Date :	September 2010
Actual Primary Completion Date :	March 2012

Arms and Interventions

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Arm	Intervention/treatment
Experimental: tiotropium; 2 inhalations once daily delivered with Respimat® inhaler	Drug: tiotropium Respimat® inhaler; to evaluate safety and efficacy tiotropium delivered with Respimat® inhaler compared to placebo.
Placebo Comparator: placebo; 2 inhalations once daily delivered with Respimat® inhaler	Drug: Placebo Respimat® inhaler; patient to receive placebo matching active drug once daily

Outcome Measures

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Primary Outcome Measures :

1. Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve 0-4 Hours (AUC0-4h) Response [ Time Frame: 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. ]
   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).
2. Trough FEV1 Response [ Time Frame: Baseline and 12 weeks ]
   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.

Secondary Outcome Measures :

1. Forced Vital Capacity (FVC) Area Under the Curve 0-4 Hours (AUC0-4h) Response [ Time Frame: 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. ]
   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).
2. Trough FVC Response [ Time Frame: Baseline and 12 weeks ]
   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.
3. Pre-bronchodilator Forced Expiratory Flow Between 25 Percent and 75 Percent of the FVC (FEF25−75) Response [ Time Frame: Baseline and 12 weeks ]
   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.
4. Percentage of Participants With at Least 1 Pulmonary Exacerbation During Double-blind Treatment [ Time Frame: 12 weeks ]
   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.
5. Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score [ Time Frame: Baseline and 12 weeks ]
   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.

Eligibility Criteria

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Ages Eligible for Study:	Child, Adult, Senior
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion criteria:

1. 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.
2. Male or female patients (children less than 12 years and adolescents >12 years).
3. Patients >=5 years of age must be able to perform acceptable spirometric maneuvers, according to the American Thoracic Society (ATS) standards.
4. Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) >25% of predicted values.
5. Pre-bronchodilator FEV1 at Visit 2 must be within 15% of FEV1 at Visit 1.
6. 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.
7. The patient or the patient's legally acceptable representative must be able to give informed consent.
8. 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.
9. Patients who are on daily inhaled antibiotic use must be stabilized for at least 6 weeks prior to Visit 1 (screening).
10. Patients having previously participated in study 205.339 can also be selected.

Exclusion criteria:

1. Patients with a known hypersensitivity to study drug
2. Patients who have participated in another study with an Investigational drug within one month preceding the screening visit.
3. Patients who are currently participating in another trial. Observational studies are allowed. Permission should be obtained from sponsor of other study.
4. Patients with known relevant substance abuse, including alcohol or drug abuse.
5. Adolescent and adult female patients who are pregnant or lactating, including females who have a positive serum pregnancy test at screening.
6. Female patients of child bearing potential who are not using a medically approved form of contraception.
7. 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.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

  Show 99 Study Locations

Sponsors and Collaborators

Boehringer Ingelheim

Investigators

Study Chair:	Boehringer Ingelheim	Boehringer Ingelheim

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Ratjen F, Koker P, Geller DE, Langellier-Cocteaux B, Le Maulf F, Kattenbeck S, Moroni-Zentgraf P, Elborn JS; Tiotropium Cystic Fibrosis Study Group. Tiotropium Respimat in cystic fibrosis: Phase 3 and Pooled phase 2/3 randomized trials. J Cyst Fibros. 2015 Sep;14(5):608-14. doi: 10.1016/j.jcf.2015.03.004. Epub 2015 Mar 26.

Responsible Party:	Boehringer Ingelheim
ClinicalTrials.gov Identifier:	NCT01179347 History of Changes
Other Study ID Numbers:	205.438; 2010-019802-17 ( EudraCT Number: EudraCT )
First Posted:	August 11, 2010
Results First Posted:	March 26, 2013
Last Update Posted:	December 24, 2013
Last Verified:	October 2013

Additional relevant MeSH terms:

Fibrosis; Cystic Fibrosis; Pathologic Processes; Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Infant, Newborn, 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