Tiotropium Bromide in Cystic Fibrosis | NCT01179347

ID	Type	Description	Link
2010-019802-17	EudraCT Number	EudraCT

Status Module

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
tiotropium	Experimental	2 inhalations once daily delivered with Respimat® inhaler	Drug: tiotropium Respimat® inhaler
placebo	Placebo Comparator	2 inhalations once daily delivered with Respimat® inhaler	Drug: Placebo Respimat® inhaler

Name	Type	Description	Arm Group Labels	Other Names
tiotropium Respimat® inhaler	Drug	to evaluate safety and efficacy tiotropium delivered with Respimat® inhaler compared to placebo.	tiotropium

Outcomes Module

Primary Outcomes

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 Outcomes

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).

Eligibility Module

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.

Name	Affiliation	Role
Boehringer Ingelheim	Boehringer Ingelheim	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
205.438.01004 Boehringer Ingelheim Investigational Site		Tuscon	Arizona		United States
205.438.01011 Boehringer Ingelheim Investigational Site

PubMed Identifier	Type	Citation	Retractions
25819269	Derived	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.

Label	URL
Related Info	View source

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Placebo	Matching Placebo once daily (qd) delivered by the Respimat inhaler as add-on therapy to usual care in patients with cystic fibrosis.
FG001	Tio R5 qd	Tiotropium 5 mcg qd delivered by the Respimat inhaler as add-on therapy to usual care in patients with cystic fibrosis.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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).

Full Analysis Set (FAS) with imputation reduced to patients with observed wash-out compliance. The FAS was defined as all patients in the treated set who had at least 1 baseline pulmonary function test (PFT) measurement and at least 1 post-baseline on-treatment PFT measurement. No patients <5 years of age were included in the FAS.

Posted

Mean

Standard Error

Percent of predicted

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.

ID	Title	Description
OG000	Placebo	Matching Placebo once daily (qd) delivered by the Respimat inhaler as add-on therapy to usual care in patients with cystic fibrosis.
OG001	Tio R5 qd	Tiotropium 5 mcg qd delivered by the Respimat inhaler as add-on therapy to usual care in patients with cystic fibrosis.

Units	Counts
Participants	OG000146 OG001292

Title

Denominators

Categories

Title	Measurements
	OG0000.87± 0.80 OG0012.51± 0.57

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Hierarchical testing procedure was applied for both co-primary endpoints to maintain the overall alpha level. If and only if statistical superiority of the Tio R5 qd compared to Placebo in FEV1 AUC0-4h was demonstrated at the 1 sided alpha level of 0.025, confirmatory comparison in the second co-primary endpoint, at the same alpha level of 0.025 could be done .	Mixed Models Analysis	Restricted maximum likelihood (REML)-based MMRM. Adjusted for treatment, visit, treatment-by-visit, age group, baseline and baseline-by-visit.	0.092	Two-sided p-value.	Mean Difference (Final Values)	1.64	Standard Error of the Mean	0.97		95	-0.27	3.55			Tio R5 qd minus Placebo.

Primary

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.

Posted

Mean

Standard Error

Percent of predicted

Baseline and 12 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo once daily (qd) delivered by the Respimat inhaler as add-on therapy to usual care in patients with cystic fibrosis.
OG001	Tio R5 qd	Tiotropium 5 mcg qd delivered by the Respimat inhaler as add-on therapy to usual care in patients with cystic fibrosis.

Units	Counts

Secondary

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).

Posted

Mean

Standard Error

Percent of predicted

ID	Title	Description
OG000	Placebo	Matching Placebo once daily (qd) delivered by the Respimat inhaler as add-on therapy to usual care in patients with cystic fibrosis.
OG001	Tio R5 qd	Tiotropium 5 mcg qd delivered by the Respimat inhaler as add-on therapy to usual care in patients with cystic fibrosis.

Secondary

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.

Posted

Mean

Standard Error

Percent of predicted

Baseline and 12 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo once daily (qd) delivered by the Respimat inhaler as add-on therapy to usual care in patients with cystic fibrosis.
OG001	Tio R5 qd	Tiotropium 5 mcg qd delivered by the Respimat inhaler as add-on therapy to usual care in patients with cystic fibrosis.

Units	Counts

Secondary

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.

Posted

Mean

Standard Error

Percent of predicted

Baseline and 12 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo once daily (qd) delivered by the Respimat inhaler as add-on therapy to usual care in patients with cystic fibrosis.
OG001	Tio R5 qd	Tiotropium 5 mcg qd delivered by the Respimat inhaler as add-on therapy to usual care in patients with cystic fibrosis.

Secondary

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.

FAS reduced to patients having RSSQ information on day 29, 57 or 85.

Posted

Number

Percentage of Participants

12 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo once daily (qd) delivered by the Respimat inhaler as add-on therapy to usual care in patients with cystic fibrosis.
OG001	Tio R5 qd	Tiotropium 5 mcg qd delivered by the Respimat inhaler as add-on therapy to usual care in patients with cystic fibrosis.

Units	Counts
Participants	OG000

Secondary

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.

FAS reduced to patients having CFQ-R information at baseline and at week 12.

Posted

Mean

Standard Deviation

Units on a scale

Baseline and 12 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo once daily (qd) delivered by the Respimat inhaler as add-on therapy to usual care in patients with cystic fibrosis.
OG001	Tio R5 qd	Tiotropium 5 mcg qd delivered by the Respimat inhaler as add-on therapy to usual care in patients with cystic fibrosis.

Units	Counts

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Ventricular extrasystoles	Cardiac disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG0031 affected308 at risk
Cystic fibrosis	Congenital, familial and genetic disorders	MedDRA 14.1	Systematic Assessment	EG0002 affected155 at risk EG0016 affected308 at risk EG0027 affected147 at risk EG003
Cystic fibrosis lung	Congenital, familial and genetic disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0012 affected308 at risk EG0023 affected147 at risk EG003
Cystic fibrosis related diabetes	Congenital, familial and genetic disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0021 affected147 at risk EG003
Abdominal pain upper	Gastrointestinal disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0011 affected308 at risk EG0021 affected147 at risk EG003
Distal intestinal obstruction syndrome	Gastrointestinal disorders	MedDRA 14.1	Systematic Assessment	EG0001 affected155 at risk EG0012 affected308 at risk EG0020 affected147 at risk EG003
Inguinal hernia	Gastrointestinal disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Intestinal obstruction	Gastrointestinal disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0021 affected147 at risk EG003
Oesophageal varices haemorrhage	Gastrointestinal disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Tooth impacted	Gastrointestinal disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0011 affected308 at risk EG0020 affected147 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0021 affected147 at risk EG003
Chest discomfort	General disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0011 affected308 at risk EG0020 affected147 at risk EG003
Device occlusion	General disorders	MedDRA 14.1	Systematic Assessment	EG0001 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Pyrexia	General disorders	MedDRA 14.1	Systematic Assessment	EG0001 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Cholelithiasis	Hepatobiliary disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0021 affected147 at risk EG003
Drug hypersensitivity	Immune system disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0021 affected147 at risk EG003
Hypersensitivity	Immune system disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0021 affected147 at risk EG003
Acute sinusitis	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0021 affected147 at risk EG003
Aspergillosis	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Bronchitis	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0012 affected308 at risk EG0023 affected147 at risk EG003
Bronchopneumonia	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0001 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Bronchopulmonary aspergillosis allergic	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0021 affected147 at risk EG003
Chronic sinusitis	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0021 affected147 at risk EG003
Infective pulmonary exacerbation of cystic fibrosis	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0002 affected155 at risk EG0014 affected308 at risk EG0023 affected147 at risk EG003
Lobar pneumonia	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0011 affected308 at risk EG0021 affected147 at risk EG003
Lower respiratory tract infection	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0011 affected308 at risk EG0020 affected147 at risk EG003
Lung infection	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0011 affected308 at risk EG0020 affected147 at risk EG003
Lung infection pseudomonal	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0001 affected155 at risk EG0011 affected308 at risk EG0020 affected147 at risk EG003
Pharyngitis	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0011 affected308 at risk EG0020 affected147 at risk EG003
Pneumonia	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0015 affected308 at risk EG0021 affected147 at risk EG003
Pneumonia staphylococcal	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0001 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Pseudomonas infection	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Respiratory tract infection bacterial	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0011 affected308 at risk EG0020 affected147 at risk EG003
Sinusitis	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0021 affected147 at risk EG003
Stenotrophomonas infection	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0011 affected308 at risk EG0020 affected147 at risk EG003
Viral infection	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0001 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Fall	Injury, poisoning and procedural complications	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0011 affected308 at risk EG0020 affected147 at risk EG003
Foot fracture	Injury, poisoning and procedural complications	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Meniscus lesion	Injury, poisoning and procedural complications	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Radius fracture	Injury, poisoning and procedural complications	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0011 affected308 at risk EG0020 affected147 at risk EG003
Wrist fracture	Injury, poisoning and procedural complications	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0011 affected308 at risk EG0020 affected147 at risk EG003
Bacterial test positive	Investigations	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0011 affected308 at risk EG0020 affected147 at risk EG003
Blood creatinine increased	Investigations	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0011 affected308 at risk EG0020 affected147 at risk EG003
Forced expiratory volume decreased	Investigations	MedDRA 14.1	Systematic Assessment	EG0001 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Oxygen saturation decreased	Investigations	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0021 affected147 at risk EG003
Pulmonary function test decreased	Investigations	MedDRA 14.1	Systematic Assessment	EG0001 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Weight decreased	Investigations	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0021 affected147 at risk EG003
Muscle spasms	Musculoskeletal and connective tissue disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Anxiety	Psychiatric disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0021 affected147 at risk EG003
Depression	Psychiatric disorders	MedDRA 14.1	Systematic Assessment	EG0001 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Urethral stenosis	Renal and urinary disorders	MedDRA 14.1	Systematic Assessment	EG0001 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Bronchospasm	Respiratory, thoracic and mediastinal disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0011 affected308 at risk EG0020 affected147 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0011 affected308 at risk EG0020 affected147 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Haemoptysis	Respiratory, thoracic and mediastinal disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0011 affected308 at risk EG0020 affected147 at risk EG003
Lung disorder	Respiratory, thoracic and mediastinal disorders	MedDRA 14.1	Systematic Assessment	EG0002 affected155 at risk EG0015 affected308 at risk EG0022 affected147 at risk EG003
Lung infiltration	Respiratory, thoracic and mediastinal disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0021 affected147 at risk EG003
Nasal polyps	Respiratory, thoracic and mediastinal disorders	MedDRA 14.1	Systematic Assessment	EG0001 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Productive cough	Respiratory, thoracic and mediastinal disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0011 affected308 at risk EG0020 affected147 at risk EG003
Pulmonary congestion	Respiratory, thoracic and mediastinal disorders	MedDRA 14.1	Systematic Assessment	EG0001 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Sleep apnoea syndrome	Respiratory, thoracic and mediastinal disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0021 affected147 at risk EG003
Sputum increased	Respiratory, thoracic and mediastinal disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0011 affected308 at risk EG0020 affected147 at risk EG003
Dermatitis allergic	Skin and subcutaneous tissue disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0021 affected147 at risk EG003
Antibiotic prophylaxis	Surgical and medical procedures	MedDRA 14.1	Systematic Assessment	EG0001 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Central venous catheter removal	Surgical and medical procedures	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0021 affected147 at risk EG003
Central venous catheterisation	Surgical and medical procedures	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0010 affected308 at risk EG0021 affected147 at risk EG003
Jugular vein thrombosis	Vascular disorders	MedDRA 14.1	Systematic Assessment	EG0000 affected155 at risk EG0011 affected308 at risk EG0020 affected147 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Statistical Information
Cystic fibrosis	Congenital, familial and genetic disorders	MedDRA 14.1	EG0000 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG00316 affected308 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA 14.1	EG0000 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA 14.1	EG0000 affected155 at risk EG0010 affected308 at risk EG0028 affected147 at risk EG003
Pyrexia	General disorders	MedDRA 14.1	EG00010 affected155 at risk EG00115 affected308 at risk EG00213 affected147 at risk EG003
Bronchitis	Infections and infestations	MedDRA 14.1	EG0000 affected155 at risk EG0010 affected308 at risk EG00210 affected147 at risk EG003
Nasopharyngitis	Infections and infestations	MedDRA 14.1	EG0000 affected155 at risk EG0010 affected308 at risk EG00211 affected147 at risk EG003
Pharyngitis	Infections and infestations	MedDRA 14.1	EG0000 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Upper respiratory tract infection	Infections and infestations	MedDRA 14.1	EG0000 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Headache	Nervous system disorders	MedDRA 14.1	EG0000 affected155 at risk EG0010 affected308 at risk EG0028 affected147 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 14.1	EG00020 affected155 at risk EG00155 affected308 at risk EG00230 affected147 at risk EG003
Lung disorder	Respiratory, thoracic and mediastinal disorders	MedDRA 14.1	EG0000 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA 14.1	EG0000 affected155 at risk EG0010 affected308 at risk EG0029 affected147 at risk EG003
Sputum increased	Respiratory, thoracic and mediastinal disorders	MedDRA 14.1	EG0000 affected155 at risk EG0010 affected308 at risk EG0020 affected147 at risk EG003

ID	Term
D010182	Pancreatic Diseases
D004066	Digestive System Diseases
D008171	Lung Diseases
D012140	Respiratory Tract Diseases
D030342	Genetic Diseases, Inborn
D009358	Congenital, Hereditary, and Neonatal Diseases and Abnormalities
D007232	Infant, Newborn, Diseases

ID	Title	Description
BG000	Placebo	Matching Placebo once daily (qd) delivered by the Respimat inhaler as add-on therapy to usual care in patients with cystic fibrosis.
BG001	Tio R5 qd	Tiotropium 5 mcg qd delivered by the Respimat inhaler as add-on therapy to usual care in patients with cystic fibrosis.
BG002	Total	Total of all reporting groups

ID	Title	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo Randomized Group Over the Double-Blind Period	13	155	27	155
EG001	Tio 5mcg Randomized Group Over the Double-Blind Period	36	308	63	308
EG002	Placebo Randomized Group Over the Open-Label Period	24	147	56	147
EG003	Tio 5mcg Randomized Group Over the Study	62	308	186	308