Clinical Trials Register

Summary
EudraCT Number:	2005-005615-21
Sponsor's Protocol Code Number:	205.341
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2006-07-07
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2005-005615-21

A.3

Full title of the trial

A Randomised, Double-Blind, Placebo-Controlled, Crossover Efficacy and Safety Evaluation of 8-Week Treatment Periods of Two Doses [5 µg (2 actuations of 2.5 µg) and µg (2 actuations of 5 µg)] of Tiotropium Inhalation Solution Delivered by the Respimat® Inhaler as Add-on Therapy in Patients with severe persistent Asthma.

A.4.1

Sponsor's protocol code number

205.341

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Boehringer Ingelheim Pharma GmbH & Co. KG
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Information not present in EudraCT
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Tiotropium, 5 microgram, solution for inhalation
D.3.4	Pharmaceutical form	Inhalation vapour, solution
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tiotropium bromide
D.3.9.2	Current sponsor code	Ba 679 BR
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2,5 as bromide to per actuation
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	Information not present in EudraCT
D.3.11.8	Extractive medicinal product	Information not present in EudraCT
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Information not present in EudraCT
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Tiotropium, 10 microgram, solution for inhalation
D.3.4	Pharmaceutical form	Inhalation vapour, solution
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tiotropium bromide
D.3.9.2	Current sponsor code	Ba 679 BR
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5 as bromide to per actuation
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	Information not present in EudraCT
D.3.11.8	Extractive medicinal product	Information not present in EudraCT
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Inhalation vapour, solution
D.8.4	Route of administration of the placebo	Inhalation use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with severe persistent asthma

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to examine efficacy and safety of at least one of two doses [5 mcg (2 actuations of 2.5 mcg) and 10 mcg (2 actuations of 5 mcg)] of tiotropium inhalation solution delivered by the Respimat inhaler once daily as add-on therapy compared to placebo at the end of the 8-week periods of randomised treatment.

E.2.2

Secondary objectives of the trial

To assess the safety of tiotropium add-on therapy in severe asthmatics treated with inhaled steroids and long-acting beta-adrenergics

E.2.3

Trial contains a sub-study

Information not present in EudraCT

E.3

Principal inclusion criteria

1. All patients must sign and date an Informed Consent Form consistent with ICH-GCP guidelines and local legalisation prior to participation in the trial (i.e. prior to any study procedures, including any pre-study washout of medications and medication restrictions for pulmonary function test at Visit 1).
2. Male or female patients 18 years of age or older, but not older than 75 years.
3. Patients must have an ACQ mean score at screening (Visit1) of >/= 1.5.
4. Patients must be symptomatic (as defined in inclusion criterion #3) and at least 6 weeks on a high, stable dose of inhaled corticosteroids* + a long-acting beta adrenergic (additional sustained release theophylline and/or leukotriene modifier and/or oral glucocorticosteroids (cf. exclusion criterion No.13) are allowed in stable doses)
*
budesonide DPI >/=1000 μg per day
beclamethasone CFC >/=1000 μg per day
beclamethasone HFA >/=500 μg per day
Fluticasone >/= 500 μg per day
Flunisolide >/=2000 μg per day

mometasone furoate >/=800 μg per day

triamcinolone acetonide >/=2000 μg per day

Ciclesonide >/= 640 μg per day

5. Patients must be never smokers or ex-smokers with a cigarette smoking history of <10 pack-years (and smoking cessation at least one year prior to study enrolment).
6. All patients must have at least a 5 year history of asthma at the time enrolled into the study (confirmed in the past and documented by an increased hyperresponsiveness to histamine or methacholine; a trial of glucocorticosteroids or a bronchodilator reversibility to a beta-2-adrenergic drug > 15%; or a PEF variability > 15%), and a current diagnosis of severe, persistent asthma and must meet the following spirometric criteria:
Post bronchodilator (i.e. 30 minutes after inhalation of 4 puffs of 100 μg salbutamol) FEV1 </=80% of predicted normal and FEV1 </= 70% of FVC (At visit 1).

Predicted normal values will be calculated according to ECSC [R94-1408]:
Males: FEV1 predicted (L) = 4.30 x [height (m)] – 0.029 x [age (yrs)] – 2.49
Females: FEV1 predicted (L) = 3.95 x [height (m)] - 0.025 x [age (yrs)] – 2.60
Patients with ages 18-25 will have predicted FEV1 calculated with age 25
7. Patients must be able to inhale medication in a competent manner from the Respimat® inhaler.
8. Patients must be able to perform technically acceptable pulmonary function tests and PEF and FEV1 measurements with the electronic peak flow meter and must be able to perform all necessary recordings in the electronic diary as part of the electronic peak flow meter.

E.4

Principal exclusion criteria

1. Patients with a significant disease other than asthma; a significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the study, (ii) influence the results of the study, or (iii) cause concern regarding the patient’s ability to participate in the study
2. Patients with clinically relevant abnormal baseline haematology or blood chemistry will be excluded.
3. Patients with a recent history (i.e., six months or less) of myocardial infarction.
4. Patients who have been hospitalized for heart failure (NYHA class III or IV) within the past year.
5. Patients with any unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year.
6. Patients with malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years. Patients with treated basal cell carcinoma are allowed.
7. Patients with lung diseases other than asthma (e.g. COPD).
8. Patients with known active tuberculosis.
9. Patients with significant alcohol or drug abuse within the past two years.
10. Patients who have undergone thoracotomy with pulmonary resection. Patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1.
11. Patients who are in a pulmonary rehabilitation program.
12. Patients who are being treated with Omalizumab (Xolair®)
13. Patients using oral corticosteroid medication at stable doses exceeding 5 mg/d prednisolone or prednisolone equivalent every day or 10 mg/d prednisolone or prednisolone equivalent every second day.
14. Patients who are being treated with beta-blocker medication. Topical cardio-selective beta-blocker eye medication for treatment of non-narrow angle glaucoma are allowed.
15. Patients with known hypersensitivity to anticholinergic drugs or any other components of the tiotropium inhalation solution.
16. Pre-menopausal women (last menstruation ≤ 1 year prior to informed consent) who are not surgically sterile; or are nursing or pregnant; or are of child-bearing potential and are not practicing acceptable means of birth control, do not plan to continue using this method throughout the trial and do not agree to submit to periodic pregnancy testing during participation in the trial. Acceptable means of birth control include the transdermal patch, oral, implantable or injectable contraceptives, Intra Uterine Devices (IUDs), condoms, sexual abstinence and vasectomised partner. No exceptions will be made
17. Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to Visit 1.
18. Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva®) within four weeks prior to Visit 1.
19. Patients with any respiratory infections in the four weeks prior to the Screening Visit (Visit 1) or during the 2-week baseline period. In the case of a respiratory infection during the baseline period the latter may be extended up to six weeks.
20. Patients who are currently participating in another study.
21. Patients with prostatic hyperplasia, bladder-neck obstruction, or known narrow-angle glaucoma.
22. Patients with moderate to severe renal impairment (creatinine clearance ≤ 50 mL/min).

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is the peak FEV1 response (within 3 hours post dosing) determined at the end of the 8-week treatment period.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Information not present in EudraCT

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.5

The trial involves multiple Member States

Yes

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.7

Trial has a data monitoring committee

Information not present in EudraCT

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

End of trial is the last visit of the last subject undergoing the trial.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.3

Elderly (>=65 years)

Yes

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Information not present in EudraCT

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2006-07-07.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Information not present in EudraCT

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

115

F.4.2.2

In the whole clinical trial

115

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

At Visit 5 a physical examination including vital signs (blood pressure and pulse rate) will be conducted at the end of the visit after all PFT measurements.In case of an AE during the three week follow-up period, patients will be requested to visit the site for assessment of the AE.This telephone call or subsequent visit marks the trial completion. Additionally, all SAEs that occur within 30 days after a patient terminates study medication must be reported.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2006-08-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2006-07-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2008-02-20

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