Clinical Trials Register

Summary
EudraCT Number:	2012-001873-10
Sponsor's Protocol Code Number:	205.441
National Competent Authority:	Slovenia - JAZMP
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-09-03
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

Slovenia - JAZMP

A.2

EudraCT number

2012-001873-10

A.3

Full title of the trial

A randomised, double- blind, 2 way cross-over study to determine 24-hour FEV1-time profile of inhaled tiotropium, delivered via the Respimat® inhaler, after 4 weeks of once daily [5 µg in the evening (2 actuations of 2.5 µg)] or twice daily [2.5 µg in the morning and evening (2 actuations of 1.25 µg)] administration in patients with moderate persistent asthma.

Randomizirana, dvojno slepa, dvosmerno navzkrižna študija za določanje 24-urnega profila vrednosti FEV1 po uporabi tiotropija, inhaliranega s pomočjo inhalatorja Respimat®, in sicer po 4 tednih enkrat dnevnega odmerjanja [5 µg zvečer (2 vpiha po 2,5 µg)] ali dvakrat dnevnega odmerjanja [2,5 µg zjutraj in zvečer (vsakokrat 2 vpiha po 1,25 µg)] pri bolnikih z zmerno persistentno astmo

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Comparison of two daily dose regimens of tiotropium 5 µg once daily and tiotropium 2.5 µg twice daily for 4 weeks on top of maintenance therapy with an inhaled corticosteroid controller medication

Štiritedenska primerjava dveh dnevnih režimov odmerjanja tiotropija 5 µg enkrat na dan, in tiotropija 2,5 µg dvakrat na dan poleg vzdrževalnega zdravljenja z vdihovanjem kortikosteroidonih zdravil

A.4.1

Sponsor's protocol code number

205.441

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Boehringer Ingelheim RCV GmbH & Co KG
B.1.3.4	Country	Austria
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	Boehringer Ingelheim
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Boehringer Ingelheim Pharma GmbH & Co. KG
B.5.2	Functional name of contact point	QRPE PSC CT Information Disclosure
B.5.3	Address:
B.5.3.1	Street Address	Binger Strasse 173
B.5.3.2	Town/ city	Ingelheim am Rhein
B.5.3.4	Country	Germany
B.5.4	Telephone number	498002430127
B.5.5	Fax number	498008217119
B.5.6	E-mail	clintriage.rdg@boehringer-ingelheim.com

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	Yes
D.2.1.1.1	Trade name	Spiriva Respimat 2.5 microgram, solution for inhalation
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim Pharma GmbH Co KG
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	Inhalation solution
D.3.4.1	Specific paediatric formulation	No
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.3.9.1	CAS number	411207-31-3
D.3.9.3	Other descriptive name	TIOTROPIUM BROMIDE MONOHYDRATE
D.3.9.4	EV Substance Code	SUB21897
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	3.124
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)	No
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	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Yes
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	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
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	No
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 Respimat 1.25 µg
D.3.4	Pharmaceutical form	Inhalation solution
D.3.4.1	Specific paediatric formulation	No
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.3.9.1	CAS number	411207-31-3
D.3.9.3	Other descriptive name	TIOTROPIUM BROMIDE MONOHYDRATE
D.3.9.4	EV Substance Code	SUB21897
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	1.562
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)	No
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	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Yes
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	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
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 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

E.1.1.1

Medical condition in easily understood language

Asthma bronchial

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.0
E.1.2	Level	LLT
E.1.2	Classification code	10003555
E.1.2	Term	Asthma bronchial
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Determine the 24-hour FEV1-profile of tiotropium solution for inhalation after 4 weeks treatment periods of 5 µg tiotropium administered once daily in the evening and 2.5 µg tiotropium administered twice daily (morning and evening) with the Respimat inhaler.

In addition, in a subset of patients the pharmacokinetics of tiotropium in patients with asthma will be characterized.
The objective of the pharmacokinetic subinvestigation is to compare the 24 hours pharmacokinetic profile of 5 µg tiotropium administered once daily and 2.5µg tiotropium administered twice daily.

E.2.2

Secondary objectives of the trial

Not Applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. All patients must sign and date an Informed Consent Form consistent with ICH-GCP guidelines and local legislation prior to participation in the trial
2. Male or female patients aged at least 18 years at Visit 0 but not more than 75 years at Visit 0.
Diagnosis
3. All patients must have at least a 3 months history of asthma at the time of enrolment (signing ICF) into the trial. The initial diagnosis of asthma must have been made before the patient's age of 40. If the patient is > 40 years and the diagnosis has not yet been recorded in the patient's medical files, the investigator should assess whether the patient's medical history
4. All patients must have a pre-bronchodilator FEV1 ≥ 60% predicted and ≤ 90% of predicted normal at Visit 1. Predicted normal values will be calculated according to ECSC [R94-1408] (see Appendix 10.3). Variation of absolute pre-bronchodilator FEV1 values at Visit 1 and Visit 2 (randomisation visit) must be within ± 30%.
5. Patient’s diagnosis of asthma has to be confirmed at Visit 1 with bronchodilator reversibility (ie 10 minutes prior to and 15-30 minutes after inhalation of 400 μg salbutamol) defined as an FEV1 increase of ≥ 12% and ≥ 200 mL. NOTE: If this is not achieved at the screening visit the reversibility test including ACQ may be repeated once within two weeks.
Symptoms
6. All patients must have a diagnosis of moderate persistent asthma and must be symptomatic despite their current maintenance treatment with medium doses of ICS.
7. All patients must be symptomatic at Visit 1 (screening visit) and Visit 2 (randomisation visit) as defined by an ACQ mean score of ≥ 1.5.
8. All patients must have maintenance treatment with stable medium daily dose of ICS (alone or in a fixed-dose combination with a LABA or SABA) for at least 4 weeks prior to Visit 1.
9. Patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment (Visit 0) and who have a smoking history of less than 10 pack-years at Visit 0.
10. Patients must be able to use the Respimat® inhaler correctly.
11. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of the AM3® (e-diary) compliance of at least 80% is required.
12. Patients taking a chronic pulmonary medication allowed by the study protocol must be willing to continue this therapy for the entire duration of the study (exception: times of acute disease deterioration).

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 trial, or (ii) influence the results of the trial, or (iii) cause concern regarding the patient's ability to participate in the trial.
2. Patients with a clinically relevant abnormal screening hematology or blood chemistry at Visit 1 if the abnormality defines a significant disease as defined in exclusion criterion no. 1.
3. Patients requiring more than 12 puffs of rescue medication (salbutamol MDI) per 24 hours for more than 2 consecutive days between Visit 1 and Visit 2 (screening period).
4. Patients with a recent history (ie six months or less) of Acute Coronary Syndrome (STEMI, non-STEMI, Unstable Angina Pectoris) prior to Visit 1 (screening).
5. Patients who have been hospitalised for cardiac failure during the past year prior to Visit 1 (screening).
6. Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year prior to Visit 1 (screening).
7. Patients with lung diseases other than asthma (eg COPD).
8. Patients with known active tuberculosis.
9. Patients with malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years prior to Visit 1 (screening). Patients with treated basal cell carcinoma are allowed.
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 with significant alcohol or drug abuse on Investigator’s assessment within the past two years prior to Visit 1 (screening).
12. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to Visit 1 (screening).
13. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the study medication delivery systems.
14. Pregnant or nursing women, including female patients with positive ß-HCG test at Visit 1.
15. Female patients of child-bearing potential not using highly effective method of birth control. As defined in ICH (M3) [R09-1400], note 3, highly effective methods of birth control are defined as those, alone or in combination, that result in a low failure rate (ie less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomised partner. Barrier contraceptives (eg male condom or diaphragm) are acceptable if used in combination with spermicides (eg foam, gel).
Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least two years.
16. Patients who have been treated with restricted medication (refer to Table 4.2.2.1) prior to Visit 1 and/or during the screening period.
17. Patients with any asthma exacerbation or any respiratory tract infection in the four weeks prior to Visit 1 or during the screening period. Visit 1 and/or Visit 2 should be postponed in case of an asthma exacerbation or respiratory tract infection. Refer to Section 6.1 for information on re-scheduling of visits.
18. Patients who are currently participating in another trial or who have been participating in another trial within one month prior to Visit 0, and patients who have previously been randomised in this trial.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy variable will be the forced expiratory volume in one second (FEV1).
The primary endpoint is the FEV1 AUC0-24h (L) response determined at the end of each 4-week randomised treatment period. The FEV1 AUC0-24h is defined as the mean FEV1 over the 24-hour observation period (0-24 h) normalized for time after inhalation of the last evening dose of study medication. The mean FEV1 will be calculated as area under the curve from zero time to 24 hours, using the trapezoidal rule divided by the corresponding duration (ie 24 hours) to give the result in litres. The pre-dose FEV1 measurement obtained at the end of each 4-week treatment period prior to inhalation of the last evening dose of study medication will be assigned to zero time. Value recorded at 11h 50min and at 23h 50min post dosing will be assigned to 12 and 24 hours, respectively.
FEV1 AUC0-24h response is defined as the change of FEV1 AUC0-24h from the baseline FEV1 value, which is the measurement obtained on Visit 2 (randomisation visit) prior to the first evening dose of randomised study medication.

E.5.1.1

Timepoint(s) of evaluation of this end point

At the end of each 4-week randomised treatment period.

E.5.2

Secondary end point(s)

1. FEV1 AUC0-12h (L) response determined at the end of each 4-week period of randomised treatment.
2. FEV1 AUC12-24h (L) response determined at the end of each 4-week period of randomised treatment.
FEV1 AUC over the first 12 hours (0-12 h) and the second 12 hours will be calculated similar to FEV1 AUC0-24h. AUC0-12h and AUC12-24h responses will be calculated similar to FEV1 AUC0-24h response.
3. Peak FEV1 (L) response, determined at the end of each 4-week period of randomised treatment, is defined as the highest FEV1 reading observed within the 24-hour period following inhalation of the last evening dose of study medication.
4. Trough FEV1 (L) response, determined at the end of each 4-week period of randomised treatment, is defined as the FEV1 value just prior to the last evening dose of study medication.
5. Forced vital capacity (FVC) AUC0-24h response determined at the end of each 4-week period of randomised treatment.
6. FVC AUC0-12h response (L) determined at the end of each 4-week period of randomised treatment.
7. FVC AUC12-24h response (L) determined at the end of each 4-week period of randomised treatment.
8. Peak FVC (L) response determined at the end of each 4-week period of randomised treatment.
9. Trough FVC (L) responses determined at the end of each 4-week period of randomised treatment.
AUC0-12h, AUC12-24h, AUC0-24h, trough and peak FVC responses will be calculated similar to FEV1 response endpoints.
10. Peak expiratory flow (PEF) AUC0-24h (L/min) response determined at the end of each 4-week period of randomised treatment.
PEF AUC0-24h response will be calculated similar to FEV1 AUC0-24h response.

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end of each 4-week randomised 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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

5 mcg once daily versus 2.5 mcg twice daily

E.8.2.4

Number of treatment arms in the trial

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.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

E.8.7

Trial has a data monitoring committee

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

LVLS (last visit of the last subject)

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

E.8.9.2

In all countries concerned by the trial days

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.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

F.4.2.2

In the whole clinical trial

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)

None

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

2012-09-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-08-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-06-20

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