Clinical Trials Register

Summary
EudraCT Number:	2009-018004-18
Sponsor's Protocol Code Number:	205.418
National Competent Authority:	Latvia - SAM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-07-16
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

Latvia - SAM

A.2

EudraCT number

2009-018004-18

A.3

Full title of the trial

A Phase III randomised, double-blind, placebo-controlled, parallel-group trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 μg once daily) compared with placebo and salmeterol HFA MDI (50 μg twice daily) over 24 weeks in patients with moderate persistent asthma

A.3.1

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

Evaluation of tiotropium 2.5 and 5 mcg once daily delivered via the Respimat® inhaler compared to placebo and salmeterol HydroFluoroAlkane (HFA) Metered Dose Inhaler (MDI) (50 mcg twice daily) in patient with moderate persistent asthma I

A.4.1

Sponsor's protocol code number

205.418

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01172808

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 RCV GmbH&Co KG
B.4.2	Country	Austria
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.5.3.3	Post code	55216
B.5.3.4	Country	Germany
B.5.4	Telephone number	+1800243 0127
B.5.5	Fax number	+1800821 7119
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 International GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Spiriva Respimat 2.5 mcg
D.3.2	Product code	Tiotropium Respimat
D.3.4	Pharmaceutical form	Inhalation vapour, 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.3.9.2	Current sponsor code	Ba 679 Br
D.3.9.3	Other descriptive name	TIOTROPIUM BROMIDE MONOHYDRATE
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)	Yes
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	No
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 mcg
D.3.2	Product code	Tiotropium Respimat 1.25 mcg
D.3.4	Pharmaceutical form	Inhalation vapour, 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.3.9.2	Current sponsor code	Ba 679 Br
D.3.9.3	Other descriptive name	TIOTROPIUM BROMIDE MONOHYDRATE
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.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
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	Serevent Evohaler (according to UK SPC)
D.2.1.1.2	Name of the Marketing Authorisation holder	GlaxoWellcome UK Ltd, Trading as Allen & Hanburys
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Salmeterol pressurised inhalation suspension
D.3.4	Pharmaceutical form	Pressurised inhalation, suspension
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	SALMETEROL
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	25
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	No
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 vapour
D.8.4	Route of administration of the placebo	Inhalation use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Pressurised inhalation
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

Moderate persistent asthma

E.1.1.1

Medical condition in easily understood language

Moderate persistent asthma

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	13.1
E.1.2	Level	PT
E.1.2	Classification code	10003553
E.1.2	Term	Asthma
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

Evaluate the long term (24 weeks) efficacy of two doses (2.5 µg and 5 µg) of tiotropium inhalation solution (administered once daily) compared to placebo and to salmeterol (50 µg; administered twice daily) on top of maintenance therapy with inhaled corticosteroid controller medication in patients with moderate persistent asthma.

E.2.2

Secondary objectives of the trial

Evaluate the long term (24 weeks) safety of two doses (2.5 μg and 5 μg) of tiotropium inhalation solution (administered once daily) compared to placebo and to salmeterol (50 μg; administered twice daily) on top of maintenance therapy with inhaled corticosteroid controller medication in patients with moderate persistent asthma.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Outpatients of either sex, aged 18-75 years
Diagnosis of moderate persistent asthma.
Asthma diagnosis made before age of 40.
At leaset a 3 month history of asthma.
Pre-bronchodilator FEV1 ≥ 60% and ≤ 90% of predicted at Visit 1.
Increase in FEV1 of ≥ 12% and ≥ 200 mL 15 to 30 min after 400 µg salbutamol (albuterol) at Visit 1.
Maintenance treatment with medium dose of inhaled corticosteroids for at least 4 weeks before Visit 1.
Symptomatic despite their current maintenance treatment with ICS (ACQ ≥ 1.5).
Variation in absolute pre-BD FEV1 values Visit 1 compared to Visit 2 within ± 30%.
Never-smokers or ex-smokers (stopped at least one year prior to enrolment + smoking history of less than 10 pack years).

E.4

Principal exclusion criteria

Patients with a significant disease other than asthma.
Patients with a clinically relevant abnormal screening haematology or blood chemistry if the abnormalitiy defines a significant disease.
Patients with a recent history (i.e. six months or less) of myocardial infarction.
Patients who have been hospitalised for cardiac failure during the past year.
Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year.
Patients with lung diseases other than asthma (e.g. COPD).
Patients with known active tuberculosis.
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.
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.
Patients with significant alcohol or drug abuse within the past two years.
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).
Pregnant or nursing woman.
Women of childbearing potential not using a highly effective method of birth control.
Patients with any asthma exacerbation or any respiratory tract infection in the four weeks prior to Visit 1 or during the screening period.

E.5 End points

E.5.1

Primary end point(s)

The co-primary endpoints are
1. Peak forced expiratory volume in one second (FEV1) response (within 3 hours post dosing) determined at the end of the 24-week treatment period.
2. Trough forced expiratory volume in one second (FEV1) response determined at the end of the 24-week treatment period.

Primary endpoint Meta-Analysis (combined data 205.418 and 205.419 trial):
1. The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period on combined data from the two twin trials 205.418 and 205.419.

E.5.1.1

Timepoint(s) of evaluation of this end point

At 24 weeks of treatment

E.5.2

Secondary end point(s)

1. Peak (within 3 hours post dosing) and trough forced vital capacity
(FVC) determined at the end of the 24-week treatment period.
2. FEV1 (AUC0-3h) and FVC (AUC0-3h) at the end of the 24-week
treatment period.
3. Individual in-clinic FEV1, FVC and PEF measurements at all time
points including peak, trough and AUC0-3h during the 24-week treatment period.
4. Quality of Life as assessed by standardised Asthma Quality of Life
Questionnaire (AQLQ (S)) at all clinic visits during the 24-week
treatment period.
5. PEF am/pm: change from baseline in mean weekly pre-dose morning
and evening PEF measured by patients at home in the last week of the
24-week treatment period.
6. Use of PRN salbutamol (albuterol) rescue medication during the 24-
week treatment period.
7. Asthma symptoms as assessed by the patient's electronic diary during the 24-week treatment period.
8. Asthma symptom free days as assessed by the patient's electronic
diary during the 24-week treatment period.
9. The responder rate as assessed by the ACQ determined at the end of the 24-week treatment period for each trial separately.

Additionally in a subset of patients:
10. FEV1 (AUC0-12h), FEV1 (AUC12-24h), FEV1 (AUC0-24h), FVC (AUC0-12h), FVC (AUC12-24h), FVC (AUC0-24h) after 24-week treatment
11. Individual FEV1 and FVC measurements at 5 and 15 minutes post
dose including peak and AUC0-3h.

E.5.2.1

Timepoint(s) of evaluation of this end point

During or at the end of the 24 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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

Yes

E.8.2.3

Other

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Brazil

China

Guatemala

India

Japan

Latvia

Mexico

Peru

Poland

Russian Federation

United States

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

The trial will be considered complete as soon as the last patient has completed the follow up visit.

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:

900

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

135

F.4.2

For a multinational trial

F.4.2.1

In the EEA

230

F.4.2.2

In the whole clinical trial

1000

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)

All patients will receive their normal treatment of asthma.

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

2010-09-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-08-05

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2012-11-13

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