Clinical Trials Register

Summary
EudraCT Number:	2010-019685-87
Sponsor's Protocol Code Number:	RO-2455-404-RD
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-03-30
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

Austria - BASG

A.2

EudraCT number

2010-019685-87

A.3

Full title of the trial

Effect of roflumilast on exacerbation rate in patients with COPD treated with fixed combinations of LABA and ICS. A 52-week, randomised double-blind trial with roflumilast 500 μg versus placebo

A.3.1

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

The trial investigates the effect of 500 μg roflumilast tablets once daily
versus placebo on exacerbation rate and pulmonary function in patients
with Chronic Obstructive Pulmonary Disease (COPD) who are treated
with a fixed combination of long-acting β2-agonists (LABA) and inhaled
glucocorticosteroids (ICS). Additionally it provides data on safety and
tolerability in COPD patients treated with a fixed combination of LABA
and ICS.

A.3.2

Name or abbreviated title of the trial where available

REACT

A.4.1

Sponsor's protocol code number

RO-2455-404-RD

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	Takeda Pharma A/S
B.1.3.4	Country	Denmark
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	Takeda Pharma A/S
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Takeda Pharma A/S
B.5.2	Functional name of contact point	Clinical Trial Operations
B.5.3	Address:
B.5.3.1	Street Address	Langebjerg 1
B.5.3.2	Town/ city	Roskilde 46754269
B.5.3.3	Post code	4000
B.5.3.4	Country	Denmark
B.5.4	Telephone number	+4546771 691
B.5.5	Fax number	+4546754 269
B.5.6	E-mail	ask.aabenhus@takeda.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	Daxas
D.2.1.1.2	Name of the Marketing Authorisation holder	Nycomed GmbH
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Roflumilast 500 µg film-coated tablet
D.3.2	Product code	BY217
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ROFLUMILAST
D.3.9.1	CAS number	162401323
D.3.9.2	Current sponsor code	BY217
D.3.9.3	Other descriptive name	N/A
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	500
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	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

severe chronic obstructive pulmonary disease (COPD)

E.1.1.1

Medical condition in easily understood language

In all patient information material COPD is used. There is no term in trivial language available.

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10010952
E.1.2	Term	COPD
E.1.2	System Organ Class	100000004855

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To investigate the effect of roflumilast 500 μg tablets once daily versus placebo on exacerbation rate, pulmonary function and major adverse cardiovascular events (MACE) in COPD patients who are concomitantly treated with a fixed combination of long-acting β2-agonists (LABA) and inhaled glucocorticosteroids (ICS).

E.2.2

Secondary objectives of the trial

To obtain data on safety and tolerability of roflumilast in COPD patients concomitantly treated with a fixed combination of LABA and ICS.

To further characterise the population pharmacokinetic profile of roflumilast and roflumilast N-oxide.

To further characterise the pharmacokinetics/pharmacodynamics (PK/PD) relationship of roflumilast, roflumilast N-oxide and ‘total phosphodiesterase 4 inhibitory’ activity (tPDE4i) in terms of efficacy and relevant safety aspects.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

According to Protocol Amendment 1, dated 02 May 2012.

1. Giving written informed consent
2. History of COPD (according to GOLD 2009) for at least 12 months prior to baseline Visit V0 associated with chronic productive cough for 3 months in each of the 2 years prior to baseline Visit V0 (with other causes of productive cough excluded)
3. Age ≥ 40 years
4. Forced expiratory volume after one second (FEV1)/forced vital capacity (FVC) ratio (post-bronchodilator) < 70%
5. FEV1 (post-bronchodilator) ≤ 50% of predicted
6. At least two documented moderate or severe COPD exacerbations, separated by at least 10 days, within one year prior to baseline Visit V0
7. Patients must be pre-treated with LABA and ICS for at least 12 months before baseline Visit V0. Up to 3 months before baseline Visit V0 free or fixed combinations of LABA and ICS are allowed, including changes in dose, active substances, and brands. In the last 3 months before baseline Visit V0 patients must be pre-treated with fixed combinations of LABA and ICS at a constant dose (maximum approved dosage strength of the combination).
8. Former smoker (defined as smoking cessation at least one year ago) or current smoker both with a smoking history of at least 20 pack years

E.4

Principal exclusion criteria

According to Protocol Amendment 1, dated 02 May 2012.

Criteria affecting the read-out parameters of the trial:
1. Moderate or severe COPD exacerbation and/or COPD exacerbations treated with antibiotics ongoing at the baseline Visit V0
2. Lower respiratory tract infection not resolved 4 weeks prior to the baseline Visit V0
3. Diagnosis of asthma and/or other relevant lung disease (e.g. history of primary bronchiectases, cystic fibrosis, bronchiolitis, lung resection, lung cancer, interstitial lung disease [e.g. fibrosis, silicosis, sarcoidosis], or active tuberculosis)
4. Current participation in a pulmonary rehabilitation program or completion of a pulmonary rehabilitation program within 3 months preceding the baseline Visit V0. However, physical exercise maintenance following the completion of the initial pulmonary rehabilitation program and which is continuously performed within 3 months preceding baseline Visit V0 and during the complete trial is allowed
5. Known alpha-1-antitrypsin deficiency

Criteria within ethical considerations in terms of general health:
6. Clinically relevant abnormal laboratory values suggesting an undiagnosed disease requiring further clinical evaluation (as assessed by the Investigator)
7. Severe psychiatric or neurological disorders
8. History of depression associated with suicidal ideation or behaviour
9. Congestive heart failure severity grade IV according to NYHA (New York Heart Association Functional Classification)
10. Haemodynamically significant cardiac arrhythmias or heart valve deformations
11. Computed tomography (CT) or chest x-ray findings indicating an acute pulmonary disease other than COPD (e.g. tuberculosis, severe bronchiectasis, tumours)
12. Severe immunological diseases (e.g. known HIV infection, multiple sclerosis, lupus erythematosus, progressive multifocal leukoencephalopathy)
13. Liver impairment Child-Pugh B or C and/or active viral hepatitis
14. Severe acute infectious diseases (e.g. tuberculosis, or acute hepatitis)
15. Any diagnosis of a malignant disease (except basal cell carcinoma) within 5 years before trial start
16. Alcohol or drug abuse within the past year
17. Suspected hypersensitivity to roflumilast or rescue medication or ingredients thereof, or any other contraindication for the use thereof
18. Female patients of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire trial duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, unless they are surgically sterilized/hysterectomised or post-menopausal > 1 year or who are not using any other method of contraception considered sufficiently reliable by the Investigator in individual cases
19. Pregnancy, breast feeding, planned oocyte donation or oocyte implantation
20. Planned donation of germ cells, blood, organs or bone marrow during the course of the trial
21. Participation in another trial (use of investigational product) within 30 days preceding the baseline Visit V0 or re-entry of patients previously enrolled in this trial
22. Suspected inability or unwillingness to comply with trial procedures (e.g. language problems, psychological disorders, number and timing of visits at the site)
23. Suffering from any concomitant disease that might interfere with trial procedures or evaluations
24. Use of disallowed drugs (see below)
25. Employee at the investigational site, relative or spouse of the Investigator

E.5 End points

E.5.1

Primary end point(s)

Rate of moderate or severe COPD exacerbations per patient per year. Moderate exacerbations are defined as requiring oral or parenteral glucocorticosteroids, severe as requiring hospitalisation and/or leading to death

E.5.1.1

Timepoint(s) of evaluation of this end point

The 1-year treatment period is considered appropriate to investigate the
primary endpoint, reduction of exacerbation rate, taking into account the
seasonal variation of COPD exacerbations during the year

E.5.2

Secondary end point(s)

Key secondary Endpoints
1. Change from randomisation (V2) over 52 weeks of treatment in postbronchodilator
FEV1 [L]
2. Rate of severe COPD exacerbations per patient per year.
Other secondary endpoints:
1. Spirometry - Lung Function
2. Diary endpoints: Use of rescue medication, COPD symptoms score.
3. Quality of Life (COPD Assessment Test (CAT)
4. Time to mortality and time to trial withdrawal
5. Major adverse cardiovascular events
6. Pharmacokinetic profiles and parameters
7. Safety

E.5.2.1

Timepoint(s) of evaluation of this end point

Over 52 weeks of treatment for end-points COPD exacerbations, Lung Function, COPD Symptoms , Use of rescue medication, Quality of Life (COPD Assessment Test), Major Adverse Cardiovascular Events. Other end-points are evaluated at timing of occurence.

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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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)

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

116

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

Australia

Belgium

Brazil

Canada

Denmark

France

Germany

Greece

Hungary

Israel

Italy

Austria

Korea, Democratic People's Republic of

Netherlands

Poland

Russian Federation

Slovakia

South Africa

Spain

Turkey

United Kingdom

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

For all randomised patients who completed the trial treatment period as scheduled, one follow-up visit with further protocol-specified assessments is implemented 12 weeks after end of the treatment period. All parties involved in the trial will remain blinded between the end of the treatment period and the follow-up visit (VFU). The end-of-trial is defined as database hard-lock, which will be subsequently to the follow-up visit of the last patient

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