Clinical Trials Register

Summary
EudraCT Number:	2011-002101-29
Sponsor's Protocol Code Number:	RO-2499-401-RD
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2011-07-27
Trial 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

Germany - BfArM

A.2

EudraCT number

2011-002101-29

A.3

Full title of the trial

A randomised, double-blind, 4-weeks cross-over trial to investigate the effect of 500 µg roflumilast tablets once-daily versus placebo on pulmonary function, asthma symptoms and inflammatory markers in subjects with asthma not adequately controlled with a combination of at least medium dose ICS/LABA maintenance therapy.

A.3.1

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

Efficacy of Roflumilast in Treatment of Severe Asthma

A.3.2

Name or abbreviated title of the trial where available

Efficacy of Roflumilast in Treatment of Severe Uncontrolled Asthma

A.4.1

Sponsor's protocol code number

RO-2499-401-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	Nycomed GmbH
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	Nycomed GmbH
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	Nycomed GmbH
B.5.2	Functional name of contact point	Susanne Wolf
B.5.3	Address:
B.5.3.1	Street Address	Byk-Gulden-Straße 2
B.5.3.2	Town/ city	Konstanz
B.5.3.3	Post code	78467
B.5.3.4	Country	Germany
B.5.4	Telephone number	0049753184 4515
B.5.5	Fax number	004975318494515
B.5.6	E-mail	susanne.wolf@nycomed.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	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.3.1	Product name	roflumilast
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	162401-32-3
D.3.9.2	Current sponsor code	BY217
D.3.9.4	EV Substance Code	SUB10358MIG
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 uncontrolled asthma

E.1.1.1

Medical condition in easily understood language

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	14.0
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

The main objective of the trial is to investigate the effect of 500 µg roflumilast tablets taken once-daily, versus placebo, on pulmonary function in subjects with asthma not adequately controlled with a combination of at least medium dose inhaled corticosteroids/long-acting inhaled beta2-agonist (ICS/LABA) maintenance therapy.

E.2.2

Secondary objectives of the trial

Secondary objectives are to investigate the effect of 500 µg roflumilast tablets taken once-daily, versus placebo, on asthma symptoms, inflammatory markers, safety and tolerability.
In addition, the effect on fractioned exhaled nitric oxide (FeNO) and on inflammatory markers in induced sputum will be investigated in selected trial centres as exploratory objectives in a sub-study.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

There is no separate title for the sub-study. Instead, in addition to the main trial objectives, the effect of roflumilast 500 µg on fractioned exhaled nitric oxide (FeNO) and on inflammatory markers in induced sputum will be investigated in selected trial centres as exploratory objectives.

E.3

Principal inclusion criteria

- Written informed consent.
- Age 18 years or above.
- Documented physician diagnosis of severe asthma consistent with the Global Initiative for Asthma (GINA) clinical features (step 4) for at least 6 months.
- Treated with a fixed or free combination of at least medium-dose ICS plus LABA for at least 3 months prior to baseline period with stable treatment for at least 4 weeks before Visit (V2).
- GINA-defined uncontrolled asthma or an asthma control questionnaire (ACQ-7) score ≥ 1.5 despite at least medium dose ICS/LABA therapy within 4 weeks prior to baseline (V0).
- Pre-bronchodilator forced expiratory volume in 1 second (FEV1) 40–85% of predicted at V0. For subjects participating in the sputum sub-study only: FEV1 > 55% of predicted and > 1 Litre.
- Non-smokers or ex-smokers (defined as: smoking cessation at least 1 year ago) with a smoking history of ≤10 pack years.
- Airway obstruction proven to be reversible by an improvement of FEV1 of at least 12% and 200 ml after inhalation of a short-acting bronchodilator. This can be either documented in the medical history (with supporting spirometry recordings) in the previous 12 months or demonstrated during screening.
- Subjects who, with the exception of asthma, are in good health.

E.4

Principal exclusion criteria

- Severe asthma exacerbation2 not resolved 4 weeks prior to baseline visit V0.
- Lower respiratory tract infection not resolved 4 weeks prior to baseline visit V0.
- A diagnosis of Chronic Obstructive Pulmonary Disease (COPD) based on GOLD criteria and/or other relevant forms of lung disease (e.g. history of primary bronchiectasis, cystic fibrosis, idiopathic (pan)bronchiolitis or bronchiolitis obliterans, bronchopulmonary allergic aspergillosis, Churg-Strauss Syndrome, paradoxical vocal cord closure, lung resection, lung cancer, interstitial lung disease [e.g. fibrosis, silicosis, sarcoidosis], or active tuberculosis) that may interfere with the evaluation of a treatment response.
- Current participation in a pulmonary rehabilitation program or completion of a pulmonary rehabilitation program within 3 months preceding V0.
- History of clinically significant allergies or idiosyncrasies to roflumilast, or any inactive ingredient(s) of these products.
- History of severe allergy to any drugs, food or beverages.
- Females of childbearing potential3 not willing to use acceptable contraceptive methods such as hormonal contraceptives (oral, injection or implant) or intrauterine contraceptive devices or who started such methods less than 2 months prior to screening or who are not willing to use a double barrier method of contraception (diaphragm plus condom).
- Lactating or pregnant females. A positive pregnancy test before the first administration of investigational medicinal product or breastfeeding.
- Male subjects planning to father during clinical trial conduct or within 3 months after the last planned dose of trial treatment.
- Planned donation of germ cells, blood, organs or bone marrow during the course of the trial.
- Subjects previously enrolled in the current clinical trial (see Section 5.7 of the protocol: Replacement and re-enrolment policy for replacement and re-enrolment policy).
- Suffering from concomitant disease or condition including those that might interfere with trial procedures or evaluations.
- Use of disallowed drugs listed in Section 6.8.2 of the protocol: Disallowed medication.

E.5 End points

E.5.1

Primary end point(s)

Change in morning pre-dose (trough) FEV1 (L) from visit V2 (end of baseline) and visit V4 (end of washout), to the last post-randomisation measurement of the respective treatment period.

E.5.1.1

Timepoint(s) of evaluation of this end point

Evaluation from visit V2 (end of baseline) and visit V4 (end of washout), to the last post-randomisation measurement of the respective treatment period

E.5.2

Secondary end point(s)

Change from visit V2 (end of baseline) and visit V4 (end of washout period) to the last post-randomisation measurement of the respective treatment period in:
• Forced vital capacity (FVC [L]), forced expiratory flow 25-75%
(FEF25-75% [L/s]) and peak expiratory flow (PEF [L/min])
• Morning PEF from home PEF measurements
• Asthma symptoms, i.e. day- and night-time asthma symptom score
• Rescue medication (salbutamol) usage
• Asthma exacerbations (severity, frequencies, number of days, duration)

Exploratory endpoints
• Inflammatory markers in blood:
o Total and differential white blood cell (WBC) counts
(absolute [cells/VOL and percentage])
o Inflammatory mediators (Human InflammationMAP® v.1; Rules Based Medicine [RBM])

Further exploratory endpoints from sub-study only
• Differential inflammatory cell count in induced sputum (eosinophils, neutrophils, macrophages, lymphocytes, epithelial cells)
• Molecular markers of inflammation in induced sputum supernatant, including for example Interleukin (IL)- 5, IL-8, matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinase (TIMP), myeloperoxidase (MPO)
• Fractioned exhaled Nitric Oxide (FeNO)

E.5.2.1

Timepoint(s) of evaluation of this end point

Evaluation from visit V2 (end of baseline) and visit V4 (end of washout period) to the last post-randomisation measurement of the respective 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

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)

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

Yes

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.8.2.4

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

South Africa

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 end of the clinical trial is defined as database hard-lock. The database will be hard-locked after the Blinded Data Review Meeting (BDRM) when it is declared complete and accurate.

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 months

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.2.1	Number of subjects for this age range:	110
F.1.3	Elderly (>=65 years)	No
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	30
F.4.2	For a multinational trial
F.4.2.2	In the whole clinical trial	110

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

2011-08-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-09-22

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2012-01-26

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