Clinical Trials Register

Summary
EudraCT Number:	2013-001788-21
Sponsor's Protocol Code Number:	RO-2455-302-RD
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-02-20
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

Germany - BfArM

A.2

EudraCT number

2013-001788-21

A.3

Full title of the trial

A multicenter, randomized, double-blind phase 3 study to evaluate tolerability and
pharmacokinetics of 500μg roflumilast once daily with an up-titration regimen in COPD, including an open-label down-titration period evaluating tolerability and pharmacokinetics of 250μg roflumilast once daily in subjects not tolerating 500μg roflumilast once-daily.

A.3.1

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

Study to evaluate how to optimise the use of roflumilast in subjects who
have a lung disease called chronic obstructive pulmonary disease (COPD).

A.3.2

Name or abbreviated title of the trial where available

Evaluation of tolerability and pharmacokinetics of roflumilast (250μg and 500μg)

A.4.1

Sponsor's protocol code number

RO-2455-302-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 DEVELOPMENT CENTRE EUROPE LTD
B.1.3.4	Country	United Kingdom
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 DEVELOPMENT CENTRE EUROPE LTD
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	TAKEDA DEVELOPMENT CENTRE EUROPE LTD
B.5.2	Functional name of contact point	CLINICAL STUDY MANAGER
B.5.3	Address:
B.5.3.1	Street Address	61 ALDWYCH
B.5.3.2	Town/ city	LONDON
B.5.3.3	Post code	WC2B 4AE
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+442031168483
B.5.6	E-mail	nyree.williamson@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	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	Roflumilast 250 μg
D.3.4	Pharmaceutical form	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.3.9.4	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	250
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.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	Yes
D.2.1.1.1	Trade name	Daliresp™
D.2.1.1.2	Name of the Marketing Authorisation holder	Forest Pharmaceuticals inc
D.2.1.2	Country which granted the Marketing Authorisation	United States
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
D.3.4	Pharmaceutical form	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.3.9.4	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	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

chronic obstructive pulmonary disease (COPD)

E.1.1.1

Medical condition in easily understood language

lung disease in which the lungs are damaged, making it hard to breathe.

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

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

To evaluate discontinuation rates of roflumilast 500μg OD using an up-titration regimen with either 250μg OD or 500μg EOD for the first 4 weeks of treatment followed by 500μg OD for 8 weeks compared with continuous treatment of 500μg OD during the entire 12-week main period.

To evaluate if subjects who do not tolerate roflumilast 500μg OD have a drug exposure with 250μg roflumilast OD similar to that observed in other subjects with the 500μg OD dose.

E.2.2

Secondary objectives of the trial

To evaluate the gastro-intestinal tolerability of roflumilast 500μg OD with an up-titration regimen compared with continuous treatment of 500μg OD.
To evaluate the safety, discontinuations and tolerability especially the gastro-intestinal tolerability of roflumilast 250μg OD in subjects not tolerating the 500μg OD dose.
To evaluate the safety of roflumilast 500μg OD with an up-titration regimen compared with continuous treatment of 500μg OD.
To evaluate the efficacy of roflumilast 500μg OD with an up-titration regimen on lung function compared with continuous treatment of 500μg OD.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
3. The subject has a history of COPD (according to GOLD 2013[1]) for at least 12 months prior to Screening (Visit V0) associated with chronic productive cough for 3 months in each of the 2 years prior to Screening (Visit V0, with other causes of productive cough excluded).
4. The subject shows a post-bronchodilator FEV1 of ≤50% of predicted.
5. The subject shows an FEV1/forced vital capacity (FVC) ratio (post-bronchodilator) <70%.
6. The subject has at least one documented COPD exacerbation within one year prior to Screening (Visit V0).
7. The subject is on standard of care COPD maintenance treatment including LABAs, long acting anticholinergics, or any combination thereof taken on a constant daily dose within 12 weeks prior to Screening (Visit V0)
8. The subject must be a former smoker (defined as smoking cessation at least one year ago) or current smoker both with a smoking history of at least 10 pack years.
9. The subject is male or female and aged 40 or older.
10. A female subject of childbearing potential* who is sexually active with a nonsterilized* male partner agrees to use routinely adequate contraception* from signing of informed consent throughout the duration of the study and for 30 days after the last dose of study medication..

E.4

Principal exclusion criteria

1. The subject has a COPD exacerbation ongoing at the Screening (Visit V0), or has a COPD exacerbation between V0 and V1.
2. The subject has a lower respiratory tract infection not resolved 4 weeks prior to Screening (Visit V0).
3. The subject has a diagnosis of asthma and/or other relevant lung disease (eg, history of primary bronchiectases, cystic fibrosis, bronchiolitis, lung resection, lung cancer, interstitial lung disease [eg, fibrosis, silicosis, sarcoidosis], or active tuberculosis).
4. The subject has a known α1-antitrypsin deficiency.
5. The subject has taken roflumilast within 6 months of Screening (Visit V0).
Criteria within ethical considerations in terms of general health
6. The subject has clinically relevant abnormal laboratory values suggesting an undiagnosed disease requiring further clinical evaluation (as assessed by the investigator).
7. The subject has a history of severe psychiatric or neurological disorders.
8. The subject has a history of depression associated with suicidal ideation or behavior.
9. The subject has congestive heart failure severity grade IV according to NYHA Functional Classification.
10. The subject has hemodynamically significant cardiac arrhythmias or heart valve deformations.
11. The subject has CT or chest x-ray findings indicating an acute pulmonary disease other than COPD (eg, tuberculosis, severe bronchiectasis, tumors).
12. The subject has severe immunological diseases (eg, known human immune deficiency virus (HIV) infection, multiple sclerosis, lupus erythematosus, progressive multifocal leukoencephalopathy).
13. The subject has liver impairment Child-Pugh B or C and/or active viral hepatitis.
14. The subject has severe acute infectious diseases (eg, tuberculosis, or acute hepatitis).
15. The subject has a history of malignant disease (except basal cell carcinoma) within 5 years before Screening (Visit V0).
16. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within one year before Screening (Visit V0).
17. The subject has a history of hypersensitivity or allergies to roflumilast or rescue medication or ingredients thereof, or any other contraindication for the use thereof.
18. If female, the subject is pregnant or lactating or intending to become pregnant before, during, or within 30 days after participating in this study; or intending to donate ova during such time period.
19. The subject intends to donate blood, organs, or bone marrow during the course of the study.
20. The subject has received any investigational compound within 30 days prior to Screening (Visit V0), is currently participating in another interventional clinical study, or has been previously enrolled in this study.
21. The subject is suspected to be unable or unwilling to comply with study procedures (eg, language problems, psychological disorders, number and timing of visits at the center).
22. The subject suffers from any concomitant disease that might interfere with study procedures or evaluations.
23. The subject is required to take excluded medications (see Section 7.4).
24. The subject is an immediate family member, study center employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling), or may consent under duress.

E.5 End points

E.5.1

Primary end point(s)

Percentage of subjects prematurely discontinuing study treatment due to any reason (during main period ie, Visit V1 to Vend).

E.5.1.1

Timepoint(s) of evaluation of this end point

up to week 12

E.5.2

Secondary end point(s)

• Percentage of subjects with adverse events of interest to evaluate tolerability - diarrhea, nausea, headache, decreased appetite, insomnia and abdominal pain (main period, V1 to Vend)
• Change in pre-bronchodilator FEV1 during the down-titration period, from V0DT to VendDT
• Percentage of subjects prematurely discontinuing study treatment due to any reason (during down-titration period, V0DT to VendDT)
Other secondary endpoints for this study are:
• Change in pre-bronchodilator FVC and pre-bronchodilator FEV1 from V1 to V2, V3, V4 and Vend (during main period of the study)
• To characterize the efficacy of roflumilast 250μg OD on lung function during a down-titration period, in subjects who do not tolerate roflumilast 500μg OD
• Change in subject-assessed treatment satisfaction scores from V1 to V2, V3, V4 and Vend (during main period of the study)
• To characterize subject-assessed treatment satisfaction of roflumilast 250μg OD during a down-titration period, in subjects who do not tolerate roflumilast 500μg OD.

E.5.2.1

Timepoint(s) of evaluation of this end point

as shown in the list above, up to week 12

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

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)

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

Yes

E.8.1.7.1

Other trial design description

open-label in down titration period

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

Lower dose of drug (250ug) and a different dosing regime of the 500 ug dose

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

126

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

Korea, Republic of

Philippines

Russian Federation

South Africa

Thailand

Ukraine

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-trial is defined as database hard-lock, which will be subsequent 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

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:

1000

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

400

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

145

F.4.2

For a multinational trial

F.4.2.1

In the EEA

700

F.4.2.2

In the whole clinical trial

1400

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)

subjects will return to standard of care

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

2014-05-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-07-02

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-11-30

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