Clinical Trials Register

Summary
EudraCT Number:	2014-001946-10
Sponsor's Protocol Code Number:	E-RES/35/13-N08
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2014-06-19
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

Bulgarian Drug Agency

A.2

EudraCT number

2014-001946-10

A.3

Full title of the trial

A randomised, single dose, open label, two-period crossover study evaluating bioequivalence of salmeterol xinafoate HFA pMDI 25μg per actuation manufactured by Cipla Ltd, India (test product) with salmeterol xinafoate HFA pMDI 25μg per actuation (Serevent™ Evohaler™), supplied by Allen and Hanburys, UK (reference product) when administered by a volumatic spacer to paediatric asthma subjects.

A.3.1

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

A research study to find out whether a product to be tested (salmeterol xinafoate HFA pMDI 25 μg per actuation, manufactured by Cipla Ltd, India) is equivalent to the already existing formulation (salmeterol xinafoate HFA pMDI 25 μg per actuation (Serevent Evohaler™), supplied by Allen and Hanburys, UK) when administered by a volumatic spacer device to children with asthma

A.4.1

Sponsor's protocol code number

E-RES/35/13-N08

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	Cipla Ltd.
B.1.3.4	Country	India
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	Cipla Ltd.
B.4.2	Country	India
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Cipla Ltd.
B.5.2	Functional name of contact point	Dr. Paul Michael Dorinsky
B.5.3	Address:
B.5.3.1	Street Address	Cipla R&D, North Block, New Building, 4th Floor, LBS Marg, Vikhroli (W)
B.5.3.2	Town/ city	Mumbai, Maharashtra
B.5.3.3	Post code	400083
B.5.3.4	Country	India
B.5.4	Telephone number	+1919939-4404
B.5.5	Fax number	+912225785298
B.5.6	E-mail	paul.dorinsky@cipla.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	Sereflo™ CFC-free Inhaler™ 25 micrograms per actuation
D.2.1.1.2	Name of the Marketing Authorisation holder	Cipla (EU) Limited
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 xinafoate HFA pMDI 25 μg per actuation manufactured by CIPLA
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 Xinafoate
D.3.9.1	CAS number	94749-08-3
D.3.9.3	Other descriptive name	SALMETEROL XINAFOATE
D.3.9.4	EV Substance Code	SUB04314MIG
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.IMP: 2
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™ 25 micrograms Evohaler™
D.2.1.1.2	Name of the Marketing Authorisation holder	Glaxo Wellcome UK Ltd
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.3.4	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 Xinafoate
D.3.9.1	CAS number	94749-08-3
D.3.9.3	Other descriptive name	SALMETEROL XINAFOATE
D.3.9.4	EV Substance Code	SUB04314MIG
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

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	17.1
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

Pharmacokinetic Objective:
Phase I
To estimate intra-subject Coefficient of Variation (CV) in order to determine the sample size needed to establish bioequivalence between the test and reference product.
Phase II
To compare rate and extent of absorption of the test product, salmeterol xinafoate HFA pMDI 25 μg per actuation, with that of the reference product, SereventTM EvohalerTM (containing salmeterol xinafoate 25 μg per actuation), after single dose administration to paediatric asthma subjects with the aid of a volumatic spacer device.

E.2.2

Secondary objectives of the trial

Safety Objective:
To compare the safety and tolerability of the test and reference product in paediatric asthma subjects.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Informed consent by the subject’s parent /legal guardian/Assent (if possible also by the subject) given in a written form after being provided with detailed information about the nature, risks and scope of the clinical trial as well as the expected desirable and adverse effects of the drug.
2. Male or female (pre-menarchal and pre–pubescent) subjects aged 4 to 11 years.
3. Subjects not weighing less than 12 Kgs.
4. Body mass index (BMI) within the 5th to 125th percentile of the appropriate BMI designated charts based on stature-for-age and weight-for-age and by gender.
5. Subjects, who are stable on treatment with same dose of ICS and salbutamol sulphate as needed for the past 2 weeks prior to screening.
6. Subjects with physician diagnosed asthma as per the GINA guidelines.
7. Subjects aged 6 to 11 years with a FEV1 ≥ 80% predicted at screening or subjects aged 4 to 5 years with a PEF >80% predicted or >85% of their personal best.
8. Subjects with no evidence of significant underlying disease other than asthma during the pre-study screening evaluation, medical history, laboratory tests, vital signs, and physical examination.
9. Subjects who agree to avoid strenuous physical exertion for at least 48 hours prior to dosing of each study period.
10. Subjects agree to abstain from consuming grapefruit or its products for at least 96 hours prior to dosing and until the last blood sample is withdrawn in a particular period
11. Subjects agree to abstain from consuming citrus fruits or their products and xanthine containing products (chocolate, tea, coffee or cola drink), for at least 2 hours prior to dosing and until the last blood sample is withdrawn in a particular period.
12. Subjects who agree to be available for the entire duration of the study and have the ability to understand and communicate effectively with the investigators and study personnel.
13. Subjects who are able to correctly use the pMDI with the volumatic spacer device, following training received from qualified site personnel.

E.4

Principal exclusion criteria

1. History of severe or life threatening asthma defined as any asthma episode associated with hypercapnea, intubation or admission to an intensive care unit.
2. Any use of salmeterol within 4 weeks prior to the Visit S.
3. Unstable asthma as evidenced by any change in asthma therapy within 2 weeks prior to screening or use of more than 4 puffs of rescue medication (salbutamol sulphate) per day within 1 week prior to screening.
4. Unstable asthma as evidenced by any change in asthma therapy within the last 3 months or admission to hospital due to asthma during or within the last 6 months before subject’s participation in the trial.
5. More than 1 short course of oral/systemic corticosteroids within 6 months preceding the Visit S, or any oral/systemic corticosteroids in the preceding 3 months.
6. Evidence of active concomitant pulmonary disease other than asthma (subjects with stable allergic rhinitis will be permitted as long as there are no changes in the treatment and the medications do not interfere with the analytical assay methods).
7. Subjects who have suffered any clinically significant illness in the two weeks prior to dosing or who have been hospitalised within 3 months preceding the start of the study.
8. Acute upper respiratory tract infection (URTI) that has not resolved within 4 weeks of the Visit S.
9. Acute lower respiratory tract infection (LRTI) that has not resolved within 8 weeks of the Visit S.
10. History of any clinically significant disease including but not limited to concomitant severe decompensated systemic disease (cardiovascular, renal, hepatic, endocrine, gastrointestinal, psychological, haematological, neurological, or immunological).
11. Clinically significant abnormal laboratory values.
12. Subjects who have a history of severe food allergy.
13. Known or suspected hypersensitivity to salmeterol xinafoate or any other constituents of the investigational products.
14. Use of any medication (prescription, non-prescription or herbal) other than salbutamol sulphate and the subject’s regular ICS within 4 weeks prior to the first dose of study medication unless complete elimination from the body can be assumed for the drug on the basis of the terminal elimination half-life (at least 5 times the elimination half-life to be elapsed) until the first dose of study medication.
15. Use of drugs which can specifically induce or inhibit enzyme Cytochrome P450 3A4 (CYP3A4) within 4 weeks prior to the first dose of the study medication.
16. Treatment with any investigational drug in the 3 months preceding the Visit S or 5 times the elimination half-life of that drug, whichever is longer.
17. Donation of blood in excess of 50 mL within 90 days prior to receiving the first dose of study medication.
18. Legal incapacity or other circumstances that render the subject’s parent or legal guardian unable to understand the nature, scope and possible consequences of the study.
19. In the investigator’s opinion, subjects unlikely to comply with the study procedures.
20. Subjects previously randomised into this study.

E.5 End points

E.5.1

Primary end point(s)

Primary variables:
AUC(0-4hrs) and AUC(0-30min)

Secondary variables:
Cmax, tmax

E.5.1.1

Timepoint(s) of evaluation of this end point

At the end of trial

E.5.2

Secondary end point(s)

The following safety variables will also be evaluated in the study:
- Adverse events
- Vital signs
- Overall well-being
- Laboratory assessments (haematology, biochemistry and urinalysis)

E.5.2.1

Timepoint(s) of evaluation of this end point

On an ongoing basis

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

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

Yes

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

Yes

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)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

Yes

E.8.2.2

Placebo

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

Yes

E.8.4

The trial involves multiple sites in the 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

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

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Children

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

2014-08-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-07-30

P. End of Trial
P.	End of Trial Status	Ongoing

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