Clinical Trials Register

Summary
EudraCT Number:	2015-000801-38
Sponsor's Protocol Code Number:	KFL3502
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-01-13
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Sweden - MPA

A.2

EudraCT number

2015-000801-38

A.3

Full title of the trial

A two-arm, randomised, assessor-blind, parallel group study to evaluate the effect of fluticasone/formoterol breath actuated inhaler (BAI) and Relvar Ellipta DPI on ventilation heterogeneity in subjects with partially controlled or uncontrolled asthma.

A.3.1

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

A study to compare the effects of fluticasone / formoterol BAI against Relvar® Ellipta® dry powder inhaler (DPI) on asthma

A.3.2

Name or abbreviated title of the trial where available

KFL3502

A.4.1

Sponsor's protocol code number

KFL3502

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	Mundipharma Research Limited
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	Mundipharma Research 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	Secret Files OY
B.5.2	Functional name of contact point	Clinical Research Organisation
B.5.3	Address:
B.5.3.1	Street Address	Äyritie 16
B.5.3.2	Town/ city	Vantaa
B.5.3.3	Post code	01510
B.5.3.4	Country	Finland
B.5.4	Telephone number	0035840 594 1360
B.5.5	Fax number	0035810296 1308
B.5.6	E-mail	harriet.colliander@secret-files.fi

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	Flutiform 125micrograms / 5 micrograms per actuation pressurised inhalation, suspension
D.2.1.1.2	Name of the Marketing Authorisation holder	Napp Pharmaceuticals 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	Fluticasone/ formoterol BAI 125/5 µg
D.3.2	Product code	K-haler
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	Fluticasone Propionate
D.3.9.1	CAS number	80474-14-2
D.3.9.3	Other descriptive name	FLUTICASONE PROPIONATE
D.3.9.4	EV Substance Code	SUB02241MIG
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	125
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Formoterol fumarate dihydrate
D.3.9.3	Other descriptive name	FORMOTEROL FUMARATE DIHYDRATE
D.3.9.4	EV Substance Code	SUB25660
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	5
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	Relvar Ellipta
D.2.1.1.2	Name of the Marketing Authorisation holder	Glaxo Group 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	Relvar Ellipta DPI (99/22µg)
D.3.4	Pharmaceutical form	Inhalation powder, pre-dispensed
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	FLUTICASONE FUROATE
D.3.9.1	CAS number	397864-44-7
D.3.9.4	EV Substance Code	SUB26593
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	92
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	VILANTEROL
D.3.9.1	CAS number	503068-34-6
D.3.9.4	EV Substance Code	SUB77409
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	22
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 Bronciale

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	18.1
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.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
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.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10068462
E.1.2	Term	Eosinophilic 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

To show the improvement of small airway (as measured by airway resistance) in patient's taking fluticasone/formoterol breath actuated inhaler (BAI).

E.2.2

Secondary objectives of the trial

- To show that fluticasone/formoterol breath actuated inhaler (BAI) has a better
effect on small airway (as measured by airway resistance) than Relvar Ellipta Dry
Powder Inhaler (DPI.)

- To compare the effect of fluticasone/formoterol BAI and Relvar Ellipta DPI on
other measures of ventilation heterogeneity (the uneven distribution of
breathed in air within the lung).

- To compare the effect of fluticasone/formoterol BAI and Relvar Ellipta DPI on
small airway function, volume and resistance using imaging techniques (CT&MRI
scans)

- To evaluate the control of a patient's asthma and their general health status
after treatment with fluticasone/formoterol BAI and Relvar Ellipta DPI

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Participants to be included in the study are those who meet all of the following criteria:

Inclusion criteria (for participants on Seretide Accuhaler 250/50 μg at screening):
1. Male and female participants ≥18 years old.
2. Female participants less than one year post-menopausal must have a negative urine
pregnancy test recorded at the screening visit prior to the first dose of study
medication, be non-lactating, and willing to use adequate and highly effective
methods of contraception throughout the study. A highly effective method of birth
control is defined as those which result in a low failure rate (i.e., less than
1% per year) when used consistently and correctly such as sterilisation,
implants, injectables, combined oral contraceptives, some IUDs (Intrauterine
Device, hormonal), true sexual abstinence, where this is in line with the
preferred and usual lifestyle of the participant, or vasectomised partner.
Note: Periodic abstinence (calendar, ovulation, symptothermal, post-ovulation
methods), declaration of abstinence for duration of study, and withdrawal are not
acceptable methods of contraception).
3. Documented clinical history of asthma for ≥ 6 months prior to screening visit.
4. Using Seretide Accuhaler at a stable dose of 250/50 μg BID at screening for ≥ 8
weeks.
5. Uncontrolled asthma as defined by Asthma Control Questionnaire (ACQ-6) score ≥1.0.
6. R5-R20 ≥ 0.10 kPa/L/s as measured on impulse oscillometry during the screening
visit.
7. Historical evidence (within past 24 months) of eosinophilic airways disease,
evidenced by sputum eosinophil count ≥ 3% and/or FeNO ≥ 35 ppb.
8. Good compliance with current asthma medication(s) in the Investigators opinion.
9. Willing and able to substitute pre-study prescribed inhaled asthma medication for
the entire duration of the study.
10. Willing and able to attend all study visits.
11. Written informed consent obtained.

Inclusion criteria (for participants on equivalent /higher dose or other ICS-LABAs or higher dose of Seretide at screening):
1. Male and females participants ≥18 years old.
2. Female participants less than one year post-menopausal must have a negative urine
pregnancy test recorded at the screening visit prior to the first dose of study
medication, be non-lactating, and willing to use adequate and highly effective
methods of contraception throughout the study. A highly effective method of birth
control is defined as those which result in a low failure rate (i.e., less than
1% per year) when used consistently and correctly such as sterilisation,
implants, injectables, combined oral contraceptives, some IUDs (Intrauterine
Device, hormonal), true sexual abstinence where this is in line with the
preferred and usual lifestyle of the participant, or vasectomised partner. Note:
Periodic abstinence (calendar, ovulation, symptothermal, post-ovulation methods),
declaration of abstinence for duration of study, and withdrawal are not
acceptable methods of contraception).
3. Documented clinical history of asthma for ≥ 6 months prior to screening visit.
4. R5-R20 ≥ 0.07 kPa/L/s as measured on impulse oscillometry during the screening
visit.
5. Historical evidence (within past 24 months) of eosinophilic airways disease,
evidenced by sputum eosinophil count ≥ 3% and/or FeNO ≥ 35 ppb.
6. Good compliance with current asthma medication(s) in the Investigators opinion.
7. Willing and able to substitute pre-study prescribed inhaled asthma medication for
the entire duration of the study.
8. Willing and able to attend all study visits.
9. Written informed consent obtained

E.4

Principal exclusion criteria

Participants to be excluded from the study are those who meet any of the following criteria:
1. Any severe chronic respiratory disease other than asthma.
2. Participant has a smoking history ≥ 10 “pack years” (i.e., at least 1 pack of 20
cigarettes /day for 10 years or 10 packs/day for 1 year, etc.).
3. Current smoking history within 12 months prior to the Screening Visit.
4. Near fatal or life-threatening (including intubation) asthma within the past year.
5. Known history of systemic (injectable or oral) corticosteroid medication within 1
month of Visit 1.
6. Evidence of a clinically unstable disease as determined by medical history or
physical examination that, in the investigator’s opinion, precludes entry into
the study. ‘Clinically unstable’ is defined as any disease that, in the opinion
of the Investigator, would put the participant at risk through study participation,
or which would affect the outcome of the study.
7. In the investigator’s opinion a clinically significant upper or lower respiratory
infection within 4 weeks prior to Visit 1.
8. Current evidence or known history of alcohol and/or substance abuse within 12
months prior to the Screening Visit.
9. Participant has taken β-blocking agents, tricyclic antidepressants, monoamine oxidase
inhibitors, astemizole, quinidine type antiarrhythmics, or potent CYP 3A4
inhibitors such as ketoconazole within 1 week prior to Screening Visit.
10. Current use of bronchodilators / anti-inflammatory agents other than those
specified in the protocol.
11. Known or suspected sensitivity to study drug or excipients.
12. Participation in a clinical drug study within 30 days of the screening visit.
13. Current participation in a clinical study

Exclusion Criteria for subset of participants undergoing OE-MRI and HD-CT
1. Contraindication for MRI scanning (as assessed by local MRI safety
questionnaire), which includes but is not limited to: presence of non-MRI
compatible artificial heart valves, hydrocephalus shunts, intracranial aneurysm
clips, joint replacements or metal implants, pacemakers or other cardiac rhythm
management devices, claustrophobia, history of metal in the eye, presence of
shrapnel from a war injury, callipers or braces, dentures, dental plates or
hearing aids that include metal and cannot be removed, history of epilepsy or
black-outs, ear implants, piercings that cannot be removed, intrauterine
contraceptive device or coil.
2. Inability to stay in the supine position for the duration of the scanning
procedure
3. Obesity (body weight >140 kg).

Randomisation Criteria required following Run-in
1. R5-R20 ≥ 0.10 kPa/L/s
2. ACQ-6 score ≥1.0

E.5 End points

E.5.1

Primary end point(s)

The primary objective of the study is to demonstrate improvement of peripheral airway resistance (R5-R20) from baseline with fluticasone/formoterol breath actuated inhaler (BAI) based on the mean change in R5-R20 from baseline to week 8.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 8

E.5.2

Secondary end point(s)

Secondary endpoints – Impulse oscillometry (IOS)
• Change in R5-R20 from baseline to week 4 and 9
• Change in R5 (total airway resistance) from baseline to week 4, 8 and 9
• Change in AX (Area under reactance) from baseline to week 4, 8 and 9
• Change in Fres (resonant frequency) from baseline to week 4, 8 and 9
• Change in X5 (reactance at 5Hz) from baseline to week 4, 8 and 9
• Change in delta X5 (within breath reactance difference) from baseline to week 4, 8
and 9

Secondary endpoints – Body plethysmography
• Change in sRaw from baseline to week 8
• Change in lung volumes (RV, TLC, FRC) from baseline to week 8
• Change in RV/TLC from baseline to week 8

Secondary endpoints – Multiple breath nitrogen washout (MBNWT)
• Change in Scond (ventilation heterogeneity in convection dependent airways) from
baseline to week 8 and 9
• Change in Sacin (ventilation heterogeneity in diffusion-dependent airways) from
baseline to week 8 and 9
• Change in lung clearance index (LCI) from baseline to week 8 and 9

Secondary endpoints – Functional respiratory Imaging (FRI)
• Change in FRI parameters from baseline to week 8 and 9
o Lung and Lobar Volumes at FRC and TLC
o Airway Volumes at FRC and TLC (iVaw)
o Air Trapping
o Airway Resistance (iRaw)
o Internal Lobar Airflow Distribution
o Airway Wall Thickness (iVaww)
o Aerosol deposition concentrations

Secondary endpoints – Oxygen enhanced – Magnetic Resonance Imaging (OE-MRI)
• Change in the below parameters from baseline to week 8 and 9;
o Maximal change in the partial pressure of oxygen in lung tissue (Δ PO2max_l).
PO2 is determined from the change in OE-MRI signal due to the inhalation of
elevated levels of oxygen while being scanned. Δ PO2max is the maximum observed
Δ PO2 during the dynamic OE-MRI scanning procedure.
o Median wash-in time (τ_up_l) and wash-out time (τ_down_l). Wash-in and wash-out
times are derived using an exponential model of the kinetics of oxygen delivery
and washout during the dynamic OE-MRI procedure Interquartile range and
histogram skewness (IE γ_1) of wash-in time (τ_up_l) and wash-out time.
Measurements of the heterogeneity of oxygen delivery kinetics across the lung
will reflect local obstruction.

Secondary endpoints – Spirometry
• Change in pre-dose FEV1, FEF25-75, FVC from baseline to weeks 4 and 8

Secondary PRO endpoints
• Change in ACQ-6 and AQLQ from baseline to week 4 and 8
• Average rescue medication use from baseline to week 8

E.5.2.1

Timepoint(s) of evaluation of this end point

Between Week 8 and 9

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

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

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

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

assessor blind

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

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

Australia

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

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

120

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)

The BAI will not be available until the MAA process is complete. This is expected to be during 2017. At the end of the study participants will be prescribed asthma medication according to the clinician's medical judgement.

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

2016-02-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-01-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-08-14

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IMP with orphan designation in the indication
Orphan Designation Number:
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