Clinical Trials Register

Summary
EudraCT Number:	2018-000222-61
Sponsor's Protocol Code Number:	DS8201-A-U302
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-10-03
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

France - ANSM

A.2

EudraCT number

2018-000222-61

A.3

Full title of the trial

A Phase 3, multicenter, randomized, open-label, active-controlled study of DS-8201a, an anti-HER2-antibody drug
conjugate, versus ado-trastuzumab emtansine (T-DM1) for HER2-positive, unresectable and/or metastatic breast cancer subjects previously treated with trastuzumab and taxane

Etude de phase III, multicentrique, randomisée, en ouvert, comparant le DS-8201a, un anticorps conjugué anti-HER2, au traitement de référence, l’ado-trastuzumab emtansine (T-DM1), chez les patients atteints d’un cancer du sein HER2 positif, non résécable et/ou métastatique, préalablement traités par trastuzumab et taxanes.

A.3.1

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

Testing a new targeted therapy (DS-8201a) against ado-trastuzumab emtansine (T-DM1) for patients with advanced-stage breast cancer previously treated with trastuzumab and taxane.

Comparaison d’un nouveau traitement ciblé (DS-8201a) à l’ado-trastuzumab emtansine (T-DM1) chez des patients atteints d’un cancer du sein de stade avancé précédemment traités par trastuzumab et taxane.

A.4.1

Sponsor's protocol code number

DS8201-A-U302

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03529110

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	Daiichi Sankyo Inc.
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	Daiichi Sankyo Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Daiichi Sankyo Inc.
B.5.2	Functional name of contact point	Not Available
B.5.3	Address:
B.5.3.1	Street Address	211 Mt Airy Rd
B.5.3.2	Town/ city	Basking Ridge
B.5.3.3	Post code	NJ 07920
B.5.3.4	Country	United States
B.5.4	Telephone number	+1 908 992 6400
B.5.6	E-mail	eu_cta@dsi.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.3.2	Product code	DS-8201a
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	trastuzumab deruxtecan
D.3.9.2	Current sponsor code	DS-8201a
D.3.9.3	Other descriptive name	Anti-HER2 antibody-drug conjugate
D.3.9.4	EV Substance Code	SUB188940
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Kadcyla
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration 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.3.4	Pharmaceutical form	Powder for concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	trastuzumab emtansine
D.3.9.1	CAS number	1018448-65-1
D.3.9.3	Other descriptive name	trastuzumab emtansine
D.3.9.4	EV Substance Code	SUB35467
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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

Unresectable/metastatic breast cancer with human epidermal growth factor receptor 2 (HER2)-positive expression

Cancer du sein non résécable/métastatique avec expression positive du récepteur 2 du facteur de croissance épidermique humain (HER2)

E.1.1.1

Medical condition in easily understood language

advanced-stage breast cancer

Cancer du sein avancé

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10027475
E.1.2	Term	Metastatic breast cancer
E.1.2	System Organ Class	100000004864

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 compare the efficacy of DS 8201a to T-DM1 as measured by progression-free survival (PFS).

Comparer l’efficacité du DS-8201a et celle du T-DM1 telle que mesurée par la survie sans progression (SSP).

E.2.2

Secondary objectives of the trial

• To further compare the efficacy of DS-8201a to T-DM1 on:
- Overall survival (OS);
- Objective response rate (ORR);
- Duration of response (DoR);
- Clinical benefit rate (CBR).
• To further determine pharmacokinetics (PK) of DS-8201a.
• To further evaluate safety of DS-8201a compared to T-DM1.
• To evaluate Health Economics and Outcomes Research (HEOR) endpoints for DS 8201a compared to T-DM1.

•Comparer de manière plus approfondie l’efficacité du DS-8201a par rapport à celle du T-DM1 au regard des critères suivants :
-survie globale (SG) ;
-taux de réponse objective (TRO) ;
-durée de réponse (DR) ;
-taux de bénéfice clinique (TBC).
•Déterminer de manière plus approfondie la pharmacocinétique (PK) du DS-8201a.
•Évaluer de manière plus approfondie la sécurité d’emploi du DS-8201a par rapport à celle du T-DM1.
•Évaluer les critères d’évaluation liés à la recherche sur l’économie de la santé et les résultats (HEOR, Health Economics and Outcomes Research) pour le DS-8201a par rapport au T-DM1.
Objectifs exploratoires :
•Évaluer les biomarqueurs potentiels (par exemple, dosage sérique du domaine extracellulaire du récepteur HER2 [HER2ECD]).
•Évaluer les relations entre exposition et réponse pour les critères d’évaluation de l’efficacité et de la sécurité d’emploi.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Adults ≥18 years old. (Please follow local regulatory requirements if the legal age of consent for study participation is >18 y old.)
• Pathologically documented breast cancer that:
- is unresectable or metastatic
- has confirmed HER2 positive expression as determined according to American Society of Clinical Oncology – College of American Pathologists guidelines evaluated at a central laboratory.
- was previously treated with trastuzumab and taxane in the advanced/metastatic setting or progressed within 6 mo after neoadjuvant or adjuvant treatment involving a regimen including trastuzumab and taxane.
• Documented radiologic progression (during or after most recent treatment or within 6 mo after completing adjuvant therapy).
• Subjects must be HER2 positive as confirmed by central laboratory assessment of most recent tumor tissue sample available.
• Male and female subjects of reproductive/childbearing potential must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 4.5 mo after the last dose of DS 8201a or 7 mo after the last dose of T-DM1
• Adequate renal function, defined as:
- Creatinine clearance ≥ 30 mL/min, as calculated using the Cockcroft-Gault equation
• Adequate hepatic function, defined as:
- Total bilirubin ≤ 1.5 × upper limit of normal (ULN) if no liver metastases or < 3 × ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline
and
- Aspartate transaminase (AST)/alanine transaminase (ALT) ≤ 5 × ULN

•Adultes âgés de ≥ 18 ans. (Veuillez suivre les exigences règlementaires locales si l’âge légal du consentement pour la participation à l’étude est > 18 ans.)
•Cancer du sein confirmé à l’anatomopathologie qui :
-est non résécable ou métastatique ;
-présente une expression HER2 positive confirmée, telle que déterminée par évaluation en laboratoire central selon les directives de l’American Society of Clinical Oncology – College of American Pathologists (Société américaine d’oncologie clinique – École des pathologistes américains) ;
-a déjà été traité par trastuzumab et taxane dans un contexte de stade avancé/métastatique ou a progressé dans les 6 mois suivant un traitement néoadjuvant ou adjuvant impliquant un schéma posologique incluant trastuzumab et taxane.
•Progression radiologique documentée (pendant ou après le traitement le plus récent ou dans les 6 mois suivant la fin du traitement adjuvant).
•Les patients doivent être positifs pour HER2, comme confirmé par l’évaluation par le laboratoire central de l’échantillon de tissu tumoral le plus récent disponible. Si aucun tissu archivé n’est disponible, une biopsie fraîche est nécessaire.
•Les patients de sexe masculin ou féminin aptes à procréer/en âge d’avoir des enfants doivent accepter d’utiliser une forme de contraception très efficace ou s’abstenir de rapports sexuels pendant l’étude et jusqu’à la fin de l’étude, ainsi que pendant au moins 4,5 mois après la dernière dose de DS-8201a ou 7 mois après la dernière dose de T-DM1.
•Fonction rénale adéquate, définie par :
-clairance de la créatinine ≥ 30 ml/min, comme calculée au moyen de l’équation de Cockcroft-Gault.
•Fonction hépatique adéquate, définie par :
-bilirubine totale ≤ 1,5 × limite supérieure de la normale (LSN) en l’absence de métastases hépatiques ou < 3 × LSN en présence d’un syndrome de Gilbert documenté (hyperbilirubinémie non conjuguée) ou de métastases hépatiques à la référence ; et
-aspartate aminotransférase (ASAT) ou alanine aminotransférase (ALAT) ≤ 5 × LSN.

E.4

Principal exclusion criteria

• Prior treatment with an anti-HER2-antibody drug conjugate (ADC).
• Uncontrolled or significant cardiovascular disease, including any of the following:
- History of myocardial infarction within 6 mo before randomization
- History of symptomatic congestive heart failure (New York Heart Association Class II to IV)
- Troponin levels consistent with myocardial infarction as defined according to the manufacturer within 28 d prior to randomization
- Corrected QT interval prolongation to > 470 ms (females) or > 450 ms (male) based on average of Screening triplicate 12 lead electrocardiogram (ECG)
- Left ventricular ejection fraction (LVEF) < 50% within 28 d prior to randomization
• Has a history of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.
• Spinal cord compression or clinically active central nervous system (CNS) metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.
- Subjects with clinically inactive brain metastases may be included in the study.
- Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment.

•Traitement préalable avec un conjugué anticorps-médicament (CAM) anti-HER2.
•Maladie cardiovasculaire non contrôlée ou significative, notamment l’une quelconque des pathologies suivantes :
-antécédents d’infarctus du myocarde (dans les 6 mois qui précèdent la randomisation) ;
-antécédents d’insuffisance cardiaque congestive symptomatique (de classe II à IV sur l’échelle de la New York Heart Association) ;
-taux de troponine compatibles avec un infarctus du myocarde, comme défini selon le fabricant, dans les 28 jours précédant la randomisation ;
-allongement de l’intervalle QT corrigé (QTc) à > 470 msec (femmes) ou > 450 msec (hommes) d’après la moyenne d’un électrocardiogramme (ECG) à 12 dérivations réalisé en triple exemplaire lors de la sélection ;
-fraction d’éjection ventriculaire gauche (FEVG) < 50 % dans les 28 jours avant la randomisation.
•Patient ayant des antécédents de pneumopathie interstitielle (PI)/pneumonite (non infectieuse) ayant nécessité des stéroïdes, présentant une PI/pneumonite ou suspecté de présenter une PI/pneumonite qui ne peut être exclue lors de l’examen d’imagerie réalisé lors de la sélection.
•Patient présentant une compression médullaire ou des métastases du système nerveux central (SNC) cliniquement actives, défini comme un patient non traité et symptomatique, ou ayant besoin d’un traitement par corticoïdes ou anticonvulsivants pour contrôler les symptômes associés.
-Les patients qui présentent des métastases cérébrales cliniquement inactives peuvent être inclus dans l’étude.
-Les patients dont les métastases cérébrales traitées ne sont plus symptomatiques et n’ayant besoin d’aucun traitement par corticothérapie ou anticonvulsivants peuvent être inclus dans l’étude s’ils se sont rétablis de tous les effets toxiques aigus de la radiothérapie. Au moins 2 semaines doivent s’être écoulées entre la fin de la radiothérapie du cerveau entier et l’inclusion dans l’étude.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is PFS as determined by blinded independent central review (BICR).

SSP tel que déterminée par le BICR.

E.5.1.1

Timepoint(s) of evaluation of this end point

The end of the study hypothesis-testing period is defined as the date when approximately 331 PFS events per blinded independent central review (BICR) have been observed.

L’analyse principale de la SSP sera effectuée lorsqu’environ 331 événements de SSP évalués par le BICR auront été observés.

E.5.2

Secondary end point(s)

The secondary efficacy endpoints are:
• OS
• ORR based on BICR and investigator assessment
• DoR based on BICR and investigator assessment
• CBR based on BICR and investigator assessment
• PFS based on investigator assessment

•SG.
•TRO basé sur le BICR et l’évaluation de l’investigateur.
•DR basée sur le BICR et l’évaluation de l’investigateur.
•TBC basé sur le BICR et l’évaluation de l’investigateur.
•SSP basée sur l’évaluation de l’investigateur.

E.5.2.1

Timepoint(s) of evaluation of this end point

If the test of the primary endpoint, PFS based on BICR, is statistically significant, selected secondary endpoints will be tested.

Si l'analyse du critère principal, SSP tel que déterminée par le BICR, est statistiquement significative, les critères secondaires sélectionnés seront analysés.

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

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

Yes

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

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

Belgium

Brazil

Canada

China

France

Germany

Hong Kong

Italy

Japan

Korea, Republic of

Spain

Taiwan

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

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 study hypothesis-testing period is defined as the date when approximately 331 PFS events per BICR have been observed. The study closure is defined as the date when the last subject discontinues study treatment and applicable follow-up occurs, or the study is ended by the Sponsor.

La fin de la période de test de l’hypothèse de l’étude est définie comme la date à laquelle environ 331 événements de SSP auront été observés d’après l’examen central indépendant en aveugle (blinded independant central review, BICR). La clôture de l'étude est définie comme la date à laquelle le dernier patient arrêt le traitement de l'étude avec le suivi correspondant ou l'étude est arrêté par le promoteur.

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

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:

285

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

215

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

194

F.4.2.2

In the whole clinical trial

500

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. If there is evidence that the subject is receiving benefit from treatment even though the subject has met a criterion for discontinuation as listed above, the subject may remain on study treatment after discussion with and approval from the Sponsor Medical Monitor.

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

2018-11-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-03-06

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

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