Clinical Trials Register

Summary
EudraCT Number:	2014-000174-19
Sponsor's Protocol Code Number:	9345
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-01-15
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2014-000174-19

A.3

Full title of the trial

Efficacy and Safety of Eltrombopag in Patients with Acquired Moderate Aplastic Anemia (EMAA) who are treated with Ciclosporin A

Prospective Randomized Multicenter Study comparing Thrombopoetin-Receptor agonist Eltrombopag (Revolade®, GlaxoSmithKline) with Placebo in Patients with Acquired Moderate Aplastic Anemia who are treated with Ciclosporin A

Wirksamkeit und Sicherheit von Eltrombopag in Kombination in Patienten mit Erworbener Moderater Aplastischer Anämie (EMAA), die mit Ciclosporin A behandelt werden

Eine prospektive, randomisierte, multizentrische klinische Studie zum Vergleich des Thrombopoetinrezeptor-Agonist Eltrombopag mit Placebo in Patienten mit Erworbener Moderater Aplastischer Anämie (EMAA), die mit Ciclosporin behandelt werden

Efficacité et tolérance de l’eltrombopag auprès de patients atteints d’aplasie médullaire modérée acquise traités avec de la ciclosporine (Etude EMAA)

Etude prospective multicentrique randomisée visant à évaluer l’adjonction d’un agoniste de récepteur de la thrombopoïétine (Eltrombopag, Revolade, GlaxoSmithKline) auprès de patients atteints d’aplasie médullaire modérée acquise traités avec la ciclosporine (EMAA)

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

EMAA

A.4.1

Sponsor's protocol code number

9345

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	Universitätsklinikum Ulm (Clinique universitaire dÚlm)
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	GlaxoSmithKline GmbH & Co. KG
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	Universitätsklinikum Ulm
B.5.2	Functional name of contact point	Britta Höchsmann
B.5.3	Address:
B.5.3.1	Street Address	Helmholtzstraße 10
B.5.3.2	Town/ city	Ulm
B.5.3.3	Post code	89081
B.5.3.4	Country	Germany
B.5.4	Telephone number	0049731150560
B.5.5	Fax number	0049731150500
B.5.6	E-mail	b.hoechsmann@blutspende.de

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	Revolade 75 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	GlaxoSmithKline
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.3.1	Product name	Eltrombopag
D.3.2	Product code	SB497115
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	Eltrombopag
D.3.9.1	CAS number	496775-62-3
D.3.9.2	Current sponsor code	SB497115
D.3.9.3	Other descriptive name	ELTROMBOPAG OLAMINE
D.3.9.4	EV Substance Code	SUB30141
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	75
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

Moderate Aplastic Anemia

Aplasie médullaire modérée

E.1.1.1

Medical condition in easily understood language

Moderate Aplastic Anemia (MAA) is a non-malignant blood disorder.

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The aim of this study is to improve treatment of Moderate Aplastic Anemia by evaluating the safety and efficiency of Eltrombopag as a new treatment option in patients with Moderate Aplastic Anemia who receive CSA as background treatment according to current practice.

The primary objective of this trial is the evaluation of the superiority of Eltrombopag on top of background treatment with Ciclosporin (CSA) regarding hematologic response (PR + CR) at 6 months in comparison with treatment with CSA alone in untreated MAA patient.

L’objectif principal de l’étude est de démontrer la supériorité du bras eltrombopag associé au traitement de référence (la ciclosporine, CSA) vis à vis de l’utilisation de CSA seule en terme de réponse hématologique à 6 mois de traitement.

E.2.2

Secondary objectives of the trial

The secondary objective of this trial is to investigate the impact of Eltrombopag added to background therapy with CSA therapy on all outcome measures, safety and quality of life in untreated AA patients. As well as the evaluation of telomere lengths and telomerase mutations as biomarkers for response on Eltrombopag therapy in MAA and the evaluation of the new Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria (PNH) specific quality of life questionnaire QLQ-AA/PNH.

for more details see protocoll vers. 1.15, page

Les objectifs secondaires de l’étude décrits ci-dessous sont d’examiner l’influence exercée par l’ajout de l’eltrombopag au traitement de référence par CSA sur l’ensemble des critères d’évaluation, la tolérance et la qualité de vie de patients atteints d’AMm non traités (questionnaires spécifiques). En outre, il est prévu d’évaluer la longueur des télomères et les mutations du complexe télomérase en tant que biomarqueurs de la réponse au traitement.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Current diagnosis Moderate Aplastic Anemia without prior specific therapy.

MAA is defined as Aplastic Anemia fulfilling the following criteria:
• no evidence for other disease causing marrow failure
• hypocellular bone marrow for age
• depression of at least two out of three peripheral blood counts below the normal values:
absolute neutrophil count (ANC) <1.2 G/L
platelet count < 70 G/L
absolute reticulocyte count < 60 G/L
without fulfilling the criteria for SAA

In this study need for treatment is defined as:

a) transfusion-independent MAA and:
ANC < 1.0 G/L
or hemoglobin < 8.5 g/dl and reticulocyte count < 60 G/L
or platelet count less < 30 G/L
or significant clinical symptoms (infections, bleeding, anemia)

b) transfusion-dependent moderate aplastic anemia
Platelet transfusion dependency is defined as prophylactic transfusion (platelet counts < 10 G/L with no bleeding) or therapeutic transfusion
Red cell transfusion dependency is defined as transfusion of at least 4 units of packed red blood cell concentrates (PRBC) in the 12 weeks prior to study entry

A signed and dated informed consent.

1. Diagnostic d’aplasie médullaire modérée (AMm) sans traitement spécifique préalable.

L’AMm est une anémie aplasique définie de la manière suivante :
• moelle osseuse hypocellulaire en fonction de l’âge
• diminution d’au moins deux valeurs sanguines périphériques sur les trois valeurs suivantes en dessous des valeurs normales :

Nombre absolu de neutrophiles (ANC) <1.2 G/L, nombre de plaquettes < 70 G/L, nombre absolu de réticulocytes < 60 G/L, sans correspondre aux critères d’une aplasie médullaire sévère.

• aucune autre maladie de la moelle osseuse

2. Les indications thérapeutiques d’une AMm sont les suivantes:

a) AMm non transfusée, lorsque :

Neutrophiles < 1.0 G/L

ou hémoglobine < 8.5 g/dl et nombre de réticulocytes < 60 G/L

ou nombre de plaquettes < 30 G/L

ou présence de symptômes cliniques significatifs (infections, hémorragies, anémie)

b) AMm et dépendance transfusionnelle

La dépendance transfusionnelle de plaquettes est définie comme transfusion prophylactique (nombre de plaquettes <10 G/L sans hémorragies) ou comme transfusion thérapeutique (signe hémorragique)

La dépendance transfusionnelle de culot globulaire est définie comme transfusion d’au moins 4 unités de concentré d’érythrocytes (packed red blood cell concentrates – PRBC) dans les 12 semaines précédent l’inclusion.

3. Déclaration d’information et de consentement du patient signée

E.4

Principal exclusion criteria

1. Age < 18 years
2. Severe or Very Severe Aplastic Anemia (hypocellularity of
bone marrow 25% and depression of two of the three
peripheral counts: ANC < 0.5 G/L, platelet count < 20 G/L,
reticulocyte count < 20 G/L)
3. Diagnosis of Fanconi anemia
4. Clonal myeloid disorders based on cytogenetic findings
performed within 12 weeks of study entry. Especially
patients with cytogenetic abnormalities which are recurrent
in MDS are not eligible for the study. The karyotypic
abnormalities which qualifies for the diagnosis of MDS are
listed in the Appendix. (according to revised WHO 2008
criteria)] (exception: Paroxysmal Nocturnal Hemoglobinuria,
which is not excluded)
5. Bone marrow reticulin fibrosis of grade 3 or greater
6. Severe concurrent diseases precluding the patient's ability
to tolerate protocol therapy
7. SGPT >3 times the upper limit of normal if
this elevation is progressive, or persistent for 4 weeks, or
accompanied by increased direct bilirubin, or accompanied
by clinical symptoms of liver injury or evidence for hepatic
decompensation
8. Infection not adequately responding to appropriate therapy
9. HIV-positivity, patients with
Hepatitis B or Hepatitis C are only in combination with
hepatic failure excluded (see criteria 7))
10. Moribund status with a likely death within 3 months
11. History of malignancy other than localized tumors
diagnosed more than one year previously and treated
surgically with curative intent (for instance squamous cell or
other skin cancers, stage 1, breast cancer, cervical
carcinoma in situ...).
12. Prior specific treatment of Aplastic Anemia with
immunossupression or androgens or interleukin2-receptor-
antibodies. The use of these drugs in context of other
disorders before diagnosis of aplastic anemia is not an
exclusion criteria if these treatments were finished longer
than 6 months before study entry.
13. Treatment with other hematological effective drugs (including
growth factors )within 3 months before study entry as well as treatment with corticosteroids within 3 weeks before enrollment
13. Known Hypersensitivity to Eltrombopag or its components
14. Current nursing, pregnancy, or unwillingness to take oral
contraceptives or use a barrier method of birth control to
refrain from pregnancy as well as a missing or positive pregnancy test within the last 14 days before inclusion for women of childbearing potential during
the course of this study
15. Inability to understand the investigational nature of the
study or to give informed consent.
16. Renal failure with creatinine > 2x upper limit of normal.

1. Age < 18 ans

2. Aplasie médullaire sévère ou très sévère (hypocellularité de la moelle osseuse de 25% et diminution d’au moins deux des trois valeurs sanguines à : Neutrophiles < 0.5 G/L, nombre de plaquettes < 20 G/L, nombre de réticulocytes < 20 G/L)

3. Diagnostic d’anémie de Fanconi

4. Trouble myéloïde clonal diagnostiqué sur la base d’examens cytogénétiques, effectués dans l’espace de 12 semaines avant l’inclusion prévue dans l’étude ; notamment les patients présentant des anomalies cytogénétiques signe d’un syndrome myélodysplasique ne peuvent pas participer à cette étude.

5. Myélofibrose

6. Autres maladies graves qui empêchent le patient de tolérer le traitement conformément au protocole

7. ALAT > 3 fois supérieures au niveau normal lorsque cette augmentation est persistante ou progressive pendant quatre semaines, ou qu’elle est accompagnée par des valeurs de bilirubine élevées ou par des symptômes cliniques d’une atteinte hépatique, ou par une preuve d’une décompensation hépatique

8. Infection non contrôlée

9. Test VIH positif, infection active avec l’hépatite B ou C

10. Patients moribonds indiquant la possibilité d’un décès du patient dans les 3 mois qui suivent.

11. Antécédent de cancer traité par chimiothérapie

12. Traitement spécifique de l’aplasie médullaire précédent à l’étude. L’administration d’immunosuppresseurs, d’androgènes ou d’anti-IL2 n’est pas un critère d’exclusion dans le contexte d’autres maladies si l’administration a été effectuée plus de six mois avant l’inclusion.

13. Traitement avec d’autres médicaments actifs au niveau hématologique (y compris les facteurs de croissance) dans les trois mois avant l’inclusion ainsi que le traitement aux corticoïdes dans les trois semaines précédant l’inclusion.

14. Hypersensibilité connue à l’eltrombopag ou à ses composants

15. Hypersensibilité à la ciclosporine connue

16. Allaitement en cours, grossesse ou refus de la prise de contraceptifs ou de l’utilisation d’autres méthodes de contraception au cours de cette étude par les femmes en âge de procréer

17. Incapacité des candidats de comprendre la nature de l’étude ou de consentir à la participation / de donner un consentement informé

18. Troubles rénaux avec un taux de créatinine > 2 fois la normale.

19. Hypertension artérielle non contrôlée

20. Participation à une autre étude clinique qui prévoyait un traitement avec un autre médicament expérimental avec un délai de carence de 30 jours avant l’inclusion.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the study is the hematologic response rate (CR + PR) at 6 months.

Taux de réponse hématologique 6 mois après le début du traitement

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months

6 mois après le début du traitement

E.5.2

Secondary end point(s)

• Trilineage hematological response rate (CR and PR) at 3, 6, 12 and 18 months.
• single lineage response at 3, 6, 12 and 18 months
• cumulative incidence of response
• time to best hematological and single lineage response
• proportion of patients with need for transfusions and number of units transfused (PRBC and PC) since start of treatment
• cumulative incidence of progress to SAA/VSAA or intensive immunosuppressive treatment with ATG
• toxicity profile as measured using the CTCAE criteria for patients receiving placebo in comparison to patients receiving eltrombopag, both on top of background treatment with CSA
• relapse rate at 6, 12 and 18 months
• cumulative incidence of relapse (from best hematological response)
• overall survival
• failure-free survival
• telomere lengths and presence of telomerase mutations as biomarkers for response.
• quality of life as assessed by quality of life instruments (FACIT-F SCALE and EORTC QLQ-C30, partly in addition with the QLQ-AA/PNH)

• Réponse des 3 lignées hématopoïétiques (RC et RP) après 2, 4, 6, 12 et 18 mois de traitement
• Délai pour atteindre la meilleure réponse hématologique
• Persistance de besoin transfusionnel
• Incidence cumulée d’évolution vers l’aplasie médullaire sévère ou la nécessité d’une nouvelle ligne thérapeutique
• Profil de toxicité mesuré par rapport aux critères de terminologie CTCAE
• Incidence de rechute après 2, 4, 6, 12 et 18 mois
• Taux de survie globale
• Taux de survie sans évènement
• Longueur des télomères et présence de mutations dans le complexe télomérase en tant que biomarqueurs de la réponse à l’eltrombopag
• Evaluation de la qualité de vie relevée à l’aide de FACIT-F SCALE et de EORTC QLQ-C30, et partiellement de QLQ-AA/HPN

E.5.2.1

Timepoint(s) of evaluation of this end point

2, 4, 6, 12, 18 months

2, 4, 6, 12 et 18 mois

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

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

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

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)

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

France

Germany

Italy

Netherlands

Switzerland

United Kingdom

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

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:

116

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

116

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

Information not present in EudraCT

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

109

F.4.2.2

In the whole clinical trial

116

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)

After conclusion of the trial patients will receive further standard medical care as usual for this kind of disease.

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

2021-08-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-07-28

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2025-01-30

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials