Clinical Trials Register

Summary
EudraCT Number:	2018-001129-15
Sponsor's Protocol Code Number:	CETB115EES03
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-07-17
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

Spain - AEMPS

A.2

EudraCT number

2018-001129-15

A.3

Full title of the trial

The ELTION study – A multicenter open-label interventional study of Eltrombopag in patients with poor graft function after allogeneic hematopoietic stem cell transplantation

ELTION- Estudio multicéntrico, abierto, intervencionista, de Eltrombopag en pacientes con injerto pobre post trasplante alogénico de progenitores hematopoyéticos

A.3.1

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

The ELTION study – A multicenter open-label interventional study of Eltrombopag in patients with poor graft function after allogeneic hematopoietic stem cell transplantation

ELTION- Estudio multicéntrico, abierto, intervencionista, de Eltrombopag en pacientes con injerto pobre post trasplante alogénico de progenitores hematopoyéticos

A.3.2

Name or abbreviated title of the trial where available

ELTION

A.4.1

Sponsor's protocol code number

CETB115EES03

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	Novartis Farmacéutica S.A.
B.1.3.4	Country	Spain
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	Novartis Farmacéutica S.A.
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Farmacéutica S.A.
B.5.2	Functional name of contact point	Trial Monitoring Organization (TMO)
B.5.3	Address:
B.5.3.1	Street Address	Gran via de les corts catalanes, 764
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08013
B.5.3.4	Country	Spain
B.5.4	Telephone number	34900353036
B.5.5	Fax number	34932479903
B.5.6	E-mail	eecc.novartis@novartis.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	REVOLADE
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	ETB115
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	496775-61-2
D.3.9.2	Current sponsor code	ETB115
D.3.9.4	EV Substance Code	SUB30140
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	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	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
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	ETB115
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	496775-61-2
D.3.9.2	Current sponsor code	ETB115
D.3.9.4	EV Substance Code	SUB30140
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	50
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

Patients with poor graft function after allogeneic-hematopoietic stem cells transplantation (allo-HSCT).
Patients diagnosed with primary or secondary poor graft function (PGF) defined as two or more cytopenias after day +30 post-transplant: Platelet count <20,000/ µL (mandatory), absolute neutrophil count (ANC) <1,000/µL, Hemoglobin <100 g/L.

Pacientes con función del injerto pobre post-trasplante de células madre alogénicas hematopoyéticas (alo-HSCT).
Pacientes diagnosticados con función de injerto pobre primario o secundario definida como dos o más citopenias después del día +30 post-trasplante: recuento de plaquetas <20,000 / μL (obligatorio), neutrófilos absolutos recuento (ANC) <1,000 / μL, Hemoglobina <100 g / L.

E.1.1.1

Medical condition in easily understood language

Patients with poor graft function after allogeneic-hematopoietic stem cells transplantation.

Pacientes con mala función del injerto post-trasplante de células madre alogénicas hematopoyéticas.

E.1.1.2

Therapeutic area

Not possible to specify

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	10067862
E.1.2	Term	Allogeneic stem cell transplantation
E.1.2	System Organ Class	100000004865

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to evaluate the efficacy of eltrombopag for poor graft function on overall hematologic response (partial and complete), as determined by platelet, hemoglobin and neutrophil counts by 16 weeks after the initiation of eltrombopag.

El objetivo principal de este estudio es evaluar la eficacia de eltrombopag en el injerto pobre en la respuesta hematológica global (parcial y completa), determinada mediante el recuento de plaquetas, hemoglobina y neutrófilos durante las 16 semanas posteriores al inicio de eltrombopag.

E.2.2

Secondary objectives of the trial

1. To determine the response in each haematological lineage separately
2. To evaluate the long-term efficacy of eltrombopag on overall hematologic response (partial and complete) at 24 and 36 weeks after the initiation of eltrombopag.
3. To evaluate the transfusion independence for red blood cells (RBC) and/or platelets after the initiation of eltrombopag (see Section Efficacy assessments for endpoint)
4. To evaluate the reduction and discontinuation of concomitant granulocyte colony-stimulating factor (G-CSF) and/or erythropoietin (EPO) therapy (see Section Efficacy assessments for endpoint).
5. To evaluate the overall survival and survival rate at 24 and 36 weeks
6. To evaluate the safety of eltrombopag. Safety will be assessed by frequency and severity of adverse events (AEs), serious AEs (SAEs) based on the Common Terminology Criteria for AEs (CTCAE v4.03) and AEs leading to discontinuation.

1. Determinar la respuesta en cada linaje hematológico por separado
2. Evaluar la eficacia de eltrombopag a largo plazo en la respuesta hematológica global (parcial y completa) a las 24 y a las 36 semanas después del inicio de eltrombopag.
3. Evaluar la independencia de la transfusión en los hematíes (RBC) y/o plaquetas después del inicio de eltrombopag (véase el apartado Evaluaciones de eficacia en variables).
4. Evaluar la reducción y discontinuación del factor estimulante de colonias granulocitarias concomitante (G-CSF) y/o terapia de eritropoyetina (EPO) (véase el apartado Evaluaciones de eficacia en variables).
5. Evaluar la supervivencia global y la tasa de supervivencia a las 24 y 36 semanas.
6. Evaluar la seguridad de eltrombopag. Se evaluará la seguridad mediante la frecuencia y gravedad de acontecimientos adversos (AA), AA graves (AAG) basados en los Criterios de terminología común de AA (CTCAE v4.03) y AA que conlleven la discontinuación.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patient must be able to understand and communicate with the investigator and comply with the requirements of the study and must provide written, signed and dated informed consent form before any study assessment is performed
2. Male of female patients ≥ 18 years of age
3. Patients diagnosed with primary or secondary poor graft function (PGF) defined as two or more cytopenias after day +30 post-transplant (re-tested in a peripheral blood analysis at screening):
a. Platelet count <20,000/ µL (mandatory)
b. Absolute neutrophil count (ANC) <1,000/µL
c. Hemoglobin <100 g/L
4. Presence of >90% of donor chimerism.
5. Karnofsky status ≥90%

1. El paciente debe ser capaz de comprender y comunicarse con el investigador y cumplir los requisitos del estudio y debe presentar un consentimiento informado escrito, fechado y firmado antes de que se realice cualquier evaluación del estudio.
2. Pacientes de ambos sexos ≥ 18 años de edad.
3. Pacientes diagnosticados con injerto pobre (IP) primario o secundario definido como 2 o más citopenias después del día +30 post trasplante (reevaluado en un análisis de sangre periférica en la selección):
a. Recuento de plaquetas < 20 000/µl (obligatorio).
b. Recuento absoluto de neutrófilos (RAN) < 1000/µl.
c. Hemoglobina < 100 g/l.
4. Presencia de > 90 % de quimerismo de donante.
5. Estado de Karnofsky ≥ 90 %

E.4

Principal exclusion criteria

1. Pregnant or nursing (lactating women).
2. Evidence of active acute or chronic graft versus host disease (GVHD).
3. Evidence of any clonal abnormality on cytogenetics (in the screening bone marrow analysis).
4. Evidence of bone marrow involvement or progression of the underlying disease assessed by sensitive methods (flow cytometry and/or molecular methods).
5. Evidence of thrombotic microangiopathy.
6. Evidence of possible causes of cytopenias other than PGF (active infections, mielotoxic drugs, hypersplenism…).
7. Prior use of any thrombopoietin receptor (TPO-R) agonists for PGF.
8. AST or ALT levels >3 x ULN.
9. Creatinine level ≥1.5 x ULN.
10. Total bilirubin level ≥1.5 x ULN.
11. Previous thromboembolic event.
12. Hypersensitivity to eltrombopag or its components.
13. Severe heart disease, significant abnormally ECG in screening visit or congenital long QT syndrome.
14. Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment.

1. Mujeres embarazadas o en periodo de lactancia.
2. Evidencia de enfermedad activa de injerto contra huésped aguda o crónica (EICH).
3. Evidencia de cualquier anomalía clonal en citogenética (en el análisis de médula ósea de la selección).
4. Evidencia de afectación de la médula ósea o progresión de las enfermedades preexistentes evaluadas mediante métodos sensibles (citometría de flujo o métodos moleculares).
5. Evidencia de microangiopatía trombótica.
6. Evidencia de causas posibles de citopenias, salvo IP, (infecciones activas, fármacos mielotóxicos, hiperesplenismo...).
7. Uso anterior de cualquier agonista del receptor de trombopoyetina (R de TPO) para IP.
8. Niveles de ALT o AST >3 x LSN.
9. Nivel de creatinina ≥1,5 x LSN.
10. Nivel de bilirrubina total ≥ 1,5 x LSN
11. Acontecimiento tromboembólicoprevio.
12. Hipersensibilidad a eltrombopag o sus componentes.
13. Enfermedad cardíaca grave, anomalía significativa del ECG en la visita de selección o síndrome del segmento TQ largo congénito.
14. Administración de un fármaco en investigación durante los 30 días o 5 vidas medias anteriores a la primera dosis del tratamiento del estudio, aquel periodo que sea más largo.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is the percentage of patients who have a response (partial and complete), by 16 weeks after the initiation of eltrombopag.

La variable principal de eficacia es el porcentaje de pacientes que presentan una respuesta (parcial y completa) durante las 16 semanas tras el inicio de eltrombopag.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 16.

Semana 16

E.5.2

Secondary end point(s)

- Percentage of patients who have a response in the neutrophil lineage (defined as ANC >1,000/ μL or ≥ 1500/ μL, confirmed in two consecutive blood tests separated a minimum of 7 days.
- Percentage of patients who have a response in the platelet lineage (defined as Platelet count >20,000/μL or ≥ 100000/μL , confirmed in two consecutive blood tests separated a minimum of 7 days.
- Percentage of patients who have a response in the hemoglobin lineage (defined as Hb >100 g/L or ≥ 110 g/ L , confirmed in two consecutive blood tests separated a minimum of 7 days.
- Percentage of patients who maintain a partial or complete response at 24 and 36 weeks
- Percentage of patients previously transfusion-dependent who do no longer require platelets and/or RBC transfusions before and after the first 16 weeks of treatment with eltrombopag.
- Time period in which patients do not receive platelets and/or RBC transfusions.
- Percentage of patients who discontinue or reduce by ≥50% the use of concomitant G-CSF and/or EPO therapy.
- Overall survival.
- Overall survival rate at weeks 24 and 36.

- Porcentaje de pacientes que tiene una respuesta en el linaje de neutrófilos (definido como RAN ≥ 1000/µl o ≥ 1500/µl, según las respuestas hematológicas definidas en el objetivo principal) confirmado en dos analíticas consecutivas separadas entre sí por un mínimo de 7 días.
- Porcentaje de pacientes que tiene una respuesta en el linaje de plaquetas (definido como recuento de plaquetas ≥ 20 000/µl o ≥ 100 000/µl, según las respuestas hematológicas definidas en el objetivo principal) confirmado en dos analíticas consecutivas separadas entre sí por un mínimo de 7 días.
- Porcentaje de pacientes que tienen una respuesta en el linaje de hemoglobina (definido como Hb ≥ 100 g/l o 110 g/l, según las respuestas hematológicas definidas en el objetivo principal) confirmado en dos analíticas consecutivas separadas entre sí por un mínimo de 7 días.
- El porcentaje de pacientes que mantienen una respuesta parcial o completa en las semanas 24 y 36.
- El porcentaje de pacientes que anteriormente eran dependientes de una transfusión y que ya no requieren transfusiones de plaquetas y/o RBC antes y después de las primeras 16 semanas de tratamiento con eltrombopag.
- El periodo de tiempo en el que los pacientes no reciben transfusiones de plaquetas y/o RBC.
- El porcentaje de pacientes que discontinúan o reducen en un ≥ 50 % el uso de G-CSF concomitante o terapia de EPO.
- Supervivencia global.
- Tasa de supervivencia global en las semanas 24 y 36.

E.5.2.1

Timepoint(s) of evaluation of this end point

week 24 and week 36

Semana 24 y semana 36

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

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)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

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

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

E.8.2.3

Other

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

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

última visita del último paciente

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

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

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.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

Nada

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

2018-08-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-07-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-11-03

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