Clinical Trials Register

Summary
EudraCT Number:	2010-022890-33
Sponsor's Protocol Code Number:	Eqol_MDS
National Competent Authority:	Slovenia - JAZMP
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-12-16
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

Slovenia - JAZMP

A.2

EudraCT number

2010-022890-33

A.3

Full title of the trial

Eltrombopag for the treatment of thrombocytopenia due to low- and intermediate risk myelodysplastic syndromes.

A.3.1

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

Eltrombopag for the treatment of thrombocytopenia due to low- and intermediate risk myelodysplastic syndromes.

A.3.2

Name or abbreviated title of the trial where available

Eqol_MDS

A.4.1

Sponsor's protocol code number

Eqol_MDS

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	ASSOCIAZIONE QOL-ONE
B.1.3.4	Country	Italy
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	ASSOCIAZIONE QOLONE
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CLINRES FARMACIJA D.O.O.
B.5.2	Functional name of contact point	DIRECTOR
B.5.3	Address:
B.5.3.1	Street Address	VILHARJEVA CESTA 29
B.5.3.2	Town/ city	LJUBLJANA
B.5.3.3	Post code	1000
B.5.3.4	Country	Slovenia
B.5.4	Telephone number	+386059074007
B.5.5	Fax number	+386059074009
B.5.6	E-mail	mt@clinres.si

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	GlaxoSmithKline Trading Services Limited
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.3.4	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	SB-497115 (ELTROMBOPAG)
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	GlaxoSmithKline Trading Services Limited
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.3.4	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	SB-497115 (ELTROMBOPAG)
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.IMP: 3
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.3.1	Product name	Eltrombopag
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	SB-497115 (ELTROMBOPAG)
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	100
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

Adult subjects (18 years of age or older) with low or intermediate-1 IPSS risk MDS and thrombocytopenia

E.1.1.1

Medical condition in easily understood language

Myelodysplastic syndrome, a neoplasm of the bone marrow, characterized by altered blood cell growth and subsequent severe reduction in platelet counts at high risk of hemorrhage

E.1.1.2

Therapeutic area

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

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	HLT
E.1.2	Classification code	10028536
E.1.2	Term	Myelodysplastic syndromes
E.1.2	System Organ Class	100000004851

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

Phase 1
To evaluate the effect of treatment relative to placebo on:
1. response rate: the proportion of patients achieving a complete response (CR) or response (R) during the treatment period (see Platelet Response Section 7.1.) [20];
2. safety and tolerability in terms of frequency of adverse events (AE) and serious adverse events (SAE).

Phase 2
To evaluate the effect of treatment relative to placebo on:
1. duration of platelet response;
2. long-term safety and tolerability

E.2.2

Secondary objectives of the trial

To evaluate the effect of treatment relative to placebo on:
1. quality of life (QoL) scores;
2. number of monthly platelet transfusions;
3. duration of transfusion independence;
4. time to response (time from starting treatment to time of achievement of CR or PR) as measured by the MDS response criteria;
5. incidence and severity of bleeding using the WHO Bleeding Scale (see Section 8: WHO Bleeding Scale);
6. overall survival (OS) at 2 and at 5 years;
7. leukemia-free survival (LFS) at 2 and at 5 years [21] (events for LFS are defined as death and progression to AML);
8. to evaluate eltrombopag population pharmacokinetics.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Adult subjects (18 years of age or older) with low or intermediate-1 IPSS risk MDS and stable disease.
2. Subjects must have a platelet count taken within the 4 weeks prior to randomization that is <30 Gi/L.
3. Subjects must be ineligible or relapsed or refractory to receive other treatment options (such as azacitidine or lenalidomide) and must be ineligible to receive intensive chemotherapy or autologous/allogeneic stem cell transplantation.
4. Subjects must have platelet count and platelet transfusion data available over a
period of 8 weeks prior to randomization.
5. During the 2 months prior to randomization, subjects must have a baseline BM
examination which includes cytomorphology and cytogenetics. Histopathology
should be performed.
6. Erythropoiesis-stimulating agents (ESAs) in anemic subjects or granulocyte colonystimulating
factor (G-CSF) in subjects with severe neutropenia and recurrent
infections are allowed during the study as per accepted standards [23]. Subjects
who enter the study on ESAs or G-CSF should continue at the same dose schedule
until the optimal dose of study medication has been established.
7. ECOG Performance Status 0-3 (Appendix 4).
8. Subject is able to understand and comply with protocol requirements and instructions.
9. Subject has signed and dated informed consent.
10. Adequate baseline organ function defined by the criteria below:
total bilirubin (except for Gilbert’s Syndrome) ≤ 1.5xULN
ALT and AST ≤ 3xULN
creatinine ≤ 2xULN
albumin must not be below the lower limit of normal by more than 20%.
11. Subject is practicing an acceptable method of contraception. Female subjects (or female partners of male subjects) must either be of non-childbearing potential (hysterectomy, bilateral oophorectomy, bilateral tubal ligation or post-menopausal >1 year), or of childbearing potential and use of an highly effective method of contraception from 2 weeks prior to administration of study medication, throughout the study, and 28 days after completion or premature discontinuation from the study.

E.4

Principal exclusion criteria

1. MDS with intermediate-2 or high IPSS risk
2. History of treatment for cancer other than MDS with systemic chemotherapy and/or radiotherapy within the last 2 years.
3. History of treatment with romiplostim or other TPO-R agonists.
4. Pre-existing cardiovascular disease (including congestive heart failure, New York Heart Association [NYHA] Grade III/IV), or arrhythmia known to increase the risk of thromboembolic events (e.g. persistent atrial fibrillation), or subjects with a QTc >450 msec (QTc >480 msec for subjects with Bundle Branch Block).
5. BM fibrosis that leads to an inability to aspirate marrow for assessment.
6. Peripheral monocytosis > 1000/uL prior to Day 1 of study medication.
7. Leukocytosis >=25,000/uL prior to Day 1 of study medication.
8. Female subjects who are nursing or pregnant (positive serum or urine Beta-human chorionic gonadotropin [B-hCG] pregnancy test) at screening or pre-dose on Day 1.
9. Current alcohol or drug abuse.
10. Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication.
11. Active and uncontrolled infections.
12. Subjects infected with Hepatitis B, C or Human Immunodeficiency Virus (HIV).

E.5 End points

E.5.1

Primary end point(s)

Phase 1
1. Proportion of patients obtaining CR or R during the six month treatment period.
2. Safety and tolerability parameters including non-hematological laboratory Grade 3/Grade 4 toxicities, change in bone marrow blast counts from baseline and adverse events.

Phase 2
1. Duration of platelet response.
2. Long-term safety and tolerability.

E.5.1.1

Timepoint(s) of evaluation of this end point

six months

E.5.2

Secondary end point(s)

1. Changes in quality of life (QoL) scores.
2. Frequency of platelet transfusions during the treatment and follow-up periods
3. Duration of platelet transfusion independence.
4. Difference in time to response (time from starting treatment to time of achievement of CR or R).
5. Duration of response during the treatment and follow-up periods.
6. Incidence and severity of bleeding using the WHO Bleeding Scale.
7. OS and LFS.
8. Eltrombopag population pharmacokinetic parameters and plasma concentration data. The relationship between eltrombopag pharmacokinetics and relevant safety and efficacy endpoints will be explored, as data permit.

E.5.2.1

Timepoint(s) of evaluation of this end point

five years

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

Yes

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)

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

Yes

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)

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

E.8.6.2

Trial being conducted completely outside of the EEA

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:

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.4.2

For a multinational trial

F.4.2.1

In the EEA

174

F.4.2.2

In the whole clinical trial

174

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)

BEST AVAILABLE TREATMENT

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

2017-01-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-12-21

P. End of Trial
P.	End of Trial Status	Completed

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