Clinical Trials Register

Summary
EudraCT Number:	2013-000918-37
Sponsor's Protocol Code Number:	TRC112121
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-04-23
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2013-000918-37

A.3

Full title of the trial

A randomized, double-blind, placebo-controlled, phase III, multi-centre study of eltrombopag or placebo in combination with azacitidine in subjects with IPSS intermediate-1, intermediate 2 and high-risk myelodysplastic syndromes (MDS)

SUPPORT: A StUdy of eltromboPag in myelodysPlastic SyndrOmes Receiving azaciTidine

A.3.1

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

A study of eltrombopag in combination with azacitidine for subjects with low platelet counts due to intermediate 1, intermediate 2 or high risk Myelodysplastic Syndromes (MDS)

A.3.2

Name or abbreviated title of the trial where available

Phase III study of eltrombopag in advanced MDS subjects receiving azacitidine treatment

A.4.1

Sponsor's protocol code number

TRC112121

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1151-1913

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	GlaxoSmithKline Research and Development Ltd
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	GlaxoSmithKline Research & Development Ltd.
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	GlaxoSmithKline Research & Development Ltd.
B.5.2	Functional name of contact point	Clinical Trials Helpdesk
B.5.3	Address:
B.5.3.1	Street Address	1-3, Iron Bridge Roadesk
B.5.3.2	Town/ city	Uxbridge, Middlesexadesk
B.5.3.3	Post code	UB11 1BU
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+442089904466
B.5.5	Fax number	+442089904466
B.5.6	E-mail	GSKClinicalSupportHD@gsk.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	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.3.2	Product code	SB-497115
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: 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	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.3.2	Product code	SB-497115
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	49775-61-2
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	200
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.3.2	Product code	SB-497115
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	300
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
D.8 Placebo: 2
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

Thrombocytopenic patients with myelodysplastic syndromes

E.1.1.1

Medical condition in easily understood language

Low platelet count due to myelodysplastic syndrome

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	SOC
E.1.2	Classification code	10029104
E.1.2	Term	Neoplasms benign, malignant and unspecified (incl cysts and polyps)
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10028534
E.1.2	Term	Myelodysplastic syndrome NOS
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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 primary objective of this study is to determine the effect of eltrombopag versus placebo on the proportion of subjects who are platelet transfusion free during the first 4 cycles of azacitidine therapy.

E.2.2

Secondary objectives of the trial

Secondary objectives compare the following in
subjects treated with eltrombopag/azacitidine versus
placebo/azacitidine:
Overall survival (OS)
Disease Response
Hematologic improvement (HI)
Platelet and red blood cell (RBC) transfusions
Bleeding adverse events (AEs) greater than Grade 3 Bleeding AEs
Azacitidine treatment
Safety and tolerability
Health related quality of life (HRQoL)
Medical resource utilization (MRU)
Pharmacokinetic
Characterize the pharmacokinetics of steady-state eltrombopag in subjects with MDS treated with
azacitidine

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Genetic and translational Research" (Appendix 1 to the protocol dated 19-12-2013) The objectives of genetic research are to investigate the relationship between genetic variants and:
• Response to medicine, including any treatment regimens under investigation in this study or any concomitant medicines;
• MDS susceptibility, severity, clonality, and progression and related conditions

E.3

Principal inclusion criteria

Subjects eligible for enrolment in the study must meet all of the following criteria. The eligibility criteria are to be met during the screening period, defined as the period up to 28 days prior to randomization on Day 1.
1. Age ≥ 18 years.
2. Intermediate 1, intermediate 2 or high risk MDS by IPSS.
3. At least one platelet count < 75 Gi/L.
4. Eastern Cooperative Oncology Group (ECOG) Status 0-2.
5. Adequate baseline organ function defined by the criteria below
• total bilirubin less than 1.5x the upper limit of normal (ULN) except for Gilbert’s syndrome or cases clearly not indicative of inadequate liver function (i.e. elevation of indirect [haemolytic] bilirubin in the absence of ALT abnormality)
• alanine aminotransferase (ALT) less than 3xULN
• creatinine less than 2.5xULN
6. Subjects with a QTc <450msec or <480msec for subjects with bundle branch block.
The QTc is the QT interval corrected for heart rate according to Fridericia’s formula (QTcF), machine or manual overread.
For subject eligibility and withdrawal, QTcF will be used.
For purposes of data analysis, QTcF will be used.
The QTc should be based on single or averaged QTc values of triplicate
electrocardiograms (ECGs) obtained over a brief recording period
7. Subject is able to understand and comply with protocol requirements and instructions.
8. Subject has signed and dated informed consent.
9. Women must be either of non-child bearing potential, or women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study.
10. Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days of first dose of study treatment and agree to use effective contraception
(as defined in Section 7.3.3) during the study and for 30 days following the last dose of study treatment.
11. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception (as described in Section 7.3.3) from time of randomization until 16 weeks after the last dose of study treatment.
12. French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

E.4

Principal exclusion criteria

Subjects meeting any of the following criteria at the time of randomization must not be enrolled in the study:
1. Previous treatment with hypomethylating agent or induction chemotherapy for MDS.
2. History of treatment with eltrombopag, romiplostim or other TPO-R agonists.
3. Previous allogeneic stem-cell transplantation.
4. Known thrombophilic risk factors. Exception: Subjects for whom the potential benefits of participating in the study outweigh the potential risks of thromboembolic events, as determined by the investigator.
5. Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of investigational product (eltrombopag/placebo).
6. Active and uncontrolled infections, including hepatitis B or C.
7. Known Human Immunodeficiency Virus (HIV) infection.
8. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to eltrombopag or its excipient, or azacitidine, that contraindicates the subjects’ participation.
9. Pregnant or lactating female.
10. Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions that could interfere with subject’s safety, obtaining informed consent or compliance with the study procedures.
11. French subjects: the French subject has participated in any study using an investigational drug during the previous 30 days.

E.5 End points

E.5.1

Primary end point(s)

Cycle 1-4 platelet transfusion independence (The proportion of subjects who are platelet transfusion free during Cycles 1-4 of azacitidine
therapy)

E.5.1.1

Timepoint(s) of evaluation of this end point

Primary endpoint to be evaluated once all subjects recruited into study have completed 6 cycles, withdrawn from the study or died.

E.5.2

Secondary end point(s)

Secondary endpoints compare the following in subjects treated with eltrombopag/azacitidine versus placebo/azacitidine.
OS
Disease Response Disease response (per 2006 International Working
Group (IWG) criteria)
Duration of Disease Response
Progression Free Survival
Time to Progression
Proportion of subjects that progress to AML
Time to AML progression

HI in platelets, neutrophils and haemoglobin (per 2006 IWG criteria)
Duration of HI of platelets, neutrophils, and hemoglobin

Number of platelet and RBC transfusions
Duration of platelet and RBC transfusion independence

Bleeding AEs greater than Grade 3

Azacitidine dose delays and dose reductions

Evaluation of adverse event reporting (including bleeding and transfusion-related adverse events), and clinical laboratory tests

EQ-5D-3L, EORTC-QLQ-C30, FACIT-Fatigue subscale, independent questions regarding the value of transfusion independence

Event and use of site specific medical resources

Pharmacokinetic
Evaluation of covariates, and estimates of between and within subject variability

E.5.2.1

Timepoint(s) of evaluation of this end point

Once at least 140 subjects have completed 4 cycles, withdrawn or died:
-Interim IDMC analysis for futility of the primary endpoint of Cycle 1-4 transfusion independence.
The IDMC will also meet at predefined times to identify potential treatment harm
Once all recruited 350 subjects have completed 6 cycles, withdrawn or died:
-The primary endpoint of Cycle 1-4 transfusion independence will be tested.
-Interim analysis for the key secondary endpoint of OS.*
-Analysis of all other secondary endpoints
Once 275 events (deaths) occur:
-Final analysis for the key secondary endpoint of OS
*The endpoint of OS will be tested only if the null hypothesis for the test of Cycle 1-4 transfusion independence is rejected.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

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

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

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

Belgium

Canada

Denmark

France

Greece

Ireland

Italy

Austria

Norway

Sweden

Argentina

Australia

Brazil

Czech Republic

Germany

Hong Kong

Hungary

Korea, Republic of

Spain

Thailand

Israel

Mexico

Peru

Poland

Russian Federation

Switzerland

Taiwan

Turkey

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

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

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:

158

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

192

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

163

F.4.2.2

In the whole clinical trial

350

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 investigator is responsible for ensuring that consideration has been given for the post-study care of the patient's medical condition whether or not GSK is providing specific post-study treatment. Please refer to section 6.3 of the protocol for more details.

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

2014-06-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-05-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-12-17

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