Clinical Trials Register

Summary
EudraCT Number:	2011-004608-39
Sponsor's Protocol Code Number:	ITP0511
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:	2013-03-11
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2011-004608-39

A.3

Full title of the trial

Eltrombopag in patients with delayed
post transplant thrombocytopenia

Eltrombopag in pazienti
con trombocitopenia ritardata post-trapianto

A.3.1

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

Study about the effect of a drug (Eltrombopag)which is administered in patients with delayed post transplant thrombocytopenia, a relative decrease of platelets in blood (small blood components that help the clotting process by sticking to the lining of blood vessels).

Studio sull'effetto di un farmaco (Eltrombopag) in pazienti affetti da trombocitopenia, ovvero una diminuzione delle piastrine (piccole cellule circolanti nel sangue, che partecipano all'emostasi, cioè all'insieme di eventi che determinano l'arresto del sanguinamento quando un vaso viene leso), che si presenta successivamente ad un trapianto di cellule staminali (cellule in grado di differenziarsi in altri tipi di cellule).

A.4.1

Sponsor's protocol code number

ITP0511

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01791101

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	G.I.M.EM.A. Gruppo Italiano Malattie EMatologiche dell'Adulto
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	A.I.L. Associazione Italiana contro le Leucemie
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	GlaxoSmithKline S.p.A.
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	Fondazione GIMEMA
B.5.2	Functional name of contact point	Centro Dati Gimema
B.5.3	Address:
B.5.3.1	Street Address	Casilina 5
B.5.3.2	Town/ city	Rome
B.5.3.3	Post code	00182
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390670390521
B.5.5	Fax number	+390670390540
B.5.6	E-mail	gimema@gimema.it

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 olamina
D.3.2	Product code	SB-497115
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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

delayed
post transplant thrombocytopenia

trombocitopenia ritardata post-trapianto

E.1.1.1

Medical condition in easily understood language

thrombocytopenia: a relative decrease of platelets in blood (small blood components that help the clotting process by sticking to the lining of blood vessels).

trombocitopenia:diminuzione delle piastrine (piccole cellule del sangue, che partecipano all'emostasi,insieme di eventi che determinano l'arresto del sanguinamento quando un vaso viene leso).

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	15.1
E.1.2	Level	HLT
E.1.2	Classification code	10043555
E.1.2	Term	Thrombocytopenias
E.1.2	System Organ Class	100000004851

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 effect of eltrombopag in increasing the platelet count in patients with post SCT delayed thrombocytopenia.

L’obiettivo primario dello studio è valutare l’effetto di eltrombopag nell’aumentare la conta piastrinica in pazienti con trombocitopenia ritardata post trapianto SCT.

E.2.2

Secondary objectives of the trial

Secondary objectives are:
• Safety profile;
• Overall survival (OS);
• Bleeding events;
• Incidence of bleeding events;
Exploratory objectives:
• Relationship between baseline TPO serum level and response to therapy;
• Modifications of T-reg activity during therapy.

Gli obiettivi secondari sono:
• Profilo di sicurezza;
• Overall survival (OS);
• Sanguinamenti;
• Incidenza e severità della manifestazioni emorragiche;
Obiettivi esploratori:
• Correlazione tra i livelli sierici al basale di trombopoietina plasmatica (TPO) e la risposta alla terapia;
• Modificazioni dell’attività di T-reg durante la terapia.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age ≥ 18 years;
• Patients develop delayed thrombocytopenia, i.e. Platelet count  50 x 109/l 3 months after SCT;
• Patients underwent allogeneic SCT with match related or unrelated donor;
• Patients develop cGVHD-related delayed thrombocytopenia. The definition of cGVHD-related delayed thrombocytopenia is: platelet count  50 x 109/l from month 3 from SCT and presence of any clinical, radiological and/or laboratory finding indicative of cGVHD (all grades);
• Patients underwent SCT because of lymphoma (Hodgkin or non-Hodgkin, indolent or aggressive), or multiple myeloma;
• Sexually active males who accept to use a condom during intercourse while taking the drug and for 6 months after stopping treatment as they should not father a child in this period. A condom is required to be used also by vasectomised men (as well as during intercourse with a male partner) in order to prevent delivery of the drug via seminal fluid.
• Female subjects of non-childbearing potential may be enrolled in the study; For this study population, non-childbearing potential is defined as current tubal ligation, hysterectomy, ovariectomy or post-menopause
OR
Female subjects of childbearing potential may be enrolled in the study, if the subject has practiced adequate contraception for 30 days prior to start of eltrombopag, has a negative pregnancy test prior to start of eltrombopag, and has agreed to continue adequate contraception during the entire treatment period and for 6 months after completion of the treatment.
• Written informed consent obtained from the subject.

• Età ≥ 18 anni;
• Pazienti che sviluppano trombocitopenia ritardata con conta piastrinica  50 x 109/l 3 mesi dopo SCT;
• Pazienti sottoposti a SCT allogenico con donatore familiare o non correlato;
• Pazienti che sviluppano trombocitopenia ritardata cGVHD-relata. La definizione trombocitopenia ritardata cGVHD-relata è: conta piastrinica  50 x 109/l dal terzo mese dall’SCT e presenza di qualsiasi rilievo clinico, radiologico e/o di laboratorio indicativo di cGVHD (tutti i gradi);
• Pazienti che si siano sottoposti a SCT a causa di un linfoma (Hodgkin o non-Hodgkin, indolente o aggressivo), o mieloma multiplo;
• Maschi sessualmente attivi che accettino di usare il preservativo durante il rapporto sessuale mentre assumono il farmaco e per 6 mesi dopo l’interruzione del trattamento, poiché non devono avere figli in questo periodo.
• Soggetti di sesso femminile non potenzialmente fertili possono essere arruolati nello studio; per questa popolazione in studio, la non potenziale fertilità è definita come attuale legatura delle tube, isterectomia, ovariectomia o post-menopausa
oppure
Soggetti di sesso femminile potenzialmente fertili possono essere arruolati nello studio, se il soggetto ha praticato una contraccezione efficace nei 30 giorni precedenti all’inizio di eltrombopag, ha un test di gravidanza negativo prima dell’inizio di eltrombopag ed ha acconsentito a continuare una adeguata contraccezione durante l’intero periodo di trattamento e per i 6 mesi dopo il completamento del trattamento.
• Consenso informato scritto ottenuto dal soggetto.

E.4

Principal exclusion criteria

• Patients underwent SCT with aplo-identical donor or cord blood;
• Patients underwent SCT for diseases different from lymphoma or multiple myeloma;
• Patients have life threatening bleeding complications;
• Patients have an expected survival < 1 month;
• Patients have delayed thrombocytopenia related to medical conditions other then cGVHD;
• Patients have progressive non stabilized cGVHD necessitating intensification of immune suppressive treatment in the last 2 weeks;
• Patients need to introduce or increase the dosage of steroids, any other immune suppressive or cytotoxic agent at the time of enrolment into the study or start of eltrombopag; patients already in treatment with a fixed, stabilized dosage of steroids or other immune suppressive agents because of cGVHD may be included into the study;
• Patients received concomitant erythropoietin treatment;
• Patients have active deep venous thrombosis (DVT);
• Patients have venous occlusive disease (VOD);
• Patients have grade 3-4 hyper bilirubinemia; elevation of hepatic enzymes because of cGVHD should not be considered criteria of exclusion. Patients with baseline elevation of hepatic enzymes will be monitored carefully in order to point out possible addictive eltrombopag-related hepatotoxicity;
• Patients have hepatic cirrhosis;
• Patients have transplant related-microangiopathy;
• Patients have active infections (CMV reactivation included);
• Patients have hypersensitive to study drug;
• Patients are unable to stop medications that are known to cause a drug-drug interaction with eltrombopag.

Pazienti che si siano sottoposti a SCT con donatore aplo-identico o da cordone;
• Pazienti che si siano sottoposti a SCT per patologie diverse da linfoma o mieloma multiplo
• Pazienti che abbiano complicazioni da sanguinamento che li pongano a rischio di vita;
• Pazienti che abbiano una sopravvivenza attesa inferiore ad un mese;
• Pazienti che abbiano una trombocitopenia ritardata correlata a condizioni mediche diverse da cGVHD;
• Pazienti che abbiano una cGVHD progressiva non stabilizzata che necessiti di un’intensificazione del trattamento immunosoppressivo nelle ultime 2 settimane;
• Pazienti che necessitino di introdurre o aumentare la dose di steroidi o di qualsiasi altro agente immunosoppressivo o citotossico al momento dell’arruolamento nello studio o all’inizio di eltrombopag; pazienti già in trattamento con una dose fissa e stabile di steroidi o di qualsiasi altro agente immunosoppressivo dovuto a cGVHD possono essere inclusi nello studio;
• Pazienti che ricevono un trattamento concomitante con eritropoietina;
• Pazienti con trombosi venosa profonda (DVT) attiva;
• Pazienti con patologia venosa occlusiva (VOD) attiva;
• Pazienti che abbiano iperbilirubinemia di grado 3-4; un aumento degli enzimi epatici dovuto a cGVHD non dovrebbe essere considerato un criterio di esclusione. Pazienti con un aumento degli enzimi epatici al basale saranno accuratamente monitorati al fine di segnalare possibile epatotossicità aggiuntive correlate a eltrombopag;
• Pazienti che abbiano cirrosi epatica;
• Pazienti che abbiano microangiopatia correlata al trapianto;
• Pazienti che abbiano infezioni attive (incluso riattivazione CMV);
• Pazienti che siano ipersensibili al farmaco sperimentale;
• Pazienti che non possano interrompere i trattamenti che sono noti causare interazioni farmaco-farmaco con eltrombopag.

E.5 End points

E.5.1

Primary end point(s)

Response rate (OR), i.e. the number of patients who achieve both a platelet count ≥ 50 x 109/L and have doubled their baseline platelet count, two months after treatment with eltrombopag. The primary endpoint will be considered for all the treated population according to the intention-to-treat and in the evaluable population, i.e. all patients treated with eltrombopag for at least 3 weeks or who interrupted eltrombopag because of toxic events. A transient increase of platelet count after the administration of iv immunoglobulin given for anti- microbial purpose will not be considered criteria of response.

Response rate (OR)

E.5.1.1

Timepoint(s) of evaluation of this end point

two months after treatment with eltrombopag

Due mesi dopo il trattamento con eltrombopag

E.5.2

Secondary end point(s)

Safety profile
Incidence of AEs according to NCI Common Terminology Criteria for Adverse Events v 4.0 [NCI CTCAE] toxicity scale.

Overall Survival
OS will be evaluated with Kaplan Meyer and compared with historical patients who developed post SCT delayed thrombocytopenia.

Bleeding events
Bleeding events will be evaluated according to the WHO bleeding scale (grade 0, no bleeding; grade 1, petechiae; grade 2, mild blood loss; grade 3, gross blood loss; grade 4, debilitating blood loss).

TPO serum level
TPO will be measured using a Human TPO duo-set assay (R&D System). This assay employs the quantitative sandwich enzyme immunoassay technique to evaluate the concentration of TPO in plasma or serum.

T-reg activity
T-reg activity will be evaluated by flow cytometric analysis of CD4+ CD25+ FOXP3+ lymphocytes in a mixed lymphocyte population.

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end of the treatment

At the end of the study

Alla fine del trattamento

Alla fine dello studio

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

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

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

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

Nessuno

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	G.I.M.EM.A.
G.4.3.4	Network Country	Italy

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-05-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-03-26

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

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