Clinical Trials Register

Summary
EudraCT Number:	2011-001897-25
Sponsor's Protocol Code Number:	EFC12153-JAKARTA
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:	2011-12-27
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

2011-001897-25

A.3

Full title of the trial

A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 3-Arm Study of SAR302503 in Patients with Intermediate-2 or High-Risk Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis with Splenomegaly

Studio di fase III, multicentrico, randomizzato, in doppio cieco, a 3 bracci, controllato con placebo, con SAR302503 somministrato in pazienti con splenomegalia affetti da mielofibrosi primaria o da mielofibrosi post-policitemia vera o da mielofibrosi post-trombocitemia essenziale, di grado 2-intermedio o ad alto rischio.

A.3.1

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

Phase 3 Study of SAR302503 in patients with Myelofibrosis

Studio di Fase III in pazienti con mielofibrosi

A.4.1

Sponsor's protocol code number

EFC12153-JAKARTA

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	SANOFI- AVENTIS RECHERCHE ET DÉVELOPPEMENT
B.1.3.4	Country	France
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	sanofi-aventis recherche & de'veloppement
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Sanofi-Aventis Spa
B.5.2	Functional name of contact point	contact point
B.5.3	Address:
B.5.3.1	Street Address	viale L. Bodio 37/B
B.5.3.2	Town/ city	MILANO
B.5.3.3	Post code	20158
B.5.3.4	Country	Italy
B.5.4	Telephone number	800.226343
B.5.5	Fax number	0039 02.3939.4168
B.5.6	E-mail	informazioni.medicoscientifiche@sanofi-aventis.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	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/10/810 and EU/3/10/811 and EU/3/10/794
D.3 Description of the IMP
D.3.2	Product code	SAR302503
D.3.4	Pharmaceutical form	Capsule, hard
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.3.9.2	Current sponsor code	SAR302503
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.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/10/810 and EU/3/10/811 and EU/3/10/794
D.3 Description of the IMP
D.3.2	Product code	SAR302503
D.3.4	Pharmaceutical form	Capsule, hard
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.3.9.2	Current sponsor code	SAR302503
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	Capsule, hard
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

Primary myelofibrosis, post-polycythemia vera myelofibrosis, or post- essential thrombocythemia myelofibrosis

mielofibrosi primaria o mielofibrosi post-policitemia vera o da mielofibrosi post-trombocitemia essenziale

E.1.1.1

Medical condition in easily understood language

blood disorder in which the bone marrow makes too many red blood cells, or blood disorder in which the bone marrow makes too many platelets

malattia del sangue nella quale il midollo osseo produce troppi globuli rossi o troppe piastrine

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10018864
E.1.2	Term	Haematopoietic neoplasm 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

To evaluate the efficacy of daily oral doses of 400 mg or 500 mg of SAR302503 (Investigational Medicinal Product, IMP) compared to placebo in the reduction of spleen volume as determined by magnetic resonance imaging (MRI) (or computed tomography scan in patients with contraindications for MRI).

•Dimostrare l’efficacia di SAR302503 (farmaco sperimentale) somministrato una volta al giorno per via orale alle dosi di 400 o 500 mg in confronto a placebo nel ridurre il volume della milza misurato mediante risonanza magnetica (o TAC in caso i pazienti abbiano controindicazioni alla risonanza magnetica).

E.2.2

Secondary objectives of the trial

To evaluate the effect on Myelofibrosis (MF)-associated symptoms (key MF symptoms) as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) diary. To evaluate the Overall Survival of patients treated with either 400 mg/day or 500 mg/day of IMP as compared to placebo. To evaluate the Progression Free Survival of patients treated with either 400 mg/day or 500 mg/day of IMP as compared to placebo. To evaluate the durability of splenic response. To evaluate the safety of IMP

•Misurare gli effetti sui sintomi associati alla mielofibrosi (sintomi chiave della mielofibrosi), utilizzando il diario “Myelofibrosis Symptom Assessment Form (MF-SAF)”.
•Valutare la sopravvivenza globale dei pazienti trattati con farmaco sperimentale alle dosi di 400 mg o 500 mg al giorno in confronto a placebo.
•Valutare la sopravvivenza libera da progressione dei pazienti trattati con il farmaco sperimentale alle dosi di 400 mg o 500 mg al giorno in confronto a placebo.
•Valutare la durata della risposta della milza.
•Valutare il profilo di tollerabilità del farmaco sperimentale

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

PHARMACOGENETIC:
Vers:1
Date:2011/07/26
Title:A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 3-Arm Study of SAR302503 in Patients with Intermediate-2 or High-Risk Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis with Splenomegaly
Objectives:pharmacogenetics explores the effect of genes on the variability of drug responses and/or drug metabolism among people taking the same medicine

FARMACOGENETICA:
Vers:1
Data:2011/07/26
Titolo:bla
Obiettivi:bla

E.3

Principal inclusion criteria

Diagnosis of Primary Myelofibrosis (MF) or Post-Polycythemia Vera MF or Post-Essential Thrombocythemia MF, according to the 2008 World Health Organization and International Working Group of Myelofibrosis Research and Treatment (IWG-MRT) criteria. MF classified as high-risk or intermediate-risk level 2, as defined by modified IWG-MRT criteria. Enlarged spleen, palpable at least 5 cm below costal margin. At least 18 years of age. Eastern Cooperative Oncology Group performance status of 0, 1, or 2 at study entry. The following laboratory values within 14 days prior to the initiation of IMP or placebo: Absolute Neutrophil Count (ANC) ≥1.0 x 10exp9/L Platelet count ≥50 x 10exp9/L Serum creatinine ≤1.5 x Upper Limit of Normal (ULN) Serum amylase and lipase ≤1.5 x ULN Direct bilirubin ≤2.0 x ULN Aspartate aminotransferase or alanine aminotransferase ≤3 x ULN; higher values (ie, ≤5 x ULN) are allowed if clinically compatible with hepatic extramedullary hematopoiesis.

I 01. Diagnosi di mielofibrosi primaria, o di mielofibrosi post-policitemia vera o di mielofibrosi post-trombocitemia essenziale in accordo ai criteri del 2008 della World Health Organization e ai criteri IWG-MRT.
I 02. Mielofibrosi di grado 2-intermedio o ad alto rischio come definito dai criteri modificati IWG-MRT.
I 03. Milza ingrossata, palpabile per almeno 5 cm al di sotto del margine costale.
I 04. Almeno 18 anni di età.
I 05. ECOG, performance status pari a 0, 1, o 2 all’ingresso nello studio.
I 06. I seguenti valori di laboratorio entro 14 giorni prima dell'inizio del farmaco sperimentale o del placebo:
• conta assoluta dei neutrofili (ANC) ≥1,0  109/l
• conta delle piastrine ≥ 50  109/l
• creatinina sierica ≤1,5 volte il limite superiore di normalità (ULN).
• amilasi sierica o lipasi ≤1,5 volte il limite superiore di normalità (ULN).
I 07. Bilirubina diretta ≤2 volte il limite superiore di normalità (ULN).
I 08. Alanina aminotransferasi (ALT) e aspartato aminotransferasi (AST) ≤ 3 volte il limite superiore di normalità; valori più alti (≤ 5 volte il limite superiore di normalità) sono permessi se clinicamente compatibili con ematopoiesi epatica extramidollare.

E.4

Principal exclusion criteria

Splenectomy. Any chemotherapy (eg, hydroxyurea), immunomodulatory drug therapy (eg, thalidomide, interferon-alpha), Anagrelide, immunosuppressive therapy, corticosteroids >10 mg/day prednisone or equivalent, or growth factor treatment (eg, erythropoietin), or hormones (eg, androgens, danazol) within 14 days prior to initiation of IMP or placebo; darbepoetin use within 28 days prior to initiation of IMP or placebo. Patients who have had exposure to hydroxyurea (eg, hydrea) in the past may be enrolled into the study as long as it has not been administered within 14 days prior to initiation of IMP or placebo. Major surgery within 28 days or radiation within 6 months prior to initiation of IMP or placebo. Prior treatment with a Janus Kinase 2 (JAK2) inhibitor.

E 01. Splenectomia.
E 02. Pazienti sottoposti a terapia entro 14 giorni prima dell’inizio del farmaco sperimentale o del placebo con qualsiasi chemioterapico (ad esempio, idrossiurea), con qualsiasi terapia farmacologica immunomodulatoria (ad esempio, talidomide, interferone alfa), anagrelide, terapia immunosoppressiva, con corticosteroidi prednisone o equivalente assunti ad un dosaggio superiore a 10 mg al giorno, o terapia con fattori di crescita (ad esempio, eritropoietina), o ormoni (ad esempio, androgeni, danazolo); darbepoetina utilizzata nei 28 giorni precedenti l’inizio del farmaco sperimentale o del placebo. I pazienti che sono stati esposti all’idrossiurea (ad esempio, Hydrea) in passato possono essere arruolati nello studio se non è stata somministrata nei 14 giorni precedenti l’inizio del farmaco sperimentale o del placebo.
E 03. Pazienti sottoposti a intervento chirurgico importante nei 28 giorni precedenti l’inizio del trattamento in studio o a radioterapia nei 6 mesi precedenti l’inizio del farmaco sperimentale o del placebo.
E 04. Trattamenti precedenti con altri inibitori JAK2.

E.5 End points

E.5.1

Primary end point(s)

Response Rate (RR), defined as the proportion of patients who have a ≥ 35% reduction in volume of spleen size at the end of Cycle 6, and confirmed 4 weeks thereafter

•Tasso di risposta (RR), definita come la percentuale di pazienti che hanno una riduzione del volume della milza ≥ 35% alla fine del ciclo 6, confermata 4 settimane dopo.

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months

6 mesi

E.5.2

Secondary end point(s)

Symptom Response Rate (SRR): Proportion of patients with ≥50% reduction from baseline to the end of Cycle 6 in the total symptom score. This assessment will be conducted through the modified MFSAF diary,which will be completed during the week prior to Day 1 of each treatment cycle up to Cycle 6, at end of Cycle 6, the EOT visit, and the 30-day follow-up visit. OS (overall survival) of either 400 mg/day or 500 mg/day of IMP as compared to placebo. PFS (progression free survival) of either 400 mg/day or 500 mg/day of IMP as compared to placebo. Proportion of patients who have ≥25% reduction in volume of spleen size at end of Cycle 6, and confirmed 4 weeks thereafter. Duration of spleen response, measured by MRI (or CT scan in patients with contraindications for MRI. Safety, as assessed by clinical, laboratory, ECG, and vital sign events; graded by the NCI CTCAE v4.03.

• Tasso di risposta dei sintomi (SRR): percentuale di pazienti con una riduzione ≥ 50% del punteggio totale dei sintomi alla fine del ciclo 6 rispetto al basale. Questa valutazione sarà effettuata attraverso il diario MF-SAF, che sarà completato durante la settimana prima del giorno 1 di ciascun ciclo di trattamento fino al ciclo 6, alla fine del ciclo 6, alla visita di fine trattamento e alla visita di follow-up a 30 giorni.
• Sopravvivenza globale (OS) sia con la dose di 400 mg al giorno, sia con la dose di 500 mg al giorno di farmaco sperimentale in confronto a placebo.
• Sopravvivenza libera da progressione (PFS) sia con la dose di 400 mg al giorno, sia con la dose di 500 mg al giorno di farmaco sperimentale in confronto a placebo.
• Percentuale di pazienti che hanno una riduzione del volume della milza ≥ 25% alla fine del ciclo 6, confermata 4 settimane dopo.
• Durata della risposta della milza, misurata tramite risonanza magnetica (o tramite TAC in pazienti con controindicazioni ad eseguire la risonanza magnetica).
• Tollerabilità, valutata mediante i parametri clinici, di laboratorio, gli ECG e i segni vitali, il cui grado sarà valutato in base ai criteri NCI CTCAE 4.03.

E.5.2.1

Timepoint(s) of evaluation of this end point

6 months to approximately 5 year(s)

da 6 mesi a circa 5 anni

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

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

E.8.1.6

Cross over

Yes

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

Australia

Brazil

Canada

Israel

Korea, Democratic People's Republic of

Mexico

Russian Federation

Singapore

South Africa

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

LPLS

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

Number of subjects for this age range:

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:

112

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

113

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

F.4.2.2

In the whole clinical trial

225

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

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2011-08-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-08-29

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-07-04

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Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
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