Clinical Trials Register

Summary
EudraCT Number:	2011-000261-12
Sponsor's Protocol Code Number:	CNTO328MDS2001
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2011-07-01
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

2011-000261-12

A.3

Full title of the trial

A Phase 2, Randomized, Double-blind, Placebo-controlled, Multicenter
Study Comparing Siltuximab Plus Best Supportive Care to Placebo Plus
Best Supportive Care in Anemic Subjects with International Prognostic
Scoring System Low- or Intermediate-1-Risk Myelodysplastic Syndrome

Ensayo fase 2, multicéntrico, aleatorizado, doble ciego y controlado con placebo para comparar siltuximab más la mejor terapia de soporte con placebo más la mejor terapia de soporte en sujetos anémicos con síndrome mielodisplásico de riesgo bajo o intermedio-1 conforme al sistema de clasificación IPSS (International Prognostic Scoring System)

A.3.1

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

A.4.1

Sponsor's protocol code number

CNTO328MDS2001

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	Janssen-Cilag International N.V.
B.1.3.4	Country	Belgium
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	Janssen Research & Development
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	Janssen-Cilag International N.V.
B.5.2	Functional name of contact point	Clinical Registry Group
B.5.3	Address:
B.5.3.1	Street Address	Janssen Biologics BV - Clinical Registry Group, Archimedesweg, 29
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333CM
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	..31 071 524 21 66.
B.5.5	Fax number	..31 071 524 21 10.
B.5.6	E-mail	ClinicalTrialsEU@jnj.its.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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Siltuximab
D.3.2	Product code	CNTO328
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Siltuximab
D.3.9.2	Current sponsor code	CNTO328
D.3.9.3	Other descriptive name	Anti IL-6 quimérico múrido-humano
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	400
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Yes
D.3.11.13.1	Other medicinal product type	Anticuerpo monoclonal

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	Powder for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Anemia associated with Low- or Intermediate-1-Risk Myelodysplastic
Syndrome

Tratamiento de la anemia asociada a síntrome mielodisplástico de riesgo Bajo o Intermedio-1

E.1.1.1

Medical condition in easily understood language

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
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.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10002272
E.1.2	Term	Anemia
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

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 is to assess the clinical efficacy of siltuximab,
demonstrated by a reduction in RBC transfusions to treat the anemia of
MDS.

El objetivo principal es evaluar la eficacia clínica del siltuximab, demostrada por una reducción de las transfusiones de eritrocitos para tratar la anemia asociada al SMD.

E.2.2

Secondary objectives of the trial

• To demonstrate symptomatic improvement of subjects treated with
siltuximab compared with the placebo group
• To compare the number of RBC units transfused to treat the anemia of
MDS, and the proportion of subjects treated with siltuximab who do not
require a RBC transfusion to treat the anemia of MDS, from Week 5 to
Week 12, compared with the placebo group
• To assess the change in hemoglobin among MDS subjects treated with
siltuximab compared with the placebo group
• To compare disease progression (proportion of bone marrow blasts
and cytogenetic change) for subjects treated with siltuximab compared
with the placebo group
• To assess the safety profile of siltuximab and RBC transfusions among
subjects with Low- or Intermediate-1 (INT-1)-risk MDS
• To assess the pharmacodynamics, pharmacokinetics, and antibodies
to siltuximab (immunogenicity) in MDS subjects
•See protocol for additional objectives

Demostrar mejoría síntomas de sujetos con siltuximab frente a placebo. Comparar el nº unidades de eritrocitos transfundidas para tratar anemia asociada a SMD y proporción sujetos en siltuximab que no precisan transfusión de eritrocitos para tratar la anemia asociada al SMD, entre Semanas 5 y 12, frente a placebo. Cambio de hemoglobina en sujetos con SMD tratados con siltuximab y placebo. Comparar progresión enfermedad (%blastocitos en médula ósea y cambio citogenético) en sujetos con siltuximab frente a placebo. Evaluar perfil seguridad de siltuximab y de las transfusiones de eritrocitos en sujetos con SMD de riesgo Bajo o INT-1. Evaluar PD, PK y anticuerpos contra siltuximab (inmunogenia) en sujetos SMD. Investigar perfil de biomarcadores que pronostique la respuesta al siltuximab en sujetos SMD. Realizar validación inicial de encuesta de pacientes (NCA-SS). Evaluar utilización de recursos y productividad.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. At least 18 years of age (or the legal age of consent in the jurisdiction
in which the study is taking place)
2. Confirmed diagnosis of MDS, according to WHO or FAB pathologic
classification, with an IPSS score 0, 0.5, or 1.0, indicating Low- or INT-1-
risk disease. Subjects with 5q- or PDGFR gene mutations are eligible if
they are intolerant to or have failed prior specific therapy (eg,
lenalidomide and imatinib mesylate).
3. Documented RBC transfusion of at least 2 units of RBC for the
treatment of the anemia of MDS in the 8 weeks preceding the start of the
Screening Period.
4. Adequate iron stores, demonstrated by either the presence of
stainable iron in the bone marrow or a serum ferritin of > 100 ng/mL
5. ECOG performance status score of 0 to 2
6. Symptomatic anemia (defined by a score > 0 on the NCA-SS).
7. Women of childbearing potential must agree to use adequate birth
control measures during the study and for 3 months after receiving the
last dose of study agent, and have a negative serum or urine beta human
chorionic gonadotropin (beta hCG) pregnancy test at screening. Men
must agree to use a double barrier method of birth control and to not
donate sperm during the study and for 3 months after receiving the last
dose of study agent
8.Be willing and able to adhere to the prohibitions and restrictions
specified in this protocol
9.Sign (or their legally acceptable representatives must sign) an
informed consent document indicating that they understand the purpose
of and procedures required for the study and are willing to participate in
the study.

1. Al menos 18 años de edad (o la edad legal para consentir en la jurisdicción donde se esté llevando a cabo el estudio).
2. Diagnóstico confirmado de SMD, según la clasificación anatomopatológica FAB o de la OMS, con una puntuación IPSS de 0, 0,5 o 1,0, que indica una enfermedad de riesgo bajo o INT-1. Los sujetos con mutaciones génicas de 5q o PDGFR podrán participar si presentan intolerancia o no han respondido a un tratamiento específico previo (por ejemplo, lenalidomida y mesilato de imatinib).
3. Transfusión documentada de al menos 2 unidades de eritrocitos para el tratamiento de la anemia asociada al SMD en las 8 semanas previas al comienzo del período de selección.
4. Depósitos de hierro suficientes, confirmados por la presencia de hierro tingible en la médula ósea o un valor de ferritina sérica > 100 ng/ml.
5. Puntuación de capacidad funcional del ECOG entre 0 y 2.
6. Anemia sintomática (definida por una puntuación > 0 en el cuestionario NCA-SS).
7. Las mujeres con capacidad reproductiva deben comprometerse a utilizar métodos anticonceptivos adecuados durante el estudio y durante los 3 meses siguientes a la última dosis del fármaco del estudio y tener un resultado negativo de una prueba de embarazo basada en la subunidad beta de la gonadotropina coriónica humana (β-hCG) en suero u orina en la visita de selección. Los varones deberán comprometerse a utilizar un método anticonceptivo de doble barrera y a no donar semen durante el estudio y durante 3 meses después de recibir la última dosis del fármaco del estudio.
8. Ser capaz y estar dispuesto a cumplir las prohibiciones y restricciones especificadas en este protocolo.
9. Los sujetos (o sus representantes legales) deben firmar un documento de consentimiento informado que indique que entienden el objetivo del estudio y los procedimientos que exige y que están dispuestos a participar en él.

E.4

Principal exclusion criteria

1.Had treatment with ESAs, androgens, hypomethylating agents,
immunomodulatory drugs (IMiDs), or other agents targeting IL-6 or its
receptor within 4 weeks of randomization
2.Any condition that, in the opinion of the investigator, would make
participation not be in the best interest (eg, compromise the well-being)
of the subject or that could prevent, limit, or confound the
protocolspecified
assessments (eg, has a history of clinically significant,
uncontrolled disease of the pulmonary, cardiovascular, endocrine,
neurologic, gastrointestinal, or genitourinary systems that is not
attributable to MDS). Subjects with Chronic Myelomonocytic Leukemia
(CMML) are to be excluded from the study.
3.Causes other than MDS contributing to anemia, such as Vitamin B12 or
folate deficiency, bleeding, hemolysis, hemoglobinopathy, or chronic
renal failure
4.Known unmanageable allergies, hypersensitivity, or intolerance to
monoclonal antibodies or to murine, chimeric, or human proteins or their
excipients
5.A history of seropositivity for human immunodeficiency virus (HIV),
hepatitis B virus (HBV), or hepatitis C virus (HCV) (Note: HBV
antibodypositivity
is not a reason for exclusion from the study)
6.Received an investigational drug (including investigational vaccines)
or used an invasive investigational medical device within 30 days or 5
half lives before randomization or is currently enrolled in an
investigational study
7.Had a modification of an effective preexisting therapy for the explicit
purpose of entering the study.
8.Is a woman who is pregnant, or breast-feeding, or planning to become
pregnant or is a man who plans to father a child while enrolled in this study or within 12 weeks after the last dose of study agent
9.Had hospitalization for infection or major surgery, (eg, requiring
general anesthesia) within 2 weeks before randomization or will not
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have fully recovered from surgery.
Note: subjects with planned surgical procedures to be conducted under
local anesthesia may participate
10.Been vaccinated with live, attenuated vaccines within 4 weeks of
randomization
11.Has clinically significant laboratory abnormalities:
•Platelets < 20 x 109/L
•Estimated glomerular filtration rate (eGFR) <=20 mL/min
•Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≥
2.5 x upper limit of normal (ULN)
•Bilirubin > 2.5 x ULN
•Alkaline phosphatase ≥ 3 x ULN
12.Is an employee of the investigator or study site, with direct
involvement in the proposed study or other studies under the direction
of that investigator or study site, as well as family members of the
employees or the investigator
NOTE: Investigators should ensure that all study enrollment criteria
have been met at screening. If a subject's status (including laboratory
results) changes after screening but before the first dose of study agent
is given such that they now meet an exclusion criterion, then they should
be excluded from participation in the study.

1. Ha recibido tratamiento con FEE (fármacos estimuladores de la eritropoyesis), andrógenos, fármacos hipometilantes, fármacos inmunomoduladores (FIM) u otros fármacos que actúen sobre la IL 6 o su receptor en las 4 semanas previas a la aleatorización.
2. Cualquier condición que, a juicio del investigador, haría que la participación en el estudio no fuera lo mejor (por ejemplo, compromiso del bienestar) para el paciente o que podría impedir, limitar o generar confusión en las evaluaciones especificadas en el protocolo (por ejemplo, antecedentes de enfermedad clínicamente significativa e incontrolada de los sistemas pulmonar, cardiovascular, endocrino, nervioso, digestivo o aparato genitourinario no atribuible al SMD). Los sujetos con leucemia mielomonocítica crónica (LMMC) deben ser excluidos del estudio.
3. Causas distintas del SMD que contribuyen a la anemia, como el déficit de vitamina B12 o folato, hemorragia, hemólisis, hemoglobinopatía o insuficiencia renal crónica.
4. Alergias, hipersensibilidad o intolerancia conocidas y no controlables a anticuerpos monoclonales, a proteínas múridas, quiméricas o humanas o a sus excipientes.
5. Antecedentes de seropositividad para el virus de la inmunodeficiencia humana (VIH), el virus de la hepatitis B (VHB) o el virus de la hepatitis C (VHC). (Nota: la positividad para anticuerpos contra el VHB no es motivo de exclusión del estudio).
6. Haber recibido un fármaco experimental (incluidas las vacunas experimentales) o haber utilizado un producto sanitario experimental invasivo en los 30 días o 5 semividas previos a la aleatorización o participar actualmente en un estudio de investigación.
7. Haber modificado un tratamiento previo eficaz con la finalidad expresa de participar en el estudio.
8. Ser una mujer que está embarazada, esta amamantando o tiene intención de quedarse embarazada o es un varón que planea tener un hijo durante su participación en este estudio o en las 12 semanas siguientes a la última dosis del fármaco del estudio.
9. Haber sido hospitalizado a causa de una infección o cirugía mayor (por ejemplo, con necesidad de anestesia general) en las 2 semanas previas a la aleatorización o no habrerse recuperado totalmente de la cirugía.
Nota: podrán participar los sujetos con intervenciones quirúrgicas programadas que se llevarán a cabo bajo anestesia local.
10. Haber sido vacunado con vacunas de virus vivos atenuados durante las 4 semanas previas a la aleatorización.
11. Presentar anomalías analíticas clínicamente significativas:
Plaquetas < 20 x 109/l
Índice de filtración glomerular estimado (IFGe) 20 ml/min
Aspartato-aminotransferasa (AST)/alanina-aminotransferasa (ALT) 2,5 x límite superior de la normalidad (LSN)
Bilirrubina > 2,5 x LSN
Fosfatasa alcalina 3 x LSN
12. Ser empleado del investigador o del centro de estudio con participación directa en el estudio propuesto o en otros bajo la dirección de ese investigador o centro de estudio, así como los familiares de los empleados o del investigador.

E.5 End points

E.5.1

Primary end point(s)

Proporción de sujetos que consigan una reducción de transfusiones.Se evaluará en un intervalo de 8 semanas, de la 5 a la 12. Los criterios secundarios: valoracón de hemoglobina(en la semana 12) , examen aspirado médula (en la Semana 13 y cada 24 semanas durante el tratamiento) y valoración de síntomas de la anémia (a diario durante 12 semanas, depues mensual para el resto del periodo de tratamiento).

E.5.1.1

Timepoint(s) of evaluation of this end point

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

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

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

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

Yes

E.8.1.7.1

Other trial design description

Abierto,continua hasta fallecimiento,aparición toxicidad inaceptable,retirada CI o limite clinico

Open; study will continue until death, unacceptable toxicity, withdraw

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

Belgium

Netherlands

Russian Federation

Spain

Sweden

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

El limite clínico es 24 semanas después de la aleatorización del último paciente. El fin del estudio se alcanzará 36 semanas después de la aleatorización 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

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