Clinical Trials Register

Summary
EudraCT Number:	2011-000261-12
Sponsor's Protocol Code Number:	CNTO328MDS2001
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-08-31
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

Netherlands - Competent Authority

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

A.3.1

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

A 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

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	31071 524 21 66
B.5.5	Fax number	31071524 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	Chimeric murine human anti-IL-6
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	monoclonal antibody

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

E.1.1.1

Medical condition in easily understood language

Myelodysplastic Syndrome

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.

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

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.

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.

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients achieving a reduction in RBC transfusions

E.5.1.1

Timepoint(s) of evaluation of this end point

8 week period from week 5 to week 12

E.5.2

Secondary end point(s)

1. Hemoglobin Assessment
2. Bone Marrow Examination
3. Anemia Symptom Assessment

E.5.2.1

Timepoint(s) of evaluation of this end point

1. At Week 12
2. At Week 13 and every 24 weeks during treatment
3. Daily for 12 weeks, then monthly for remainder of treatment period

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

Open; study will continue until death, unacceptable toxicity, withdraw consent, or clinical cutoff

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

Clinical cut-off is 24 weeks after the last patient has been randomized.
Study end is 36 weeks after the last patient has been randomized.

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