Clinical Trials Register

Summary
EudraCT Number:	2010-022243-38
Sponsor's Protocol Code Number:	CNTO136ARA3003
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:	2012-12-11
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

2010-022243-38

A.3

Full title of the trial

A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Study of CNTO 136 (sirukumab), a Human Anti-IL-6 Monoclonal Antibody, Administered Subcutaneously, in Subjects with Active Rheumatoid Arthritis Despite Anti-TNF-Alpha Therapy

Studio multicentrico, randomizzato, in doppio cieco, controllato verso placebo, a gruppi paralleli su CNTO 136 (sirukumab), un anticorpo monoclonale anti-IL6 umano, somministrato per via sottocutanea a soggetti con artrite reumatoide attiva che non rispondono alla terapia anti-TNF alfa

A.3.1

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

A Study of CNTO 136 (sirukumab), a Human Anti-IL-6 Monoclonal Antibody, Administered Subcutaneously, in Patients with Active Rheumatoid Arthritis Despite Anti-TNF-Alpha Therapy

Studio su CNTO 136 (sirukumab), un anticorpo monoclonale (mAb) anti-IL6 umano, somministrato per via sottocutanea (SC) a soggetti con artrite reumatoide attiva che non rispondono alla terapia anti-TNFα

A.4.1

Sponsor's protocol code number

CNTO136ARA3003

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 and Development, LLC
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,
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	31 (0)71 524 21 66
B.5.5	Fax number	31 (0)71 524 21 10
B.5.6	E-mail	ClinicalTrialsEU@its.jnj.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	Sirukumab
D.3.2	Product code	CNTO136
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Sirukumab
D.3.9.2	Current sponsor code	CNTO 136
D.3.9.3	Other descriptive name	Human anti-IL6 monoclonal antibody
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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	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	Yes
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	Anticorpo Monoclonale
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	Sirukumab
D.3.2	Product code	CNTO136
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Sirukumab
D.3.9.2	Current sponsor code	CNTO 136
D.3.9.3	Other descriptive name	Human anti-IL6 monoclonal antibody
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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	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	Yes
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	Anticorpo Monoclonale

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	Solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Rheumatoid Arthritis

Artrite reumatoide

E.1.1.1

Medical condition in easily understood language

Active rheumatoid arthritis despite anti-TNF-alpha therapy

Artrite reumatoide attiva che non risponde alla terapia anti-TNF alfa

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10039073
E.1.2	Term	Rheumatoid arthritis
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue 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 efficacy of sirukumab as measured by the reduction of the signs and symptoms of RA in subjects with active RA who are refractory to an anti-TNF alpha agent.

Valutare l'efficacia di sirukumab mediante misurazione della riduzione dei segni e sintomi di Artrite Reumatoide nei pazienti con Artrite Reumatoide attiva che sono refrattari all'agente anti-TNF alfa

E.2.2

Secondary objectives of the trial

The secondary objectives are to assess the following for sirukumab in subjects with active RA who are refractory to anti-TNF alpha agents: -Safety -Physical function -Population pharmacokinetics -Immunogenicity -Pharmacodynamics

Valutare nei pazienti con Artrite Reumatoide attiva che sono refrattari agli agenti anti-TNF alfa i seguenti punti: - Sicurezza; - Funzione fisica; - Popolazione farmacocinetica; - Immunogenicità; - Farmacodinamica

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

OTHER SUBSTUDIES:
The goal of the pharmacogenetics component is to collect DNA to allow the identification of genetic factors that may influence the pharmacokinetics, pharmacodynamics, efficacy, or tolerability of sirukumab and to identify genetic factors associated with RA. DNA samples may be used to help address emerging issues and to enable the development of safer, more effective, and ultimately individualized therapies.

ALTRI SOTTOSTUDI:
Raccogliere il DNA per permettere l'identificazione dei fattori genetici che possono influenzare la farmacocinetica, farmacodinamica, efficacia, o tollerabilità di sirukumab e per [v. protocollo]

E.3

Principal inclusion criteria

- Have a diagnosis of rheumatoid arthritis (RA) for at least 3 months before screening - Have moderately to severely active RA with at least 4 of 68 tender joints and 4 of 66 swollen joints, at screening and at baseline - Have had anti-tumor necrosis factor (TNF)-alpha therapy and were unresponsive by 1 of the following 2 reasons: Lack of benefit to at least 1 anti-TNF-alpha biologic therapy, as assessed by the treating physician, after at least 12 weeks of etanercept, yisaipu, adalimumab, golimumab,or certolizumab pegol therapy and/or at least a 14-week dosage regimen (ie, at least 4 doses) of infliximab; Intolerance to at least 2 anti-TNF-alpha biologic therapies, as assessed by the treating physician, to etanercept, yisaipu, adalimumab, golimumab, certolizumab pegol, or infliximab or have documented intolerance to an anti-TNF-alpha agent as described above that precludes further administration of anti-TNF-alpha agents - If using oral corticosteroids, must be on a stable dose equivalent to <=10 mg/day of prednisone for at least 2 weeks prior to the first administration of study agent. If currently not using corticosteroids, must not have received oral corticosteroids for at least 2 weeks prior to the first administration of study agent - If using non nonsteroidal anti-inflammatory drug (NSAIDs) or other analgesics for RA, must be on a stable dose for at least 2 weeks prior to the first administration of study agent - If using non-biologic DMARDs such as methotrexate (MTX), sulfasalazine (SSZ), hydroxychloroquine, chloroquine, or bucillamine, must be on a stable dose for at least 4 weeks prior to the first administration of study agent and should have no serious toxic side effects attributable to the DMARD - C-reactive protein (CRP) >= 8.00 mg/L at screening

- Diagnosi di artrite reumatoide (AR) da almeno 3 mesi prima dello screening - AR in fase attiva da moderata a grave con almeno 4 articolazioni dolenti su 68 e 4 articolazioni tumefatte su 66, allo screening e al basale - Assenza di risposta alla terapia antifattore di necrosi tumorale (TNF)-alfa per 1 dei 2 motivi seguenti: mancanza di beneficio in seguito ad almeno 1 terapia con agenti biologici anti-TNF-alfa, in base alla valutazione del medico curante, dopo almeno 12 settimane di trattamento con etanercept, yisaipu, adalimumab, golimumab o certolizumab pegol e/o almeno 14 settimane (ovvero almeno 4 dosi) di infliximab; intolleranza ad almeno 2 terapie con agenti biologici anti-TNF-alfa, in base alla valutazione del medico curante, tra cui etanercept, yisaipu, adalimumab, golimumab, certolizumab pegol o infliximab o intolleranza documentata a un agente anti-TNF-alfa tra quelli appena descritti che preclude la somministrazione di altri agenti anti-TNF-alfa - Se è in atto un trattamento con corticosteroidi orali, la dose deve essere stabile ed equivalente a ≤ 10 mg/die di prednisone da almeno 2 settimane prima della prima somministrazione del farmaco in studio. In caso contrario, un eventuale trattamento con corticosteroidi orali non deve iniziare nelle 2 settimane precedenti la prima somministrazione del farmaco in studio - L’eventuale assunzione di farmaci antinfiammatori non steroidei (FANS) o altri analgesici per l’AR deve avvenire a una dose stabile da almeno 2 settimane precedenti la prima somministrazione del farmaco in studio - L’eventuale assunzione di antireumatici (DMARD) non biologici come metotrexato (MTX), sulfasalazina (SSZ), idrossiclorochina, clorochina o bucillamina deve avvenire a una dose stabile da almeno 4 settimane prima della prima somministrazione del farmaco in studio e non essere associata a effetti indesiderati tossici seri - Livelli di proteina C-reattiva (PCR) ≥ 8,00 mg/L allo screening

E.4

Principal exclusion criteria

- Has received infliximab, golimumab, adalimumab, certolizumab pegol, etanercept, or yisaipu within 3 months of the first study agent administration - Has a history of intolerance to tocilizumab that precluded further treatment with it, or inadequate response to 3 months of tocilizumab (anti-IL-6 receptor) therapy - Has used B-cell-depleting therapy (eg, rituximab) within 7 months of first study agent administration or have evidence during screening of abnormally low B-cell level caused by previous B-cell depletion therapy - Has used anakinra within 4 weeks of first study agent administration - Has used any other biologic therapy for the treatment of RA within 8 weeks of the first study agent administration - Has received intra-articular (IA), intramuscular (IM), or intravenous (IV) corticosteroids for RA, including adrenocorticotrophic hormone during the 4 weeks prior to first study agent administration - Has received leflunomide within 24 months before the first study agent administration and has not undergone a drug elimination procedure, unless the M1 metabolite is measured and is undetectable - Has a history of cyclophosphamide or cytotoxic agent use - Has received cyclosporine A, azathioprine, tacrolimus, mycophenolate mofetil, oral or parenteral gold, or D-penicillamine within 4 weeks of the first study agent administration - Has received an investigational drug (including investigational vaccines) or used an investigational medical device within 3 months or 5 half lives, whichever is longer, before the first study agent administration

- Terapia a base di infliximab, golimumab, adalimumab, certolizumab pegol, etanercept o yisaipu nei 3 mesi precedenti la prima somministrazione del farmaco in studio - Storia di intolleranza a tocilizumab, che ha precluso la continuazione del trattamento, o risposta inadeguata a 3 mesi di terapia con tocilizumab (recettore dell’anti-IL6) - Terapia di deplezione delle cellule B (p.es. rituximab) nei 7 mesi precedenti la prima somministrazione del farmaco in studio o evidenze, durante lo screening, di livelli di cellule B particolarmente bassi causati da una precedente terapia di deplezione delle cellule B - Uso di anakinra nelle 4 settimane precedenti la prima somministrazione del farmaco in studio - Uso di qualsiasi altra terapia biologica per il trattamento dell’AR nelle 8 settimane precedenti la prima somministrazione del farmaco in studio - Uso di corticosteroidi per via intrarticolare (IA), intramuscolare (IM) o endovenosa (EV) per l’AR, incluso l’ormone adrenocorticotropo, nelle 4 settimane precedenti la prima somministrazione del farmaco in studio - Assunzione di leflunomide nei 24 mesi precedenti la prima somministrazione del farmaco in studio senza seguire la procedura per l’eliminazione del farmaco, salvo dalla misurazione del metabolita M1 non risultino livelli rilevabili - Precedente assunzione di ciclofosfamide o di un agente citotossico - Assunzione di ciclosporina A, azatioprina, tacrolimus, micofenolato mofetile, sali d’oro per via orale o parenterale o D-penicillamina nelle 4 settimane precedenti la prima somministrazione del farmaco in studio - Trattamento con un farmaco sperimentale (inclusi i vaccini sperimentali) o uso di un dispositivo medico sperimentale nei 3 mesi o nelle 5 emivite, a seconda di quale periodo sia più lungo, precedenti la prima somministrazione del farmaco in studio

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients with an ACR 20 response

Percentuale di pazienti che raggiungono una risposta secondo i criteri ACR 20

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 16

Settimana 16

E.5.2

Secondary end point(s)

1. Change from baseline in HAQ-DI 2. Proportion of patients with an ACR 50 response 3. Proportion of patients with DAS28 (CRP) remission

1. Variazione nel punteggio HAQ-DI rispetto al basale 2. Percentuale di soggetti che presentano una risposta secondo i criteri ACR 50 3. Percentuale di soggetti che presentano una remissione in base al punteggio DAS28 (CRP)

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Week 24 2. Week 24 3. Week 24

1. Settimana 24 2. Settimana 24 3. Settimana 24

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

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

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

Argentina

Australia

Brazil

Canada

China

Croatia

Japan

Korea, Republic of

Taiwan

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

The study will end when the last subject completes the Week 52 visit and transitions into the LTE study OR completes 16 Weeks safety follow-up after the last study agent administration, whichever is later.

Quando l'ultimo soggetto completerà la visita alla settim 52 e passerà allo studio LTE oppure completerà il follow-up di sicurezza alla settim 16 dopo la somministrazione dell'ultima dose di farmaco, a seconda di quale delle due si verifichi dopo.

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:

864

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

126

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

296

F.4.2.2

In the whole clinical trial

990

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)

Subjects for whom CNTO 136 is effective can continue in a long term extension study upon completion of the CNTO136ARA3002 study (week 52) and can be treated for a maximum total duration of 5 years after which the therapy may be commercially available in their country

I pazienti che trarranno giovamento dal trattamento con CNTO 136, potranno entrare a far parte dello studio di estensione a lungo termine dopo il completmento dello studio CNTO136ARA3002 (settimana 52) e potranno essere trattati per una durata massima di 5 anni, dopo i quali la terapia potrebbe essere commercializzata nella loro nazione di appartenenza.

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

2012-11-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-10-19

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-01-12

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IMP with orphan designation in the indication
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