Clinical Trials Register

Summary
EudraCT Number:	2007-000872-18
Sponsor's Protocol Code Number:	WA18221
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2008-02-14
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

Germany - PEI

A.2

EudraCT number

2007-000872-18

A.3

Full title of the trial

A 12-week randomized, double blind, placebo-controlled, parallel group, 2-arm study to evaluate the efficacy and safety of tocilizumab in patients with active systemic juvenile idiopathic arthritis (sJIA); with a 92-week single arm open-label extension to examine the long term use of tocilizumab, followed by a 3 year open label continuation of the study to examine the long term use of tocilizumab.

A.3.1

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

The effect of tocilizumab in children who have arthritis which can include fever, rash, inflammation of the lungs or heart, or enlarged spleen, liver or lymph nodes.

A.3.2

Name or abbreviated title of the trial where available

TENDER

A.4.1

Sponsor's protocol code number

WA18221

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00642460

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/71/2010

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	F. Hoffmann-La Roche Ltd.
B.1.3.4	Country	Switzerland
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	F. Hoffmann-La Roche Ltd
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	F. Hoffmann-La Roche Ltd.
B.5.2	Functional name of contact point	Trial Information Support Line-TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.6	E-mail	global.rochegenentechtrials@roche.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	Yes
D.2.1.1.1	Trade name	RoActemra
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration 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	RoActemra
D.3.2	Product code	RO4877533 (TCZ)
D.3.4	Pharmaceutical form	Concentrate 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	tocilizumab
D.3.9.1	CAS number	375823-41-9
D.3.9.2	Current sponsor code	RO4877533
D.3.9.3	Other descriptive name	IL-6 receptor inhibitor, recombinant humanized 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	20
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	IL-6 receptor inhibitor, recombinant humanized 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	Concentrate 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

Systemic Juvenile Idiopathic Arthritis (sJIA)

E.1.1.1

Medical condition in easily understood language

Children with sJIA have arthritis and often have daily fever with rash, in addition to inflammation of the lining of the lung or heart, liver or spleen enlargement, or enlargement of the lymph nodes.

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

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	10059176
E.1.2	Term	Juvenile idiopathic arthritis
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

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

Part I: Primary Objectives:
1. To assess the efficacy of tocilizumab versus placebo in combination with stable ongoing therapy, with regard to signs and symptoms in sJIA patients with persistent activity and an inadequate response to NSAIDs and systemic corticosteroids.
2. To evaluate the short term safety of tocilizumab versus placebo in combination with stable ongoing therapy, with regard to adverse events and laboratory assessments in patients with sJIA with persistent activity and an inadequate response to NSAIDs and corticosteroids.
Part II: Primary Objectives:
1. To evaluate the safety of tocilizumab in chronic administration;
2. To assess the effect of tocilizumab to enable the reduction or elimination of corticosteroids
Part III: Primary Objectives
1. To assess the long-term safety of 8 mg/kg tocilizumab in children > 30 kg and 12 mg/kg tocilizumab in children < 30 kg with regard to adverse events and laboratory result abnormalities;

E.2.2

Secondary objectives of the trial

Part I
1. To assess the efficacy of tocilizumab versus placebo in combination with stable ongoing therapy, with regard to common systemic features in sJIA patients with persistent activity and an inadequate response to NSAIDs and corticosteroids;
2. To assess the efficacy of treatment with tocilizumab to permit concomitant corticosteroid reduction;
Part II
1. To assess the durability and magnitude of the tocilizumab efficacy response in patients with sJIA including meeting the definition of inactive disease and clinical remission;
2. To assess the efficacy of treatment with tocilizumab to permit concomitant medication reductions;
Part III:
1. To assess the efficacy of treatment with tocilizumab to permit concomitant medication reductions (corticosteroids, methotrexate, NSAIDs);

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• patients aged 2 - 17 years of age;
• systemic JIA with >= 6 months persistent activity;
• presence of active disease (>=5 active joints, or >=2 active joints + fever + steroids);
• inadequate clinical response to NSAIDs and corticosteroids due to toxicity or lack of efficacy.

E.4

Principal exclusion criteria

• wheelchair bound or bed-ridden;
• any other autoimmune, rheumatic disease or overlap syndrome other than sJIA;
• intravenous long-acting corticosteroids or intra-articular corticosteroids within 4 weeks of baseline, or throughout study;
• DMARDs (other than methotrexate);
• previous treatment with tocilizumab.

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint:
The proportion of patients with at least 30% improvement in JIA
core set (JIA ACR30 response) at week 12 (JIA Core Set assessed
in comparison to baseline) and absence of fever*
*Absence of fever is defined as no temperature measurement ≥ 37.5° C.
in the preceding seven days

E.5.1.1

Timepoint(s) of evaluation of this end point

week 12

E.5.2

Secondary end point(s)

Proportion of patients with JIA core set ACR 30/50/70/90 response [ Time Frame: Week 12 ]
Mean percent change in JIA core set ACR score [ Time Frame: Week 12 ]
Proportion of patients with fever [ Time Frame: Week 12 ]
Change in laboratory indicators (hsCRP, Hb, platelets, leukocytes) [ Time Frame: Week 12 ]
Concomitant corticosteroid reduction [ Time Frame: Week 12 ]
Immunogenicity: anti-tocilizumab antibodies (HAHA) [ Time Frame: 260 weeks ]
Pharmacokinetics/Pharmacodynamics: tocilizumab, Interleukin-6 (IL-6), sIL-6R [ Time Frame: 260 weeks ]
Concomitant medication reduction (corticosteroids, methotrexate, NSAIDs) [ Time Frame: 260 weeks ]
Duration of response (inactive disease, clinical remission) [ Time Frame: 260 weeks ]

E.5.2.1

Timepoint(s) of evaluation of this end point

week 12 / week 260

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)

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

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

Information not present in EudraCT

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

Belgium

Brazil

Canada

Czech Republic

Germany

Greece

Italy

Mexico

Netherlands

Norway

Poland

Slovakia

Spain

United Kingdom

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 end of the study will occur when the last participating patient completes the last scheduled visit of Part III, or when the sponsor decides to discontinue the development
program.

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

Yes

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

The study will recruit paediatric patients form the age of 2 years old. Written informed consent for study participation will be obtained from parents or legal guardian depending on the level of the patient’s understanding.

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

108

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)

If tocilizumab is not commercially available for sJIA when the study is completed, arrangements will be made to continue to supply tocilizumab to the patients unless the sponsor decides to discontinue the development program for tocilizumab.

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	PRINTO
G.4.3.4	Network Country	Italy
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	PRCSG
G.4.3.4	Network Country	United States

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2008-05-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-07-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-08-05

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