Clinical Trials Register

Summary
EudraCT Number:	2005-002423-13
Sponsor's Protocol Code Number:	WA18695
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:	2005-11-04
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

2005-002423-13

A.3

Full title of the trial

Long-term extension study of safety during treatment with tocilizumab (MRA) in patients completing treatment in WA 17822

Studio di estensione sulla sicurezza a lungo termine del trattamento con MRA nei pazienti che hanno completato lo studio WA17822

A.3.1

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

Long-term extension study of safety during treatment with tocilizumab (MRA) in patients completing treatment in WA 17822

Studio di estensione sulla sicurezza a lungo termine del trattamento con MRA nei pazienti che hanno completato lo studio WA17822

A.4.1

Sponsor's protocol code number

WA18695

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	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	Roche S.p.A.
B.5.2	Functional name of contact point	E.A.T.U.
B.5.3	Address:
B.5.3.1	Street Address	Viale G. B. Stucchi, 110
B.5.3.2	Town/ city	Monza
B.5.3.3	Post code	20900
B.5.3.4	Country	Italy
B.5.5	Fax number	+39 (0)39 247 5085
B.5.6	E-mail	italy.info_cta@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	United Kingdom
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.3.4	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	RoActemra
D.3.9.1	CAS number	375823-41-9
D.3.9.2	Current sponsor code	Ro 487-75333
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	200
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	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

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.1.1.2

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

To assess the long-term safety of 8 mg/kg tocilizumab (MRA) with regard to adverse events and laboratory result abnormalities

Verificare la sicurezza a lungo termine di 8 mg/kg di tocilizumab (MRA) riguardo ad eventi avversi e ad anormalita` dei parametri di laboratorio

E.2.2

Secondary objectives of the trial

To explore the possibility of reducing concomitant steroid treatment To determine the long-term efficacy of 8 mg/kg tocilizumab (MRA) with regard to reduction in signs and symptoms To better understand and predict tocilizumab (MRA) efficacy, response, safety, progression of RA and associated diseases with regard to its effect on biomarkers

Esplorare la possibilita` di ridurre il trattamento concomitante con gli steroidi Determinare l efficacia a lungo termine di 8 mg/kg di tocilizumab (MRA) riguardo alla riduzione dei segni e dei sintomi Capire meglio e prevedere l efficacia,la risposta e la sicurezza di MRA sulla progressione dell AR e delle malattie ad essa associate e i suoi effetti sui marcatori biologici

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Completion of 24 weeks of treatment with tocilizumab (MRA) in WA17822, and scheduled to receive the first tocilizumab (MRA) infusion in WA18695 between 4 and 12 weeks after the last iv infusion in WA17822. Patients that are prevented from enrollment prior to 12 weeks after the last iv infusion in WA17822 due to administrative delays outside of the control of the investigator and upon discussion with Roche may be included if they meet all other inclusion criteria, but will undergo a separate analysis of the study results. 2) Able and willing to give written informed consent and comply with the requirements of the study protocol. 3) Have received methotrexate at a stable dose of between 10 and 25 mg/week (p.o. or parenteral) since the last administration of study drug in WA17822. 4) Oral corticosteroids (≤10 mg/day prednisone or equivalent) and NSAIDS (up to the maximum recommended dose) are permitted if dose stable since the last administration of study drug in WA17822. 5) Must be willing to receive oral folate (at least 5 mg/week). 6) Females of child-bearing potential and males with female partners of childbearing potential may participate in this trial only if using a reliable means of contraception (e.g. physical barrier (patient and partner), contraceptive pill or patch, spermicide and barrier, or IUD). 7) If female and of child-bearing potential, the patient must have a negative urine pregnancy test at baseline.

E.4

Principal exclusion criteria

1) Treatment with any investigational agent since the last administration of study drug in WA17822. 2) Previous treatment with any cell depleting therapies, including investigational agents (e.g. CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19 and anti-CD20) 3) Treatment with iv gamma globulin, plasmapheresis or Prosorba column since the last administration of study drug in WA17822. 4) Treatment with an anti-TNF or anti-IL1 agent, or a T-cell costimulation modulator since the last administration of study drug in WA17822. 5) Parenteral, intramuscular or intra-articular corticosteroids within 6 weeks prior to baseline in WA18695. 6) Immunization with a live/attenuated vaccine since the last administration of study drug in WA17822. 7) Any previous treatment with alkylating agents such as cyclophosphamide or chlorambucil, or with total lymphoid irradiation. 8) History of severe allergic or anaphylactic reaction to human, humanized or murine monoclonal antibodies. 9) Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (incl. obstructive pulmonary disease), renal, hepatic, endocrine (incl. uncontrolled diabetes mellitus), immunologic or gastrointestinal disease; history of diverticulitis, diverticulosis requiring antibiotic treatment or chronic ulcerative lower GI disease such as Crohn s disease, ulcerative colitis or other symptomatic lower GI conditions that might predispose to perforations for whom a favourable benefit/risk assessment for study continuation cannot be documented. 10) Known active or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis and atypical mycobacterial disease, clinically significant abnormalities on chest X-ray as determined by the investigator, HIV, hepatitis B and C, and Herpes zoster, but excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with iv antibiotics within four weeks prior to baseline or oral antibiotics within two weeks prior to baseline. 11) Evidence of active malignant disease, malignancies diagnosed within the previous 10 years (including hematological malignancies and solid tumors, except basal cell carcinoma of the skin that has been excised and cured), or breast cancer diagnosed within the previous 20 years. 12) Patients whose AST or ALT ≥ 3 times ULN, bilirubin > 2 times ULN or > 2.5 mg/dL (43 umol/L), neutrophils < 1000/mm3 (1 x 103 /uL or 1 GI/L), or who have an infection.

E.5 End points

E.5.1

Primary end point(s)

The safety of tocilizumab (MRA) with regard to adverse events and laboratory result abnormalities. Concomitant steroid treatment will be summarized by visit. Number of patients who withdraw from treatment. The proportion of patients achieving an ACR20, ACR50 and ACR70 response by visit. The proportion of patients who maintain an ACR20,ACR50 or ACR70 response consecutively for 24, 48, 96 and 264 weeks. The individual components of the ACR core set will be summarized by visit. Change in Disease Activity Score (DAS28) from baseline to weeks 24, 48, 96 and 264. The proportion of patients who are categorical DAS28 responders (EULAR response) at 24, 48, 96 and 264 weeks. The proportion of patients who remain categorical DAS28 responders (EULAR response) consecutively for 24, 48, 96 and 264 weeks.

sicurezza di tocilizumab (MRA) riguardo ad effetti collaterali e a risultati anormali dei parametri di laboratorio. trattamenti concomitanti con steroidi saranno riassunti per visita. numero di pazienti che interrompono il trattamento. proporzione di pazienti che raggiunge una risposta ACR20, ACR50 e ACR70 per visita. proporzione di pazienti che mantiene una risposta ACR20, ACR50 o ACR70 per 24, 48, 96 e 264 settimane consecutivamente. singoli componenti della risposta ACR saranno riassuntiper visita cambiamenti dell indice di attivita` di malattia DAS 28 (Disease Activity Score) dalla prima dose di 8 mg/kg di tocilizumab (MRA) alle settimane 24, 48, 96 e 264 cambiamenti del DAS28 dalla visita basale dello studio WA18695 alle settimane 24, 48, 96 e 264. proporzione dei pazienti classificati come DAS responders (risposta EULAR) alle settimane 24, 48, 96 e 264 proporzione dei pazienti classificati come DAS responders (risposta EULAR) alle settimane 24, 48, 96 e 264 consecutivamente.

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

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

studio in aperto

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

Fine studio definita come LPLV o decisione dello Sponsor di interrompere il programma di sviluppo del farmaco

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.1.3

Elderly (>=65 years)

Yes

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

255

F.4.2.2

In the whole clinical trial

630

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)

Lo studio durera` 264 settimane indipendentemente dalla disponibilita` in commercio di tocilizumab. Se Tocilizumab non fosse reso disponibile sul mercato, il medico assegnera` al paziente la terapia standard al termine dello studio.

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

2005-09-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2005-09-21

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2012-05-02

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