Clinical Trials Register

Summary
EudraCT Number:	2005-002909-23
Sponsor's Protocol Code Number:	WA18696
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:	2006-03-14
Trial results	Removed from public view

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

2005-002909-23

A.3

Full title of the trial

Long-term extension study of safety during treatment with tocilizumab (MRA) in patients completing treatment in MRA core studies.

Studio di estensione sulla sicurezza a lungo termine del trattamento con tocilizumab (MRA) nei pazienti che hanno completato precedenti studi con MRA.

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 MRA core studies.

Studio di estensione sulla sicurezza a lungo termine del trattamento con tocilizumab (MRA) nei pazienti che hanno completato precedenti studi con MRA.

A.4.1

Sponsor's protocol code number

WA18696

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	Ro Actemra
D.3.9.1	CAS number	375823-41-9
D.3.9.2	Current sponsor code	Ro 487-7533
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	Yes
D.3.11.13.1	Other medicinal product type	Anticorpo monoclonale

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 MRA with regard to adverse events and laboratory result abnormalities.

Valutare la sicurezza a lungo termine di MRA in riferimento agli eventi avversi e alle anormalita' dei parametri di laboratorio.

E.2.2

Secondary objectives of the trial

To explore the possibility to reduce concomitant steroid treatment. To determine the long-term efficacy of MRA with regard to reduction in signs and symptoms.

Esplorare la possibilita` di ridurre il trattamento concomitante con farmaci steroidei.Determinare l efficacia a lungo termine di MRA in riferimento alla riduzione dei segni e dei sintomi.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Completion of treatment as specified in the core studies, and scheduled to receive the first tocilizumab (MRA) infusion in WA18696 between 4 and 12 weeks after the last iv infusion in the core studies.Patients that are prevented from enrollment prior to 12 weeks after the last infusion in the core studies due to administrative delays outside 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 MTX or other allowable DMARD (defined in Section 4.4) at a stable dose and route of administration since the last administration of study drug in the core studies. Patients enrolled from study WA17824, will receive tocilizumab (MRA) 8 mg/kg monotherapy or combination therapy at the discretion of the investigator. 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 the core studies. 5) If taking MTX, 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.

1. Pazienti che abbiano completato il trattamento con MRA cosi` come specificato negli studi principali e che devono ricevere la prima dose di MRA nello studio WA18696 tra 4 e 12 settimane dopo l ultima infusione e.v. di MRA negli studi WA18062, WA18063 e WA17824. I pazienti che non possono essere arruolati entro 12 settimane dalla loro ultima infusione negli studi principali a causa di ritardi amministrativi fuori dal controllo dello sperimentatore e dopo discussione con Roche possono essere inclusi nello studio se soddisfano tutti gli altri criteri, ma saranno sottoposti ad una separate analisi dei risultati dello studio. 2. Pazienti in grado di capire e firmare il consenso informato e di rispettare le procedure richieste dallo studio. 3. Pazienti che hanno ricevuto MTX oppure un altro DMARD consentito (definito nella Sez. 4.4) a dose e via di somministrazione stabili all ultima infusione di farmaco negli studi principali. I pazienti che hanno completato lo studio WA17824 riceveranno 8 mg/kg di tocilizumab (MRA) in monoterapia o in combinazione a discrezione dello sperimentatore. 4. Sono consentiti corticosteroidi orali (<10 mg/giorno prednisone o equivalente) e FANS (fino al massimo dosaggio consigliato) purche` a dosaggio stabile dall ultima infusione di farmaco negli studi principali. 5. Se stanno assumendo MTX, i pazienti devono essere disposti a ricevere folato orale (almeno 5 mg/week). 6. Donne in eta` fertile e uomini con una compagna in eta` fertile possono partecipare allo studio soltanto se utilizzano un metodo contraccettivo affidabile (es. barriera fisica (paziente e partner), pillola o cerotto, spermicida e barriera o spirale). 7. Se e` una donna in eta` fertile, la paziente deve avere un risultato negativo al test di gravidanza sulle urine al basale.

E.4

Principal exclusion criteria

1) Treatment with any investigational agent since the last administration of study drug in the core studies. 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 the core studies. 4) Treatment with an anti-TNF or anti-IL1 agent, or a T-cell costimulation modulator or any biologic or participation in any research study since the last administration of study drug in the core studies. 5) Parenteral, intramuscular or intra-articular corticosteroids within 6 weeks prior to baseline in WA18696. 6) Immunization with a live/attenuated vaccine since the last administration of study drug in the core studies. 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, including solid tumors and hematologic malignancies diagnosed within the previous 10 years (except basal cell carcinoma of the skin that has been excised and cured), breast cancer diagnosed within the previous 20 years. 12) Patients whose AST or ALT ≥ 3 times ULN, bilirubin > 2 times ULN and > 2.5 mg/dL (43 umol/L), neutrophils < 1000/mm3 (1 x 103 /uL or 1 GI/L), or who have an infection (see section 7.3).

1. Trattamento con qualsiasi agente sperimentale dall ultima infusione di farmaco negli studi principali 2. Precedenti trattamenti con terapie depletive a livello cellulare, compresi agenti sperimentali (es. CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19 ed anti-CD20). 3. Trattamento con gamma globulina e.v., plasmaferesi o colonna Prosorba dall ultima infusione di farmaco negli studi principali 4. Trattamento con terapie anti-TNF o anti-IL1 o modulatori della costimolazione dei linfociti T o qualsiasi biologico o la partecipazione a qualsiasi studio di ricerca dall ultima infusione di farmaco negli studi principali. 5. Corticosteroidi per via parenterale, intra-articolare o intramuscolare durante le 6 settimane prima della visita basale del WA18696. 6. Somministrazione di vaccino vivo/attenuato dall ultima infusione di farmaco negli studi principali. 7. Predecente trattamento con agenti alchilanti, come ciclofosfamide o clorambucile o con irradiazione totale dei linfonodi. 8. Anamnesi di reazioni allergiche severe o anafilattiche verso anticorpi monoclonali umani o murini. 9. Evidenza di severa patologia concomitante e non controllata a carico degli apparati cardiovascolare, polmonare (compreso malattia polmonare ostruttiva), renale, epatica, gastrointestinale, endocrino (compreso il diabete mellito incontrollato) immunologico o gastrointestinale; Storia di diverticolite, diverticolite che richiede trattametno antibiotico o malattia cronica ulcerativa del tratto inferiore gastrointestinale come la malattia di Chron, colite ulcerativa o altre condizioni sintomatiche del tratto inferiore gastrointestinale che potrebbero predisporre a performazioni per le quali una valutazione beneficio/rischio favorevole alla continuazione dello studio non puo` essere documentata. 10. Precedenti o attuali infezioni attive ricorrenti batteriche, virali, micotiche, micobatteriche o altre infezioni (incluse ma non limitate a tubercolosi, malattia micobatterica atipica, alterazioni clinicamente significative, a giudizio del medico, visibili mediante a radiografia toracica, HIV, epatite B e C, e herpes zoster, ma con esclusione delle infezioni micotiche del letto ungueale), o qualsiasi episodio importante di infezione per cui e` stata necessaria una ospedalizzazione od una terapia endovena con antibiotici entro le 4 settimane precedenti il basale oppure antibiotici orali nelle 2 settimane prima del basale. 11. Evidenza di malattia maligna attiva, incluso tumori solidi e neoplasie ematologiche diagnosticate nei 10 anni precedenti (eccetto il carcinoma a cellule basali della cute gia` asportato e guarito), tumore al seno diagnosticato nei 20 anni precedenti. 12. Pazienti con AST o ALT ≥3 volte il limite superiore di normalita` (ULN), bilirubina >2 volte ULN e >2.5 mg/dL (43 umol/L), neutrofili < 1000/mm3 (1 x 103 /uL o 1 GI/L), o che abbiano un infezione (vedi sez. 7.3).

E.5 End points

E.5.1

Primary end point(s)

The primary parameters of interest are safety and long-term efficacy. The following endpoints will be summarized descriptively: The safety of 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) by visit. The proportion of patients who remain categorical DAS28 responders (EULAR response) consecutively for 24, 48, 96 and 264 weeks. The proportion of patients who change from monotherapy to combination treatment by visit.

I principali parametri di interesse sono la sicurezza e l efficacia a lungo termine. Gli end points saranno di seguito descritti brevemente: sicurezza di tocilizumab (MRA) in riferimento ad eventi avversi ed a risultati anormali dei parametri di laboratorio. trattamenti concomitanti con steroidi saranno riassunti ad ogni 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 riassunti per 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 WA18696 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 che rimane nella categoria dei DAS responders (risposta EULAR) per 24, 48, 96 e 264 settimane consecutivamente. proporzione di pazienti che passano dalla monoterapia alla terapia di combinazione ad ogni visita.

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

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

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

La sperimentazione si concludera` con l`ultima visita dell`ultimo soggetto o con la decisione dello sponsor di interrompere il programma di sviluppo.

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

650

F.4.2.2

In the whole clinical trial

2420

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` commerciale di tocilizumab. Se tocilizumab non diverra` commercialmente disponibile alla fine dello studio, il medico provvedera` a trattare il paziente con terapia standard.

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

2006-04-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2006-03-06

P. End of Trial
P.	End of Trial Status	Completed

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