Clinical Trials Register

Summary
EudraCT Number:	2005-002396-33
Sponsor's Protocol Code Number:	WA17044
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:	2006-03-01
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

2005-002396-33

A.3

Full title of the trial

A randomised, double-blind, international study to evaluate the efficacy and safety of various re-treatment regimens of rituximab in combination with methotrexate in RA patients with an inadequate response to methotrexate.

Studio internazionale, randomizzato, in doppio cieco, per valutare l efficacia e la sicurezza di vari regimi di ritrattamento con Rituximab in combinazione con metotrexate in pazienti con Artrite Reumatoide che hanno avuto una risposta inadeguata a metotrexate.

A.4.1

Sponsor's protocol code number

WA17044

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	Clinical Operations
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.5.4	Telephone number	+39 039 247 5070
B.5.5	Fax number	+39 039 247 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	Mabthera
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	Rituximab
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	500
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	Non Applicabile

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 determine if a second course with an increased dose of rituximab is associated with improved responses compared to re-treatment with the same dose.

Valutare se un secondo ciclo con un aumentata dose di Rituximab e` associato ad un miglioramento della risposta rispetto al ritrattamento con la stessa dose.

E.2.2

Secondary objectives of the trial

2. To determine response rates to two courses of 2 × 500 mg rituximab and two courses of 2 × 1000 mg rituximab. 3. To investigate the pharmacokinetics of rituximab associated with 2 courses of treatment.

2.Valutare il grado di risposta in seguito a trattamento con due cicli di 2 x 500 mg e con due cicli di 2 x 1000 mg di Rituximab.3.Esplorare i parametri di farmacocinetica di Rituximab associati a 2 cicli di trattamento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Able and willing to give written informed consent and comply with the requirements of the study protocol. 2. Patients with rheumatoid arthritis for at least 6 months, diagnosed according to the revised 1987 ACR criteria for the classification of rheumatoid arthritis. 3. Receiving treatment on an outpatient basis. 4. Swollen joint count (SJC) ≥ 8 (66 joint count), and tender joint count (TJC) ≥ 8 (68 joint count) at screening and baseline. 5. At screening, either CRP ≥ 0.6 mg/dL (6 mg/L) OR ESR ≥ 28 mm/h. 6. Minimum age 18 years. 7. Glucocorticoids ≤ 10 mg/day prednisolone or equivalent permitted if stable for at least 4 weeks prior to baseline. 8. Use of NSAIDs is permitted if stable for at least 2 weeks prior to baseline. 9. For patients of reproductive potential (males and females), use of a reliable means of contraception (e.g. hormonal contraceptive, patch, intrauterine device, physical barrier) throughout study participation. Protocol WA17044 - 4 TARGET POPULATION (Cont.) 10. Must have an inadequate response to MTX and have been receiving and tolerating this at a dose of 10-25 mg/wk (p.o. or parenteral) for at least 12 weeks, with the last 4 weeks prior to baseline at a stable dose. MabThera (Rituximab) (Re-treatment should occur within 2 weeks. If more than 4 weeks elapses the patient is required to be reassessed for eligibility) Entry criterion for absolute neutrophil count (not below 1.5 × 103/μL) was met at the last blood sample analysis. Patient has not developed contra-indications for receiving rituximab, such as: a) Any new or uncontrolled concomitant disease such as, but not limited to cardiovascular disease, nervous system, pulmonary, renal, hepatic, endocrine or gastrointestinal disorders. For patients who have entered the study and have been found to be HBsAg negative, HBcAb positive negative hepatitis B viral DNA (<29 IU/mL) and AST/ALT ≤2.5× ULN results within the last 12 weeks.

1. Pazienti in grado di capire e firmare il consenso informato e di rispettare le procedure richieste dallo studio. 2. Pazienti con artrite reumatoide da almeno 6 mesi, diagnosticata secondo i criteri dell American College of Rheumatology (ACR) del 1987. 3. Pazienti che ricevono trattamenti ambulatorialmente. 4. Conta delle articolazioni tumefatte (SJC)  8 (su 66 articolazioni) e conta delle articolazioni dolenti (TJC)  8 (su 68 articolazioni) allo screening e al baseline. 5. Allo screening: Proteina C reattiva (PCR) > 0.6 mg/dL (6 mg/L) oppure VES > 28 mm/h. 6. Eta` minima: 18 anni. 7. Sono consentiti glucocorticoidi (< 10 mg/giorno prednisolone o equivalente) purche` a dosaggio stabile da almeno 4 settimane prima del baseline. 8. E consentito l uso di FANS purche` a dosaggio stabile da almeno 2 settimane prima del baseline. 9. Pazienti in eta` fertile (donne e uomini) possono partecipare allo studio soltanto se utilizzano metodi contraccetivi affidabili (es. contraccettivi ormonali, cerotto, dispositivo intrauterino, barriera fisica) per tutta la durata della partecipazione allo studio. 10. I pazienti devono avere una risposta inadeguata al metotrexate (MTX) e devono aver ricevuto e tollerato MTX a un dosaggio di 10-25 mg/settimana (p.o. o parenterale) per almeno 12 settimane, con le ultime 4 settimane prima del baseline a dosaggio stabile. Il ritrattamenti dovrebbero essere somministrati entro 2 settimane dalla valutazione di eleggibilita` del paziente; se trascorressero piu` di 4 settimane, sarebbe necessario rivalutare l eleggibilita` del paziente. Criteri di inclusione da rispettare all ultimo prelievo di sangue: conta assoluta dei neutrofili non inferiore a 1.5 x 103/uL. I pazienti non devono aver sviluppato contro-indicazioni al trattamento con Rituximab, incluse: a. Patologie nuove o non-controllate come ad esempio (ma non limitatamente a) malattie cardiovascolari, del sistema nervoso, polmonari, renali, epatiche, endocrine o disordini gastrointestinali Per i pazienti entrati nello studio con HBsAg negativo, HBcAb positivo: negativita` alla valutazione del DNA del virus dell epatite B (<29 UI/ml) e AST/ALT < 2.5 ULN entro le ultime 12 settimane.

E.4

Principal exclusion criteria

1. Rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA (including but not limited to vasculitis, pulmonary fibrosis or Felty s syndrome). Secondary Sjogren s syndrome or secondary limited cutaneous vasculitis with RA is permitted. 2. Functional class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis. 3. History of, or current, inflammatory joint disease other than RA (e.g., gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease) or other systemic autoimmune disorder (e.g., SLE, inflammatory bowel disease, scleroderma, inflammatory myopathy, mixed connective tissue disease or other overlap syndrome). 4. Diagnosis of juvenile idiopathic arthritis (JIA) or juvenile rheumatoid arthritis (JRA) and/or RA before age 16. Exclusions Related to General Health 5. Any surgical procedure, including bone/joint surgery/ Synovectomy (including joint fusion or replacement) within 12 weeks prior to baseline or planned within 48 weeks of randomization. 6. Lack of peripheral venous access. 7. Pregnancy or lactation. 8. Significant cardiac or pulmonary disease (including obstructive pulmonary disease). 9. Evidence of significant uncontrolled concomitant disease such as nervous system, renal, hepatic, endocrine or gastrointestinal disorders which, in the investigator s opinion, would preclude patient participation. 10. Primary or secondary immunodeficiency (history of, or currently active), including known history of HIV infection. 11. Known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with i.v. anti-infectives within 4 weeks of baseline or oral anti-infectives within 2 weeks prior to baseline. 12. History of deep space/tissue infection (e.g. fasciitis, abscess, osteomyelitis) within 52 weeks of baseline. 13. History of serious recurrent or chronic infection (to check for chest infection a chest x-ray will be performed at screening if not performed within 12 weeks of screening). 14. History of cancer, including solid tumors, hematologic malignancies and carcinoma in situ (except basal cell and squamous cell carcinoma of the skin that have been excised and cured). Protocol WA17044 - 5 TARGET POPULATION (Cont.) 15. Any neurological (congenital or acquired), vascular or systemic disorder which could affect any of the efficacy assessments, in particular, joint pain and swelling (e.g. Parkinson s disease, cerebral palsy, diabetic neuropathy). 16. Currently active alcohol or drug abuse or history of alcohol or drug abuse within 24 weeks prior to baseline.

Criteri di Esclusione: Criteri di Esclusione correlati all Artrite Reumatoide 1. Malattie reumatiche autoimmuni diverse dall AR, o significativi coinvolgimenti a livello sistemico secondari ad AR (inclusi ma non limitati a vasculiti, fibrosi polmonare o sindrome di Felty). La concomitanza della sindrome di Sjogren secondaria o della vasculite cutanea circoscritta secondaria ad AR sono accettate. 2. Appartenenza alla IV classe di capacita` funzionale (criteri ACR). 3. Precedente anamnesi, o attuale malattia articolare infiammatoria diversa da AR (es. gotta, artrite reattiva, artrite psoriasica, spondiloartropatia sieronegativa, malattia di Lyme) o altra malattia sistemica autoimmune (es. LES, malattia infiammatoria intestinale, sclerodermia, miopatia infiammatoria, connettivite mista o altra sindrome concomitante). 4. Diagnosi di artrite idiopatica giovanile (JIA) o artrite reumatoide giovanile (JRA) e/o artrite reumatoide prima dei 16 anni. Criteri di Esclusione generali 5. Interventi chirurgici, compresi chirurgia/sinovectomia delle ossa/articolazioni (comprese fusioni o sostituzioni articolari) nelle 12 settimane prima del baseline o in caso di intervento pianificato entro le 48 settimane dalla randomizzazione. 6. Assenza di accesso venoso periferico. 7. Donne in stato di gravidanza o allattamento. 8. Significative malattie cardiache o polmonari (incluse malattie polmonari ostruttive). 9. Evidenza di severa patologia concomitante e non controllata a carico del sistema nervoso, renale, epatico, endocrino o gastrointestinale che, nell opinione del medico, possono precludere la partecipazione del paziente. 10. Immunodeficienza primaria o secondaria (precedente o attiva allo stato attuale), inclusa storia di infezione da HIV. 11. Infezioni attive di ogni tipo (escluse infezioni micotiche del letto ungueale), o qualsiasi episodio importante per cui e` stata necessaria una ospedalizzazione od una terapia endovena con anti-infettivi entro le 4 settimane precedenti il baseline oppure anti-infettivi orali nelle 2 settimane prima del baseline. 12. Storia di infezioni tissutali profonde (e.g. fasciti, ascessi, osteomieliti) entro 52 settimane dalla selezione. 13. Storia di infezioni serie ricorrenti o croniche (per controllare le infezioni del torace sara` effettuata una radiografia toracica allo screening, se non gia` effettutata nelle 12 settimane prima dello screening). 14. Storia di neoplasie, inclusi tumori solidi, neoplasie ematologiche e carcinoma in situ (eccetto carcinoma della cute a cellule basali e cellule squamose gia` asportato e guarito). 15. Patologie neurologiche (congenite o acquisite), vascolari o sistemiche che potrebbero interferire con la valutazione dell efficacia, in particolare, con il dolore articolare e la tumefazione (es. morbo di Parkinsons, paralisi cerebrale, neuropatia diabetica). 16. Abuso di alcool o droghe o storia di etilismo o tossicodipendenza nelle 24 settimane precedenti il baseline.

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients with an ACR20 response at Week 48.

Proporzione di pazienti con una risposta ACR20 alla settimana 48.

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

Yes

E.6.10

Pharmacogenetic

Yes

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

differente dose e regime di trattamento

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

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

I pazienti riceveranno il trattamento per un max. di 240 settimane o fino alla disponibilita` commerciale di rituximab per questa popolazione di pazienti o il 31 Dicembre 2010,seguito da un follow up di safety di almeno 1 anno.

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	No
F.1.1	Number of subjects for this age range:	0
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
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	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	50
F.4.2	For a multinational trial
F.4.2.1	In the EEA	224
F.4.2.2	In the whole clinical trial	375

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

2005-11-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2005-11-04

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-03-25

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