Clinical Trials Register

Summary
EudraCT Number:	2011-006001-10
Sponsor's Protocol Code Number:	RTX500/1000
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2012-03-14
Trial 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

2011-006001-10

A.3

Full title of the trial

Efficacy of rituximab at the dose of 500 mg e.v., two infusions two weeks apart, versus rituximab at the usual dose of 1000 mg, two infusions two weeks apart, in patients affected by rheumatoid arthritis, who had been previously treated with rituximab at the standard dose for at least two cycles obtaining a good clinical response

Valutazione di efficacia di Rituximab al dosaggio di 500mg e.v., 2 infusioni a distanza di 2 settimane, in confronto al dosaggio standard di 1000mg e.v., 2 infusioni a distanza di 2 settimane nel mantenimento della buona risposta clinica in pazienti affetti da artrite reumatoide, gia' trattati con Rituximab al dosaggio standard per almeno 2 cicli

A.3.1

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

A.4.1

Sponsor's protocol code number

RTX500/1000

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	A.O. UNIVERSITARIA INTEGRATA DI VERONA
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Reparto Reumatologia
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AOUI Verona
B.5.2	Functional name of contact point	Unita' Operativa di Reumatologia
B.5.3	Address:
B.5.3.1	Street Address	Policlinico GB Rossi, Piazzale L.A. Scuro, 10
B.5.3.2	Town/ city	Verona
B.5.3.3	Post code	37134
B.5.3.4	Country	Italy
B.5.4	Telephone number	045 6338565
B.5.5	Fax number	045 6338686
B.5.6	E-mail	segreteria.reumatologia@ateneo.univr.it

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
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*EV 1FL 50ML 500MG
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE SpA
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Injection
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.3.9.1	CAS number	174722-31-7
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	SUB12570MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000
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	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	Yes
D.2.1.1.1	Trade name	MABTHERA*EV 1FL 50ML 500MG
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE SpA
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Injection
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.3.9.1	CAS number	174722-31-7
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	SUB12570MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
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	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

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

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	LLT
E.1.2	Classification code	10003268
E.1.2	Term	Arthritis rheumatoid
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 aim of the present study is to evaluate if rituximab at the dose of 500 mg e.v., two infusions two weeks apart, is as effective as rituximab at the usual dose of 1000 mg, two infusions two weeks apart, in patients affected by rheumatoid arthritis who have been previously treated with rituximab at the standard dose for at least two cycles obtaining a good clinical response

Scopo del presente studio è quello di valutare in soggetti affetti da artrite reumatoide già in terapia con rituximab, che abbiano ricevuto almeno 2 cicli di terapia alla posologia standard di 1 g x 2 per ogni ciclo, che abbiano ottenuto una buona risposta clinica, se la posologia di 500 mg x 2 sia in grado di mantenere la risposta favorevole precedentemente ottenuta con la posologia standard in confronto a soggetti che continueranno ad essere trattati con 1 g x 2 per ogni ciclo

E.2.2

Secondary objectives of the trial

-Evaluation of the number of tender joints -Evaluation of the number of swollen joints -Evaluation of the ESR and C-reactive protein -Evaluation of the number of patients in clinical remission (DAS28 < 2.6) -Evaluation of the progression of the anatomic damage by hand and feet X-ray examination -Evaluation of the adverse reactions -Evaluation of the number of B-lymphocytes -Detection of anti-rituximab antibodies -rituximab serum concentration -evaluation of hematosis, kidney and liver function -evaluation of the difference regarding DAS28 at the entry to the study and at the subsequent clinical evaluations until the end of the study

-Valutazione del numero di articolazioni dolorabili -Valutazione del numero di articolazioni tumefatte -Valutazione dei reattanti della fase acuta (PCR, VES) -Valutazione del numero di pazienti in remissione (DAS28 <2.6) -Valutazione della progressione del danno anatomico visibile radiologicamente -Valutazione dell’incidenza di eventi avversi -Valutazione dei livelli di linfociti B circolanti -Valutazione in merito alla comparsa di anticorpi anti-farmaco -Concentrazione ematica farmaco -valutazione ematosi, funzione epatica e renale -valutazione differenza del DAS28 tra il basale (T0) e ogni successiva valutazione valutazione fino alla fine dello studio

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients affected by rheumatoid arthritis, diagnosed in agreement with the American College of Rheumatology 1987 criteria, who had been previously treated with rituximab at the usual dose of 1000 mg, two infusions two weeks apart, for at least two cycles, obtaining a good clinical response (reduction of at least 1.2 points of Disease Activity Score DAS28, as observed at the last visit, in comparison with the basal value, before the rituximab treatment start). The patients had previously failed, for inefficacy or intolerance, therapy with either methotrexate and TNF blockers. Age of the patients > 18 years.

- Pazienti affetti da artrite reumatoide, diagnosticata secondo i criteri ACR del 1987, già in terapia con rituximab alla posologia di 1 g x 2 per ciclo, che abbiano già ricevuto almeno 2 cicli di terapia, ottenendo una buona risposta (riduzione di almeno 1.2 punti del DAS28 rilevata all’ultima visita disponibile, rispetto al dato ottenuto prima dell’inizio della terapia). I pazienti in precedenza sono risultati non responsivi o intolleranti dapprima al Methotrexate e quindi a uno o più farmaci anti-TNF (infliximab, etanercept, adalimumab). - Potranno essere arruolati sia pazienti che stanno ricevendo in associazione a rituximab il Methotrexate o altro immunosoppressore, sia pazienti che - a causa di intolleranza o per scelta personale - hanno interrotto in precedenza l’assunzione di Methotrexate e stanno quindi ricevendo il rituximab in monoterapia. - Potranno essere arruolati sia pazienti afferenti al Day Service Polispecialistico che pazienti ricoverati in regime ordinario, seguiti presso l’USOD di Reumatologia del Policlinico G.B. Rossi di Verona - Età dei pazienti > 18 anni.

E.4

Principal exclusion criteria

- Hypersensitivity to the drug or to murine proteins or to any component of the product - severe, active infections - severe heart failure (New York Heart Association class IV) or severe uncontrolled heart disease

- Ipersensibilità al principio attivo o ad uno qualsiasi degli eccipienti o alle proteine di origine murina. - Infezioni attive, gravi - Scompenso cardiaco grave (classe IV New York Heart Association) o malattia cardiaca grave e non controllabile.

E.5 End points

E.5.1

Primary end point(s)

Difference regarding DAS28 at the entry to the study and at the end (T14 – 27 months after the entry) between group A (rituximab 500 mg) and group B (rituximab 1000 mg)

Differenza del DAS28 tra il basale (T0) e la fine dello studio (T14) fra il gruppo A, trattato con rituximab 500 mg x 2 per ogni ciclo rispetto al gruppo B, trattato con rituximab 1000 mg x 2 per ogni ciclo.

E.5.1.1

Timepoint(s) of evaluation of this end point

baseline and T14

baseline e T14

E.5.2

Secondary end point(s)

-number of tender joints -number of swollen joints -concentration of PCR -ESR -number of patients in clinical remission (DAS28 < 2.6) -progression of the anatomic damage by hand and feet X-ray examination -Incidence of adverse reactions -number of B-lymphocytes -Presence of anti-rituximab antibodies -rituximab serum concentration -concentration of hematochemical factors -concentration of kidney and liver related factor -difference regarding DAS28 at the entry to the study and at the subsequent clinical evaluations until the end of the study

-numero di articolazioni dolorabili -numero di articolazioni tumefatte -CONCENTRAZIONE PCR -VES -numero di pazienti in remissione (DAS28 <2.6) -progressione del danno anatomico visibile radiologicamente -incidenza di eventi avversi -livello di linfociti B circolanti -presenza di anticorpi anti-farmaco -Concentrazione ematica farmaco -concentrazione fattori ematochimici -concentrazione fattori legati a funzione epatica e renale -differenza del DAS28 tra il basale (T0) e ogni successiva valutazione valutazione fino alla fine dello studio

E.5.2.1

Timepoint(s) of evaluation of this end point

baseline, T2, T3, T5, T6, T8, T9, T11, T12, T14

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

E.6.7

Pharmacodynamic

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

Yes

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

- Stesso farmaco ad altro dosaggio

- same IMP used at different dosage

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

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

LVLS

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2012-03-14.

Yes

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

F.4.2.2

In the whole clinical trial

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)

At the end of the study, patients will continue rituximab treatment in case of maintenance of a good clinical response. On the basis of clinical judgment (loss of efficacy or adverse reactions), the treatment might be opportunely changed in agreement with the guidelines for the management of rheumatoid arthritis.

Al termine dello studio, in caso di mantenimento di una buona risposta clinica, i pazienti continueranno a ricevere il farmaco rituximab.
In caso di perdita di efficacia o di insorgenza di effetti collaterali, il paziente verrà trattato secondo le linee guida di trattamento dell’artrite reumatoide.

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

2012-03-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-03-07

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2014-10-03

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