Clinical Trials Register

Summary
EudraCT Number:	2012-001102-14
Sponsor's Protocol Code Number:	Ritazarem
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-05-16
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

Spain - AEMPS

A.2

EudraCT number

2012-001102-14

A.3

Full title of the trial

An international, open label, randomised controlled trial comparing rituximab with azathioprine as maintenance therapy in relapsing ANCA-associated vasculitis

Estudio internacional, abierto, aleatorizado, controlado, comparando rituximab con azatioprina en el mantenimiento de la remisión en vasculitis asociadas a anticuerpos anti-citoplasma del neutrófilo (ANCA).

A.3.1

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

RITAZAREM: A trial of rituximab versus azathioprine for maintenance of remission in ANCA vasculitis

RITAZAREM: Ensyo clínico de rituximab versus azatioprina en el mantenimiento de la remisión de la vasculitis ANCA

A.3.2

Name or abbreviated title of the trial where available

RITAZAREM: Rituximab vasculitis maintenance study

RITAZAREM: Estudio Rituximax manetenimiento vasculitis

A.4.1

Sponsor's protocol code number

Ritazarem

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	Cambridge University Hospitals NHS Foundation Trust
B.1.3.4	Country	United Kingdom
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	Arthritis Research UK
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	Roche
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	Cambridge University Hospitals NHS Foundation Trust
B.5.2	Functional name of contact point	Carrie Bayliss
B.5.3	Address:
B.5.3.1	Street Address	Cambridge Clinical Trials Unit, Box 111, Addenbrooke's Hospital, Hills Road
B.5.3.2	Town/ city	Cambridge
B.5.3.3	Post code	CB2 0QQ
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01223 348158
B.5.5	Fax number	01223 596471
B.5.6	E-mail	cctu@addenbrookes.nhs.uk

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 Pharma AG
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	Rituximab
D.3.4	Pharmaceutical form	Concentrate for solution for injection/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.3.9.1	CAS number	174722-31-7
D.3.9.4	EV Substance Code	AS2
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)	Yes
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	No
D.IMP: 2
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	Azathioprine
D.2.1.1.2	Name of the Marketing Authorisation holder	Ucb Pharma, S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Azathioprine
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Azathioprine
D.3.9.1	CAS number	446-86-6
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1 to 2
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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

ANCA vasculitis.

Vasculitis ANCA

E.1.1.1

Medical condition in easily understood language

An autoimmune disease in which blood vessels are inflamed by overactive defense mechanisms which usually protect against infection.

Enfermedad autoinmune en la que los vasos sanguíneos están deteriorados por hiperactividad de los mecanismos de defensa que generalmente protegen contra la infección.

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	16.0
E.1.2	Level	LLT
E.1.2	Classification code	10047889
E.1.2	Term	Wegeners granulomatosis
E.1.2	System Organ Class	10047065 - Vascular disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.0
E.1.2	Level	LLT
E.1.2	Classification code	10047888
E.1.2	Term	Wegener's granulomatosis
E.1.2	System Organ Class	10047065 - Vascular disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.0
E.1.2	Level	PT
E.1.2	Classification code	10063344
E.1.2	Term	Microscopic polyangiitis
E.1.2	System Organ Class	10047065 - Vascular disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.0
E.1.2	Level	PT
E.1.2	Classification code	10050894
E.1.2	Term	Anti-neutrophil cytoplasmic antibody positive vasculitis
E.1.2	System Organ Class	10021428 - Immune system 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

The principle research objective is to demonstrate the superiority of rituximab against azathioprine in the prevention of disease flare in ANCA-associated vasculitis patients with relapsing disease

El objetivo principal del estudio es demostrar la superioridad de rituximab versus azatioprina en la prevención de recurrencias en la vasculitis asociada a ANCA en pacientes con enfermedad recidivante

E.2.2

Secondary objectives of the trial

The secondary objectives are to demonstrate: 1. Sustained disease remission beyond the 24 month treatment period 2. Long term safety of rituximab administration 3. The optimal remission maintenance therapy in ANCA-associated vasculitis following induction of disease remission with rituximab

Los objetivos secundarios son demostrar: 1. la remisión sostenida más allá de los 24 meses de tratamiento, 2. seguridad a largo plazo de la administración de rituximab, 3. la terapia de mantenimiento de la remisión óptima tras la inducción de la remisión de la enfermedad con rituximab.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Written informed consent 2.A diagnosis of ANCA Associated Vasculitis (AAV) [granulomatosis with polyangiitis or microscopic polyangiitis], according to the definitions of the Chapel Hill Consensus Conference 3.Current or historical ANCA positivity either by ELISA or immunofluorescence 4.Disease flare relapse defined by one major or three minor disease activity items on the Birmingham Vasculitis Activity Score for Wegener?s (BVAS/WG), in patients that have previously achieved remission following at least 3 months of induction therapy, with a combination of glucocorticoids and an immunosuppressive agent (cyclophosphamide or methotrexate or rituximab) 5.Aged 15 years and over

1) Consentimiento informado por escrito (individuos de edad igual o superior a los 15 años de edad)
2) Diagnóstico de vasculitis asociada a ANCA (poliangiitis granulomatosa (Wegener) o poliangiitis microscópica) según las definiciones de consenso de la conferencia de Chapel Hill.
3) ANCA positivo (actual o previo) por ELISA o por inmunofluorescencia.
4) Presencia de una recurrencia definida por 1 item mayor o 3 menores de la puntuación BVAS (Birmingham Vasculitis Activity Score) adaptada a granulomatosis de Wegener (BVAS/WG) en pacientes que han alcanzado previamente la remisión tras una terapia de inducción.

E.4

Principal exclusion criteria

1.Age less than 15 years (age less than 18 years at centres that do not treat paediatric patients) 2.Exclusions related to medication: Previous therapy with: a.Any biological B cell depleting agent (such as rituximab or belimumab) within the past 6 months b.Alemtuzumab or anti-thymocyte globulin within the last 12 months c.IVIg, infliximab, etanercept, adalimumab, abatacept or plasma exchange in past 3 months d.Any investigational agent within 28 days of screening, or 5 half lives of the investigational drug (whichever is longer) 3.Exclusions related to general health: a.Significant or uncontrolled medical disease not related to AAV, which in the investigators opinion would preclude patient participation b.Presence of another multisystem autoimmune disease, including Churg Strauss syndrome, systemic lupus erythematosus, anti-GBM disease, or cryoglobulinaemic vasculitis c.Any concomitant condition anticipated to likely require greater than 4 weeks per year of oral or systemic glucocorticoid use and which would preclude compliance with the glucocorticoid protocol (e.g. poorly-controlled asthma, COPD, psoriasis, or inflammatory bowel disease) d.History of severe allergic or anaphylactic reactions to humanised or murine chimeric monoclonal antibodies e.Known infection with HIV (HIV testing will not be a requirement for trial entry); a past or current history of hepatitis B virus or hepatitis C virus infection. f.Ongoing or recent (last 12 months) evidence of active tuberculosis or known active infection (screening for tuberculosis is part of ?standard of care? in patients with established AAV) or evidence of untreated latent tuberculosis. Screening for tuberculosis is as per local practice. g.History of malignancy within the past five years or any evidence of persistent malignancy, except fully excised basal cell or squamous cell carcinomas of the skin, or cervical carcinoma in situ which has been treated or excised in a curative procedure. h.Pregnancy or inadequate contraception in pre-menopausal women i.Breast feeding or lactating women 4.Exclusion criteria related to laboratory parameters: a)Bone marrow suppression as evidenced by a total white count < 4 x109/l, haemoglobin < 7 gm/dl or platelet count < 100,000/?l b)Aspartate aminotransferase or alanine aminotransferase or amylase > 2.5 times the upper limit of normal, unless attributed to vasculitis

1) Edad < 15 años (<18 años en centros que no admiten pacientes pediátricos)
2) Tratamiento previo con agentes biológicos dirigidos hacia linfocitos B (como rituximab o belimumab) en los 6 meses previos.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the time to disease relapse (either minor or major relapse) from randomisation.

La variable principal del estudio es el tiempo transcurrido hasta la primera recurrencia /ya sea mayor o menor) desde la aleatorización

E.5.1.1

Timepoint(s) of evaluation of this end point

36 months

36 meses

E.5.2

Secondary end point(s)

Secondary endpoints: 1. Proportion of patients who maintain remission at 24 and 48 months 2. Time to a major or second minor relapse 3. Cumulative accrual of damage as measured by the combined damage assessment score (CDA) 4. Health-related quality of life as measured using SF-36 5. Cumulative glucocorticoid exposure 6. Severe adverse event rate 7. Infection (treated with either intravenous or oral antibiotics) rate

Variables secundarias: 1. Porcentaje de pacientes que mantienen la remisión a los 24 y a los 48 meses 2. Tiempo transcurrido hasta la segunda recurrencia (mayor o menor) 3. Daño permanente acumulado medido mediante la puntuación obtenida a través de la valoración de daño combinado (combined damage assessment score o CDA) 4. Calidad de vida en relación a la salud, mediante la utilización del cuestionario SF-36 5. Dosis acumulada de corticoides 6. Incidencia de Acontecimientos Adversos Graves 7. Incidencia de infecciones (tratadas con antibióticos ya sea orales o endovenosos).

E.5.2.1

Timepoint(s) of evaluation of this end point

3. The combined damage assessment score (CDA) is completed at months 0, 4, 12 and 24. 4. Health-related quality of life as measured using SF-36 is completed at months 0, 4, 12 and 24. 6 & 7. Severe adverse event rate and infection (treated with either intravenous or oral antibiotics) rate will be monitored throughout the trial.

3. Daño permanente acumulado se completará - meses 0, 4, 12 y 24. 4. Calidad de vida (SF-36) - meses 0, 4, 12 y 24. 6 & 7. Incidencia de Acontecimientos Adversos Graves e incidencia de infecciones - durante todo el estudio

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

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

Yes

E.8.2.2

Placebo

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

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

Australia

Austria

Canada

Czech Republic

Denmark

Germany

Ireland

Italy

Mexico

Netherlands

New Zealand

Poland

Spain

Sweden

Switzerland

United Kingdom

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 trial will end when the final patient has completed 12 months of follow up (has been in the trial for 36 months in total).

El estudio finalizará cuando el último paciente complete los 12 meses de seguimiento.

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.1.1.1

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

100

F.4.2.2

In the whole clinical trial

190

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)

Upon completion of the trial all participants will return to the standard of care treatment as offered by their hospital for management of their vasculitis. In some cases this will not include treatment with rituximab. There are no plans for the continued provision of rituximab outside of this clinical trial.

Tras la finalización del estudio todos los pacientes volverán al tratamiento estándar de su enfermedad

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-06-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-05-17

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-11-29

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