Clinical Trials Register

Summary
EudraCT Number:	2011-006115-59
Sponsor's Protocol Code Number:	GNM-2011
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2012-06-08
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

2011-006115-59

A.3

Full title of the trial

"A Randomized Controlled Trial of Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (IMN)"

''Trial controllato randomizzato Rituximab Versus steroide e ciclofosfamide nel trattamento della nefropatia membranosa idiopatica (IMN)''

A.3.1

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

"A Randomized Controlled Trial of Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (IMN)"

"Trial controllato randomizzato Rituximab Versus steroide e ciclofosfamide nel trattamento della nefropatia membranosa idiopatica (IMN)"

A.3.2

Name or abbreviated title of the trial where available

GNM-2011

A.4.1

Sponsor's protocol code number

GNM-2011

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	AZIENDA OSPEDALIERA SPEDALI CIVILI DI BRESCIA
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	Azienda Spedali Civili di Brescia
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	AO Spedali Civili di Brescia
B.5.2	Functional name of contact point	coordinamento ricerca clinica
B.5.3	Address:
B.5.3.1	Street Address	p.le spedali civili 1
B.5.3.2	Town/ city	brescia
B.5.3.3	Post code	25125
B.5.3.4	Country	Italy
B.5.4	Telephone number	0303996851
B.5.5	Fax number	0303996125
B.5.6	E-mail	carmen.terraroli@spedalicivili.brescia.it

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*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	Solution for 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.3.9.1	CAS number	174722-31-7
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	10
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.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	URBASON*IM EV 1F 250MG+1F 5ML
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	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.3.9.1	CAS number	83-43-2
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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.IMP: 3
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	MEDROL*10CPR DIV 4MG
D.2.1.1.2	Name of the Marketing Authorisation holder	PFIZER ITALIA Srl
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	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.3.9.1	CAS number	83-43-2
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	.4
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.IMP: 4
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	ENDOXAN BAXTER*50CPR RIV 50MG
D.2.1.1.2	Name of the Marketing Authorisation holder	BAXTER 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	Coated 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.3.9.1	CAS number	50-18-0
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	.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

MN is an autoimmune disease, suggesting that the disease may be triggered by isotype specific autoantibodies directed against podocyte enzymes and podocyte receptors that are recognized as antigens. The key role of IgG antibodies formation in the pathogenesis of IMN suggests that B cell depletion may favourably impact the evolution of the glomerular disease and reduce proteinuria. We propose this study in order to test in a randomized controlled trial the hyp

La glomerulonefrite membranosa idiopatica è una malattia autoimmune, e potrebbe esser scatenata da specifici anticorpi diretti contro proteine podocitarie e recettori dei podociti che vengono riconosciuti come antigeni, inclusi i recettori M-type fosfolipasi-2, Aldoso-reduttasi e Superossido manganese dismutasi. Il ruolo chiave della formazione di anticorpi IgG nella patogenesi di IMN suggerisce che l

E.1.1.1

Medical condition in easily understood language

A Randomized Controlled Trial of Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (IMN)

Trial controllato randomizzato Rituximab Versus steroide e ciclofosfamide nel trattamento della nefropatia membranosa idiopatica (IMN)

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02]

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	10018372
E.1.2	Term	Glomerulonephritis membranous
E.1.2	System Organ Class	10038359 - Renal and urinary 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 primary outcome was the difference in the probability of complete remission (proteinuria <0.3 g / day) at one year (see design and power considerations).

differenza nella probabilità di completa remissione (proteinuria < 0.3 g/die) a un anno (vedi disegno e considerazioni di potenza).

E.2.2

Secondary objectives of the trial

Differences in terms of:
Levels of proteinuria at time 0, 6.12, 18, 24 and 36 months;
Composite end point of CR (complete remission) or PR (partial remission) at 6, 12, 18, 24, and 36 months;
Mortality ';
Estimated glomerular filtration rate (MDRD formula) at 6, 12, 18, 24, and 36 months;
Value of serum creatinine (mg / dl) at 6, 12, 18, 24, and 36 months;
Frequency and number of relapses;
Frequency of autoantibodies anti-phospholipase A2 receptor (anti-PLA2R), anti-superoxide dismutase 2 (SOD2 anti-), anti-aldose reductase (anti-AR), anti-alpha-enolase (anti-α-enolase) at time 0 and after 3, 6.12, 18, 24 and 36 months after therapy.

Differenze in termini di:
• Livelli di proteinuria a tempo 0,6,12,18,24 e 36 mesi;
• End-point composito di CR (Completa Remissione) o PR (Parziale Remissione) a 6,12,18,24,e 36 mesi;
• Mortalita’;
• Velocità di filtrazione glomerulare stimata (MDRD formula) a 6,12,18,24,e 36 mesi;
• Valore di creatinina sierica (mg/dl) a 6,12,18,24,e 36 mesi;
• Frequenza e numero di recidive;
• Frequenza di auto-anticorpi anti-fosfolipasi A2 recettore (anti-PLA2R); anti-superossido dismutasi 2 (anti-SOD2); anti-aldoso-reduttasi (anti-AR); anti-alfa-enolasi (anti-α-enolasi) al tempo 0 e dopo 3,6,12,18,24 e 36 mesi dalla terapia.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Biopsy diagnosis of idiopathic MN, performed in the last 24 months
2. Proteinuria> 3.5 g/24h in three measurements (one measurement for 3 weeks)
3. Estimated GFR (MDRD formula) ≥ 50ml/min/1.73m2 treated with ACE inhibitors / ARBs
4. Physiological or surgically menopausal women, women who implement an approved method of contraception
5. Failure in treatment with ACE inhibitors or ARBs to be first 3 months of treatment with RTX

1. Diagnosi bioptica di MN idiopatica, eseguita negli ultimi 24 mesi
2. Età > 18 anni
3. Proteinuria > 3.5 g/24h in tre misurazioni (una misurazione per 3 settimane)
4. VFG stimata (MDRD formula) ≥ 50ml/min/1.73m2 in terapia con ace inibitori/sartani
5. Donne che si impegnano a NON intraprendere una gravidanza
6. Uomini partner di donne in età fertile che si impegnano a NON far intraprendere una gravidanza
7. Insuccesso nel trattamento con ACE inibitori o sartani da 3 mesi prima della terapia con RTX

E.4

Principal exclusion criteria

1. Serum creatinine> 2.0mg/dl; eGFR <50 ml/min/1.73m2,
2. Previous treatment with rituximab, steroids, alkylating agents, calcineurin inhibitor, ACTH, MMF, azathioprine
3. Presence of active infection
4. Secondary causes of MN (eg hepatitis B, SLE, drugs, tumors). Testing for HIV, hepatitis B and C run less than 6 months before study
5. Diabetes mellitus type 1 and 2
6. Pregnancy or breast-feeding for safety

1. Creatinina sierica >2.0mg/dl; VFG stimata< 50 ml/min/1.73m2,
2. Precedente trattamento con Rituximab, Steroide, Agente alchilante, Inibitore calcineurine, ACTH, MMF, Azatioprina
3. Presenza di infezione attiva
4. Cause secondarie di MN (esempio epatite B, SLE, farmaci, neoplasie). Test per HIV, epatite B e C eseguito meno di 6 mesi prima dell’arruolamento nello studio
5. Diabete mellito di tipo 1 e 2
6. Gravidanza o allattamento per problemi di sicurezza

E.5 End points

E.5.1

Primary end point(s)

The primary outcome was the difference in the probability of complete remission (proteinuria <0.3 g / day) at one year

differenza nella probabilità di completa remissione (proteinuria < 0.3 g/die) a un anno

E.5.1.1

Timepoint(s) of evaluation of this end point

one year

1 anno

E.5.2

Secondary end point(s)

Differenze in termini di:
• Livelli di proteinuria a tempo 0, 6,12, 18, 24 e 36 mesi;
• End-point composito di CR (Completa Remissione) o PR (Parziale Remissione) a 6, 12, 18, 24, e 36 mesi;
• Mortalita’;
• Velocità di filtrazione glomerulare stimata (MDRD formula) a 6, 12, 18, 24, e 36 mesi;
• Valore di creatinina sierica (mg/dl) a 6, 12, 18, 24, e 36 mesi;
• Frequenza e numero di recidive;
• Frequenza di auto-anticorpi anti-fosfolipasi A2 recettore (anti-PLA2R); anti-superossido dismutasi 2 (anti-SOD2); anti-aldoso-reduttasi (anti-AR); anti-alfa-enolasi (anti-α-enolasi) al tempo 0 e dopo 3, 6,12, 18, 24 e 36 mesi dalla terapia.

E.5.2.1

Timepoint(s) of evaluation of this end point

three years

3 anni

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

E.6.5

Efficacy

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

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

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

inability of the target enrollments

impossibilità raggiungimneto del target arruolamenti

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

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

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.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)

patient will be treated according to SSN

i pazienti saranno trattati secondo le linee guida nazionali e internazionali a carico del SSN

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

2012-06-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-01-10

P. End of Trial
P.	End of Trial Status	Ongoing

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