Clinical Trials Register

Summary
EudraCT Number:	2015-000569-30
Sponsor's Protocol Code Number:	OFA1
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:	2020-11-05
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

2015-000569-30

A.3

Full title of the trial

Ofatumumab in children with steroid- and calcineurin-inhibitor-resistant nephrotic syndrome: a double-blind randomized, controlled, superiority trial

Uso di Ofatumumab nei bambini affetti da sindrome nefrosica idiopatica resistente alla terapia steroidea e con inibitori delle calcineurine: trial clinico di superiorit¿ randomizzato, controllato, in doppio cieco

A.3.1

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

Ofatumumab in children with nephrotic syndrome resistant to common therapy

Ofatumumab in bambini con sindrome nefrosica resistente alla terapia con cortisone.

A.3.2

Name or abbreviated title of the trial where available

Ofatumumab in children with steroid - resistant INS

Uso di Ofatumumab per sindrome nefrosica idiopatica corticoresistente

A.4.1

Sponsor's protocol code number

OFA1

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	IRCCS ISTITUTO GIANNINA GASLINI
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	Fondazione Malattie Renali del Bambino-Onlus
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	IRCCS Giannina Gaslini
B.5.2	Functional name of contact point	UOSD Epidemiologia, biostatistica e
B.5.3	Address:
B.5.3.1	Street Address	Via Gaslini 5
B.5.3.2	Town/ city	Genova
B.5.3.3	Post code	16147
B.5.3.4	Country	Italy
B.5.4	Telephone number	01056363462
B.5.5	Fax number	0108981116
B.5.6	E-mail	comitatoetico@ospedale-gaslini.ge.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	ARZERRA - 100 MG - CONCENTRATO PER SOLUZIONE PER INFUSIONE - USO ENDOVENOSO - FLACONE(VETRO) - 5 ML(20MG/ML) 3 FLACONI
D.2.1.1.2	Name of the Marketing Authorisation holder	GLAXO GROUP LIMITED
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.3.1	Product name	ofatumumab
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	Ofatumumab
D.3.9.1	CAS number	679818-59-8
D.3.9.2	Current sponsor code	Ofatumumab
D.3.9.3	Other descriptive name	Ofatumumab
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Steroid- and calcineurin-inhibitor-resistant nephrotic syndrome

Sindrome nefrosica resistente alla terapia con steroide ed inibitori delle calcineurine

E.1.1.1

Medical condition in easily understood language

nephrotic syndrome resistant to standard therapy (steroidd and immunosuppressant)

Sindrome nefrosica che non risponde alla terapia standard con cortisone e immunosoppressori

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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10072914
E.1.2	Term	Steroid-resistant nephrotic syndrome
E.1.2	System Organ Class	100000004857

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 demonstrate that Ofatumumab can induce stable complete or partial remission without other drugs within 6 months of infusion and for at least 12 months thereafter.
We will test whether Ofatumumab is superior to placebo in reducing proteinuria within 6 months and for at least one year in DR-INS patients.

Dimostrare la capacit¿ di Ofatumumab di indurre una remissione stabile (completa o parziale) dopo la sospensione di tutte le altre terapie entro 6 mesi dall¿infusione e per almeno 12 mesi.
A tal fine, testeremo la superiorit¿ di Ofatumumab verso placebo nella riduzione della proteinuria entro sei mesi e per almeno un anno nei pazienti affetti da sindrome nefrosica idiopatica steroido resistente.

E.2.2

Secondary objectives of the trial

Exclusion of acute and long-term side effects is an important secondary objective

esclusione di effetti collaterali in acuto e a lungo termine correlati alla somministrazione del farmaco.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

-Drug resistance: it signifies lack of antiproteinuric effect of a double therapy based on steroid plus CNI or mofetil mycophenolate (MMF).
Steroid resistance is defined by failure to achieve complete remission after 6 weeks with prednisone 60 mg/m2.
CNI (cyclosporine/tacrolimus) resistance is defined by failure to achieve complete remission within 6 months after the plasma concentration of cyclosporine (started at dosage of 4 mg/kg/day) or tacrolimus (started at dosage of 0,1 mg/kg/day) reached effective plasma concentrations.
Mofetil Mycophenolate resistance is defined by failure to achieve complete remission after at least 6 months of treatment with 1200mg/mq/day.
-Parents’/guardian’s written informed consent, and child’s assent given before any study-related procedure not part of the subject’s normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to his or her future medical care.
-Age between 2 and 18 years
-Histological pattern of minimal change disease, mesangial proliferation with IgM deposits or focal segmental glomerulosclerosis

-Resistenza ai farmaci: assenza di effetto antiproteinurico di una doppia terapia basata sull’uso di steroide associato ad inibitori delle calcineurine o micofenolato mofetile. La resistenza allo steroide è definita come l’impossibilità di ottenere una remissione completa dopo 6 settimane di terapia con prednisone 60 mg/m2. La resistenza agli inibitori delle calcineurine (ciclosporina/tacrolimus) è definita come l’impossibilità a raggiungere una remissione completa dopo almeno 6 mesi di trattamento con ciclosporina (4mg/kg/die) o tacrolimus (0,1 mg/kg/die). La resistenza al micofenolato mofetile è definita come l’impossibilità a raggiungere la remissione completa dopo almeno 6 mesi di trattamento al dosaggio di 1200 mg/mq/die.
-Consenso informato scritto dei genitori o del tutore legale e assenso del minore prima di intraprendere qualsiasi procedura correlate allo studio, con la consapevolezza da parte del soggetto che il consenso possa essere ritirato in qualsiasi momento, senza che ciò costituisca un pregiudizio nel suo trattamento futuro.
-Età compresa tra 2 e 18 anni.
–Pattern istologico di malattia a lesion minime, glomerulonefrite mesangioproliferativa a depositi di IgM o glomerulosclerosi focale e segmentaria.

E.4

Principal exclusion criteria

-Positivity to autoimmunity tests (ANA, dsDNA, ANCA).
-Reduction of C3 levels.
-eGFR < 30 ml/min/1.73 m2 valuated according to revised Bedside Schwartz Formula for patients between 2 and 17 years and with CKD-EPI Creatinine 2009 Equation for 18 years old patients.
-Hystological pattern characterized by elements suggestive for congenital disease: diffuse mesangial sclerosis without IgM deposits, cystic-like tubular dilatation, mitochondrial abnormalities evident on electron microscopy, IF suggestive for congenital collagen 4 disease.
-Histological pattern not suitable with INS in the pediatric age (membranous glomerulonephritis, lupus nephritis, diffuse and/or localized vasculitis, amyloidosis)
-Homozygous or heterozygous mutations of podocitary genes, commonly involved in the etiology of INS (NPHS1, NPHS2, NPHS3, NPHS6, WT1, COQ2, COQ6, MYO1E, SMARCAL1, LAMB2, SCARB2, CD2AP, TRPC6, ACTN4, INF2, LMX1B, MYH9 )
-Pregnancy
-Neoplasm
-Infections: Previous or actual HBV (with HBeAb positivity) or HCV

-Positività a test autoimmuni (ANA, ds DNA, ANCA)
-Riduzione dei livelli plasmatici della componente C3 del complemento.
-Filtrato glomerulare (estimated glomerular filtration rate, eGFR) < 30 ml/min/1.73 m2 calcolato secondo la Formula di Schwartz per I pazienti di età compresa tra 2 e 17 anni e second l’equazione CKD-EPI Creatinine 2009 per I pazienti di 18 anni.
-Pattern istologico caratterizzato da elementi suggestivi per malattia congenita: sclerosi mesangiale diffusa senza depositi di IgM, dilatazione tubulare cistica, anomalie mitocondriali visibili al microscopio elettronico, immunofluorescenza suggestiva per malattia congenita del collageno di tipo 4.
-Pattern istologico non compatibile con INS dell’età pediatrica (glomerulo nefrite membranosa, nefrite lupica, vasculite localizzata e/o diffusa, amiloidosi).
-Mutazioni in omozigosi o eterozigosi per geni podocitari, comunemente coinvolti nella genesi dell’INS (NPHS1, NPHS2, NPHS3, NPHS6, WT1, COQ2, COQ6, MYO1E, SMARCAL1, LAMB2, SCARB2, CD2AP, TRPC6, ACTN4, INF2, LMX1B, MYH9).
-Gravidanza
-Neoplasie
-Infezioni: infezione pregressa o attuale da HBV (con positività per anticorpi anti HBe) o HCV.

E.5 End points

E.5.1

Primary end point(s)

Complete or partial disease remission at 6 months from randomization.
Complete remission in defined by urinary protein/creatinine ratio (uPCR) <200 mg/g (<20mg/mmol) for 3 consecutive days. Partial remission is defined as proteinuria reduction of 50% or greater from the presenting value and absolute uPCR between 200 and 2000 mg/g. for 3 consecutive days.

presenza di remissione di malattia completa o parziale a 6 mesi dalla randomizzazione.
La remissione completa è definita da un rapporto proteinuria/creatininuria (uPCR) <200 mg/g (<20mg/mmol) per 3 giorni consecutivi. La remissione parziale è definita da una riduzione della proteinuria =50% rispetto al valore iniziale e da un rapport proteinuria/creatininuria tra 200 e 2000 mg/g per tre giorni consecutivi

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months

6 mesi

E.5.2

Secondary end point(s)

complete or partial disease remission at 12 months from randomization;

remissione completa o parziale a 12 mesi dalla randomizzazione.

E.5.2.1

Timepoint(s) of evaluation of this end point

12 months

12 mesi

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Yes

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

Yes

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.8.5.1

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

Information not present in EudraCT

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

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

Yes

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

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)

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

children less then 6 years old

minori di et¿ inferiore ai 6 anni

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 randomized in control group should be treated with IMP in case of demonstrated efficacy. Patients in active group will continue exams and treatmentaccording to clinical practice.

Al termine dello studio i soggetti randomizzati nel gruppo di controllo potranno essere trattati con l'IMP nel caso in cui questo si sia rivelato efficace. I pazienti nel gruppo attivo proseguiranno accertamenti e cure secondo pratica clinica

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

2015-06-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-06-16

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

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