Clinical Trials Register

Summary
EudraCT Number:	2018-001042-33
Sponsor's Protocol Code Number:	OFA3
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:
Date on which this record was first entered in the EudraCT database:	2018-10-11
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

2018-001042-33

A.3

Full title of the trial

Efficacy of humanized anti-CD20 antibodies (Ofatumumab) in the treatment of childhood steroid-dependent nephrotic syndrome and development of cell biomarkers predicting outcome.

Efficacia dell’anticorpo umanizzato anti-CD20 (Ofatumumab) nel trattamento della sindrome nefrosica steroido dipendente e sviluppo di biomarkers predittivi dell’evoluzione della malattia.

A.3.1

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

Efficacy of Ofatumumab in children with steroid-dependent nephrotic syndrome a

Efficacia di Ofatumumab in bambini con sindrome nefrosica steroido-dipendente.

A.3.2

Name or abbreviated title of the trial where available

The OFA3 trial

Il trial OFA3.

A.4.1

Sponsor's protocol code number

OFA3

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	Ministero salute per Ricera finalizzata
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 Istituto Giannina Gaslini
B.5.2	Functional name of contact point	Stefania Gamba
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	16133
B.5.3.4	Country	Italy
B.5.4	Telephone number	003901056363407
B.5.5	Fax number	00390103760883
B.5.6	E-mail	stefaniagamba@gaslini.org

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
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis
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.3.9.4	EV Substance Code	SUB25221
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	20/1
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	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	Myfenax
D.2.1.1.2	Name of the Marketing Authorisation holder	teva
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	Capsule, hard
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	MYCOPHENOLATE MOFETIL
D.3.9.3	Other descriptive name	MYCOPHENOLATE MOFETIL
D.3.9.4	EV Substance Code	SUB03360MIG
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	250
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	Myfenax
D.2.1.1.2	Name of the Marketing Authorisation holder	teva
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.3.8	INN - Proposed INN	MYCOPHENOLATE MOFETIL
D.3.9.3	Other descriptive name	MYCOPHENOLATE MOFETIL
D.3.9.4	EV Substance Code	SUB03360MIG
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	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

steroid dependent nephrotic syndrome

SINDROME NEFROSICA STEROIDE DIPENDENTE

E.1.1.1

Medical condition in easily understood language

steroid dependent nephrotic syndrome

SINDROME NEFROSICA STEROIDE DIPENDENTE

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	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10018365
E.1.2	Term	Glomerulonephritis and nephrotic syndrome
E.1.2	System Organ Class	100000004857

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

to test whether Ofatumumab is able to achieve and maintain drug-free disease remission in patients with steroid-dependent nephrotic syndrome at 12 months. This outcome will be compared to MMF, the drug recommended by Clinical Practice Guidelines (KDIGO) as benchmark of the treatment. The objective of the proposal is therefore to test whether Ofatumumab is superior to MMF in maintaining oral drug-free disease remission (complete or partial remission) for 12months in patients with SDNS.

testare se Ofatumumab sia superiore a MMF nel mantenimento di una remissione di malattia (completa o parziale) senza l’utilizzo di farmaci per os a 12 mesi nei bambini affetti da INS dipendente da terapia steroidea.

E.2.2

Secondary objectives of the trial

To reduce the risk of relapse in a longer follow-up of 24 months in the same group of patients. To verify the occurrence of side-effects in the short (30 days), mid (90 days) and long-term periods (2 years).
To analyze B and T cell lymphocyte subsets pre and post-therapy with Ofatumumab in order to study reconstitution of immune competence in these patients versus patients treated with MMF and to identify biomarkers of response to Ofatumumab and predictors of disease relapse.

testare se Ofatumumab sia superiore a MMF nella riduzione del rischio di recidiva in un periodo di follow up di 24 mesi nei bambini affetti da INS dipendente da terapia steroidea.
L’occorrenza di effetti collaterali (es. eventi avversi derivanti dall’utilizzo del farmaco in acuto e a lungo termine) e l’analisi del pattern dei linfociti B e T pre e post terapia con Ofatumumab costituiscono degli ulteriori obiettivi di questo studio.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Age between 3 and 24 years
- Prednison dependent steroid syndrome 0.3-1mg/Kg/day and receive prednisone for at least six months before enrolment. Steroid dependence is defined by two consecutive relapse during corticosteroid therapy or within 14 days of ceasing therapy.
- Ability to provide consent and assent: 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 any time without prejudice to his or her future medical care.

-Età compresa tra 3 e 24 anni
- Sindrome nefrosica steroid dipendente 0.3-1 mg/kg/die e assunzione di terapi steroidea per almeno sei mesi precedent all’arruolamento.
La corticodipendenza è definita come la presenza di due recidive consecutive in corso di terapia steroidea o entro 14 giorni dalla sua sospensione.
-Capacità di fornire un consenso/assenso: il consenso informato del genitore/tutore e l’assenso del bambino devono essere ottenuti prima di intraprendere qualsiasi procedura dello studio che non sia parte della normale assistenza del paziente e con la consapevolezza che tale consenso possa essere ritirato in qualsiasi momento, senza che ciò comporti un pregiudizio in merito al trattamento futuro del soggetto

E.4

Principal exclusion criteria

-Positivity to autoimmunity tests (ANA, nDNA, ANCA)
-Reduction of C3 levels.
-eGFR<90/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.
-Pregnancy
-Neoplasm
-Infections: previous or actual HBV (with HBeAb positivity) or HCV infection
-CD20 B lymphocytes count <2,5%
-Treatment with Rituximab or cyclophosphamide in the last 6 months

Positività a test autoimmuni (ANA, ds DNA, ANCA)
Riduzione dei livelli plasmatici della componente C3 del complemento.
-Filtrato glomerulare (estimated glomerular filtration rate, eGFR) < 90 ml/min/1.73 m2 calcolato secondo la Formula di Schwartz per i pazienti di età compresa tra 2 e 17 anni e secondo l’equazione CKD-EPI Creatinine 2009 per i pazienti di 18 anni.
-Gravidanza
-Neoplasie -Infezioni: infezione pregressa o attuale da HBV (con positività per anticorpi anti HBe) o HCV.
-Conta dei linfociti B CD20 positivi <2,5%
-Trattamento con Rituximab o ciclofosfamide negli ultimi 6 mesi.

E.5 End points

E.5.1

Primary end point(s)

Risk relapse within 12 months without steroid administration

rischio di recidiva a 12 mesi, senza la somministrazione di steroide

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months

12 mesi

E.5.2

Secondary end point(s)

evaluation of circolant cellular popolations as biomarkers or predictors of treatment with anti CD20

valutazione delle popolazioni cellulari circolanti come biomarkers o predittori della risposta al trattamento con anti CD20

E.5.2.1

Timepoint(s) of evaluation of this end point

0, 1, 3, 6, 12, 18, 24 months

0, 1, 3, 6, 12, 18, 24 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

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

Yes

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

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

Number of subjects for this age range:

120

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

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

pediatric population

popolazione pediatrica

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

160

F.4.2

For a multinational trial

F.4.2.1

In the EEA

160

F.4.2.2

In the whole clinical trial

160

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)

none

non differente dalla 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

2018-08-01

Ethics Committee Opinion of the trial application

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status

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