Clinical Trials Register

Summary
EudraCT Number:	2017-003839-11
Sponsor's Protocol Code Number:	1352_0PBG_2017
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:	2017-12-01
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

2017-003839-11

A.3

Full title of the trial

Belimumab for the treatment of frequently relapsing nephrotic syndrome open label phase II trial. BELNEPH STUDY

BELNEPH: Studio prospettico aperto di fase II sull’uso del Belimumab per il trattamento di pazienti pediatrici affetti da sindrome nefrosica corticosensibile a frequenti recidive

A.3.1

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

Belimumab for the treatment of frequently relapsing nephrotic syndrome

Studioper il trattamento di pazienti pediatrici affetti da sindrome nefrosica corticosensibile a frequenti recidive

A.3.2

Name or abbreviated title of the trial where available

BELNEPH STUDY

BELNEPH

A.4.1

Sponsor's protocol code number

1352_0PBG_2017

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 Ospedale PedT..trico Bambino Gesù
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	OPBG Foundation
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	Associazione per la Cura del Bambino Nefropatico - 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	OPBG
B.5.2	Functional name of contact point	Marina Vivarelli
B.5.3	Address:
B.5.3.1	Street Address	Viale San Paolo, 15
B.5.3.2	Town/ city	Rome
B.5.3.3	Post code	00146
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390668592997
B.5.6	E-mail	marina.vivarelli@opbg.net

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	Benlysta
D.2.1.1.2	Name of the Marketing Authorisation holder	Glaxo Group Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	belimumab
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.3.11 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	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

frequently relapsing nephrotic syndrome

sindrome nefrosica corticosensibile a frequenti recidive

E.1.1.1

Medical condition in easily understood language

nephrotic syndrome

sindrome nefrosica corticosensibile

E.1.1.2

Therapeutic area

Diseases [C] - Male diseases of the urinary and reproductive systems [C12]

MedDRA Classification

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 aim of the study is to test the safety of belimumab 10 mg/kg given i.v. at day 0, 14, 28 and subsequently every 4 weeks for a total of 12 months to patients with frequently relapsing forms of nephrotic syndrome, defined as two or more relapses per 6 months (or 4 or more per 12 month period) following the initial therapy or a relapse therapy (Vivarelli et al 2016).

L’obiettivo primario dello studio è quello di valutare la sicurezza di belimumab 10 mg/kg somministrato e.v. ai giorni 0, 14, 28 e in seguito ogni 4 settimane per un totale di 12 mesi a pazienti pediatrici affetti da INS a frequenti recidive, definita come due o più recidive in 6 mesi (o 4 o più recidive in 12 mesi) (Vivarelli et al 2016) dopo aver indotto la remissione dell’ultimo episodio di proteinuria nefrosica (recidiva o esordio). La recidiva è definita come stick urine 3+ per 3 giorni consecutivi o 1+-3+ per 7 giorni consecutivi.

E.2.2

Secondary objectives of the trial

- to evaluate whether the therapeutic use of belimumab is able to prevent disease relapse despite tapering of prednisone in children with frequently relapsing nephrotic syndrome;
- to evaluate the immunomodulatory effect of belimumab on B cell subpopulations in children with frequently relapsing nephrotic syndrome.

1) valutare se l’impiego terapeutico di belimumab è efficace nel prevenire recidive di malattia nonostante la riduzione del prednisone in pazienti pediatrici affetti da INS a frequenti recidive
2) valutare l’effetto immunomodulatorio di belimumab sulle sottopopolazioni di linfociti B in pazienti pediatrici affetti da INS a frequenti recidive.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

a. Age ≥3 years and <18 years, at enrolment
b. Frequently relapsing forms of INS, defined as two or more relapses per 6 months (or 4 or more per 12 month period) following the initial therapy or a relapse therapy (Vivarelli 2016). Relapse is defined as 3+ positive dipsticks on 3 consecutive days or by positive dipsticks (1+ to 3+) for 7 consecutive days.
c. Normal renal function (creatinine clearance > 90 ml/min/1.73 m2, as calculated by the Schwartz formula)
d. Remission of INS at enrolment
e. Patients that are on maintenance PDN treatment at a dose higher than 10 mg/m2 on alternate days
f. Expected compliance from the patient and his parents to the study protocol
g. Signed Informed Consent Form (ICF)/Assent by the subject’s parent(s) or legal representative(s). Children will be informed about the study and will be asked to give their assent as appropriate, depending on age.
h. If applicable, female participants must have pregnancy test by beta-HCG dosing and be negative.

a. Età ≥3 anni e <18 anni, al momento dell’arruolamento
b. Forme di INS a frequenti recidive, definite come 2 o più recidive in 6 mesi o 4 o più in 12 mesi dopo la terapia per indurre la remissione dall’esordio o dall’ultima recidiva (Vivareli et al 2016). Si definisce recidiva una proteinuria di 3+ allo stick urine per 3 giorni consecutivi o di 1+-3+ allo stick urine per 7 giorni consecutivi.
c. Funzione renale conservata, definite come clearance della creatinine > 90 ml/min/1.73 m2, calcolata con la formula di Schwartz)
d. Remissione di proteinuria, definite come stick urine 0 o trace per almeno 3 giorni consecutive al momento dell’arruolamento
e. Pazienti in terapia di mantenimento con PDN ad una dose superior a 10 mg/m2 a giorni alterni
f. Compliance presunta da parte del paziente e della famiglia al protocollo di studio per tutta la sua durata
g. Firma del consenso informato da parte del/I genitore/I o tutore/I legale/I del soggetto. I pazienti riceveranno informazioni e spiegazioni e firmeranno consensi formulati in base alla loro età.
h. Se in età fertile, soggetti di sesso femminile dovranno durante l’arruolamento risultare negativi ad un test di gravidanza effettuato mediante dosaggio di beta-HCG.

E.4

Principal exclusion criteria

a. Patients suffering from co-morbidities that are not related to INS, including malignancies
b. Patients with the following infections: HIV, hepatitis B and
c. Patients with any other chronic infectious condition
d. Patients with steroid-resistant INS
e. Patients that have achieved remission in more than 21 days during their last relapse (i.e. patients at risk of secondary steroid resistance)
f. Patients that have relapsed in the past year while receiving more than 30 mg/m2 of PDN on alternate days (i.e. severe steroid dependence that may require immediate initiation of additional immunosuppressive medication)
g. Patients that are have been treated with other immunosuppressive drugs in the last 12 months, particularly with drugs that inhibit B cell function (cyclophosphamide, micophenolate mofetil)
h. Patients that have been treated with rituximab
i. Patients that have received live vaccines in the 30 days previous to study initiation

a. pazienti con co-morbidità non correlate alla INS
b. pazienti con le seguenti infezioni: HIV, epatite B e C
c. pazienti con altre infezioni croniche
d. pazienti con forme steroido-resistenti di INS
e. pazienti con remissione raggiunta in > 21 giorni durante l’ultima recidiva (pazienti a rischio di steroido-resistenza secondaria)
f. pazienti che hanno presentato recidive nell’ultimo anno quando stavano in terapia con prednisone a più di 30 mg/m2 a giorni alterni (ossia con forme steroido-dipendenti severe che possono richiedere l’inizio immediato di terapia immunosuppressiva di seconda linea)
g. pazienti che abbiano ricevuto farmaci immunosoppressivi di seconda linea negli ultimi 12 mesi, in particolare se inibiscono la funzione dei linfociti B (ciclofosfamide, micofenolato mofetile)
h. pazienti trattati con rituximab
i. pazienti che abbiano ricevuto vaccini vivi nei 30 giorni precedenti l’inizio dello studio

E.5 End points

E.5.1

Primary end point(s)

The primary end-point is the frequency of allergic reactions and other adverse events. Serious adverse events will be recorded from the time of obtaining informed consent throughout the study period. The time stop for collecting evidence will be every 6 months and at 24 months. Subjects who discontinue the study prematurely will continue to be monitored for safety.

La frequenza di reazioni allergiche e di altri eventi avversi. Tutti gli eventuali eventi avversi saranno valutati e registrati dal momento dell’arruolamento fino alla conclusione dello studio. Il time stop delle evidenze sarà ogni 6 mesi e a 24 mesi. Soggetti arruolati che interrompono lo studio prematuramente continueranno ad essere monitorati.

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months and at 24 months

ogni 6 mesi e a 24 mesi

E.5.2

Secondary end point(s)

- the percentage of patients in remission at 6 and 12 months
- the total dose of prednisone/kg of body weight administered in the 12 months of treatment with belimumab.

1) la percentuale di pazienti in remissione a 6 e a 12 mesi di trattamento con belimumab
2) la dose totale di prednisone/kg di peso corporeo somministrata durante i 12 mesi di trattamento con belimumab a ciascun paziente arruolato

E.5.2.1

Timepoint(s) of evaluation of this end point

at 6 and 12 months

a 6 e a 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

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

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.8.5

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

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:

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)

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

minors

minore

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)

None

Nessuno

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

2018-03-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-11-15

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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