Clinical Trials Register

Summary
EudraCT Number:	2020-004982-37
Sponsor's Protocol Code Number:	NBK155/1/2020
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2020-12-30
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2020-004982-37

A.3

Full title of the trial

Early rituximab treatment in children with idiopathic nephrotic syndrome Eng. ERICONS - Early RITUXIMAB in Childhood Onset Nephrotic Syndrome

Wczesne leczenie rituximabem dzieci z idiopatycznym zespołem nerczycowym Ang. ERICONS – Early RITUXIMAB in Childhood Onset Nephrotic Syndrome

A.3.1

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

Early rituximab treatment in children with idiopathic nephrotic syndrome Eng. ERICONS - Early RITUXIMAB in Childhood Onset Nephrotic Syndrome

Wczesne leczenie rituximabem dzieci z idiopatycznym zespołem nerczycowym Ang. ERICONS – Early RITUXIMAB in Childhood Onset Nephrotic Syndrome

A.3.2

Name or abbreviated title of the trial where available

ERICONS

A.4.1

Sponsor's protocol code number

NBK155/1/2020

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	MEDICAL UNIVERSITY OF GDAŃSK
B.1.3.4	Country	Poland
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	Medical Research Agency
B.4.2	Country	Poland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	MEDICAL UNIVERSITY OF GDAŃSK
B.5.2	Functional name of contact point	Trial coordinator - A. Żurowska
B.5.3	Address:
B.5.3.1	Street Address	ul. Dębinki 7
B.5.3.2	Town/ city	Gdańsk
B.5.3.3	Post code	80-211
B.5.3.4	Country	Poland
B.5.4	Telephone number	+4858349 28 50
B.5.6	E-mail	nefped@gumed.edu.pl

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 100mg, concentrate for solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	MabThera 100mg concentrate for solution for infusion
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	Yes
D.3.11.13.1	Other medicinal product type	Monoclonal antibody

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

NEPHROTIC SYNDROME

IDIOPATYCZNY ZESPÓŁ NERCZYCOWY

E.1.1.1

Medical condition in easily understood language

NEPHROTIC SYNDROME

IDIOPATYCZNY ZESPÓŁ NERCZYCOWY

E.1.1.2

Therapeutic area

Diseases [C] - Symptoms and general pathology [C23]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10029164
E.1.2	Term	Nephrotic syndrome
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

Assessment of the duration of disease remission in the study group compared to placebo

Ocena czasu trwania remisji choroby w grupie badanej w porównaniu do placebo

E.2.2

Secondary objectives of the trial

1. Assessment of treatment failure in the study group compared to placebo
2. Assessment of the total dose of steroids administered in the test group compared to placebo
3. Assessment of B-cell depletion as an indicator of the risk of recurrence in the study group compared to placebo
4. Assessment of the duration of remission in the unblinded phase of the study
5. Optimizing RTX dosing
6. Assessment of the impact of the presence of anti-RTX antibodies on the effectiveness and presence of allergic reactions
7. Assessment of the effect of hypogammaglobulinemia on the duration of remission in the study group compared to placebo
8. Understanding the risk factors for the disease and how to respond to treatment with steroid-dependent NS

1. Ocena niepowodzenia leczenia w grupie badanej w porównaniu do placebo
2. Ocena całkowitej dawki podawanych steroidów w grupie badanej w porównaniu do placebo
3. Ocena deplecji limfocytów B jako wskaźnika ryzyka nawrotu w grupie badanej w porównaniu do placebo
4. Ocena czasu trwania remisji w odślepionej fazie badania
5. Optymalizacja dawkowania RTX
6. Ocena wpływu obecności przeciwciał anty-RTX na skuteczność działania i obecność reakcji alergicznych
7. Ocena wpływu hipogammaglobulinemii na czas trwania remisji w grupie badanej w porównaniu do placebo
8. Poznanie czynników ryzyka zachorowania i sposobu reakcji na leczenie steroidozależnego ZN

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

A patient will be included in the study if he or she meets the following inclusion criteria:
1. Expresses the willingness to participate in the study and after obtaining information about the study, the patient / legal guardians will sign an informed consent form for participation in the study
2. Age at study entry> 2 years (> 24 months of age) and under 16 years of age
3. Meet the criteria for diagnosis of idiopathic steroid-dependent nephrotic syndrome (two relapses during steroid dose reduction or within two weeks of stopping steroid therapy) or nephrotic syndrome with frequent relapses (two or more relapses in 6 months or four or more relapses in a period of 12 months)
4. Remission of NS immediately prior to study entry, defined as the absence or trace of protein in the urinalysis [uPCR <0.2 mg protein / mg creatinine (<20 mg protein / mmol creatinine) or <1+ in the test strip] for 3 consecutive days
5. Patients of childbearing age (conception) will commit to abstinence or to use effective contraception during the study period and up to 12 months after stopping RTX treatment; girls of childbearing potential will have a negative pregnancy test on qualifying for treatment initiation

Pacjent będzie włączony do badania, jeśli spełni następujące kryteria włączenia:
1. Wyrazi chęć udziału w badaniu i po uzyskaniu informacji na temat badania pacjent/opiekunowie prawni podpiszą formularz świadomej zgody na udział w badaniu
2. Wiek w momencie włączenia do badania > 2 lat (> 24 m.ż.) i poniżej 16 lat
3. Spełni kryteria rozpoznania idiopatycznego steroidozależnego zespołu nerczycowego (dwa nawroty podczas redukcji dawki steroidów lub w ciągu dwóch tygodni od zakończenia steroidoterapii) lub zespołu nerczycowego z częstymi nawrotami (dwa lub więcej nawrotów w ciągu 6 miesięcy albo cztery lub więcej nawrotów w okresie 12 miesięcy)
4. Remisja ZN bezpośrednio przed włączeniem do badania definiowana jako brak lub ślad białka w badaniu ogólnym moczu [uPCR < 0,2 mg białka/mg kreatyniny (< 20 mg białka/mmol kreatyniny) lub < 1+ w teście paskowym] przez 3 kolejne dni
5. Pacjenci w wieku rozrodczym (koncepcyjnym) zobowiążą się do wstrzemięźliwości seksualnej lub stosowania skutecznej antykoncepcji w okresie badania i do 12 miesięcy od zakończenia leczenia RTX; dziewczynki w wieku rozrodczym będą miały ujemny wynik testu ciążowego w momencie kwalifikacji do rozpoczęcia leczenia

E.4

Principal exclusion criteria

1. Previous use of immunosuppressants such as cyclophosphamide, cyclosporin A, tacrolimus, mycophenolate mofetil, levamisole
2. Diagnosis of steroid-resistant NS, nephritic syndrome or secondary NS
3. Previous severe infection (tuberculosis, systemic mycosis), HIV, HCV, HBV infection
4. Active infection
5. Severe heart diseases (heart failure, myocardial infarction, severe heart rhythm disturbances)
6. Vaccinations with live vaccines within 4 weeks prior to study inclusion
7. Poorly controlled hypertension
8. Abnormal kidney function (eGFR <90 ml / min)
9. Autoimmune disease (IgA vasculitis, systemic lupus)
10. Current or history of cancer
11. Status after organ transplantation
12. Allergy to methylprednisolone, paracetamol, cetirizine, co-trimoxazole
13. Laboratory abnormalities: leukocyte count <3000 / µl, neutrocyte count <1500 / µl, platelet count <75,000 / µl, severe liver dysfunction: ALT or AST 2.5 times upper limit of normal
14. Prior treatment with monoclonal antibodies
15. Use of another study drug within the 6 months prior to study entry, or participation in other studies at screening
16. Severe immunodeficiency
17. Pregnancy, breastfeeding or refusal to use methods of contraception in case of the ability to become pregnant (pregnancy test required - beta hCG in the blood serum at enrollment in the study)
18. Hypersensitivity to the active substance, murine proteins or to any of the excipients of the test drug (i.e. sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, hydrochloric acid, water for injections)

1. Wcześniejsze stosowanie leków immunosupresyjnych takich jak cyklofosfamid, cyklosporyna A, takrolimus, mykofenolan mofetylu, lewamizol
2. Rozpoznanie steroidoopornego ZN, zespołu nefrytycznego lub wtórnego ZN
3. Przebyta ciężka infekcja (gruźlica, grzybica układowa), zakażenie wirusem HIV, HCV, HBV
4. Aktywna infekcja
5. Ciężkie choroby serca (niewydolność serca, zawał mięśnia sercowego, ciężkie zaburzenia rytmu serca)
6. Szczepienia szczepionkami żywymi w ciągu 4 tygodni przed włączeniem do badania
7. Źle kontrolowane nadciśnienie tętnicze
8. Nieprawidłowa funkcja nerek (eGFR < 90 ml/min)
9. Choroba autoimmunologiczna (zapalenie naczyń IgA, toczeń układowy)
10. Choroba nowotworowa obecnie lub w wywiadzie
11. Stan po przeszczepieniu narządu
12. Uczulenie na metyloprednizolon, paracetamol, cetyryzynę, kotrimoksazol
13. Nieprawidłowości w badaniach laboratoryjnych: liczba leukocytów<3000/µl, liczba neutrocytów <1500/ µl, liczba płytek krwi < 75,000/µl, ciężka dysfunkcja wątroby: ALAT lub AspAT 2,5 x powyżej górnej granicy normy
14. Wcześniejsze leczenie przeciwciałami monoklonalnymi
15. Stosowanie innego badanego leku w ciągu 6 miesięcy przed włączeniem do badania lub udział w innych badaniach w momencie kwalifikacji
16. Ciężkie niedobory odporności
17. Ciąża, karmienie piersią lub odmowa stosowania metod zapobiegania ciąży w przypadku zdolności do zajścia w ciążę (wymagany test ciążowy – beta hCG w surowicy krwi przy włączaniu do badania)
18. Nadwrażliwość na substancję czynną, białka mysie lub na którąkolwiek substancję pomocniczą leku badanego (tj. cytrynian sodu, polisorbat 80, chlorek sodu, wodorotlenek sodu, kwas solny, woda do wstrzykiwań)

E.5 End points

E.5.1

Primary end point(s)

Relapse-free time (defined as proteinuria persisting ≥ 3 days during the blinded phase (days 1 to 365))

Czas wolny od nawrotu choroby (definiowanego jako wystąpienie białkomoczu utrzymującego się ≥ 3 dni w trakcie trwania fazy zaślepionej (od 1 do 365 dnia))

E.5.1.1

Timepoint(s) of evaluation of this end point

From the time of randomization to the time of first relapse after study drug administration (1-365 days)

Od momentu randomizacji do czasu pierwszego nawrotu po podaniu leku badanego (1-365 dni)

E.5.2

Secondary end point(s)

1. Total dose of steroids administered
2. Time from resolution of depletion to relapse
3. Relapse-free time during the unblinded phase (from the study drug administration to the 365 observation day)
4. a. Pharmacokinetics of RTX
b. Correlation of RTX concentration with disease relapse
c. Assessment of C4d, sC5b-9 (TCC) concentration and serum CDC activity
5. Correlation of anti-RTX antibodies with therapy failure
Correlation of the presence of anti-RTX antibodies with allergic symptoms
6. Correlation of serum immunoglobulin levels with the presence of proteinuria
Correlation of serum immunoglobulin levels with the presence of infection
7.a. Patient genotype determination (genome wide association study, GWAS)
b. Determination of the immunophenotype of patients (subpopulations of B and T lymphocytes)
c. Cytokine determination

1. Całkowita dawka podawanych steroidów
2. Czas od ustąpienia deplecji do nawrotu
3. Czas wolny od nawrotu choroby w trakcie trwania fazy odślepionej (od dnia podania leku badanego do 365 dnia obserwacji)
4. a. Farmakokinetyka RTX
b. Korelacja stężenia RTX z nawrotem choroby
c. Ocena stężenia C4d, sC5b-9 (TCC) oraz aktywności CDC surowicy
5. Korelacja obecności przeciwciał anty-RTX z niepowodzeniem terapii
Korelacja obecności przeciwciał anty-RTX z objawami alergicznymi
6. Korelacja stężenia immunoglobulin w surowicy z obecnością białkomoczu
Korelacja stężenia immunoglobulin w surowicy z obecnością zakażenia
7. a. Oznaczenie genotypu chorych (badanie asocjacyjne całego genomu, GWAS)
b. Oznaczenie immunofenotypu chorych (subpopulacji limfocytów B i T)
c. Oznaczenie cytokin

E.5.2.1

Timepoint(s) of evaluation of this end point

1.12 months
2. Day1(before administration),2,8 (before administration), 9,29,85,169, 365,relapse*
3. From the time of study drug administration after relapse until the next relapse (1-365 days)
4.a, b. Day1 (before and after administration), 2,8(before and after administration), 9,29,85,169,365,relapse*
c. Day1 (before and after administration), 2,8(before and after administration), 9, relapse*
5. Day1 (before and after administration), 2,8(before and after administration), 9,29,85,169,365,relapse*
6. Day -1,7,29,57,85,113,141,169,197,253,309,365,relapse*
7.a. Day 29
b. Day1(before administration),2,8 (before administration), 9,29,85,169, 365, relapse*
c. Day1(before administration),2,8 (before administration), 9,29,85,169, 365, relapse*
*first relapse in the blind and open phase

1. 12 miesięcy
2. Dzień 1 (przed podaniem), 2, 8 (przed podaniem), 9, 29, 85, 169, 365, nawrót*
3. Od momentu podania leku badanego po nawrocie do czasu kolejnego nawrotu (1-365 dni)
4. a, b. Dzień 1 (przed i po podaniu), 2, 8 (przed i po podaniu), 9, 29, 85, 169, 365, nawrót*
c. Dzień 1 (przed i po podaniu), 2, 8 (przed i po podaniu), 9, nawrót*
5. Dzień 1 (przed i po podaniu), 2, 8 (przed i po podaniu), 9, 29, 85, 169, 365, nawrót*
6. Dzień -1, 7, 29, 57, 85, 113, 141, 169, 197, 253, 309, 365, nawrót*
7. a. Dzień 29
b. Dzień 1 (przed podaniem), 2, 8 (przed podaniem), 9, 29, 85, 169, 365, nawrót*
c. Dzień 1 (przed podaniem), 2, 8 (przed podaniem), 9, 29, 85, 169, 365, nawrót*
*pierwszy nawrót w fazie zaślepionej i otwartej

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

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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

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

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

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

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2020-12-30.

Yes

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

minority

małoletność

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)

Further RTX treatment of patients who took part in the study will be at the discretion of the treatment center. Study drug treatment is not planned to be continued after the completion of the study.

Dalsze leczenie RTX pacjentów, którzy brali w badaniu, będzie uzależnione od decyzji ośrodka leczącego. Nie planuje się kontynuacji leczenia lekiem badanym po ukończeniu badania.

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

2021-05-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-03-04

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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IMP with orphan designation in the indication
Orphan Designation Number:
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