Clinical Trials Register

Summary
EudraCT Number:	2021-000835-30
Sponsor's Protocol Code Number:	MONET
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:	2021-08-30
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2021-000835-30

A.3

Full title of the trial

RESCUE THERAPY WITH THE HUMAN ANTI-CD38 ANTIBODY MOR202 (FELZARTAMAB) IN PATIENTS WITH MEMBRANOUS NEPHROPATHY WHO FAILED ANTI-CD20 TARGETED THERAPY: A PILOT, PROOF-OF-CONCEPT STUDY

“Rescue therapy” con MOR202, un anticorpo anti-CD38, in pazienti con nefropatia membranosa resistenti alla terapia con anticorpi anti-CD20

A.3.1

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

MOR202 for refractory MN

Impiego di Felzartamab in pazienti con nefropatia membranosa resistenti alla terapia con anticorpi anti-CD20

A.3.2

Name or abbreviated title of the trial where available

MOR202 for refractory MN

MOR202 nella nefropatia membranosa resistente

A.4.1

Sponsor's protocol code number

MONET

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 DI RICERCHE FARMACOLOGICHE MARIO NEGRI
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	MorphoSys AG
B.4.2	Country	United States
B.4.1	Name of organisation providing support	Istituto di Ricerche Farmacologiche Mario Negri IRCCS
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	Istituto di Ricerche Farmacologiche Mario Negri IRCCS
B.5.2	Functional name of contact point	Lab. Att. Regolatorie Studi Clinici
B.5.3	Address:
B.5.3.1	Street Address	via G.B. Camozzi, 3
B.5.3.2	Town/ city	Ranica
B.5.3.3	Post code	24020
B.5.3.4	Country	Italy
B.5.4	Telephone number	0354535307
B.5.5	Fax number	0354535372
B.5.6	E-mail	paola.boccardo@marionegri.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	No
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	MOR202
D.3.2	Product code	[MOR202]
D.3.4	Pharmaceutical form	Lyophilisate 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.3.9.1	CAS number	2197117-39-1
D.3.9.2	Current sponsor code	MOR202
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	16
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)	Yes
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

Membranous Nephropathy who Failed Anti-CD20 Target Therapy.

Nefropatia membranosa resistente alla terapia con anti-CD20.

E.1.1.1

Medical condition in easily understood language

Membranous Nephropathy who Failed Anti-CD20 Target Therapy.

Nefropatia membranosa resistente alla terapia con anti-CD20.

E.1.1.2

Therapeutic area

Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10027170
E.1.2	Term	Membranous nephropathy
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 evaluate the efficacy of MOR202 in reducing and/or abrogating urinary protein excretion in MN patients with nephrotic-range proteinuria who are resistant to or dependent from anti-CD20 antibodies.

Valutare l’efficacia di MOR202 nel ridurre e/o eliminare l'escrezione urinaria di proteine nei pazienti affetti da NM con proteinuria nel range nefrosico resistenti o dipendenti dagli anticorpi anti-CD20.

E.2.2

Secondary objectives of the trial

To assess, in MN patients with nephrotic-range proteinuria who are resistant to or dependent from anti-CD20 antibodies:
- The clinical efficacy of MOR202 over the whole follow-up period.
- The effect of MOR202 on anti-PLA2R and anti-THSD7A levels over time.
- The incidence of immunological and clinical relapses after the MOR202-induced immunologic and/or clinical NS remission.
- The effects of MOR202 on renal function, glomerular permselectivity and metabolic parameters over time.
- The consequences of MOR202 administration on circulating NK-, T- and B-cell subsets.
- The effects of MOR202 on patient-perceived outcomes.
- The immunogenicity and pharmacokinetic profile of MOR202.
- The safety of MOR202 administration.

Valutare, in pazienti affetti da NM con proteinuria nel range nefrosico resistenti o dipendenti da anticorpi anti-CD20:
- L’efficacia clinica di MOR202 durante tutto il periodo di follow-up.
- L’effetto nel tempo di MOR202 sui livelli di anti-PLA2R e anti-THSD7A.
- L'incidenza di recidive immunologiche e cliniche dopo la remissione immunologica e/o clinica di NS indotta da MOR202.
- Gli effetti nel tempo di MOR202 sulla funzione renale, sulla permselettività glomerulare e sui parametri metabolici.
- Le conseguenze della somministrazione di MOR202 sui sottogruppi di cellule NK, T e B circolanti.
- Gli effetti di MOR202 sugli outcome percepiti dal paziente.
- L'immunogenicità e il profilo farmacocinetico di MOR202.
- La sicurezza della somministrazione di MOR202.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Age =18 years.
- Biopsy-proven membranous nephropathy with or without detectable circulating anti-PLA2R or anti-THSD7A antibodies.
- Background treatment with RAS blocking agents (ACE inhibitor and/or ARBs), at maximum tolerated doses and adequately controlled blood pressure (BP <140/90 mmHg in at least three consecutive readings at screening).
- One condition between:
• Anti-CD20 Resistance: residual proteinuria =3.5 g/day (mean of three consecutive 24-hour urine collections), with less than 50% reduction compared to pre-treatment values at least 12 months after anti-CD20 antibody therapy.
• Anti-CD20 Dependence: frequently relapsing NS (nephrotic-range proteinuria for >50% of time in the last five years or since disease onset, whichever is shorter) despite repeated treatments with anti-CD20 antibodies.
- Estimated GFR >30 ml/min/1.73m2 (CKD-EPI equation) and less than 50% of sclerotic glomeruli in patients receiving renal biopsy.
- A minimum 12-month wash-out from last anti-CD20 therapy with rituximab and/or other monoclonal antibodies.
- No immunosuppressive therapy with steroid, cyclophosphamide, cyclosporine, mycophenolate mofetil or any other immunosuppressant over the last 6 months; in case of therapies administered for less than 2 weeks, no washout time will be required prior to inclusion.
- Completed anti SARS Cov 2 Vaccination
- Written informed consent

- Età =18 anni;
- Nefropatia membranosa confermata da biopsia con o senza anticorpi circolanti anti-PLA2R o anti-THSD7A rilevabili.
- Terapia con agenti bloccanti RAS (ACE inibitori e/o ARB), alle dosi massime tollerate e pressione sanguigna adeguatamente controllata (PA <140/90 mmHg in almeno 3 letture consecutive allo screening).
- Una delle seguenti condizioni:
• Resistenza agli anti-CD20: proteinuria residua =3,5 g/die (media di 3 raccolte consecutive di urine nelle 24 ore), con una riduzione inferiore al 50% rispetto ai valori pre-trattamento ad almeno 12 mesi dalla terapia con anticorpi anti-CD20.
• Dipendenza da anti-CD20: SN frequentemente recidivante (proteinuria nel range nefrosico per >50% del tempo negli ultimi 5 anni o dall'esordio della malattia, se insorta più recentemente), nonostante trattamenti ripetuti con anticorpi anti-CD20.
- GFR stimata >30 ml/min/1.73m2 (calcolato con l’equazione CKD-EPI) e meno del 50% di glomeruli sclerotici (valutato nei pazienti sottoposti a biopsia renale).
- Wash-out minimo di 12 mesi dall’ultima terapia anti-CD20 con rituximab e/o altri anticopri monoclonali.
- Nessuna terapia immunosoppressiva con steroidi, ciclofosfamide,ciclosporina, micofenolato mofetil o altri farmaci immunosoppressori negli ultimi 6 mesi.; In caso di terapie somministrate per un periodo inferiore alle due settimane, non verrà richiesto nessun periodo di washout prima dell’inclusione nello studio
- Ciclo vaccinale anti SARS Cov 2 completato
- Consenso informato scritto.

E.4

Principal exclusion criteria

- Clinically relevant neutropenia (neutrophils < 1.5 x 109/L), anemia (Hb levels <9.0 g/dL), thrombocytopenia (platelet count < 150.000/mm3), hypogammaglobulinemia (serum immunoglobulin =5.0 g/L), increased liver transaminase or bilirubin levels (total bilirubin, aspartate aminotransferase or alanine aminotransferase >1.5 x ULN, alkaline phosphatase >3.0 x ULN).
- Significant uncontrolled cardiovascular disease (including arterial or venous thrombotic or embolic events over the last three months) or cardiac insufficiency (New York Heart Association [NYHA] class IV) as judged by the investigator.
- Clinically relevant findings on a 12-lead electrocardiogram (ECG) as determined by the investigator at screening.
- History of significant cerebrovascular disease (stroke or transitory ischemic attack over the last three months) or sensory or motor neuropathy of toxicity = grade 3.
- Any clinical condition that in the investigator judgment could affect the possibility to complete the study or could have a major confounding effect on study findings and data interpretation.
- Known intolerance to the study drug or its excipients
- Any viral, bacterial or fungal infection without complete symptoms resolution from at least two weeks.
- Serologic or virologic markers positive for HIV, hepatitis C (patients with positive antihepatitis C virus [anti-HCV] antibody but negative HCV RNA polymerase chain reaction [PCR] can enroll) or active or latent hepatitis B (patients with positive hepatitis B surface antigen [HBsAg] are excluded). Patients with isolated positive hepatitis B core antibody [anti-HBc], hepatitis B virus (HBV) DNA test by PCR must be non-detectable to enroll.
- History of malignancy within the prior 5 years.
- Participation in other clinical trials within 4 weeks of signing the consent form.
- Expected need of anti SARS Cov 2 vaccination during the study period
- Pregnancy or breast-feeding.
- Childbearing potential in males and females non using an highly effective method of contraception according to 2020 CTFG Recommendations related to contraception and pregnancy testing in clinical trials (https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contraception_guidance_Version_1.1_updated.pdf).
- Legal incapacity or limited legal capacity.

- Neutropenia clinicamente rilevante (neutrofili <1,5x109/L), anemia (livelli di Hb <9.0g/dL), trombocitopenia (conta piastrinica <150.000/mm3), ipogammaglobulinemia (immunoglobulina sierica =5.0g/L), transaminasi epatiche o livelli di bilirubina aumentati (bilirubina totale, aspartato transaminasi o alanina aminotransferasi >1.5xULN, fosfatasi alcalina >3.0xULN);
- Malattia cardiovascolare non controllata importante a giudizio dello sperimentatore (compresi eventi trombotici o embolici arteriosi o venosi nei 3 mesi precedenti) o insufficienza cardiaca (di classe IV in accordo con la NYHA).
- Anomalie clinicamente rilevabili sull’ECG), allo screening.
- Storia di malattia cerebrovascolare importante (ictus o attacco ischemico transitorio negli ultimi 3 mesi), oppure di neuropatia sensoriale o motoria di tossicità = grado 3.
- Qualsiasi condizione clinica che, a parere dello sperimentatore, possa condizionare la possibilità di completare lo studio o avere un significativo effetto confondente sui risultati dello studio e sulla interpretazione dei dati.
- Intolleranza nota al farmaco sperimentale o ai suoi eccipienti
- Qualsiasi infezione virale, batterica o fungina non completamente risolta da almeno due settimane
- Marcatori sierologici e virologici positivi per HIV, epatite C (possono essere arruolati i pazienti positivi agli anticorpi contro l’epatite C [anti-HCV], ma negativi alla PCR per HCV RNA), oppure a epatite B attiva o latente (sono esclusi i pazienti positivi all’antigene di superficie dell’epatite B [HBsAg]). Per l’arruolamento di pazienti positivi all’anticorpo core dell’epatite B [anti-Hbc], il test per il DNA del virus dell’epatite B (HBV) mediante PCR deve risultare non rilevabile.
- Storia di tumori maligni nei 5 anni precedenti.
- Partecipazione ad altri studi clinici nelle 4 settimane precedenti alla firma del modulo di consenso.
- Gravidanza o allattamento al seno.
- Vaccinazione anti SARS CoV 2 programmata durante lo studio
- Soggetti maschi e femmine in età fertile che non utilizzano un metodo contraccettivo ritenuto efficace secondo le Raccomandazioni CTFG del 2020 relative alla contraccezione e ai test di gravidanza negli studi clinici (accessibile all’indirizzo: https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contraception_guidance_Version_1.1_updated.pdf);
- Incapacità legale o capacità legale limitata.

E.5 End points

E.5.1

Primary end point(s)

Primary Outcome
- Reduction in 24-hour urinary protein excretion at 12 months after the first MOR202 administration compared to baseline.
Co-primary Outcome
- Composite endpoint of complete remission (24-hour urinary protein excretion <0.3 g or urinary protein to creatinine ratio < 300 mg/g, with serum albumin > 3.5 g/dL) or partial remission (24-hour urinary protein excretion <3.5 g or urinary protein to creatinine ratio < 3500 mg/g, with at least 50% reduction compared to baseline) of nephrotic syndrome at 12 months from the first infusion;

Primari e Co-primari
Valutare l’efficacia di MOR202 nel ridurre e/o eliminare l'escrezione urinaria di proteine nei pazienti affetti da NM con proteinuria nel range nefrosico resistenti o dipendenti dagli anticorpi anti-CD20.

E.5.1.1

Timepoint(s) of evaluation of this end point

At screening, basa, after 1, 4 and 24 months after the first IMP infusion visits.

Alle visite di screening, basale, dopo 1, 4 e 24 mesi dalla prima somministrazione di farmaco.

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)

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

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

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

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.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)

aaaaaa

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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

2021-07-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-10-12

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

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