Clinical Trials Register

Summary
EudraCT Number:	2018-004947-21
Sponsor's Protocol Code Number:	CLAD19
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-04-28
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

2018-004947-21

A.3

Full title of the trial

Exploring the intrathecal anti-inflammatory effect of cladribine and its relationship with clinical efficacy

Studio sull’effetto antiinfiammatorio intratecale della Cladribina e la sua relazione con l’efficacia clinica

A.3.1

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

Exploring the intrathecal anti-inflammatory effect of cladribine and its relationship with clinical efficacy

Studio sull’effetto antiinfiammatorio intratecale della Cladribina e la sua relazione con l’efficacia clinica

A.3.2

Name or abbreviated title of the trial where available

CLAD19

A.4.1

Sponsor's protocol code number

CLAD19

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	Azienda Ospedaliera Universitaria Integrata Verona
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	Merck Serono Spa
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	AOUI Verona
B.5.2	Functional name of contact point	Unità Ricerca Clinica
B.5.3	Address:
B.5.3.1	Street Address	P.le Stefani, 1
B.5.3.2	Town/ city	Verona
B.5.3.3	Post code	37126
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390458127043
B.5.5	Fax number	+390458122814
B.5.6	E-mail	supporto.noprofit@aovr.veneto.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	MAVENCLAD 6CPR 10mg
D.2.1.1.2	Name of the Marketing Authorisation holder	MERCK SERONO SPA
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	MAVENCLAD 6CPR 10 mg
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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

highly active relapsing multiple sclerosis

Sclerosi multipla recidivante remittente con alta attività di malattia

E.1.1.1

Medical condition in easily understood language

multiple sclerosis

sclerosi Multipla

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

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	10063399
E.1.2	Term	Relapsing-remitting multiple sclerosis
E.1.2	System Organ Class	10029205 - Nervous system 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

Verify whether a decrease of CSF levels of CXCL13 at the end of treatment (T24) with cladribine compared to the levels of CXCL13 before the treatment (T-3 -T-1) with cladribine is related to the achievement of “no evidence of disease activity” (NEDA).

Verificare se una riduzione di livelli di CXCL13 nel CSF alla fine di 24 mesi di trattamento con Cladribina rispetto al pre-trattamento (T-3 T-1), si associ al raggiungimento della “no evidence of disease activity” (NEDA).

E.2.2

Secondary objectives of the trial

Describe and compared the individual change in CSF levels of CXCL13 at the end of cladribine treatment
Verify the decrease of CXCL13 in serum of patients treated with cladribine at the end of treatment compared to pre-treatment
Describe potential changes in oligoclonal IgG bands in CSF of patients treated with cladribine at the end of treatment compared to pre-treatment
Evaluate the transcriptomic profile obtained by the correspondent CSF cell pellet and identify mRNAs or gene sets whose expression is significantly associated to change in CXCL13CSF levels and disease activity after 2 years of cladribine treatment.
Describe the correlations between change in the CSF levels of CXCL13 and disability progression, annual relapse rate and new WM
Describe the correlations between change in the CSF levels of CXCL13 with advanced MRI parameters (new cortical lesions, n of chronic enlarging T2 lesions, global Cortical Thickness change) after 2 years of cladribine treatment

Descrivere i cambiamenti individuali nei livelli di CXCL13 nel CSF alla fine del trattamento con Cladribina rispetto al pre-trattamento
Verificare la riduzione dei livelli di CXCL13 nel siero alla fine del trattamento con Cladribina rispetto al pre-trattamento
Descrivere potenziali cambiamenti nelle bande IgG oligoclonali nelCSF alla fine del trattamento con Cladribina rispetto al pretrattamento
Valutare il profilo transcrittomico ottenuto dal corrispondente pellet di cellule CSF e identificare mRNA o set genici la cui espressione è significativamente associata a cambiamenti nei livelli di CSFCXCL13e attività di malattia dopo il trattamento con Cladribina
Descrivere le correlazioni tra i livelli diCXCL13nel CSFcon:progressione della disabilità;tasso annuale di recidive;nuove lesioni di WM
Descrivere le correlazioni tra i livelli di CXCL13 nel CSF con i parametri di MRI avanzati:nuove lesioni corticali, n. di lesioni croniche aumentate e cambiamenti a livello di spessore corticale

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

-Treatment with Cladribine when provided by the local Authority (AOUI Verona), started at least 30 days before the enrolment.
-At least 2 cc of CSF and 10 cc of blood acquired before the beginning of the cladribine treatment and stored at -80°C
-Male or female subject ≥18 years affected by highly active RRMS defined by at least two relapses in the previous year
-EDSS ≤5.0

- Trattamento con Cladribina, quando fornita dall’AOUI, iniziato almeno 30 giorni prima del reclutamento.
- Acquisizione di almeno 2 cc di CSF e 10 cc di sangue prima dell’inizio del trattamento con Cladribina, storati a -80°.
- Maschi o femmine adulti
- età ≥18 e < 65aa
- Diagnosi di Sclerosi Multipla Recidivante Remittente con alta attività di malattia, definita da almeno due ricadute nell’ultimo anno.
- Punteggio EDSS ≤ 5.0.
- Donne non in gravidanza né allattamento a T0 fino ad almeno una settimana dopo la somministrazione dell’ultima dose del secondo anno.
- Assunzione di efficaci trattamenti contraccettivi (metodi contraccettivi: ormonali combinati estroprogestinici orali/intravaginali/transdermici, ormonali progesterinici orali/iniettabili/impiantabili, dispositive intrauterine, dispositive di rilascio ormonali intrauterine, occlusion tubarica bilaterale, partner vasectomizzato, astinenza sessuale). dalle 4 settimane precedenti l’inizio del trattamento con Cladribina fino ad almeno 6 mesi dopo la somministrazione dell’ultima dose

E.4

Principal exclusion criteria

-Previous treatment with other DMT
-Positive result to HBV, HCV, HIV, Quantiferon, and pregnancy test
-Ongoing immunosuppressive therapy (including chronic use of steroid)
-Active malignancy or history of malignancy
-Evidence or suspicion of PML on Magnetic Resonance Imaging (MRI)

-Precedente trattamento con altra DMT.
-Diagnosi di Sclerosi Multipla Primaria Progressiva.
-Presenza di disturbi reumatici.
-Conta dei linfociti al di fuori dei normali limiti prima dell'inizio del primo ciclo di trattamento (secondo i valori normativi del laboratorio ospedaliero locale).
- Presenza o sospetto di PML alla RM.
- Positività all'HIV, positività al test dell'anticorpo per l'epatite C, positività al test dell'antigene di superficie per l’epatite B, positività al test dell'anticorpo di nucleo per IgG e/o IgM.
- Storia di tubercolosi (TB), presenza di tubercolosi attiva o tubercolosi latente rilevata dal test QuantiFERON-TB Gold.
- Soggetti immunocompromessi, compresi i soggetti che attualmente ricevono terapia immunosoppressiva / agenti chemioterapici.
-Malignità attiva o storia di neoplasia.
-Ha ricevuto un vaccino vivo entro 6 settimane prima della somministrazione di Cladribina o intende ricevere una vaccinazione viva durante lo studio.
-Gravidanza rilevata attraverso test di gravidanza su sangue effettuato a T0

E.5 End points

E.5.1

Primary end point(s)

Decrement of CXCL13 expression level in NEDA group of patients with respect to no-NEDA group of patients at the end of the treatment.

- Livello di CXCL13 nei pazienti del gruppo NEDA rispetto a quelli del gruppo no-NEDA dopo 2 anni di trattamento con Cladribina.

E.5.1.1

Timepoint(s) of evaluation of this end point

2 years of treatment with Cladribine

2 anni di trattamento con Cladribina

E.5.2

Secondary end point(s)

-CXCL13 change in liquor.
-CXCL13 change in serum.
-Level of oligoclonal IgG bands (OCB) in CSF between pre-treatment (T-3T-1) and T24.
-Genome-wide sequencing-based expression data (pre-treatment T-3T-1) of the two groups (NEDA or no-NEDA).
-To examine the relationship between each NEDA parameters and CXCL13 expression levels these variables will be used: CXCL13 mean between the group of patients which experience at least one relapse and that without any relapse (in T-3T-1 and in T24); EDSS change (T0-T24) and CXCL13 expression level change T-3T-1/T24 ; WM number lesions change (T-3T-1/T24) and CXCL13 value change T-3T-1/T24.
-Change in global Cth and in the number of chronic enlarging T2 lesions during the 2 years, change in the CSF levels of CXCL13. Finally, an unpaired t-test will be used to compare the CXCL13 mean between the group of patients that experience at least one new cortical lesion and that do not experience new cortical lesions.

- Livello di CXCL13 nel liquor.
- Livello di CXCL13 nel siero.
- Livello delle bande IgG oligoclonai (OCB) nel CSF alla fine del trattamento con Cladribina (2 anni; T24) rispetto al pre-trattamento (T-3→T-1)).
- Genome-wide sequencing-based expression data (pre-treatment T-3→T-1) nei due gruppi (NEDA e no-NEDA).
- Per esaminare la relazione tra i parametri NEDA e i livelli di espressione CXCL13 verranno utilizzate le seguenti variabili: media di CXCL13 tra il gruppo di pazienti con almeno una recidiva e quello senza alcuna recidiva (T-3→T-1 - T24); cambiamenti nei punteggi di EDSS tra T0 e T24 e variazioni del livello di CXCL13 tra pre-trattamento (T-3→T-1) e T24; numero di lesioni di WM (T-3→T-1 – T24) e cambiamenti nel livello di CXCL13 (T-3→T-1 – T24).
- Cambiamenti a livello dell’atrofia globale e del numero di lesioni croniche aumentate in sequenze T2 nel corso dei 24 mesi, correlati a cambiamenti di valori di CXCL13. Confronto delle medie di CXCL13 tra il gruppo di pazienti con almeno una nuova lesione corticale e quello senza alcuna nuova lesione.

E.5.2.1

Timepoint(s) of evaluation of this end point

2years of treatment with cladribine

2 anni di trattamento con Cladribina

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

E.6.4

Safety

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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.8.3

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

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

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)

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)

patients will continue to be treated as per normal clinical practice

I pazienti continueranno ad essere trattati come da normale 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

2019-06-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-06-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-12-18

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