Clinical Trials Register

Summary
EudraCT Number:	2020-005899-36
Sponsor's Protocol Code Number:	CLOU064C12301
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:	2021-11-26
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

2020-005899-36

A.3

Full title of the trial

A randomized, double-blind, double-dummy, parallel-group study, comparing the efficacy and safety of remibrutinib versus teriflunomide in participants with relapsing multiple sclerosis, followed by extended treatment with open-label remibrutinib

Studio randomizzato, in doppio cieco, con doppio placebo, a gruppi paralleli per confrontare l’efficacia e la sicurezza di remibrutinib verso teriflunomide in pazienti affetti da sclerosi multipla recidivante, seguito da un’estensione del trattamento con remibrutinib in aperto

A.3.1

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

Efficacy and safety of remibrutinib compared to teriflunomide in participants with relapsing multiple sclerosis, followed by long term treatment with remibrutinib

Efficacia e sicurezza di remibrutinib rispetto a teriflunomide in pazienti affetti da sclerosi multipla recidivante, seguita da un trattamento a lungo termine con remibrutinib

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

CLOU064C12301

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	NOVARTIS PHARMA AG
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	NOVARTIS FARMA S.p.A.
B.5.2	Functional name of contact point	Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	viale Luigi Sturzo 43
B.5.3.2	Town/ city	Milano (MI)
B.5.3.3	Post code	20154
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390296541
B.5.5	Fax number	0039029659066
B.5.6	E-mail	info.studiclinici@novartis.com

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	remibrutinib
D.3.2	Product code	[LOU064C1]
D.3.4	Pharmaceutical form	Film-coated 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	Remibrutinib
D.3.9.2	Current sponsor code	-
D.3.9.3	Other descriptive name	LOU064C1
D.3.9.4	EV Substance Code	SUB204118
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	100
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	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)	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: 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	Aubagio
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-Aventis Groupe - EU/1/13/838/001-006
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Teriflunomide
D.3.2	Product code	[L04AA31]
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	Teriflunomide
D.3.9.1	CAS number	108605-62-5
D.3.9.2	Current sponsor code	-
D.3.9.4	EV Substance Code	SUB25218
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	14
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	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)	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	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.2.5	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	colestiramina
D.3.2	Product code	[-]
D.3.4	Pharmaceutical form	Powder for oral suspension
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	COLESTIRAMINA
D.3.9.2	Current sponsor code	-
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	4
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	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)	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: 4
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.2.5	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	Carbone vegetale polvere
D.3.2	Product code	[-]
D.3.4	Pharmaceutical form	Powder for oral suspension
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	CARBONE VEGETALE
D.3.9.2	Current sponsor code	-
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(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	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)	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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Multiple Sclerosis

Sclerosi Multipla

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	21.0
E.1.2	Level	PT
E.1.2	Classification code	10080700
E.1.2	Term	Relapsing 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

Core part:
Demonstrate that remibrutinib is superior to teriflunomide in reducing the frequency of confirmed relapses
Extension part:
To assess long-term safety, tolerability and efficacy parameters in participants treated with remibrutinib

L’obiettivo primario di questo studio è di dimostrare che remibrutinib è superiore a teriflunomide nel ridurre la frequenza di recidive confermate. Il quesito clinico primario di interesse è: qual è l’effetto di remibrutinib rispetto a teriflunomide (Aubagio®) sulla frequenza di recidive confermate misurate tramite il tasso di recidiva annualizzato (Annual Relapse Rate – ARR) in p affetti da RMS, indipendentemente dall’interruzione del trattamento per qualsiasi motivo.

E.2.2

Secondary objectives of the trial

Core
Assess whether remibrutinib is superior to teriflunomide in
¿ Delaying disability progression based on the pooled data from both identical pivotal studies
¿ Reducing new inflammatory activity on MRI, based on MRI cohort data
¿ Reducing neuronal damage
¿ Disease-Activity-free status based on pooled data from both identical pivotal studies (MRI Cohort)
Extension (exploratory)
¿Explore effect of remibrutinib versus terifunomide on brain MRI, relationship between remibrutinib exposure (PK) and efficacy and safety endpoints and relationship between potential biomarkers and their
relationship with disease activity, disease course and treatment response
¿Perform exploratory pharmacogenetic analysis based on blood samples for DNA (optional)
¿ Explore the effect of remibrutinib versus teriflunomide on disease activity free status and effect of remibrutinib versus teriflunomide on disability progression independent of relapse activity
See protocol for complete list of objectives

Principali obiettivi secondari (Parte principale) Valutare se remibrutinib è superiore a teriflunomide nel ritardare la progressione della disabilità in base ai dati aggregati derivanti da entrambi gli identici studi pivotali. Il principale quesito clinico di interesse secondario è: valutare l’effetto di remibrutinib rispetto a teriflunomide sulla progressione della disabilità misurata tramite progressione della disabilità confermata a 3 mesi e a 6 mesi (3-month and 6-month Confirmed Disability Progression – 3mCDP, 6mCDP) in pazienti affetti da RMS, indipendentemente dall’interruzione del trattamento per qualsiasi motivo. . Per ulteriori dettagli, fare riferimento alla sinossi. Parte di estensione Valutare i parametri di sicurezza, tollerabilità ed efficacia a lungo termine in pazienti trattati con remibrutinib.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Pharmacogenetics
Version: -
Date: 20/10/2021
Title: DNA sampling / Pharmacogenetics
Objectives: The study includes an optional genetic research component. The purpose XML File Identifier: 5HuXcg6ZSiK3s7FJYadKJvBYnnI= Page 15/33 of genetic research may be to better understand the safety and efficacy of remibrutinib, or to learn more about human diseases, or to help develop ways to detect, monitor and treat diseases. As technology changes over time, the most appropriate technology will be used at the time the exploratory genetic research is performed. This may include the study of the entire genome. The use of DNA to search for biomarkers of disease and drug action is exploratory.

Other types of substudies
Specify title, date and version of each substudy with relative objectives: 2) MRI Cohort
Only selected sites will participate in the MRI cohort; it is planned that approximately 400 participants will be included in this MRI cohort after signature of an additional (optional) consent. All eligible participants
from these selected sites will undergo MRI scanning of the brain (see protocol for details).
MRI scans will be transmitted by the sites to the central MRI reading center, designated by Novartis, for quality checks and central read.
Further details on the image acquisition can be found in the MRI manual of the central MRI reading center. Details regarding the central read can be found in the central MRI reading center independent review charter.
Each MRI scan performed for the study needs to be previewed by a local neuroradiologist/radiologist. The Investigator must be contacted in case of unexpected findings (e.g. not consistent with MS) detected on the MRI scan for safety actions and AE reporting.
The MRIs required for the MRI cohort as part of this study are defined in the protocol. Routine MRIs that are mandated by the local treatment guidelines or local Health Authority will be conducted outside the trial (not sent to the central MRI reading center or included in the study database) for any participant.
3) Additional Biomarker assessment
Transcriptomic profiling may be assessed, using RNA from whole blood. mRNA expression patterns and patterns of other RNA species, will be derived from application of various technologies which may include
sequencing of cDNA libraries related to the RNA extracted from blood.
These analyses will be used to examine the effect of remibrutinib on transient RNA and may support the identification of pathways/markers that characterize the disease or response of treatment with remibrutinib.
Due to exploratory nature, the data will not be recorded in the clinical database. For this Transcriptomics (RNA) assessment, PAXgene whole blood samples (one aliquot with 2.5 ml blood) will be collected at designated visits and stored for long-term storage. Transcriptomic assessment will be triggered based on results obtained in this study or other MS studies.
4) PK sub-study
There will be two pharmacokinetic assessments (PK) cohorts, for "rich"
and "sparse" sampling. "Rich PK sampling" will be performed in a
minimum of 160 randomized participants (to ensure these are available for 80 completers per treatment arm), and requires sampling at Day 28 (M1) at pre-dose (0 h) and post-dose at the following times after dosing: 0.5 hour (± 15 mins), 1.0 hour (±15 mins), 2.0 hours (±15 mins), 3.0
hours (±30 mins) and 4.0 hours (±30 mins), and at M6 at pre-dose (0 h)
and at 1.0 hour (±15 mins) post-dose. "Sparse PK sampling" will be performed in all other randomized participants and requires sampling at
Day 28 (M1) and M6 at both pre-dose (0 h) and 1.0 hour (±15 mins) post-dose at both visits. PK assessments are only performed during the Core Part of the study.

Farmacogenetica
Versione: -
Data: 20/10/2021
Titolo: -
Obiettivi: -

Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Si prega di fare riferimento alla Lettera di accompagnamento.

E.3

Principal inclusion criteria

1. Signed informed consent obtained prior to any assessment performed (confirm at screening visit)
2. Male or female participants 18 to 55 years of age (inclusive) at screening
3. Diagnosis of RMS according to the 2017 McDonald diagnostic criteria (this would include relapsing-remitting course (RRMS) or secondary progressive (SPMS) course with disease activity) as confirmed at screening visit.
4. At least: 1 documented relapse within the previous year, OR 2 documented relapses within the previous 2 years, prior to screening, OR 1 active Gadolinium (Gd)-enhancing lesion in the 12 months prior to screening
5. EDSS score of 0 to 5.5 (inclusive) at screening and randomization
6. Neurologically stable within 1 month prior to screening and randomization (including no MS relapse in this period)
Please see protocol for complete detailed list of inclusion criteria

• Consenso informato firmato ottenuto prima dell’effettuazione di qualsiasi valutazione (conferma alla visita di screening).
• Partecipanti di sesso maschile o femminile di età compresa tra 18 e 55 anni (estremi inclusi) allo screening.
• Diagnosi di RMS in base ai criteri diagnostici McDonald 2017 (questi comprendono RRMS o SPMS attiva) come confermato alla visita di screening.
• Almeno: 1 recidiva documentata nell’anno precedente, OPPURE 2 recidive documentate nei 2 anni precedentilo screening, OPPURE 1 lesione attiva captante gadolinio nei 12 mesi precedenti lo screening.
• Punteggio EDSS compreso tra 0 e 5.5 (estremi inclusi) allo screening e alla randomizzazione.
• Pazienti neurologicamente stabili nel mese precedente lo screening e la randomizzazione (compresa l’assenza di recidive di sclerosi multipla in questo periodo). Inserire tutti i criteri di inclusione elencati nel protocollo

E.4

Principal exclusion criteria

1. Diagnosis of primary progressive multiple sclerosis (PPMS) according to the 2017 revision of the McDonald diagnostic criteria (Thompson et al 2018) at screening
2. Disease duration of more than 10 years in participants with EDSS score of 2 or less at screening
3. History of clinically significant CNS disease (e.g. stroke, traumatic brain or spinal injury, history or presence of myelopathy) or neurological disorders which may mimic MS at screening
4. Ongoing substance abuse (drug or alcohol) or any other factor (e.g. serious psychiatric condition) that may interfere with the participant's ability to cooperate and comply with the study procedures prior to randomization
5. History of malignancy of any organ system (other than complete resection of localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases, at
screening
6. Participants with history of confirmed Progressive Multifocal Leukoencephalopathy (PML) or Neurological symptoms consistent with PML prior to randomization
7. Women of child bearing potential unless they are using highly effective methods of contraception while taking study treatment and for at least 4 weeks after stopping study medication
8. Sexually active males, unless they agree to use a condom while taking study treatment and for at least 4 weeks after stopping double blind study medication
Please see protocol for complete detailed list of exclusion criteria

• Durata della malattia superiore a 10 anni in pazienti con punteggio EDSS uguale o inferiore a 2 allo screening.
• Anamnesi di malattia clinicamente significativa del sistema nervoso centrale (Central Nervous System – CNS) (ad es. ictus, danno traumatico cerebrale o spinale, anamnesi o presenza di mielomiopatia) o disturbi neurologici che potrebbero mimare la MS allo screening.
• Partecipanti con anamnesi confermata di leucoencefalopatia multifocale progressiva (Progressive Multifocal Leukoencephalopathy – PML) o sintomi neurologici coerenti con PML prima della randomizzazione.
• Punteggio/risposta “Sì” all’item 4 o all’item 5 della sezione relativa all’ideazione suicidaria della scala C-SSRS (Columbia Suicide Severity Rating Scale), se tale ideazione si è manifestata nei 6 mesi precedenti, o “Sì” a qualsiasi item della sezione relativa al comportamento suicidario, ad eccezione della sezione relativa al comportamento autolesionista non suicidario (item incluso anch’esso nella sezione relativa al comportamento suicidario), se tale comportamento si è manifestato nei 2 anni precedenti, prima della randomizzazione.
• Partecipanti che sono stati sottoposti a splenectomia.
• Infezioni sistemiche batteriche, virali, parassitiche o micotiche attive clinicamente significative a giudizio dello sperimentatore prima della randomizzazione (ad es. infezioni che necessitano di ospedalizzazione o somministrazione di antibiotici per via endovenosa).
• Malattia cronica attiva del sistema immunitario (compresa malattia stabile trattata con immunoterapia, ad es. leflunomide, metotrexato) diversa dalla MS (ad es. artrite reumatoide, lupus sistemico eritematoso, ecc.) ad eccezione di diabete e disturbi della tiroide ben controllati.
• Pazienti con nota sindrome da immunodeficienza [sindrome da immunodeficienza acquisita (Acquired Immunodeficiency Syndrome - AIDS), carenza immunitaria ereditaria, carenza immunitaria farmaco-indotta], o che presentano un test positivo per anticorpi per virus dell’immunodeficienza umana (Human Immunodeficiency Virus – HIV), allo screening.
• Intervallo QT a riposo corretto da formula di Fridericia (QTcF) = 450 msec (uomini) o = 460 msec (donne) pre-trattamento (prima della randomizzazione).
• Utilizzo di farmaci non consentiti prima dello screening/della randomizzazione.
• Necessità di trattamento anticoagulante [ad es. warfarin o nuovi anticoagulanti (Novel Anti-Coagulants – NOAC)] o utilizzo di duplice terapia anti-piastrinica (ad es. acido acetilsalicilico + clopidogrel). È consentito l’uso di acido acetilsalicilico fino a 100 mg/die o clopidogrel.
• Rischio emorragico o disturbi della coagulazione significativi, allo screening.
• Partecipanti che hanno ricevuto qualsiasi vaccino vivo o vivo-attenuato (compresi, a titolo esemplificativo ma non esaustivo, virus della varicella zoster o morbillo, polio orale, influenza nasale) nelle 6 settimane precedenti la randomizzazione o che necessitano di sottoporsi a tali vaccinazioni in qualsiasi momento durante il trattamento in studio.

E.5 End points

E.5.1

Primary end point(s)

Core part:
Annualized relapse rate (ARR) of confirmed relapses
Extension Part:
¿ Adverse events, laboratory data, vital signs, electrocardiogram (ECG), Columbia Suicide Severity Rating
¿ ARR, number of new or enlarging T2 lesions on MRI per year (annualized T2 lesion rate), time to 6mCDP (EDSS), change in SDMT, NfL, Patient Reported Outcomes scores

Parte centrale:
Tasso di recidiva annualizzato (ARR) di recidive confermate
Parte di estensione:
¿ Eventi avversi, dati di laboratorio, segni vitali, elettrocardiogramma (ECG), Columbia Suicide Severity Rating
¿ ARR, numero di lesioni T2 nuove o ingrandite alla risonanza magnetica per anno (tasso di lesioni T2 annualizzato), tempo a 6mCDP (EDSS), variazione dei punteggi SDMT, NfL, esiti riportati dal paziente

E.5.1.1

Timepoint(s) of evaluation of this end point

Up to 30 months

Fino a 30 mesi

E.5.2

Secondary end point(s)

Core part:
¿ Time to 3-month confirmed disability progression (3mCDP) on Expanded Disability Status Scale (EDSS)
¿ Time to 6-month confirmed disability progression (6mCDP) on EDSS
¿ Number of new or enlarging T2 lesions on MRI per year (annualized T2 lesion rate)
¿ Total number of Gd-enhancing T1 lesions per MRI scan
¿ Neurofilament light chain (NfL) concentration in serum
¿ Percentage of participants with No Evidence of Disease Activity-3 (NEDA-3), as assessed by absence of confirmed MS relapses, 6mCDP and new/enlarging T2 lesions on MRI
Extension part (exploratory)
¿ Annualized rate of brain volume loss (BVL), based on percentage brain volume change from baseline
¿ Change from baseline in cortical grey matter volume, hemispheric white matter volume and thalamus volume
¿ Slowly Expanding Lesions (SEL) in MRI
¿ T2 lesions, ARR, 3mCDP, safety endpoints etc. (as applicable)
¿ NfL, GFAP, total IgG, total IgM, B-cells, T2 lesions, ARR, 3mCDP etc. (as applicable)
¿ Evaluate the relationship of genetic polymorphisms data with drug metabolism, the indication, the drug target pathway, and treatment response
¿ Percentage of participants with NEDA-4, as assessed by the absence of confirmed MS relapses, 6mCDP, new/enlarging T2 lesions on MRI and brain volume loss > -0.4%/year
¿ Time to 3mCDP, 6mCDP

Parte centrale:
¿ Tempo alla progressione della disabilità confermata di 3 mesi (3mCDP) sulla scala estesa dello stato di disabilità (EDSS)
¿ Tempo alla progressione della disabilità confermata di 6 mesi (6mCDP) su EDSS
¿ Numero di lesioni T2 nuove o in espansione alla risonanza magnetica per anno (tasso di lesioni T2 annualizzato)
¿ Numero totale di lesioni T1 captanti Gd per risonanza magnetica
¿ Concentrazione della catena leggera del neurofilamento (NfL) nel siero
¿ Percentuale di partecipanti con No Evidence of Disease Activity-3 (NEDA-3), come valutato dall'assenza di recidive confermate della SM, 6mCDP e lesioni T2 nuove/ingrandite alla risonanza magnetica
Parte di estensione (esplorativa)
¿ Tasso annualizzato di perdita di volume cerebrale (BVL), basato sulla variazione percentuale del volume cerebrale rispetto al basale
¿ Variazione rispetto al basale del volume della sostanza grigia corticale, del volume della sostanza bianca emisferica e del volume del talamo
¿ Lesioni a Lenta Espansione (SEL) in MRI
¿ Lesioni T2, ARR, 3mCDP, endpoint di sicurezza ecc. (se applicabile)
¿ NfL, GFAP, IgG totali, IgM totali, cellule B, lesioni T2, ARR, 3mCDP ecc. (se applicabile)
¿ Valutare la relazione dei dati sui polimorfismi genetici con il metabolismo del farmaco, l'indicazione, la via del target del farmaco e la risposta al trattamento
¿ Percentuale di partecipanti con NEDA-4, valutata in base all'assenza di recidive confermate della SM, 6mCDP, lesioni T2 nuove/ingrandite alla risonanza magnetica e perdita di volume cerebrale > -0,4%/anno
¿ Tempo a 3 mCDP, 6 mCDP

E.5.2.1

Timepoint(s) of evaluation of this end point

Up to 30 months

Fino a 30 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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

Tollerabilità

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

Yes

E.8.1.7.1

Other trial design description

Double-dummy

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Chile

Colombia

Guatemala

Malaysia

Switzerland

Hong Kong

China

India

Russian Federation

Serbia

United Kingdom

United States

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

LSLV

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:

800

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

344

F.4.2.2

In the whole clinical trial

800

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)

Participants who complete the core part of the study on study drug, can continue in the planned extension part. The investigator must provide follow-up medical care for all participants who do not enter the extension part or are prematurely withdrawn from the study, or must refer them for appropriate ongoing care.

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

2022-02-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-03-09

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

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Orphan Designation Number:
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