A study to investigate long-term safety and tolerability of tolebrutinib in participants with multiple sclerosis

Status Not authorised · 2 EU/EEA countries · 7 sites · Protocol LTS17043

Overview

Sponsor-declared trial summary

Phase Therapeutic confirmatory (Phase III)

Status Not authorised

Participants planned 1,627

Countries 2

Sites 7

Nervous system diseases

To determine the long-term safety and tolerability of tolebrutinib in participants with relapsing multiple sclerosis (RMS) and progressive multiple sclerosis (PMS)

Key facts

Sponsor: Sanofi-Aventis Research & Development
Participant type: Patients
Age range: 18-64 years, 65+ years
Gender: Male and Female
Therapeutic area: Diseases [C] - Nervous System Diseases [C10]
Decision date (initial): 2023-11-27
Transition trial: No
Low-intervention: No
Rare-disease indication: No
Vulnerable population: Yes
Funding sources: Sanofi-Aventis Research & Development

External identifiers

EU CT number: 2023-503631-18-00
WHO UTN: U1111-1287-6797

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To determine the long-term safety and tolerability of tolebrutinib in participants with relapsing multiple sclerosis (RMS) and progressive multiple sclerosis (PMS)

Secondary objectives 1

To assess long-term efficacy of open label (OL) tolebrutinib on disability progression, relapse rate (only in participants with RMS), and magnetic resonance imaging (MRI) parameters in participants with RMS and PMS

Conditions and MedDRA coding

Nervous system diseases

Version	Level	Code	Term	System organ class
21.1	PT	10063400	Secondary progressive multiple sclerosis	100000004852
21.1	PT	10067063	Progressive relapsing multiple sclerosis	100000004852
21.0	PT	10080700	Relapsing multiple sclerosis	100000004852

Regulatory references

EU CT number	Title	Sponsor
2018-004731-76	Long-term extension safety and efficacy study of SAR442168 in participants with relapsing multiple sclerosis, Dlhodobá štúdia sledujúca bezpečnosť a účinnosť SAR442168 u pacientov s relapsujúcou sklerózou multiplex, Dlouhodobá studie sledující bezpečnost a účinnost SAR442168 u pacientů s relabující roztroušenou sklerózou, Dlouhodobá studie sledující bezpečnost a účinnost SAR442168 u pacientů s relabující roztroušenou sklerózou, Estudio de extensión a largo plazo de seguridad y eficacia de SAR442168 en participantes con esclerosis múltiple recurrente
2020-000637-41	A Phase 3, randomized, double-blind efficacy and safety study comparing SAR442168 to teriflunomide (Aubagio®) in participants with relapsing forms of multiple sclerosis , Randomizovaná, dvojitě zaslepená studie fáze 3 hodnotící účinnost a bezpečnost přípravku SAR442168 ve srovnání s teriflunomidem (Aubagio®) u pacientů s relabujícími formami roztroušené sklerózy (GEMINI 1), Randomizovaná, dvojitě zaslepená studie fáze 3 hodnotící účinnost a bezpečnost přípravku SAR442168 ve srovnání s teriflunomidem (Aubagio®) u pacientů s relabujícími formami roztroušené sklerózy (GEMINI 1), Randomizovaná, dvojitě zaslepená studie fáze 3 hodnotící účinnost a bezpečnost přípravku SAR442168 ve srovnání s teriflunomidem (Aubagio®) u pacientů s relabujícími formami roztroušené sklerózy (GEMINI 1), Randomizovaná, dvojitě zaslepená studie fáze 3 hodnotící účinnost a bezpečnost přípravku SAR442168 ve srovnání s teriflunomidem (Aubagio®) u pacientů s relabujícími formami roztroušené sklerózy (GEMINI 1), Studio di Fase 3, randomizzato, in doppio cieco, di efficacia e sicurezza che confronta SAR442168 verso teriflunomide (Aubagio®) in partecipanti affetti da forme recidivanti di sclerosi multipla

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 3

Participants with RMS, PPMS, or NRSPMS who completed the Phase 2b LTS (LTS16004) or 1 of the 4 Phase 3 pivotal tolebrutinib trials (EFC16033, EFC16034, EFC16645, EFC16035) on IMP.
OR - The Phase 2b LTS (LTS16004) or Phase 3 tolebrutinib pivotal trial participants who temporarily discontinued IMP due to a national emergency and completed the trial visits.
ToleDYNAMIC Substudy: Inclusion criteria are those of the main study

Exclusion criteria 11

The participant is at risk for or has a persistent chronic, active (including fever higher than 38°C and clinically unstable), or recurring systemic infection, as judged by the Investigator
For participants initiating OL tolebrutinib in the LTS17043 study: Participants at risk of developing or having reactivation of hepatitis, ie, results at the unblinding visit (RMS) or opt-in visit (PMS) for serological markers for hepatitis B and C viruses indicating acute or chronic infection
Active alcohol use disorder or a history of alcohol or drug abuse within 1 year prior to the opt-in visit
Current alcohol intake equal to or exceeding the following at the opt-in visit: more than 2 drinks per day for men and more than 1 drink per day for women
Abnormal ECG during the opt-in visit considered in the Investigator’s judgment to be clinically significant, such as QTcF >500 msec, in the context of this study.
A bleeding disorder, known platelet dysfunction, abnormal platelet count (<100,000/microliter), history of significant bleeding event or other conditions and planned procedures that may predispose the participant to excessive bleeding during the study, as judged by the Investigator.
For participants initiating OL tolebrutinib in the LTS17043 study: Confirmed unblinding visit (RMS) or opt-in visit (PMS) alanine aminotransferase (ALT) more than 1.5 × upper limit of normal (ULN) OR aspartate aminotransferase (AST) more than 1.5 × ULN OR alkaline phosphatase more than 2 × ULN (unless caused by non-liver-related disorder or explained by a stable chronic liver disorder) OR total bilirubin more than 1.5 × ULN (unless due to Gilbert syndrome or non-liver-related disorder).
Acute liver disease, cirrhosis, chronic liver disease (unless considered stable for more than 6 months).
Participants who developed clinically relevant cardiovascular, hepatic, endocrine, neuropsychiatric or other major systemic disease making implementation of the protocol or interpretation of the trial results difficult or that would put the patient at risk by participating in the trial, as judged by the Investigator.
The participant is receiving treatment during the study period with drugs not permitted by the study protocol, including potent and moderate inducers of cytochrome P450 (CYP) 3A or potent inhibitors of CYP2C8 hepatic enzymes.
ToleDYNAMIC Substudy: Exclusion criteria are those of the main study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

Number of Participants with Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESIs) and AEs leading to permanent study intervention discontinuation
Number of Participants with Potentially clinically significant abnormalities (PCSAs

Secondary endpoints 5

Time to onset of 6-month confirmed disability worsening (CDW for RMS) or confirmed disability progression (CDP for PPMS and NRSPMS) for participants from pivotal studies
Annualized Relapse Rate (ARR) for RMS only
Number of new and/or enlarging T2-hyperintense lesions per year
Change from baseline in total volume of T2-hyperintense lesions
ToleDYNAMIC substudy Change from baseline in biomarkers

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Tolebrutinib

PRD10454961 · Product

Active substance: Tolebrutinib
Substance synonyms: SAR442168, PRN2246, 4-amino-1,3-dihydro-1-((3R)-1-(1-oxo-2-propen-1-yl)-3-piperidinyl)-3-(4-phenoxyphenyl)-2H-imidazo(4,5-C)pyridin-2-one, 4-amino-3-(4-phenoxyphenyl)-1-((3R)-1-(prop-2-enoyl)piperidin-3-yl)-1,3-dihydro-2H-imidazo(4,5-c)pyridin-2-one
Pharmaceutical form: FILM-COATED TABLET
Route of administration: ORAL USE
Max daily dose: 60 mg milligram(s)
Max total dose: 60 mg milligram(s)
Max treatment duration: 36 Month(s)
Authorisation status: Not Authorised
MA holder: SANOFI AVENTIS RECHERCHE ET DEVELOPPEMENT (SAR)
Paediatric formulation: No
Orphan designation: No

Comparator 1

AUBAGIO 14 mg film-coated tablets

PRD2675141 · Product

Active substance: Teriflunomide
Pharmaceutical form: FILM-COATED TABLET
Route of administration: ORAL USE
Max daily dose: 14 mg milligram(s)
Max total dose: 14 mg milligram(s)
Max treatment duration: 36 Month(s)
Authorisation status: Authorised
ATC code: L04AA31 — -
Marketing authorisation: EU/1/13/838/002
MA holder: SANOFI WINTHROP INDUSTRIE
MA country: EU
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Placebo 2

Matched Placebo for Comparator Teriflunomide

N/A · Product

Other product name: N/A
Pharmaceutical form: N/A
ATC code: N/A — N/A
Marketing authorisation: N/A
MA holder: N/A
MA country: Iceland
Paediatric formulation: No

Matched Placebo to Test

N/A · Product

Other product name: N/A
Pharmaceutical form: N/A
ATC code: N/A — N/A
Marketing authorisation: N/A
MA holder: N/A
MA country: Iceland
Paediatric formulation: No

Auxiliary 3

V08C · Product

Active substance: Magnetic Resonance Imaging Contrast Media
Pharmaceutical form: -
Route of administration: SOLUTION FOR INJECTION
Max daily dose: 0 DF dosage form
Max total dose: 0 DF dosage form
Max treatment duration: 1 Day(s)
Authorisation status: Authorised
ATC code: V08C — MAGNETIC RESONANCE IMAGING CONTRAST MEDIA
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Anhydrous Cholestyramine

SCP30086892 · ATC

Active substance: Anhydrous Cholestyramine
Route of administration: ORAL USE
Max daily dose: 0 DF dosage form
Max total dose: 0 DF dosage form
Max treatment duration: 1 Day(s)
Authorisation status: Authorised
ATC code: C10AC01 — COLESTYRAMINE
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

SCP4987633 · ATC

Pharmaceutical form: -
Route of administration: ORAL
Max daily dose: 0 DF dosage form
Max total dose: 0 DF dosage form
Max treatment duration: 1 Day(s)
Authorisation status: Authorised
ATC code: A07B — INTESTINAL ADSORBENTS
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Sanofi-Aventis Research & Development

Sponsor organisation: Sanofi-Aventis Research & Development
Address: 1 Avenue Pierre Brossolette
City: Chilly Mazarin
Postcode: 91380
Country: France

Scientific contact point

Organisation: Sanofi-Aventis Research & Development
Contact name: Clinical Sciences and Operations

Public contact point

Organisation: Sanofi-Aventis Research & Development
Contact name: Clinical Sciences and Operations

Third parties 6

Organisation	City, country	Duties
PetMobile Kft. ORG-100047817	Budakalasz, Hungary	Code 14
Eresearchtechnology Inc. ORG-100013039	Philadelphia, United States	E-data capture
Pharmalink Sp. z o.o. ORG-100019134	Lodz, Poland	Code 14
Centrala Farmaceutyczna Cefarm S.A. ORG-100019105	Warsaw, Poland	Other
Centrala Farmaceutyczna Cefarm S.A. ORG-100019105	Radomsko, Poland	Code 14, Other
Labcorp Central Laboratory Services S.a.r.l. ORG-100011524	Meyrin, Switzerland	Laboratory analysis

Locations

2 EU/EEA countries · 7 investigational sites

By country

Country	MS status	Planned subjects	Sites
Denmark	Not authorised	20	3
Netherlands	Not authorised	55	4
Rest of world Japan, India, Tunisia, Korea, Republic of, Peru, Malaysia, Brazil, Turkey, South Africa, Taiwan, Colombia, United States, Australia, China, Mexico, Argentina, Chile, Hong Kong, Serbia, United Arab Emirates, Canada, Israel, United Kingdom, Singapore, Georgia, Thailand, Egypt	—	1,552	—

Investigational sites

Denmark

3 sites · Not authorised

Region Midtjylland

Neurology, Physiotherapy and Occupational Therapy, Hospitalsparken 15, 7400, Herning

Odense University Hospital

Neurolog, J B Winsloews Vej 4, 5000, Odense C

Sydvestjysk Sygehus

Neurology, Finsensgade 35, 6700, Esbjerg

Netherlands

4 sites · Not authorised

Zuyderland Medisch Centrum Stichting

Department of Neurology, Henri Dunantstraat 5, 6419 PC, Heerlen

Stichting Martini Ziekenhuis

Department of Neurology, Van Swietenplein 1, 9728 NT, Groningen

Brain Research Center Amsterdam B.V.

Department of Neurology, Cronenburg 2, 1081 GN, Amsterdam

Amphia Hospital

Department of Neurology, Molengracht 21, 4818 CK, Breda

Application history

1 submissions — initial application plus substantial / non-substantial modifications

#	Type	Code	Submitted	Reference MS	Conclusion	Decision date
1	INITIAL	IN	2023-08-07	Denmark	Not acceptable 2023-11-27	2023-11-27