Clinical Trials Register

Summary
EudraCT Number:	2021-003898-59
Sponsor's Protocol Code Number:	EFC17262
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-10-06
Trial results	View 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

2021-003898-59

A.3

Full title of the trial

A Phase 3, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of tolebrutinib (SAR442168) in adults with generalized myasthenia gravis (MG)

Studio di fase 3, randomizzato, in doppio cieco, controllato verso placebo, a gruppi paralleli per valutare l’efficacia e la sicurezza di tolebrutinib (SAR442168) in adulti affetti da miastenia grave generalizzata.

A.3.1

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

Efficacy and safety of tolebrutinib (SAR442168) tablets in adult participants with generalized myasthenia gravis

Efficacia e sicurezza delle compresse di tolebrutinib (SAR442168) in partecipanti adulti/e con miastenia grave generalizzata

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

EFC17262

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1265-6378

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	SANOFI-AVENTIS RECHERCHE E DEVELOPPEMENT
B.1.3.4	Country	France
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	Sanofi-Aventis Recherche & Développement
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	SANOFI s.r.l
B.5.2	Functional name of contact point	CONTACT POINT
B.5.3	Address:
B.5.3.1	Street Address	VIALE LUIGI BODIO 37/B
B.5.3.2	Town/ city	MILANO
B.5.3.3	Post code	20158
B.5.3.4	Country	Italy
B.5.4	Telephone number	800536389
B.5.5	Fax number	00000000
B.5.6	E-mail	informazioni.medicoscientifiche@sanofi.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	Tolebrutininb
D.3.2	Product code	[SAR442168]
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	Tolebrutinib
D.3.9.1	CAS number	1971920-73-6
D.3.9.2	Current sponsor code	SAR442168
D.3.9.3	Other descriptive name	PRN2246
D.3.9.4	EV Substance Code	SUB195428
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	60
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.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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Myasthenia gravis

Miastenia Grave

E.1.1.1

Medical condition in easily understood language

Myasthenia gravis

Miastenia Grave

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	10028417
E.1.2	Term	Myasthenia gravis
E.1.2	System Organ Class	10029205 - Nervous system disorders

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

DB period:
• To evaluate the efficacy of tolebrutinib compared to placebo as measured by myasthenia gravis-activities of daily living (MG-ADL) score
in participants with gMG who are receiving SoC
OLE:
• To evaluate the long-term safety and tolerability of tolebrutinib in participants with gMG who are receiving SoC

Periodo in DC:
Valutare l’efficacia di tolebrutinib al giorno rispetto al placebo misurata in base al punteggio relativo alle attività della vita quotidiana nella miastenia grave (MG-ADL) in partecipanti con MGg che stanno ricevendo il SoC
OLE
Valutare la sicurezza e la tollerabilità a lungo termine di tolebrutinib al giorno in partecipanti con MGg che stanno ricevendo il SoC

E.2.2

Secondary objectives of the trial

DB period:
• To evaluate the efficacy of tolebrutinib compared to placebo on additional efficacy measurements: Quantitative MG (QMG), MG Impairment Index (MGII), MG quality of life 15-item Scale (MG-QOL15), MG-ADL in participants with gMG who are receiving SoC
• To evaluate the safety and tolerability of tolebrutinib compared to placebo in participants with gMG who are receiving SoC
OLE:
• To evaluate the long-term efficacy of tolebrutinib in participants with gMG who are receiving SoC

Periodo in DC
Valutare l’efficacia di tolebrutinib o rispetto al placebo per misurazioni di efficacia aggiuntive: Qunatitativo MG (QMG), Indice di Compromissione MG (MGII), scala della qualità della vita a 15 voci per MG (MG-QoL15), MG-ADL in partecipanti con MGg che stanno ricevendo il SoC
Valutare la sicurezza e la tollerabilità di tolebrutinib rispetto al placebo in partecipanti con MGg che stanno ricevendo il SoC
OLE
Valutare l’efficacia a lungo termine di tolebrutinib in partecipanti con MGg che stanno ricevendo il SoC

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Participants must be 18 years of age to 85 years of age inclusive, at the time of signing the informed consent
- Participants with a diagnosis of gMG at screening with generalized muscle weakness meeting the clinical criteria for diagnosis of MG, as defined by the MGFA Clinical Classification Class II, III, or IV, and likely not in need of a respirator for the duration of the study, as judged by the Investigator
- Positive serologic testing for anti-AChR or anti-MuSK autoantibody at screening OR
- Seronegative for both anti-AChR and anti-MuSK autoantibodies and with prior diagnosis supported by >/=1 of the following 3 tests:
a) History of abnormal neuromuscular transmission demonstrated by single-fiber electromyography or repetitive nerve stimulation
b) History of positive edrophonium chloride test
c) Participant has demonstrated improvement in gMG signs on oral acetylcholinesterase inhibitors as assessed by the treating physician.
- The participant must have a total score >/=6 on MG-ADL scale at screening and D1 with greater than half of the score attributed to non-ocular items

I/Le partecipanti devono avere un’età compresa tra 18 e 85 anni, inclusi, al momento della firma del consenso informato.
Partecipanti con diagnosi di MGg allo screening con debolezza muscolare generalizzata che soddisfano i criteri clinici per la diagnosi di MG, come definito dalla Classificazione clinica MGFA di Classe II, III o IV, e che probabilmente non avranno bisogno di un respiratore per tutta la durata dello studio, in base al giudizio dello sperimentatore.
-Test sierologico positivo per autoanticorpi anti-AChR o anti-MuSK allo screening OPPURE
- Sieronegativo sia per gli autoanticorpi anti-AChR che per anti-MuSK e con precedente diagnosi supportata da >/=1 dei seguenti 3 test:
a)Anamnesi di trasmissione neuromuscolare anomala dimostrata da elettromiografia a singola fibra o stimolazione nervosa ripetitiva
b)Anamnesi di test positivo all’edrofonio cloruro
c) Il/La partecipante ha dimostrato un miglioramento nei segni della MGg con inibitori dell’acetilcolinesterasi orali, come valutato dal medico curante.
Il/La partecipante deve avere un punteggio >/=6 sulla scala MG-ADL alle visite di screening e del Giorno 1 con più della metà del punteggio attribuito alle voci non oculari.

E.4

Principal exclusion criteria

Participants are excluded from the study if any of the following criteria apply:
- MGFA Class I (ocular MG) or Class V
- Participants having undergone thymectomy within 6 months of screening or having a planned thymectomy during the trial period.
- The participant has a history of infection or may be at risk for infection:
A history of active or latent tuberculosis (TB); Participants at risk of developing or having reactivation of hepatitis; Persistent chronic or active recurring infection requiring treatment with antibiotics, antivirals, or antifungals; Fever within 4 weeks of the Screening Visit (>/=38°C; however, if due to brief and mild ear, nose, throat viral infection participant may be included based on the Investigator's judgment); A history of infection with human immunodeficiency virus (HIV); A history of T-lymphocyte or T-lymphocyte-receptor vaccination, transplantation (including solid organ, stem cell, and bone marrow transplantation) and/or antirejection therapy.
- Any malignancy within the past 5 years prior Screening Visit (except for effectively treated carcinoma in situ of the cervix, adequately treated non-metastatic squamous or basal cell carcinoma of the skin and malignant thymoma that have been resected or are considered as cured by any treatment with no evidence of metastatic disease for >/=3 years) will be exclusionary
- Conditions that may predispose the participant to excessive bleeding
- Confirmed screening ALT >3 × ULN
- The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

In presenza di uno dei seguenti criteri i/le partecipanti saranno esclusi/e dallo studio:
- MGFA Classe I (MG oculare) o Classe V.
- Partecipanti che hanno subito una timectomia nei 6 mesi precedenti allo screening o timectomia programmata durante il periodo dello studio.
- Il/La partecipante presenta un’anamnesi di infezione o può essere a rischio di infezione:
Anamnesi di tubercolosi (TB) attiva o latente; Partecipanti a rischio di sviluppo o riattivazione dell’epatite, Infezione persistente cronica o attiva ricorrente che renda necessario un trattamento con antibiotici, antivirali o antimicotici; Febbre entro 4 settimane dalla Visita di screening (>/=38 °C; tuttavia, se a causa di un’infezione virale breve e lieve a orecchio, naso, gola, il/la partecipante può essere incluso/a in base al giudizio dello sperimentatore); Anamnesi di infezione da virus dell’immunodeficienza umana (HIV); Anamnesi di vaccinazione con linfociti T o recettori dei linfociti T, trapianto (incluso trapianto di organo solido, cellule staminali e midollo osseo) e/o terapia antirigetto.
Sarà causa di esclusione qualsiasi tumore maligno nei 5 anni precedenti la visita di screening (fatta eccezione per il carcinoma in situ della cervice trattato in maniera efficace, il carcinoma cutaneo a cellule squamose o basali non metastatico adeguatamente trattato e iltimoma maligno che siano stati resecati o siano considerati curati per mezzo di qualsiasi trattamento senza evidenza di malattia metastatica per >/=3 anni).
Condizioni che possono predisporre il/la partecipante a sanguinamento eccessivo.
ALT confermata allo screening >3 × ULN.
Le informazioni di cui sopra non intendono contenere tutte le considerazioni relative alla potenziale partecipazione di un paziente a una sperimentazione clinica.

E.5 End points

E.5.1

Primary end point(s)

1- DB period: Change from baseline in MG-ADL total score ; The MG-ADL is a categorical scale that assesses the impact on daily function of 8 signs symptoms that are typically affected in MG. Each item is assessed on a 4-point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function (total score 0 to 24).
2 - OLE: Number of participants with adverse events (AEs) /SAEs ;
Incidence of adverse events (AEs) and serious adverse events (SAEs)

1- Periodo in DC: Variazione rispetto al basale del punteggio totale MG-ADL. La MG-ADL è una scala categorica che valuta l'impatto sulla funzione quotidiana di 8 segni sintomi che sono tipicamente colpiti dalla MG. Ogni elemento viene valutato su una scala a 4 punti in cui un punteggio di 0 rappresenta la funzione normale e un punteggio di 3 rappresenta la perdita della capacità di svolgere tale funzione (punteggio totale da 0 a 24).
2- Periodo OLE: Numero di partecipanti con eventi avversi (AE)/SAE;
Incidenza di eventi avversi (EA) ed eventi avversi gravi (SAE)

E.5.1.1

Timepoint(s) of evaluation of this end point

1 : Baseline, Week 26
2 : From Week 26 until Week 130

1: visita basale, Settimana 26
2: dalla Settimana 26 fino alla Settimana130

E.5.2

Secondary end point(s)

1 - Change from baseline in QMG total score ; Quantitative Myasthenia Gravis is clinician-reported outcome/assessment to assess muscle weakness in people with MG. The QMG consists of 13 items ranging from 0 to 3 with 3 being the most severe.
2 - Change from baseline in MGII total score ; The Myasthenia Gravis Impairment Index (MGII) is a measure of MG impairment focused on the severity of MG impairment and the concept of fatigability. Consists of a 22-item patient-reported questionnaire with 6 clinician assessment items. Higher scores indicate greater disease severity.
3 - Change from baseline in MG-QOL15 survey score ; The MG-QoL15 is a 15-item measure of people with MG QoL instrument that will be self-reported by the participant. The domains covered by the questionnaire are mobility (9 items), symptoms (3 items), general contentment (1 item) and emotional well-being (2 items).
4 - Proportion of participants with >/= 2-point reduction from baseline in MG-ADL total score
5 - Proportion of participants with >/= 3-point reduction from baseline in QMG total score
6 - DB: Number of participants with AEs /SAEs
7 - OLE: Change from baseline in MG-ADL total score
8 - OLE: Proportion of participants achieving a reduction from baseline in daily dose of oral corticosteroids (OCS)

1 - Variazione rispetto al basale del punteggio QMG; il punteggio quantitativo della miastenia grave è l'esito/valutazione riportata dal medico per valutare la debolezza muscolare nelle presone con MG. Il QMG è composto da 13 elementi che vanno da 0 a 3 con 3 che è il più grave
2- Variazione rispetto al basale del punteggio MGII; Il Myasthenia Gravis Impairment Index (MGII) è una misura della compromissione della MG focalizzata sulla gravità della compromissione della MG e sul concetto di affaticabilità. Consiste in un questionario di 22 voci riferito dal paziente con 6 voci di valutazione del medico. Punteggi più alti indicano una maggiore gravità della malattia
3 - Variazione rispetto al basale nel punteggio del questionario MG-QoL15; La MG-QoL15 è una misura di 15 elementi di persone con strumento MG QoL che sarà auto-riferita dal partecipante. I domini coperti dal questionario sono mobilità (9 item), sintomi (3 item), contentezza generale (1 item) e benessere emotivo (2 item).
4- Percentuale di partecipanti con riduzione >/=2 punti nel punteggio totale MG-ADL
5 - Percentuale di partecipanti con miglioramento (riduzione) >/=3 punti nel punteggio QMG totale
6 - DC: Numero di partecipanti con EA, EA seri
7 - OLE: Variazione rispetto al basale nel punteggio totale MG-ADL
8 - OLE: Percentuale di partecipanti che ottengono una riduzione rispetto al basale della dose giornaliera di OCS nel tempo

E.5.2.1

Timepoint(s) of evaluation of this end point

1, 2, 3 : DB period: Baseline, Week 26
OLE: Baseline, Week 130

4, 5 : DB period: From Baseline until Week 26
OLE: From Baseline until Week 130

6 : From Baseline until Week 26
7 : Baseline, Week 130
8 : From Baseline until Week 130

1,2,3 : Periodo DC: Visita Basale, Settimana 26;
OLE: Basale, settimna 130

4,5: Periodo DC Dalla visita Basale fino alla settimana 26;
OLE: dalla visita Basale alla Settimana 130

6: Dalla visita Basale fino alla settimana 26
7: Basale, settimana 130
8: Dalla visita Basale fino alla settimana 130

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

Yes

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

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

Canada

China

Japan

Russian Federation

United States

Germany

Hungary

Italy

Poland

Spain

United Kingdom

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:

160

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

192

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)

None

Nessuno

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

2021-11-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-11-10

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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