Clinical Trials Register

Summary
EudraCT Number:	2021-003898-59
Sponsor's Protocol Code Number:	EFC17262
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-10-14
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

Spain - AEMPS

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)

Estudio fase 3, aleatorizado, doble ciego, controlado con placebo, de grupos paralelos para evaluar la eficacia y seguridad de tolebrutinib (SAR442168) en adultos con miastenia gravis generalizada (MGg)

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

Eficacia y seguridad de comprimidos de Tolebrutinib (SAR442168) en participantes adultos con miastenia gravis generalizada

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 & Développement
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-Aventis, S.A
B.5.2	Functional name of contact point	Unidad de Estudios Clínicos
B.5.3	Address:
B.5.3.1	Street Address	C/ Josep Pla 2, 4ª planta
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08019
B.5.3.4	Country	Spain
B.5.4	Telephone number	+3493485 94 00
B.5.6	E-mail	es-unidadestudiosclinicos@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	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
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 gravis

E.1.1.1

Medical condition in easily understood language

Myasthenia gravis

Miastenia gravis

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

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 doble ciego (DC):
•Evaluar la eficacia de tolebrutinib en comparación con placebo, medida por la puntuación de miastenia gravis en las actividades de la vida diaria en pacientes con MGg que están recibiendo la atención estándar
OLE:
Extensión abierta (EA):
• Evaluar la seguridad y tolerabilidad a largo plazo de tolebrutinib en participantes con MGg que están recibiendo la atención estándar.

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 doble ciego (DC):
•Evaluar la eficacia de Tolebrutinib comparado con placebo en medidas de eficacia adicionales:
MG Cuantitativa (QMG), MG Índice de deterioro (MGII), MG escala de calidad de vida de 15-aspectos (MG-QOL15), MG-ADL en participantes con MGg que están recibiendo la atención estándar
•Evaluar la seguridad y tolerabilidad de Tolebrutinib comparado con placebo en participantes con MGg que están recibiendo la atención estándar
OLE:
Extensión abierta:
•Evaluar la eficacia a largo plazo de tolebrutinib en participantes con MGg que están recibiendo la atención estándar.

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

-Los participantes deben tener entre 18 y 85 años de edad inclusive, en el momento de la firma del consentimiento informado
- Los participantes con un diagnóstico de MGg en la selección con debilidad muscular generalizada que cumplan los criterios clínicos para el diagnóstico de MG, definidos mediante la Clasificación Clínica MGFA como Clase II, IIII, o IV y que probablemente no necesiten un respirador a lo largo de la duración del estudio, a criterio del investigador
-Test serológico positivo para autoanticuerpos anti-AChR o anti-MuSK en la selección O
_Seronegativos para ambos autoanticuerpos anti-AChR y anti-MuSK y con diagnóstico previo apoyado en ≥1 de los siguientes 3 tests:
a) Historia de transmisión neuromuscular anormal demostrada mediante electromiografía de fibra única o estimulación nerviosa repetitiva
b) Historia de test positivo del cloruro de edofronio
c) Los participantes han demostrado mejoría en los signos de MGg durante el tratamiento con inhibidores orales de la acetilcolinesterasa evaluados por el médico tratante
-El participante debe tener una puntuación total ≥6 en la escala MG-ADL en la selección y D1 con más de la mitad de la puntuación atribuida a aspectos no-oculares

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.

Los participantes son excluidos del estudio si cumplen alguno de los siguientes criterios:
-MGFA Clase I (MG ocular) o Clase V
-Participantes a los que se les ha realizado una timectomía en los 6 meses previos a la selección o tienen planeada una timectomía durante el periodo del ensayo
El participante tiene antecedentes de infección o puede estar en riesgo de infección: Antecedentes de tuberculosis (TB) activa o latente; Participantes en riesgo de desarrollar o reactivación de hepatitis; Infección recurrente crónica o activa persistente que requiere tratamiento con antibióticos, antivirales o antifúngicos; Fiebre dentro de las 4 semanas posteriores a la visita de selección (≥38 ° C; sin embargo, si se debe a una infección viral de oído, nariz o garganta leve y breve, el participante puede incluirse según
el criterio del investigador); Antecedentes de infección por el virus de la inmunodeficiencia humana (VIH); Antecedentes de vacunación de linfocitos T o receptores de linfocitos T, trasplante (incluido el trasplante de órganos sólidos, células madre y médula ósea) y / o terapia antirrechazo
- Cualquier neoplasia maligna en los últimos 5 años antes de la visita de selección (excepto carcinoma in situ del cuello uterino tratado de manera eficaz, carcinoma de células basales o escamoso no metastásico de piel tratado adecuadamente y timoma maligno que se haya resecado o se considere curado por cualquier tratamiento sin evidencia de enfermedad metastásica durante ≥3 años) será excluyente
Condiciones que predispongan a un sangrado excesivo al participante
-ALT >3 x límite superior normal confirmado en la selección
-La información superior no pretende contener todas las consideraciones relevantes para la posible participación de un paciente en un ensayo clínico

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 Doble Ciego (DC):
Cambio desde el inicio en la puntuación total de MG-ADL; La MG-ADL es una escala categórica que evalúa el impacto en la función diaria de 8 signos síntomas que suelen verse afectados en la MG. Cada aspecto se evalúa en una escala de 4 puntos donde una puntuación de 0 representa una función normal y una puntuación de 3 representa la pérdida de capacidad para realizar esa función (puntuación total de 0 a 24).

2 - OLE: Número de participantes con eventos adversos (EAs)/EASs; Incidencia de eventos adversos (EAs) y eventos adversos serios (EASs)

E.5.1.1

Timepoint(s) of evaluation of this end point

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

1: Inicio, Semana 26
2: Desde la Semana 26 hasta la Semana 130

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-Cambio desde el inicio en la puntuación total de QMG; La Miastenia Gravis cuantitativa (QMG) es un resultado/evaluación informados por el médico para evaluar la debilidad muscular en personas con MG. La QMG consta de 13 ítems que van de 0 a 3, siendo 3 el más grave.
2- Cambio desde el inicio en la puntuación total de MGII; El índice de deterioro de la Miastenia Gravis (MGII) es una medida del deterioro de la MG centrada en la gravedad del deterioro de la MG y el concepto de fatiga. Consiste en un cuestionario informado por el paciente de 22 aspectos con 6 ítems de evaluación del médico. Las puntuaciones más altas indican una mayor gravedad de la enfermedad.
3- Cambio desde el inicio en la puntuación de la encuesta MG-QOL15; El MG-QoL15 es una medida de 15 aspectos de las personas con el instrumento MG QoL que será auto-informado por el participante. Los dominios cubiertos por el cuestionario son movilidad (9 ítems), síntomas (3 ítems), satisfacción general (1 ítem) y bienestar emocional (2 ítems).
4-Proporción de participantes con reducción de ≥ 2 puntos desde el inicio en la puntuación total MG-ADL
5-Proporción de participantes con reducción de ≥ 3-puntos desde el inicio en la puntuación total QMG
6-Doble Ciego: Número de participantes con EAs/EASs
7-Extensión Abierta: Cambio desde el inicio en la puntuación total MG-ADL
8- Extensión Abierta: Proporción de participantes que consiguen una reducción desde el inicio en la dosis diaria de corticosteroides orales

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 Doble Ciego: Inicio, Semana 26
OLE: Baseline, Week 130

4,5: Periodo Doble Ciego: Desde el Inicio hasta la Semana 26
OLE: Desde el Inicio hasta la Semana 130

6: Desde el Inicio hasta Semana 26
7: Inicio, Semana 130
8: Desde el Inicio hasta la Semana 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

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

La última visita del último paciente

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 months

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

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

2022-01-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-12-28

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

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