Clinical Trials Register

Summary
EudraCT Number:	2020-000637-41
Sponsor's Protocol Code Number:	EFC16033
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-09-07
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

Sweden - MPA

A.2

EudraCT number

2020-000637-41

A.3

Full title of the trial

A Phase 3, randomized, double-blind efficacy and safety study comparing SAR442168 to teriflunomide (Aubagio®) in participants with relapsing forms of multiple sclerosis

A.3.1

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

Relapsing Forms of multiple sclerosis (RMS) study of Bruton's Tyrosine Kinase (BTK) inhibitor Tolebrutinib (SAR442168) (GEMINI 1)

A.3.2

Name or abbreviated title of the trial where available

GEMINI 1

A.4.1

Sponsor's protocol code number

EFC16033

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1238-1418

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	Genzyme Corporation
B.1.3.4	Country	United States
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	Genzyme Corporation
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Sanofi AB
B.5.2	Functional name of contact point	Clinical Study Unit
B.5.3	Address:
B.5.3.1	Street Address	Box 30052
B.5.3.2	Town/ city	Stockholm
B.5.3.3	Post code	10425
B.5.3.4	Country	Sweden
B.5.4	Telephone number	+46 86345000
B.5.6	E-mail	clinicaltrials.sweden@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.3.2	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	Not available
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.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
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	HMR1726
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	TERIFLUNOMIDE
D.3.9.1	CAS number	108605-62-5
D.3.9.2	Current sponsor code	HMR1726
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	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
D.8 Placebo: 2
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

Relapsing Multiple Sclerosis

E.1.1.1

Medical condition in easily understood language

Relapsing Multiple Sclerosis

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

To assess efficacy of daily SAR442168 compared to a daily dose of 14 mg teriflunomide (Aubagio) measured by annualized adjudicated relapse rate (ARR) in participants with relapsing forms of MS

E.2.2

Secondary objectives of the trial

- To assess efficacy of SAR442168 compared to teriflunomide (Aubagio) on disability progression, MRI lesions, cognitive performance and quality of life
- To evaluate the safety and tolerability of daily SAR442168
- To evaluate population pharmacokinetics (PK) of SAR442168 and relevant metabolites and its relationship to efficacy and safety
- To evaluate pharmacodynamics (PD) of SAR442168

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- The participant must be 18 to 55 years of age, inclusive, at the time of signing the informed consent
- The participant must have been diagnosed with RMS according to the 2017 revision of the McDonald diagnostic criteria
- The participant has an expanded disability status scale (EDSS) score ≤5.5 at the first Screening Visit
- The participant must have at least 1 of the following prior to screening:
-- ≥1 documented relapse within the previous year OR
-- ≥2 documented relapses within the previous 2 years, OR
-- ≥1 documented Gd enhancing lesion on an MRI scan within the previous year
- Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
- Male participants are eligible to participate if they agree to the following during the intervention period and until accelerated elimination procedure:
Refrain from donating sperm
Plus either:
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
OR
Must agree to use contraception/barrier as detailed below
Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant
- A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions apply:
Is not a Woman of child-bearing potential (WOCBP)
OR
Is a WOCBP and agrees to use a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, during the intervention period and until accelerated elimination procedure is completed (or for at least 10 days after the last dose of SAR442168, if the case was unblinded
- A WOCBP must have a negative highly sensitive pregnancy test at screening and within 24 hours before the first dose of study intervention
- If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
- The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
- The participant must have given written informed consent prior to undertaking any study related procedure. This includes consent to comply with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. In countries where the legal age of maturity is greater than 18 years, a specific ICF for such legally minor participants must also be signed by the participant’s legally authorized representative

E.4

Principal exclusion criteria

- The participant has been diagnosed with primary progressive multiplesclerosis (PPMS) according to the 2017 revision of the McDonald diagnostic criteria or with nonrelapsing secondary progressive multiplesclerosis (SPMS)
- The participant has a history of infection or may be at risk for infection including but not limited to: HIV, transplantation, live attenuated vaccines, progressive multifocal leukoencephalopathy, tuberculosis, hepatitis B or C, any persistent chronic or active recurring infection
- Clinically significant laboratory abnormalities (including evidence of liver injury) or electrocardiogram abnormalities at Screening.
- The participant has conditions or situations that would adversely affect participation in this study, including but not limited to:
-- A short life expectancy due to pre-existing health condition(s) as determined by their treating neurologist
-- Medical condition(s) or concomitant disease(s) making them nonevaluable for the primary efficacy endpoint or that would adversely affect participation in this study, as judged by the Investigator
-- A requirement for concomitant treatment that could bias the primary evaluation
- The participant has a history of or currently has concomitant medical or clinical conditions that would adversely affect participation in this study
The participant has any of the following:
-- A bleeding disorder or known platelet dysfunction at any time prior to the screening visit
-- A platelet count <150 000/μL at the screening visit
- The participant has a lymphocyte count below the lower limit of normal (LLN) at the screening visit
- The presence of psychiatric disturbance or substance abuse
Prior/concomitant therapy
- The participant is receiving potent and moderate inducers of cytochrome P450 (CYP) 3A or potent inhibitors of CYP2C8 hepatic enzymes
- The participant is receiving anticoagulant/antiplatelet therapies

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial

E.5 End points

E.5.1

Primary end point(s)

Annualized Adjudicated Relapse Rate : Number of confirmed protocol defined relapses ; Annualized Adjudicated Relapse Rate : Number of confirmed protocol defined adjudicated relapses

E.5.1.1

Timepoint(s) of evaluation of this end point

Up to approximately 36 months

E.5.2

Secondary end point(s)

1 - Time to onset of confirmed disability worsening confirmed over at least 6 months ; Time to onset of confirmed disability worsening (CDW), confirmed over at least 6 months, defined as follows:
-- increase of ≥1.5 points from the baseline expanded disability status scale (EDSS) score when the baseline score is 0
OR
-- increase of ≥1.0 point from the baseline EDSS score when the baseline score is 0.5 to ≤5.5
OR
-- increase of ≥0.5 point from the baseline EDSS score when the baseline score is >5.5
2 - Time to onset of CDW, assessed by the EDSS score and confirmed over at least 3 month
3 - Total number of new and/or enlarging T2 hyperintense lesions as detected by MRI from Month 6 through the end of study
4 - Total of Gd-enhancing T1 hyperintense lesions as detected by MRI from 6 months through the EOS
5 - Change in cognitive function ; Change in cognitive function from baseline to the EOS as assessed by SDMTand by CVLT-II where available
6 - Time to confirmed disability improvement ; Time to confirmed disability improvement (CDI), defined as a ≥1.0 point decrease on the EDSS from the baseline EDSS score confirmed over at least 6 months
7 - Percent Change in Brain volume loss (BVL) ; Brain volume loss (BVL) rate as detected by brain MRI from Month 6 to the EOS
8 - Change in Multiple Sclerosis Quality of Life ; Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) from the baseline through the EOS
9 - Number of participants with adverse events (AEs) leading to permanent study intervention discontinuation, and adverse events of special interest (AESI)
10 - Population Pharmacokinetics ;
Plasma concentration of SAR442168 (population PK assessment) at 6 Months
Plasma concentration of SAR442168 (population PK assessment) at 9 Months
Plasma concentration of SAR442168 (population PK assessment) at 12 Months
11 - Change in plasma NfL ; Change in plasma neurofilament light chain (NfL) levels at the EOS compared to baseline
12 - Change in lymphocyte Phenotype ; Change in lymphocyte phenotype subsets in whole blood at the EOS compared to baseline in a subset of participants
13 - Changes in plasma Immunoglobulin levels ; Changes in serum immunoglobulin level at the EOS compared to baseline
14 - Change in CHI3L1 levels ; Change in serum Chi3L1 levels at the EOS compared to baseline

E.5.2.1

Timepoint(s) of evaluation of this end point

1, 2 - Up to approximately 36 months
3, 4, 5, 6, 7, 8 - From 6 months up to approximately 36 months
9 - From screening until end of study approximately 36 months
10 - 6 Months
9 Months
12 Months
11, 12, 13, 14 - From Baseline until end of study (up to 36 months)

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)

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

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

Ukraine

Hong Kong

Taiwan

Belarus

Canada

China

Japan

Mexico

Russian Federation

United States

Austria

Bulgaria

Czechia

Denmark

Estonia

Finland

Germany

Italy

Lithuania

Poland

Romania

Spain

Sweden

Türkiye

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

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:

1200

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

367

F.4.2.2

In the whole clinical trial

1200

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 completing the study will be offered to participate in a long term safety study

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

2020-09-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-10-16

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

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