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A Phase 3, randomized, double-blind efficacy and safety study comparing SAR442168 to teriflunomide (Aubagio) in participants with relapsing forms of multiple sclerosis (GEMINI 1)

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

974

The mean age of the randomized population was 36.7 years (range: 18 to 55 years), 67.7% of participants were female, and 82.2% were White.

- Randomized: 974 (tolebrutinib: 486, teriflunomide: 488) - Treated: 974 (tolebrutinib: 486, teriflunomide: 488) - Study intervention permanently discontinued: 247 (tolebrutinib: 119, teriflunomide: 128) - Completed study: 824 (tolebrutinib: 409, teriflunomide: 415) - Discontinued from study: 149 (tolebrutinib 77, teriflunomide 72)

The percentage of participants with any treatment-emergent adverse events (TEAEs) was similar in both intervention groups (83.7% in the tolebrutinib group and 86.7% in the teriflunomide group). The system organ class (SOC) with the highest percentage of participants with TEAEs in both intervention groups was Infections and infestations (296 [60.9%] participants in the tolebrutinib group and 288 [59.0%] in the teriflunomide group). The percentage of participants with any treatment-emergent serious adverse events (SAEs) was similar in both intervention groups (42 [8.6%] participants in the tolebrutinib group and 40 [8.2%] in the teriflunomide group), with the highest percentage of participants experiencing an event in the Infections and infestations SOC (11 [2.3%] participants in the tolebrutinib group and 8 [1.6%] in the teriflunomide group). The majority of treatment-emergent SAEs were considered to be not related to the investigational medical product by the Investigator. There were no deaths reported during the study. The overall permanent study intervention discontinuation rate due to TEAEs was similar in both intervention groups (23 [4.7%] participants in the tolebrutinib group and 24 [4.9%] in the teriflunomide group). The number (%) of participants with any treatment-emergent AESI was similar between the tolebrutinib and teriflunomide groups (53 [10.9%] versus 57 [11.7%]). The most commonly reported AESI was alanine aminotransferase (ALT) increase (ie, ALT >3 x upper limit normal [ULN]), occurring in 29 (6.0%) participants in the tolebrutinib group and 32 (6.6%) in the teriflunomide group.

Primary endpoint: The study did not meet its primary efficacy endpoint. The adjusted annualized relapse rate (ARR) was low and did not differ between tolebrutinib and teriflunomide (0.130 versus 0.122, relative risk [RR]: 1.061, 95% confidence interval [CI]: 0.808 to 1.393, p=0.6691). Secondary endpoints: The least square (LS) mean (standard error [SE]) percent reduction in brain volume at the EOS compared to Month 6 was -0.688 (0.0369) in the tolebrutinib group as compared to -0.884 (0.0368) in the teriflunomide group (LS mean difference [95% CI]: 0.196 [0.093 to 0.298]." The adjusted mean number of new gadolinium (Gd)-enhancing T1-hyperintense lesions per scan was 0.530 in the tolebrutinib group as compared to 0.285 in the teriflunomide group (RR [95% CI]: 1.860 [1.358 to 2.548]), while the adjusted mean number of new and/or enlarging T2-hyperintense lesions per year was 5.611 in the tolebrutinib group as compared to 5.175 in the teriflunomide group (RR [95% CI]: 1.084 [0.876 to 1.342]). The LS mean (SE) change from baseline at the EOS in the Symbol Digit Modalities Test (SDMT) number of correct substitutions Z-score was 0.364 (0.0318) in the tolebrutinib group and 0.329 (0.0318) in the teriflunomide group (LS mean difference [95% CI]: 0.035 [-0.053 to 0.124]). The LS mean (SE) change from baseline at the EOS in the California Verbal Learning Test Second Edition (CVLT-II) total correct normalized T-score was 17.700 (0.7236) in the tolebrutinib group and 15.827 (0.7241) in the teriflunomide group (LS mean difference [95% CI]: 1.873 [-0.135 to 3.880]).

A total of 974 participants were randomized (tolebrutinib: 486, teriflunomide: 488). There was no significant difference in the adjusted ARR between tolebrutinib and teriflunomide. However, the ARR values were low for both intervention groups. Tolebrutinib treatment resulted in a reduction in disability accumulation. Tolebrutinib treatment was overall well tolerated in study participants, with appropriate liver monitoring.

April. 08, 2025

https://www.nejm.org/doi/full/10.1056/NEJMoa2415985

No

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

https://jrct.mhlw.go.jp/latest-detail/jRCT2021200035

Obara Kentaro

Sanofi K.K.

Tokyo Opera City Tower, 3-20-2, Nishi Shinjuku, Shinjuku-ku, Tokyo 163-1488, Japan

clinical-trials-jp@sanofi.com

Clinical Study Unit

Sanofi K.K.

Tokyo Opera City Tower, 3-20-2, Nishi Shinjuku, Shinjuku-ku, Tokyo 163-1488, Japan

+81-3-6301-3670

clinical-trials-jp@sanofi.com

Complete

Dec. 25, 2020

Interventional

randomized controlled trial

double blind

active control

parallel assignment

treatment purpose

- 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:
a) >=1 documented relapse within the previous year OR
b) >=2 documented relapses within the previous 2 years, OR
c) >=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.

Participants are excluded from the study if any of the following criteria apply:
- The participant has been diagnosed with primary progressive multiple sclerosis (PPMS) according to the 2017 revision of the McDonald diagnostic criteria or with nonrelapsing secondary progressive multiple sclerosis (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/microL 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.

Both

Relapsing Multiple Sclerosis

Drug: SAR442168 (Tolebrutinib)
Pharmaceutical form: Tablet, Route of administration: Oral
Drug: Placebo to match SAR442168 (Tolebrutinib)
Pharmaceutical form: Tablet, Route of administration: Oral
Drug: Teriflunomide HMR1726
Pharmaceutical form: Tablet, Route of administration: Oral
Drug: Placebo to match Teriflunomide
Pharmaceutical form: Tablet, Route of administration: Oral

1. Annualized Adjudicated Relapse Rate : Number of confirmed adjudicated protocol defined relapses [ Time Frame: Up to approximately 36 months ]
Number of confirmed adjudicated protocol defined relapses

1. Time to onset of confirmed disability worsening confirmed over at least 6 months [ Time Frame: Up to approximately 36 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 - 5.
2. Time to onset of CDW, assessed by the EDSS score and confirmed over at least 3 months [ Time Frame: Up to approximately 36 months ]
3. Total number of new and/or enlarging T2 hyperintense lesions as detected by MRI from Month 6 through the end of study (EOS) [ Time Frame: From 6 months up to approximately 36 months ]"
4. Total of Gd-enhancing T1 hyperintense lesions as detected by MRI from 6 months through the EOS [ Time Frame: From 6 months up to approximately 36 months ]
5. Change in cognitive function [ Time Frame: From Baseline up to approximately 36 months ]
Change in cognitive function from baseline to the end of study (EOS) as assessed by SDMT and by CVLT-II where available
6. Time to confirmed disability improvement [ Time Frame: From Baseline up to approximately 36 months ]
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) [ Time Frame: From 6 months up to approximately 36 months ]
Brain volume loss (BVL) rate as detected by brain MRI from Month 6 to the EOS
8. Change in Multiple Sclerosis Quality of Life [ Time Frame: From Baseline up to approximately 36 months ]
Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) from the baseline through the EOS
9. Number of participants with adverse events A(Es) leading to permanent study intervention discontinuation, and adverse events of special interest (AESI) [ Time Frame: From screening until end of study approximately 36 months ]
10. Population Pharmacokinetics - Concentration SAR442168 and relevant metabolites at 6 months [ Time Frame: 6 Months ]
Plasma concentration of SAR442168 (population PK assessment) at 6 Months
11. Population Pharmacokinetics Concentration of SAR442168 and relevant metabolites at 9 Months [ Time Frame: 9 Months ]
Plasma concentration of SAR442168 (population PK assessment) at 9 Months
12. Population Pharmacokinetics - Concentration of SAR442168 and relevant metabolites at 12 Months [ Time Frame: 12 Months ]
Plasma concentration of SAR442168 (population PK assessment) at 12 Months
13. Change in plasma NfL [ Time Frame: From Baseline until end of study approximately 36 months ]
Change in plasma neurofilament light chain (NfL) levels at the EOS compared to baseline
14. Change in lymphocyte Phenotype [ Time Frame: From Baseline until end of study approximately 36 months ]
Change in lymphocyte phenotype subsets in whole blood at the EOS compared to baseline in a subset of participants.
15. Changes in serum Immunoglobulin levels [ Time Frame: From Baseline until end of study (up to 36 months) ]
Changes in serum immunoglobulin level at the EOS compared to baseline
16. Change in CHI3L1 levels [ Time Frame: From Baseline until end of study approximately 36 months ]
Change in serum Chi3L1 levels at the EOS compared to baseline

+81-24-934-5432

Dec. 10, 2020

Bulgaria/Canada/Czechia/Estonia/Spain/United States/Belarus/China/Finland/Germany/Italy/Lithuania/Poland/Romania/Russian Federation/Sweden/Taiwan/Turkey/Ukraine/Denmark/Austria/Mexico/Hong Kong