Relapsing Multiple Sclerosis
Conditions
Brief summary
Primary Objective: To determine the long-term safety and tolerability of SAR442168 in RMS participants Secondary Objective: To evaluate efficacy of SAR442168 on disease activity, assessed by clinical and imaging methods
Detailed description
Approximately 62 months including the 8 weeks post-treatment visit
Interventions
DRUGTolebrutinib
Pharmaceutical form: Film coated tablet Route of administration: Oral
Sponsors
Sanofi
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Participants had to have completed treatment in the DRI15928 study * Female participants had to continue to use an acceptable effective contraception method of birth control from inclusion and until the last dose of study drug, except if she had undergone sterilization at least 3 months earlier or was postmenopausal. Menopause was defined as being amenorrheic for ≥12 months with plasma follicle stimulating hormone (FSH) level \>30 UI/L. * The participant had to have given written informed consent prior to undertaking any study related procedure.
Exclusion criteria
* The participant had a confirmed concomitant laboratory or ECG abnormality or medical condition deemed by the investigator incompatible with continuation of SAR442168 treatment. * The participant had received any live (attenuated) vaccine (including but not limited to varicella zoster, oral polio, and nasal influenza) between the last DRI15928 visit and the first treatment visit in the LTS16004 study. * The participant had received a non-study MS disease modifying treatment between the last IMP treatment in Study DRI15928 and inclusion in Study LTS16004, which by judgement of the Investigator may add unjustified risk to switching back and continuing treatment with SAR442168. Washout periods after treatment with non-study DMTs had to be respected except for interferons or glatiramer acetate treatment. * The participant was receiving strong inducers or inhibitors of CYP3A or CYP2C8 hepatic enzymes. * The participant was receiving anticoagulant/antiplatelet therapies, including: * Acetylsalicylic acid (aspirin) * Antiplatelet drugs (eg, clopidogrel) * Warfarin (vitamin K antagonist) * Heparin, including low molecular weight heparin (antithrombin agents) * Dabigatran (direct thrombin inhibitor) * Apixaban, edoxaban, rivaroxaban (direct factor Xa inhibitors) Note: All above drugs needed to be stopped at least 5 half-lives before study drug administration except for aspirin, which needed to be stopped at least 8 days beforehand. * Prior/concurrent clinical study experience. The participant was taking part in another interventional clinical trial of another drug substance. * Uncooperative behavior or any condition that could make the participant potentially non-adherent with the study procedures * The participant was pregnant or was a breastfeeding woman. The above information was not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | From first dose of study drug (Day 1) up to maximum exposure, 39 weeks in Part A and 222 weeks in Part B | An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. An SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. TEAEs were defined as AEs that developed, worsened or became serious during the respective on-treatment periods. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Number of New Gadolinium (Gd)-Enhancing T1-hyperintense Lesions at Week 240 Relative to Week 192 | Weeks 192 and 240 | Magnetic resonance imaging (MRI) of the brain was performed to identify number of new Gd-enhancing T1-hyperintense lesions. Central review was used to identify new Gd-enhancing T1-hyperintense lesions not present at the previous MRI. mITT=modified intent-to-treat; SAP= statistical analysis plan. Only those participants with data collected at specified timepoints are reported. |
| Mean Number of New or Enlarging T2 Lesions at Week 240 Relative to Week 192 | Weeks 192 and 240 | MRI of the brain was performed to identify number of new or enlarging T2 lesions. Central review was used to identify new or enlarging T2 lesions not present at the previous MRI; the values were standardized to per month values by dividing by the number of months (4-week intervals) from the previous MRI to the current MRI. |
| Total Mean Number of Gd-enhancing T1-hyperintense Lesions at Week 240 Relative to Week 192 | Weeks 192 and 240 | MRI of the brain was performed to identify number of Gd-enhancing T1-hyperintense lesions. Central review was used to identify Gd-enhancing T1-hyperintense lesions not present at the previous MRI. |
| Annualized Relapse Rate (ARR) | From Baseline (enrollment in LTS16004, Day 1) to Week 240 | Multiple sclerosis (MS) relapse was defined as acute, new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination. Symptoms were attributable to MS, lasted for \>=24 hours with or without recovery, present at normal body temperature and preceded by \>=30 days of clinical stability. ARR was the total number of relapses for participants by dose group divided by the sum of the standardized study duration for participants in the dose group. |
| Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Week 240 | Baseline (Day 1 of DRI15928) and Week 240 | The EDSS is a disability scale that assesses the following 7 functional domains: visual, brainstem, pyramidal (motor), cerebellar (coordination), sensory, cerebral, and bowel/bladder. The total EDSS ranges from 0 (normal) to 10 (death due to MS) (0.5 increments from 1-10; next increase after 0 is 1). Higher scores indicated increased disability. Baseline assessed for long-term tolebrutinib treatment by change from baseline was defined as the last non-missing value prior to the first administration of randomized study drug in DRI15928 study. |
Countries
Canada, Czechia, Estonia, France, Netherlands, Russia, Spain, Ukraine, United States
Participant flow
Recruitment details
This long-term study was conducted at 37 centers in 9 countries. Of the 129 participants who completed the parent study DRI15928 (NCT03889639), 126 were screened in this study from 23-Sep-2019 to 10-Mar-2020 of which 1 failed screening due to not meeting eligibility criteria.
Pre-assignment details
A total of 125 participants were treated in this study which consisted of 2 parts: Part A (double-blind) and Part B (open-label). Part A was a short transition period until the dose of tolebrutinib to be used in Phase 3 was determined. In Part B, all participants formed a single dose group (the selected Phase 3 dose).
Participants by arm
| Arm | Count |
|---|---|
| Part A: Tolebrutinib 5 mg Participants who received tolebrutinib 5 mg orally once daily in the parent study continued to receive the same dose until the dose of tolebrutinib to be used in Phase 3 was determined. | 31 |
| Part A: Tolebrutinib 15 mg Participants who received tolebrutinib 15 mg orally once daily in the parent study continued to receive the same dose until the dose of tolebrutinib to be used in Phase 3 was determined. | 31 |
| Part A: Tolebrutinib 30 mg Participants who received tolebrutinib 30 mg orally once daily in the parent study continued to receive the same dose until the dose of tolebrutinib to be used in Phase 3 was determined. | 32 |
| Part A: Tolebrutinib 60 mg Participants who received tolebrutinib 60 mg orally once daily in the parent study continued to receive the same dose until the dose of tolebrutinib to be used in Phase 3 was determined. | 31 |
| Total | 125 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Part A (Double-blind Period):39 Weeks | Other | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part B (Open-label Period):222 Weeks | Adverse Event | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 |
| Part B (Open-label Period):222 Weeks | Other | 0 | 0 | 0 | 0 | 8 | 7 | 10 | 5 |
| Part B (Open-label Period):222 Weeks | Poor compliance to protocol | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 |
| Part B (Open-label Period):222 Weeks | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Part A: Tolebrutinib 30 mg | Total | Part A: Tolebrutinib 60 mg | Part A: Tolebrutinib 5 mg | Part A: Tolebrutinib 15 mg |
|---|---|---|---|---|---|
| Age, Continuous | 40.0 years STANDARD_DEVIATION 9.9 | 37.8 years STANDARD_DEVIATION 9.5 | 37.8 years STANDARD_DEVIATION 9 | 37.1 years STANDARD_DEVIATION 9.9 | 36.4 years STANDARD_DEVIATION 9.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 6 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 28 Participants | 115 Participants | 28 Participants | 30 Participants | 29 Participants |
| Sex: Female, Male Female | 20 Participants | 86 Participants | 23 Participants | 23 Participants | 20 Participants |
| Sex: Female, Male Male | 12 Participants | 39 Participants | 8 Participants | 8 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 31 | 0 / 32 | 0 / 31 | 0 / 30 | 0 / 31 | 0 / 32 | 0 / 31 |
| other Total, other adverse events | 12 / 31 | 6 / 31 | 15 / 32 | 16 / 31 | 24 / 30 | 24 / 31 | 24 / 32 | 25 / 31 |
| serious Total, serious adverse events | 0 / 31 | 2 / 31 | 1 / 32 | 2 / 31 | 5 / 30 | 3 / 31 | 3 / 32 | 3 / 31 |
Outcome results
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. An SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. TEAEs were defined as AEs that developed, worsened or became serious during the respective on-treatment periods.
Time frame: From first dose of study drug (Day 1) up to maximum exposure, 39 weeks in Part A and 222 weeks in Part B
Population: The safety population included all participants enrolled in this study and exposed to study drug, regardless of the amount of exposure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Tolebrutinib 5 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TEAEs | 17 Participants |
| Part A: Tolebrutinib 5 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TESAEs | 0 Participants |
| Part A: Tolebrutinib 15 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TEAEs | 17 Participants |
| Part A: Tolebrutinib 15 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TESAEs | 2 Participants |
| Part A: Tolebrutinib 30 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TEAEs | 24 Participants |
| Part A: Tolebrutinib 30 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TESAEs | 1 Participants |
| Part A: Tolebrutinib 60 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TEAEs | 20 Participants |
| Part A: Tolebrutinib 60 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TESAEs | 2 Participants |
| Part B: Tolebrutinib 5/60 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TEAEs | 26 Participants |
| Part B: Tolebrutinib 5/60 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TESAEs | 5 Participants |
| Part B: Tolebrutinib 15/60 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TEAEs | 29 Participants |
| Part B: Tolebrutinib 15/60 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TESAEs | 3 Participants |
| Part B: Tolebrutinib 30/60 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TESAEs | 3 Participants |
| Part B: Tolebrutinib 30/60 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TEAEs | 27 Participants |
| Part B: Tolebrutinib 60/60 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TEAEs | 27 Participants |
| Part B: Tolebrutinib 60/60 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TESAEs | 3 Participants |
Secondary
Annualized Relapse Rate (ARR)
Multiple sclerosis (MS) relapse was defined as acute, new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination. Symptoms were attributable to MS, lasted for \>=24 hours with or without recovery, present at normal body temperature and preceded by \>=30 days of clinical stability. ARR was the total number of relapses for participants by dose group divided by the sum of the standardized study duration for participants in the dose group.
Time frame: From Baseline (enrollment in LTS16004, Day 1) to Week 240
Population: Analysis was performed on the mITT population. As pre-specified in protocol and SAP,main objective of this study was to determine long-term efficacy of selected Phase 3 dose (60 mg).Part A was a short transition period while picking phase 3 dose;no efficacy analysis was planned for this period alone. Hence, complete efficacy data is presented by LTS16004 dose groups of 5/60, 15/60, 30/60, and 60/60 mg.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Tolebrutinib 5 mg | Annualized Relapse Rate (ARR) | 0.26 relapses per participant year |
| Part A: Tolebrutinib 15 mg | Annualized Relapse Rate (ARR) | 0.24 relapses per participant year |
| Part A: Tolebrutinib 30 mg | Annualized Relapse Rate (ARR) | 0.28 relapses per participant year |
| Part A: Tolebrutinib 60 mg | Annualized Relapse Rate (ARR) | 0.23 relapses per participant year |
Secondary
Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Week 240
The EDSS is a disability scale that assesses the following 7 functional domains: visual, brainstem, pyramidal (motor), cerebellar (coordination), sensory, cerebral, and bowel/bladder. The total EDSS ranges from 0 (normal) to 10 (death due to MS) (0.5 increments from 1-10; next increase after 0 is 1). Higher scores indicated increased disability. Baseline assessed for long-term tolebrutinib treatment by change from baseline was defined as the last non-missing value prior to the first administration of randomized study drug in DRI15928 study.
Time frame: Baseline (Day 1 of DRI15928) and Week 240
Population: Analysis was performed on the mITT population. As pre-specified in protocol and SAP,main objective of this study was to determine long-term efficacy of selected Phase 3 dose (60 mg).Part A was a short transition period while picking phase 3 dose;no efficacy analysis was planned for this period alone. Hence, complete efficacy data is presented by LTS16004 dose groups of 5/60, 15/60, 30/60, and 60/60 mg. Only those participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Tolebrutinib 5 mg | Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Week 240 | -0.10 score on a scale | Standard Deviation 0.96 |
| Part A: Tolebrutinib 15 mg | Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Week 240 | 0.24 score on a scale | Standard Deviation 0.95 |
| Part A: Tolebrutinib 30 mg | Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Week 240 | 0.38 score on a scale | Standard Deviation 0.69 |
| Part A: Tolebrutinib 60 mg | Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Week 240 | 0.29 score on a scale | Standard Deviation 0.7 |
Secondary
Mean Number of New Gadolinium (Gd)-Enhancing T1-hyperintense Lesions at Week 240 Relative to Week 192
Magnetic resonance imaging (MRI) of the brain was performed to identify number of new Gd-enhancing T1-hyperintense lesions. Central review was used to identify new Gd-enhancing T1-hyperintense lesions not present at the previous MRI. mITT=modified intent-to-treat; SAP= statistical analysis plan. Only those participants with data collected at specified timepoints are reported.
Time frame: Weeks 192 and 240
Population: The mITT population included all participants enrolled in this study who had at least 1 day of study drug exposure during study. As pre-specified in protocol and SAP, the main objective of this study was to determine the long-term efficacy of selected Phase 3 dose (60 mg). Part A was a short transition period while picking phase 3 dose; no efficacy analysis was planned for this period alone. Hence, complete efficacy data is presented by LTS16004 dose groups of 5/60, 15/60, 30/60 and 60/60 mg.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Tolebrutinib 5 mg | Mean Number of New Gadolinium (Gd)-Enhancing T1-hyperintense Lesions at Week 240 Relative to Week 192 | 0.24 number of new Gd-enhancing T1 lesions | Standard Deviation 0.54 |
| Part A: Tolebrutinib 15 mg | Mean Number of New Gadolinium (Gd)-Enhancing T1-hyperintense Lesions at Week 240 Relative to Week 192 | 0.36 number of new Gd-enhancing T1 lesions | Standard Deviation 0.66 |
| Part A: Tolebrutinib 30 mg | Mean Number of New Gadolinium (Gd)-Enhancing T1-hyperintense Lesions at Week 240 Relative to Week 192 | 0.32 number of new Gd-enhancing T1 lesions | Standard Deviation 0.75 |
| Part A: Tolebrutinib 60 mg | Mean Number of New Gadolinium (Gd)-Enhancing T1-hyperintense Lesions at Week 240 Relative to Week 192 | 0.13 number of new Gd-enhancing T1 lesions | Standard Deviation 0.45 |
Secondary
Mean Number of New or Enlarging T2 Lesions at Week 240 Relative to Week 192
MRI of the brain was performed to identify number of new or enlarging T2 lesions. Central review was used to identify new or enlarging T2 lesions not present at the previous MRI; the values were standardized to per month values by dividing by the number of months (4-week intervals) from the previous MRI to the current MRI.
Time frame: Weeks 192 and 240
Population: Analysis was performed on the mITT population. As pre-specified in protocol and SAP,main objective of this study was to determine long-term efficacy of selected Phase 3 dose (60 mg).Part A was a short transition period while picking phase 3 dose;no efficacy analysis was planned for this period alone. Hence, complete efficacy data is presented by LTS16004 dose groups of 5/60, 15/60, 30/60, and 60/60 mg. Only those participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Tolebrutinib 5 mg | Mean Number of New or Enlarging T2 Lesions at Week 240 Relative to Week 192 | 0.32 new or enlarging T2 lesions/month | Standard Deviation 0.54 |
| Part A: Tolebrutinib 15 mg | Mean Number of New or Enlarging T2 Lesions at Week 240 Relative to Week 192 | 0.37 new or enlarging T2 lesions/month | Standard Deviation 0.53 |
| Part A: Tolebrutinib 30 mg | Mean Number of New or Enlarging T2 Lesions at Week 240 Relative to Week 192 | 0.15 new or enlarging T2 lesions/month | Standard Deviation 0.3 |
| Part A: Tolebrutinib 60 mg | Mean Number of New or Enlarging T2 Lesions at Week 240 Relative to Week 192 | 0.24 new or enlarging T2 lesions/month | Standard Deviation 0.41 |
Secondary
Total Mean Number of Gd-enhancing T1-hyperintense Lesions at Week 240 Relative to Week 192
MRI of the brain was performed to identify number of Gd-enhancing T1-hyperintense lesions. Central review was used to identify Gd-enhancing T1-hyperintense lesions not present at the previous MRI.
Time frame: Weeks 192 and 240
Population: Analysis was performed on the mITT population. As pre-specified in protocol and SAP,main objective of this study was to determine long-term efficacy of selected Phase 3 dose (60 mg).Part A was a short transition period while picking phase 3 dose;no efficacy analysis was planned for this period alone. Hence, complete efficacy data is presented by LTS16004 dose groups of 5/60, 15/60, 30/60, and 60/60 mg. Only those participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Tolebrutinib 5 mg | Total Mean Number of Gd-enhancing T1-hyperintense Lesions at Week 240 Relative to Week 192 | 0.24 number of Gd-enhancing T1 lesions | Standard Deviation 0.54 |
| Part A: Tolebrutinib 15 mg | Total Mean Number of Gd-enhancing T1-hyperintense Lesions at Week 240 Relative to Week 192 | 0.36 number of Gd-enhancing T1 lesions | Standard Deviation 0.66 |
| Part A: Tolebrutinib 30 mg | Total Mean Number of Gd-enhancing T1-hyperintense Lesions at Week 240 Relative to Week 192 | 0.37 number of Gd-enhancing T1 lesions | Standard Deviation 0.76 |
| Part A: Tolebrutinib 60 mg | Total Mean Number of Gd-enhancing T1-hyperintense Lesions at Week 240 Relative to Week 192 | 0.13 number of Gd-enhancing T1 lesions | Standard Deviation 0.45 |