Multiple Sclerosis
Conditions
Brief summary
Primary Objective: To determine the efficacy of SAR441344 as measured by reduction of the number of new active brain lesions Secondary Objective: * To evaluate efficacy of SAR441344 on disease activity as assessed by other MRI measures * To evaluate the safety and tolerability of SAR441344 * To evaluate pharmacokinetics of SAR441344
Detailed description
The duration of each participant will be no longer than 320weeks in both parts of the study, including 4 weeks of screening, at maximum 292 weeks of treatment and 24 weeks of follow-up.
Interventions
DRUGSAR441344 IV
Pharmaceutical form: Solution Route of administration: IV infusion
DRUGplacebo IV
Pharmaceutical form: Solution Route of administration: IV infusion
DRUGSAR441344 SC
Pharmaceutical form: Solution Route of administration: SC injection
DRUGplacebo SC
Pharmaceutical form: Solution Route of administration: SC injection
gadolinium compound, including but not limited to Magnevist, Multihance, Prohance, or Elucirem
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Part A is a 12-week, double-blind, placebo-controlled part; Part B is an open-label SAR441344 treatment part.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* 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 (relapsing-remitting MS and secondary progressive MS participants with relapses) according to the 2017 revision of the McDonald diagnostic criteria. * The participant must have at least 1 documented relapse within the previous year, or ≥2 documented relapses within the previous 2 years, or ≥1 active Gd-enhancing brain lesion on an MRI scan in the past 6 months and prior to screening. * Body weight within 45 to 120 kg (inclusive) and body mass index (BMI) within the range 18.0 to 35.0 kg/m2 (inclusive) at Screening. * Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. * Capable of giving signed informed consent.
Exclusion criteria
* The participant was diagnosed with PPMS according to the 2017 revision of the McDonald diagnostic criteria or with non-relapsing SPMS. * The participant had conditions or situations that would adversely affect participation in this study. * The participant had a history of or currently has concomitant medical or clinical conditions that would adversely affect participation in this study. * History, clinical evidence, suspicion or significant risk for thromboembolic events, as well as myocardial infarction, stroke and/or antiphosholipid syndrome and any participants requiring antithrombotic treatment. * Allergies to humanized monoclonal antibodies or severe post-treatment hypersensitivity reactions other than localized injection site reaction, to any biological molecule. * The participant had received any of the forbidden medications/treatments within the specified time frame before any baseline assessment. * The participant had taken other investigational drug within 3 months or 5-half-live, whichever is longer, before the screening visit. * The participant had an EDSS score \>5.5 at the first screening visit. * The participant had a relapse in the 30 days prior to randomization. * Positive human immunodeficiency virus (HIV) serology (anti HIV1 and anti HIV2 antibodies) or a known history of HIV infection, active or in remission. * Abnormal laboratory test(s) at Screening. * Presence of Hepatitis B surface antigen (HBsAg) or anti-Hepatitis B core antibodies (anti-HBc Ab) at screening or within 3 months prior to first dose of study intervention. * Positive Hepatitis C antibody test result at screening or within 3 months prior to starting study intervention. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Number of New Gadolinium (Gd)-Enhancing T1--Hyperintense (GdE T1) Lesions at Week 12 Relative to Week 8 as Measured by Brain Magnetic Resonance Imaging (MRI) | Week 8 and Week 12 | Cranial (brain) MRI was performed to identify number of new GdE T1-hyperintense lesions at Week 12 relative to Week 8 MRI. Central review was used to identify new GdE T1 lesions not present at the previous MRI scans. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Number of New or Enlarging T2 Lesions at Week 12 Relative to Week 8 | Week 8 and Week 12 | Cranial (brain) MRI was performed to identify number of new or enlarging T2 lesions at Week 12 relative to Week 8. |
| Mean Total Number of GdE T1 Lesions at Week 12 | Baseline (Day 1) and Week 12 | Cranial (brain) MRI was performed to identify total number of GdE T1 lesions at Week 12. |
| Double-Blind Period: 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 12 weeks (DB TE period) | 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 or significant 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 TE period. |
| Double-Blind Period: Number of Participant With Anti-Drug Antibodies (ADAs) Against SAR441344 | From first dose of study drug (Day 1) up to 12 weeks (DB TE period) | Blood samples were collected at specified timepoints to assess the presence of ADAs against SAR441344. Treatment-emergent ADA was defined as at least 1 treatment-induced/boosted ADA. Treatment-induced ADA was defined as ADA that developed during the TE period and without pre-existing ADA (including participants without pre-treatment samples). Treatment-boosted ADA was defined as pre-existing ADA that was boosted during the TE period to a significant higher titer than the baseline. Number of participants with treatment-emergent ADA are presented. |
| Maximum Plasma Concentration (Cmax) of SAR441344 | After dose on Day 1 (first dose) and Weeks 8 (IV arm) and 10 (SC arm) (last dose) | Blood samples were collected at the specified timepoints for the assessment of Cmax. Cmax was assessed by a Bayesian approach using the population pharmacokinetic (PK) model. |
| Time to Maximum Plasma Concentration (Tmax) of SAR441344 | After dose on Day 1 (first dose) and Weeks 8 (IV arm) and 10 (SC arm) (last dose) | Blood samples were collected at the specified timepoints for the assessment of tmax. tmax was assessed by a Bayesian approach using the population PK model. |
| Area Under the Curve Over the Dosing Interval (AUC0-tau) of SAR441344 | After dose on Day 1 (first dose) and Weeks 8 (IV arm) and 10 (SC arm) (last dose) | Blood samples were collected at the specified timepoints for the assessment of AUC0-tau. AUC0-tau was assessed by a Bayesian approach using the population PK model. |
Countries
Bulgaria, Canada, Czechia, France, Germany, Russia, Spain, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
The study was conducted at 38 centers in 10 countries. A total of 176 participants were screened from 07 June 2021 to 08 June 2022, of which 47 were screen failures. Screen failures were mainly due to not meeting the eligibility criteria. Primary results are presented up to primary completion date (PCD) of 21 September 2022.
Pre-assignment details
A total of 129 participants were randomized in a 4:4:1:1 ratio to receive either intravenous (IV) SAR441344 or subcutaneous (SC) SAR441344 or IV placebo or SC placebo in Part A (double-blind \[DB\] period). After completing Part A, all participants entered Part B (open-label extension \[OLE\] period) where participants in the IV and SC placebo arms switched to corresponding IV and SC SAR441344 arms and participants from SAR441344 arms continued their previous IV or SC treatment after Week 12 visit.
Participants by arm
| Arm | Count |
|---|---|
| SC Placebo Participants received placebo matched to SAR441344 IV infusion loading dose on Day 1 followed by placebo matched to SAR441344 SC injection on Weeks 2, 4, 6, 8 and 10 in Part A (DB period). At Week 12, all participants from this arm switched to active SC SAR441344 300 mg q2w and then switched to high SC SAR441344 dose of 1800 mg q4w in Part B (OLE period). | 14 |
| IV Placebo Participants received placebo matched to SAR441344 loading dose on Day 1 followed by placebo matched to SAR441344 IV infusion at Weeks 4 and 8 in Part A (DB period). At Week 12, all participants from this arm switched to active IV SAR441344 1200 mg infusion q4w in Part B (OLE period). | 12 |
| SC SAR441344 300 mg Participants received SAR441344 600 mg IV infusion loading dose on Day 1 followed by SAR441344 300 mg SC injection on Weeks 2, 4, 6, 8 and 10 in Part A (DB period). At Week 12, participants continued to receive SAR441344 300 mg SC injection q2w and then switched to high SC SAR441344 dose of 1800 mg q4w in Part B (OLE period). | 51 |
| IV SAR441344 1200 mg Participants received SAR441344 1800 mg loading dose on Day 1 followed by SAR441344 1200 mg IV infusion at Weeks 4 and 8 in Part A (DB period). At Week 12, participants continued to receive SAR441344 1200 mg IV infusion q4w in Part B (OLE period). | 52 |
| Total | 129 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Part A: DB Period (Up to Week 12) | Adverse event: Related to Coronavirus Disease 2019 | 0 | 0 | 1 | 0 |
| Part A: DB Period (Up to Week 12) | Emergency situation due to war in Ukraine | 0 | 0 | 0 | 2 |
| Part A: DB Period (Up to Week 12) | Withdrawal by Subject | 0 | 0 | 1 | 0 |
| Part B: OLE Period (Up to Week 296) | Ongoing at the time of PCD | 0 | 0 | 63 | 62 |
Baseline characteristics
| Characteristic | SC Placebo | IV Placebo | SC SAR441344 300 mg | IV SAR441344 1200 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 31.6 years STANDARD_DEVIATION 10.8 | 32.3 years STANDARD_DEVIATION 7.7 | 38.2 years STANDARD_DEVIATION 8.9 | 37.3 years STANDARD_DEVIATION 9.3 | 36.6 years STANDARD_DEVIATION 9.4 |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 14 Participants | 12 Participants | 50 Participants | 52 Participants | 128 Participants |
| Sex: Female, Male Female | 10 Participants | 7 Participants | 31 Participants | 37 Participants | 85 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 20 Participants | 15 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 12 | 0 / 51 | 0 / 52 |
| other Total, other adverse events | 5 / 14 | 3 / 12 | 9 / 51 | 6 / 52 |
| serious Total, serious adverse events | 0 / 14 | 0 / 12 | 0 / 51 | 0 / 52 |
Outcome results
Primary
Mean Number of New Gadolinium (Gd)-Enhancing T1--Hyperintense (GdE T1) Lesions at Week 12 Relative to Week 8 as Measured by Brain Magnetic Resonance Imaging (MRI)
Cranial (brain) MRI was performed to identify number of new GdE T1-hyperintense lesions at Week 12 relative to Week 8 MRI. Central review was used to identify new GdE T1 lesions not present at the previous MRI scans.
Time frame: Week 8 and Week 12
Population: The efficacy population included all participants from the randomized population who took all Part A doses of study drug (1 SC dose skipped was allowed) and with an evaluable primary endpoint. As pre-specified in the statistical analysis plan (SAP), data for placebo arm is presented by pooling SC and IV placebo arms.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Mean Number of New Gadolinium (Gd)-Enhancing T1--Hyperintense (GdE T1) Lesions at Week 12 Relative to Week 8 as Measured by Brain Magnetic Resonance Imaging (MRI) | 1.4 number of new GdE T1 lesions per month |
| SC SAR441344 300 mg | Mean Number of New Gadolinium (Gd)-Enhancing T1--Hyperintense (GdE T1) Lesions at Week 12 Relative to Week 8 as Measured by Brain Magnetic Resonance Imaging (MRI) | 0.3 number of new GdE T1 lesions per month |
| IV SAR441344 1200 mg | Mean Number of New Gadolinium (Gd)-Enhancing T1--Hyperintense (GdE T1) Lesions at Week 12 Relative to Week 8 as Measured by Brain Magnetic Resonance Imaging (MRI) | 0.2 number of new GdE T1 lesions per month |
Comparison: Negative binomial regression model adjusting for the categorical baseline GdE T1 lesion count (presence/absence) as covariate, treatment as factor, with offset equal to the log of the duration (in months) between the Week 12 MRI and previous MRI at Week 8.95% CI: [0.08, 0.56]
Comparison: Negative binomial regression model adjusting for the categorical baseline GdE T1 lesion count (presence/absence) as covariate, treatment as factor, with offset equal to the log of the duration (in months) between the Week 12 MRI and previous MRI at Week 8.95% CI: [0.03, 0.38]
Secondary
Area Under the Curve Over the Dosing Interval (AUC0-tau) of SAR441344
Blood samples were collected at the specified timepoints for the assessment of AUC0-tau. AUC0-tau was assessed by a Bayesian approach using the population PK model.
Time frame: After dose on Day 1 (first dose) and Weeks 8 (IV arm) and 10 (SC arm) (last dose)
Population: The PK population included all randomized and treated participants (safety population) with at least 1 post-baseline PK sample with adequate documentation of dosing and sampling dates and times. Only those participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Area Under the Curve Over the Dosing Interval (AUC0-tau) of SAR441344 | After first dose | 32800 mcg*hour/mL | Standard Deviation 3560 |
| Placebo | Area Under the Curve Over the Dosing Interval (AUC0-tau) of SAR441344 | After last dose | 31900 mcg*hour/mL | Standard Deviation 7580 |
| SC SAR441344 300 mg | Area Under the Curve Over the Dosing Interval (AUC0-tau) of SAR441344 | After first dose | 157000 mcg*hour/mL | Standard Deviation 23900 |
| SC SAR441344 300 mg | Area Under the Curve Over the Dosing Interval (AUC0-tau) of SAR441344 | After last dose | 190000 mcg*hour/mL | Standard Deviation 39400 |
Secondary
Double-Blind Period: 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 or significant 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 TE period.
Time frame: From first dose of study drug (Day 1) up to 12 weeks (DB TE period)
Population: The safety population included all randomized participants who took at least 1 dose (regardless of the amount) of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Double-Blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TEAEs | 5 Participants |
| Placebo | Double-Blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TESAEs | 0 Participants |
| SC SAR441344 300 mg | Double-Blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TEAEs | 3 Participants |
| SC SAR441344 300 mg | Double-Blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TESAEs | 0 Participants |
| IV SAR441344 1200 mg | Double-Blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TESAEs | 0 Participants |
| IV SAR441344 1200 mg | Double-Blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TEAEs | 23 Participants |
| IV SAR441344 1200 mg | Double-Blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TESAEs | 0 Participants |
| IV SAR441344 1200 mg | Double-Blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TEAEs | 15 Participants |
Secondary
Double-Blind Period: Number of Participant With Anti-Drug Antibodies (ADAs) Against SAR441344
Blood samples were collected at specified timepoints to assess the presence of ADAs against SAR441344. Treatment-emergent ADA was defined as at least 1 treatment-induced/boosted ADA. Treatment-induced ADA was defined as ADA that developed during the TE period and without pre-existing ADA (including participants without pre-treatment samples). Treatment-boosted ADA was defined as pre-existing ADA that was boosted during the TE period to a significant higher titer than the baseline. Number of participants with treatment-emergent ADA are presented.
Time frame: From first dose of study drug (Day 1) up to 12 weeks (DB TE period)
Population: The ADA population included all participants from the safety population treated with SAR441344 in Part A with at least 1 post-baseline ADA result (positive, negative or inconclusive).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Double-Blind Period: Number of Participant With Anti-Drug Antibodies (ADAs) Against SAR441344 | 0 Participants |
| SC SAR441344 300 mg | Double-Blind Period: Number of Participant With Anti-Drug Antibodies (ADAs) Against SAR441344 | 0 Participants |
| IV SAR441344 1200 mg | Double-Blind Period: Number of Participant With Anti-Drug Antibodies (ADAs) Against SAR441344 | 3 Participants |
| IV SAR441344 1200 mg | Double-Blind Period: Number of Participant With Anti-Drug Antibodies (ADAs) Against SAR441344 | 0 Participants |
Secondary
Maximum Plasma Concentration (Cmax) of SAR441344
Blood samples were collected at the specified timepoints for the assessment of Cmax. Cmax was assessed by a Bayesian approach using the population pharmacokinetic (PK) model.
Time frame: After dose on Day 1 (first dose) and Weeks 8 (IV arm) and 10 (SC arm) (last dose)
Population: The PK population included all randomized and treated participants (safety population) with at least 1 post-baseline PK sample with adequate documentation of dosing and sampling dates and times. Only those participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Maximum Plasma Concentration (Cmax) of SAR441344 | After first dose | 196 microgram per milliliter (mcg/mL) | Standard Deviation 34.4 |
| Placebo | Maximum Plasma Concentration (Cmax) of SAR441344 | After last dose | 101 microgram per milliliter (mcg/mL) | Standard Deviation 20.9 |
| SC SAR441344 300 mg | Maximum Plasma Concentration (Cmax) of SAR441344 | After first dose | 623 microgram per milliliter (mcg/mL) | Standard Deviation 125 |
| SC SAR441344 300 mg | Maximum Plasma Concentration (Cmax) of SAR441344 | After last dose | 580 microgram per milliliter (mcg/mL) | Standard Deviation 116 |
Secondary
Mean Number of New or Enlarging T2 Lesions at Week 12 Relative to Week 8
Cranial (brain) MRI was performed to identify number of new or enlarging T2 lesions at Week 12 relative to Week 8.
Time frame: Week 8 and Week 12
Population: The efficacy population included all participants from the randomized population who took all Part A doses of study drug (1 SC dose skipped was allowed) and with an evaluable primary endpoint. As pre-specified in the SAP, data for placebo arm is presented by pooling SC and IV placebo arms.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Number of New or Enlarging T2 Lesions at Week 12 Relative to Week 8 | 3.8 number of new or enlarging T2 lesions | Standard Deviation 6.2 |
| SC SAR441344 300 mg | Mean Number of New or Enlarging T2 Lesions at Week 12 Relative to Week 8 | 0.6 number of new or enlarging T2 lesions | Standard Deviation 1.8 |
| IV SAR441344 1200 mg | Mean Number of New or Enlarging T2 Lesions at Week 12 Relative to Week 8 | 0.3 number of new or enlarging T2 lesions | Standard Deviation 0.7 |
Secondary
Mean Total Number of GdE T1 Lesions at Week 12
Cranial (brain) MRI was performed to identify total number of GdE T1 lesions at Week 12.
Time frame: Baseline (Day 1) and Week 12
Population: The efficacy population included all participants from the randomized population who took all Part A doses of study drug (1 SC dose skipped was allowed) and with an evaluable primary endpoint. As pre-specified in the SAP, data for placebo arm is presented by pooling SC and IV placebo arms.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Total Number of GdE T1 Lesions at Week 12 | 3.7 number of GdE T1 lesions | Standard Deviation 7.4 |
| SC SAR441344 300 mg | Mean Total Number of GdE T1 Lesions at Week 12 | 0.5 number of GdE T1 lesions | Standard Deviation 1.5 |
| IV SAR441344 1200 mg | Mean Total Number of GdE T1 Lesions at Week 12 | 0.2 number of GdE T1 lesions | Standard Deviation 0.5 |
Secondary
Time to Maximum Plasma Concentration (Tmax) of SAR441344
Blood samples were collected at the specified timepoints for the assessment of tmax. tmax was assessed by a Bayesian approach using the population PK model.
Time frame: After dose on Day 1 (first dose) and Weeks 8 (IV arm) and 10 (SC arm) (last dose)
Population: The PK population included all randomized and treated participants (safety population) with at least 1 post-baseline PK sample with adequate documentation of dosing and sampling dates and times.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Time to Maximum Plasma Concentration (Tmax) of SAR441344 | After first dose | 1.5 hour |
| Placebo | Time to Maximum Plasma Concentration (Tmax) of SAR441344 | After last dose | 97.2 hour |
| SC SAR441344 300 mg | Time to Maximum Plasma Concentration (Tmax) of SAR441344 | After first dose | 1.5 hour |
| SC SAR441344 300 mg | Time to Maximum Plasma Concentration (Tmax) of SAR441344 | After last dose | 1.38 hour |