A Study to Evaluate the Effect of SAR443820 on Serum Neurofilament Levels in Male and Female Adult Participants With Multiple Sclerosis

• ClinicalTrials.gov Identifier: NCT05630547
• Recruitment Status: Active, not recruiting
• First Posted: November 29, 2022
• Last Update Posted: November 3, 2023
• Sponsor: Sanofi
• Information provided by (Responsible Party): Sanofi

Study Description

Brief Summary:

This is a Phase 2, randomized, double-blind, placebo-controlled 2 parallel-arm study to assess the effect on serum neurofilament light chain (sNfL), safety and tolerability of oral SAR443820 compared to placebo in male and female participants aged 18 to 60 years with relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) (relapsing or non-relapsing), or primary progressive multiple sclerosis (PPMS) followed by an open-label long-term extension period.

The total study duration is approximately 100 weeks and includes the following:

4-week screening period 48-week double-blind treatment period (Part A) 48-week open-label long-term extension period (Part B)

Condition or disease	Intervention/treatment	Phase
Multiple Sclerosis	Drug: SAR443820; Other: Placebo	Phase 2

Detailed Description:

Approximately 100 weeks

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 174 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Double-blinded treatment (Part A) and open-label long-term extension period (Part B)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Double-blind, Randomized, Placebo-controlled Study Evaluating the Effect of SAR443820 on Serum Neurofilament Levels in Participants With Multiple Sclerosis, Followed by an Open-label Long-term Extension Period
• Actual Study Start Date: December 19, 2022
• Estimated Primary Completion Date: September 3, 2025
• Estimated Study Completion Date: September 3, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: SAR443820; Oral SAR443820	Drug: SAR443820; Tablet by oral administration
Placebo Comparator: Placebo; Oral placebo	Other: Placebo; Tablet by oral administration

Outcome Measures

Primary Outcome Measures :

1. Part A: Week 48 sNfL levels relative to baseline [ Time Frame: From baseline (Week 0) to Week 48 ]
2. Part B: Week 96 sNfL levels relative to baseline [ Time Frame: From baseline (Week 0) to Week 96 ]

Secondary Outcome Measures :

1. Part A: Cumulative number of new gadolinium (Gd)-enhancing T1 hyperintense lesions as detected by magnetic resonance imaging (MRI) [ Time Frame: Baseline (Week 0) to Week 48 ]
   The sum of the individual number of new Gd enhancing T1 hyperintense lesions at all scheduled visits starting after baseline up to and including the Week 48 visit.
2. Part A: Cumulative number of new and/or enlarging T2 hyperintense lesions as detected by MRI [ Time Frame: Baseline (Week 0) to Week 48 ]
   The sum of the individual number of new and/or enlarging T2 lesions at all scheduled visits starting after baseline up to and including the Week 48 visit.
3. Part A: Time to onset of 12 weeks confirmed disability progression (CDP) from baseline as assessed by the Expanded Disability Status Scale (EDSS) score [ Time Frame: Up to Week 48 ]
   Standard EDSS assessments of 7 functional domains (visual, brainstem, pyramidal [motor], cerebellar [coordination], sensory, cerebral, and bowel/bladder) scoring will be performed by assessing neurological symptoms in each of these domains. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), where higher scores indicats worst outcomes. Confirmed disease progressions (CDPs) are defined as an increase in EDSS score (defined as an increase of ≥1.0 point from the baseline EDSS score when the baseline score is ≤5.5 or an increase of ≥0.5 points from the baseline EDSS score when the baseline score is >5.5).
4. Part A: Time to onset of sustained 20% increase in 9-Hole Peg Test (9-HPT) confirmed over at least 12 weeks [ Time Frame: Up to Week 48 ]
5. Part A: Time to onset of sustained 20% increase in timed 25-foot walk test (T25-FW) confirmed over at least 12 weeks [ Time Frame: Up to Week 48 ]
6. Part A: Change from baseline in EDSS Plus [ Time Frame: From baseline (Week 0) to Week 48 ]
   The EDSS-plus event is defined as disability progression on at least 1 of 3 components, EDSS score, or T25-FW test, or 9-HPT. Disability criteria for the individual components are defined as follows: 1) Disability progression on the EDSS is defined as an increase of ≥1.0 point from the baseline EDSS score when the baseline score is ≤5.5 or an increase of ≥0.5 points from the baseline EDSS score when the baseline score is >5.5. 2) Disability progression on the T25-FW test is defined as an increase (worsening) of ≥20% from the baseline score. 3) Disability progression on the 9-HPT is defined as an increase (worsening) of ≥20% from the baseline score.
7. Part A: Annualized relapse rate (ARR) of RMS population (relapsing SPMS and RRMS) [ Time Frame: Up to Week 48 ]
8. Part A: Percent change from baseline in brain volume loss (BVL) as detected by brain MRI [ Time Frame: From baseline (Week 0) to Weeks 48 ]
9. Part A: Change from baseline in the volume of slowly expanding lesions (SELs) [ Time Frame: From baseline (Week 0) to Weeks 12, 24, 36 and 48 ]
10. Part A: Change from baseline in the number of SELs [ Time Frame: From baseline (Week 0) to Weeks 12, 24, 36 and 48 ]
11. Part A: Change from baseline in the intensity (T1) of SELs [ Time Frame: From baseline (Week 0) to Weeks 12, 24, 36 and 48 ]
12. Part A: Change from baseline in the normalized T1 intensity in lesions [ Time Frame: From baseline (Week 0) to Weeks 12, 24, 36 and 48 ]
13. Part A: Change from baseline in the total number of non-enhancing lesions [ Time Frame: From baseline (Week 0) to Weeks 12, 24, 36 and 48 ]
14. Part A: Change from baseline in the volume of non-enhancing lesions [ Time Frame: From baseline (Week 0) to Weeks 12, 24, 36 and 48 ]
15. Part A: Change from baseline in the number of phase rim lesions (PRL) will be conducted at 3 Tesla (3T) capable sites [ Time Frame: From baseline (Week 0) to Weeks 12, 24, 36 and 48 ]
16. Part A: Incidence of adverse event (AE) [ Time Frame: Week 0 to Week 48 ]
17. Part A: Incidence of serious adverse event (SAE) [ Time Frame: Week 0 to Week 48 ]
18. Part A: Incidence of treatment emergent adverse event (TEAE) [ Time Frame: Week 0 to Week 48 ]
19. Part A: Incidence of potentially clinically significant abnormality (PCSA) in laboratory tests [ Time Frame: Week 0 to Week 48 ]
20. Part A: Plasma concentration of SAR443820 [ Time Frame: Up to Week 36 ]
    Pre-dose concentration at steady state (Ctrough,ss)
21. Part B: Percent change from baseline in BVL as detected by brain MRI [ Time Frame: From baseline (Week 0) to Week 96 ]
22. Part B: Change from baseline in the volume of slowly expanding lesions (SELs) [ Time Frame: From baseline (Week 0) to Weeks 96 ]
23. Part B: Change from baseline in the number of SELs [ Time Frame: From baseline (Week 0) to Weeks 96 ]
24. Part B: Change from baseline in the intensity (T1) of SELs [ Time Frame: From baseline (Week 0) to Weeks 96 ]
25. Part B: Change from baseline in the normalized T1 intensity in lesions [ Time Frame: From baseline (Week 0) to Weeks 96 ]
26. Part B: Change from baseline in the total number of non-enhancing lesions [ Time Frame: From baseline (Week 0) to Weeks 96 ]
27. Part B: Change from baseline in the volume of non-enhancing lesions [ Time Frame: From baseline (Week 0) to Weeks 96 ]
28. Part B: Change from baseline in the number of PRLs (same participants/centers from Part A with 3T capability) [ Time Frame: From baseline (Week 0) to Weeks 96 ]
29. Part B: Incidence of AE [ Time Frame: Week 48 to Week 96 ]
30. Part B: Incidence of SAE [ Time Frame: Week 48 to Week 96 ]
31. Part B: Incidence of TEAE [ Time Frame: Week 48 to Week 96 ]
32. Part B: Incidence of potentially clinically significant abnormality (PCSA) in laboratory tests [ Time Frame: Week 48 to Week 96 ]
33. Part B: Incidence of PCSA in ECG [ Time Frame: Week 48 to Week 96 ]
34. Part B: Incidence of PCSA in vital signs [ Time Frame: Week 48 to Week 96 ]
35. Part B: Cumulative number of new Gd-enhancing lesions as detected by T1-weighted MRI [ Time Frame: Week 48 to Week 96 ]
36. Part B: number of new or enlarging T2-hyperintense lesions on MRI [ Time Frame: Week 48 to Week 96 ]
37. Part B: ARR of RMS population (relapsing SPMS and RRMS) [ Time Frame: Up to Week 96 ]
38. Part B: Time to onset of composite CDP (CCDP), confirmed over at least 12 weeks (3-month CCDP), by the EDSS Plus composite (EDSS score increase, OR 20% increase in the T25-FW test, OR 20% increase in the 9-HPT) [ Time Frame: Up to Week 96 ]
    The EDSS-plus event is defined as disability progression on at least 1 of 3 components, EDSS score, or T25-FW test, or 9-HPT. Disability criteria for the individual components are defined as follows: 1) Disability progression on the EDSS is defined as an increase of ≥1.0 point from the baseline EDSS score when the baseline score is ≤5.5 or an increase of ≥0.5 points from the baseline EDSS score when the baseline score is >5.5. 2) Disability progression on the T25-FW test is defined as an increase (worsening) of ≥20% from the baseline score. 3) Disability progression on the 9-HPT is defined as an increase (worsening) of ≥20% from the baseline score.
39. Part B: Time to onset of 12 weeks CDP as assessed by the EDSS score [ Time Frame: Up to Week 96 ]
40. Part B: Time to onset of sustained 20% increase in 9-HPT confirmed over at least 12 weeks [ Time Frame: Up to Week 96 ]
41. Part B: Time to onset of sustained 20% increase T25-FW test confirmed over at least 12 weeks [ Time Frame: Up to Week 96 ]
42. Part B: Change from baseline in EDSS Plus [ Time Frame: From baseline (Week 0) to Week 96 ]
    The EDSS-plus event is defined as disability progression on at least 1 of 3 components, EDSS score, or T25-FW test, or 9-HPT. Disability criteria for the individual components are defined as follows: 1) Disability progression on the EDSS is defined as an increase of ≥1.0 point from the baseline EDSS score when the baseline score is ≤5.5 or an increase of ≥0.5 points from the baseline EDSS score when the baseline score is >5.5. 2) Disability progression on the T25-FW test is defined as an increase (worsening) of ≥20% from the baseline score. 3) Disability progression on the 9-HPT is defined as an increase (worsening) of ≥20% from the baseline score.
43. Part B: Change in Multiple Sclerosis Impact Scale -29 version 2 (MSIS-29v2) physical and psychological domains scoring [ Time Frame: From baseline (Week 0) to Week 96 ]
    The Multiple Sclerosis Impact Scale with 29 items (MSIS-29m) evaluates the specific physical and psychological impact of MS from a patient's perspective. This patient reported outcome (PRO) instrument has 2 subscales: 1) a physical impact score (20 items) and 2) a psychological impact score (9 items). The physical and psychological impact subscales of the MSIS-29v2m range from 0 to 100, with higher scores indicating greater physical or psychological impact.
44. Part B: Change in Multiple Sclerosis Walking Scale 12 items (MSWS-12 [ Time Frame: From baseline (Week 0) to Week 96 ]
    The Multiple Sclerosis Walking Scale (MSWS-12m) measures the impact of walking impairment in patients with MS. This PRO instrument has 12 items with a global score ranging from 0 to 100. A higher score indicates better quality of life.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Male or female, 18 to 60 years (inclusive) of age, at the time of signing the informed consent.
• Participants with diagnosis of RRMS, SPMS (relapsing or non-relapsing) or primary progressive subtype according to the 2017 revision of the McDonald diagnostic criteria (SPMS diagnostic criteria according to initial relapsing remitting disease course followed by progression with or without occasional relapses, minor remissions, and plateaus; progression denotes the continuous worsening of neurological impairment over at least 6 months).
• Participants with Expanded Disability Status Scale (EDSS) score of 26 inclusive at screening.
• Participants who are either untreated or in the opinion of the Investigator are stable on an allowed disease-modifying therapy (DMT) (interferons, glatiramer acetate, fumarates, or teriflunomide) for at least the past 3 months, AND not anticipated to require a change in multiple sclerosis (MS) treatment for the duration of Part A and Part B (through Week 96); in Part B changes in dose of allowed DMTs or transition to other allowed DMTs is permitted).
• Participants with body weight at least 45 kg and body mass index (BMI) at least 18.0 kg/m^2.
• Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

Exclusion Criteria:

• Participants with immunodeficiency syndromes or other autoimmune diseases requiring immunosuppressive therapy
• Participants with a history of seizures or epilepsy (history of febrile seizure during childhood is allowed).
• Participants with known clinical relapse (acute or subacute episodes of new or increasing neurological dysfunction followed by full or partial recovery, in absence of fever or infection) within 8 weeks of screening.
• Participants with neurological disease history other than MS, eg, head trauma within 3 months, cerebrovascular disease, and vascular dementia.
• Participants with a history of recent serious infection (eg, pneumonia, septicemia) within 4 weeks of screening; an infection requiring hospitalization or intravenous antibiotics, antivirals, or antifungals within 4 weeks of screening; or chronic bacterial infections (such as tuberculosis) deemed unacceptable, as per Investigator's judgment.
• Participants who have significant cognitive impairment, psychiatric disease, other neurodegenerative disorders (eg, Parkinson disease or Alzheimer disease), substance abuse, or any other conditions that would make the participants unsuitable for participating in the study or could interfere with assessment or completing the study in the opinion of the Investigator.
• Participants with a documented history of attempted suicide over the 24 weeks prior to the Screening Visit, presents with suicidal ideation of category 4 or 5 on the Columbia Suicide Severity Rating Scale (CSSRS), or if in the Investigator's judgment, the participant is at risk for a suicide attempt.
• Participants with a history of unstable or severe cardiac, pulmonary, oncological, hepatic, or renal disease or another medically significant illness other than MS precluding their safe participation in this study.
• Participants who received a live vaccine within 14 days before the Screening Visit.
• Participants with a known history of allergy to any ingredients of SAR443820 (mannitol, lactose monohydrate, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol, and microcrystalline cellulose). - Participants with a current use of any medications that are moderate or strong inhibitors or strong inducers of cytochrome P450 3A4 (CYP3A4).
• Participants with a current use of any of the following medications/treatments: fampridine/dalfampridine, ofatumumab, fingolimod, cladribine, siponimod, ponesimod, ozanimod, alemtuzumab, mitoxantrone, ocrelizumab, natalizumab, or similar approved compounds but with different trade names and any unapproved treatments or therapies for MS; any DMTs newly approved after January 2023 that are marketed at any time during the course of the double-blind study period. These medications are not allowed within 5 half-lives before the Screening Visit and for the duration of Part A and Part B.
• Participants who have prior/concurrent clinical study enrollment, ie, the participant has taken other investigational drugs within 4 weeks or 5 half-lives, whichever is longer, before the first Screening Visit; concurrent or recent participation in non-interventional studies may be permitted.

Participants with abnormal laboratory test(s) at the Screening Visit:

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) more than 3.0 x upper limit of normal (ULN)
• Bilirubin more than 1.5 x ULN; unless the participant has documented Gilbert syndrome (isolated bilirubin more than 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin less than 35%)
• Serum albumin less than 3.5 g/dL
• Estimated Glomerular filtration rate less than 60 mL/min/1.73 m^2 (Modification of Diet in Renal Disease [MDRD])
• Other abnormal laboratory values or electrocardiogram (ECG) changes that are deemed clinically significant as per Investigator's judgment
• The above information is not intended to contain all considerations relevant to a potential participation in a clinical trial

Contacts and Locations

Locations

Belgium

Investigational Site Number : 0560001

Bruxelles, Belgium, BE-1200

Investigational Site Number : 0560002

Gent, Belgium, 9000

Investigational Site Number : 0560003

Overpelt, Belgium, 3900

Bulgaria

Investigational Site Number : 1000001

Sofia, Bulgaria, 1407

Investigational Site Number : 1000002

Sofia, Bulgaria, 1431

Investigational Site Number : 1000003

Sofia, Bulgaria, 1680

Canada, Ontario

Investigational Site Number : 1240002

Ottawa, Ontario, Canada, K1H 8L6

Investigational Site Number : 1240004

Toronto, Ontario, Canada, M5B 1W8

Canada, Quebec

Investigational Site Number : 1240001

Gatineau, Quebec, Canada, J8Y 1W2

Investigational Site Number : 1240003

Levis, Quebec, Canada, G6W0M5

Chile

Investigational Site Number : 1520002

Santiago, Reg Metropolitana De Santiago, Chile, 7650568

Investigational Site Number : 1520001

Santiago, Reg Metropolitana De Santiago, Chile, 8380456

China

Investigational Site Number : 1560003

Chengdu, China, 610041

Investigational Site Number : 1560002

Shanghai, China, 200040

Investigational Site Number : 1560001

Tianjin, China, 300052

Investigational Site Number : 1560004

Xi'an, China, 710038

France

Investigational Site Number : 2500004

Caen, France, 14033

Investigational Site Number : 2500002

Nice, France, 06001

Investigational Site Number : 2500001

Paris, France, 75013

Investigational Site Number : 2500003

Strasbourg, France, 67098

Germany

Investigational Site Number : 2760004

Berlin, Germany, 10117

Investigational Site Number : 2760005

Potsdam, Germany, 14471

Investigational Site Number : 2760006

Ulm, Germany, 89073

Investigational Site Number : 2760002

Würzburg, Germany, 97074

Italy

Investigational Site Number : 3800001

Pozzilli, Isernia, Italy, 86077

Investigational Site Number : 3800005

Cagliari, Italy, 09126

Investigational Site Number : 3800002

Milano, Italy, 20132

Investigational Site Number : 3800003

Milano, Italy, 20133

Investigational Site Number : 3800004

Roma, Italy, 00149

Poland

Investigational Site Number : 6160003

Lublin, Lubuskie, Poland, 20-954

Investigational Site Number : 6160002

Katowice, Slaskie, Poland, 40-571

Investigational Site Number : 6160005

Katowice, Slaskie, Poland, 40-686

Investigational Site Number : 6160004

Plewiska, Wielkopolskie, Poland, 62-064

Investigational Site Number : 6160001

Krakow, Poland, 31-503

Investigational Site Number : 6160006

Zabrze, Poland, 41-800

Spain

Investigational Site Number : 7240002

Sevilla, Andalucia, Spain, 41009

Investigational Site Number : 7240001

Barcelona, Barcelona [Barcelona], Spain, 08035

Investigational Site Number : 7240004

Madrid / Madrid, Madrid, Comunidad De, Spain, 28007

Investigational Site Number : 7240003

Madrid, Madrid, Comunidad De, Spain, 28040

Investigational Site Number : 7240006

Madrid, Spain, 28034

Investigational Site Number : 7240005

Murcia, Spain, 30120

Sponsors and Collaborators

Sanofi

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

More Information

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT05630547
• Other Study ID Numbers: ACT16753; U1111-1271-1257 ( Registry Identifier: ICTRP )
• First Posted: November 29, 2022
• Last Update Posted: November 3, 2023
• Last Verified: November 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: 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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Multiple Sclerosis; Sclerosis; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases