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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Sanofi-Aventis Recherche & Developpement

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

19 Dec 2022 → 21 Nov 2024

Decision date (initial)

2024-04-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Sanofi Aventis Recherche et Developpement

External identifiers

EU CT number

2023-509078-45-00

EudraCT number

2022-000049-34

WHO UTN

U1111-1271-1257

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Efficacy, Safety, Pharmacokinetic

- Part A: To assess the effect of SAR443820 compared to placebo on serum neurofilament (sNfL)
- Part B: To assess long-term trends in durability of sNfL

Secondary objectives 7

1. Part A: To evaluate efficacy of SAR443820 compared to placebo on imaging and clinical endpoints
2. Part A: To explore effect of SAR443820 compared to placebo on brain volume and chronic lesions
3. Part A: To assess the safety and tolerability of SAR443820
4. Part A: To assess pharmacokinetic (PK) of SAR443820
5. Part B: To explore the effect of SAR443820 on brain volume and chronic lesions
6. Part B: To assess the long-term safety and tolerability of SAR443820
7. Part B: To evaluate long-term effect of SAR443820 on disease progression and activity assessed by other clinical and imaging measures on physical function and patient-reported outcomes (PROs)

Conditions and MedDRA coding

Multiple sclerosis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Male or female, 18 to 60 years (inclusive) of age, at the time of signing the informed consent
2. 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)
3. Participants with Expanded Disability Status Scale (EDSS) score of 2 6 inclusive at screening
4. 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)
5. Participants with body weight at least 45 kg and body mass index (BMI) at least 18.0 kg/m^2
6. 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 14

1. Participants with immunodeficiency syndromes or other autoimmune diseases requiring immunosuppressive therapy
2. Participants with a history of seizures or epilepsy (history of febrile seizure during childhood is allowed)
3. 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
4. Participants with a neurological disease history other than MS, eg, head trauma within 3 months, cerebrovascular disease, and vascular dementia
5. 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
6. Participants who have significant cognitive impairment, psychiatric disease, other neurodegenerative disorders (eg, Parkinson disease or Alzheimer disease), substance abuse (including a history of alcohol 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
7. 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 (C SSRS), or if in the Investigator's judgment, the participant is at risk for a suicide attempt
8. 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
9. Participants who received a live vaccine within 14 days before the Screening Visit
10. 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)
11. Participants with a current use of any medications that are moderate or strong inhibitors or strong inducers of cytochrome P450 3A4 (CYP3A4)
12. 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
13. 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
14. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Part A: Week 48 sNfL levels relative to baseline
2. Part B: Week 96 sNfL levels relative to baseline

Secondary endpoints 44

1. Part A: Cumulative number of new gadolinium (Gd)-enhancing T1 hyperintense lesions as detected by magnetic resonance imaging (MRI)
2. Part A: Cumulative number of new and/or enlarging T2 hyperintense lesions as detected by MRI
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
4. Part A: Time to onset of sustained 20% increase in 9-Hole Peg Test (9-HPT) confirmed over at least 12 weeks
5. Part A: Time to onset of sustained 20% increase in timed 25-foot walk test (T25-FW) confirmed over at least 12 weeks
6. Part A: Change from baseline in EDSS Plus
7. Part A: Annualized relapse rate (ARR) of RMS population (relapsing SPMS and RRMS)
8. Part A: Percent change from baseline in brain volume loss (BVL) as detected by brain MRI
9. Part A: Change from baseline in the volume of slowly expanding lesions (SELs)
10. Part A: Change from baseline in the number of SELs
11. Part A: Change from baseline in the intensity (T1) of SELs
12. Part A: Change from baseline in the normalized T1 intensity in lesions
13. Part A: Change from baseline in the total number of non-enhancing lesions
14. Part A: Change from baseline in the volume of non-enhancing lesions
15. Part A: Change from baseline in the number of phase rim lesions (PRL) will be conducted at 3 Tesla (3T) capable sites
16. Part A: Incidence of adverse event (AE)
17. Part A: Incidence of serious adverse event (SAE)
18. Part A: Incidence of treatment emergent adverse event (TEAE)
19. Part A: Incidence of potentially clinically significant abnormality (PCSA) in laboratory tests
20. Part A: Plasma concentration of SAR443820
21. Part B: Percent change from baseline in BVL as detected by brain MRI
22. Part B: Change from baseline in the volume of slowly expanding lesions (SELs)
23. Part B: Change from baseline in the number of SELs
24. Part B: Change from baseline in the intensity (T1) of SELs
25. Part B: Change from baseline in the normalized T1 intensity in lesions
26. Part B: Change from baseline in the total number of non-enhancing lesions
27. Part B: Change from baseline in the volume of non-enhancing lesions
28. Part B: Change from baseline in the number of PRLs (same participants/centers from Part A with 3T capability)
29. Part B: Incidence of AE
30. Part B: Incidence of SAE
31. Part B: Incidence of TEAE
32. Part B: Incidence of potentially clinically significant abnormality (PCSA) in laboratory tests
33. Part B: Incidence of PCSA in ECG
34. Part B: Incidence of PCSA in vital signs
35. Part B: Cumulative number of new Gd-enhancing lesions as detected by T1-weighted MRI
36. Part B: number of new or enlarging T2-hyperintense lesions on MRI
37. Part B: ARR of RMS population (relapsing SPMS and RRMS)
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)
39. Part B: Time to onset of 12 weeks CDP as assessed by the EDSS score
40. Part B: Time to onset of sustained 20% increase in 9-HPT confirmed over at least 12 weeks
41. Part B: Time to onset of sustained 20% increase T25-FW test confirmed over at least 12 weeks
42. Part B: Change from baseline in EDSS Plus
43. Part B: Change in Multiple Sclerosis Impact Scale -29 version 2 (MSIS-29v2) physical and psychological domains scoring
44. Part B: Change in Multiple Sclerosis Walking Scale 12 items (MSWS-12)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Sanofi-Aventis Recherche & Developpement

Sponsor organisation

Sanofi-Aventis Recherche & Developpement

Address

82 Avenue Raspail

City

Gentilly

Postcode

94250

Country

France

Scientific contact point

Organisation

Sanofi-Aventis Recherche & Developpement

Contact name

Clinical Sciences and Operations

Public contact point

Organisation

Sanofi-Aventis Recherche & Developpement

Contact name

Clinical Sciences and Operations

Third parties 13

Locations

7 EU/EEA countries · 25 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications