Primary Progressive Multiple Sclerosis (PPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (PERSEUS) (PERSEUS)

• ClinicalTrials.gov Identifier: NCT04458051
• Recruitment Status: Recruiting
• First Posted: July 7, 2020
• Last Update Posted: April 25, 2024
• Sponsor: Sanofi
• Information provided by (Responsible Party): Sanofi

Tracking Information

• First Submitted Date: July 1, 2020
• First Posted Date: July 7, 2020
• Last Update Posted Date: April 25, 2024
• Actual Study Start Date: August 13, 2020
• Estimated Primary Completion Date: July 25, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 12, 2023)

3-month composite Confirmed Disability Progression (cCDP) [ Time Frame: Up to approximately 60 months ]

Time to onset of 3-month cCDP defined as follows: Increase over at least 3 months of ≥1.0 point from the baseline expanded disability status scale (EDSS) score when the baseline score is ≤5.5, or ≥0.5 points when the baseline EDSS score is >5.5, or ≥20% from the baseline T25-FW, or ≥20% from the baseline 9-HPT

Original Primary Outcome Measures (submitted: July 1, 2020)

6 month Confirmed Disability Progression (CDP) [ Time Frame: Up to approximately 48 months ]

Time to onset of 6 month CDP defined as follows: Increase of ≥1.0 point from the baseline expanded disability status scale (EDSS) score when the baseline score is ≤5.5, or Increase of ≥0.5 points when the baseline EDSS score is >5.5

Current Secondary Outcome Measures (submitted: December 12, 2023)

• 6-month Confirmed Disability Progression (CDP) [ Time Frame: Up to approximately 60 months ]
  Time to onset of 6-month CDP as assessed by EDSS score
• 6-month composite Confirmed Disability Progression (cCDP) [ Time Frame: Up to approximately 60 months ]
  Time to onset of 6-month cCDP
• Change in T2 hyperintense lesions by MRI [ Time Frame: From screening MRI to approximately 60 months ]
  Total number of new and/or enlarging T2 hyperintense lesions as detected by MRI after baseline up to and including the end of study (EOS)
• Time to onset of confirmed disability improvement (CDI) [ Time Frame: Up to approximately 60 months ]
  Time to onset of CDI defined as ≥1.0-point decrease on the EDSS score from baseline confirmed over at least 6 months
• Percent change in Brain volume (BV) [ Time Frame: From 6 months up to approximately 60 months ]
  Percent change in brain volume (BV) as detected by brain MRI at the EOS compared to month 6
• Change in cognitive function as assessed by SDMT [ Time Frame: From Baseline up to approximately 60 months ]
  Change in cognitive function at the EOS compared to baseline as assessed by the Symbol Digit Modalities Test (SDMT)
• Change in cognitive function as assessed by CVLT-II [ Time Frame: From Baseline up to approximately 60 months ]
  Change in cognitive function at the EOS compared to baseline as assessed by the California Verbal Learning Test II (CVLT-II) where available
• Change in Multiple Sclerosis Quality of Life [ Time Frame: From Baseline up to approximately 60 months ]
  Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) at the EOS compared to baseline
• Safety and Tolerability [ Time Frame: From screening up to approximately 60 months ]
  Number of participants with adverse events (AEs), Serious AEs, AEs leading to permanent study intervention discontinuation, and adverse events of special interest (AESI)
• Population pharmacokinetics [ Time Frame: Months 6, 9 and 12 ]
  Plasma concentration of SAR442168 (population PK assessment) at Months 6, 9, and 12
• Change in plasma neurofilament light chain (NfL) [ Time Frame: From Baseline up to approximately 60 months ]
  Change in NfL levels from at the EOS compared to baseline
• Change in lymphocyte phenotype subsets [ Time Frame: From Baseline up to approximately 60 months ]
  Change in lymphocyte phenotype subsets in whole blood at the EOS compared to baseline in a subset of participants
• Changes in serum Immunoglobulin level [ Time Frame: From Baseline up to approximately 60 months ]
  Changes in serum Immunoglobulin level at the EOS compared to baseline
• Change in serum chitinase-3 like protein 1 (Chi3L1) [ Time Frame: From Baseline up to approximately 60 months ]
  Change in serum Chi3L1 at EOS compared to baseline

Original Secondary Outcome Measures (submitted: July 1, 2020)

• 3-month confirmed disability progression (CDP) [ Time Frame: Up to approximately 48 months ]
  Time to onset of 3-month CDP as assessed by EDSS score
• 3-month change in 9-hole peg test (9-HPT) [ Time Frame: Up to approximately 48 months ]
  Time to onset of sustained 20% increase in the 9-HPT test confirmed over at least 3 months
• 3-month change in timed 25 foot walk (T25-FW) [ Time Frame: Up to approximately 48 months ]
  Time to onset of sustained 20% increase in the T25-FW confirmed over at least 3 months
• Change in T2 hyperintense lesions by MRI [ Time Frame: From Baseline up to 48 approximately months ]
  Total number of new and/or enlarging T2 hyperintense lesions as detected by MRI after baseline up to and including the end of study (EOS)
• Time to onset of confirmed disability improvement (CDI) [ Time Frame: From Baseline up to 48 approximately months ]
  Time to onset of CDI defined as ≥1.0 point decrease on the EDSS score from baseline confirmed over at least 6 months
• Percent change in Brain volume loss (BVL) [ Time Frame: From 6 months up to approximately 48 months - ]
  Percent change in brain volume loss (BVL) as detected by brain MRI at the EOS compared to month 6
• Change in cognitive function as assessed by the Symbol Digit Modalities Test (SDMT) [ Time Frame: From Baseline up to approximately 48 months ]
  Change in cognitive function at the EOS compared to baseline as assessed by the SDMT
• Change in cognitive function as assessed by the California Verbal Learning Test II (CVLT-II) [ Time Frame: From Baseline up to approximately 48 months ]
  Change in cognitive function at the EOS compared to baseline as assessed by the CVLT-II
• Change in Multiple Sclerosis Quality of Life [ Time Frame: From Baseline up to approximately 48 months ]
  Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) at the EOS compared to baseline
• Safety and Tolerability [ Time Frame: From screening up to approximately 48 months ]
  Number of participants with adverse events (AEs), Serious AEs, AEs leading to permanent study intervention discontinuation, and adverse events of special interest (AESI)
• Population pharmacokinetics [ Time Frame: Months 6, 9 and 12 ]
  Plasma concentration of SAR442168 (population PK assessment) at Months 6, 9, and 12
• Change in plasma neurofilament light chain (NfL) [ Time Frame: From Baseline up to approximately 48 months ]
  Change in NfL levels from at the EOS compared to baseline
• Change in lymphocyte phenotype subsets [ Time Frame: From Baseline up to approximately 48 months ]
  Change in lymphocyte phenotype subsets in whole blood at the EOS compared to baseline
• Changes in serum Immunoglobulin level [ Time Frame: From Baseline up to approximately 48 months ]
  Changes in serum Immunoglobulin level at the EOS compared to baseline
• Change in serum chitinase-3 like protein 1 (Chi3L1) [ Time Frame: From Baseline up to approximately 48 months - ]
  Change in serum chitinase-3 like protein 1 (Chi3L1) from baseline to EOS

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Primary Progressive Multiple Sclerosis (PPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (PERSEUS)
• Official Title: A Phase 3, Randomized, Double-blind, Efficacy and Safety Study Comparing SAR442168 to Placebo in Participants With Primary Progressive Multiple Sclerosis (PERSEUS)

Brief Summary

Primary Objective:

To determine the efficacy of SAR442168 compared to placebo in delaying disability progression in primary progressive multiple sclerosis (PPMS)

Secondary Objectives:

To evaluate efficacy of SAR442168 compared to placebo on clinical endpoints, magnetic resonance imaging (MRI) lesions, cognitive performance, physical function, and quality of life To evaluate safety and tolerability of SAR442168 To evaluate population pharmacokinetics (PK) of SAR442168 in PPMS and its relationship to efficacy and safety To evaluate pharmacodynamics of SAR442168

• Detailed Description: Study duration will vary per participant in this event driven trial with a treatment duration of approximately 12 to 60 months.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Primary Progressive Multiple Sclerosis

Intervention

• Drug: Tolebrutinib
  Pharmaceutical form: Film-coated Tablet Route of administration: Oral
  Other Name: SAR442168
• Drug: Placebo
  Pharmaceutical form: Film-coated Tablet Route of administration: Oral

Study Arms

• Experimental: SAR442168
  Dose 1 of oral SAR442168 once daily
  Intervention: Drug: Tolebrutinib
• Placebo Comparator: Placebo
  Placebo to match the SAR442168 once daily
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 12, 2023): 700
• Original Estimated Enrollment (submitted: July 1, 2020): 990
• Estimated Study Completion Date: July 25, 2025
• Estimated Primary Completion Date: July 25, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria: - 18 to 55 years of age inclusive

• Diagnosis of PPMS according to the 2017 McDonald criteria
• Expanded disability status scale (EDSS) score between 2.0 to 6.5 points, at screening inclusive
• Positive cerebrospinal fluid oligoclonal bands and/or elevated Immunoglobulin G (IgG) index either during screening or documented previous history.
• Contraceptive use consistent with local regulations for individuals participating in clinical studies
• Participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a woman of childbearing potential (WOCBP) or is a WOCBP and agrees to use an acceptable contraceptive method
• the participant must not have access to ocrelizumab (eg, ocrelizumab not available on the national market or not reimbursed for the approved indication).
• the participant must have access to and be eligible to be treated with ocrelizumab but: 1) does not tolerate it due to side effects or safety reasons; and/or 2) has failed ocrelizumab treatment due to perceived lack of efficacy Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply:
• Participant has conditions that would adversely affect study participation such as short life expectancy.
• Evidence of infection with human immunodeficiency virus (HIV), transplantation, progressive multifocal leukoencephalopathy (PML), active hepatitis B or C, active or latent tuberculosis or other active infection that would adversely affect study participation.
• Persistent chronic or active or recurring system infection that may adversely affect participation or IMP administration in this study as judged by the investigator
• History of malignancy within 5 years prior to screening.
• History of alcohol or drug abuse within 1 year prior to Screening.
• Hospitalized for psychiatric disease within 2 years prior to Screening.
• Clinically significant laboratory abnormalities (including evidence of liver injury) or electrocardiogram abnormalities at Screening.
• A bleeding disorder or known platelet dysfunction at any time prior to the screening visit.
• A platelet count <150 000/μL at the screening visit.
• A history of significant bleeding event within 6 months prior to screening, according to the Investigator's judgment such as, but not limited to cerebral or gastrointestinal
• Lymphocyte count below the lower limit of normal at Screening.
• Recent live (attenuated) vaccine within 2 months before the first treatment visit.
• Recent major surgery (within 4 weeks of Screening) or planned major surgery during the study.
• The participant has received medications/treatments for MS within a specified time frame.
• Receiving potent and moderate inducers of cytochrome P450 3A (CYP3A) or potent inhibitors of CYP2C8 hepatic enzymes.
• Receiving anticoagulant or antiplatelet therapy (such as aspirin >81mg/day, clopidogrel, warfarin).
• Contraindications to magnetic resonance imaging (MRI). NOTE: Other Inclusion/Exclusion criteria may apply. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 55 Years (Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Trial Transparency email recommended (Toll free number for US & Canada); 800-633-1610 ext option 6; Contact-US@sanofi.com

• Listed Location Countries: Argentina, Australia, Austria, Belarus, Belgium, Bulgaria, Canada, Chile, China, Colombia, Croatia, Czechia, Denmark, Estonia, France, Georgia, Germany, Greece, Hungary, India, Israel, Italy, Japan, Latvia, Mexico, Netherlands, Norway, Peru, Poland, Portugal, Romania, Russian Federation, Serbia, Singapore, South Africa, Spain, Sweden, Turkey, Ukraine, United Kingdom, United States
• Removed Location Countries: Switzerland

Administrative Information

• NCT Number: NCT04458051
• Other Study ID Numbers: EFC16035; U1111-1238-1318 ( Registry Identifier: ICTRP ); 2020-000645-14 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

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

• Current Responsible Party: Sanofi
• Original Responsible Party: Same as current
• Current Study Sponsor: Sanofi
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

• PRS Account: Sanofi
• Verification Date: April 2024