Tolebrutinib, a Brain-penetrant Bruton's Tyrosine Kinase Inhibitor, for the Modulation of Chronically Inflamed White Matter Lesions in Multiple Sclerosis

NCT04742400 | Active Not Recruiting Phase 2 Results FDA Drug

• 2 other identifiers: 21001021-N-0010
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Some multiple sclerosis (MS) lesions stay inflamed for very long periods of time. This type of inflammation is not affected by any MS medications. These lesions can lead to slow worsening of MS symptoms. Researchers want to see if a new drug can help. Objective: To see if tolebrutinib can help clear inflammation in MS brain lesions. Eligibility: Adults ages 18 and older with MS who are on an anti-CD20 therapy. Design: Participants will be screened under protocol #89-N-0045. Participants will have a medical history. They will have physical and neurological exams. They will have blood and urine tests. The progression of their MS will be assessed. Participants will have MRIs of the brain. The MRI scanner is shaped like a cylinder. It uses a magnetic field and radio waves to take pictures of the body. During the MRIs, participants will lie on a table that slides in and out of the scanner. Soft padding or a coil will be placed around their head. Participants may have electrocardiograms to measure the heart s electrical activity. Participants may have lumbar punctures ( spinal taps ). A small needle will be inserted into the spinal canal in the lower back. Fluid will be collected. Some participants will take tolebrutinib pills by mouth once a day for at least 96 weeks. They will stop their anti-CD20 therapy. They will have at least 10 study visits. Some participants will not take tolebrutinib. They will stay on their anti-CD20 therapy. They will have 5 study visits. Participation will last at least 96 weeks.

Conditions

Multiple Sclerosis

Keywords

MS; BTK Inhibitor

Outcome Measures

Primary Outcomes (1)

• Disappearance of Paramagnetic Rim Lesions at 48 Weeks of 60 mg of Tolebrutinib.

  Paramagnetic rims indicate the presence of inflammation and ongoing demyelination and axonal transection at the lesion edge. The lesions under study were present for at least 6 months. The results represent the number of participants in whom at least the paramagnetic rim has disappeared in at least 1 lesion at the end of 48 weeks of tolebrutinib 60 mg.

  48 weeks

Secondary Outcomes (2)

• Safety and Tolerability of Tolebrutinib.

  each patient visit

• Repair of Chronically Inflamed White Matter Lesions

  baseline vs. 96 weeks

Study Arms (3)

Tolebrutinib (Cohort A)

EXPERIMENTAL

Tolebrutinib 60 mg/day for 48 weeks, Tolebrutinib 120 mg/day for 96 weeks

Drug: tolebrutinib 60mg; Drug: tolebrutinib 120mg

Tolebrutinib (cohort B)

EXPERIMENTAL

Tolebrutinib 120 mg daily

Drug: tolebrutinib 120mg

tolebrutinib (initial cohort)

EXPERIMENTAL

Tolebrutinib 60 mg daily

Drug: tolebrutinib 60mg

Interventions

tolebrutinib 60mg DRUG

60 mg orally

Tolebrutinib (Cohort A); tolebrutinib (initial cohort)

tolebrutinib 120mg DRUG

120 mg orally

Tolebrutinib (Cohort A); Tolebrutinib (cohort B)

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• In order to be eligible to participate in this study, an individual must meet all of the following criteria:
• Able to provide informed consent
• Willingness to comply with all study procedures and availability for the duration of the study
• Male or female, aged greater than or equal to 18
• Diagnosed with multiple sclerosis according to the 2017 revision of the McDonald diagnostic criteria, with no new lesion formation by comparison of baseline MRI scan with a historical MRI scan at least 6 months prior
• On anti-CD20 antibody treatment for at least 6 months, with the most recent dose at most 6 months prior to enrollment.
• Willing to forego further anti-CD20 antibody treatment for the duration of the study
• Fully vaccinated against SARS-CoV-2 by Day 0. At the time of this writing, Fully vaccinated is defined as:
• Two weeks out from the second dose of a two-dose vaccine series (Moderna, Pfizer-BioNTech); or
• Two weeks out from a single-dose vaccine (Johnson \& Johnson/Janssen)
• Has a prior 7-tesla MRI scan, no more than 1 year prior to enrollment, demonstrating at least one white matter lesion with a paramagnetic rim
• For females of reproductive potential: agrees to use highly effective contraception for at least 1 month prior to dosing and to use such a method during study participation and for an additional 12 weeks after the end of tolebrutinib administration
• QuantiFERON-TB Gold negative; skin testing (e.g., tuberculin skin test) will be allowed if blood testing is not available or the blood test result is indeterminate
• Agrees to adhere to Lifestyle Considerations throughout study duration
• Agrees not to participate in any other interventional study while participating in this protocol

You may not qualify if:

• An individual who meets any of the following criteria will be excluded from participation in this study:
• Pregnancy or lactation
• MS relapse in the 6 months prior to dosing
• Febrile illness within 4 weeks prior to dosing, or persistent chronic or active infection requiring treatment with systemic antibiotics, antivirals, or antifungals.
• Treatment with another investigational drug or other investigational intervention within 3 months prior to baseline
• Contraindications for 7-tesla MRI
• Presence of screening laboratory or ECG values outside normal limits that are considered in the PI or MAI s judgment to be clinically significant, including but not limited to:
• Presence of liver injury defined as underlying hepatobiliary disease or screening alanine aminotransferase (ALT) more than 1.5 times the upper limit of normal (ULN)
• At screening, positive for hepatitis B surface antigen and/or hepatitis B core antibody and/or positive for hepatitis C antibody
• Any of the following:
• Bleeding disorder or known platelet dysfunction at any time prior to the first screening visit
• Platelet count less than 150,000/microL at the screening visit
• Lymphocyte count less than 1000 cells/dL at the screening visit
• Is HIV-positive
• Has received any live (attenuated) vaccine (including but not limited to varicella zoster, oral polio, and nasal influenza) within 2 months before dosing

Sponsors & Collaborators

• National Institute of Neurological Disorders and Stroke (NINDS): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Multiple Sclerosis

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Results Point of Contact

• Title: Daniel Reich, MD
• Organization: National Institutes of Health

reichds@ninds.nih.gov

301-496-1801

Study Officials

• Daniel S Reich, M.D.

  National Institute of Neurological Disorders and Stroke (NINDS)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 5, 2021
• First Posted: February 8, 2021
• Study Start: April 15, 2021
• Primary Completion: June 15, 2023
• Study Completion: December 31, 2025
• Last Updated: August 13, 2024
• Results First Posted: August 13, 2024

Record last verified: 2024-05-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: CSR
• Time Frame: 6 months after publication
• Access Criteria: IPD will be shared under tech transfer agreements.

Locations

US (1)