Myelin Repair Therapy for Multiple Sclerosis

(ReINFORCE Trial)

Overseen By Ari J Green, MD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of California, San Francisco

Must not be taking: Corticosteroids, Alemtuzumab, Mitoxantrone, others

Disqualifiers: Brain atrophy, Cardiac block, Cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

Duration: 12 weeks

44 Participants Needed

Trial Summary

What is the purpose of this trial?

The clinical trial is intended to assess for clinical evidence of Clemastine Fumarate as a myelin repair therapy in patients with acute inflammatory injury-causing demyelination as measured by multi-parametric MRI assessments. No reparative therapies exist for the treatment of acute demyelinating lesions. Clemastine fumarate was identified along with a series of other antimuscarinic medications as a potential remyelinating agent using the micropillar screen (BIMA) developed at the University of California, San Francisco (UCSF). Following in vivo validation, an FDA IND exemption was granted to investigate clemastine for the treatment of multiple sclerosis in the context of chronic optic neuropathy. That pilot study was recently completed and is the first randomized control trial documenting efficacy for a putative remyelinating agent for the treatment of MS. The preselected primary efficacy endpoint (visual evoked potential) was met and a strong trend to benefit was seen for the principal secondary endpoint assessing function (low contrast visual acuity). That trial number was 13-11577. This study seeks to follow up on that study and examine clemastine fumarate's protective and reparative effects in the context of acute demyelinating brain lesions as imaged by multi-parametric MRI assessments. The investigators will be assessing the effects of clemastine fumarate as a remyelinating therapy and assessing its effect on MRI metrics of lesions found in patients with a confirmed diagnosis of acute inflammatory injury-causing demyelination. In addition to using conventional multi-parametric MRI assessments, this study will also evaluate a new MRI technique called Ultrashort Echo Time (UTE) MRI to assess the effects of clemastine fumarate as a remyelinating therapy of acute lesions found in patients with a confirmed diagnosis of acute inflammatory injury-causing demyelination and compare it to the other assessments.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot use any other remyelinating therapy or have had certain treatments like alemtuzumab, mitoxantrone, or cyclophosphamide. It's best to discuss your current medications with the trial team.

How is the drug Clemastine Fumarate different from other multiple sclerosis treatments?

Clemastine Fumarate is unique because it is being studied for its potential to repair myelin (the protective covering of nerves) in multiple sclerosis, which is different from other treatments that mainly focus on reducing relapses and slowing disability progression. ^{1 2 3 4 5}

Research Team

Ari J Green, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for adults aged 18-55 with relapsing-remitting multiple sclerosis and disease duration under 15 years. Participants must use effective birth control, not be pregnant or breastfeeding, and have no severe medical issues or recent drug/alcohol abuse. They can't have certain treatments like corticosteroids within the last month or a new lesion on their latest MRI.

Inclusion Criteria

Written informed consent must be obtained prior to any assessment being performed

I have relapsing-remitting MS diagnosed within the last 15 years.

I am a woman not at risk of becoming pregnant due to menopause, surgery, effective birth control, or not having heterosexual sex.

Exclusion Criteria

Pregnancy, breastfeeding or planning to become pregnant

Any dental braces or permanent or undetachable metals in the jaw or face

I have not taken corticosteroids in the last 30 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Clemastine Fumarate or placebo for 90 days, with dosage adjustments during the period

12 weeks

Regular visits for monitoring and MRI assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment, with MRI assessments at 3 and 6 months

6 months

Visits at 3-month and 6-month intervals

Treatment Details

Interventions

• Clemastine Fumarate
• Placebo

Trial Overview The study tests Clemastine Fumarate as a potential myelin repair therapy against a placebo in patients with acute demyelinating brain lesions using advanced MRI techniques to measure its effects.

Participant Groups

Group I: Placebo, then Clemastine 12 mg, then Clemastine 8 mg Experimental Treatment 2 Interventions

Group 1 will receive the placebo for the first 90 days. Then, they will switch to clemastine (treatment) for 90 days. They will receive clemastine 12 mg for 14 days followed by clemastine 8 mg for the remaining 76 days.

Group II: Clemastine 12 mg, then clemastine 8 mg, then Placebo Experimental Treatment 2 Interventions

Group 1 will receive the treatment (clemastine) for the first 90 days. They will receive clemastine 12 mg for 14 days followed by clemastine 8 mg for 76 days, and then switch to the placebo (a sugar pill) for the remaining 90 days

Clemastine Fumarate is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Clemastine for:

• Allergic rhinitis
• Urticaria
• Pruritus

Approved in European Union as Clemastine for:

• Allergic rhinitis
• Urticaria
• Pruritus

Approved in Canada as Clemastine for:

• Allergic rhinitis
• Urticaria
• Pruritus

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Findings from Research

In a study of 735 patients with relapsing-remitting multiple sclerosis, dimethyl-fumarate (DMF) reduced the annual relapse rate by 63.2%, with 85% of patients relapse-free at 12 months.

DMF was found to be safe, with the most common side effects being flushing (37.2%) and gastro-enteric issues (31.1%), and it showed significant benefits for both treatment-naïve patients and those switching from other therapies due to tolerability or efficacy concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two-year real-life efficacy, tolerability and safety of dimethyl fumarate in an Italian multicentre study. Mallucci, G., Annovazzi, P., Miante, S., et al.[2018]

In a study of 2113 patients with relapsing-remitting multiple sclerosis (RRMS), dimethyl fumarate and fingolimod were found to have similar effectiveness in reducing relapse rates and preventing disability worsening, with no significant differences in outcomes.

Both treatments showed comparable results for both treatment-naïve patients and those switching from other disease-modifying therapies, indicating that either medication can be a viable first-line option for managing RRMS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative analysis of dimethyl fumarate and fingolimod in relapsing-remitting multiple sclerosis. Lorscheider, J., Benkert, P., Lienert, C., et al.[2021]

In a study of patients with multiple sclerosis, dimethyl fumarate (DMF) treatment led to a significant decrease in CD4(+) and CD8(+) memory T cells, suggesting a targeted effect on these immune cells.

DMF treatment also resulted in a shift in T helper cell populations, increasing anti-inflammatory TH2 cells while decreasing pro-inflammatory TH1 cells, which may benefit patients with TH1-driven disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dimethyl fumarate treatment alters circulating T helper cell subsets in multiple sclerosis. Gross, CC., Schulte-Mecklenbeck, A., Klinsing, S., et al.[2022]

Dimethyl fumarate has been shown to significantly reduce relapse rates in patients with relapsing-remitting multiple sclerosis (MS), with a reduction of 34% to 49% in the proportion of patients experiencing relapses over two years, based on two phase III trials (DEFINE and CONFIRM).

The safety profile of dimethyl fumarate is comparable to placebo, with serious adverse effects occurring at similar rates; however, some patients experienced intolerable flushing and gastrointestinal issues, leading to discontinuation in 3% and 4% of cases, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dimethyl fumarate (Tecfidera): a new oral agent for multiple sclerosis. Venci, JV., Gandhi, MA.[2015]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Two-year real-life efficacy, tolerability and safety of dimethyl fumarate in an Italian multicentre study. [2018]

2. Germany pubmed.ncbi.nlm.nih.gov

Comparative analysis of dimethyl fumarate and fingolimod in relapsing-remitting multiple sclerosis. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Dimethyl fumarate treatment alters circulating T helper cell subsets in multiple sclerosis. [2022]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Dimethyl fumarate in the management of multiple sclerosis: appropriate patient selection and special considerations. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Dimethyl fumarate (Tecfidera): a new oral agent for multiple sclerosis. [2015]