Assessing Changes in Multi-parametric MRI in MS Patients Taking Clemastine Fumarate as a Myelin Repair Therapy

NCT ID: NCT05359653

Last Updated: 2024-07-01

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 74 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-08-01
• Study Completion Date: 2025-06-01

Brief Summary

The clinical trial is intended to assess for clinical evidence of Clemastine Fumarate as a myelin repair therapy in patients with chronic inflammatory injury-causing demyelination as measured by multi-parametric MRI assessments.

No reparative therapies exist for the treatment of multiple sclerosis. 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 chronic 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 chronic lesions found in patients with a confirmed diagnosis of relapsing-remitting multiple sclerosis.

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 chronic lesions found in patients with a confirmed diagnosis of relapsing-remitting multiple sclerosis and compare it to the other assessments.

Detailed Description

Treatments capable of remyelination are a major unmet need for multiple sclerosis and other diseases that involve myelin damage, loss, or dysfunction in the central nervous system (CNS). Chronic demyelination of axons is believed to be injurious to neurons and serves as a major contributor to irreversible cell loss that underlies permanent disability. Available MS treatments are primarily immunosuppressing, without directly addressing or fully preventing axonal degeneration and disability. Clemastine fumarate was identified along with a series of other antimuscarinic medications as a potential remyelinating agent using the micropillar screen (BIMA) developed at UCSF. The screen demonstrated that clemastine promoted the differentiation of the endogenous oligodendrocyte precursor cells (OPCs) into mature myelinating oligodendrocytes. Following in vivo validation, an FDA investigational new drug (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 clinical trial is intended to assess magnetic resonance imaging evidence of remyelination using Clemastine Fumarate in patients with chronic demyelinated lesions. Specifically speaking, the primary objective will assess various multi-parametric MRI sequences on the corpus callosum region, a region that animal models studies identified as a promising candidate for assessing remyelination. The aim was to help define the potential for MRI in measuring remyelination in MS, determine the optimal sequences and location for measuring myelin recovery, and help guide trial design for future remyelinating trials. Finally, the study is designed to assess tolerability and clinical efficacy of Clemastine using outcomes intended to assess for (a) adverse events and (b) recovery of myelin.

Conditions

Multiple Sclerosis (MS); Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis, Primary Progressive; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis Relapse; Multiple Sclerosis Brain Lesion; Multiple Sclerosis Benign

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Clemastine 8 mg, then Placebo

Group 1 will receive the treatment (clemastine 8mg/day) for the first 90 days and then switch to the placebo (a sugar pill) for the remaining 90 days

Group Type: EXPERIMENTAL

Clemastine Fumarate

Intervention Type: DRUG

8 mg Clemastine tablet. Clemastine fumarate was approved by the Food and Drug Administration (FDA) for the treatment of allergic rhinitis (seasonal allergies) in 1977 and was approved for over-the-counter marketing in 1992. Clemastine is not FDA approved as a remyelinating therapy

Placebo

Intervention Type: DRUG

Matched sugar tablet

Placebo, then Clemastine 8 mg

Group 2 will receive the placebo (a sugar pill) for the first 90 days and then switch to the treatment (clemastine 8mg/day) for the remaining 90 days

Group Type: EXPERIMENTAL

Clemastine Fumarate

Intervention Type: DRUG

8 mg Clemastine tablet. Clemastine fumarate was approved by the Food and Drug Administration (FDA) for the treatment of allergic rhinitis (seasonal allergies) in 1977 and was approved for over-the-counter marketing in 1992. Clemastine is not FDA approved as a remyelinating therapy

Placebo

Intervention Type: DRUG

Matched sugar tablet

Interventions

Clemastine Fumarate

8 mg Clemastine tablet. Clemastine fumarate was approved by the Food and Drug Administration (FDA) for the treatment of allergic rhinitis (seasonal allergies) in 1977 and was approved for over-the-counter marketing in 1992. Clemastine is not FDA approved as a remyelinating therapy

Intervention Type: DRUG

Placebo

Matched sugar tablet

Intervention Type: DRUG

Other Intervention Names

Clemastine; Dayhist; Dayhist Allergy; Sugar pill

Eligibility Criteria

Inclusion Criteria

• Written informed consent must be obtained prior to any assessment being performed.
• Patients diagnosed with relapsing remitting multiple sclerosis and a disease duration of < 15 years
• Male or female patients aged 18-55 years (inclusive)
• Use of appropriate contraception during period of trial (women). Before entry women must be:

• Post-menopausal for at least 1 year OR
• Surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, male partner vasectomy or otherwise incapable of pregnancy) OR
• Practicing a highly effective method of birth control if sexually active, including hormonal prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double barrier method (e.g., condoms, diaphragm or cervical cap with spermicidal foam, cream or gel), or male partner sterilization consistent with local regulations regarding use of birth control methods for patients participating in clinical trials, for the duration of their participation in the study OR
• Not heterosexually active (patients who are not heterosexually active at screening must agree to utilize a highly effective method of birth control if they become heterosexually active during their participation in the study) OR
• Practicing true abstinence (when this is in line with the preferred and usual lifestyle of the subject) Period abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods) is not an acceptable method.

Exclusion Criteria

• Radiologic identification of marked brain atrophy relative to patients age based on recent MRI and interpretation of expert neuroradiologist or PI
• New lesion in most recent MRI (within 3 months)
• Hypersensitivity to clemastine or other arylalkylamine antihistamines, or any of the excipients.
• Treatment with corticosteroids within 30 days prior to screening.
• Expanded Disability Status Scale (EDSS) ≥ 4.5
• History of significant cardiac conduction block.
• History of cancer.
• Suicidal ideation or behavior in 6 months prior to baseline.
• Pregnancy, breastfeeding or planning to become pregnant.
• Involved with other study protocols simultaneously without prior approval.
• Concomitant use of any other putative remyelinating therapy as determined by the investigator.
• Prior treatment with total lymphoid irradiation, T cell or T cell receptor vaccination.
• Prior treatment with alemtuzumab, mitoxantrone, or cyclophosphamide.
• Serum creatinine > 1.5 mg/dL; aspartate transaminase (AST), alanine transaminase (ALT), or alkaline phosphatase > 2 times the upper limit of normal. (Reported within 72 hours)
• History of drug or alcohol abuse within the past year.
• Untreated B12 deficiency (as determined by B12 serological assessments and metabolites including methylmalonic acid [MMA] and homocysteine) or untreated hypothyroidism.
• Clinically significant cardiac, metabolic, hematologic, hepatic, immunologic, urologic, endocrinologic, neurologic, pulmonary, psychiatric, dermatologic, allergic, renal, or other major diseases that in the PI's judgment may affect the interpretation of study results or patient safety.
• History of or presence of clinically significant medical illness or laboratory abnormality that, in the opinion of the investigator would preclude participation in the study
• Inability to participate in MRI, including extreme claustrophobia.
• Any dental braces or permanent or undetachable metals in the jaw or face.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

United States Department of Defense

FED

Sponsor Role: collaborator

University of California, San Francisco

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ari J Green, MD, MCR

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Locations

Sandler Neurosciences Building, Neurological Clinical Research Unit

San Francisco, California, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Harkeerat Halait, BS

Role: CONTACT

Harkeerat.Halait@ucsf.edu

415-745-1304

Angelica Montevirgen

Role: CONTACT

Angelica.Montevirgen@ucsf.edu

415-745-1304

Facility Contacts

Harkeerat Halait, BS

Role: primary

Harkeerat.Halait@ucsf.edu

415-745-1304

Angelica Montevirgen, BS

Role: backup

Angelica.Montevirgen@ucsf.edu

415-745-1304

References

Mei F, Fancy SPJ, Shen YA, Niu J, Zhao C, Presley B, Miao E, Lee S, Mayoral SR, Redmond SA, Etxeberria A, Xiao L, Franklin RJM, Green A, Hauser SL, Chan JR. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat Med. 2014 Aug;20(8):954-960. doi: 10.1038/nm.3618. Epub 2014 Jul 6.

Reference Type: BACKGROUND

PMID: 24997607 (View on PubMed)

Marques JP, Kober T, Krueger G, van der Zwaag W, Van de Moortele PF, Gruetter R. MP2RAGE, a self bias-field corrected sequence for improved segmentation and T1-mapping at high field. Neuroimage. 2010 Jan 15;49(2):1271-81. doi: 10.1016/j.neuroimage.2009.10.002. Epub 2009 Oct 9.

Reference Type: BACKGROUND

PMID: 19819338 (View on PubMed)

Sheth V, Shao H, Chen J, Vandenberg S, Corey-Bloom J, Bydder GM, Du J. Magnetic resonance imaging of myelin using ultrashort Echo time (UTE) pulse sequences: Phantom, specimen, volunteer and multiple sclerosis patient studies. Neuroimage. 2016 Aug 1;136:37-44. doi: 10.1016/j.neuroimage.2016.05.012. Epub 2016 May 5.

Reference Type: BACKGROUND

PMID: 27155128 (View on PubMed)

Green AJ, Gelfand JM, Cree BA, Bevan C, Boscardin WJ, Mei F, Inman J, Arnow S, Devereux M, Abounasr A, Nobuta H, Zhu A, Friessen M, Gerona R, von Budingen HC, Henry RG, Hauser SL, Chan JR. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017 Dec 2;390(10111):2481-2489. doi: 10.1016/S0140-6736(17)32346-2. Epub 2017 Oct 10.

Reference Type: BACKGROUND

PMID: 29029896 (View on PubMed)

Gagliardo A, Galli F, Grippo A, Amantini A, Martinelli C, Amato MP, Borsini W. Motor evoked potentials in multiple sclerosis patients without walking limitation: amplitude vs. conduction time abnormalities. J Neurol. 2007 Feb;254(2):220-7. doi: 10.1007/s00415-006-0334-5. Epub 2007 Feb 17.

Reference Type: BACKGROUND

PMID: 17308868 (View on PubMed)

Other Identifiers

22-36052

Identifier Type: -

Identifier Source: org_study_id