Assessing Changes in Multi-parametric MRI in Patients With Acute Demyelinating Lesions Taking Clemastine Fumarate as a Myelin Repair Therapy

Phase 2Not Yet RecruitingNCT06065670

University of California, San Francisco44 enrolled

Overview

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.

Treatments capable of remyelination are a major unmet need for demyelinating diseases that involve myelin damage, loss, or dysfunction in the central nervous system (CNS). Acute 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 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 acute 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 acute lesions, 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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Interventions

Clemastine FumarateDRUG

12 or 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

PlaceboDRUG

Matched sugar tablet

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 Years

Medical Language ↔ Plain English

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.

Locations (1)

Sandler Neurosciences Building, Neurological Clinical Research Unit

San Francisco, California, United States

Outcomes

Primary Outcomes

Corpus Callosum Myelin Water Fraction

The efficacy of clemastine relative to placebo at increasing the myelin water fraction (MWF) (measured in %) from magnetic resonance imaging of the corpus callosum.

Time frame: This will be assessed at the baseline visit.

Change from Baseline in Corpus Callosum Myelin Water Fraction at 3 Months

The efficacy of clemastine relative to placebo at increasing the myelin water fraction (MWF) (measured in %) from magnetic resonance imaging of the corpus callosum. Change = (3-month % - Baseline %)

Time frame: This will be assessed at the baseline and 3 month visits.

Change from Baseline in Corpus Callosum Myelin Water Fraction at 6 Months

The efficacy of clemastine relative to placebo at increasing the myelin water fraction (MWF) (measured in %) from magnetic resonance imaging of the corpus callosum. Change = (6-month % - Baseline %)

Time frame: This will be assessed at the baseline and 6 month visits.

Corpus Callosum T1 Relaxation Time

The efficacy of clemastine relative to placebo at shortening the T1 relaxation time (measured in seconds) within the corpus callosum using T1 mapping protocols in an MRI.

Time frame: This will be assessed at the baseline visit.

Change from Baseline in Corpus Callosum T1 Relaxation Time at 3 Months

The efficacy of clemastine relative to placebo at shortening the T1 relaxation time (measured in seconds) within the corpus callosum using T1 mapping protocols in an MRI. (3-month time - Baseline time)

Time frame: This will be assessed at the baseline and 3-month visits.

Change from Baseline in Corpus Callosum T1 Relaxation Time at 6 Months

The efficacy of clemastine relative to placebo at shortening the T1 relaxation time (measured in seconds) within the corpus callosum using T1 mapping protocols in an MRI. (6-month time - Baseline time)

Time frame: This will be assessed at the baseline and 6-month visits.

Corpus Callosum UTE Fraction

The efficacy of clemastine relative to placebo at increasing the ultrashort echo time (UTE) fraction (measured in %) derived from magnetic resonance imaging of the corpus callosum.

Time frame: This will be assessed at the baseline visit.

Change from Baseline in Corpus Callosum UTE Fraction at 3 Months

The efficacy of clemastine relative to placebo at increasing the ultrashort echo time (UTE) fraction (measured in %) derived from magnetic resonance imaging of the corpus callosum. Change = (3-month % - Baseline %)

Time frame: This will be assessed at the baseline and 3-month visits.

Change from Baseline in Corpus Callosum UTE Fraction at 6 Months

Time frame: This will be assessed at the baseline and 6-month visits.

Secondary Outcomes

Optic Radiation Myelin Water Fraction

The efficacy of Clemastine relative to placebo at increasing the MWF (measured in %) of the optic radiation.

Time frame: This will be assessed at the baseline visit.

Change from Baseline in Optic Radiation Myelin Water Fraction at 3 Months

The efficacy of Clemastine relative to placebo at increasing the MWF (measured in %) of the optic radiation. Change = (3-month % - Baseline %)

Time frame: This will be assessed at the baseline and 3-month visits.

Change from Baseline in Optic Radiation Myelin Water Fraction at 6 Months

The efficacy of Clemastine relative to placebo at increasing the MWF (measured in %) of the optic radiation. Change = (6-month % - Baseline %)

Time frame: This will be assessed at the baseline and 6-month visits.

Corticospinal Tract Myelin Water Fraction

The efficacy of clemastine relative to placebo at increasing the MWF (measured in %) of the corticospinal tract.

Time frame: This will be assessed at the baseline visit.

Change from Baseline in Corticospinal Tract Myelin Water Fraction at 3 Months

The efficacy of clemastine relative to placebo at increasing the MWF (measured in %) of the corticospinal tract. (3-month % - Baseline %)

Time frame: This will be assessed at the baseline and 3-month visits.

Change from Baseline in Corticospinal Tract Myelin Water Fraction at 6 Months

The efficacy of clemastine relative to placebo at increasing the MWF (measured in %) of the corticospinal tract. (6-month % - Baseline %)

Time frame: This will be assessed at the baseline and 6-month visits.

Optic Radiation T1 Relaxation time

To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the optic radiation.

Central Contacts

Harkeerat Halait, BS

CONTACT

415-745-1304 Harkeerat.Halait@ucsf.edu

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Time frame: This will be assessed at the baseline visit.

Change from Baseline in Optic Radiation T1 Relaxation time at 3 Months

To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the optic radiation. (3-month time - Baseline time)

Time frame: This will be assessed at the baseline and 3-month visits.

Change from Baseline in Optic Radiation T1 Relaxation time at 6 Months

To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the optic radiation. (6-month time - Baseline time)

Time frame: This will be assessed at the baseline and 6-month visits.

Corticospinal Tract T1 Relaxation Time

To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the corticospinal tract.

Time frame: This will be assessed at the baseline visit.

Change from Baseline in Corticospinal Tract T1 Relaxation Time at 3 Months

To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the corticospinal tract. (3-month time - Baseline time)

Time frame: This will be assessed at the baseline and 3-month visits.

Change from Baseline in Corticospinal Tract T1 Relaxation Time at 6 Months

To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the corticospinal tract. (6-month time - Baseline time)

Time frame: This will be assessed at the baseline and 6-month visits.

Optic radiation UTE Fraction

The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the optic radiation.

Time frame: This will be assessed at the baseline visit.

Change from Baseline in Optic radiation UTE Fraction at 3 Months

The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the optic radiation. Change = (3-month % - Baseline %)

Time frame: This will be assessed at the baseline and 3-month visits.

Change from Baseline in Optic radiation UTE Fraction at 6 Months

The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the optic radiation. Change = (6-month % - Baseline %)

Time frame: This will be assessed at the baseline and 6-month visits.

Corticospinal Tract UTE Fraction

The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the corticospinal tract.

Time frame: This will be assessed at the baseline visit.

Change from Baseline in Corticospinal Tract UTE Fraction at 3 Months

The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the corticospinal tract. (3-month % - Baseline %)

Time frame: This will be assessed at the baseline and 3-month visits.

Change from Baseline in Corticospinal Tract UTE Fraction at 6 Months

The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the corticospinal tract. (6-month % - Baseline %)

Time frame: This will be assessed at the baseline and 6-month visits.

Lesion of interest (LOI) MWF

The efficacy of clemastine relative to placebo at increasing MWF (measured in %) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs.

Time frame: This will be assessed at the baseline visit.

Change from Baseline in Lesion of interest (LOI) MWF at 3 Months

The efficacy of clemastine relative to placebo at increasing MWF (measured in %) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs. Change = (3-month % - Baseline %)

Time frame: This will be assessed at the baseline and 3-month visits.

Change from Baseline in Lesion of interest (LOI) MWF at 6 Months

The efficacy of clemastine relative to placebo at increasing MWF (measured in %) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs. Change = (6-month % - Baseline %)

Time frame: This will be assessed at the baseline and 6-month visits.

LOI T1 Relaxation Time

The efficacy of clemastine relative to placebo at increasing T1 relaxation time (measured in seconds) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs.

Time frame: This will be assessed at the baseline visit.

Change from Baseline in LOI T1 Relaxation Time at 3 Months

The efficacy of clemastine relative to placebo at increasing T1 relaxation time (measured in seconds) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs. Change = (3-month time - Baseline time)

Time frame: This will be assessed at the baseline and 3-month visits.

Change from Baseline in LOI T1 Relaxation Time at 6 Months

Time frame: This will be assessed at the baseline and 6-month visits.

LOI UTE Fraction

The efficacy of clemastine relative to placebo at increasing UTE fraction (measured in %) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs.

Time frame: This will be assessed at the baseline visit.

Change from Baseline in LOI UTE Fraction at 3 Months

The efficacy of clemastine relative to placebo at increasing UTE fraction (measured in %) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs. Change = (3-month % - Baseline %)

Time frame: This will be assessed at the baseline and 3-month visits.

Change from Baseline in LOI UTE Fraction at 6 Months

Time frame: This will be assessed at the baseline and 6-month visits.

Whole Brain MWF

The efficacy of clemastine relative to placebo at increasing MWF (measured in %) across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter.

Time frame: This will be assessed at the baseline visit.

Change from Baseline in Whole Brain MWF at 3 Months

Time frame: This will be assessed at the baseline and 3-month visits.

Change from Baseline in Whole Brain MWF at 6 Months

Time frame: This will be assessed at the baseline and 6-month visits.

Whole Brain T1 Relaxation Time

The efficacy of clemastine relative to placebo at increasing T1 relaxation time (measured in seconds) across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter.

Time frame: This will be assessed at the baseline visit.

Change from Baseline in Whole Brain T1 Relaxation Time at 3 Months

Time frame: This will be assessed at the baseline and 3-month visits.

Change from Baseline in Whole Brain T1 Relaxation Time at 6 Months

Time frame: This will be assessed at the baseline and 6-month visits.

Whole Brain UTE Fraction

The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter.

Time frame: This will be assessed at the baseline visit.

Change from Baseline in Whole Brain UTE Fraction at 3 Months

Time frame: This will be assessed at the baseline and 3-month visits.

Change from Baseline in Whole Brain UTE Fraction at 6 Months

Time frame: This will be assessed at the baseline and 6-month visits.

Clemastine Tolerability

The tolerability of Clemastine in this population. This will include a special focus with regards to fatigue as this is a major symptom for patients suffering from demyelinating lesions using the Fatigue Scale for Motor and Cognitive Functions (FSMC). The FSMC is scored from 1 through 5 for each question. A high score of 100 indicates a high level of fatigue. The lowest score, 20, indicates low level of fatigue.

Time frame: This will be assessed at the baseline visit.

Change from Baseline in Clemastine Tolerability at 3 Months

Time frame: This will be assessed at the baseline and 3-month visits.

Change from Baseline in Clemastine Tolerability at 6 Months

Time frame: This will be assessed at the baseline and 6-month visits.

Assessing Changes in Multi-parametric MRI in Patients With Acute Demyelinating Lesions Taking Clemastine Fumarate as a Myelin Repair Therapy

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts