ReVIVE: Assessing Changes in Multi-parametric MRI in MS Patients Taking Clemastine Fumarate as a Myelin Repair Therapy
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 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 |
Drug: 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
Other Names:
Drug: Placebo
Matched sugar tablet
Other Names:
|
| Experimental: 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 |
Drug: 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
Other Names:
Drug: Placebo
Matched sugar tablet
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Corpus Callosum Myelin Water Fraction [This will be assessed at the baseline visit.]
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 from Baseline in Corpus Callosum Myelin Water Fraction at 3 Months [This will be assessed at the baseline and 3-month visits.]
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 %)
- Change from Baseline in Corpus Callosum Myelin Water Fraction at 6 Months [This will be assessed at the baseline and 6-month visits.]
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 %)
- Corpus Callosum T1 Relaxation Time [This will be assessed at the baseline visit.]
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.
- Change from Baseline in Corpus Callosum T1 Relaxation Time at 3 Months [This will be assessed at the baseline and 3-month visits.]
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. Change = (3-month time - Baseline time)
- Change from Baseline in Corpus Callosum T1 Relaxation Time at 6 Months [This will be assessed at the baseline and 6-month visits.]
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. Change = (6-month time - Baseline time)
- Corpus Callosum UTE Fraction [This will be assessed at the baseline visit.]
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 from Baseline in Corpus Callosum UTE Fraction at 3 Months [This will be assessed at the baseline and 3-month visits.]
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 %)
- Change from Baseline in Corpus Callosum UTE Fraction at 6 Months [This will be assessed at the baseline and 6-month visits.]
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 = (6-month % - Baseline %)
Secondary Outcome Measures
- Optic Radiation Myelin Water Fraction [This will be assessed at the baseline visit.]
The efficacy of Clemastine relative to placebo at increasing the MWF (measured in %) of the optic radiation.
- Change from Baseline in Optic Radiation Myelin Water Fraction at 3 Months [This will be assessed at the baseline and 3-month visits.]
The efficacy of clemastine relative to placebo at increasing the MWF (measured in %) of the optic radiation. Change = (3-month % - Baseline %)
- Change from Baseline in Optic Radiation Myelin Water Fraction at 6 Months [This will be assessed at the baseline and 6-month visits.]
The efficacy of clemastine relative to placebo at increasing the MWF (measured in %) of the optic radiation. Change = (6-month % - Baseline %)
- Corticospinal Tract Myelin Water Fraction [This will be assessed at the baseline visit.]
The efficacy of clemastine relative to placebo at increasing the MWF (measured in %) of the corticospinal tract.
- Change from Baseline in Corticospinal Tract Myelin Water Fraction at 3 Months [This will be assessed at the baseline and 3-month visits.]
The efficacy of clemastine relative to placebo at increasing the MWF (measured in %) of the corticospinal tract. Change = (3-month % - Baseline %)
- Change from Baseline in Corticospinal Tract Myelin Water Fraction at 6 Months [This will be assessed at the baseline and 6-month visits.]
The efficacy of clemastine relative to placebo at increasing the MWF (measured in %) of the corticospinal tract. Change = (6-month % - Baseline %)
- Optic Radiation T1 Relaxation time [This will be assessed at the baseline visit.]
To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the optic radiation.
- Change from Baseline in Optic Radiation T1 Relaxation Time at 3 Months [This will be assessed at the baseline and 3-month visits.]
To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the optic radiation. Change = (3-month time - Baseline time)
- Change from Baseline in Optic Radiation T1 Relaxation Time at 6 Months [This will be assessed at the baseline and 6-month visits.]
To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the optic radiation. Change = (6-month % - Baseline %)
- Corticospinal Tract T1 Relaxation Time [This will be assessed at the baseline visit.]
To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the corticospinal tract.
- Change from Baseline in Corticospinal T1 Relaxation Time at 3 Months [This will be assessed at the baseline and 3-month visits.]
To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the corticospinal tract. Change = (3-month time - Baseline time)
- Change from Baseline in Corticospinal Tract T1 Relaxation Time at 6 Months [This will be assessed at the baseline and 6-month visits.]
To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the corticospinal tract. Change = (6-month % - Baseline %)
- Optic radiation UTE Fraction [This will be assessed at the baseline visit.]
The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the optic radiation.
- Change from Baseline in Optic radiation UTE Fraction at 3 Months [This will be assessed at the baseline and 3-month visits.]
The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the optic radiation. Change = (3-month % - Baseline %)
- Change from Baseline in Optic radiation UTE Fraction at 6 Months [This will be assessed at the baseline and 6-month visits.]
The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the optic radiation. Change = (6-month % - Baseline %)
- Corticospinal Tract UTE Fraction [This will be assessed at the baseline visit.]
The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the corticospinal tract.
- Change from Baseline in Corticospinal Tract UTE Fraction at 3 Months [This will be assessed at the baseline and 3-month visits.]
The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the corticospinal tract. Change = (3-month % - Baseline %)
- Change from Baseline in Corticospinal Tract UTE Fraction at 6 Months [This will be assessed at the baseline and 6-month visits.]
The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the corticospinal tract. Change = (6-month % - Baseline %)
- Lesion of interest (LOI) MWF [This will be assessed at the baseline visit.]
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 from Baseline in LOI MWF at 3 Months [This will be assessed at the baseline and 3-month visits.]
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 %)
- Change from Baseline in LOI MWF at 6 Months [This will be assessed at the baseline and 6-month visits.]
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 %)
- LOI T1 Relaxation Time [This will be assessed at the baseline visit.]
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 from Baseline in LOI T1 Relaxation Time at 3 Months [This will be assessed at the baseline and 3-month visits.]
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)
- Change from Baseline in LOI T1 Relaxation Time at 6 Months [This will be assessed at the baseline and 6-month visits.]
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 = (6-month time - Baseline time)
- LOI UTE Fraction [This will be assessed at the baseline visit.]
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 from Baseline in LOI UTE Fraction at 3 Months [This will be assessed at the baseline and 3-month visits.]
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 %)
- Change from Baseline in LOI UTE Fraction at 6 Months [This will be assessed at the baseline and 6-month visits.]
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 = (6-month % - Baseline %)
- Whole Brain MWF [This will be assessed at the baseline visit.]
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.
- Change from Baseline in Whole Brain MWF at 3 Months [This will be assessed at the baseline and 3-month visits.]
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. Change = (3-month % - Baseline %)
- Change from Baseline in Whole Brain MWF at 6 Months [This will be assessed at the baseline and 6-month visits.]
The efficacy of clemastine relative to placebo at increasing MWF (measured in %) values across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter. Change = (6-month % - Baseline %)
- Whole Brain T1 Relaxation Time [This will be assessed at the baseline visit.]
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.
- Change from Baseline in Whole Brain T1 Relaxation Time at 3 Months [This will be assessed at the baseline and 3-month visits.]
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. Change = (3-month time - Baseline time)
- Change from Baseline in Whole Brain T1 Relaxation Time at 6 Months [This will be assessed at the baseline and 6-month visits.]
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. Change = (6-month time - Baseline time)
- Whole Brain UTE Fraction [This will be assessed at the baseline visit.]
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.
- Change from Baseline in Whole Brain UTE Values at 3 Months [This will be assessed at the baseline and 3-month visits.]
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. Change = (3-month % - Baseline %)
- Change from Baseline in Whole Brain UTE Values at 6 Months [This will be assessed at the baseline and 6-month visits.]
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. Change = (6-month % - Baseline %)
- Clemastine Tolerability [This will be assessed at the baseline visit.]
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 multiple sclerosis.
- Change from Baseline in Clemastine Tolerability at 3 Months [This will be assessed at the baseline and 3-month visits.]
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 multiple sclerosis. Change = (3-month tolerability - Baseline tolerability)
- Change from Baseline in Clemastine Tolerability at 6 Months [This will be assessed at the baseline and 6-month visits.]
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 multiple sclerosis. Change = (6-month tolerability - Baseline tolerability)
- Informative Outcomes [This will be assessed at the baseline visit.]
Which secondary or tertiary outcomes are likely to be informative for future remyelinating trials in optic neuritis (and other related indications).
- Informative Outcomes at 3 Months [This will be assessed at the 3-month visit.]
Which secondary or tertiary outcomes are likely to be informative for future remyelinating trials in optic neuritis (and other related indications).
- Informative Outcomes at 6 Months [This will be assessed at the 6-month visit.]
Which secondary or tertiary outcomes are likely to be informative for future remyelinating trials in optic neuritis (and other related indications).
Eligibility Criteria
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)
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Hypersensitivity to clemastine or other arylalkylamine antihistamines, or any of the excipients.
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Treatment with corticosteroids within 30 days prior to screening.
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Expanded Disability Status Scale (EDSS) ≥ 4.5
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History of significant cardiac conduction block.
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History of cancer.
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Suicidal ideation or behavior in 6 months prior to baseline.
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Pregnancy, breastfeeding or planning to become pregnant.
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Involved with other study protocols simultaneously without prior approval.
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Concomitant use of any other putative remyelinating therapy as determined by the investigator.
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Prior treatment with total lymphoid irradiation, T cell or T cell receptor vaccination.
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Prior treatment with alemtuzumab, mitoxantrone, or cyclophosphamide.
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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)
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History of drug or alcohol abuse within the past year.
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Untreated B12 deficiency (as determined by B12 serological assessments and metabolites including methylmalonic acid [MMA] and homocysteine) or untreated hypothyroidism.
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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.
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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
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Inability to participate in MRI, including extreme claustrophobia.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Sandler Neurosciences Building, Neurological Clinical Research Unit | San Francisco | California | United States | 94107 |
Sponsors and Collaborators
- University of California, San Francisco
- United States Department of Defense
Investigators
- Principal Investigator: Ari J Green, MD, MCR, University of California, San Francisco
Study Documents (Full-Text)
None provided.More Information
Publications
- 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. Epub 2007 Feb 17.
- 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 Büdingen 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.
- 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.
- 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.
- 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.
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